Preexposure HIV Prophylaxis

More than 2.5 million new HIV-1 infections occur yearly worldwide in the absence of an effective vaccine. Preexposure chemoprophylaxis with antiretroviral medications is a concept that has been widely recognized as a potential way to prevent new infections among those at risk. This article aims to give the rationale and discuss the potential of antiretroviral therapy (ART) to prevent transmission of HIV-1 infection.[1]

Preexposure chemoprophylaxis (PrEP) with antiretroviral medications (ARVs) is a concept that has been widely recognized as a method for primary prevention for individuals with ongoing risks for becoming infected with HIV.[1]

Overview

The idea of treatment as prevention for HIV-1 infection has gathered tremendous enthusiasm and is driven by the following developments:

• Failure of behavioral and biological prevention efforts

• Biological plausibility of the use of ARV for prevention

• Cheaper, safer, and simpler ARV regimens

• Recent clinical trials that show promise for the intervention

PrEP has the potential to contribute to effective and safe HIV prevention when it is used as follows:

• Targeted to individuals at high risk for HIV acquisition

• Delivered as part of a comprehensive set of prevention services

• Accompanied by regular monitoring

Prevention services should include the following:

• Risk-reduction and PrEP medication adherence counseling

• Ready access to condoms

• Diagnosis and treatment of sexually transmitted infections (STIs)

Monitoring should include the following:

• HIV status

• Side effects

• Adherence

• Risk behaviors

Candidate drugs

The ideal chemoprophylactic agent should have the following characteristics:

• A long half-life

• Achieve high concentrations in monocytes, macrophages, and genital secretions

• Have a high barrier for genetic resistance

• Safe and inexpensive

The most widely studied ARV for PrEP, tenofovir DF (disoproxil fumarate), has many of these desirable characteristics. Most of the current clinical trials of PrEP involve tenofovir with or without emtricitabine. Emtricitabine/tenofovir DF (Truvada) was approved by the FDA in July 2012 for PrEP against sexual HIV acquisition by men who have sex with men (MSM), as well as for heterosexually active serodiscordant women and men.

The fixed-dose combination of emtricitabine/tenofovir AF (alafenamide) 200 mg/25 mg (Descovy) is also approved for at-risk adults and adolescents for HIV-1 pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sex, excluding those who have receptive vaginal sex. 

An extended-release IM injection, cabotegravir (Apretude), was approved by the FDA for PReP for adults and adolescents in December 2021. It is administered as a gluteal IM injection every 2 months. A phase 3 clinical trial demonstrated cabotegravir IM was superior to daily oral TDF-FTC in preventing HIV infection. The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis.[2]

Potential concerns

Potential concerns regarding PrEP include the development of drug resistance and facilitation of behavioral changes.

Drug resistance

• HIV infection transmitted despite PrEP may be from a strain with acquired drug resistance

• The genetic barrier to resistance for tenofovir is high but low with emtricitabine

• Emergence of drug resistance could become a problem with more widespread use of ARVs for prophylaxis

Behavioral changes

A possibility exists that offering PrEP may encourage increased high-risk sexual activity and disinhibition. However, no evidence of increased high-risk sexual activity was demonstrated in the few observational studies that addressed this.[3, 4]

Identification of individuals at high risk

When considering emtricitabine/tenofovir for PrEP, it is important to identify individuals at high risk. High-risk patients include those who have partner(s) known to be HIV-1 infected or who engage in sexual activity within a high prevalence area or social network and exhibit one or more of the following:

• Inconsistent or no condom use

• Diagnosis of sexually transmitted infections

• Exchange of sex for commodities (eg, money, food, shelter, drugs)

• Use of illicit drugs or alcohol dependence

• Incarceration partner(s) of unknown HIV-1 status with any of the factors listed above

Patient education and monitoring

When prescribing emtricitabine/tenofovir for PrEP, health care providers must do the following[5] :

• Prescribe emtricitabine/tenofovir as part of a comprehensive prevention strategy because this drug combination is not always effective in preventing the acquisition of HIV-1 infection

• Counsel all uninfected individuals to strictly adhere to the recommended emtricitabine/tenofovir dosing schedule because in clinical trials, the combination’s effectiveness in reducing the risk of acquiring HIV-1 correlated strongly with adherence, as demonstrated by measurable drug levels

• Confirm a negative HIV-1 test immediately prior to initiating emtricitabine/tenofovir for a PrEP indication

• If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposure is suspected, delay starting PrEP for at least 1 month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection

CDC guidelines and evaluation for preexposure prophylaxis

Guidance from the CDC includes consideration for emtricitabine/tenofovir for use as PrEP among the following high-risk groups:

• MSM who engage in high-risk behaviors.[6]

• Heterosexually active adults, including women who may become pregnant while taking PrEP and serodiscordant couples[7]

• Persons who inject illicit drugs.[8]

The guidelines include the following recommendations:

• Evaluate for inconsistent use of other effective risk-reduction measures (eg, condom use)

• Ascertain that the risk for HIV acquisition is high (eg, frequent partner change or concurrent partners in a geographic setting with high HIV prevalence)

• To reduce the risk of transmission of drug resistance, do not start PrEP in persons with signs or symptoms of acute viral infection unless HIV-uninfected status is confirmed by HIV RNA testing or a repeat antibody test is performed after the viral syndrome resolves

Antiretroviral therapy (ART) for primary prevention of HIV is gaining enthusiasm because most biological and behavioral preventive strategies have failed to decrease HIV acquisition. Moreover, an effective preventive vaccine remains years away. Sexual transmission of HIV is strongly correlated with concentration of HIV in the blood and in genital secretions. Growing observational and modeling data suggest that antiretrovirals (ARVs) can be used to decrease infectivity of patients with chronic HIV, presumably by decreasing plasma and genital tract HIV concentrations, and also to protect at-risk uninfected individuals.[9] With the ever-expanding formulary and increased tolerability and availability of drugs, optimism is growing regarding ART preexposure prophylaxis (PrEP) being an effective method for primary prevention for individuals with ongoing risks for becoming infected with HIV.

The ideal chemoprophylactic agent should have a long half-life, achieve high concentrations in monocytes macrophages and genital secretions, have a high barrier for genetic resistance, and should be safe and inexpensive. The most widely studied ARV for PrEP, tenofovir DF, has many of these desirable characteristics. Most of the current clinical trials of PrEP involve tenofovir with or without emtricitabine. However, concerns exist that widespread use of PrEP could result in the selection and transmission of drug-resistant strains. Protease inhibitors are highly protein bound and achieve lower concentrations in the genital tract than tenofovir.[10]  

Maraviroc, an oral CCR5 co-receptor antagonist, achieves good genital and rectal concentrations and could be a potential candidate drug for PrEP.

The optimal number of drugs for chemoprophylaxis is unknown. The potential advantages of using a single agent include simplicity, lower risk for drug toxicity, and cost. These should be weighed against the risk of drug resistance if HIV infection occurs despite prophylaxis. If more than one drug is used for preexposure prophylaxis, they should work at different stages of the viral life cycle and have a higher genetic barrier to infection to decrease the risk for drug resistance.

On July 16, 2012, the FDA approved the antiretroviral combination of emtricitabine/tenofovir DF (Truvada), along with safe sex practices for PrEP to reduce the risk for sexually acquired HIV-1 in adults at high risk. As a condition of approval, the FDA is requiring Truvada’s manufacturer, Gilead Sciences, to study those who acquire HIV while taking emtricitabine/tenofovir to determine if anyone can develop a resistance to the drug. The company also needs to collect data on individuals who become pregnant while taking the drug since safety risks to the fetus remain unknown.

Since the initial publication of guidelines recommending the combination of emtricitabine and tenofovir disoproxil as the agent of choice for PrEP, tenofovir alafenamide (TAF) has become one of the drugs of choice for treatment of active HIV disease, given its more favorable side-effect profile. Daily administration of emtricitabine 200 mg plus tenofovir alafenamide (AF) 25 mg (Descovy) was approved in October 2019 for at-risk adults and adolescents for HIV-1 pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sex, excluding those who have receptive vaginal sex.[11]

ART has been shown to suppress but not eliminate the shedding of HIV in genital secretions.[12] The preventive benefits of ART have been shown in observational studies involving couples, ecologic community studies, and in a clinical trial.[3, 13, 14]  Several observational studies have reported decreased acquisition of HIV-1 by sexual partners of patients receiving antiretroviral therapy.[3, 14] Ecologic studies in the community have shown a reduction in the incidence of new cases of HIV-1 after expanded use of ART.[15, 16]

In a large, randomized, controlled, multicontinental, trial that enrolled 1750 serodiscordant heterosexual and male homosexual couples, all index cases had 350-550 CD4 cells/µL at baseline and were randomly assigned to immediate ART treatment initiation or delayed treatment until 2 consecutive measurements of 200-250 CD4 cells/µL or an AIDS-defining illness. All serodiscordant couples were given prevention and adherence counseling and provided with free condoms. In the immediate treatment arm, over 1585 person years, one HIV transmission to a partner occurred that was linked by virological genomic analysis to that of the index case.

In the delayed treatment arm, over 1567 person years, 27 linked HIV transmissions occurred, yielding a rate ratio of 0.04 (95% CI 0.00-0.27). When considering all HIV infections, 35 HIV transmissions occurred in the delayed arm and four transmissions in the immediate arm (rate ratio 0.11; 95% CI 0.04-0.32).[13] A Cochrane review, which included the above RCT and seven observational studies, concluded that ART is a potent intervention for prevention of HIV in discordant couples. They estimated a summary rate ratio of 0.16 (95% CI 0.07, 0.35) for the observational studies alone in favor of using PrEP.[17]

In 2016, the HPTN 052 trial randomized serodiscordant heterosexual couples either to receive immediate ART initiation or to defer ART therapy until CD4 counts fell below 250 cells/µL or an AIDS-defining event occurred. Among 1763 couples, 886 were in the immediate arm and 877 were in the delayed arm. Couples were counseled regarding condom use and safe sexual practices. A total of 46 genetically linked transmissions were reported during the trial period, of which 43 occurred in the delayed arm versus three in the immediate arm. No genetically linked HIV transmissions occurred among patients who were virologically suppressed.[18]

Extended-release IM injection for PrEP

An extended-release IM injection, cabotegravir (Apretude), was approved by the FDA for PReP for adults and adolescents in December 2021. It is administered as a gluteal IM injection every 2 months. A phase 3 clinical trial demonstrated cabotegravir IM was superior to daily oral TDF-FTC in preventing HIV infection. The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis.[2]  

Daily oral PrEP

The approval of emtricitabine/tenofovir (Truvada) was based on two clinical trials, the Pre-exposure Prophylaxis Initiative (iPrEx) trial and the Partners PrEP trial.

The first trial was sponsored by the US National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. The iPrEx multinational study found that once-daily emtricitabine plus tenofovir disoproxil fumarate (FTC-TDF) reduced the risk of acquiring HIV by 44% in a study population of high-risk, HIV-negative men or transgender women who have sex with men.[4]

The second trial is the Partners PrEP trial, sponsored by the University of Washington and the Bill and Melinda Gates Foundation. In this trial of heterosexual couples where one partner was infected and condoms were used routinely, a 75% reduction was observed in risk of acquiring HIV infection with use of emtricitabine/tenofovir.[19]

On June 12, 2013, the Thailand Ministry of Health and the CDC published results from a randomized controlled trial of a daily oral dose of 300 mg of tenofovir disoproxil fumarate (TDF, Viread) that showed efficacy in reducing the acquisition of HIV infection among injecting drug users (IDUs).[20] Based on these findings, the CDC updated its interim guidance for PrEP and now recommends that tenofovir/emtricitabine (TDF/FTC, Truvada) be considered as one of several prevention options for persons at very high risk for HIV acquisition through the injection of illicit drugs.[8]

Results showed that daily oral PrEP with tenofovir 300 mg reduced the risk of acquiring HIV by approximately 49%. Among 2400 study participants, those who took the medication consistently had higher levels of protection. In a separate analysis of participants known to be adherent, because they were observed taking their medication and had tenofovir detected in their blood, the risk of HIV acquisition was reduced by approximately 74%.[20]

Since the publication of these trials, new data have further supported the previously noted benefits of PrEP.

The PROUD trial, published in January 2016, was a pragmatic open-label study performed in 13 sexual health clinics in the United Kingdom. The study enrolled MSM who were sexually active and practicing receptive condomless anal sex during the 90 days prior to recruitment. Patients were randomly assigned to receive immediate PrEP with daily TDF/FTC or to defer treatment for 12 months. The trial enrolled 544 patients (279 in the immediate group, 269 deferred). Early during the trial, the benefit of PrEP became overwhelmingly evident, and all patients were offered treatment. The immediate PrEP arm had a total of three infections, while the deferred arm had 20 new infections. This resulted in an 86% risk reduction of HIV transmission. Both groups experienced many cases of STI and showed no significant change in sexual behavior. The success of this trial, which was conducted under real-world circumstances, speaks to the practical applicability of these data.[21]

The IPERGAY trial was published in December 2015. This trial, performed in France and Canada, sought to test the efficacy of on-demand, event-driven use of TDF/FTC among high-risk MSM. It was a randomized placebo-controlled trial in which individuals were instructed to take TDF/FTC preceding and after sex versus placebo. Of 414 randomized patients, 199 were in the final treatment group and 200 were in the placebo group. Sexual education, condoms, and counseling were offered equally to both groups. On average, both groups took approximately 15 pills per months. There were two HIV infections in the treatment arm and 14 in the placebo group. The two patients who became infected in the treatment arm were not actively taking medications, amounting to an 86% risk reduction in the risk of HIV acquisition.[22]

While these data are certainly provocative, given how often the patients were engaging in sexual activity, the number of pills taken averages around three pills per week, making it difficult to fully endorse the practice of on-demand PrEP in all patients.

Recently, the novel long-acting injectable integrase inhibitor cabotegravir was tested for feasibility and acceptability as an agent for use in pre-exposure prophylaxis. A trial comparing its efficacy versus TDF/FTC is currently underway.[23]  In May 2020, a planned interim review of the study results showed that overall HIV acquisition in both groups was low.  However, when comparing the cabotegravir group to the TDF/FTC group, there was a statistically significant decrease in HIV incidence. The HIV incidence in the cabotegravir group was 0.41% (95% confidence interval [CI] 0.22%-0.69%) compared with 1.22% (95% CI 0.87%-1.67%) in those taking TDF/FTC.[24]   Despite these preliminary results cabotegravir is not yet FDA approved for PrEP. 

Although most data cited above concerns adults, trial data assessing the safety and feasibility of PrEP in adolescent MSM aged 15-17 years were published in 2017.[25] In this study, 78 patients were enrolled using selection criteria similar to that used for initiating PrEP in adults and were given daily TDF/FTC. Forty-six patients (64%) completed 48 weeks of follow-up. Most participants had detectable levels of the study drug. High levels of tenofovir, consistent with reception of four or more doses per week, which is considered highly protective against HIV acquisition, were detected in 54% at Week 4, 47% at Week 8, 49% at Week 12, 28% at Week 24, 17% at Week 36, and 22% at Week 48. The study demonstrated that PrEP is feasible and safe in this patient population, although adherence seemed to decrease over time. This may justify more frequent follow-up than is expected in adults to provide more effective care and to ensure appropriate adherence and protection.

Drug resistance

A major concern regarding the use of PrEP is the possibility of acquired drug resistance if HIV infection is transmitted. The genetic barrier to resistance for tenofovir is high but low with emtricitabine. The iPrEx trial that evaluated chemoprophylaxis in men who have sex with men (MSM), did not show any incident tenofovir resistance. However, with a poor adherence level among patients in the intervention arm, the possibility is not eliminated.[4] Emergence of drug resistance could be a potential problem in the future with more widespread use of antiretrovirals for prophylaxis, although such concerns have yet to come to fruition.

HIV transmissions have been reported among a handful of patients taking effective PrEP regimens. These have mostly involved transmission of HIV with multiclass–drug-resistance mutations,[26] reinforcing the need for ongoing condom use in patients who are taking PrEP.

Behavioral changes

A possibility exists that offering PrEP may encourage increased high-risk sexual activity and disinhibition. Recent data have shown an increase in condomless sex among patients taking PrEP, raising concern for transmission of STIs.[27] More studies are evaluating the effect of these changes in behavior.

Individuals at high risk

When considering emtricitabine/tenofovir for PrEP it is important to identify individuals at high risk. High-risk patients include those who have partner(s) known to be HIV-1 infected, or who engage in sexual activity within a high prevalence area or social network and exhibit one or more of the following: inconsistent or no condom use, diagnosis of sexually transmitted infections, exchange of sex for commodities (such as money, food, shelter, or drugs), use of illicit drugs or alcohol dependence, or incarceration partner(s) of unknown HIV-1 status with any of the factors listed above.

Patient education and monitoring

When prescribing emtricitabine/tenofovir for PrEP, healthcare providers must[5] :

• Prescribe emtricitabine/tenofovir as part of a comprehensive prevention strategy because this drug combination is not always effective in preventing the acquisition of HIV-1 infection.

• Counsel all uninfected individuals to strictly adhere to the recommended emtricitabine/tenofovir dosing schedule because the effectiveness of Truvada in reducing the risk of acquiring HIV-1 was strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials.

• Confirm a negative HIV-1 test immediately prior to initiating emtricitabine/tenofovir for a PrEP indication. If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures are suspected, delay starting PrEP for at least 1 month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.

The CDC first issued guidelines for preexposure prophylaxis (PrEP) in May 2014. These were updated in 2017 to incorporate the growing body of data.[28] Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg (Truvada) has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults and adolescents weighing at least 35 kg. Daily emtricitabine/tenofovir is one prevention option that is part of the general guidelines for HIV prevention.

In October 2019, the FDA approved the fixed-dose combination of tenofovir alafenamide (TAF) 25 mg plus FTC 200 mg (Descovy) for at-risk adults and adolescents for HIV-1 pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sex, excluding those who have receptive vaginal sex.[11]

The guidelines apply to the following specific populations:

• Sexually-active adult men who have sex with men (MSM) who are at substantial risk of HIV acquisition; evidence level IA

• Adult heterosexually active men and women who are at substantial risk of HIV acquisition; evidence level IA

• Adult injection drug users (IDUs) at substantial risk of HIV acquisition; evidence level IA

• Heterosexually-active women and men whose partners are known to have HIV infection (HIV-discordant couples); PrEP should be discussed with this population as one of several options to protect the uninfected partner during conception and pregnancy so that an informed decision can be made in awareness of what is known and unknown about benefits and risks of PrEP for mother and fetus; evidence level IIB

PrEP treatment guidelines include:

• Acute and chronic HIV infection must be excluded by symptom history and HIV testing immediately before PrEP is prescribed; evidence level IA

• The only medication regimen approved by the FDA and recommended for PrEP with all the populations specified in the CDC guideline is daily TDF 300 mg coformulated with FTC 200 mg (Truvada); evidence level IA

• TDF alone has shown substantial efficacy and safety in trials with IDUs and heterosexually active adults and can be considered as an alternative regimen for these populations, but not for MSM, among whom its efficacy has not been studied; evidence level IC

• Use of other ART medications for PrEP, either in place of or in addition to TDF/FTC (or TDF) is not recommended; evidence level IIIA

• Oral PrEP for coitally-timed or other noncontinuous daily use is not recommended; evidence level IIIA

Based on the iPrEx results, interim CDC guidelines were issued in January 2011 for emtricitabine/tenofovir for use as PrEP among men who have sex with men (MSM) who continue to engage in high-risk behaviors. The use of tenofovir/emtricitabine may be considered on a case-by-case basis, with the clinician fully explaining the limitations of such an intervention. These guidelines only applied to MSM who continue to engage in high-risk behavior and did not apply to other at-risk populations (eg, injection drug users, heterosexuals, or serodiscordant couples).[6]

When considering MSM for initiation of PrEP medications, it is important to evaluate for inconsistent use of other effective risk-reduction measures (eg, condom use), as well as ascertain that the risk for HIV acquisition is high (eg, frequent partner change or concurrent partners in a geographic setting with high HIV prevalence); these patients might benefit most from the addition of PrEP to their HIV prevention regimen. PrEP should not be started in persons with signs or symptoms of acute viral infection unless HIV-uninfected status is confirmed by HIV RNA testing or a repeat antibody test performed after the viral syndrome resolves to reduce the risk of transmission of drug resistance.

Following the publication of final results from the TDF2 and Partners PrEP trials in August 2012, the CDC published interim guidance to help clinicians safely and effectively provide PrEP for heterosexually-active adults. This guidance included recommendations similar to those for MSM, as well as new recommendations relevant to women who may become pregnant while taking PrEP and to serodiscordant couples.[7]

Results from a randomized controlled trial showed tenofovir disoproxil fumarate (TDF, Viread) 300 mg/day was effective in reducing the acquisition of HIV infection among injecting drug users (IDUs).[20] Based on these findings, the CDC updated its interim guidance for PrEP and now recommends that tenofovir/emtricitabine (TDF/FTC, Truvada) be considered as one of several prevention options for persons at very high risk for HIV acquisition through the injection of illicit drugs.[8]

TDF/FTC was FDA-approved for PrEP against sexual HIV acquisition by MSM, and in heterosexually-active serodiscordant women and men in July 2012 and contains the same dose of tenofovir used in the June 2013 trial by Choopanya et al. Although use of TDF/FTC without sexual HIV acquisition is considered off-label, prevention services for IDUs target both injection and sexual risk behaviors, and therefore the CDC recommends the combination product.

Guidelines on the use of HIV pre-exposure prophylaxis (PrEP) were released in March 2019 by the British HIV Association (BHIVA)/British Association for Sexual Health and HIV (BASHH).[29]

PrEP Recommendations in Men Who Have Sex With Men (MSM)

HIV‐negative MSM who are at an increased risk of HIV acquisition because of condomless anal intercourse in the preceding 6 months and ongoing condomless anal intercourse should be offered daily or on‐demand oral tenofovir disoproxil/emtricitabine (TD‐FTC) as PrEP.

HIV‐negative MSM engaging in condomless anal intercourse with a partner who is HIV-positive should be offered daily or on‐demand oral TD‐FTC as PrEP, unless the partner has been on antiretroviral therapy (ART) for at least 6 months and has a plasma viral load of < 200 copies/mL.

PrEP Recommendations in Heterosexual Individuals

HIV‐negative heterosexual men and women engaging in condomless intercourse with a partner who is HIV-positive should be offered daily oral TD‐FTC as PrEP, unless the partner has been on ART for at least 6 months and has a plasma viral load of < 200 copies/mL.

Heterosexual men and women with ongoing risk factors for HIV acquisition should be offered daily oral TD‐FTC as PrEP on a case‐by‐case basis.

Tenofovir disoproxil fumarate (TDF) alone can be offered to heterosexual men and women if FTC is contraindicated.

PrEP Recommendations in Trans Women

HIV‐negative trans women who are at an increased risk of HIV acquisition through condomless anal intercourse in the preceding 6 months and ongoing condomless intercourse should be offered daily oral TD-FTC as PrEP.

HIV‐negative trans women and trans men engaging in condomless intercourse with a partner who is HIV-positive should be offered daily oral TD‐FTC as PrEP, unless the partner has been on ART for at least 6 months and has a plasma viral load of < 200 copies/mL.

PrEP Recommendations in Young People

HIV‐negative young MSM (aged 15-25 years) who are at an increased risk of HIV acquisition because of condomless anal intercourse in the preceding 6 months and ongoing condomless anal intercourse should be offered daily or on‐demand oral TD‐FTC as PrEP.

HIV‐negative young people engaging in condomless anal intercourse with a partner who is HIV-positive should be offered TD‐FTC as PrEP, unless the partner has been on ART for at least 6 months and has a plasma viral load of < 200 copies/mL.

HIV‐negative young trans women who are at an increased risk of HIV acquisition because of condomless anal intercourse in the preceding 6 months and ongoing condomless anal intercourse should be offered daily oral TD‐FTC as PrEP.

Recommendations for Initiating and Discontinuing PrEP

If anal intercourse represents the HIV acquisition risk, PrEP can be initiated as a double-dose of TD‐FTC taken 2-24 hours before intercourse and continued daily until 48 hours following the last sexual risk.

If PrEP for anal intercourse has been interrupted but less than 7 days have elapsed since the last TD‐FTC dose, PrEP can be re‐initiated with a single dose of TD‐FTC.

If vaginal intercourse represents the risk for HIV acquisition, PrEP should be initiated as a daily regimen 7 days before the likely exposure risk and continued daily for 7 days following the last sexual risk.

Recommendations for Baseline Testing

Baseline HIV testing with a combined antigen/antibody serology test should be performed before PrEP is initiated.

Same‐day PrEP initiation may occur in individuals who have a negative result on a third‐generation or higher blood‐based point‐of‐care test (POCT) on the same day or a negative result on a combined HIV antigen/antibody test within the preceding 4 weeks.

HIV viral load should be considered if a high‐risk exposure has occurred within the preceding 4 weeks.

PrEP should be deferred until an HIV RNA result is available in individuals who report condomless anal intercourse in the preceding 4 weeks and who have symptoms that suggest HIV seroconversion.

Baseline hepatitis B virus (HBV) screening should be performed in individuals with unknown HBV status, and vaccination should be initiated in nonimmune persons.

A specialist in viral hepatitis/coinfection should assess patients with evidence of chronic HBV infection to decide whether to continue or to terminate therapy.

On‐demand PrEP dosing should not be offered to individuals with chronic HBV infection.

MSM and other individuals at risk for hepatitis C virus (HCV) infection should undergo baseline HCV screening.

A full baseline sexually transmitted infection (STI) screen should be performed, including syphilis serology and nucleic acid amplification testing (NAAT) for gonococcal and chlamydial infection at exposure sites (genital, rectal, pharyngeal).

Baseline renal function should be assessed with serum creatinine testing, estimated glomerular filtration rate (eGFR), and urinalysis; PrEP can be initiated while results are pending.

The eGFR should be >60 mL/min/1.73 m2 in persons starting TDF. If the eGFR is less than this, PrEP should be considered on a case-by-case basis.

Suboptimal Adherence to PrEP

If fewer than four doses of the daily PrEP regimen are taken per week, it is unlikely to be effective. Despite this, no evidence has shown that four instead of seven doses per week is adequate.

Recommendations for Monitoring During PrEP

Individuals on PrEP should undergo HIV testing every 3 months with a laboratory combined HIV antigen/antibody test or a blood‐based POCT.

Individuals on PrEP with symptoms that suggest HIV seroconversion should undergo combined HIV antigen/antibody testing and HIV viral load testing.

If primary HIV infection is confirmed, baseline resistance testing should be performed to evaluate for evidence of resistance‐associated mutations to tenofovir or emtricitabine, along with other mutations.

All individuals on PrEP should undergo screening for bacterial STIs every 3 months. MSM, trans women, and others with an ongoing HCV risk should also undergo HCV testing every 3 months.

Recommendations for Terminating PrEP

PrEP should be discontinued if an HIV test shows a positive result, and the patient should be immediately referred to an HIV specialist.

Suboptimal adherence to PrEP is a relative contraindication to continued use.

HBV infection should be excluded prior to discontinuing TD‐FTC in patients without vaccine-induced immunity.

The US Preventive Services Task Force (USPSTF) issued a statement on June 11, 2019, recommending offering preexposure prophylaxis (PrEP) for HIV infection to persons at high risk for infection.[30]

The PrEP recommendation also means that private insurers will be required to cover the cost of PrEP drugs, according to rules established by the Affordable Care Act.

Individuals at risk of HIV infection include men who have sex with men (MSM), individuals who are at risk because of heterosexual contact, and individuals who inject drugs. Certain risk factors or behaviors can further increase the likelihood of infection.

Risk assessment

MSM who are sexually active and meet at least one of the following criteria should be considered for PrEP:

• Is in a sexual relationship with a partner who has HIV infection
• Reports inconsistent condom use during anal sex (receptive or insertive)
• Has had a sexually transmitted infection (STI; syphilis, gonorrhea, or chlamydia) within the preceding 6 months

Heterosexually active men and women who meet one of the following criteria should be considered for PrEP:

• Is in a sexual relationship with a partner who has HIV infection
• Reports inconsistent condom use during sex with a partner of unknown HIV status who is considered to be at high risk (eg, a man who has sex with men and women or an individual who injects drugs)
• Has had an STI (syphilis or gonorrhea) within the preceding 6 months

Individuals who inject drugs and meet one of the following criteria should be considered for PreP:

• Shares drug injection equipment
• Is at risk of sexual HIV acquisition

Another group at high risk of HIV infection are individuals who engage in transactional sex (eg, for money, drugs, or housing), including commercial sex workers or persons trafficked for sex work. They should also be considerfed for PrEP based on the above criteria.

Preventive medication

Combined tenofovir disoproxil fumarate and emtricitabine administered orally once a day is the only formulation of PrEP that is FDA-approved in the United States for use in persons at risk of sexually transmitted HIV infection.

It is estimated that approximately 25% of MSM and 19% of injection drug users would be eligible for daily PrEP.[31] Despite these numbers and some signs of overall progress in engaging eligible patients in care,[32] a significant number of at-risk patients remain unware of PrEP availability. This is especially true in some of the most at-risk populations, such as Black MSM.[33] Continuing efforts in provider education are paramount for successful implementation of these programs.

The idea of treatment as prevention for HIV-1 infection has gathered tremendous enthusiasm and is driven by a) failure of behavioral and biological prevention efforts; b) biological plausibility of the use of ARV for prevention; c) cheaper, safer, and simpler ART regimens; and d) recent clinical trials that show promise for the intervention.

PrEP has the potential to contribute to effective and safe HIV prevention when 1) it is targeted to individuals at high risk for HIV acquisition; 2) delivered as part of a comprehensive set of prevention services, including risk-reduction and PrEP medication adherence counseling, ready access to condoms, and diagnosis and treatment of sexually transmitted infections; 3) and it is accompanied by monitoring of HIV status, side effects, adherence, and risk behaviors at regular intervals.

The FDA approval of emtricitabine/tenofovir (Truvada) for PrEP now offers options to high-risk groups including men who have sex with men and serodiscordant couples. Additionally, current CDC guidelines include additional populations (eg, IV drug users, heterosexual individuals at high risk).

In spite of the promise and the progress of PrEP, concerns about durability of protection, the balance of benefits and adverse events associated with earlier therapy, and long-term adherence and transmission of ART-resistant strains to partners remain. Longer-term studies are needed but should not preclude the implementation of this strategy. As the search for an effective vaccine continues, interventions like PrEP could significantly slow the HIV epidemic.