Abstract
IMPORTANCE
New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults.
OBJECTIVE
To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis.
EVIDENCE REVIEW
A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence.
FINDINGS
Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory assessments are recommended before treatment, and monitoring during treatment is recommended to assess response, adverse effects, and adherence. Approaches are recommended to improve linkage to and retention in care are provided. Daily tenofovir disoproxil fumarate/emtricitabine is recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk. When indicated, postexposure prophylaxis should be started as soon as possible after exposure.
CONCLUSIONS AND RELEVANCE
Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an InSTI plus 2 NRTIs. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults.
There have been substantial advances in the use of antiretroviral drugs (ARVs) for the treatment and prevention of HIV infection since the last version of these recommendations in 2014,1 warranting an update to the recommendations.
With rare exception, all HIV-infected individuals with detectable viremia, regardless of their CD4cell count, should begin anti-retroviral therapy (ART) as soon as possible after diagnosis to prevent disease progression, improve clinical outcomes, and limit transmission. This recommendation is strongly supported by recent large randomized clinical trials.2,3 New drugs that combine excellent potency with greater convenience, safety, and tolerability make lifelong viral suppression achievable and reduce the risk of viral resistance. In HIV-infected persons, ART is effective in preventing HIV transmission1,4,5 and provides individual and public health benefits. Antiretroviral therapy for individuals at risk of acquiring HIV infection (as postexposure prophylaxis [PEP] or preexposure prophylaxis [PrEP]) prevents HIV acquisition.
This revision of the recommendations discusses the latest developments in uses of ARVs, summarizing current knowledge on the following: when to start therapy, including optimal initial treatment regimens; ART for patients with opportunistic infections (OIs); when and how to switch ART; laboratory monitoring; engagement in care and ART adherence; and prevention of HIV infection.
Methods
Recommendations were developed by an international panel of 14 volunteer experts in HIV research and patient care appointed by the International Antiviral Society-USA. Potential members were screened for expertise in the field, involvement in research and care, financial relationships with commercial companies, and ability to work toward consensus. The panel convened in person and by conference calls from late 2015 to mid-2016. Teams for each major section, each with a lead writer, evaluated relevant evidence and drafted recommendations for full panel review.
Evidence used was published in the scientific literature, presented at major scientific conferences, or released as safety reports by regulatory agencies or data and safety monitoring boards since 2014.1 Literature searches in PubMed and EMBASE were designed by an expert in systematic reviews to capture publications relevant to ART in HIV infection since the 2014 iteration of the recommendations1 through April 2016. New evidence was considered in conjunction with evidence used for prior reports.1 Approximately 320 relevant citations were identified by 1 author (P.V) from an initial list of more than 3200. Relevant abstracts publicly presented at scientific conferences since June 2014 were identified by panel members. Manufacturers of ARVs provided lists of relevant scientific publications or abstracts presented at peer-reviewed conferences.
These recommendations are focused on adults (defined as aged ≥18 years) with or at risk of HIV infection in settings in which most ARVs are available (approved by regulatory bodies or in expanded access) or in late-stage development (new drug application filed). Recommendations were made by consensus and rated according to the strength of the recommendation and the quality of the evidence (Table 1). Recommendations that have not changed substantially or for which few relevant data have become available since 2014 are included in the 2014 treatment recommendations1 along with detailed discussion and citations. Where appropriate, prior citations were included. Further details about the recommendations development process, panel selection, summary of evidence collection and literature search strategies, and the sponsor (International Antiviral Society–USA) and its policies are available in the Supplement.
Table 1.
Strength of Recommendation and Quality of Evidence Rating Scalea
| Rating | Definition |
|---|---|
| Strength of recommendation |
|
| A | Strong support for the recommendation |
| B | Moderate support for the recommendation |
| C | Limited support for the recommendation |
| Quality of evidence |
|
| Ia | Evidence from ≥1 randomized clinical trials published in the peer-reviewed literature |
| Ib | Evidence from ≥1 randomized clinical trials presented in abstract form at peer-reviewed scientific meetings |
| IIa | Evidence from nonrandomized clinical trials or cohort or case-control studies published in the peer-reviewed literature |
| IIb | Evidence from nonrandomized clinical trials or cohort or case-control studies presented in abstract form at peer-reviewed scientific meetings |
| III | Recommendation based on the panel’s analysis of the accumulated available evidence |
Adapted in part from the Canadian Task Force on Periodic Health Examination.6
When to Start
Initiation of Therapy
Recommendations for when to start ART are summarized in Box 1. ART is recommended for all HIV-infected patients with detectable viremia, regardless of CD4 cell count (evidence rating AIa). Randomized clinical trial data now further confirm previous recommendations for early initiation of ART in adults1,7 because of the individual-level clinical benefit (reduction in AIDS-related events, non–AIDS-related events, and all-cause mortality) (Table 2)2,3,8 and a decreased risk of HIV transmission.4
Box 1. Recommendations for When to Start Antiretroviral Therapya.
Antiretroviral therapy (ART) is recommended for all viremic patients with established HIV infection, regardless of CD4 cell count (evidence rating AIa).
Initiation of ART is recommended as soon as possible in the setting of acute HIV infection (evidence rating BIII).
Planned discontinuation of early ART after a specific duration of treatment is not recommended outside a research setting (evidence rating AIa).b
Initiation of ART is recommended for individuals who have persistent undetectable viral load without ART but have declining CD4 cell counts (evidence rating BIII).
a See text for essential details and cautions.
b The recommendation or the evidence rating has not changed substantially since the 2014 report.
Table 2.
Summary Results of 3 Key Randomized Clinical Trials of Immediate vs Deferred Antiretroviral Therapy (ART) in ART-Naive HIV-Infected Individuals
| Source | No. of Participants in Study (CD4 Cell Count Parameter) |
Duration of Follow-up, mo |
Study End Point | No. (%) With Outcome in Immediate ART Group |
No. (%) With Outcome in Deferred ART Group |
Hazard Ratio (95% CI) for Immediate vs Deferred ART |
|---|---|---|---|---|---|---|
| Lundgren et al,2 2015 |
4685 (>500/µL) | 36 | Primary end point (AIDS, serious non–AIDS-related events, death) |
42 (1.8) [0.6/100 patient-years of observation] |
96 (4.1) [1.38/100 patient-years of observation] |
0.43 (0.3–0.62) |
| AIDS-related events | 14 (0.6) | 50 (2.1) | 0.28 (0.15–0.50) | |||
| Serious non–AIDS-related events |
29 (1.3) | 47 (2.0) | 0.61 (0.38–0.97) | |||
| All-cause mortality | 12 (0.5) | 21 (0.9) | 0.58 (0.28–1.17) | |||
| Danel et al,3 2015 |
2056 | 30 | Primary end point (AIDS, non–AIDS-related cancer or bacterial disease, death) |
64 (6.2) [2.8/100 patient-years of observation] |
111 (10.9) [4.9/100 patient-years of observation] |
0.56 (0.41–0.76) |
| AIDS-related events | 33 (3.2) | 65 (6.4) | ||||
| Mortality | 21 (2.0) | 26 (2.5) | ||||
| 843 (Baseline >500/µL) |
30 | Subgroup of participants with baseline CD4 cell count >500/µL (primary end point) |
23 (2.2) [2.4/100 patient-years of observation] |
38 (3.7) [4.1/100 patient-years of observation] |
0.56 (0.33–0.94) | |
| Grinsztejn et al,8 2014 |
1763 (350/µL-550/µL) |
24 | Primary end point (AIDS, non–AIDS-related events, severe bacterial infections, death) |
57 (6.4) | 77 (8.8) | 0.73 (0.52–1.03) |
| AIDS | 40 (4.5) | 61 (7.0) | 0.64 (0.43–0.96) | |||
| Non–AIDS-related events |
12 (1.4) | 9 (1.0) | 1.35 (0.57–3.19) | |||
| Death | 11 (1.2) | 15 (1.7) | 0.73 (0.34–1.59) |
Patients should understand the goals of treatment and be willing to initiate therapy. Baseline resistance testing is recommended for all patients, but initiating therapy prior to availability of the results may be appropriate in some cases. Recent data suggest little transmitted drug resistance to integrase strand transfer inhibitors (InSTIs) and protease inhibitors (PIs) but not nonnucleoside reverse transcriptase inhibitors (NNRTIs).9–11
Current Investigational Approaches to Starting Therapy
Initiation of ART is recommended as soon as possible in the setting of acute HIV infection (evidence rating BIII).1 Initiation prior to the development of HIV antibody positivity reduces the size of the latent HIV reservoir, reduces immune activation, and may protect against infection of central memory T cells. Benefits are maximal during the first few weeks after HIV infection but are apparent up to the first 6 months after infection.12–16 However, early therapy does not prevent the establishment of the latent HIV reservoir. Planned discontinuation of early ART after a specific duration of treatment is not recommended outside research settings; the benefits do not persist and the subsequent viral rebound is associated with increased clinical events and the potential for transmission (evidence rating AIa).16–18
Initiation of ART on the same day as diagnosis of HIV infection has been implemented in several cities.19,20 Evaluation of the long-term effectiveness and limitations of this strategy is needed.
Initiation of ART in “elite controllers” (defined as patients with confirmed HIV infection and persistent undetectable HIV RNA without ART) remains controversial. Elite controllers may still benefit from ART because they have higher levels of immune activation and an increased risk of cardiovascular disease and hospitalization compared with individuals achieving virologic suppression with ART.21 Initiation of treatment, however, is recommended for infected persons who have persistent undetectable viral load without ART but have declining CD4 cell counts (evidence rating BIII).
Recommended Initial Regimens
Recommendations for initial antiretroviral regimens are summarizedin Box 2. Among adherent individuals, initial ART with 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a third active drug from a different class achieves and maintains similar virologic suppression rates in nearly all patients.22–26 Clinicians and patients have many options and may select a regimen based on considerations other than antiviral potency. Considerations include short- and long-term adverse effects, ease of administration, drug interactions, risk of resistance if virologic failure occurs, and cost. Patients with more than 100 000 HIV RNA copies/mL or fewer than 200 CD4 cells/µL remain a subset in whom ART potency is particularly important, as certain regimens have suboptimal virologic suppression in this setting.1,7,27–35
Box 2. Recommendations for Initial ART Regimensa.
- Recommended initial regimens (listed in alphabetic order by InSTI component):
HLA-B*5701 testing should be performed prior to abacavir use (evidence rating AIa); those who test positive should not be given abacavir (evidence rating AIa).
Tenofovir disoproxil fumarate is not recommended for individuals with or at risk of kidney or bone disease (osteopenia or osteoporosis) (evidence rating BIII).
Recommended initial regimens for individuals in whom an InSTI is not an option (listed in alphabetic order by InSTI component):
Initial 2-drug regimens are recommended only in rare situations in which a patient cannot take abacavir, TAF, or TDF (evidence rating BIa).
HIV-infected pregnant women should initiate ART for their own health and to reduce the likelihood of HIV transmission to their infant (evidence rating AIa).c
For HIV-infected patients with hepatitis B virus coinfection should initiate ART that contains TDF or TAF (evidence rating AIa), lamivudine or emtricitabine, and a third component (evidence rating AIa).
Entecavir may be used to treat hepatitis B virus infection (evidence rating AIII). If HIV RNA is not suppressed, entecavir should be avoided because it can select for drug-resistant HIV (evidence rating AIII).
HIV-infected patients with hepatitis C virus coinfection should start an ART regimen with drugs that do not have significant drug interactions with hepatitis C virus therapies (evidence rating AIIa).
Tenofovir disoproxil fumarate is not recommended for patients with osteopenia or osteoporosis (evidence rating BIII).
Monitoring for development of kidney disease with estimated glomerular filtration rate, urinalysis, and testing for glycosuria and albuminuria or proteinuria is recommended when ART is initiated or changed and every 6 months (along with HIV RNA) once HIV RNA is stable (evidence rating BIII).
Tenofovir disoproxil fumarate should be avoided or dose adjusted in patients with a creatinine clearance rate below 60 mL/min (evidence rating AIa).
Tenofovir alafenamide is not recommended in patients with a creatinine clearance rate below 30 mL/min (evidence rating AIa).
Tenofovir disoproxil fumarate or TAF should be discontinued if a patient’s renal function worsens, particularly if there is evidence of proximal tubular dysfunction (evidence rating AIIa).
HIV-infected patients with end-stage renal disease should be evaluated for kidney transplantation with expectation of high rates of patient and graft survival (evidence rating AIIa).
Abbreviations: ART, antiretroviral therapy; InSTI, integrase strand transfer; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
a See text for essential details and cautions. Components separated with a slash (/) indicate that they are available as coformulations.
b TDF may be substituted for TAF if TAF is not available for the patient.
c The recommendation or the evidence rating has not changed substantially since the 2014 report.
Optimal Initial Regimens
InSTI-based regimens are optimal for initial therapy. Recommended initial ART for most patients are (regimens are listed in alphabetic order by InSTI component; see Table 3) dolutegravir/abacavir/lamivudine (evidence rating AIa), dolutegravir plus tenofovir alafenamide (TAF)/emtricitabine (AIa), elvitegravir/cobicistat/TAF/emtricitabine (evidence rating AIa), and raltegravir plus TAF/emtricitabine (evidence rating AIII). (Components separated with a slash [/] indicate that they are available as coformulations.)
Table 3.
Recommended Initial Antiretroviral Therapy Regimensa
| Regimen | Rating |
|---|---|
| Dolutegravir/abacavir/lamivudine | AIa |
| Dolutegravir plus tenofovir alafenamide/emtricitabineb | AIa |
| Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabineb | AIa |
| Raltegravir plus tenofovir alafenamide/emtricitabineb | AIII |
Regimens are listed in alphabetic order by integrase strand transfer inhibitor component. Components separated with a slash (/) indicate that they are available as coformulations.
In settings in which tenofovir alafenamide/emtricitabine is not available, tenofovir disoproxil fumarate (with emtricitabine or lamivudine) remains an effective and generally well-tolerated option. Given the limited long-term experience with tenofovir alafenamide, some clinicians may prefer to continue using tenofovir disoproxil fumarate pending broader experience with tenofovir alafenamide in clinical practice.
If TAF is not available, tenofovir disoproxil fumarate (TDF) is an effective and generally well-tolerated option. Given the limited long-termexperience with TAF, some clinicians mayprefer to continue using TDF pending broader experience with TAF in clinical practice.
InSTIs as Components of the Initial Regimen
In the SINGLE study, dolutegravir plus abacavir/lamivudine was superior to efavirenz/TDF/emtricitabine.36 Similar results were observed in the FLAMINGO study (comparing dolutegravir with ritonavir-boosted [/r] darunavir),37 in the WAVES study (comparing cobicistat-boosted [/c] elvitegravir with atazanavir/r in HIV-infected women),38 and in the AIDS Clinical Trials Group 5257 study (comparing raltegravir with atazanavir/r or darunavir/r).39
No clinical trial has directly compared all 3 currently available InSTIs. In treatment-naive patients, dolutegravir was noninferior to raltegravir, with no resistance to dolutegravir observed in that treatment group.40 In treatment-experienced patients, dolutegravir was superior to raltegravir41 and elvitegravir was noninferior to raltegravir.42 The InSTIs differ in several important features that may influence treatment choice (Table 4).
Table 4.
Advantages and Disadvantages of Currently Available Integrase Strand Transfer Inhibitors
| Dolutegravir | Elvitegravir | Raltegravir | |
|---|---|---|---|
| Year of US Food and Drug Administration approval |
2013 | 2012 | 2007 |
| Advantages | Superior to efavirenz and ritonavir-boosted darunavir in comparative clinical trials36,37 Once-daily dosing Coformulated with abacavir/lamivudine as part of a complete initial regimen Dolutegravir (not coformulated) pill size is small Lowest risk of resistance with virologic failure36,37,40,43 Relatively few drug interactions Can be taken with or without food Superior to raltegravir in treatment-experienced patients |
Superior to ritonavir-boosted atazanavir in comparative clinical trial in HIV-infected women38 Once-daily dosing Coformulated with tenofovir disoproxil fumarate/emtricitabine or tenofovir alafenamide/emtricitabine as a complete regimen |
Superior to ritonavir-boosted atazanavir and ritonavir-boosted darunavir in comparative clinical trial39 Longest safety record Fewest drug interactions Can be taken with or without food |
| Disadvantages | Only available coformulation is with abacavir/lamivudine Raises serum creatinine owing to inhibition of tubular secretion of creatinine Higher rates of insomnia and headache than comparators in some studies36,37 Largest tablet among coformulated single-pill regimens |
Requires pharmacokinetic boosting with cobicistat or ritonavir for once-daily dosing Most drug interactions Cobicistat raises serum creatinine owing to inhibition of tubular secretion of creatinine Should be taken with food |
Currently must be taken twice daily (formulation consisting of 2 pills given once daily in development) Not coformulated as part of a complete regimen |
Abacavir as a Component of the Initial Regimen
Abacavir is a component of the recommended regimen of dolute-gravir/abacavir/lamivudine. Approximately half of individuals who are positive for the HLA-B*5701 allele experience a hypersensitivity reaction to abacavir that may be life threatening.44 HLA-B*5701 testing should be performed prior to abacavir use (evidence rating AIa); those who test positive should not be given abacavir (evidence rating AIa). Allergy to abacavir should be listed in the medical record.
Although some prior comparisons of abacavir/lamivudine and TDF/emtricitabine demonstrated an efficacy advantage of TDF/emtricitabine,45,46 these differences have not been observed in studies that use dolutegravir. In the SINGLE study, all patients in the dolutegravir-containing group used abacavir/lamivudine.36 In the SPRING-2 and FLAMINGO studies, a minority of dolutegravirtreated patients used abacavir/lamivudine, and no differences in efficacy were found based on NRTI selection.
The association between abacavir and an increased risk of myocardial infarction remains controversial.1,7,34,35 More studies have now been published describing the association,47–49 but the data remain inconclusive. For now, abacavir should be used with caution in patients who have or who are at high risk of cardiovascular disease.
TAF as a Component of the Initial Regimen
Compared with TDF, TAF yields a lower plasma level of tenofovir and higher intracellular concentration of the active antiviral component tenofovir diphosphate. This results in fewer tenofovir associated toxic effects, such as proximal renal tubular toxicity and reductions in bone mineral density. One report suggested the possibility of elevated liver enzymes with TDF use, but the clinical significance is uncertain.50
TAF and TDF were compared in prospective clinical trials of initial therapy51,52 and in switch strategies from TDF in patients with virologic suppression and no history of resistance or treatment failure.53,54 To date, only elvitegravir/c has been used in studies of TAF as initial therapy, but a broader range of third drugs has been used in switch studies.
Compared with TDF, TAF has little or no effect on bone density and little or no kidney toxicity. Specifically, proximal tubulopathy has not been observed to date with TAF, which has less effect on renal tubular and overall proteinuria and estimated glomerular filtration rate (eGFR) than TDF. TAF reduces lipids less than TDF; however, this difference does not affect the ratio of total to highdensity lipoprotein cholesterol. To date, no cases of clinical renal disease are directly ascribed to TAF. Tolerability of TAF and TDF is comparable, as are rates of HIV suppression, resistance with virologic failure, and increases in CD4 cell count.
The daily dose of TAF (25 mg or 10 mg) is lower than that of TDF (300 mg). For HIV treatment, TAF is currently available only in coformulations, consisting of emtricitabine/TAF; rilpivirine/emtricitabine/TAF; and elvitegravir/cobicistat/emtricitabine/TAF. Unlike TDF, TAF should not be used with rifamycins, and there are limited data on its safety and efficacy for pregnant women.
Non–InSTI-Containing (or Non–NRTI-Containing) Initial Regimens
Several non–InSTI-containing regimens suppress HIV RNA in the majority of patients who are adherent to therapy. These may be optimal for a given patient based on individual clinical characteristics, preferences, or owing to financial considerations or lack of InSTI availability. These regimens are acceptable therapeutic options. These options are listed in Table 5.
Table 5.
Advantages and Disadvantages of Initial Antiretroviral Therapy Options for Patients in Whom InSTIs Are Not an Optiona
| Darunavir (Boosted With Cobicistat or Ritonavir) Plus TAF/Emtricitabine, TDF/Emtricitabine, or Abacavir/Lamivudineb |
Efavirenz/TDF/Emtricitabine | Rilpivirine/TAF (or TDF)/Emtricitabine | |
|---|---|---|---|
| Advantages | Low risk of resistance with virologic failure, even with intermittent adherence |
High efficacy in patients with baseline HIV RNA >100 000 copies/mL Extensive experience in patients with concomitant tuberculosis Widely available globally |
Lowest risk of rash among NNRTI-based therapies Low risk of metabolic adverse effects Smallest tablet among single-pill regimens |
| Disadvantages | Requires pharmacokinetic boosting; many drug interactions Ritonavir-boosted darunavir inferior to raltegravir and dolutegravir in separate comparative clinical trials37,39 Results of comparative, fully powered studies of cobicistat-boosted darunavir as initial therapy are not yet available |
Relatively high rate of rash No single-tablet form available with TAF High rates of neuropsychiatric adverse effects Increased risk of suicidality in 1 study55; avoid in patients with history of depression |
Not recommended for patients with HIV RNA >100 000 copies/mL or CD4 cell count <200/µL owing to increased risk of virologic failure Must be taken with a meal to optimize absorption Should not be administered with proton pump inhibitors; stagger dosing if given with an H2 blocker |
Abbreviations: InSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
Nonnucleoside reverse transcriptase inhibitor–based regimens should not be used without baseline resistance data because of the possible presence of transmitted NNRTI-resistant virus. In the rare circumstance in which maraviroc might be included in initial therapy, initiation should not occur before confirmation of CC chemokine receptor 5 tropism.
Cautions on the use of abacavir and TAF or TDF are described in the text.
Initial therapy with 2 active drugs is under investigation. This strategy may offer cost or toxicity advantages over the current 3-drug regimens.56 To date, only 2 adequately powered randomized clinical trials have demonstrated noninferior outcomes of 2-drug therapy compared with 3-drug regimens. Lopinavir/r plus lamivudine was noninferior to lopinavir/r plus 2 NRTIs in one study,57 and darunavir/r plus raltegravir was noninferior to darunavir/r plus 2 NRTIs in another.58 However, these 2-drug regimens have limitations. Lopinavir/r induces relatively high rates of gastrointestinal adverse effects and hyperlipidemia. Darunavir/r plus raltegravir was associated with higher rates of treatment failure in patients with a CD4 cell count below 200/µL or an HIV RNA level above 100 000 copies/mL. A small single-group trial of dolutegravir plus lamivudine in 20 patients demonstrated promising results.59
Initial 2-drug regimens are recommended only in the rare situations in which a patient cannot take abacavir, TAF, or TDF (evidence rating BIa); [darunavir/c or darunavir/r] plus [raltegravir or dolutegravir] or plus [lamivudine or emtricitabine] may be considered, but the former strategy may be less effective in those with CD4 cell counts below 200/µL or HIV RNA levels above 100 000 copies/mL. Of note, there are no adequately powered studies of initial therapy of other listed 2-drug regimens besides darunavir/r plus raltegravir or lopinavir/r plus lamivudine; efficacy is assumed from other clinical trials.57,58
Special Considerations
Pregnancy
HIV-infected pregnant women should initiate ART for their own health and to reduce the likelihood of HIV transmission to the infant (evidence rating AIa). Nucleoside reverse transcriptase inhibitor options include abacavir/lamivudine (if the patient is HLA-B*5701 negative), TDF/emtricitabine, or zidovudine/lamivudine. Zidovudine/lamivudine is the regimen with the longest clinical experience, but it has more toxic effects. Raltegravir is the recommended InSTI for use during pregnancy. Recommended boosted PIs include atazanavir/r (once daily) or darunavir/r (twice daily). The recommended NNRTI is efavirenz when initiated after the first 8 weeks of pregnancy. If an HIV-infected woman who is taking efavirenz becomes pregnant, the regimen may be continued; changing it risks loss of virologic control.
Hepatitis B Virus Coinfection
HIV-infected patients with hepatitisBvirus(HBV) coinfection should initiate a recommended ART regimen that contains TDF or TAF (evidence rating AIa), lamivudine or emtricitabine, and a third component.60–62 Lamivudine and emtricitabine each have substantial antiviral activity against HBV. However, there is a high risk of HBV resistance and viral breakthrough if these drugs are used without TDF or TAF, and neither is recommended alone for HBV in coinfection. Entecavir may be used to treat HBV infection (evidence rating AIII). If HIV RNA is not suppressed, entecavir should be avoided because it can select for lamivudine- and emtricitabine-resistant HIV (evidence rating AIII).
Hepatitis C Virus Coinfection
HIV-infected patients with hepatitis C virus (HCV) coinfection should start an ART regimen with drugs that do not have significant drug interactions with HCV therapies (evidence rating AIIa). The recommended regimens that have the fewest drug interactions with current HCV treatments are dolutegravir/abacavir/lamivudine and dolutegravir or raltegravir plus TAF/emtricitabine. Clinicians should consult current HCV treatment guidelines prior to using any other ART regimens, particularly those that include NNRTIs, boosted HIV PIs, or elvitegravir/c.63
Bone Disease
Osteoporosis and fractures are increased with HIV infection.64 During the first 1 to 2 years after initiation of ART, patients may lose 2% to 6% of their bone mineral density at the hip and spine. Patients who receive TDF-containing regimens have a greater initial decline in bone mineral density than those who take a TAF- or abacavir-containing regimen. For this reason, TDF is not recommended for patients with osteopenia or osteoporosis (evidence rating BIII).
Kidney Disease
Monitoring for development of kidney disease with eGFR, urinalysis, and testing for glycosuria and albuminuria or proteinuria is recommended when ART is initiated or changed and every 6 months (along with HIV RNA) once HIV RNA is stable (evidence rating BIII).65 In cohort studies, TDF (especially with a boosted PI) increased the risk of chronic kidney disease.66 Tenofovir disoproxil fumarate is not recommended for patients with an eGFR below 60 mL/min.65 The options are abacavir (which does not require dose adjustment in this setting) or TAF (if creatinine clearance is above 30 mL/min) (evidence rating AIIa). Long-term data on TAF in patients with preexisting renal disease are limited.67 Tenofovir disoproxil fumarate or TAF should be discontinued if renal function worsens, particularly if there is evidence of proximal tubular dysfunction (eg, euglycemic glycosuria or urinary phosphate wasting) (evidence rating AIIa). The safety of TAF in patients with active TDF-associated proximal tubulopathy has not been determined. If possible, TAF should be initiated only after tubulopathy has resolved, with monitoring for recurrence. HIV-infected patients with end-stage renal disease should be evaluated for kidney transplantation with the expectation of high rates of patient and graft survival (evidence rating AIIa).
Cost Considerations
In highly resourced countries, approximately 75% to 80% of annual HIV care expenditures are spent on medications.68 Even at full price, ART is cost-effective.69 In the United States, drug pricing discounts are common, but the amount of discount remains unknown to clinicians and patients, making it difficult to use pricing as a component of treatment decisions.
As more drugs become available in less-expensive generic formulations, payers may begin to use “societal benefit” as a criterion for selection of the initial regimen. One modeling study showed a savings of up to $900 million annually with routine use of a generic efavirenz-based regimen in the United States over a branded version of the same regimen.70 Although relative efficacy in viral suppression is lower with an efavirenz-based regimen than with InSTI-based regimens, the differences are modest and driven by tolerability rather than potency.71
Where resource constraints limit the ability of a health system to provide widespread treatment to all HIV-infected persons, a strategy of using generic formulations of recommended regimens first with use of more expensive drugs for those who demonstrate intolerance may be reasonable. Such policy decisions should be determined in consultation with HIV experts in the locale where the policy is being considered.
Interface of ART and OIs
When to Start ART in the Setting of Active OIs
Recommendations for ART in the setting of OIs are summarized in Box 3. ART should be started as soon as possible but within the first 2 weeks after diagnosis for most OIs,1 with the possible exception of acute cryptococcal meningitis (evidence rating AIa). In a randomized clinical trial of ART initiation in the setting of cryptococcal meningitis in resource-constrained settings, mortality was higher when ART was started within the first 1 to 2 weeks of diagnosis; mortality was lower when ART was delayed until 5 weeks after diagnosis.72 However, in the United States, Canada, and Europe, where there may be greater access to optimal antifungal therapy (eg, flucytosine),73 frequent monitoring, and appropriate management of high intracranial pressure and other underlying conditions, earlier initiation of ART, within 2 weeks of diagnosis, is preferred.74 Although a randomized clinical trial found no survival benefit of early initiation of ART for HIV-infected persons with active tuberculosis and CD4 cell counts greater than 220/µL,75 there was no increased harm, and the improved survival observed in the SAPiT, CAMELIA, and STRIDE trials, particularly for those with lower CD4 cell counts,1,76–78 supports the recommendation to start ART within the first 2 weeks of initiation of tuberculosis treatment for those with CD4 cell counts of 50/µL or less and within the first 2 to 8 weeks for those with CD4 cell counts above 50/µL (evidence rating AIa). Of note, earlier initiation of ART in persons with active tuberculosis, particularly tuberculosis meningitis, may be associated with higher rates of immune reconstitution inflammatory syndrome and may complicate management of adverse drug reactions,79 thus mandating careful monitoring in this setting.
Box 3. ART and Opportunistic Infection Recommendationsa.
ART should be started within the first 2 weeks after diagnosis for most acute opportunistic infections, with the possible exception of acute cryptococcal meningitis (evidence rating AIa).b
ART should be started within the first 2 weeks of initiation of tuberculosis treatment for those with CD4 cell counts of 50/µL or less and within the first 2 to 8 weeks for those with CD4 cell counts above 50/µL (evidence rating AIa).
Neither tenofovir alafenamide nor cobicistat-boosted elvitegravir is recommended with rifamycin drugs (evidence rating AIIb). A boosted protease inhibitor–based regimen should be used only if an integrase strand transfer inhibitor is not an option, and rifabutin, 150 mg/d, should be substituted for rifampin in the antituberculosis regimen (evidence rating AIa).
Primary Mycobacterium avium complex prophylaxis is not recommended if effective ART is initiated immediately and viral suppression achieved (evidence rating AIIa).
Primary Pneumocystis pneumonia prophylaxis is recommended for patients who meet CD4 cell count criteria (evidence rating AIa), even if taking ART.
Abbreviation: ART, antiretroviral therapy.
a See text for essential details and cautions.
b The recommendation or the evidence rating has not changed substantially since the 2014 report.
Recommended Initial ART in the Setting of OIs
Drug interactions and tolerability are important considerations when choosing an initial ART regimen in persons with an acute OI. Azole antifungal agents and rifamycins are of particular concern. The choices for ART in the setting of rifamycin-based antituberculosis therapy have been expanded; efavirenz, 600 mg daily; raltegravir, 400 mg twice daily; or dolutegravir, 50 mg twice daily in combination with 2 NRTIs are acceptable, with InSTI-based regimens recommended.76–78,80–83 Neither TAF nor elvitegravir/c is recommended with rifamycin drugs because of potential adverse drug interactions (evidence rating AIIb). A boosted PI-based regimen should be used only if an InSTI-based regimen is not an option, and rifabutin, 150 mg daily, should be substituted for rifampin in the antituberculosis regimen (evidence rating AIa).84–86
A 3-month, once-weekly regimen of isoniazid and rifapentine for treatment of latent tuberculosis infection is as effective as 9 months of isoniazid alone in HIV-infected individuals.87–89 Highdose daily rifapentine can be safely administered with efavirenz, allowing the 3-month regimen to be administered with efavirenz-based ART.80,90 Although raltegravir exposure was increased when administered with once-weekly rifapentine,91 the regimen was well tolerated, supporting use of raltegravir-based regimens. There are no pharmacokinetic data on rifapentine with dolutegravir. However, extrapolation from available data on rifampin and the similarities between rifapentine and rifampin pharmacokinetics supports dolutegravir use in this context, with similar dose adjustments as suggested for antituberculosis therapy.
CD4 Cell Count Monitoring and Primary OI Prophylaxis
Recommendations regarding when to initiate, whether to continue, and when to stop prophylaxis for OIs have been based on CD4 cell counts prior to and after initiation of ART. With ART recommended for all HIV-infected persons regardless of CD4 cell count, the incidence of AIDS-associated OIs and associated mortality continues to decline. For persons achieving virologic suppression with ART, the incidence of Mycobacterium avium complex (MAC) disease has declined sufficiently that mortality is not substantially different once MAC disease develops for those who did vs did not receive primary MAC prophylaxis.92,93 Thus, primary MAC prophylaxis is not recommended if effective ART is initiated immediately (evidence rating AIIa). Although similar trends are seen with Pneumocystis jirovecii pneumonia as with MAC,92,94 Pneumocystis pneumonia is the most common AIDS-related OI and carries a higher risk of early mortality than MAC disease.92 In the absence of stronger data, initiatingprimary prophylaxis for Pneumocystis pneumonia is still recommended for those who meet CD4 cell count criteria (evidence rating AIa).
When and How to Switch
Recommendations for when and how to switch antiretroviral regimens are summarized in Box 4. With improvements in ART, the need to switch therapy because of virologic failure and drug resistance has decreased. However, these improvements provide a rationale for switching therapy in some patients who have virologic suppression with older regimens that are less convenient or that have more adverse or toxic effects. Reasons to consider switching therapy in such patients include adverse effects, simplification (reducing doses or pills), drug-drug interactions, pregnancy or plans for pregnancy, and food restrictions.
Box 4. Recommendations for When and How to Switch Antiretroviral Regimensa.
Data support possible switching from an older regimen to a single-pill regimen in certain patients with virologic suppression (see text).b
Induction maintenance strategies (switching from 3- to 2-drug regimens in patients with virologic suppression [see text]) are not recommended at this time (evidence rating BIIa).
Patients taking efavirenz should be questioned carefully about the possibility of subtle neuropsychiatric adverse effects (eg, dizziness, sleep disturbances, cognitive changes, depression) that they may be unaware of or may not attribute to the drug (evidence rating BIII).
Review of treatment history and results of prior resistance tests is recommended before any treatment switches are made (evidence rating AIa).
If there is no increase in price, switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide is reasonable even if patients are not experiencing TDF-related toxic effects (evidence rating BIa).
Switching from a boosted protease inhibitor to a nonnucleoside reverse transcriptase inhibitor or an integrase strand transfer inhibitor (with the possible exception of dolutegravir) or switching from twice-daily ritonavir-boosted darunavir to once-daily cobicistat-boosted darunavir is not recommended without consideration of a patient’s viral resistance profile (evidence rating AIII).
a See text for essential details and cautions.
b The recommendation or the evidence rating has not changed substantially since the 2014 report.
Study data support switching from an older regimen to one of a number of single-pill regimens: dolutegravir/abacavir/lamivudine,95 elvitegravir/cobicistat/emtricitabine/TAF,53 elvitegravir/cobicistat/emtricitabine/TDF,96,97 or rilpivirine/emtricitabine/TDF.98 Data also support a switch from suppressive TDF/emtricitabine–based regimens to TAF/emtricitabine–based regimens.60 The lack of randomized clinical trial data does not preclude the possibility of a switch, provided certain caveats are considered.
Induction maintenance approaches have been evaluated in which patients with virologic suppression switch from a 3-drugto a 2-drugmaintenance regimen.99–102 Although trials provide some support for this approach, it remains investigational, and induction maintenance strategies are not recommended at this time (evidence rating BIIa).
For patients experiencing adverse effects or drug toxicities or requesting modification or simplification of their regimen, the decision to switch is relatively easy. Situations exist in which practitioners should recommend a switch even for patients who are satisfied with their current regimen and appear to be doing well. These include when patients are taking regimens containing stavudine, didanosine, or zidovudine, largely because of long-term toxic effects, or older PIs that have higher pill burdens and greater metabolic toxicities than darunavir or atazanavir. Some drugs that are no longer recommended for initial use may often be safely continued for patients who are tolerating them. For example, although nevirapine and efavirenz have substantial early toxic effects, they are safe and tolerable in the long term. Patients taking efavirenz should be questioned carefully about the possibility of subtle neuropsychiatric adverse effects (eg, dizziness, sleep disturbances, cognitive changes, depression) that they may be unaware of or may not attribute to the drug (evidence rating BIII).
With the availability of TAF in its coformulations, it is possible to switch from TDF to TAF. Although the presumption of greater renal and bone safety is primarily based on surrogate markers (ie, bone density as a marker for fracture risk; eGFR and proteinuria for renal safety), these markers consistently suggest superior safety of TAF vs TDF. One exception may be modest lipid elevations due to the loss of the lipid-lowering effects of TDF. If there is no increase in the price of TAF vs that of TDF, switching from TDF to TAF is reasonable even if patients are not experiencing TDF-related toxic effects (evidence rating BIa).
For patients with virologic suppression, it is important to consider the possibility of drug resistance and whether the genetic barriers to resistance of the existing and proposed switch regimens are high or low. The risk of switching from a high-barrier regimen to a low-barrier regimen in patients with preexisting drug resistance has been well demonstrated.103 When possible, switches to a regimen with a lower resistance barrier should be made only after reviewing the treatment and resistance history(evidence rating AIa). When this information is not available, a proviral DNA genotype test may be helpful. The clinical utility of these assays has not yet been established, but they may be useful in detecting mutations that have been archived in resting CD4 cells but that are no longer detectable by standard commercial resistance assays.104,105 Results must be interpreted with caution because they can sometimes fail to detect existing mutations.106 Some switches in the setting of viral suppression may be safe regardless of resistance (eg, TDF to TAF, efavirenz to rilpivirine or etravirine, raltegravir or elvitegravir to dolutegravir, or lopinavir/r to boosted darunavir). Switching from a boosted PI to an NNRTI or an InSTI (with the possible exception of dolutegravir) or switching from twice-daily darunavir/r to once-daily darunavir/c is not advised without considering resistance history because of the reduced resistance barrier of the regimen (evidence rating AIII).
The drug-drug interactions that affect the choice of initial regimen also must be considered when switching. Whether baseline viral load should be considered before switching therapy is not clear; baseline HIV RNA levels above 100 000 copies/mL were not associated with virologic failure when patients with virologic suppression with a PI-based regimen switched to a rilpivirine-containing regimen.98
The approach to virologic failure of an initial NNRTI-, PI-, or InSTI-based regimen has been addressed previously.1 Failure of initial regimens that were chosen based on baseline resistance test results is generally due to poor adherence or, less commonly, to drug-drug interactions. Thus, adherence and drug interactions must be addressed before initiating the new regimen.
Laboratory Monitoring
Initiation of Therapy
Recommendations for laboratory monitoring are summarized in Box 5. As close to the time of HIV diagnosis as possible and prior to beginning ART, CD4 cell count, plasma HIV RNA, serologies for hepatitis A, B, and C, serum chemistries, estimated creatinine clearance, complete blood cell count, and urine glucose and protein should be measured (evidence rating AIII). Genotypic resistance assays for reverse transcriptase and protease should be ordered for all patients (evidence rating AIIa). Transmitted resistance to InSTIs has been documented but is uncommon at present, with little increase over time107–109; thus, routine pretreatment screening for integrase resistance is not currently recommended unless there is reason to believe that the infecting virus may have come from a source in whom InSTI-containing treatment failed (evidence rating BIII).1 Screening for syphilis and 3-site (as appropriate) mucosal nucleic acid amplification testing for chlamydia and gonorrhea should also occur at the time of HIV diagnosis, and a fasting lipid profile should be obtained (evidence rating AIII). Other laboratory assessments should be individualized, in keeping with current guidelines.110,111 HLA-B*5701 and CC chemokine receptor 5 tropism testing results must be confirmed prior to initiating therapy with abacavir and maraviroc, respectively.1
Box 5. Recommendations for Laboratory Monitoringa.
Recommended pre-ART tests include CD4 cell count, plasma HIV-1 RNA, serologies for hepatitis A, B, and C, serum chemistries, estimated creatinine clearance rate, complete blood cell count, urine glucose and protein, sexually transmitted infection screening, and fasting lipid profile (evidence rating AIII).
Genotypic testing for reverse transcriptase and protease resistance mutations is recommended prior to treatment initiation (evidence rating AIIa).
Routine screening for integrase resistance is currently not recommended prior to treatment initiation unless the source virus is suspected to have been from someone in whom treatment containing an integrase strand transfer inhibitor failed (evidence rating BIII).
Screening for syphilis and 3-site (as appropriate) mucosal nucleic acid amplification testing for chlamydia and gonorrhea should occur at the time of HIV diagnosis and a fasting lipid profile should be obtained (evidence rating AIII).
If ART is initiated on the first clinic visit, all laboratory specimens should be drawn prior to the first dose of ART; resistance testing results should be used to modify the regimen as necessary (evidence rating AIII).
HIV RNA level should be monitored every 4 to 6 weeks after treatment is initiated or changed until virus is undetectable (evidence rating AIa).b
Therapeutic drug monitoring is not recommended except in specific circumstances (evidence rating BIII).b
After viral suppression is achieved, HIV RNA should be monitored every 3 months until suppressed for 1 year and at least every 6 months thereafter for adherent patients who remain clinically stable (evidence rating AIII).
If pretreatment CD4 cell count is below 200/µL, reassessment is recommended every 3 to 4 months until viral load is reliably suppressed and CD4 cell count is above 350/µL for 1 year. Thereafter, CD4 cell counts should be assessed at 6-month intervals until virus has been suppressed for at least 2 years and CD4 cell count is persistently stable above 500/µL (evidence rating AIII).
When virus has been suppressed for at least 2 years and CD4 cell count is persistently above 500/µL, repeat monitoring of CD4 cell count is not recommended unless virologic failure (evidence rating AIIa) or intercurrent immunosuppressive conditions occur or immunosuppressive treatments are initiated (evidence rating AIII).
If the HIV RNA level remains above the limit of quantification by 24 weeks after starting new treatment or if rebound above 50 copies/mL occurs at any time, the assay should be repeated within 4 weeks to exclude impending virologic failure (evidence rating AIIa).
Tropism testing is recommended at the time of virologic failure of a CC chemokine receptor 5 inhibitor (evidence rating AIa).
For patients with persistent quantifiable HIV RNA between 50 and 200 copies/mL, reassessment for causes of virologic failure, evaluation again within 4 weeks, and close monitoring are recommended (evidence rating BIII).b
Abbreviation: ART, antiretroviral therapy.
a See text for essential details and cautions.
b The recommendation or the evidence rating has not changed substantially since the 2014 report.
If ART is being initiated on the first clinic visit, all laboratory specimens should be drawn prior to the first dose of ART; resistance testing results should be used to modify the regimen as necessary (evidence rating AIII). A similar process should be used for rapid ART initiation for acute or advanced HIV infection.
Ongoing Therapy
HIV RNA level should be monitored every 4 to 6 weeks after treatment is initiated or changed until it is undetectable, generally below 20 to 50 copies/mL (evidence rating AIa). Virologic suppression should occur within 24 weeks of ART initiation even when initiated during acute infection.112 Failure to achieve suppression by 24 weeks should prompt evaluation for virologic failure. After suppression is achieved, HIV RNA should be monitored every 3 months until suppression has been sustained for 1 year and at least every 6 months thereafter for adherent patients who remain clinically stable (evidence rating AIII). Therapeutic drug monitoring is not recommended except in specific circumstances, as previously described (evidence rating BIII).1
CD4 cell count is used to determine the need for OI prophylaxis. If pretreatment CD4 cell count is below 200/µL, reassessment is recommended every 3 to 4 months until HIV RNA is reliably suppressed and CD4 cell count is above 350/µL for 1 year. Thereafter, CD4 cell counts should be assessed at 6-month intervals until virus has been suppressed for at least 2 years and CD4 cell count is persistently stable above 500/µL (evidence rating AIII). Subsequently, repeat monitoring is not recommended unless virologic failure or intercurrent immunosuppressive conditions occur or immunosuppressive treatments are initiated (evidence rating AIII).1,113 Monitoring for safety, including measures of renal and hepatic function and fasting lipids, should be individualized based on age, co-morbid conditions, and concurrent medications. Screening for sexually transmitted infections should be conducted according to guidelines, local prevalence, and patient risk.114
Virologic Failure
Virologic failure is defined as a confirmed plasma HIV RNA above 200 copies/mL. If the HIV RNA level remains above the limit of quantification by 24 weeks or if rebound above 50 copies/mL occurs at any time, the assay should be repeated within 4 weeks to exclude impending virologic failure (evidence rating AIIa). The clinician should discuss adherence and tolerability with the patient and review the complete medication list, including nonprescribed supplements, to ensure that drug-drug interactions are not compromising therapeutic efficacy. Drug-food interactions should also be explored. Genotypic resistance testing should occur at the time of confirmed virologic failure, although amplification may not be successful for HIV RNA levels below 500 to 1000 copies/mL; proviral DNA assays to estimate archived resistance may be considered. With CC chemokine receptor 5 inhibitors, tropism testing is recommended at the time of virologic failure (evidence rating AIa). CD4 cell count assessment is recommended in the setting of viral rebound (evidence rating AIIa).
Management of Low-Level Viremia
Although any detectable virus has been associated with viral rebound in some studies,115,116 measurable HIV RNA between 20 and 50 copies/mL did not increase the risk of virologic failure in 1 study.117 Data are inconsistent about long-term effects of persistent HIV RNA between 50 and 200 copies/mL,116,118 and current data are insufficient to guide clinical management. Such patients should be reassessed for causes of virologic failure, evaluated again within 4 weeks, and monitored closely (evidence rating BIII). Decisions to change therapy should be individualized based on ART options, resistance history, and clinical circumstances. Treatment should be changed in patients with persistent HIV RNA above 200 copies/mL.119
Viral Resistance
Although transmitted viruses with resistance mutations can revert to wild type, baseline resistance testing should be performed regardless of the duration of infection because many mutations have little effect on viral fitness and may persist for years.120–122 Nonnucleoside reverse transcriptase inhibitor mutations are the most common transmitted resistance mutations (4.5%-10%); NRTI (4.0%-4.5%) and PI mutations are less common (2.8%-3.4%).107,123 Virologic failure with an InSTI-containing regimen requires integrase resistance testing, as integrase resistance has been described in up to 6.8% of patients.124 Resistance testing is less reliable if a patient has stopped ART for longer than 1 month when the sample is collected. The absence of resistance mutations does not confirm absence of resistance in this setting.
Engagement in Care and ART Adherence
Recommendations for engagement in care and ART adherence are summarized in Box 6.
Box 6. Recommendations for Engagement in Care and ART Adherencea.
Routine opt-out HIV screening is recommended in primary medical care settings and emergency departments and for all pregnant women (evidence rating AIII).
Systematic monitoring of time to care linkage following initial HIV diagnosis, retention in care, ART adherence, and rates of viral suppression is recommended in all care settings (evidence rating AIIa).
Brief case management is recommended after HIV diagnosis (evidence rating AIa).
Rapid intervention following a missed clinic visit is recommended (evidence rating AIIa).
Integration of directly observed ART in methadone maintenance programs (evidence rating BIa) and as a treatment strategy among persons with substance use disorders (evidence rating BIa) and those who are incarcerated or released to the community (evidence rating CIII)is recommended to enhance adherence and viral suppression
Personal telephone and interactive text reminders in advance of scheduled appointments and shortly following missed appointments (eg, 24–48 hours) are recommended (evidence rating AIa).
Adherence monitoring using patients’ self-reports by validated adherence instruments and pharmacy refill data are recommended (evidence rating AIIa).
Opioid substitution therapy for opioid-dependent patients is recommended (evidence rating AIIa).
Routine screening for depression is recommended (evidence rating AIII).
Abbreviation: ART, antiretroviral therapy.
a See text for essential details and cautions. All recomendations are new or evidence ratings have changed substantially since the 2014 report.
Achieving the full benefits of treatment and prevention afforded by ART requires early diagnosis, rapid linkage to care, continuous retention in care, and uninterrupted access and adherence to ART. Late diagnosis and presentation for HIV care are global challenges that have improved only modestly over decades.125,126 To avoid missed opportunities for earlier diagnosis,127 routine opt-out HIV screening is recommended in primary medical care settings and emergency departments and for all pregnant women (evidence rating AIII).128,129
Even in highly resourced settings such as the United States, roughly 90% of new HIV infections are attributable to individuals with undiagnosed infection (30%) or who have received a diagnosis but are not engaged in HIV care (61%).130 Systematic monitoring of time from diagnosis to care linkage, retention in care, ART adherence, and rates of viral suppression is recommended to identify and address barriers and to optimize individual and public health out-comes (evidence rating AIIa).7
Monitoring through integration of surveillance data with clinicaldata systems shows promise in improving health outcomes. Real time surveillance-based messaging through an HIV health information exchange has increased engagement rates for individuals who were no longer in HIV care but were receiving non-HIV medical care at nearby sites.131 Coordination with public health surveillance data systems is important, when possible, to improve linkage to, retention in, and reengagement in care.7,132
Evidence-based interventions to improve engagement in care are limited and have been described elsewhere.133–135 Brief case management improved rates of linkage to care (within 6 months) and is recommended after diagnosis (evidence rating AIa).136,137 Linkage to and retention in care may be enhanced through expedited care entry and rapid ART initiation within days of diagnosis,19,20 and adequately powered intervention trials using this approach are planned. Patient navigation and intensive outreach can improve retention in care138,139 but are most appropriate for a subset of patients at greatest risk because of the high resource requirements and cost. A patient navigation intervention with or without financial incentives improved engagement in care following inpatient hospitalization but did not show sustained improvement of viral suppression.140 Integration of directly observed ART in methadone maintenance programs (evidence rating BIa)141 and as a treatment strategy among persons with substance use disorders (evidence rating BIa)142 and those who are incarcerated or released to the community (evidence rating CIII)143 is recommended to enhance adherence and viral suppression.134
Missed clinic visits predict clinical events, including mortality,144 and rapid intervention following a missed visit is recommended (evidence rating AIIa). Personal telephone and interactive short message service (SMS; text) reminders in advance of scheduled appointments and shortly following missed appointments (eg, 24–48 hours) improved retention in HIV medical care across various settings and are recommended (evidence rating AIa).145,146
Viral load measurement is not recommended for screening for ART adherence; clinicians should directly screen for adherence, ideally to identify and intervene in ART nonadherence prior to viral rebound. Adherence monitoring using patients’ self-reports via validated adherence instruments and pharmacy refill data are recommended (evidence rating AIIa).134 Self-reports typically overestimate adherence, but degree of self-reported nonadherence predicts virologic failure and even mortality.147,148 Other interventions that improved ART adherence and some that improved viral suppression are described elsewhere.134,135
Active substance use is associated with poor adherence. Opioid substitution therapy for opioid-dependent patients improves retention in care and is recommended (evidence rating AIIa).149 Depression is associated with poor adherence, and routine screening for depression is recommended (evidence rating AIII).110,134 Depression treatment improved ART adherence150 and HIV outcomes151; however, 3 US-based randomized clinical trials of antidepressant treatment showed no effect on ART adherence.152–154 More intensive behavioral interventions integrating depression and adherence counseling showed improvement in both outcomes.155–157
Prevention
Recommendations for prevention of HIV infection are summarized in Box 7. Use of ARVs has expanded beyond treatment of HIV infection. ART for pregnant women can eliminate mother-to-child transmission.158–160 With “treatment as prevention,” heterosexual transmission can be prevented if the HIV-infected partner achieves viral suppression.4,161–163 An increasingly robust observational data set suggests similar benefit for decreasing transmission among men who have sex with men.5,164 Data are not available for persons who inject drugs, but the assumption is that there would be a similar benefit. In addition, ARVs are effective as PrEP in reducing the risk of HIV acquisition.
Box 7. Recommendations for Prevention of HIV Infectiona.
ART is recommended for all HIV-infected individuals with detectable viremia, not only because of individual health benefits but also because of the reduced infectiousness of individuals achieving virologic suppression with ART (evidence rating AIa).
PrEP should be considered for anyone from a population whose HIV incidence is at least 2% per year (evidence rating AIa) or HIV-seronegative partners of HIV-infected persons who do not have viral suppression
Daily (rather than intermittent) TDF/emtricitabine is the recommended PrEP regimen (evidence rating AIa).
Tenofovir disoproxil fumarate–based PrEP is not recommended for individuals with osteopenia or osteoporosis (evidence rating AIII) or a creatinine clearance rate of less than 60 mL/min (evidence rating AIIa) and should be used with caution in patients with chronic hepatitis B virus infection (evidence rating BIIa).
Tenofovir alafenamide/emtricitabine is not recommended for PrEP until effectiveness has been demonstrated in clinical trials (evidence rating AIII). Use of non–TDF-containing PrEP or augmentation of TDF/emtricitabine PrEP with other agents is not recommended (evidence rating AIII).
HIV testing, preferably with a combination antigen-antibody assay (AIII), serum creatinine, and estimated creatinine clearance is recommended prior to initiation of PrEP (evidence rating AIa).
Oral, rectal, urine, and vaginal sexually transmitted infection screening, including for syphilis, chlamydia, and gonorrhea, is recommended as appropriate, and any sexually transmitted infections should be treated (evidence rating BIII).
Vaccination against hepatitis A and hepatitis B for those who are not immune and human papillomavirus vaccination are recommended (evidence rating AIII).
Vaccination is recommended for women aged 13 to 26 years and for men aged 13 to 21 years who have not been vaccinated previously or who have not completed the 3-dose series. Men aged 22 to 26 years may be vaccinated (evidence rating AIa).
Follow-up at intervals of no longer than every 3 months is recommended to allow for HIV testing (evidence rating AIII) and sexually transmitted infection screening (evidence rating BIIb).
Creatinine assessment may be performed at least every 6 months (evidence rating AIII) and perhaps more frequently for some patients (eg, aged >50 years, taking hypertension or diabetes medications, or with estimated glomerular filtration rates at threshold) (evidence rating CIII).
Ongoing discussions about adherence are recommended, especially in the absence of proven PrEP adherence interventions (evidence rating CIII).
Patients taking PrEP who have suspected HIV infection, on clinical grounds or while awaiting HIV RNA confirmation of equivocal screening test results, should have a boosted protease inhibitor (ie, boosted darunavir) and and/or dolutegravir added to TDF/emtricitabine pending HIV RNA and resistance testing results (evidence rating AIII).
Postexposure prophylaxis is recommended as soon as possible after exposure without waiting for confirmation of HIV serostatus of the source patient or results of HIV RNA or resistance testing (evidence rating AIII).
Tenofovir disoproxil fumarate/emtricitabine plus twice-daily raltegravir or once-daily dolutegravir is recommended by the Centers for Disease Control and Prevention for postexposure prophylaxis; TDF/emtricitabine with cobicistat- or ritonavir-boosted darunavir or TDF/emtricitabine/cobicistat/elvitegravir are reasonable regimens (evidence rating AIIb).
Postexposure prophylaxis regimens should be continued for 28 days, and HIV serostatus should be reassessed at 4 to 6 weeks, 3 months, and 6 months after exposure (evidence rating AIIb); shorter follow-up (eg, 3 or 4 months) may be possible with a fourth-generation assay.
Abbreviations: ART, antiretroviral therapy; PrEP, preexposure prophylaxis; TDF, tenofovir disoproxil fumarate.
a See text for essential details and cautions. All recommendations are new or evidence ratings have changed substantially since the 2014 report. Components separated with a slash (/) indicate that they are available as coformulations.
Treatment as Prevention
ART is recommended for all HIV-infected individuals with detectable viremia, not only because of individual health benefits but also because of the reduced infectiousness of ART-treated individuals with virologic suppression (evidence rating AIa).
Preexposure Prophylaxis
PrEP is an effective HIV prevention tool that is part of a “prevention package” for HIV-seronegative persons at risk. Detailed sexual, substance use, and medical histories are important for deciding whether to provide PrEP. Individuals who are candidates for PrEP include anyone from a population with an HIV incidence of at least 2% per year (evidence rating AIa) or HIV-seronegative partners of HIV-infected persons who do not have viral suppression. Guidelines for identifying candidates for PrEP have been published.165–167 Of note, PrEP does not prevent other sexually transmitted infections.
Daily TDF/emtricitabine with high adherence is highly effective for HIV prevention and is the recommended regimen (evidence rating AIa).168–173 Intermittent, event-driven PrEP was effective in a single study among a highly sexually active population.174 There is evidence that 4 or more doses of PrEP per week confers protection against HIV infection through anal sex169,175,176; in the eventdriven study, the average number of doses taken was 4 per week, which may account for the observed success of this strategy. Less than daily dosing may not be effective for vaginal exposures according to pharmacologic modeling data.177,178 Therefore, daily dosing of TDF/emtricitabine for PrEP is recommended (evidence rating AIa), and there are currently insufficient data to recommend intermittent dosing.
In a single randomized clinical trial of TDF alone in persons who inject drugs, 49% were protected against HIV infection overall but 74% were protected when drug was detected.179 Data on efficacy of PrEP for transgender individuals are limited.169,180 Data on drug-drug interactions between PrEP agents and cross-sex hormone therapy and data on PrEP in transgender women do not exist and are needed.
Because of the TDF component, TDF-based PrEP is not recommended for those with osteopenia or osteoporosis (evidence rating AIII) or a creatinine clearance rate of less than 60 mL/min (evidence rating AIIa) and should be used with caution in those with HBV coinfection (out of concern for flares of hepatitis or hepatic decompensation on cessation of treatment, particularly among patients with cirrhosis) (evidence rating BIIa).
Approximately 9%168 to 14%175 of individuals receiving PrEP experience gastrointestinal adverse effects, which are often self-limited. Glomerular dysfunction with decreases in creatinine clearance rate may occur181,182 and to date have been reversible with discontinuation. Rechallenge with the PrEP regimen is often possible.183,184 Tenofovir disoproxil fumarate–based PrEP has been associated with a 1% to 1.5% loss of bone mineral density at 48 weeks at the hip and spine,185–187 with return to baseline on discontinuation of PrEP.188 Individuals at high risk of osteopenia or osteoporosis should carefully weigh risks and benefits of PrEP.
HIV testing, preferably with a combination antigen-antibody assay (evidence rating AIII), serum creatinine, estimated creatinine clearance, and hepatitis B surface antigen must be performed prior to initiation of PrEP (evidence rating AIa). For high-incidence populations, especially those with a history of recent exposure, an HIV RNA assay may be helpful in excluding acute HIV infection prior to PrEP. Oral, rectal, urine, and vaginal sexually transmitted infection screening, including serologic testing for syphilis and nucleic acid amplification testing for chlamydia and gonorrhea, is recommended as appropriate, and any sexually transmitted infections should be treated (evidence rating BIII). Vaccination against hepatitis A and hepatitis B viruses is recommended for those who are not immune (evidence rating AIII). Vaccination is recommended for women aged 13 to 26 years and for men aged 13 to 21 years who have not been vaccinated previously or who have not completed the 3-dose series. Men aged 22 to 26 years may be vaccinated (evidence rating AIa).189 Women should be screened for pregnancy.
Intervals of follow-up should be no longer than every 3 months to allow for HIV testing (by antigen-antibody assay unless symptoms or signs of acute HIV infection are present, in which case HIV RNA testing should be ordered) (evidence rating AIII) and sexually transmitted infection screening (evidence rating BIIb).190 Creatinine assessment may be performed at least every 6 months (evidence rating AIII) and perhaps more frequently for some patients (eg, those aged >50 years, taking hypertension or diabetes medications, or with eGFRs at threshold)181,191 (evidence rating CIII). Adherence is crucial to the success of PrEP, and ongoing discussions about adherence are important, especially in the absence of proven PrEP adherence interventions (evidence rating CIII).
Any positive HIV screening testresult for a patient receiving PrEP should prompt immediate confirmatory testing for HIV RNA and genotype testing if confirmed. Patients using PrEP who have suspected HIV infection, on clinical grounds or while awaiting HIV RNA confirmation of equivocal screening test results, should have a boosted PI (ie, boosted darunavir) and/or dolutegravir added to TDF/emtricitabine pending HIV RNA and resistance testing results (evidence rating AIII). Resistance has been observed rarely and most commonly (although not universally) when PrEP with TDF/emtricitabine is initiated during occult acute HIV infection and most commonly with M184V/I alone. Transmission of multiclassresistant HIV despite daily PrEP use was recently reported in a gay man in North America.192
Currently, there are no human data to support the efficacy of other oral HIV ARVs for PrEP. Despite an attractive safety profile and a promising result in an animal study,193 tenofovir diphosphate levels in genital compartment tissues were low following administration of a single dose of TAF.194 Tenofovir alafenamide/emtricitabine is not recommended for PrEP until effectiveness has been demonstrated in clinical trials (evidence rating AIII). Use of non– TDF-containing PrEP or augmentation of TDF/emtricitabine PrEP with other agents is not recommended (evidence rating AIII).
Postexposure Prophylaxis
PEP is an emergency intervention designed to abort HIV acquisition in the event of occupational (ie, needlestick or mucous membrane splash) or nonoccupational (ie, sexual or injecting drug use) exposure to HIV-infected blood or potentially infectious bodily fluids. A case-control study estimated an efficacy rate of 81% for zidovudine monoprophylaxis.167,195 Efficacy is likely higher for combination PEP, but no data exist.195 PEP is recommended as soon as possible without waiting for confirmation of HIV serostatus of the source patient or results of HIV RNA or resistance testing (evidence rating AIII). The majority of guidelines recommend PEP initiation only within 72 hours of exposure.196 Baseline assessments should include HIV antibody testing(ideally, a combination antibody/antigen test), sexually transmitted infection testing, pregnancy testing for women of childbearing potential, and hepatitis B and C serologies. The Centers for Disease Control and Prevention recommend TDF/emtricitabine plus twice-daily raltegravir or once-daily dolutegravir196; TDF/emtricitabine with boosted darunavir or TDF/emtricitabine/cobicistat/elvitegravir are reasonable alternatives (evidence rating AIIb). PEP should be continued for 28 days, and HIV serostatus should be reassessed4weeks to 6 weeks, 3 months, and 6 months after exposure (evidence rating AIIb), although shorter serologic follow-up (eg, at 3 or 4 months) may be possible if using a fourth-generation assay. Persons who repeatedly seek PEP should be considered for PrEP, as daily PrEP may be more protective than repeated episodes of PEP.165
Future Directions
Up to 96% of patients who remain in care and receive ART have un-detectable plasma HIVRNA levels.22–26 Newer therapies must be potent, simple, safe, and tolerable to be competitive or fulfill a specific niche, such as activity against multidrugresistant variants or availability as long-acting formulations.
Long-acting ART may allow patients who have difficulty with daily oral therapy to maintain suppression, allow for directly observed therapy in clinical or nontraditional settings, and provide treatment during periods when oral therapy is difficult (eg, surgery, travel, mental illness, or transitions from hospitalization to outpatient care). With a combination of a nanoformulated NNRTI (long-acting rilpivirine) and an InSTI (injectable cabotegravir), virologic suppression was maintained for 32 weeks when given intramuscularly once every 4 weeks or 8weeks.197 Other long-acting therapies being evaluated in clude implantable sustained-release platforms, nanoparticles, viral vector delivery, monoclonal antibodies, and longer-acting oral therapy.198,199 Long-acting ART has the potential to reduce the need for daily adherence to oral therapy, but suboptimal adherence to long-acting ART may also have adverse consequences, as delayed or missed treatment could mean prolonged periods with subtherapeutic ART levels, increasing the risk of suboptimal drug concentrations. Therefore, patients at high risk of suboptimal adherence may require comprehensive treatment strategies to avoid delayed or missed doses. Furthermore, what makes therapies long-acting (eg, peptides in viral vectors, depot formulations, pharmacologic enhancers, etc) may have their own drug interactions or long-term toxic effects, and further evaluation is needed.
Injectable and other long-acting preparations for PrEP are currently in clinical development, including long-acting rilpivirine and long-acting cabotegravir200 and a vaginal ring containing the NNRTI dapivirine, which had a 27% to 30% efficacy in preventing HIV infection among women in sub-Saharan Africa.201,202
Another investigational approach for both HIV treatment and prevention is therapies using broadly neutralizing antibodies, which may offer a new opportunity to clear replicating virus,203,204 clear infected cells,205 and provide passive immunization to protect at-risk individuals.206 The hurdles for these therapies include the requirement for parenteral dosing, potential development of antiidiotypic antibodies, and potential resistance to broadly neutralizing antibodies in infected patients.
Ultimately, if a cure for HIV infection could be developed, the consequences of the infection (eg, chronic inflammation and immune damage) and the need for ART would be eliminated. An ideal cure would also eliminate the need for routine monitoring and the stigma of having been infected with HIV. This target is a high bar. There are 2 potential types of cure: (1) a functional cure, in which an infected person controls infection without therapy and without the consequences of HIV-related immune activation or inflammation and (2) an eradication cure, in which all replication-competent virus is purged from an infected individual. The current search for a cure is both aspirational and necessary to build the foundation of knowledge to design and test cure strategies. Current strategies include reactivating latent virus and purging it from reservoirs (ie, “shock and kill”),207 gene therapy (knocking in protective genes such as fusion peptide or silencing RNA208–210 or knocking out susceptible genes such as CCR5211 or the provirus), and immune enhancement (eg, therapeutic vaccines and immune checkpoint modulators).212 Similar to ART, a successful cure strategy may require more than 1 agent delivered simultaneously or in a series. To gain widespread use, functional or eradication cure strategies must have limited risk, given the safety and effectiveness of current ART.
In addition, to further maximize the enormous potential benefit of ART on the global HIV epidemic, newer, less toxic drugs must be made available in all countries; health care systems must be strengthened, including increased focus on early diagnosis and timely linkage to and retention in care; and routine viral load monitoring must be implemented to identify treatment failures early and minimize the emergence of resistance. Widespread implementation of early diagnosis and treatment requires a global effort to reduce stigma and discrimination and to ensure that HIV-infected individuals seek help without restrictions.
Conclusions
Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment, with recommended initial regimens consisting of an InSTI plus 2 NRTIs. PrEP should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults.
Supplementary Material
Acknowledgments
Funding/Support: The work is sponsored and funded by the International Antiviral Society–USA (IAS-USA), a mission-based, nonmembership, 501(c)(3) not-for-profit organization. In the last 5 years, the IAS-USA has received grants for selected CME activities that are pooled (ie, no single company supports any single effort) from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Therapeutics, Merck, Mylan, Pfizer, Salix Pharmaceuticals, and ViiV Healthcare.
Role of the Sponsor/Funder: The IAS-USA determined the need to update recommendations, selected the panel members, and provided administrative support and oversight. The panel designed and conducted the work; collected, managed, analyzed, and interpreted the data; and prepared, reviewed, and approved the manuscript.
Additional Contributions: We thank Rachel D. Lastra, BA, IAS-USA, for administrative and editorial support, and Hacsi Horváth, MA, Global Health Sciences at University of California, San Francisco, for conducting the PubMed and EMBASE literature searches.
Footnotes
Supplemental content at jama.com
Author Contributions: Dr Günthard had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: Günthard, Saag, Benson, Del Rio, Eron, Gallant, Hoy, Mugavero, Sax, Thompson, Gandhi, Landovitz, Smith, Volberding.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: Günthard, Saag, Benson, Del Rio, Eron, Gallant, Hoy, Mugavero, Sax, Thompson, Gandhi, Landovitz, Smith, Volberding.
Obtained funding: Volberding.
Administrative, technical, or material support: Del Rio, Hoy, Sax, Jacobsen, Volberding.
Study supervision: Günthard, Saag, Volberding.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Günthard reports receipt of grants from the Swiss National Science Foundation, Swiss HIV Cohort Study, University of Zurich, Yvonne Jacob Foundation, and Gilead Sciences; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences; and travel reimbursement from Gilead, Bristol-Myers Squibb, and Janssen. Dr Saag reports receipt of grants from Bristol-Myers Squibb, AbbVie, Merck, Gilead Sciences, Janssen, and ViiV Healthcare and serving as a scientific advisor to Bristol-Myers Squibb, Merck, and Gilead. Dr Benson reports data and safety membership board membership for GlaxoSmithKline, grants to and/or contracts with her institution from Gilead Sciences and MBio, and scientific advisory board membership for MBio. Dr Eron reports receipt of grants from and/or service as a consultant to Bristol-Myers Squibb, Janssen, ViiV Healthcare, AbbVie, Gilead Sciences, and Merck. Dr Gallant reports grants from and/or service as a consultant to AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Sangamo Biosciences, and ViiV Healthcare/GlaxoSmithKline. Dr Hoy reports advisory board fees paid to her institution from Gilead Sciences, ViiV Healthcare, Merck Sharp & Dohme, and AbbVie. Dr Mugavero reports receipt of grants from Bristol-Myers Squibb and fees for grant review from Gilead Sciences. Dr Sax reports consultancy/advisory board membership for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline/ViiV Healthcare, Gilead Sciences, Janssen, and Merck and receipt of grants from Bristol-Myers Squibb, GlaxoSmithKline/ViiV Healthcare, and Gilead. Dr Thompson reports institutional research contracts between the AIDS Research Consortium of Atlanta and Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Pfizer, Roche Molecular Systems, Taimed, Tobira Therapeutics, and ViiV Healthcare; she received no payments directly from these entities. Dr Gandhi reports receipt of grants from Gilead Sciences, Merck, ViiV Healthcare, and EBSCO. Dr Landovitz reports service as a consultant to and nonfinancial support from Gilead Sciences. Dr Smith reports receipt of grants from and/or service as a consultant to ViiV Healthcare, FluxErgy, and Testing Talent Services. Dr Volberding reports scientific advisory board membership for Bristol-Myers Squibb and Gilead Sciences and data and safety monitoring board membership for Merck. No other disclosures were reported.
REFERENCES
- 1.Günthard HF, Aberg JA, Eron JJ, et al. International Antiviral Society-USA Panel. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA. 2014;312(4):410–425. doi: 10.1001/jama.2014.8722. [DOI] [PubMed] [Google Scholar]
- 2.Lundgren JD, Babiker AG, Gordin F, et al. INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795–807. doi: 10.1056/NEJMoa1506816. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Danel C, Moh R, Gabillard D, et al. TEMPRANO ANRS 12136 Study Group. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373(9):808–822. doi: 10.1056/NEJMoa1507198. [DOI] [PubMed] [Google Scholar]
- 4.Cohen MS, Chen YQ, McCauley M, et al. HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493–505. doi: 10.1056/NEJMoa1105243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Rodger A, Bruun T, Cambiano V, et al. HIV transmission risk through condomless sex if HIV+ partner on suppressive ART: PARTNER study. Presented at: Conference on Retroviruses and Opportunistic Infections; March 3–6, 2014; Boston, MA. [Google Scholar]
- 6.Canadian Task Force on the Periodic Health Examination. The periodic health examination. Can Med Assoc J. 1979;121(9):1193–1254. [PMC free article] [PubMed] [Google Scholar]
- 7.Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012;308(4):387–402. doi: 10.1001/jama.2012.7961. [DOI] [PubMed] [Google Scholar]
- 8.Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. HPTN 052-ACTG Study Team. Effects of early vs delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis. 2014;14(4):281–290. doi: 10.1016/S1473-3099(13)70692-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Panichsillapakit T, Smith DM, Wertheim JO, Richman DD, Little SJ, Mehta SR. Prevalence of transmitted HIV drug resistance among recently infected persons in San Diego, CA 1996–2013. J Acquir Immune Defic Syndr. 2016;71(2):228–236. doi: 10.1097/QAI.0000000000000831. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Yang WL, Kouyos R, Scherrer AU, et al. Swiss HIV Cohort Study. Assessing the paradox between transmitted and acquired HIV type 1 drug resistance mutations in the Swiss HIV Cohort Study from 1998 to 2012. J Infect Dis. 2015;212(1):28–38. doi: 10.1093/infdis/jiv012. [DOI] [PubMed] [Google Scholar]
- 11.Hofstra LM, Sauvageot N, Albert J, et al. SPREAD Program. Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe. Clin Infect Dis. 2016;62(5):655–663. doi: 10.1093/cid/civ963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Buzon MJ, Martin-Gayo E, Pereyra F, et al. Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells. J Virol. 2014;88(17):10056–10065. doi: 10.1128/JVI.01046-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Ananworanich J, Schuetz A, Vandergeeten C, et al. RV254/SEARCH 010 Study Group. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One. 2012;7(3):e33948. doi: 10.1371/journal.pone.0033948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Schuetz A, Deleage C, Sereti I, et al. RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS Pathog. 2014;10(12):e1004543. doi: 10.1371/journal.ppat.1004543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Laanani M, Ghosn J, Essat A, et al. Agence Nationale de Recherche sur le Sida PRIMO Cohort Study Group. Impact of the timing of initiation of antiretroviral therapy during primary HIV-1 infection on the decay of cell-associated HIV-DNA. Clin Infect Dis. 2015;60(11):1715–1721. doi: 10.1093/cid/civ171. [DOI] [PubMed] [Google Scholar]
- 16.Chéret A, Bacchus-Souffan C, Avettand-Fenoël V, et al. OPTIPRIM ANRS-147 Study Group. Combined ART started during acute HIV infection protects central memory CD4 T cells and can induce remission. J Antimicrob Chemother. 2015;70(7):2108–2120. doi: 10.1093/jac/dkv084. [DOI] [PubMed] [Google Scholar]
- 17.El-Sadr WM, Lundgren J, Neaton JD, et al. Strategies for Management of Antiretroviral Therapy Study Group. CD4 count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–2296. doi: 10.1056/NEJMoa062360. [DOI] [PubMed] [Google Scholar]
- 18.Marzel A, Shilaih M, Yang WL, et al. Swiss HIV Cohort Study. HIV-1 transmission during recent infection and during treatment interruptions as major drivers of new infections in the Swiss HIV Cohort Study. Clin Infect Dis. 2016;62(1):115–122. doi: 10.1093/cid/civ732. [DOI] [PubMed] [Google Scholar]
- 19.Pilcher C, Hatano H, Dasgupta A, et al. Providing same day, observed ART to newly diagnosed HIV+ outpatients is associated with improved virologic suppression. Presented at: Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention; July 19–22, 2015; Vancouver, BC, Canada. Abstract WEAD0105 LB. [Google Scholar]
- 20.Rosen S, Maskew M, Fox MP, et al. Initiating ART at a patient’s first clinic visit: the RapIT randomized trial. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. Abstract 28. [Google Scholar]
- 21.Crowell TA, Gebo KA, Blankson JN, et al. HIV Research Network. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection. J Infect Dis. 2015;211(11):1692–1702. doi: 10.1093/infdis/jiu809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Simoni JM, Nance RM, Delaney JA, et al. HIV viral load in US clinics over time: trends and predictors from CNICS. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 23.Gisslen M, Svedhem V, Lindborg L, et al. The Swedish HIV treatement cascade. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 24.Moore DM, Cui Z, Lachowsky NJ, et al. Recent increases in virologic suppression among HIV-positive MSM in Vancouver, Canada. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 25.Gaolathe T, Wirth K, Holme MP, et al. Botswana is close to meeting UNAIDS 2020 goals of 90-90-90 coverage. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 26.Kohler P, Schmidt AJ, Cavassini M, et al. Swiss HIV Cohort Study. The HIV care cascade in Switzerland: reaching the UNAIDS/WHO targets for patients diagnosed with HIV. AIDS. 2015;29(18):2509–2515. doi: 10.1097/QAD.0000000000000878. [DOI] [PubMed] [Google Scholar]
- 27.Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1996: recommendations of an international panel. JAMA. 1996;276(2):146–154. [PubMed] [Google Scholar]
- 28.Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society-USA panel. JAMA. 1997;277(24):1962–1969. [PubMed] [Google Scholar]
- 29.Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA panel. JAMA. 1998;280(1):78–86. doi: 10.1001/jama.280.1.78. [DOI] [PubMed] [Google Scholar]
- 30.Carpenter CCJ, Cooper DA, Fischl MA, et al. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA panel. JAMA. 2000;283(3):381–390. doi: 10.1001/jama.283.3.381. [DOI] [PubMed] [Google Scholar]
- 31.Yeni PG, Hammer SM, Carpenter CCJ, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA panel. JAMA. 2002;288(2):222–235. doi: 10.1001/jama.288.2.222. [DOI] [PubMed] [Google Scholar]
- 32.Yeni PG, Hammer SM, Hirsch MS, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA panel. JAMA. 2004;292(2):251–265. doi: 10.1001/jama.292.2.251. [DOI] [PubMed] [Google Scholar]
- 33.Hammer SM, Saag MS, Schechter M, et al. International AIDS Society-USA Panel. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296(7):827–843. doi: 10.1001/jama.296.7.827. [DOI] [PubMed] [Google Scholar]
- 34.Hammer SM, Eron JJ, Jr, Reiss P, et al. International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300(5):555–570. doi: 10.1001/jama.300.5.555. [DOI] [PubMed] [Google Scholar]
- 35.Thompson MA, Aberg JA, Cahn P, et al. International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010;304(3):321–333. doi: 10.1001/jama.2010.1004. [DOI] [PubMed] [Google Scholar]
- 36.Walmsley SL, Antela A, Clumeck N, et al. SINGLE Investigators Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807–1818. doi: 10.1056/NEJMoa1215541. [DOI] [PubMed] [Google Scholar]
- 37.Clotet B, Feinberg J, van Lunzen J, et al. ING114915 Study Team. Once-daily dolutegravir vs darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383(9936):2222–2231. doi: 10.1016/S0140-6736(14)60084-2. [DOI] [PubMed] [Google Scholar]
- 38.Squires K, Kityo C, Hodder S, et al. Elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) is superior to ritonavir (RTV) boosted atazanavir (ATV) plus FTC/TDF in treatment naive women with HIV-1 infection (WAVES study). Presented at: Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention; July 18–22, 2015; Vancouver, BC, Canada. Abstract MOLBPE08. [Google Scholar]
- 39.Ofotokun I, Na LH, Landovitz RJ, et al. AIDS Clinical Trials Group A5257 Team; AIDS Clinical Trials Group A5257 Team. Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir vs raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis. 2015;60(12):1842–1851. doi: 10.1093/cid/civ193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Raffi F, Rachlis A, Stellbrink HJ, et al. SPRING-2 Study Group. Once-daily dolutegravir vs raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735–743. doi: 10.1016/S0140-6736(12)61853-4. [DOI] [PubMed] [Google Scholar]
- 41.Cahn P, Pozniak AL, Mingrone H, et al. Extended SAILING Study Team. Dolutegravir vs raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700–708. doi: 10.1016/S0140-6736(13)61221-0. [DOI] [PubMed] [Google Scholar]
- 42.Elion R, Molina JM, Ramón Arribas López J, et al. Study 145 Team. A randomized phase 3 study comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experienced subjects with HIV-1 infection: 96-week results. J Acquir Immune Defic Syndr. 2013;63(4):494–497. doi: 10.1097/QAI.0b013e318298469c. [DOI] [PubMed] [Google Scholar]
- 43.Raffi F, Jaeger H, Quiros-Roldan E, et al. Extended SPRING-2 Study Group. Once-daily dolutegravir vs twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927–935. doi: 10.1016/S1473-3099(13)70257-3. [DOI] [PubMed] [Google Scholar]
- 44.Mallal S, Phillips E, Carosi G, et al. PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568–579. doi: 10.1056/NEJMoa0706135. [DOI] [PubMed] [Google Scholar]
- 45.Sax PE, Tierney C, Collier AC, et al. AIDS Clinical Trials Group Study A5202 Team. Abacavir-lamivudine vs tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361(23):2230–2240. doi: 10.1056/NEJMoa0906768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine vs tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr. 2010;55(1):49–57. doi: 10.1097/QAI.0b013e3181dd911e. [DOI] [PubMed] [Google Scholar]
- 47.Marcus JL, Neugebauer RS, Leyden WA, et al. Use of abacavir and risk of cardiovascular disease among HIV-infected individuals. J Acquir Immune Defic Syndr. 2016;71(4):413–419. doi: 10.1097/QAI.0000000000000881. [DOI] [PubMed] [Google Scholar]
- 48.Young J, Xiao Y, Moodie EE, et al. Swiss HIV Cohort Study. Effect of cumulating exposure to abacavir on the risk of cardiovascular disease events in patients from the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr. 2015;69(4):413–421. doi: 10.1097/QAI.0000000000000662. [DOI] [PubMed] [Google Scholar]
- 49.Sabin CA, Reiss P, Ryom L, et al. D:A:D Study Group. Is there continued evidence for an association between abacavir usage and myocardial infarction risk in individuals with HIV? a cohort collaboration. BMC Med. 2016;14(1):61. doi: 10.1186/s12916-016-0588-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Kovari H, Sabin CA, Ledergerber B, et al. Antiretroviral drugs and risk of chronic alanine aminotransferase elevation in human immunodeficiency virus (HIV)-monoinfected persons: the Data Collection on Adverse Events of Anti-HIV Drugs study. Open Forum Infect Dis. 2016;3(1) doi: 10.1093/ofid/ofw009. ofw009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Sax PE, Wohl D, Yin MT, et al. GS-US-292-0104/0111 Study Team. Tenofovir alafenamide vs tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606–2615. doi: 10.1016/S0140-6736(15)60616-X. [DOI] [PubMed] [Google Scholar]
- 52.Wohl D, Oka S, Clumeck N, et al. GS-US-292-01040111 and Study Team. Brief report: a randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: week 96 results. J Acquir Immune Defic Syndr. 2016;72(1):58–64. doi: 10.1097/QAI.0000000000000940. [DOI] [PubMed] [Google Scholar]
- 53.Mills A, Arribas JR, Andrade-Villanueva J, et al. GS-US-292-0109 Team. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016;16(1):43–52. doi: 10.1016/S1473-3099(15)00348-5. [DOI] [PubMed] [Google Scholar]
- 54.Gallant J, Daar E, Raffi F, et al. Switching tenofovir DF to tenofovir alafenamide in virologically suppressed adults. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 55.Mollan KR, Smurzynski M, Eron JJ, et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med. 2014;161(1):1–10. doi: 10.7326/M14-0293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Girouard MP, Sax PE, Parker RA, et al. The cost-effectiveness and budget impact of 2-drug dolutegravir-lamivudine regimens for the treatment of HIV infection in the United States. Clin Infect Dis. 2016;62(6):784–791. doi: 10.1093/cid/civ981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Cahn P, Andrade-Villanueva J, Arribas JR, et al. GARDEL Study Group. Dual therapy with lopinavir and ritonavir plus lamivudine vs triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis. 2014;14(7):572–580. doi: 10.1016/S1473-3099(14)70736-4. [DOI] [PubMed] [Google Scholar]
- 58.Raffi F, Babiker AG, Richert L, et al. NEAT001/ANRS143 Study Group. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. 2014;384(9958):1942–1951. doi: 10.1016/S0140-6736(14)61170-3. [DOI] [PubMed] [Google Scholar]
- 59.Figueroa MI, Sued O, Patterson P, et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: first results of the PADDLE trial. Presented at: 15th European AIDS Conference; October 21–24, 2015; Barcelona, Spain. Abstract LBPS4/1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV. 2016;3(4):e158–e165. doi: 10.1016/S2352-3018(16)00024-2. [DOI] [PubMed] [Google Scholar]
- 61.Buti M, Gane E, Seto WK, et al. A phase 3 study of tenofovir alafenamide compared with tenofovir disoproxil fumarate in patients with HBeAg-negative, chronic hepatitis B: week 48 efficacy and safety results. Presented at: International Liver Congress; April 13–17, 2016; Barcelona, Spain. Abstract GS06. [Google Scholar]
- 62.Chan HLY, Fung S, Seto WK, et al. A phase 3 study of tenofovir alafenamide compared with tenofovir disoproxil fumarate in patients with HBeAg-positive chronic HBV: week 48 efficacy and safety results. Presented at: International Liver Congress; April 13–17, 2016; Barcelona, Spain. Abstract GS12. [Google Scholar]
- 63.American Association for the Study of Liver Diseases and Infectious Diseases Society of America. [Accessed April 20, 2016];HCV guidance: recommendations for testing, managing, and treating hepatitis C. http://hcvguidelines.org/
- 64.Borges AH, Hoy J, Florence E, et al. Antiretrovirals, fractures, and osteonecrosis in a large European HIV cohort. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. Abstract 46. [Google Scholar]
- 65.Lucas GM, Ross MJ, Stock PG, et al. HIV Medicine Association of the Infectious Diseases Society of America Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(9):e96–e138. doi: 10.1093/cid/ciu617. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Mocroft A, Lundgren JD, Ross M, et al. Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) Study. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study. Lancet HIV. 2016;3(1):e23–e32. doi: 10.1016/S2352-3018(15)00211-8. [DOI] [PubMed] [Google Scholar]
- 67.Pozniak A, Arribas JR, Gupta SK, et al. Safety of tenofovir alafenamide in renal impairment. Presented at: 22nd Conference on Retroviruses and Opportunistic Infections; February 23–26, 2015; Seattle, WA. [Google Scholar]
- 68.Chen RY, Accortt NA, Westfall AO, et al. Distribution of health care expenditures for HIV-infected patients. Clin Infect Dis. 2006;42(7):1003–1010. doi: 10.1086/500453. [DOI] [PubMed] [Google Scholar]
- 69.Freedberg KA, Losina E, Weinstein MC, et al. The cost effectiveness of combination antiretroviral therapy for HIV disease. N Engl J Med. 2001;344(11):824–831. doi: 10.1056/NEJM200103153441108. [DOI] [PubMed] [Google Scholar]
- 70.Walensky RP, Sax PE, Nakamura YM, et al. Economic savings vs health losses: the cost-effectiveness of generic antiretroviral therapy in the United States. Ann Intern Med. 2013;158(2):84–92. doi: 10.7326/0003-4819-158-2-201301150-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015;70(5):515–519. doi: 10.1097/QAI.0000000000000790. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Boulware DR, Meya DB, Muzoora C, et al. COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014;370(26):2487–2498. doi: 10.1056/NEJMoa1312884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(3):291–322. doi: 10.1086/649858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Ingle SM, Miro JM, Furrer H, et al. Impact of ART on mortality in cryptococcal meningitis patients: high-income settings. Presented at: 22nd Conference on Retroviruses and Opportunistic Infections; February 23–26, 2015; Seattle, WA. [Google Scholar]
- 75.Mfinanga SG, Kirenga BJ, Chanda DM, et al. Early vs delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial. Lancet Infect Dis. 2014;14(7):563–571. doi: 10.1016/S1473-3099(14)70733-9. [DOI] [PubMed] [Google Scholar]
- 76.Blanc FX, Sok T, Laureillard D, et al. CAMELIA (ANRS 1295-CIPRA KH001) Study Team. Earlier vs later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365(16):1471–1481. doi: 10.1056/NEJMoa1013911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Havlir DV, Kendall MA, Ive P, et al. AIDS Clinical Trials Group Study. A5221 Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365(16):1482–1491. doi: 10.1056/NEJMoa1013607. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Abdool Karim S, Naidoo K, Padayatchi N, et al. Optimal timing of ART during TB therapy: findings of the SAPiT trial. Presented at: 18th Conference on Retroviruses and Opportunistic Infections; February 27–March 2, 2011; Boston, MA. [Google Scholar]
- 79.Manzardo C, Guardo AC, Letang E, Plana M, Gatell JM, Miro JM. Opportunistic infections and immune reconstitution inflammatory syndrome in HIV-1-infected adults in the combined antiretroviral therapy era: a comprehensive review. Expert Rev Anti Infect Ther. 2015;13(6):751–767. doi: 10.1586/14787210.2015.1029917. [DOI] [PubMed] [Google Scholar]
- 80.Luetkemeyer AF, Rosenkranz SL, Lu D, et al. Adult AIDS Clinical Trials Group A5221 Study Team. Relationship between weight, efavirenz exposure, and virologic suppression in HIV-infected patients on rifampin-based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE Study. Clin Infect Dis. 2013;57(4):586–593. doi: 10.1093/cid/cit246. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Grinsztejn B, De Castro N, Arnold V, et al. ANRS 12 180 Reflate TB Study Group. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014;14(6):459–467. doi: 10.1016/S1473-3099(14)70711-X. [DOI] [PubMed] [Google Scholar]
- 82.Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013;62(1):21–27. doi: 10.1097/QAI.0b013e318276cda9. [DOI] [PubMed] [Google Scholar]
- 83.Friedland G, Khoo S, Jack C, Lalloo U. Administration of efavirenz (600 mg/day) with rifampicin results in highly variable levels but excellent clinical outcomes in patients treated for tuberculosis and HIV. J Antimicrob Chemother. 2006;58(6):1299–1302. doi: 10.1093/jac/dkl399. [DOI] [PubMed] [Google Scholar]
- 84.Naiker S, Conolly C, Weisner L, et al. Pharmacokinetic evaluation of different rifabutin dosing strategies in African TB patients on lopinavir/ritonavir-based ART. Presented at: 18th Conference on Retroviruses and Opportunistic Infections; February 27–March 2, 2011; Boston, MA. [Google Scholar]
- 85.Boulanger C, Hollender E, Farrell K, et al. Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis. Clin Infect Dis. 2009;49(9):1305–1311. doi: 10.1086/606056. [DOI] [PubMed] [Google Scholar]
- 86.Jenny-Avital ER, Joseph K. Rifamycin-resistant Mycobacterium tuberculosis in the highly active antiretroviral therapy era: a report of 3 relapses with acquired rifampin resistance following alternate-day rifabutin and boosted protease inhibitor therapy. Clin Infect Dis. 2009;48(10):1471–1474. doi: 10.1086/598336. [DOI] [PubMed] [Google Scholar]
- 87.Sterling TR, Scott NA, Miro JM, et al. Tuberculosis Trials Consortium the AIDS Clinical Trials Group for the PREVENT TB Trial (TBTC Study 26ACTG 5259) Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS. 2016;30(10):1607–1615. doi: 10.1097/QAD.0000000000001098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep. 2011;60(48):1650–1653. [PubMed] [Google Scholar]
- 89.Sterling T, Benson C, Scott N, et al. Three months of weekly rifapentine + INH for M tuberculosis infection in HIV-infected persons [CROI abstract 817] Top Antivir Med. 2014;22(e-1):425. [Google Scholar]
- 90.Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009;360(23):2397–2405. doi: 10.1056/NEJMoa0808427. [DOI] [PubMed] [Google Scholar]
- 91.Weiner M, Egelund EF, Engle M, et al. Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers. J Antimicrob Chemother. 2014;69(4):1079–1085. doi: 10.1093/jac/dkt483. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Djawe K, Buchacz K, Hsu L, et al. Mortality risk after AIDS-defining opportunistic illness among HIV-infected persons—San Francisco, 1981–2012. J Infect Dis. 2015;212(9):1366–1375. doi: 10.1093/infdis/jiv235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Yangco BG, Buchacz K, Baker R, Palella FJ, Armon C, Brooks JT. HIV Outpatient Study. Investigators Is primary Mycobacterium avium complex prophylaxis necessary in patients with CD4 <50 cells/µL who are virologically suppressed on cART? AIDS Patient Care STDS. 2014;28(6):280–283. doi: 10.1089/apc.2013.0270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Mocroft A, Reiss P, Kirk O, et al. Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200 cells/µL? Clin Infect Dis. 2010;51(5):611–619. doi: 10.1086/655761. [DOI] [PubMed] [Google Scholar]
- 95.Trottier B, Lake J, Logue K, et al. Switching to abacavir/dolutegravir/lamivudine combination (ABC/DTG/3TC FDC) from a PI, INI or NNRTI based regimen maintains HIV suppression. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–21, 2015; San Diego, CA. [Google Scholar]
- 96.Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir vs continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial. Lancet Infect Dis. 2014;14(7):590–599. doi: 10.1016/S1473-3099(14)70796-0. [DOI] [PubMed] [Google Scholar]
- 97.Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir vs continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis. 2014;14(7):581–589. doi: 10.1016/S1473-3099(14)70782-0. [DOI] [PubMed] [Google Scholar]
- 98.Palella FJ, Jr, Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS. 2014;28(3):335–344. doi: 10.1097/QAD.0000000000000087. [DOI] [PubMed] [Google Scholar]
- 99.Perez-Molina JA, Rubio R, Rivero A, et al. GESIDA 7011 Study Group. Dual treatment with atazanavir-ritonavir plus lamivudine vs triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week results from a randomised, open-label, non-inferiority trial. Lancet Infect Dis. 2015;15(7):775–784. doi: 10.1016/S1473-3099(15)00097-3. [DOI] [PubMed] [Google Scholar]
- 100.Arribas JR, Girard PM, Landman R, et al. OLE/RIS-EST13 Study Group. Dual treatment with lopinavir-ritonavir plus lamivudine vs triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. Lancet Infect Dis. 2015;15(7):785–792. doi: 10.1016/S1473-3099(15)00096-1. [DOI] [PubMed] [Google Scholar]
- 101.Margolis DA, Brinson CC, Smith GH, et al. LAI116482 Study Team. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviralnaive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015;15(10):1145–1155. doi: 10.1016/S1473-3099(15)00152-8. [DOI] [PubMed] [Google Scholar]
- 102.Calcagno A, Montrucchio C, Capetti A, et al. Raltegravir plus nevirapine as maintenance antiretroviral therapy in HIV-positive patients: safety, efficacy and pharmacokinetics. Curr HIV Res. 2016;14(1):54–60. doi: 10.2174/1570162x13666150929112135. [DOI] [PubMed] [Google Scholar]
- 103.Eron JJ, Young B, Cooper DA, et al. SWITCHMRK 1 and 2 Investigators Switch to a raltegravir-based regimen vs continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375(9712):396–407. doi: 10.1016/S0140-6736(09)62041-9. [DOI] [PubMed] [Google Scholar]
- 104.Derache A, Shin HS, Balamane M, et al. HIV drug resistance mutations in proviral DNA from a community treatment program. PLoS One. 2015;10(1):e0117430. doi: 10.1371/journal.pone.0117430. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105.Lübke N, Di Cristanziano V, Sierra S, et al. Proviral DNA as a target for HIV-1 resistance analysis. Intervirology. 2015;58(3):184–189. doi: 10.1159/000431093. [DOI] [PubMed] [Google Scholar]
- 106.Toma J, Tan Y, Cai S, et al. Drug resistance profiles derived from HIV-1 DNA in ARV suppressed patients correlate with historical resistance profiles obtained from HIV-1 plasma RNA. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–21, 2015; San Diego, CA. [Google Scholar]
- 107.Volpe JM, Yang O, Petropoulos CJ, Walworth CM. Absence of integrase inhibitor resistant HIV-1 transmission in the California AIDS Healthcare Foundation Network. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–21, 2015; San Diego, CA. [Google Scholar]
- 108.Casadellà M, van Ham PM, Noguera-Julian M, et al. SPREAD Programme. Primary resistance to integrase strand-transfer inhibitors in Europe. J Antimicrob Chemother. 2015;70(10):2885–2888. doi: 10.1093/jac/dkv202. [DOI] [PubMed] [Google Scholar]
- 109.Scherrer AU, Yang WL, Kouyos RD, et al. Swiss HIV Cohort Study. Successful prevention of transmission of integrase resistance in the Swiss HIV Cohort Study [published online April 29, 2016] J Infect Dis. doi: 10.1093/infdis/jiw165. [DOI] [PubMed] [Google Scholar]
- 110.Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Infectious Diseases Society of America Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58(1):1–10. doi: 10.1093/cid/cit757. [DOI] [PubMed] [Google Scholar]
- 111.European AIDS Clinical Society. [Accessed April 8, 2016];European AIDS Clinical Society Guidelines 8.0. http://www.eacsociety.org/files/2015_eacsguidelines_8_0-english_rev-20160124.pdf.
- 112.Crowell TA, Phanuphak N, Pinyakorn S, et al. Virologic failure is uncommon after treatment is initiated during acute HIV infection. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 113.Sax PE. Editorial commentary: can we break the habit of routine CD4 monitoring in HIV care? Clin Infect Dis. 2013;56(9):1344–1346. doi: 10.1093/cid/cit008. [DOI] [PubMed] [Google Scholar]
- 114.Workowski KA, Bolan GA Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1–137. [PMC free article] [PubMed] [Google Scholar]
- 115.Henrich TJ, Wood BR, Kuritzkes DR. Increased risk of virologic rebound in patients on antiviral therapy with a detectable HIV load <48 copies/mL. PLoS One. 2012;7(11):e50065. doi: 10.1371/journal.pone.0050065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Young J, Rickenbach M, Calmy A, et al. Swiss HIV Cohort Study. Transient detectable viremia and the risk of viral rebound in patients from the Swiss HIV Cohort Study. BMC Infect Dis. 2015;15:382. doi: 10.1186/s12879-015-1120-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Teira R, Munoz-Sanchez M, Suarez-Lozano I, et al. Effect of viral suppression below 20 copies of HIV-RNA per millilitre of plasma on virological outcome of treated HIV-infected patients. Presented at: 20th International AIDS Conference; July 20–25, 2014; Melbourne, Australia. [Google Scholar]
- 118.Ryscavage P, Kelly S, Li JZ, Harrigan PR, Taiwo B. Significance and clinical management of persistent low-level viremia and very-low-level viremia in HIV-1-infected patients. Antimicrob Agents Chemother. 2014;58(7):3585–3598. doi: 10.1128/AAC.00076-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119.Boillat-Blanco N, Darling KE, Schoni-Affolter F, et al. Swiss HIV Cohort Study. Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study. Antivir Ther. 2015;20(2):165–175. doi: 10.3851/IMP2815. [DOI] [PubMed] [Google Scholar]
- 120.Jain V, Sucupira MC, Bacchetti P, et al. Differential persistence of transmitted HIV-1 drug resistance mutation classes. J Infect Dis. 2011;203(8):1174–1181. doi: 10.1093/infdis/jiq167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.Pingen M, Wensing AM, Fransen K, et al. SPREAD Programme. Persistence of frequently transmitted drug-resistant HIV-1 variants can be explained by high viral replication capacity. Retrovirology. 2014;11:105. doi: 10.1186/s12977-014-0105-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122.Yang WL, Kouyos RD, Böni J, et al. Swiss HIV Cohort Study. Persistence of transmitted HIV-1 drug resistance mutations associated with fitness costs and viral genetic backgrounds. PLoS Pathog. 2015;11(3):e1004722. doi: 10.1371/journal.ppat.1004722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Baxter JD, Dunn D, White E, et al. International Network for Strategic Initiatives in Global HIV Trials START Study Group. Global HIV-1 transmitted drug resistance in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med. 2015;16(suppl 1):77–87. doi: 10.1111/hiv.12236. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124.Lepik K, Yip B, Robbins MA, et al. Prevalence and incidence of integrase drug resistance in BC, Canada, 2009–2015. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 125.Lesko CR, Cole SR, Zinski A, Poole C, Mugavero MJ. A systematic review and meta-regression of temporal trends in adult CD4(+) cell count at presentation to HIV care, 1992–2011. Clin Infect Dis. 2013;57(7):1027–1037. doi: 10.1093/cid/cit421. [DOI] [PubMed] [Google Scholar]
- 126.Siedner MJ, Ng CK, Bassett IV, Katz IT, Bangsberg DR, Tsai AC. Trends in CD4 count at presentation to care and treatment initiation in sub-Saharan Africa, 2002–2013: a meta-analysis. Clin Infect Dis. 2015;60(7):1120–1127. doi: 10.1093/cid/ciu1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Champenois K, Cousien A, Cuzin L, et al. Missed opportunities for HIV testing in newly HIV-diagnosed patients: a cross sectional study. BMC Infect Dis. 2013;13:200. doi: 10.1186/1471-2334-13-200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 128.US Preventive Services Task Force. [Accessed April 20, 2016];Human immunodeficiency virus (HIV) infection: screening. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/human-immunodeficiency-virus-hiv-infection-screening.
- 129.Branson BM, Handsfield HH, Lampe MA, et al. Centers for Disease Control and Prevention. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1–17. [PubMed] [Google Scholar]
- 130.Skarbinski J, Rosenberg E, Paz-Bailey G, et al. Human immunodeficiency virus transmission at each step of the care continuum in the United States. JAMA Intern Med. 2015;175(4):588–596. doi: 10.1001/jamainternmed.2014.8180. [DOI] [PubMed] [Google Scholar]
- 131.Magnus M, Herwehe J, Gruber D, et al. Improved HIV-related outcomes associated with implementation of a novel public health information exchange. Int J Med Inform. 2012;81(10):e30–e38. doi: 10.1016/j.ijmedinf.2012.06.005. [DOI] [PubMed] [Google Scholar]
- 132.Christopoulos KA, Scheer S, Steward WT, et al. Examining clinic-based and public health approaches to ascertainment of HIV care status. J Acquir Immune Defic Syndr. 2015;69(suppl 1):S56–S62. doi: 10.1097/QAI.0000000000000571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Marks G, Gardner LI, Craw J, Crepaz N. Entry and retention in medical care among HIV-diagnosed persons: a meta-analysis. AIDS. 2010;24(17):2665–2678. doi: 10.1097/QAD.0b013e32833f4b1b. [DOI] [PubMed] [Google Scholar]
- 134.Thompson MA, Mugavero MJ, Amico KR, et al. Guidelines for improving entry into and retention in care and antiretroviral adherence for persons with HIV: evidence-based recommendations from an International Association of Physicians in AIDS Care panel. Ann Intern Med. 2012;156(11):817–833. doi: 10.7326/0003-4819-156-11-201206050-00419. W-284-W-294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135.Centers for Disease Control and Prevention. [Accessed April 7, 2016];Compendium of evidence-based interventions and best practices for HIV prevention. http://www.cdc.gov/hiv/research/interventionresearch/compendium/lrc/index.html.
- 136.Gardner LI, Metsch LR, Anderson-Mahoney P, et al. Antiretroviral Treatment and Access Study Group. Efficacy of a brief case management intervention to link recently diagnosed HIV-infected persons to care. AIDS. 2005;19(4):423–431. doi: 10.1097/01.aids.0000161772.51900.eb. [DOI] [PubMed] [Google Scholar]
- 137.Craw JA, Gardner LI, Marks G, et al. Brief strengths-based case management promotes entry into HIV medical care: results of the antiretroviral treatment access study-II. J Acquir Immune Defic Syndr. 2008;47(5):597–606. doi: 10.1097/QAI.0b013e3181684c51. [DOI] [PubMed] [Google Scholar]
- 138.Bradford JB, Coleman S, Cunningham W. HIV system navigation: an emerging model to improve HIV care access. AIDS Patient Care STDS. 2007;21(suppl 1):S49–S58. doi: 10.1089/apc.2007.9987. [DOI] [PubMed] [Google Scholar]
- 139.Naar-King S, Bradford J, Coleman S, Green-Jones M, Cabral H, Tobias C. Retention in care of persons newly diagnosed with HIV: outcomes of the Outreach Initiative. AIDS Patient Care STDS. 2007;21(suppl 1):S40–S48. doi: 10.1089/apc.2007.9988. [DOI] [PubMed] [Google Scholar]
- 140.Metsch LR, Feaster DJ, Gooden L, et al. A patient navigation/contingency management RCT for hospitalized HIV+ substance users. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 141.Berg KM, Litwin A, Li X, Heo M, Arnsten JH. Directly observed antiretroviral therapy improves adherence and viral load in drug users attending methadone maintenance clinics: a randomized controlled trial. Drug Alcohol Depend. 2011;113(2–3):192–199. doi: 10.1016/j.drugalcdep.2010.07.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142.Maru DS, Bruce RD, Walton M, Springer SA, Altice FL. Persistence of virological benefits following directly administered antiretroviral therapy among drug users: results from a randomized controlled trial. J Acquir Immune Defic Syndr. 2009;50(2):176–181. doi: 10.1097/QAI.0b013e3181938e7e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 143.Babudieri S, Aceti A, D’Offizi GP, Carbonara S, Starnini G. Directly observed therapy to treat HIV infection in prisoners. JAMA. 2000;284(2):179–180. doi: 10.1001/jama.284.2.179. [DOI] [PubMed] [Google Scholar]
- 144.Mugavero MJ, Westfall AO, Cole SR, et al. Centers for AIDS Research Network of Integrated Clinical Systems. Beyond core indicators of retention in HIV care: missed clinic visits are independently associated with all-cause mortality. Clin Infect Dis. 2014;59(10):1471–1479. doi: 10.1093/cid/ciu603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Lester RT, Ritvo P, Mills EJ, et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet. 2010;376(9755):1838–1845. doi: 10.1016/S0140-6736(10)61997-6. [DOI] [PubMed] [Google Scholar]
- 146.Gardner LI, Giordano TP, Marks G, et al. Retention in Care Study Group. Enhanced personal contact with HIV patients improves retention in primary care: a randomized trial in 6 US HIV clinics. Clin Infect Dis. 2014;59(5):725–734. doi: 10.1093/cid/ciu357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Glass TR, Sterne JA, Schneider MP, et al. Swiss HIV Cohort Study. Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality. AIDS. 2015;29(16):2195–2200. doi: 10.1097/QAD.0000000000000782. [DOI] [PubMed] [Google Scholar]
- 148.Feldman BJ, Fredericksen RJ, Crane PK, et al. Evaluation of the single-item self-rating adherence scale for use in routine clinical care of people living with HIV. AIDS Behav. 2013;17(1):307–318. doi: 10.1007/s10461-012-0326-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 149.Nosyk B, Min JE, Colley G, et al. The causal effect of opioid substitution treatment on HAART medication refill adherence. AIDS. 2015;29(8):965–973. doi: 10.1097/QAD.0000000000000642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 150.Sin NL, DiMatteo MR. Depression treatment enhances adherence to antiretroviral therapy: a meta-analysis. Ann Behav Med. 2014;47(3):259–269. doi: 10.1007/s12160-013-9559-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.Gaynes BN, Pence BW, Atashili J, et al. Changes in HIV outcomes following depression care in a resource-limited setting: results from a pilot study in Bamenda, Cameroon. PLoS One. 2015;10(10): e0140001. doi: 10.1371/journal.pone.0140001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Pence BW, Gaynes BN, Adams JL, et al. The effect of antidepressant treatment on HIV and depression outcomes: results from a randomized trial. AIDS. 2015;29(15):1975–1986. doi: 10.1097/QAD.0000000000000797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 153.Pyne JM, Fortney JC, Curran GM, et al. Effectiveness of collaborative care for depression in human immunodeficiency virus clinics. Arch Intern Med. 2011;171(1):23–31. doi: 10.1001/archinternmed.2010.395. [DOI] [PubMed] [Google Scholar]
- 154.Tsai AC, Karasic DH, Hammer GP, et al. Directly observed antidepressant medication treatment and HIV outcomes among homeless and marginally housed HIV-positive adults: a randomized controlled trial. Am J Public Health. 2013;103(2):308–315. doi: 10.2105/AJPH.2011.300422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 155.Safren SA, O’Cleirigh C, Tan JY, et al. A randomized controlled trial of cognitive behavioral therapy for adherence and depression (CBT-AD) in HIV-infected individuals. Health Psychol. 2009;28(1):1–10. doi: 10.1037/a0012715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 156.Safren SA, O’Cleirigh CM, Bullis JR, Otto MW, Stein MD, Pollack MH. Cognitive behavioral therapy for adherence and depression (CBT-AD) in HIV-infected injection drug users: a randomized controlled trial. J Consult Clin Psychol. 2012;80(3):404–415. doi: 10.1037/a0028208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 157.Simoni JM, Wiebe JS, Sauceda JA, et al. A preliminary RCT of CBT-AD for adherence and depression among HIV-positive Latinos on the U.S.-Mexico border: the Nuevo Día study. AIDS Behav. 2013;17(8):2816–2829. doi: 10.1007/s10461-013-0538-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 158.Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011. AIDS. 2014;28(7):1049–1057. doi: 10.1097/QAD.0000000000000212. [DOI] [PubMed] [Google Scholar]
- 159.Forbes JC, Alimenti AM, Singer J, et al. Canadian Pediatric AIDS Research Group. A national review of vertical HIV transmission. AIDS. 2012;26(6):757–763. doi: 10.1097/QAD.0b013e328350995c. [DOI] [PubMed] [Google Scholar]
- 160.Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment: Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173–1180. doi: 10.1056/NEJM199411033311801. [DOI] [PubMed] [Google Scholar]
- 161.Kitahata MM, Gange SJ, Abraham AG, et al. NA-ACCORD Investigators. Effect of early vs deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18):1815–1826. doi: 10.1056/NEJMoa0807252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 162.Donnell D, Baeten JM, Kiarie J, et al. Partners in Prevention HSV/HIV Transmission Study Team. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet. 2010;375(9731):2092–2098. doi: 10.1016/S0140-6736(10)60705-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.Cohen M, Chen Y, McCauley M, et al. Final results of the HPTN 052 randomized controlled trial: antiretroviral therapy prevents HIV transmission. Presented at: Eighth International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment, and Prevention; July 19–22, 2015; Vancouver, BC, Canada. Abstract MOAC0101LB. [Google Scholar]
- 164.Bavinton BR, Jin F, Prestage G, et al. Opposites Attract Study Group. The Opposites Attract Study of viral load, HIV treatment and HIV transmission in serodiscordant homosexual male couples: design and methods. BMC Public Health. 2014;14:917. doi: 10.1186/1471-2458-14-917. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 165.Centers for Disease Control and Prevention. [Accessed March 10, 2016];Preexposure prophylaxis for the prevention of HIV infection in the United States—2014: a clinical practice guideline. http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf.
- 166.World Health Organization. [Accessed May 10, 2016];Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf. [PubMed]
- 167.Marrazzo JM, del Rio C, Holtgrave DR, et al. International Antiviral Society-USA Panel. HIV prevention in clinical care settings: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA. 2014;312(4):390–409. doi: 10.1001/jama.2014.7999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 168.Grant RM, Lama JR, Anderson PL, et al. iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587–2599. doi: 10.1056/NEJMoa1011205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 169.Grant RM, Anderson PL, McMahan V, et al. iPrEx Study Team. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014;14(9):820–829. doi: 10.1016/S1473-3099(14)70847-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 170.Volk JE, Marcus JL, Phengrasamy T, et al. No new HIV infections with increasing use of HIV preexposure prophylaxis in a clinical practice setting. Clin Infect Dis. 2015;61(10):1601–1603. doi: 10.1093/cid/civ778. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 171.McCormack S, Dunn DT, Desai M, et al. Pre-exposure Prophylaxis to Prevent the Acquisition of HIV-1 Infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet. 2016;387(10013):53–60. doi: 10.1016/S0140-6736(15)00056-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 172.Baeten JM, Donnell D, Ndase P, et al. Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399–410. doi: 10.1056/NEJMoa1108524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 173.Thigpen MC, Kebaabetswe PM, Paxton LA, et al. TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423–434. doi: 10.1056/NEJMoa1110711. [DOI] [PubMed] [Google Scholar]
- 174.Molina J-M, Charreau I, Spire B, et al. On demand PrEP with oral TDF-FTC in the open-label phase of the ANRS IPERGAY trial. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 175.Molina JM, Capitant C, Spire B, et al. ANRS IPERGAY Study Group. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373(23):2237–2246. doi: 10.1056/NEJMoa1506273. [DOI] [PubMed] [Google Scholar]
- 176.Liu AY, Cohen SE, Vittinghoff E, et al. Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern Med. 2016;176(1):75–84. doi: 10.1001/jamainternmed.2015.4683. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 177.Molina JM. Coitally dependent TDF/FTC in MSM: updates on PrEP efficacy in IPERGAY. Presented at: Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention; July 19–22, 2015; Vancouver, BC, Canada. [Google Scholar]
- 178.Cottrell ML, Yang KH, Prince HM, et al. A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine. J Infect Dis. 2016;214(1):55–64. doi: 10.1093/infdis/jiw077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Choopanya K, Martin M, Suntharasamai P, et al. Bangkok Tenofovir Study Group. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381(9883):2083–2090. doi: 10.1016/S0140-6736(13)61127-7. [DOI] [PubMed] [Google Scholar]
- 180.Deutsch MB, Mendez MF. Neurocognitive features distinguishing primary central nervous system lymphoma from other possible causes of rapidly progressive dementia. Cogn Behav Neurol. 2015;28(1):1–10. doi: 10.1097/WNN.0000000000000048. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181.Gandhi M, Glidden D, Liu AY, et al. Higher cumulative TFV/FTC levels in PrEP associated with decline in renal function. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 182.Liu AY, Vittinghoff E, Anderson PL, et al. Changes in renal function associated with TDF/FTC PrEP use in the US Demo Project. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 183.Solomon MM, Lama JR, Glidden DV, et al. iPrEx Study Team. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS. 2014;28(6):851–859. doi: 10.1097/QAD.0000000000000156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 184.Mugwanya KK, Wyatt C, Celum C, et al. Partners PrEP Study Team. Changes in glomerular kidney function among HIV-1-uninfected men and women receiving emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial. JAMA Intern Med. 2015;175(2):246–254. doi: 10.1001/jamainternmed.2014.6786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 185.Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One. 2011;6(8):e23688. doi: 10.1371/journal.pone.0023688. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 186.Kasonde M, Niska RW, Rose C, et al. Bone mineral density changes among HIV-uninfected young adults in a randomised trial of pre-exposure prophylaxis with tenofovir-emtricitabine or placebo in Botswana. PLoS One. 2014;9(3):e90111. doi: 10.1371/journal.pone.0090111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 187.Mulligan M, Rutledge B, Kapogiannis BG, et al. Bone changes in young men ages 18–22 enrolled in a pre-exposure prophylaxis (PrEP) safety and demonstration study using tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). Presented at: 15th European AIDS Conference; October 21–24, 2015; Barcelona, Spain. [Google Scholar]
- 188.Grant R, Mulligan K, McMahan V, et al. Recovery of bone mineral density after stopping oral HIV preexposure prophylaxis. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 189.Markowitz LE, Dunne EF, Saraiya M, et al. Centers for Disease Control and Prevention. Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm Rep. 2014;63(RR-05):1–30. [PubMed] [Google Scholar]
- 190.Golub SA, Pena S, Boonrai K, et al. STI data from community-based PrEP implementation suggest changes to CDC guidelines. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. Abstract 869. [Google Scholar]
- 191.Liu AY, Vittinghoff E, Anderson PL, et al. Changes in renal function associated with TDF/FTC PrEP use in the US Demo Project. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 192.Knox DC, Tan DH, Harrigan PR, Anderson PL. HIV-1 infection with multiclass resistance despite preexposure prophylaxis (PrEP). Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 193.Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 194.Garrett KL, Cottrell ML, Prince HM, et al. Concentrations of TFV and TFVdp in female mucosal tissues after a single dose of TAF. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 195.Cardo DM, Culver DH, Ciesielski CA, et al. Centers for Disease Control and Prevention Needlestick Surveillance Group. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. N Engl J Med. 1997;337(21):1485–1490. doi: 10.1056/NEJM199711203372101. [DOI] [PubMed] [Google Scholar]
- 196.Centers for Disease Control and Prevention. [Accessed April 22, 2016];Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV—United States. 2016 doi: 10.15585/mmwr.mm6517a5. http://www.cdc.gov/hiv/pdf/programresources/cdc-hiv-npep-guidelines.pdf. [DOI] [PubMed]
- 197.Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Cabotegravir + rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 198.Friedman E, Schuermann D, Rudd DJ, et al. A single monotherapy dose of MK-8591, a novel NRTI, suppresses HIV for 10 days. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 199.Grobler J, Friedman E, Barrett SE, et al. Long-acting oral and parenteral dosing of MK-8591 for HIV treatment or prophylaxis. Presented at: Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. [Google Scholar]
- 200.Markowitz M, Frank I, Grant R, et al. ÉCLAIR: phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. Abstract 106. [Google Scholar]
- 201.Baeten JM, Palanee-Phillips T, Brown ER, et al. MTN-020–ASPIRE Study Team. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women [published online February 22, 2016] N Engl J Med. doi: 10.1056/NEJMoa1506110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 202.Nel A, Kapiga S, Bekker LG, et al. Safety and efficacy of dapivirine vaginal ring for HIV-1 prevention in African women. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections; February 22–25, 2016; Boston, MA. Abstract 110LB. [Google Scholar]
- 203.Lynch RM, Boritz E, Coates EE, et al. VRC 601 Study Team. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med. 2015;7(319): 319ra206. doi: 10.1126/scitranslmed.aad5752. [DOI] [PubMed] [Google Scholar]
- 204.Caskey M, Klein F, Lorenzi JC, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015;522(7557):487–491. doi: 10.1038/nature14411. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 205.Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13(1):31–37. doi: 10.1007/s11904-016-0299-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 206.Moldt B, Le K, Carnathan DG, et al. Neutralizing antibody affords comparable protection against vaginal and rectal SHIV challenge in macaques [published online March 21, 2016] AIDS. doi: 10.1097/QAD.0000000000001102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 207.Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. The challenge of finding a cure for HIV infection. Science. 2009;323(5919):1304–1307. doi: 10.1126/science.1165706. [DOI] [PubMed] [Google Scholar]
- 208.Qin XF, An DS, Chen IS, Baltimore D. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci U S A. 2003;100(1):183–188. doi: 10.1073/pnas.232688199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 209.Burke BP, Levin BR, Zhang J, et al. Engineering cellular resistance to HIV-1 infection in vivo using a dual therapeutic lentiviral vector. Mol Ther Nucleic Acids. 2015;4:e236. doi: 10.1038/mtna.2015.10. [DOI] [PubMed] [Google Scholar]
- 210.Wolstein O, Boyd M, Millington M, et al. Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor. Mol Ther Methods Clin Dev. 2014;1:11. doi: 10.1038/mtm.2013.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 211.Tebas P, Stein D, Tang WW, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901–910. doi: 10.1056/NEJMoa1300662. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 212.Mylvaganam GH, Silvestri G, Amara RR. HIV therapeutic vaccines: moving towards a functional cure. Curr Opin Immunol. 2015;35:1–8. doi: 10.1016/j.coi.2015.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
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