Pre-Exposure Prophylaxis for HIV in Primary Care and Beyond

Abstract

HIV pre-exposure prophylaxis (PrEP) is antiretroviral medication used to prevent HIV in patients at increased risk of acquisition due to sexual practices or intravenous drug use. Despite strong evidence of efficacy and safety, PrEP is currently underutilized in the United States. Initial testing includes HIV, hepatitis B, and renal function. There are currently two oral medications approved for daily use within the U.S.; regular monitoring for HIV and renal dysfunction is required with both medications.

Introduction

According to statistics from the Centers for Disease Control and Prevention (CDC), in 2019 approximately 38 million people had HIV throughout the world, with 1.7 million new cases diagnosed worldwide that year. In the U.S., approximately 1.2 million people had HIV by the end of 2019, with almost 37,000 new cases diagnosed. HIV pre-exposure prophylaxis (PrEP) is antiretroviral medication that can be used to prevent acquisition of HIV in patients who are at increased risk. As of June 2019, offering PrEP to patients at high risk of acquiring HIV is a Grade A recommendation from the United States Preventive Services Task Force (USPSTF). A 2018 meta-analysis and systematic review including a cumulative 55,000 patients concluded that use of PrEP in those at high risk for HIV was associated with less than half the risk of HIV acquisition compared to placebo or no PrEP after four to fourteen years. Greater adherence to PrEP was associated with increased efficacy (≥70% risk reduction). Common adverse events included renal dysfunction and gastrointestinal disturbance, which were typically mild and reversible.^{1, 2} This review served as the basis for the Grade A USPSTF recommendation for PrEP. Similarly, a 2018 systematic review including four randomized-controlled trials showed that daily use of PrEP was more than 90% effective at preventing acquisition of HIV through sexual contact in those at high risk.³ Thus, PrEP is an incredibly important and effective tool in public health efforts to prevent transmission and acquisition of HIV.

Although PrEP is known to be effective in preventing HIV infection, it is underutilized in the U.S. Any licensed provider can prescribe PrEP; it is not necessary to have specific training in HIV or infectious disease. Primary care providers and those who discuss family planning, sexual health, and sexually transmitted infections with patients should be screening for HIV risk and initiating conversations about PrEP with their patients. However, a 2019 survey of outpatient primary care physicians considered to be part of a safety-net healthcare system in Tarrant County, Texas (an area with high prevalence of HIV) showed that only 35% had prescribed PrEP in the past year and that 55% had not had a conversation about PrEP with their patients in the past year; additionally, those with low knowledge of PrEP on self-report had 91% lower odds of prescribing PrEP.⁴ Similarly, a 2016 national study of family planning providers found that fewer than 40% of respondents could correctly define PrEP, correctly state its efficacy, or choose the correct HIV test following recent exposure. Only 36% of respondents had seen any PrEP guidelines; 87% wanted PrEP education.⁵

There are also known racial and gender disparities in PrEP prescribing practices. From 2012–2014, the CDC identified 468,000 women eligible for PrEP, but less than 1,500 were prescribed PrEP.⁶ In 2015, black and Hispanic men who have sex with men (MSM) had 10.5 and 4.9 times, respectively, increased incidence of HIV compared to white men; however, black and Hispanic MSM were significantly less likely than white MSM to know about PrEP, to discuss it with a health care provider, or to have used PrEP within the past year.⁷ We hope to show that screening for PrEP need and prescribing PrEP are an integral and accessible part of primary and reproductive medical care.

Prescribing and Monitoring

Patient Selection

Adolescents and adults without HIV who are at increased risk of acquiring HIV should be offered HIV pre-exposure prophylaxis (PrEP). Per CDC guidelines, patients at increased risk of acquiring HIV through sex include all sexually active adolescents and adults who have a history of no or inconsistent barrier protection use, have been diagnosed with a bacterial sexually transmitted infection in the past six months, or have a partner with known HIV. Additionally, commercial sex workers and those who have a high number of sexual contacts are considered to be at increased risk. “Sexually active” adolescents and adults are defined as those who have had anal or vaginal intercourse in the past six months. These recommendations apply to sexually active heterosexual men and women, sexually active transgender patients, and MSM. Additionally, per CDC guidelines, PrEP should be offered to patients who inject intravenous drugs whose partner(s) are HIV positive and inject IV drugs, or those who share equipment for intravenous drug injection. PrEP should also be offered to those who have been prescribed HIV post-exposure prophylaxis (PEP) and have continued high-risk behaviors and to those who have been prescribed multiple courses of PEP. See Table 1 for more detailed information on PrEP indications.⁸

Table 1.

Indication for PrEP Initiation

Risk of sexual acquisition
Any adult or adolescent: Without acute or established HIV infection With any sex with opposite sex partner OR any same sex partner (MSM persons) within the past 6 months  AND one of the following: Ongoing sexual relationship with HIV+ partner Infrequent condom use with 1+ partners of unknown HIV status at substantial risk of infection (PWID, MSM, bisexual male, transfeminine persons etc) Bacterial STI (syphilis, gonorrhea, or chlamydia in MSM, or syphilis or gonorrhea in non-MSM) in past 6 months
Risk of intravenous acquisition
Any adult or adolescent: Without acute or established HIV infection With any injection of drugs not prescribed by clinician in past 6 months  AND one of the following: Any sharing of injection or drug preparation equipment in past 6 months Risk of sexual acquisition

Prior to starting PrEP, patients must have a documented negative HIV test and no symptoms of acute HIV infection over the past month. Ideally, this should be a fourth-generation combined antigen and antibody test that is done within one week prior to starting PrEP. Since medications used for PrEP are also part of regimens used to treat HIV, patients would be at increased risk of developing resistant HIV if started on PrEP while they have active infection. Renal function must also be assessed using serum creatinine and estimated creatinine clearance (by Cockcroft-Gault calculation), as creatinine clearance less than 60 mL/minute or less than 30 mL/minute is a contraindication to starting PrEP with emtricitabine/tenofovir disoproxil fumarate (TDF/FTC, or Truvada) and emtricitabine/tenofovir alafenamide (TAF/FTC, or Descovy), respectively. Medications used for PrEP can cause rarely decreased renal function or acute renal failure, including Fanconi’s syndrome, so close monitoring is needed. Patients should also be screened for hepatitis B (HBV), since PrEP medications can be used to treat HBV. Although HBV is not a contraindication to starting PrEP, these patients need close monitoring of liver function after stopping PrEP due to potential risk for increased viral replication. If patients are found to be susceptible to HBV, they should receive the HBV vaccination series (although this should not delay initiation of PrEP). Providers should also consider testing for hepatitis C infection (HCV) as part of initial evaluation, since patients at increased risk of acquiring HIV are also at increased risk of becoming infected with HCV. Additionally, patients’ current medications must be reviewed for potential interactions with approved PrEP medications. There are a number of medications, largely psychiatric medications and infectious disease agents, which are contraindicated with PrEP. Certain other medications may increase the serum concentration of TDF and/or the drug in question; these medications require increased monitoring for dose-related renal toxicity. See Table 2 for a complete medication list. Although not a contraindication, consider avoiding concurrent high dose NSAIDs with PrEP due to potential for increased nephrotoxicity.⁸

Table 2.

PrEP Medication Drug Interactions

Monitor for dose-related renal toxicity	Contraindicated with PrEP
Acyclovir	Adefovir
Valacyclovir	Carbamazepine
Cidofovir	Fosphenytoin-phenytoin
Ganciclovir	Oxcarbazepine
Valganciclovir	Phenobarbital
Aminoglycosides	Rifabutin
High-dose or multiple NSAIDs	Rifampin
	Rifapentine

Medication Selection and Dosing for Oral PrEP

The two oral medications currently approved for PrEP are emtricitabine/tenofovir disoproxil fumarate (TDF/FTC, or Truvada) and emtricitabine/tenofovir alafenamide (TAF/FTC, or Descovy). Each medication is dosed as a single tablet once daily and can be used as PrEP for adolescents and adults weighing 35 kg or more. TDF/FTC is approved for PrEP for all patients at increased risk for HIV with creatinine clearance of at least 60 mL/minute. TAF/FTC can be used in patients with a creatinine clearance of at least 30 mL/minute. However, it should not be used for those whose increased risk is through receptive vaginal sex due to lack of data for prevention in these cases.⁸ The 2016–2017 DISCOVER study found that at 48 weeks, daily TAF/FTC was non-inferior to daily TDF/FTC for HIV PrEP and both were well tolerated; however, TAF/FTC had a better renal safety profile and fewer negative effects on bone mineral density.⁹ Longer-term data at 96 weeks again confirmed these findings, although those who had received TAF/FTC were found to have higher rates of triglyceride elevation and gained more weight.^8,10 Although TDF/FTC is known to cause osteopenia, it’s not considered clinically significant in most cases. Several studies have shown no increase in bone fracture rates.^11,12 As such, routine monitoring of bone mineral density is not indicated.¹³ Given similar outcomes and the release of TDF/FTC as generic in October 2020, utilization of TDF/FTC for patients without renal dysfunction or osteopenia is likely advantageous for cost purposes.

Efficacy of PrEP is dependent on adherence. The amount of time required to reach maximum intracellular concentration of TDF is tissue dependent: it takes up to 20 days for full penetration of cervicovaginal tissue, seven days for rectal tissue, and 20 days for serum penetration.⁸ During the time before full concentration, it’s important to emphasize alternative HIV prevention strategies, i.e., condoms. Based on pharmacokinetic studies, it appears that full efficacy of oral PrEP requires a minimum adherence of six doses per week (85% adherence) within the cervicovaginal tissue and two doses per week (28% adherence) within colorectal tissue.¹³

There is some evidence to suggest that on-demand PrEP dosing may be effective in the MSM population. A 2015 study investigated a dosing regimen driven by sex events, in which the individual takes two pills of TDF/FTC 2–24 hours prior to anal sex, a third pill 24 hours following the initial pill ingestion, and a fourth pill 24 hours later. The study authors reported an 86% relative risk reduction of HIV incidence compared to placebo. Because many of the participants in the study cohort had frequent sexual events, a post-hoc analysis investigated whether on-demand PrEP remained effective among men with less frequent encounters (15 pills or fewer each month); this analysis reported continued efficacy with a relative reduction of HIV incidence of 100% (six infections in placebo vs none in TDF/FTC group).^{14, 15} While event-driven dosing for MSM is not an FDA-approved regimen, the recommended “2-1-1” dosing schedule was outlined in the 2021 CDC guidelines and is available in Table 4.⁸ Due to lack of evidence, event-driven PrEP is not recommended for other populations, including cisgender or transgender women, transgender men having vaginal/frontal sex, men having sex with women, or people who inject drugs.¹⁶

Table 4.

Schedule for “2-1-1” Dosing

MSM should be instructed to take FCTDF as follows: 2 pills in the 2–24 hours before sex (closer to 24 hours preferred) 1 pill 24 hours after the initial two-pill dose 1 pill 48 hours after the initial two-pill dose

For subsequent sexual events, MSM should take additional doses as follows: If sex occurs on the consecutive day after completing the 2-1-1 doses, take 1 pill per day until 48 hours after the last sexual event. If a gap of <7 days occurs between the last pill and the next sexual event, resume 1 pill daily. If a gap of ≥7 days occurs between the last pill and next sexual event, start again with 2 pills.

Monitoring of Oral PrEP

Once started on PrEP, patients need ongoing monitoring, with visits recommended every three months. At each follow-up, patients should be reassessed for adherence, counseled on HIV risk reduction, and retested for development of HIV. Renal function should be measured at least yearly, and every six months for individuals age ≥ 50 years or with eCrCl < 90 mL/min at PrEP initiation. Do not withhold treatment for a rise in serum creatinine if eCrCl remains stable above 60 mL/min for F/TDF or 30 mL/min for F/TAF. Additionally, all patients on PrEP should be screened for sexually transmitted infections every three to six months based on risk profile. Patients should be assessed for risk of HIV acquisition at least yearly to determine whether PrEP should be continued. In order to ensure adequate follow-up and monitoring, PrEP prescriptions should be written for no more than 90 days at a time. See Table 3 for a summary of monitoring considerations.⁸

Table 3.

Clinical Follow-up and Monitoring on PrEP

Every 3 months: Repeat HIV testing, and assess for signs and symptoms of acute HIV Repeat pregnancy test for persons at risk of pregnancy STI testing as needed based on symptoms and risk evaluation (particularly MSM)

Every 6 months: Monitor creatinine clearance for those ≥ 50 years or with eCrCl < 90 mL/min at PrEP initiation (may require more frequent monitoring if medication interactions or other comorbidities affecting renal function, like diabetes mellitus or hypertension) STI testing for all even if asymptomatic

Every 12 months: Monitor creatinine clearance for those < 50 years or with eCrCl ≥ 90 mL/min at PrEP initiation Evaluate continued need for PrEP for HIV prevention

Injectable PrEP

In December of 2021, the FDA approved cabotegravir (CAB-LA), an injectable PrEP medication with promising efficacy and tolerability data. Prescribing and monitoring recommendations vary from that of the oral PrEP formulations. CAB can be started once acute or chronic HIV infection is ruled out; due to extended drug exposure after injection, HIV infection must be ruled out by checking an HIV-1 RNA assay, the most sensitive test available. Ideally this occurs within 1 week prior to medication initiation. There is no need to check renal function, hepatitis B serology, lipid panels, or liver function tests. For administration, 3 mL of CAB 600 mg IM suspension is injected into the gluteal muscle. Injection site reactions (pain, tenderness, induration) were common but transient in clinical trials. Patients should be informed that such reactions typically last a few days and occur most commonly with the first several injections. Over-the-counter pain medications and/or the use of warm compresses or heating pads at the injection site may provide relief. Patients should additionally be counseled about the “tail” caused by slowly declining drug levels when CAB injections are discontinued. There is a higher risk of drug-resistant HIV if HIV infection is acquired during this time.

Follow-up visits occur one month after the initial injection and bi-monthly thereafter. At each visit, an HIV-1 RNA test is performed, patients are assessed for signs or symptoms or acute infection, and CAB injection is administered. STI screening occurs per protocol as described in Table 3. Time to protection data is not yet available for CAB PrEP.⁸

Prescribing Considerations

Since the USPSTF has given a Grade A recommendation to offering PrEP to those at high risk for acquiring HIV, insurance plans must now cover PrEP. This includes both private plans and state Medicaid programs, although prior authorization may be required. Patient assistance programs are available for those who are uninsured. Additionally, Gilead and some states offer copay assistance programs.⁸

Special Populations

Adolescents

PrEP was approved for adolescents in 2018.¹⁷ Use in young people is supported by three studies, two with young MSM in the U.S., and one in South Africa, which showed efficacy in HIV prevention.^{18,19, 20} Despite PrEP’s efficacy, uptake has been poor compared to other age demographics. An analysis of 2017 prescription-level data on persons under age 24 demonstrated a wide gap between those who might benefit from PrEP and those who actually utilize it (also known as the PrEP-to-need-ratio, or PnR) in those under age 24.²¹ Additionally, the studies additionally noted that PrEP adherence was a struggle for this younger cohort, dampening the efficacy of the intervention.^{18, 19, 20} As such, the WHO suggests consideration of additional monitoring and adherence support for adolescents and young adults under age 24.²²

Pregnant and Lactating Persons

While data remains limited on PrEP use during pregnancy and lactation, outcomes thus far have been reassuring. A 2017 systematic review of 26 articles in which women received TDF alone or in combination with other drugs showed no statistically significant differences in pregnancy outcomes including incidence of pregnancy, pregnancy loss, preterm delivery before 37 weeks, low birth weight, birth defects, or maternal or infant mortality.²³ In addition, a 2016 study examining TDF/FTC use for PrEP among 50 Kenyan and Ugandan mother-infant pairs found undetectable to very low levels of of TDF in infant blood, suggesting TDF/FTC use is likely safe in lactating individuals and their infants.²⁴ Given the above data, the WHO recommends TDF/FTC-based oral PrEP for pregnant or lactating individuals who are at high risk for HIV acquisition.²⁵

People Who Use Drugs

People who use drugs (PWUD) have unique risk for HIV acquisition, with increased likelihood of both sexual and injection-related behaviors that may result in HIV transmission. Recent data from the US National Behavioral Surveillance Survey suggested that three quarters of people who inject drugs (PWID) report syringe sharing and/or condomless sex within the past year.²⁶ Data on PrEP adherence in the PWUD population is limited currently, but early data suggests that while sociodemographic and structural factors influence adherence, PWUD can access and adhere to PrEP if adequate support is provided.^{27, 28} Further studies are needed to inform care in this population, incuding consideration of alternate PrEP modalities (like injectable PrEP), integration of PrEP services within substance use disorder services, and targeting multilevel barriers to PrEP dissemination in the PWUD population.²⁹

Future Directions

Emerging modalities promise to alter the PrEP landscape and facilitate improved adherence within high-risk populations. The recent approval of injectable CAB promises a new option for those who struggle with adherence to a daily oral regimen.^{30,31, 32} The dapivirine (DPV) intra-vaginal ring, also currently under FDA review, is utilized on a monthly basis and has shown moderate efficacy at decreasing HIV transmission in African women.^{33, 34} Other possibilities are in pre-clinical and clinical development, including a once-monthly oral pill, alternative long-acting injections, and subcutaneous implants.³⁵

Conclusion

The efficacy and important public health role of PrEP for the prevention of HIV is clear, but uptake of PrEP continues to lag within many populations. Barriers to PrEP utilization exist at the social, structural, individual, and provider levels, and contribute to racial and gender disparities in PrEP use. These barriers include poor awareness of PrEP among providers and patients, misperception/miscalculation of HIV risk on the part of both patients and providers, concern about stigma and side effects, patient distrust of the healthcare system, poor access to medical care for at-risk populations, and cost. Needed interventions are diverse, and include increased education of both patients and providers, addressing systemic biases, support for patients navigating financial aid options, and expanding settings where PrEP can be accessed.³⁶ As a first step, these authors hope that provider education and further expansion of PrEP provision within primary care and family planning clinics will greatly expand access to PrEP within Missouri and beyond.