Single-Tablet Regimens in the Treatment of HIV-1 Infection

Abstract

The emergence of highly active antiretroviral therapies has decreased mortality, increased viral suppression, and significantly reduced the risk of the sexual transmission of HIV.

Together with prophylaxis for opportunistic infections, the widespread use of combination antiretroviral therapy (ART)—known as highly active antiretroviral therapy (HAART)—led to substantial gains in the life expectancy of patients infected with human immunodeficiency virus type 1 (HIV-1).^1–3 The emergence of HAARTs has decreased mortality, increased viral suppression, and significantly reduced the risk of the sexual transmission of HIV.^4–6

Since its introduction, HAART has evolved significantly with more options for triple therapy combinations that show improved efficacy, convenience, and tolerability. Single-tablet regimens (STRs) are the culmination of this evolution. The first STR was introduced in 2006, and to date, there are 5 STR options approved for use. In this review, the authors discuss the rationale and path to development of STRs, compare the currently available STRs, and discuss practical considerations in their use for the treatment of HIV-1 infection.

IS TRIPLE THERAPY THE SWEET SPOT?

Because current ART cannot eradicate HIV-1 infection due to latently infected CD4+ T-cell reservoirs, the primary goals of ART according to the HHS guidelines are to (1) reduce HIV-associated morbidity and prolong the duration and quality of survival; (2) restore and preserve immunologic function; (3) maximally and durably suppress plasma HIV viral load; and (4) prevent HIV transmission.⁷

These goals currently seem to be optimally achieved by treatment with 3 active agents, usually consisting of 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) as a backbone plus a drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a nonnucleoside reverse-transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) boosted with ritonavir or cobicistat. The most widely used NRTI backbones are abacavir plus lamivudine (ABC/3TC) or tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC). Attempts to increase the number of active drugs in a regimen (≥ 4) have generally failed to yield additional virologic or immunologic benefits. Conversely, recent attempts to decrease the number of drugs in a regimen (≤ 2) have met with mixed success.

Mega-HAART

The AIDS Clinical Trial Group (ACTG) 5095 was a randomized controlled trial (RCT) to compare the safety and efficacy of a 3-drug regimen (zidovudine/lamivudine [AZT/3TC] plus efavirenz [EFV]) vs a 4-drug regimen (AZT/3TC/ABC plus EFV) in the initial treatment of HIV-1 infection.⁸ There were no significant differences in virologic efficacy between the 3-drug and 4-drug regimens, findings that have been corroborated in subsequent studies.^9,10 Intensified (≥ 4 drugs) regimens have also failed to lead to significant decay in viral reservoir.^10,11

Dual Therapy With Newer Agents

Recent clinical studies have explored the use of fewer medications in treatment-naïve HIV-infected patients. In the GARDEL study, dual therapy consisting of lopinavir/ritonavir (LPV/RTV) plus 3TC proved to be virologically noninferior to triple therapy of LPV/RTV plus 2 NRTIs in a fixed-dose combination.¹² In a large European clinical trial (NEAT001/ANRS143), the combination of darunavir/ritonavir (DRV/RTV) plus raltegravir (RAL) was noninferior to DRV/RTV plus TDF/FTC, although more virologic failures were seen in the dual-therapy arm for patients with high baseline HIV-1 RNA viral loads or low baseline CD4+ counts.¹³

Suboptimal virologic responses also were observed with the DRV/RTV plus RAL regimen in several smaller studies: ACTG 5262 and RADAR.^14,15 Finally, a combination of DRV/RTV plus maraviroc proved virologically inferior to standard DRV/RTV plus TDF/FTC in the MODERN trial.¹⁶ Although some dual-agent regimens have shown promise, none have established consistent and durable virologic efficacy sufficient to supplant triple therapy, which is currently endorsed by treatment guidelines and forms the basis for current STRs.

CURRENT SINGLE-TABLET REGIMENS

There are currently 5 STRs available for the treatment of HIV-1 infection, 3 are among the recommended regimens for ART in treatment-naïve patients. An older, triple NRTI-based STR (AZT/3TC/ABC) has fallen out of routine use due to inferior virologic efficacy, toxicities, and better-tolerated alternative agents.¹⁷ A review of the indications for use, major clinical trials, and unique features of available STRs follows and is summarized in the Table.

Table.

Currently Available Single-Tablet Regimens

Regimen	Component Classes	FDA Approval, y	Comments
Efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC)	NNRTI + dual NRTI	2006	First approved STR; use is now limited by neuropsychiatric adverse effects
Rilpivirine/tenofovir disoproxil fumarate/emtricitabine (RPV/TDF/FTC)	NNRTI + dual NRTI	2011	Greater tolerability than that of EFV/TDF/FTC; limited efficacy in patients with baseline HIV-1 RNA > 100,000 copies/mL or CD4 count < 200 cells/mm3
Elvitegravir/cobicistat/ tenofovir DF/emtricitabine (EVG/c/TDF/FTC)a	INSTI + PK booster + dual NRTI	2012	Greater tolerability than that of EFV/TDF/FTC; contraindicated in patients with reduced renal function (creatinine clearance < 70 mL/min)
Dolutegravir/abacavir/ lamivudine (DTG/ABC/3TC)a	INSTI + dual NRTI	2014	Contraindicated in patients with HLA-B*5701 allele; virologically superior to EFV/TDF/FTC and boosted PI-based regimens; fewer drug-drug interactions than those of PI, NNRTI-based regimens, or EVG/c/TDF/FTC
Elvitegravir/cobicistat/ tenofovir alafenamide/ emtricitabine (EVG/c/TAF/FTC)a	INSTI + PK booster + dual NRTI	2015	Proven safety in patients with mild-to-moderate renal dysfunction (creatinine clearance > 30 mL/min); greater bone and renal tolerability than that of EVG/c/TDF/FTC

Abbreviations: INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleos(t)ide reverse-transcriptase inhibitor; PK, pharmacokinetic; PI, protease inhibitor; STR, single-tablet regimen.

^aIncluded in the HSS list of recommended regimens for first-line antiretroviral therapy.

Efavirenz/tenofovir DF/emtricitabine

The first widely used STR, Atripla (Bristol-Myers Squibb and Gilead Sciences) combines the NRTIs tenofovir DF and FTC with the NNRTI EFV and was released in 2006. It is indicated for use alone or in combination with other ARTs for treatment of HIV-1 infection in adults or children aged > 12 years.¹⁸ Contraindications include hypersensitivity to efavirenz or coadministration with voriconazole. Major precautions are required for patients with severe psychiatric disease or suicidality; new or worsening renal impairment; women in the first trimester of pregnancy or of childbearing age not on effective contraception; or osteoporosis or history of fragility fractures. Patients with chronic liver disease also should be monitored for hepatotoxicity.

Large RCTs confirmed the potency and durability of viral suppression of EFV/TDF/FTC in treatment-naïve patients^19,20 or in the context of antiretroviral switching for treatment simplification in patients previously suppressed with NNRTI- or PI-based regimens.²¹ This combination has been shown to be noninferior or superior to multiple PI-based,²² NNRTI-based,²³ and INSTI-based regimens.¹⁸ However, it recently was found to be associated with lower virologic response than was the INSTI-based regimen of ABC/3TC plus dolutegravir (DTG) and higher discontinuation rates than that of a TDF/FTC plus RAL regimen.^24,25 Due to lingering concerns about an EFV association with suicidality²⁶ and neural tube defects with first trimester exposure,²⁷ EFV/TDF/FTC was downgraded to an alternative regimen for treatment-naïve patients, because other available regimens are better tolerated with equal or superior efficacy.⁷

Rilpivirine/tenofovir DF/emtricitabine

Approved in 2011, Complera was the second STR (Gilead Sciences), combining the NNRTI rilpivirine (RPV) with the NRTI backbone TDF/FTC. It is indicated for use in (1) treatment-naïve adults with a baseline HIV-1 RNA ≤ 100,000 copies/mL and baseline CD4+ > 200 cells/mm³; or (2) switch therapy (changing from a previous antiretroviral regimen) in patients virologically suppressed (HIV-1 RNA ≤ 50 copies/mL) for at least 6 months without history of virologic failure or resistance to any of the component drugs.²⁸ Contraindications include administration with other drugs that significantly lower RPV concentrations, such as certain acid-lowering drugs. Although not associated with as many neuropsychiatric or teratogenic effects as EFV/TDF/FTC, this combination still requires caution in circumstances of preexisting renal impairment, severe hepatic disease, or bone disease.

Two phase 3 studies and 1 open-label phase 3b study confirmed that RPV-based STRs were noninferior to EFV-based STRs overall.^23,29 Importantly, patients with higher baseline viral loads experienced higher rates of virologic failure and higher rates of NRTI backbone resistance. Patients with baseline CD4+ < 200 cells/mm³ also had higher virologic failure rates. Because of these virologic and immunologic prerequisites for use, RPV/TDF/FTC is considered an alternative regimen for treatment-naïve patients.⁷ On the other hand, in the aforementioned studies, fewer patients in the RPV arms discontinued therapy due to adverse events (AEs), and a switch from EFV/TDF/FTC to RPV/TDF/FTC was shown to be safe and effective.³⁰ Its greater tolerability and safety profile make RPV/TDF/FTC an option for patients who do not tolerate EFV/TDF/3TC, who are pregnant, and who have a psychiatric illness.

Elvitegravir/cobicistat/tenofovir DF/emtricitabine

Released in 2012, Stribild (Gilead Sciences) was the first treatment to combine an INSTI and elvitegravir (EVG) with the pharmacologic booster cobicistat and the TDF/FTC backbone. It is indicated for use in treatment-naïve adults or as switch therapy in patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.³¹

Two double-blind, active-controlled trials established that EVG/c/TDF/FTC was virologically noninferior and had greater safety and tolerability than that of EFV/TDF/FTC³² and ATV/RTV plus DF/FTC³³ in treatment-naïve patients. It also maintained virologic suppression in patients switching from a boosted PI³⁴ or an NNRTI-based regimen.³⁵ On the basis of this efficacy and safety data, EVG/c/TDF/FTC is considered a recommended regimen for initial ART treatment.⁷ However, limitations to this regimen include significant drug-drug interactions due to potent CYP3A inhibition by cobicistat, potential renal and bone toxicity due to TDF, and cobicistat-induced inhibition of renal tubular creatinine secretion, which can lead to a mild creatinine increase (≤ 0.4 mg/dL) and may complicate renal function monitoring. Therefore, it is contraindicated in patients concomitantly taking medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance, patients with reduced renal function (estimated creatinine clearance [CrCl] < 70 mL/min), and those receiving polyvalent cationic antacids or supplements.

Dolutegravir/abacavir/lamivudine

Approved in 2014, Triumeq (ViiV Healthcare) is the first and only currently available STR with an NRTI backbone of ABC/3TC rather than a tenofovir (TFV) derivative, combined with the INSTI DTG. It is indicated for the treatment of HIV-1 infection in patients without prior resistance to the INSTI class of ART or the other component drugs in this combination pill.³⁶ The major contraindication is presence of the HLA-B*5701 allele, a polymorphism that predicts abacavir-related hypersensitivity, or moderate-to-severe hepatic impairment.³⁷ Caution is required in patients with hepatitis B virus (HBV) co-infection due to the risk of 3TC drug resistance and subsequent acute exacerbation of HBV. Coadministration with dofetilide is contraindicated, and coadministration of some medications, most notably rifampin, requires an additional dose of DTG alone be given.³⁶ Dolutegravir absorption is also decreased when coadministered with polyvalent cationic antacids or laxatives.

Dolutegravir-based regimens have been shown to be noninferior to RAL-based regimens³⁸ and superior to EFV/TDF/FTC²⁴ and boosted DRV-based regimens.³⁹ Treatment-emergent resistance to DTG has been rare, suggesting a high genetic barrier to resistance compared with that of other INSTIs. On this basis, DTG/ABC/3TC is considered a recommended regimen for initial ART treatment.⁷ Another advantage of DTG/ABC/3TC is fewer drug-drug interactions than those of PI- or NNRTI-based regimens or the EVG/c/TDF/FTC STR.^24,38,39 Limitations include the requirement to confirm a negative HLA-B* 5701 allele, the potential association of abacavir with cardiovascular (CV) events seen in some but not all studies, and a small increase in creatinine due to DTG effects on renal tubular secretion.^40–43

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine

The latest STR, Genvoya (Gilead Sciences), approved in 2015, combines the INSTI elvitegravir and cobicistat with the novel NRTI backbone alafenamide(TAF)/FTC. Like TDF, TAF is an oral prodrug of TFV, but it achieves lower plasma and higher intracellular TFV levels than does TDF, potentially leading to improved bone and renal tolerability. This combination pill is indicated for use in treatment-naïve adults and children aged ≥ 12 years as switch therapy for patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.⁴⁴ Contraindications include use of concomitant medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance. Initiation of this STR is also not recommended in patients with an estimated CrCl < 30 mL/min or with severe hepatic impairment.

In 2 phase 3 RCTs in treatment naïve patients, EVG/c/TAF/FTC was virologically noninferior to EVG/c/TDF/FTC.⁴⁵ Patients in the TAF arms had smaller declines in estimated glomerular filtration (eGFR) and reductions in bone mineral density (BMD) but higher fasting lipids compared with that of patients in the TDF arms. Switching virologically suppressed patients with mild-to-moderate renal insufficiency (eGFR 30–69 mL/min) from TDF-containing regimens to EVG/c/TDF/FTC also has demonstrated maintenance of virologic response while improving BMD and markers of renal function.⁴⁶

In November 2015, EVG/c/TAF/FTC was added as a recommended regimen for initial ART treatment in patients with CrCl ≥ 30 mL/min.⁷ Advantages of this regimen include its favorable safety profile mentioned earlier and the indication for use in patients with mild-to-moderate renal impairment, which is unique among the STRs. However, limitations still remain, including significant drug-drug interactions due to potent CYP3A inhibition and cobicistat-induced inhibition of renal tubular creatinine secretion. Also, more clinical data are needed to confirm the durability of this regimen and to assess whether its improved safety profile translates into fewer clinical outcomes such as renal failure or fractures.

SINGLE-TABLET REGIMEN PROS AND CONS

The proportion of patients on STRs has significantly increased over the past several years. A recently published report of the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women, has analyzed the use of STR. The study showed that the use of STR among ART users increased from 7% in 2006 to 27% in 2013.⁴⁷

Advantages of STRs

Potential advantages of STRs include simplicity, convenience, and adherence, especially by eliminating the risk of selective nonadherence to components of the regimens. Observational cohorts and meta-analyses are beginning to confirm these theoretical advantages. A meta-analysis of 19 RCTs including 6,312 patients demonstrated that regimens with lower pill burdens and once-daily dosing were both associated with better adherence, and fewer pills also led to improved virologic suppression.⁴⁸ In the analysis of the WIHS cohort, STR use was significantly associated with increased adherence (adjusted risk ratio: 1.05; 95% confidence interval: 1.03 to 1.08) and virologic suppression (risk ratio: 1.06; 95% confidence interval: 1.01 to 1.11).⁴⁷ Another observational cohort analysis of commercially insured HIV-infected patients showed that patients on STRs were 1.3 times more likely to achieve at least 90% adherence.⁴⁹

A recent RCT, which assigned 300 patients on stable ART to continue their current regimen or switch to EFV/TDF/FTC as an STR, demonstrated no difference in virologic suppression or patient-reported adherence between the 2 groups.²¹ However, 91% of patients in this study reported a preference for the STR regimen.⁵⁰ Single-tablet regimen recipients also have been shown to be less likely to develop treatment-emergent, drug-resistance mutations (DRMs) at the time of virologic failure. In a recently published study, patients receiving the STR EFV/FTC/TDF had a significantly lower risk of DRMs on failure than did those receiving the same components individually in a non-STR regimen.⁵¹ Finally, recent data showed that prescription errors in inpatient ART are common and often go undetected, but coformulated regimens were associated with lower error rates.⁵²

Disadvantages of STRs

Although outweighed by the advantages, there are potential disadvantages to the use of STRs. These include the inability to adjust dosages of components of the regimen for drug-drug or drug-food interactions. In particular, patients with preexisting renal impairment (estimated CrCl < 50 mL/min) have limited options and safety data for STRs. Also, STRs do not exist currently for all NRTI-anchor drug pairings. Notably, there is no available 2 NRTI plus boosted PI STR. This limitation may be important in treatment-experienced patients where PI-based regimens may be needed or in patients with comorbidities where a NRTI-sparing regimen would be considered.

Finally, at the population level, the potential benefits of STRs must be balanced with the increased costs compared with that of generic ART regimens with multiple pills. For example, a mathematical simulation model based on 2009 U.S. data suggested that switching all patients in the U.S. from the branded STR EFV/TDF/FTC to a triple regimen of generic EFV, 3TC, and branded TDF would have saved almost $1 billion per year with only a small decrement in virologic efficacy.⁵³ More cost-effectiveness analyses are needed, especially for the developing world, to inform strategies for the use of STRs to improve outcomes in the most cost-effective way globally.

WHEN TO USE STRS?

For initial ART in treatment-naïve patients, 3 of the available STRs are listed as recommended regimens by the HHS guidelines: EVG/c/TDF/FTC, DTG/ABC/3TC, or EVG/c/TAF/FTC.⁷ In choosing an initial regimen, a number of factors must be considered, including baseline HIV-1 resistance, drug-drug interactions, medical comorbidities, food restrictions, patient preference and convenience, and cost. Patients with drug-resistant HIV-1 or significant renal impairment are less ideal candidates for STRs for initial therapy. Otherwise, the determination typically depends on which of the NRTI backbone drugs, TDF or TAF vs ABC, is most appropriate. Clinicians may favor TDF-containing or TAF-containing regimens in patients with HBV co-infection, clinically significant CV disease, or patients with the HLA-B*5701 genetic polymorphism.

Conversely, clinicians may favor ABC-containing or TAF-containing regimens in patients at high risk or with preexisting metabolic bone disease or more mild renal impairment. Drug-drug and drug-supplement interactions must be carefully considered in all cases. Although listed as alternative regimens, the other available STRs—EFV/TDF/FTC or RPV/TDF/FTC—may still be the preferred regimen in select individual patients.

In patients already on ART, a switch to a STR may be considered in the following scenarios, with the caveat that most of the clinical trials evaluating switch therapy have been in patients who were virologically suppressed for 6 months on their prior regimens:

1. Improve tolerability. In the STRATEGY-NNRTI trial, patients on a stable EFV-containing regimen experienced significant improvements in neuropsychiatric AEs after switching to EVG/c/TDF/FTC.³⁵

2. Virologically suppressed patients with multiple comorbidities. Difficulty managing dyslipidemia or high CV risk might necessitate a switch from a PI-containing regimen. From the results of the SPIRIT trial⁵⁴ and the STRATEGY-PI trial,³⁴ these patients could be switched safely to RPV/TDF/FTC or EVG/c/TDF/FTC, respectively.

3. Management of virologic failure. This may be beneficial provided that drug resistance has not compromised the components of the regimen.

CONCLUSION

The potency and once-daily dosing of EFV-based regimens ushered in the era of STRs. The list of STRs has now expanded with the introduction of an RPV-based STR and, lately, 3 different INSTI-based STRs. In the current HHS guidelines, only the INSTI-based STRs are included in the recommended list, mostly because of poor tolerability of EFV/TDF/FTC and lower efficacy of RPV/TDF/FTC in patients with high baseline viremia. In general, the safety profile of STRs has been improving with newer iterations. Their main advantages are convenience, simplicity and improvements in adherence, and possibly reductions in medication errors. Due to these advantages, the percentage of patients on STRs is likely to continue rising. Further expansions of the ART armamentarium may include the development of boosted PI-based STRs as well as novel delivery strategies, such as long-acting injectable regimens.⁵⁵ In the meantime, clinicians should develop a greater familiarity with the use of the currently available STRs.