HIV pre-exposure prophylaxis

INTRODUCTION — 

Over one million new human immunodeficiency virus (HIV) infections occur yearly worldwide, with more than 30,000 annually in the United States. As there are no effective vaccines to prevent HIV transmission, behavioral and biomedical HIV prevention strategies are needed to reduce HIV acquisition.

Pre-exposure prophylaxis (PrEP) with antiretroviral agents for those without HIV has proven to be an effective HIV prevention strategy. Among persons who are adherent to PrEP, treatment can reduce the risk of HIV transmission by greater than 99 percent [1], although rare infections may still occur [2-4]. However, many people with indications for PrEP have never been prescribed PrEP. Uptake has been particularly limited in certain populations who are at greatest risk for HIV infection (eg, at-risk African Americans, Hispanic/Latin Americans, adolescents, and transgender individuals) [5-7].

This topic will review the approach to using PrEP in persons who are at risk for acquiring HIV. Other strategies to prevent HIV infection (eg, antiretroviral therapy [ART] for patients with HIV, post-exposure prophylaxis [PEP], and voluntary male circumcision) are discussed separately. (See "HIV infection: Risk factors and prevention strategies" and "Management of nonoccupational exposures to HIV and hepatitis B and C in adults" and "Management of health care personnel exposed to HIV".)

DETERMINING PREP ELIGIBILITY

Indications for PrEP — PrEP has been associated with a reduction in HIV transmission in several populations, including [8]:

●Men who have sex with men (MSM) and transgender women who report sexual behaviors associated with HIV infection (eg, condomless anal sex)

●Heterosexually active persons who have sex with partners who are at high risk of HIV infection (eg, partners from high HIV prevalence areas, partners who inject drugs)

●Persons who inject drugs

In a systematic review of randomized trials and observational studies with over 18,000 participants, oral PrEP was associated with a reduced risk of HIV infection compared with placebo or no PrEP (relative risk 0.46, 95% CI 0.33-0.66; absolute risk reduction -2.0 percent, 95 % CI,-2.8 to -1.2 after four months to four years) [9]. In six trials where adherence to PrEP was ≥70 percent, the benefit was more pronounced (1 versus 4.1 percent; RR 0.27, 95% CI 0.19-0.39). By contrast, the benefit of PrEP in those with lower risk (eg, heterosexual men who engaged in condomless sex with partners from areas of low general HIV prevalence) is less certain.

Patient assessment — All sexually active patients should receive education about HIV PrEP [10]. Clinicians should also obtain a detailed sexual and drug use history to assess the patient's risk of acquiring HIV and determine eligibility for PrEP. Key factors informing eligibility are summarized in the tables (table 1 and table 2) and reviewed in further detail below.

For transgender and nonbinary individuals, the decision to offer PrEP should be determined based on their sexual risk, as described for the populations below, since some groups (eg, transgender women who engage in sex work) are at increased risk for HIV, while others are not.

Sexual risk

Persons at highest risk of acquiring HIV — We recommend PrEP for the following patient groups who are at highest risk of acquiring HIV through sexual activity (table 3). This includes:

●Persons who have a sexual partner with uncontrolled HIV. PrEP is indicated for the patient if the partner with HIV has a detectable viral load or unknown virological status. If the partner with HIV has recently initiated antiretroviral therapy (ART), PrEP is indicated for the patient until the partner has achieved a stably suppressed viral load (typically six months after initiating ART) [11,12]. Once the partner with HIV has achieved a stably suppressed viral load, PrEP may be discontinued, provided there are no concerns about the partner's adherence to ART, and the patient does not have condomless sex with other partners. (See 'Discontinuing PrEP' below.)

Although PrEP can be considered for all individuals without HIV who have a serodiscordant partner (ie, one partner has HIV and the other does not), in clinical trials, transmission to an uninfected partner has not been reported if the partner with HIV is confirmed to have a stably suppressed plasma HIV RNA and is adherent to their ART regimen. In a prospective observational study of serodiscordant couples, there were no documented intracouple transmission events after more than 1200 couple-years of follow-up when the partner with HIV had a viral load <200 copies/mL [13]. (See "HIV infection: Risk factors and prevention strategies", section on 'Treatment as prevention'.)

●MSM and transgender women who have sex with men if:

•The patient engages or has engaged (eg, within the last 12 months) in insertive or receptive condomless anal sex with multiple or anonymous sex partners and/or a main partner with HIV risk factors, or plans to do so.

•The patient has had (eg, within the last 12 months) a documented bacterial sexually transmitted infection (STI) or other infection associated with sexual activity (eg, mpox). (See "Screening for sexually transmitted infections" and "Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox)".)

The efficacy of PrEP in reducing HIV transmission in MSM and transgender women who are at increased risk for HIV transmission has been demonstrated in several large trials [14-16]. For example, in the multinational iPrEx randomized trial that included 2470 HIV-seronegative men and 29 transgender women, treatment with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) reduced HIV infection by 44 percent compared with placebo (95% CI 15-63; 36 new HIV infections in the TDF-FTC group compared with 64 in the placebo group) [15]. The protective efficacy of TDF-FTC increased to ≥96 percent for those with drug levels that were consistent with taking at least four doses per week [1,17].

In transgender persons, particularly transgender women, the impact of gender-affirming hormone therapy on antiviral levels remains unclear. However, limited available data suggest that transgender persons who are using gender-affirming hormone therapy are adequately protected against HIV acquisition if they are fully adherent to injectable therapy or daily oral PrEP [18-22].

●Heterosexually active persons from regions with generalized HIV epidemics who engage or have engaged (eg, within the last 12 months) in condomless sex with partners of unknown HIV status, or plan to do so. According to World Health Organization (WHO), a generalized HIV epidemic is defined by a prevalence of HIV ≥3 percent [23]. This includes several countries in sub-Saharan Africa. Other guideline panels have suggested a lower prevalence threshold of ≥2 percent [24]. In Africa, two large trials demonstrated that TDF-FTC reduced the risk of HIV acquisition in heterosexual men and women by approximately 80 percent compared with placebo [25,26].

Others who may benefit from PrEP — We also suggest PrEP for individuals who are at increased risk for acquiring HIV through sexual behaviors, even if they are not in the highest risk category (table 3).

This includes the following patients from areas with a low general prevalence of HIV:

●Heterosexual cisgender women who engage or have engaged (eg, within the last 12 months) in condomless sex with male partners who are at high risk of HIV infection, or plan to do so. These partners include persons who inject drugs, bisexual male partners, and partners from areas where there is a high HIV prevalence.

Studies evaluating the efficacy of PrEP in heterosexual cisgender women have focused primarily on persons in resource-limited settings and have yielded mixed results. In some trials, oral TDF-FTC was found to have no effect on reducing transmission in females, whereas in others, transmission was reduced by approximately 70 percent overall and by more than 90 percent in those who had drug levels consistent with daily use [25,27-30]. These differences in PrEP efficacy estimates appear to be primarily due to the variable levels of adherence in the different studies. Studies that evaluated injectable therapies have had more favorable results [31,32]. (See 'Injectable therapy' below.)

●Heterosexual men who engage or have engaged (eg, within the last 12 months) in condomless sex with partners who are at high risk of HIV infection, or plan to do so. Partners at high risk of HIV infection include sex workers or persons who inject drugs.

●Heterosexual cisgender men and women recently diagnosed (eg, within the last 12 months) with syphilis or gonorrhea. We suggest PrEP for these patients because syphilis and gonorrhea infections are associated with an increased risk for HIV. We also discuss PrEP with patients diagnosed with chlamydia since PrEP should be discussed with all patients who are sexually active. However, we do not routinely offer PrEP to such patients in the absence of other risk factors, since the co-occurrence of this STI with HIV is less common than for other bacterial STIs.

Injection drug use — We suggest PrEP for people who inject drugs if they report sharing needles or equipment, even if they have initiated substance use treatment. In a double-blind trial in Thailand of 2413 HIV-seronegative males and females with a history of injection drug use, once-daily therapy with tenofovir reduced the incidence of HIV by 49 percent compared with placebo (95% CI 9.6-72.2; 17 new infections in the tenofovir group versus 33 in the placebo group) [33]. However, the findings from this study were insufficient to reliably determine the degree of protection from PrEP in persons who inject drugs since the trial only used TDF (rather than TDF-FTC, which is used for PrEP). In addition, the trial was unable to determine the degree of protection from sexual versus needle risk.

Unclear risk — PrEP is generally not needed for persons who engage in low-risk behaviors (eg, consistent condom use when engaging in anal or vaginal intercourse, no mucosal exposure to genital secretions) and those who are in mutually monogamous relationships.

However, on occasion, a patient may not endorse high-risk behaviors but still request PrEP. In such patients, we typically provide PrEP if we feel the potential risks and benefits of treatment are fully understood, and there are no underlying behavioral health issues that would impact their decision. Some individuals who engage in behaviors that put them at increased risk for HIV acquisition may not be comfortable disclosing information related to their sexual practices or substance use.

A more detailed discussion of risk factors for HIV infection is found elsewhere. (See "HIV infection: Risk factors and prevention strategies", section on 'Risk factors for infection'.)

DETERMINING PREFERENCE FOR ORAL VERSUS INJECTABLE THERAPY — 

Oral and injectable PrEP are both effective in reducing HIV transmission. The decision to use one strategy over the other depends upon availability and patient preference. In one study, HIV incidence was lower among those given a choice of which PrEP modality to use [34]. When both options are available, we review the pros and cons of the different regimens to determine which modality will optimize long-term adherence, as this equates to effectiveness (table 4). More detailed information on the safety and efficacy of the different agents is found below. (See 'Available oral agents' below and 'Efficacy and safety' below.)

Reasons for choosing an oral regimen — For some patients, oral therapy is preferred. Reasons include:

●Tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) is the most studied regimen and is well tolerated. It can also be administered as event-driven therapy for persons who engage only in anal sex (unless they have concurrent chronic hepatitis B virus [HBV] infection).

●TDF-FTC is well-suited for patients who want to start PrEP on the same day as their initial visit. Long-acting cabotegravir (cabotegravir LA) must be administered in the clinic, and this may require additional visits.

●If a patient acquires HIV while taking TDF-FTC and develops drug resistance to one of these agents, many of the preferred treatment options can still be used (table 5). By contrast, patients who acquire HIV while taking cabotegravir LA are at risk for developing resistance to integrase strand transfer inhibitors (INSTIs), which can limit first-line HIV treatment options. The risk for developing INSTI resistance may also be high if HIV transmission occurs during the six months after cabotegravir LA is discontinued [35], unless the patient promptly transitions to an alternative PrEP regimen.

●The benefit of cabotegravir LA has not been established in persons who inject drugs as their primary risk factor for HIV acquisition, although studies are underway.

●There are limited data on cabotegravir in persons who are pregnant or who desire pregnancy. Although there was no increase in the incidence of adverse birth outcomes among those who became pregnant in the randomized trial that evaluated cabotegravir LA in cisgender women, the number of pregnancies was small [31]. (See 'Persons of child bearing potential' below.)

Reasons for choosing injectable therapy — Many patients prefer injectable rather than oral therapy, if available. Cabotegravir LA is the only injectable agent that is US Food and Drug Administration (FDA) approved for PrEP. Reasons to use cabotegravir LA rather than oral therapy include:

●Not liking to take pills, difficulty adhering to a daily oral regimen, or difficulty with swallowing pills.

●Patients who are adherent to care but have challenges taking their oral regimen as prescribed (eg, unable to store medications). Injectable therapy may be particularly beneficial for cisgender females; in the clinical trials of injectable cabotegravir and lenacapavir, injectable medication was superior to oral, due in large part to decreased adherence with oral medication. (See 'Injectable therapy' below.)

●It may be a good option for persons with or at risk for kidney or bone disease. As an example, cabotegravir LA can be used regardless of kidney function and is the only option for patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m². In addition, in one unpublished report, there was an increase in bone mineral density in persons who received cabotegravir LA, whereas there was a loss of bone mineral density in those who received TDF-FTC [36].

PRETREATMENT EVALUATION — 

For those choosing an oral therapy regimen, the pretreatment evaluation also includes an assessment of kidney function, hepatitis B virus (HBV) status, and evidence of bone disease, as these factors can impact regimen selection. (See 'Additional considerations' below.)

Evaluation for all patients

HIV testing — All patients should have plasma HIV testing prior to receiving PrEP to be certain that they do not have undiagnosed HIV infection [10,37]. Although PrEP regimens contain antiretroviral agents, they are not sufficient for treatment, and a person with HIV is at risk for developing drug-resistant virus unless additional agents are added. In the iPrEX trial, most cases of HIV drug resistance occurred in patients with undiagnosed HIV at baseline [15].

Approach for most patients — For most patients, HIV testing should be obtained within the week before initiating PrEP [10]. Special considerations for those transitioning from post-exposure to pre-exposure antiretroviral prophylaxis are discussed below. (See 'Persons transitioning from post-exposure prophylaxis (PEP) to PrEP' below.)

The approach to testing (antibody/antigen versus testing for HIV RNA) depends on whether the person is planning to initiate oral versus injectable therapy and if they are initiating PrEP for the first time or restarting therapy. In all these settings, rapid tests that use oral fluid should not be used because of their lower sensitivity to detect early HIV infection.

●Treatment-naïve, initiating oral PrEP – In treatment-naïve persons initiating oral PrEP, we use a laboratory-based fourth-generation antigen/antibody assay, if possible, although a point-of-care antigen/antibody test using a finger stick can also be used. A third-generation is acceptable if an antigen/antibody test is not available but only if the clinical history clearly suggests that acute HIV infection is unlikely. (See 'Symptoms of acute HIV' below.)

Most patients with a negative antigen/antibody test can initiate oral PrEP. However, additional HIV RNA testing should be performed prior to initiating PrEP in the following groups of patients (regardless of which HIV antibody screening test is used):

•Those who describe signs or symptoms suggestive of acute HIV infection within the previous four weeks (table 6). Patients with acute HIV infection may present with a viral syndrome (eg, lymphadenopathy, fever, malaise, and/or a maculopapular eruption), and have a detectable HIV RNA in the absence of an HIV antibody and antigen in early cases.

In the iPrEx trial, 10 of the 110 participants who seroconverted during the study had a negative antibody test at baseline but were found to have a positive HIV RNA when testing was done on stored samples from enrollment [15]. Five of these patients had symptoms consistent with acute infection, underscoring the significance of eliciting a full history to determine the need for additional testing. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

•Patients with an indeterminate antigen/antibody test. (See "Screening and diagnostic testing for HIV infection in adults", section on 'Management of indeterminate test results'.)

•Patients who report a known HIV exposure (eg, recent sexual exposure to a partner with documented untreated HIV infection) within four weeks of starting PrEP, regardless of symptoms.

In settings where access to prompt HIV RNA testing is not feasible, a fourth-generation HIV antigen/antibody test can be repeated. (See "Screening and diagnostic testing for HIV infection in adults", section on 'Testing algorithm'.)

●Treatment-naïve, initiating injectable PrEP – For treatment-naïve patients initiating injectable therapy, an antigen/antibody test can be used to determine eligibility for long-acting cabotegravir (cabotegravir LA) as long as the patient has no signs or symptoms of acute HIV (table 6) and no known exposure to a person with uncontrolled HIV in the last four weeks.

For those with a negative antigen/antibody test, a baseline HIV RNA should also be obtained, but cabotegravir LA does not need to be withheld pending the results. It is important to use the most sensitive test possible in those initiating cabotegravir LA because of the long duration of drug exposure following injection. In the efficacy trials of cabotegravir LA, several patients were not diagnosed with acute HIV when they initiated PrEP, and there was a several-month delay in diagnosing their infection because of viral suppression from the medication [14]. In one of these patients, the prolonged exposure to monotherapy led to integrase strand transfer inhibitor (INSTI) resistance, constraining future treatment options.

●Treatment-experienced, reinitiating PrEP – For patients reinitiating PrEP, the United States Centers for Disease Control and Prevention (CDC) recommends that antigen/antibody and HIV RNA testing be performed if the patient received oral PrEP within the last three months or long-acting injectable PrEP within the prior 12 months [10]. In such patients, the sensitivity of antigen/antibody testing may be reduced.

Persons transitioning from post-exposure prophylaxis (PEP) to PrEP — Some patients will receive a three-drug antiretroviral regimen after a potential sexual or percutaneous exposure to HIV to reduce the risk of HIV transmission. This is referred to as post-exposure prophylaxis (PEP). (See "Management of nonoccupational exposures to HIV and hepatitis B and C in adults", section on 'HIV post-exposure management'.)

Patients who receive PEP and are at risk for repeat exposure to HIV should be offered PrEP when they complete their PEP regimen. For those who decide to transition from PEP to PrEP, a repeat HIV test (antigen/antibody test) and HIV RNA test should be performed just prior to the end of the 28-day course.

●The patient can transition from their PEP regimen to PrEP without interruption if the HIV antigen/antibody and HIV RNA tests are negative and there is no concern for acute HIV. (See 'Pretreatment evaluation' above.)

●By contrast, if there is still any suspicion for acute HIV infection (eg, discordant HIV test results, symptoms of acute infection), PEP should be continued pending further evaluation (eg, repeat plasma RNA screening). (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

Assessing barriers to PrEP adherence — Potential challenges to PrEP adherence (eg, depression, active substance use, stigma) should be identified and addressed in those initiating therapy [38]. There is a clear association between the efficacy of PrEP in decreasing HIV transmission and adherence [1,15,17,25,26,28,39-41]. In the 72-week open-label extension of the iPrEx trial that evaluated the efficacy of tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for PrEP in men who have sex with men (MSM) and transgender people, there were 4.7 infections per 100 person-years if levels indicated that no drug was taken, 2.3 infections per 100 person-years if drug concentrations suggested less than two tablets were taken per week, and 0.6 infections per 100 person-years if levels indicated that two to three tablets were taken each week [17]. No infections occurred among those who were likely taking four or more tablets each week.

Adolescents appear to have particular challenges adhering to PrEP. The Adolescent Trials Network studied daily TDF-FTC PrEP in 78 patients 15 to 17 years of age [42]. TDF-FTC was well tolerated among those who took their medication; however, adherence was suboptimal for many of the youth (protective levels of tenofovir were found in approximately 50 percent at 12 weeks when they were being seen every four weeks but only in 22 percent at 48 weeks when visits were quarterly).

The relationship between adherence and PrEP efficacy has been found in all populations (eg, MSM, transgender and cisgender women, and heterosexual men). However, patients exclusively engaging in receptive anal sex may be able to miss an occasional dose and still be protected. Data suggest that men who engage in anal sex and take about four doses of TDF-FTC per week continue to have a high level of protection [17,43]. Similarly, a pooled analysis of 11 postapproval studies of TDF-FTC PrEP use among cisgender women also found that only 1 of 1156 women who reported taking four or more doses per week acquired HIV [44].

We use patient responses to inform regimen selection and provide targeted education. We revisit barriers to PrEP adherence at every follow-up visit. Additional information on assessing adherence and providing adherence counseling are discussed below. (See 'Medication adherence' below.)

STI testing — Patients who are being considered for PrEP should be screened for common bacterial sexually transmitted infections (STIs) (table 7). STI testing should be performed even in the absence of symptoms. (See "Screening for sexually transmitted infections".)

Screening for bacterial vaginosis and trichomonas is not routinely performed as part of the work-up before initiating PrEP since these infections have not had as strong an association with HIV. However, their presence suggests that recent condomless sex has occurred, and this should lead the clinician to ask about recent sexual behaviors and potential risks of partners (table 1).

Additional considerations

Persons considering oral therapy — Patients considering oral PrEP should be evaluated for conditions that could increase their risk of developing adverse outcomes (eg, reduced kidney function and osteoporosis with TDF-FTC, weight gain and dyslipidemia with tenofovir alafenamide-emtricitabine [TAF-FTC]) (table 8). (See 'Available oral agents' below.)

●Kidney function – Serum creatinine should be measured prior to or at the time of initiating PrEP (table 8). In patients receiving TDF-FTC for PrEP, there is a low but increased risk of kidney injury. Renal effects appear to be less frequent with TAF-FTC. (See 'Available oral agents' below.)

For patients desiring oral therapy, regimen selection is dictated by the estimated glomerular filtration rate (eGFR) and the specific population (eg. cis-gender MSM versus persons who engage in vaginal sex). (See 'Patients with/at risk for kidney or bone disease' below and 'Persons who engage in vaginal sex' below.)

●Hepatitis B infection – Patients who are considering oral PrEP should be evaluated for the presence of HBV infection prior to initiating treatment. Tenofovir and emtricitabine are also used to treat chronic HBV, and such patients may experience clinically significant hepatitis flares if tenofovir is discontinued [10,37]. Although data from the iPrEx trial did not demonstrate a flare in the six hepatitis B surface antigen (HBsAg)-positive patients who discontinued TDF-FTC [45], additional data are needed to determine the exact risk.

Testing for HBV infection should include HBsAg, hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs). (See "Hepatitis B virus: Screening and diagnosis in adults".)

•No evidence of immunity – Patients without evidence of immunity (ie, anti-HBs-, anti-HBc-, HBsAg-negative) should be vaccinated against HBV since individuals who engage in high-risk sexual and drug use behaviors are at increased risk for acquiring hepatitis B. (See "Hepatitis B virus immunization in adults" and "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Transmission of HBV'.)

•Resolved HBV – Patients with resolved HBV (anti-HBs- and anti-HBc-positive) do not require vaccination, and no additional monitoring is needed if oral PrEP is initiated.

•Chronic HBV – For patients with evidence of chronic HBV infection (ie, HBsAg-positive), a tenofovir-containing PrEP regimen is well suited for those who require treatment of their HBV. Indications for treatment of chronic HBV are presented elsewhere. (See "Hepatitis B virus: Overview of management".)

However, some persons with chronic HBV do not require treatment. For such patients, discontinuing oral therapy with tenofovir could result in a flare of their HBV. For such patients, injectable therapy with cabotegravir LA may be preferred since cabotegravir is not active against HBV and can be safely discontinued if the patient no longer desires PrEP. The approach to discontinuing cabotegravir is discussed below. (See 'Discontinuing PrEP' below.)

•Isolated core antibody – Some patients may only be positive for anti-HBc. This could mean the patient has resolved (or is resolving) infection, or low-level chronic infection; it could also be a false positive. In this setting, the approach to PrEP must be determined on a case-by-case basis. Additional information on the evaluation of patients with isolated anti-HBc is found elsewhere. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Isolated anti-HBc'.)

●Hepatitis C infection – Persons who inject drugs and MSM who engage in condomless anal sex with multiple partners are at risk for hepatitis C virus (HCV) infection. Thus, such patients should be tested for HCV as part of the initial laboratory assessment. Patients who test positive should be referred for treatment. More detailed information on screening, including routine screening, is presented in a separate topic review. (See "Screening and diagnosis of chronic hepatitis C virus infection".)

It is important to note that certain agents used for the treatment of HCV (ledipasvir-sofosbuvir) may increase the level of TDF, and patients who are taking these agents should be monitored for TDF toxicity [10].

●Osteoporosis – Information should be obtained regarding a history of (or risk factors for) osteoporosis, since TDF has been associated with reductions in bone density. Bone loss appears to be greatest during the first six months and then stabilizes after that [26,46]. By contrast, TAF-FTC was not associated with loss of bone mineral density when used as PrEP in a large clinical trial [47]. A more detailed discussion of regimen selection in patients with osteoporosis is found below. (See 'Regimen selection' below.)

For patients considering oral PrEP with TDF-FTC, the need for routine bone density screening prior to initiating treatment is unclear. We typically obtain a dual-energy x-ray absorptiometry (DXA) scan only in patients who have a history of osteoporosis if testing within the prior two years is not available, as well as in those who are at high risk for osteoporosis. (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Screening' and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men", section on 'Patient selection for BMD measurement'.)

More detailed information on the risk of osteoporosis in patients receiving tenofovir is found below. (See 'Available oral agents' below.)

●Lipid testing – If TAF-FTC is being considered for PrEP, patients should have a baseline cholesterol panel performed. In clinical trials, higher rates of triglyceride elevation and weight gain were seen among men taking TAF-FTC compared with those taking TDF-FTC, although these increases were only modest [10]. In one study, there was a median of 0.05 mmol/L increase in triglycerides at 48 weeks in those who received TAF-FTC compared with no change from baseline in the TDF-FTC arm [16]. In addition, for weight, there was a 1.1 kg increase from baseline in the TAF-FTC arm versus 0.1 kg loss from baseline in the TDF-FTC arm.

Persons of child bearing potential — Persons of childbearing potential should have a pregnancy test prior to initiating PrEP. For those who are pregnant, the risk of acquiring HIV must be weighed against the risk of using antiviral medications during pregnancy and the limited data on the efficacy of PrEP during pregnancy.

Of the available oral agents, only TDF-FTC is recommended for PrEP in pregnancy [48]. Although the oral agents used for PrEP (TDF, TAF, and emtricitabine) are felt to be safe for use in pregnancy, the efficacy of TAF-FTC has not yet been established for HIV prevention in people whose risk factor is receptive vaginal exposure, particularly those who are pregnant. (See 'Persons who engage in vaginal sex' below.)

The decision to use cabotegravir must be determined on a case-by-case basis given current limited safety data. As discussed above, there was no increase in the incidence of adverse birth outcomes among those who became pregnant in the randomized trial that evaluated cabotegravir LA in cisgender women; however, the number of pregnancies was small [31]. In addition, in a follow up study, pregnancy outcomes were the same for those who continued or discontinued cabotegravir during pregnancy [49]. (See 'Determining preference for oral versus injectable therapy' above.)

A more detailed discussion of the risks of these agents during pregnancy is found elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Tenofovir' and "Safety and dosing of antiretroviral medications in pregnancy", section on 'Cabotegravir'.)

TIMING OF PREP INITIATION — 

If possible, we administer PrEP the same day as the initial visit. Studies have found that same-day PrEP can improve early retention in PrEP care [50-53]. This approach is endorsed by several guideline panels [10,54].

Laboratory testing for HIV (eg, antigen/antibody test), kidney disease, and hepatitis B virus (HBV) infection should ideally be performed prior to the patient's initial visit, with HIV testing performed in the last seven days. (See 'Pretreatment evaluation' above.)

However, if this is not possible, PrEP can be initiated pending the results of laboratory testing if there is a low suspicion for acute HIV, and there is a confirmed means of contacting the patient when results return. The harms of short-term PrEP are likely to be minimal, even if someone has undiagnosed kidney disease, HBV, or HIV.

If the test results show evidence of chronic HBV or chronic kidney disease, the PrEP regimen can be modified if needed. If the HIV antigen/antibody test returns positive, the regimen can quickly be expanded to a first-line ART regimen (table 5). (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and 'Persons considering oral therapy' above and 'Patients with/at risk for kidney or bone disease' below.)

ORAL THERAPY REGIMENS — 

Both oral and injectable regimens are available for PrEP. Factors influencing the decision to use oral versus injectable therapy are summarized in the table (table 4) and discussed in detail above. (See 'Determining preference for oral versus injectable therapy' above.)

Available oral agents — The combination of tenofovir-based antiretrovirals with emtricitabine has proven to be effective in reducing new HIV infections when used for PrEP. There are two formulations of tenofovir, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), and each is available as a single coformulated tablet with emtricitabine. Specific details on the use of these agents in different populations are discussed below. (See 'Regimen selection' below.)

●Tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) – For PrEP, once-daily TDF-FTC (tenofovir disoproxil fumarate 300 mg-emtricitabine 200 mg) is the most widely studied regimen among various populations, and if taken as prescribed, can reduce the risk of sexual HIV transmission by nearly 100 percent [17,55-57]. TDF-FTC has been studied in many different populations, as described above. (See 'Patient assessment' above.)

Clinical trials have described only mild adverse effects (eg, nausea or diarrhea in a minority of patients) compared with placebo [15], and these usually resolve during the first few weeks.

However, there is potential for mild to moderate kidney and bone toxicity with long-term use.

•Reduced kidney function – Although TDF-FTC has been associated with kidney toxicity, the risk of kidney injury is low in patients without HIV [15,25-27,58-60]. In a meta-analysis of 12 trials, oral PrEP with TDF-FTC or TDF alone was associated with an increased risk of kidney adverse events compared with placebo (relative risk, 1.43 [95% CI 1.18-1.75]; absolute risk difference, 0.56 percent [95% CI 0.09-1.04]); however, most were mild creatinine level elevations that did not require treatment discontinuation [9].

In another meta-analysis that included data from 10 randomized trials, there was an increased risk of creatinine elevations in patients who received TDF-based PrEP compared with placebo (odds ratio 1.36, 95% CI 1.09-1.71) [61]. However, of the 352 patients who experienced creatinine elevations, only 23 had increases that were greater than 1.3 times the upper limit of normal. In a separate meta-analysis that included data from 13 randomized trials, there was no difference in serious, grade 3 creatinine elevations (>1.8 to <3.5 times the upper limit of normal or an increase to 1.5 to <2.0 times the participant's baseline) among participants receiving TDF-based PrEP versus placebo or no treatment (difference 0 percent, 95% CI 0-0) [62]. However, in one report, a patient who received TDF-FTC developed Fanconi syndrome while taking concurrent nephrotoxic medications [63]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)

Certain risk factors have been associated with declines in kidney function, such as baseline estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m² and age greater than 40 [64]. Higher tenofovir concentrations have also been associated with reductions in kidney function; however, there is insufficient evidence to incorporate therapeutic drug level monitoring into routine care.

•Bone loss – In clinical trials, adults without HIV who were assigned to TDF-FTC had greater declines in z-scores at the hip, lumbar spine, and forearm compared with those taking placebo [26,46,65]. In an analysis of seven trials, there was a trend towards an increase in the rate of fractures, although the difference was not statistically different (relative rate, 1.23; 95% CI, 0.97 to 1.56) [65].

Bone loss appears to be greatest when therapy is started. In the iPrEx trial, 247 patients who received TDF-FTC and 251 who received placebo were evaluated with dual-energy x-ray absorptiometry (DXA) scans every six months [46]. After 24 weeks, modest but significant declines in bone mineral density were seen in those who received TDF-FTC (spine: net difference -0.91 percent [95% CI -1.44 to -0.38]; hip: -0.61 percent [95% CI, -0.96 to -0.27]); however, there were only small further decreases in bone mineral density to week 96. A subsequent study found that bone loss normalized in most patients approximately six months after PrEP was discontinued [66].

In adolescent men who have sex with men (MSM), the bone loss seen with TDF may pose additional risks that are not seen in adults [42,67-70]. In adolescents, bone loss seems to occur before peak bone mass is attained, and the full recovery of age-adjusted bone mineral density that is seen in adult MSM who discontinue PrEP may not occur in young MSM. In one study that included 200 MSM ages 18 to 22 years old, modest decreases in hip, spine, and whole body bone mineral density z-scores occurred after 24 weeks of TDF-FTC, with further decreases only in hip bone mineral density z-scores after 48 weeks [70]. In a pooled analyses of 91 MSM who had DXA scans performed 48 weeks after discontinuing TDF-FTC, spine and whole body bone mineral density z-scores remained below baseline, with larger declines among participants 15 to 19 years of age [69].

There are no proven strategies to attenuate bone loss in patients taking TDF-FTC. Vitamin D3 plus calcium supplementation was found to mitigate bone loss in patients with HIV taking a TDF-based antiretroviral therapy (ART) regimen [71]. Although there are no data on the use of vitamin D to attenuate PrEP-related bone loss, measures to maintain adequate vitamin D levels could theoretically be helpful [72] and are being evaluated. (See "Overview of vitamin D".)

●Tenofovir alafenamide-emtricitabine (TAF-FTC) – TAF has less potential bone and kidney toxicity compared with TDF, and, in the United States, TAF-FTC (tenofovir alafenamide 25 mg-emtricitabine 200 mg) is approved for PrEP in persons whose risk factor for HIV is unprotected anal sex [73]. However, TAF-FTC is not approved for individuals whose risk for HIV is frontal/vaginal sex or injection drug use since efficacy data are limited in these populations.

In a multinational efficacy study comparing once-daily TAF-FTC with TDF-FTC in 5387 at-risk MSM and transgender women, TAF-FTC and TDF-FTC were both effective in preventing HIV infection (HIV incidence of 0.16 per 100 person-years versus 0.34 per 100 person-years, respectively) [16]. After 15,817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period [74].

In this trial, TAF-FTC had better bone and kidney biomarker safety outcomes but was associated with mild weight gain and dyslipidemia, although the magnitude of the differences was small for all these outcomes. As an example, TAF-FTC was associated with small but statistically significant differences in eGFR at 96 weeks when compared with TDF-FTC, but adverse clinical events were rare with both, with only 13 patients discontinuing treatment due to renal adverse events (5 TAF-FTC and 8 TDF-FTC). In addition, there were no differences in significant renal adverse outcomes between the groups.

In an open-label extension of this study, 2080 MSM who continued TAF-FTC and 2128 MSM who were switched from TDF-FTC to TAF-FTC were followed for an additional 48 weeks; switching to TAF-FTC was associated with small increases in kidney function and bone mineral density but also modest increases in weight and lipid parameters [75]. Similar findings were seen at 144 weeks [74].

In cisgender women, the efficacy is less clear. In a study of 5338 cisgender women in South Africa and Uganda comparing daily oral TAF-FTC, TDF-FTC, and twice-yearly lenacapavir injections, the rate of new HIV infections in females taking TAF-FTC were similar to the estimated background HIV incidence [32]. However, high rates of adherence to TAF-FTC were associated with a lower likelihood of acquiring HIV, and rates of new infections were similar to TDF/FTC, which is known to be protective for women. More detailed information on lenacapavir is found below. (See 'Novel approaches to treatment' below.)

Regimen selection — The choice of regimen and frequency of administration depends in part upon the specific population.

Men who have sex with men

Preferred regimen — For most MSM initiating oral PrEP, we suggest once daily TDF-FTC since there is extensive experience with this agent, it is effective, and it is well tolerated (table 4). This includes transgender men who exclusively engage in anal sex. (See 'Sexual risk' above and 'Available oral agents' above.)

However, TDF-FTC should generally be avoided in those with or at risk for bone or kidney disease. The approach to regimen selection in these patients is discussed below. (See 'Patients with/at risk for kidney or bone disease' below.)

When initiating therapy in those who engage in anal sex, we encourage patients to use condoms for seven days to allow for drug concentrations that protect against HIV; this recommendation is based on pharmacokinetic data with TDF-FTC [76-78].

Some experts administer a double dose of TDF-FTC when starting PrEP, and then use a single daily dose thereafter [54]. This has the advantage of achieving protective levels sooner (generally by 48 hours) compared to single-pill daily dosing, which is likely to take four to seven days for full protection. This strategy may be particularly important for those who cannot reliably use condoms for the first seven days [54]. However, a double dose may be associated with an increase in side effects, so a single dose daily is reasonable for persons who can reliably use condoms for the first seven days.

When prescribing PrEP, we typically dispense as a 90-day supply, renewable only after HIV testing [10]. Prescribing a limited quantity of medication increases the likelihood that a patient will follow up for ongoing safety monitoring and adherence counseling. However, when a patient cannot come in for an office visit, but the provider has reason to anticipate stable medication adherence, prescribing extra medication without a recent HIV antibody test may be preferable to reduce the likelihood of a lapse in PrEP. (See 'Patient monitoring' below.)

Alternative regimens — Alternative oral options include once daily TAF-FTC and event-driven/on-demand TDF-FTC (table 4).

●TAF-FTC – Once daily TAF-FTC is a reasonable alternative for MSM who are at risk for kidney or bone disease and those who desire a smaller pill size. However, it is associated with mild but greater weight gain and slight changes in lipid parameters that are less favorable than TDF-FTC [16,75]. (See 'Available oral agents' above and 'Patients with/at risk for kidney or bone disease' below.)

There is no formal guidance regarding timing of protection with TAF-FTC, so we encourage patients to use condoms for seven days to allow for drug concentrations that protect against HIV, similar to TDF-FTC, as discussed above. It is unknown if a double dose of TAF-FTC would provide protection sooner, so pending additional data, this approach is not routinely recommended for TAF-FTC in clinical practice.

TAF-FTC should generally be avoided in transgender MSM who engage in frontal sex [10,54,79,80]. (See 'Persons who engage in vaginal sex' below.)

●Event-driven TDF-FTC – Some patients prefer event-driven (also referred to as on-demand) dosing rather than daily therapy. Event-driven therapy is reasonable for those exclusively engaging in anal sex if they can take TDF-FTC and can reliably predict when they will have condomless sex. There are robust data on the efficacy of event-driven therapy in cis-gender MSM; data in transgender persons and cis-gender persons who exclusively engage in anal sex is more limited.

We do not use event-driven PrEP in patients with chronic HBV infection since discontinuing TDF-FTC may be associated with a flare of their hepatitis. This approach is consistent with recommendations from the United States Centers for Disease Control and Prevention (CDC); however, other guidelines differ [81]. There are no data evaluating event-driven dosing with TAF-FTC.

For those who are eligible for on-demand PrEP, "2-1-1" dosing is as follows:

•A loading dose of TDF-FTC (two tablets) is taken 2 to 24 hours prior to sexual activity (closer to 24 hours is preferred). For patients who initiate on-demand/event-driven therapy more than once within a week, the second loading dose should be reduced to one tablet instead of two [82].

•One tablet is then taken 24 hours after the loading dose. If the patient continues to be sexually active, once daily TDF-FTC should be continued.

•The patient should continue taking PrEP for two more days after sexual activity has stopped.

As an example, if a patient wants to use event-driven PrEP for a single event, the person should take two pills 2 to 24 hours prior to sex (loading doses), one pill 24 hours after the loading doses, and another pill 48 hours after the loading doses.

The use of event-driven dosing was evaluated in a randomized trial of MSM who engage in condomless anal sex (IPERGAY) [82,83]. Among the 400 men who were enrolled, 16 new infections occurred, 14 in those taking placebo, and 2 in those receiving on-demand TDF-FTC, consistent with an 86 percent reduction in HIV transmission (95% CI 40-98). In a post-hoc analysis, event-driven PrEP remained effective among the 269 patients who took ≤15 pills/month (median of 9.5) [83]. In an observational study in France, largely comprised of MSM, only three HIV infections were reported among approximately 1500 study participants taking event-driven PrEP, and all had discontinued PrEP several weeks prior to infection [84-86].

Although this dosing strategy is not approved for use by the US Food and Drug Administration (FDA), which has only approved oral PrEP for daily use, the International Antiviral Society-USA and the World Health Organization (WHO) have endorsed 2-1-1 PrEP [54,81,87], and the CDC has stated that event-driven PrEP can be considered as an alternative to daily use [10].

Patients with/at risk for kidney or bone disease

●MSM with or at risk for kidney disease – The choice of agent for those with reduced kidney function depends upon the severity of kidney disease.

•For patients with an eGFR ≥60 mL/min/1.73 m² but with risk factors for kidney disease, we try to balance the different risks of TDF and TAF. As an example, in patients who also have pre-existing obesity or dyslipidemia, we favor a trial of TDF-FTC with close monitoring for decreased kidney function since TAF-FTC has been associated with mild but greater weight gain and slight changes in lipid parameters compared with TDF [16,75].

•For those with moderately reduced kidney function (eGFR between 30 and 60 mL/min/1.73 m² (calculator 1)), TAF-FTC should be used as it has been safely used in this population.

In such patients, TDF-FTC should generally be avoided since it has been associated with acute and chronic kidney disease in patients with HIV, and the safety of this agent has not been examined in patients without HIV who have an eGFR <60 mL/min/1.7³ m².

•For patients with an eGFR <30 mL/min/1.73 m² who are not on dialysis, both TDF-FTC and TAF-FTC should be avoided. For such patients, injectable medication is the best option. (See 'Injectable therapy' below.)

By contrast, for patients on dialysis, TAF-FTC can be used.

●MSM with or at risk for bone disease – TAF-FTC is preferred for those with reduced bone density. In the DISCOVER trial, a large trial comparing TAF-FTC with TDF-FTC for PrEP, TDF-FTC but not TAF-FTC was associated with bone loss [16]. (See 'Available oral agents' above.)

Some providers may also prefer to administer TAF-FTC to selected patients without bone disease, particularly adolescents, who appear to be at higher risk for loss of bone mineral density during the growth phase of bone development. However, we prefer TDF-FTC for most adolescents, since TAF-FTC has not been studied in patients <18 years of age. (See 'Available oral agents' above.)

Consideration for other populations

Transgender persons — The approach to regimen selection in transgender persons depends upon the type of sexual risk (eg, anal versus vaginal sex). As an example, preferred regimens for transgender women are similar to cisgender MSM since transgender women have been included in clinical trials evaluating once daily TDF-FTC and TAF-FTC. (See 'Preferred regimen' above.)

However, the data on event-driven PrEP in transgender persons are limited. For those who desire event-driven dosing, we discuss the risks and benefits and determine the best approach on a case-by-case basis.

●In general, we avoid event-driven dosing for those using exogenous estrogens because the drug interactions have not been fully studied and some data suggest that estrogens can lower tenofovir levels [88].

●By contrast, for those who are not taking gender-affirming hormones, we feel event-driven dosing is reasonable for those exclusively engaging in anal sex if they can take TDF-FTC since the trials in MSM can likely be extrapolated to this population. There are no data yet about the efficacy of on-demand PrEP for individuals exposed vaginally to HIV.

More detailed information on event-driven dosing is found above. (See 'Alternative regimens' above.)

Persons who inject drugs — For persons whose main risk for HIV transmission is injection drug use, we typically initiate once daily TDF-FTC. TAF-FTC and injectable agents have not been studied in this population. (See 'Injection drug use' above.)

There are no data on time to protection in persons who inject drugs. As such, we counsel patients to use additional HIV prevention strategies for at least seven days; however, some guidelines recommend 21 days [10].

For persons with kidney or bone disease, our approach depends upon the presence of other risk factors for HIV acquisition. As an example, in patients with moderately reduced kidney function, we would administer TAF-FTC to cis-gender MSM and transgender women who endorse sexual risk in addition to injection risk. However, for those who endorse vaginal sex as a risk factor for HIV acquisition in addition to injection risk, the decision must be individualized since the efficacy of TAF-FTC for PrEP has not yet been fully evaluated in injection drug users or those who engage primarily in vaginal sex.

In patients who only have injection drug use as their risk factor for HIV transmission, we think TAF-FTC is a reasonable alternative to TDF-FTC for those with an eGFR between 30 and 60 mL/min/1.73 m² (calculator 1) and those with osteoporosis. TAF achieves higher peripheral blood mononuclear cell concentrations than TDF and therefore is likely to be as effective for PrEP in the setting of injection drug use. For those with osteoporosis, we base the decision to use TAF versus TDF on the severity of bone disease, weighing the risk of potential bone loss with the uncertain efficacy of TAF-FTC.

All persons who inject drugs should receive information on other risk reduction strategies in addition to PrEP. (See "Primary care management of adults with opioid use disorder", section on 'Harm reduction interventions' and "Primary care management of adults with opioid use disorder", section on 'Managing medications for opioid use disorder in primary care'.)

Persons who engage in vaginal sex — TDF-FTC is the only oral PrEP regimen that has shown efficacy in cisgender women. (See 'Sexual risk' above and 'Available oral agents' above.)  

Because the efficacy of TAF-FTC has not been clearly established in persons who engage in vaginal sex, we use it only in settings where TDF-FTC is contraindicated and injectable therapy is not feasible. In one study, high rates of adherence to TAF-FTC were associated with a lower likelihood of acquiring HIV [32].

●TDF-FTC is preferred – For most persons whose main risk for HIV transmission is vaginal sex (also referred to as frontal sex), we initiate TDF-FTC.

Patients should also use an additional source of protection (eg, condoms or abstinence) after initiating PrEP until optimal protective levels of tenofovir are obtained. Guidelines differ as to how long these additional measures are needed due to differing interpretations of pharmacologic data. While the CDC suggests waiting 21 days to ensure adequate tissue concentrations [10], the WHO and IAS-USA guidelines suggest that protective levels are achieved after one week of daily dosing [54,89,90].

Initiating therapy with a double dose of TDF-FTC, followed by daily dosing, may help achieve protective levels sooner [54]. However, there may be an increased risk of side effects with the higher dose, and the use of an initial double dose is based on findings from event-driven therapy, which has not been studied in persons engaging in frontal/vaginal sex. (See 'Alternative regimens' above.)

There are insufficient data to recommend the routine use of TAF-FTC in persons who engage in vaginal sex [32]. In addition, there are insufficient data to recommend event-driven/on-demand dosing in this population since pharmacologic studies indicate routine, daily adherence to oral therapy in this patient group is required for adequate protection from HIV acquisition [88,91].

●Considerations for those with bone or kidney disease – If a person who engages in vaginal sex has bone or kidney disease, our approach to using oral PrEP depends on the person's risk for HIV and the degree of bone or kidney disease, as both TDF-FTC and TAF-FTC may be contraindicated. (See 'Sexual risk' above and 'Available oral agents' above.)

As examples:

•For those who have risk factors for kidney disease but still have an eGFR ≥60 mL/min/1.73 m², we give a trial of TDF-FTC with close monitoring of kidney function.

•For persons with kidney impairment (eGFR is <60 mL/min/1.73 m²), injectable therapy with long-acting cabotegravir (cabotegravir LA) is the PrEP option least likely to affect kidney function. (See 'Cabotegravir' below.)

However, if cabotegravir is not available or oral therapy is still preferred, TAF-FTC is a reasonable alternative if eGFR is between 30 and 60 mL/min/1.73 m² and adherence is likely to be high.

We avoid using TDF-FTC and TAF-FTC in those with severely reduced kidney function (eGFR is <30 mL/min/1.73 m²).

•For those with osteoporosis or osteopenia, we determine whether to use TDF-FTC by weighing the risk of HIV with the potential risk of exacerbating bone disease. Cabotegravir LA is the option least likely to affect bone health. If cabotegravir LA is not available or the patient declines injections, TAF-FTC is a reasonable alternative if adherence to oral therapy is likely to be high. (See 'Available oral agents' above.)

The use of cabotegravir LA is discussed below. (See 'Injectable therapy' below and 'Discontinuing PrEP' below.)

INJECTABLE THERAPY — 

Long-acting cabotegravir (cabotegravir LA), an injectable integrase inhibitor that is administered every eight weeks, was approved by the US Food and Drug Administration (FDA) for use as PrEP to prevent sexual acquisition of HIV in 2021. This agent is approved for use in adults and adolescents weighing at least 35 kg. Lenacapavir is another injectable agent that has shown efficacy in preventing HIV transmission in clinical trials; however, in the United States, it has not yet been approved for this indication.

Cabotegravir

Dosing and administration — Cabotegravir LA is administered as a single 600 mg (3 mL) dose injected into the gluteal muscle monthly for two months (loading regimen) and then every two months thereafter.

Oral cabotegravir (30 mg once daily) can be administered for a four-week lead-in period prior to initiating injections. This approach is reasonable for those who are concerned about the side effects of cabotegravir, including those with a history of severe atopic reactions to medications.

When administering cabotegravir LA, it is important to use a needle length that ensures cabotegravir is administered intramuscularly. As a guide, a 2-inch needle should generally be used for those with a body-mass index (BMI) of ≥30; for those with a BMI <30, a 1.5-inch needle can usually be used.

For the first two to three injections, patients may choose to take an agent such as acetaminophen or ibuprofen a couple of hours before or soon after the injection. This can be continued for one to two days if they continue to have discomfort at the injection site. Patients can also apply a warm compress or heating pad to the injection site for 15 to 20 minutes after the injection.

It is unclear when patients are sufficiently protected after initiating cabotegravir. Given the insufficient data, we counsel patients that it takes at least a week to achieve protective levels [54]. Ideally, patients should use alternative prevention strategies during this time, in addition to cabotegravir (oral or injectable). This includes abstaining from sexual behaviors that put them at increased risk for HIV transmission, using condoms, or taking daily tenofovir disoproxil fumarate-emtricitabine (TDF-FTC; using a double dose on the first day and then daily for seven days) [54]. (See 'Preferred regimen' above.)

Additional considerations

●Precautions – There are certain drug-drug interactions with cabotegravir. As an example, dose adjustment of rifabutin is recommended if it is coadministered with cabotegravir LA, and cabotegravir LA should not be used with potent inducers of UGT1A1. More detailed information on drug interactions can be found in the drug interactions program.

●Additional counseling – Patients should be given an emergency 30-day supply of oral tenofovir-based PrEP to help bridge the gap in case a patient is delayed receiving their scheduled dose. (See 'Oral therapy regimens' above and 'Missed doses' below.)

Patients should also be educated about the long half-life when discontinuing cabotegravir LA. Those who continue to engage in condomless sex after discontinuing cabotegravir LA are at risk of developing drug-resistant HIV if transmission should occur. The approach to discontinuing treatment is discussed below. (See 'Discontinuing PrEP' below.)

Missed doses — Some patients are delayed in receiving subsequent injections. We generally follow the manufacturer's recommendation regarding missed doses, as described in the drug information topic within UpToDate. The approach to missed doses depends primarily on which dose is missed (one of the two initial doses versus one of the maintenance doses).

●Missed doses during the loading period – A patient initiating cabotegravir LA must receive two injections one month apart before they can transition to every eight-week dosing. (See 'Dosing and administration' above.)

If their second injection is received more than eight weeks after their initial dose, they need to restart the loading regimen. However, some experts only repeat the loading regimen if the second dose is delayed by more than 12 weeks, based on their interpretation of pharmacokinetic data [54].

●Missed doses for those receiving every eight-week dosing – If a person knows they will be missing one of their scheduled doses by more than seven days, they can take oral PrEP (eg, TDF-FTC or oral cabotegravir 30 mg) once daily for up to two months to replace one missed injection. The first dose of oral therapy should be initiated approximately two months after the last injection dose. Injections should be restarted within three days of stopping oral PrEP.

If more than one injection is missed, the patient will need to repeat the loading regimen of cabotegravir (600 mg [3 mL] injected into the gluteal muscle monthly for two months) before resuming every other month injections. Patients should continue oral therapy for at least seven days after reinitiating injectable therapy.

If a scheduled injection is missed or delayed, and there was no oral bridge, the next dose should be administered as soon as possible. The patient should repeat the loading regimen if the injection is received more than 12 weeks after their most recent dose. Some experts only repeat the loading regimen if the patient misses an injection by more than 16 weeks (ie, two doses of cabotegravir LA) [54]; however, we prefer the more conservative approach, if possible.

Efficacy and safety — Cabotegravir LA administered every eight weeks was compared to TDF-FTC in two large, randomized trials [14,31]. The findings from these trials suggest that cabotegravir LA is superior to TDF-FTC, although this may be due in large part to superior adherence.

One trial compared these agents in 4570 men who have sex with men (MSM) and transgender women [14]. This trial was stopped early after a median follow-up of 1.4 years because there were fewer new infections in those who received cabotegravir LA (13 versus 39, respectively; hazard ratio .34 95% CI 0.18 to 0.62). However, only two of the incident infections that occurred in persons taking oral therapy had appropriate TDF-FTC levels [92]. In a subsequent analysis of the trial, with more than three years of follow-up, 44 new incident infections were identified, of which 32 were in the TDF-FTC group [35]; only two had drug levels consistent with taking at least four pills per week, which is thought to be consistent with high-level protection. In this trial, the safety of the two agents was similar, except for injection site reactions leading to discontinuation (2.4 percent versus none) [14,93].

A second trial evaluated 3224 cisgender women in sub-Saharan Africa [31]. In this trial, there were fewer infections in those who received cabotegravir LA compared with TDF-FTC (4 versus 36). Poor adherence to TDF-FTC (<2 doses per week) was observed in all but one of the incident infections that occurred in those randomized to oral therapy.

Lenacapavir — Lenacapavir, an HIV-1 capsid inhibitor, is a long-acting agent that is administered subcutaneously every six months. It is currently approved for use in combination with other antiretroviral agents for patients with multidrug-resistant HIV. Although lenacapavir is not yet approved for use as PrEP, emerging data has found that it is effective in reducing HIV transmission in several populations, including MSM, transgender and nonbinary people who have sex with men, and cisgender women [32,94].

In a randomized trial of PrEP in 3200 men and gender-diverse patients, twice yearly subcutaneous lenacapavir reduced the incidence of new HIV infection by 96 percent compared with background HIV incidence (incidence rate ratio, 0.04, 95% CI 0.01 to 0.18) [94]. Lenacapavir was also more effective than daily oral TDF-FTC in preventing new HIV infections (two new HIV infections in the lenacapavir group versus nine new infections in the TDF-FTC group, incidence rate ratio, 0.11, 95% CI 0.02 to 0.51). All nine participants in this group who were diagnosed with new HIV infection had low or no adherence to TDF-FTC treatment before diagnosis. Adverse events were similar between both groups.

Twice yearly lenacapavir has shown similar efficacy for the prevention of HIV infection in cisgender women [32]. In a double-blind trial of 5338 adolescent girls and young women in South Africa and Uganda, subcutaneous lenacapavir every 26 weeks was compared with daily oral emtricitabine-tenofovir alafenamide and daily oral emtricitabine-tenofovir disoproxil fumarate. None of the patients who received lenacapavir acquired HIV; by contrast, after one year of follow up 55 incident HIV infections were observed in those who received tenofovir alafenamide-emtricitabine (TAF-FTC) or TDF-FTC (39 and 16, respectively). Adherence to oral therapy was low, and there was no meaningful difference in HIV incidence between TAF-FTC and TDF-FTC (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). In general, all of the therapies were well tolerated; however, four participants in the lenacapavir group discontinued the trial regimen because of injection site reactions.

The use of once-yearly lenacapavir is being evaluated, and results from a phase 1 trial look promising [95].

PATIENT COUNSELING

Medication adherence — Patients should be counseled regarding the importance of taking their medication as prescribed in order to achieve adequate drug concentrations. There is a clear association between adherence to the drug regimen and the efficacy of PrEP in decreasing HIV transmission [1,15,17,25,26,28,39-41]. (See 'Assessing barriers to PrEP adherence' above.)

In addition to educating patients about the importance of adherence, adherence counseling includes reviewing their medication dose and schedule and identifying reminders and devices (eg, alarms, calendars) to help minimize structural barriers. With injectable therapy, it is important to identify barriers to reliable follow-up with clinic appointments.

Some patients may want to discontinue PrEP temporarily. It is important that clinicians educate patients about the risks of stopping therapy, such as the risk of new HIV infection and the risk of developing drug resistance [96,97]. (See 'Persons with a positive HIV test' below.)

Reducing risk of other infections — Risk reduction counseling involves providing patients with information on the benefits of condom use and/or reducing substance use in addition to using PrEP.

●Condom use – Patients should be counseled to use condoms whenever possible (in addition to using PrEP) to reduce the risk of acquiring other sexually transmitted infections (STIs) and hepatitis B and C virus [98-100]. In addition, rare cases of HIV transmission have occurred, even in the setting of appropriate PrEP medication adherence [3,4,101]. (See 'Persons with a positive HIV test' below.)

However, patients often have difficulty adhering to condom use (eg, due to substance use, challenges negotiating condom use with partners, or because of their desire for improved sexual pleasure and intimacy). In clinical trials and observational studies of men who have sex with men (MSM), approximately 30 to 50 percent of the men who received PrEP were diagnosed with a bacterial STI [15,55,56,102-105]. We do not see bacterial STIs as a reason to discontinue PrEP since the risk of HIV transmission remains low despite the large number of STIs [55,56,102,106]. As an example, in one study that followed 657 men receiving PrEP, no new HIV infections occurred over approximately seven months of follow-up, even though approximately 30 percent were diagnosed with at least one STI [55].

●Other prevention strategies – There are several strategies, in addition to condom use, that may reduce the risk of other STIs. As an example, post-exposure prophylaxis (PEP) with doxycycline has been shown to reduce the incidence of certain bacterial STIs in several randomized controlled trials. In addition, patients may benefit from vaccination against certain infections (eg, mpox and hepatitis B virus [HBV]). These are discussed in detail separately. (See "Prevention of sexually transmitted infections", section on 'Doxycycline post-exposure prophylaxis for selected individuals' and "Treatment and prevention of mpox (formerly monkeypox)", section on 'Pre-exposure prophylaxis with orthopoxvirus vaccines' and "Hepatitis B virus immunization in adults".)

●Safe injection practices – Patients who inject drugs should be educated about safe injection practices and should also be given a referral to treatment for substance use disorders. Such patients remain at risk for acquiring other viral and bacterial infections (eg, hepatitis C virus [HCV] [98,99] and Staphylococcus aureus) that can be transmitted through unsafe injection practices. Those without evidence of immunity to HBV should be immunized. (See "Hepatitis B virus immunization in adults".)

It is also important to educate patients about pharmacologic and behavioral treatments to reduce both injection and noninjection drug use. (See "Opioid use disorder: Pharmacologic management" and "Opioid use disorder: Psychosocial management".)

Symptoms of acute HIV — Patients should be educated about the signs and symptoms of acute HIV infection (eg, lymphadenopathy, fever, malaise, and/or a maculopapular eruption) (table 6). They should seek medical attention if such symptoms develop so they can be tested for HIV and initiate appropriate therapy as soon as possible if seroconversion occurs. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

MANAGEMENT ON THERAPY

Patient monitoring

General approach — Patients receiving PrEP should have regular follow-up with a medical provider. We typically see patients receiving oral PrEP one month and three months after starting treatment and then follow them every three months thereafter. Telehealth visits are appropriate for stable patients. Patients receiving injectable cabotegravir LA are followed every month for two months and every other month thereafter. (See 'Dosing and administration' above.)

Patients receiving PrEP should be monitored on a regular basis for evidence of acute HIV, sexually transmitted infections (STIs), and toxicity to the regimen (table 9). For patients taking oral PrEP, providers should confirm that patients are taking their medications as prescribed. In one study, there was a notable drop in adherence over three years, with the estimated adherence of daily PrEP dropping from approximately 96 to 74 percent [14].

Additional follow-up is necessary for patients who have been exposed to and/or have symptoms of an STI (table 7) as well as those with evidence of possible adverse reactions to treatment (eg, reduced kidney function in patients receiving tenofovir disoproxil fumarate-emtricitabine [TDF-FTC]). (See 'Persons who develop kidney abnormalities' below.)

For those taking TDF-FTC who are at high risk for osteoporosis, we obtain a repeat DXA scan after one to two years of PrEP use.

Clinicians should evaluate the need to continue PrEP (ie, ongoing risk behaviors) at least annually. The approach to discontinuing treatment is discussed below. (See 'Discontinuing PrEP' below.)

Considerations for HIV testing — Our approach to HIV testing in patients being monitored for breakthrough infection is as follows:

●Antigen/antibody testing for most patients – For most patients, we monitor for breakthrough HIV infection with a fourth-generation antigen/antibody test. Some experts use a point-of-care test at the follow-up visit, in addition to a laboratory-based antigen/antibody test [54]. (See "Screening and diagnostic testing for HIV infection in adults", section on 'Overview of available tests'.)

HIV testing should be performed every three months for patients receiving oral PrEP and every two months for those receiving injectable PrEP. Some experts also perform an antigen/antibody test one month after initiating PrEP if an HIV RNA viral load was not performed as part of baseline testing.

We agree with guidelines that recommend against routine RNA testing for monitoring [54]. Although HIV RNA testing can pick up infection sooner than antigen testing (table 10), HIV RNA testing may not be easily accessible to all populations, and the benefit of picking up the few early infections may not outweigh the cost of routine viral load testing. In the DISCOVER trial, retrospective HIV RNA testing was performed on 23 samples from persons who acquired HIV; there were only three incident cases where HIV-1 RNA was detected before serological HIV-1 test positivity, and none of those patients developed drug resistance [74].

In addition, in patients receiving cabotegravir, false-positive HIV RNA tests have been reported in those with a negative antibody/antigen test. In one study, the positive predictive value for detecting infection by HIV RNA screening in participants receiving versus those not receiving cabotegravir LA in the past six months was 9 versus 60 percent, respectively. In this study, a negative repeat HIV RNA test reliably excluded HIV acquisition [107].

●When HIV RNA testing should be performed – We obtain HIV RNA testing in patients if they meet any of the following criteria:

•Have signs or symptoms suggestive of acute HIV infection (table 6)

•The antigen/antibody tests are indeterminate

•There has been a gap in coverage or challenges with medication adherence

Although some guidelines recommend routine HIV RNA testing for patients receiving injectable PrEP [10], we prefer antigen/antibody testing for the reasons described above.

●If testing is consistent with new infection – If testing is consistent with new HIV infection, clinicians should order and document results of resistance testing and establish immediate linkage to HIV care. PrEP regimens are not sufficient for treatment of HIV. The management of patients with a positive HIV test is discussed below. (See 'Persons with a positive HIV test' below.)

Persons who develop kidney abnormalities — The approach to patients who develop evidence of kidney abnormalities on oral PrEP depends upon the specific laboratory findings (eg, elevated creatinine, new proteinuria or glycosuria).

For patients using TDF-FTC, we discontinue TDF-FTC if:

●The estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m² (calculator 1). Most creatinine elevations resolve with treatment discontinuation [15,108,109].

For most patients with an eGFR >30 mL/min/1.73 m², it is reasonable to replace TDF-FTC with tenofovir alafenamide-emtricitabine (TAF-FTC), which has been associated with fewer renal abnormalities when used as PrEP and has been approved for this indication [16]. Alternatively, cabotegravir LA can be used. (See 'Injectable therapy' above.)

●There is evidence of moderate or severe proximal tubular dysfunction or Fanconi syndrome (eg, hypophosphatemia due to hyperphosphaturia, renal glycosuria, hypouricemia, and/or aminoaciduria). (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)

In such patients, TAF-FTC should not be used. In many countries, cabotegravir LA is the only option for PrEP in this setting. However, for persons who engage in vaginal sex, a vaginal ring containing dapivirine is available in several African countries, but its efficacy is less than oral or injectable PrEP. (See 'Injectable therapy' above and 'Novel approaches to treatment' below.)

For patients whose eGFR declines significantly on TDF-FTC (eg, a 20 percent decrease) but remains above 60 mL/min/1.73 m² and for those who develop new mild proteinuria without additional evidence of proximal tube dysfunction, we also discuss switching to TAF-FTC or cabotegravir LA. These patients should also be evaluated for other causes of kidney disease, in consultation with a specialist if possible. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Urinalysis in the diagnosis of kidney disease".)

Persons who become pregnant — For persons who become pregnant, the risk of acquiring HIV must be weighed against the risk of using antiviral medications during pregnancy and the limited, albeit increasing, data on the efficacy of PrEP during pregnancy [48]. More detailed information on the use of antiretroviral agents in pregnancy is found elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy".)

Persons exposed to multidrug-resistant HIV — If a patient has a known exposure to multidrug-resistant HIV, tenofovir-emtricitabine, and potentially cabotegravir LA, may not be effective. In this setting, a post-exposure prophylaxis (PEP) regimen should be initiated that contains antiretrovirals active against the resistant virus. Such patients should be managed in consultation with an HIV specialist. (See "Management of nonoccupational exposures to HIV and hepatitis B and C in adults".)

Persons with a positive HIV test — Patients should be routinely monitored for new HIV infection while receiving PrEP (table 9). (See 'Considerations for HIV testing' above.)

●Patients on oral PrEP – For patients receiving oral PrEP, an HIV viral load test and genotype test should be obtained if an antigen/antibody is positive, even if the reflex differentiation assay is negative or indeterminate.

Pending these results, our approach to treatment depends upon the likelihood that the patient has acquired HIV.

If new infection seems unlikely (eg, no recent exposures, optimal adherence), it is reasonable to continue the PrEP regimen while awaiting the results of the viral load testing.

By contrast, if new infection seems likely (patient with poor adherence or evidence of acute HIV), we continue TDF-FTC or TAF-FTC and add a third agent with a high barrier to resistance such as dolutegravir, bictegravir, or boosted darunavir while awaiting viral load testing [110]. We do not use a non-nucleoside reverse transcriptase inhibitor as the third agent since transmitted drug resistance is more common with this class. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Patients with transmitted drug resistance'.)

The subsequent approach to treatment then depends upon the results of the viral load testing:

•If testing is consistent with acute HIV infection (positive antigen/antibody test and high viral load), we continue the HIV treatment regimen or add an integrase inhibitor with a high barrier to resistance, if not started already. Most patients will suppress their HIV viral load on the expanded regimen, even if there is resistance to tenofovir or emtricitabine (specifically, the M184V mutation).

However, if the patient is found to have multidrug resistance (eg, K65R) on genotype testing, the regimen may need to be modified (eg, an integrase inhibitor-protease inhibitor combination such as dolutegravir plus boosted darunavir). Such patients should be managed with a provider experienced in managing drug-resistant virus. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

•On rare occasions, the testing results may be discordant (positive antigen/antibody test with a negative or very low HIV viral load [eg, <100 copies/mL]). In this setting, the treatment approach is less clear, and such patients should be managed in consultation with an HIV specialist.

Obtaining a thorough history of recent risk behaviors and medication adherence patterns will help to inform the approach to clinical management. One option is to continue HIV treatment for four weeks (similar to PEP) and then discontinue treatment with all antiretroviral agents and repeat HIV testing in four weeks (or sooner if the patient reports acute retroviral symptoms). However, if the index of suspicion for acute infection is high, an alternative approach would be to continue treatment but to do more sensitive testing for occult HIV (eg, HIV proviral DNA, or ultrasensitive HIV RNA nucleic acid amplification test [NAAT] screening).

Among patients who acquire HIV while receiving oral PrEP, most are unlikely to have drug-resistant virus [15,25-27]. In a meta-analysis that evaluated drug resistance in six clinical trials, drug resistance was identified in six of the 533 patients who acquired HIV after enrollment [8].

However, in some patients, drug resistance occurs because they were infected with a drug-resistant strain. In two case reports, a patient became infected with HIV that contained drug resistance mutations for several classes of antiretroviral agents, including tenofovir and emtricitabine [2,3]. Transmission occurred despite tenofovir levels that were consistent with recent administration of the drug and long-term adherence. (See 'Persons exposed to multidrug-resistant HIV' above.)

In other patients, exposure to tenofovir was believed to cause drug resistance. This was felt to be the cause of drug resistance in 4 of the 33 women in the Fem-PrEP trial and in 2 of the 51 patients in the Partners PrEP study [27,111]. In such patients, the M184V and the less common M184I mutations are most likely to emerge since the genetic barrier to resistance for emtricitabine is low. By contrast, the genetic barrier to resistance for tenofovir is high, and, therefore, resistance to tenofovir (eg, K65R mutation) is less likely to occur. In an observational study of 204 seroconversions on PrEP in sub-Saharan Africa, 21 percent of patients had M184V/I mutations and 3 percent had K65R mutations [112]. A more detailed discussion of HIV drug resistance mutations is found elsewhere. (See "Interpretation of HIV-1 drug resistance testing".)

●Patients receiving injectable therapy – Patients with a positive HIV test result while receiving cabotegravir LA should be managed in consultation with an HIV specialist.

If an HIV antigen/antibody test is positive in a person receiving cabotegravir LA, we do not administer a new injection until the patient's HIV status has been fully assessed. Instead, patients should be started on a regimen of boosted darunavir with either TAF-FTC or TDF-FTC pending the evaluation. (See "Acute and early HIV infection: Treatment".)

•An HIV RNA should be obtained, if not done so as part of routine monitoring. (See 'Considerations for HIV testing' above.)

•In addition, a genotype should be obtained for routine and integrase testing in all patients suspected of acquiring HIV on cabotegravir LA. The regimen may then be able to be modified depending on the results.

In the trial evaluating the efficacy of cabotegravir LA, 12 patients developed new infection, and resistance testing was able to be performed in nine patients [14,92]. Five incident infections occurred in individuals with no recent exposure to cabotegravir LA (ie, no injections or last injection ≥6 months before their first HIV-positive visit). In these patients, there were low or unquantifiable concentrations of cabotegravir, and no resistance was identified. Three infections occurred during the oral lead-in period, and resistance developed in two of these patients. Resistance also developed in all six patients who received appropriately timed cabotegravir LA doses and were thought to have plasma cabotegravir concentrations that would provide protection against HIV; in these patients, resistance may have resulted from delays in detecting HIV infection [35,93].

On occasion, when both an HIV antigen/antibody test and HIV RNA test are performed at the same time, only the HIV RNA returns positive. When this occurs, the HIV RNA should be repeated, and genotype testing should be performed. If the HIV RNA was low (eg, <200 copies/mL) and can be repeated right away, antiretroviral therapy (ART) can be withheld pending the results of repeat testing. Unpublished data suggest that false-positive HIV RNA tests can be seen [107]. If repeat HIV RNA testing is negative, the test is likely a false positive, and cabotegravir LA can be resumed for PrEP.

DISCONTINUING PREP — 

Patients should continue PrEP as long as they remain at risk for acquiring HIV. (See 'Patient assessment' above.)

For persons who initiate PrEP because their partner has HIV, PrEP should be continued until their partner has achieved a stably suppressed viral load (eg, <200 copies/mL), which typically occurs by six months after initiating antiretroviral therapy (ART). Although the duration of ART required to suppress HIV in semen and cervical secretions is unclear, in a clinical trial of patients with HIV initiated on ART, there were no reports of HIV transmission when the person with HIV was on ART and achieved suppression of their plasma viral load. However, PrEP should be continued in individuals who are having condomless sex with other partners or if there is concern that the partner with HIV is not taking their ART regimen as prescribed (and therefore is at risk for virologic failure).

When a person decides to discontinue PrEP, treatment should be continued for a period of time after their last sexual encounter. In addition, HIV testing should be performed at the time they discontinue PrEP.

●Persons receiving oral PrEP – It is unclear how long patients should continue oral PrEP after their last sexual exposure.

For cisgender men who have sex with men (MSM), we typically continue PrEP for two days after their last sexual exposure based on the efficacy of the 2-1-1 event-driven PrEP regimen. (See 'Alternative regimens' above.)

By contrast, for other populations, guidelines recommend that PrEP be continued for seven days after the last high-risk exposure [54,76].

For patients with chronic hepatitis B virus (HBV) infection, the decision to switch to an alternative agent for treatment of HBV after PrEP is discontinued or to monitor for HBV flare should be discussed with a provider experienced in the management of HBV. This is particularly important for patients with cirrhosis. (See "Hepatitis B virus: Overview of management".)

●Persons receiving cabotegravir LA – Patients who discontinue injectable PrEP but continue to engage in high-risk sexual behaviors or sharing of injection equipment should be encouraged to transition to oral PrEP with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) or tenofovir alafenamide-emtricitabine (TAF-FTC) to reduce the risk of acquiring HIV.

It is particularly important for persons to use an alternative method to prevent HIV during the six months after discontinuing cabotegravir LA. This covers the period when levels of cabotegravir are detectable but not protective, and patients are at highest risk of developing drug-resistant HIV should transmission occur [35]. Those who cannot take tenofovir but continue to have sexual risk should use condoms consistently.

NOVEL APPROACHES TO TREATMENT

●Dapivirine ring – A vaginal ring containing dapivirine, a non-nucleoside reverse transcriptase inhibitor, has been approved by the World Health Organization (WHO) as an HIV prevention modality [113] and is available in some European and African countries. The dapivirine ring is not approved by the US Food and Drug Administration (FDA).

In a randomized trial of 2629 cisgender African women who received a monthly vaginal ring containing dapivirine or placebo, the incidence of HIV infection was reduced by 27 percent (71 versus 97 infections; 95% CI 1-46) in those assigned to dapivirine [114]. When data from sites with reduced retention and adherence were excluded, the incidence of HIV infection was reduced by 37 percent (95% CI 12-56). Findings from a separate study reported similar results [115]. However, data from subsequent analyses suggest that women who are highly adherent to the product have much greater levels of protection (eg, >70 percent) [116,117].

The dapivirine ring has also been evaluated in two open-label studies to assess real-world effectiveness, and data support a modest but important degree of efficacy [118,119]. In one open-labeled trial of 1456 women who had access to the dapivirine vaginal ring, acceptance rates were high, and HIV incidence was 2.7 per 100 person-years compared with an expected incidence of 4.4 per 100 person-years.

●Investigational approaches

•Topical agents – Topical formulations (eg, gels) are not commercially available for PrEP. Although topical administration remains an attractive intervention because early studies suggested that it is safe and can achieve high drug concentrations in the genital mucosa [78], the results of randomized trials evaluating the efficacy of tenofovir vaginal gel have been conflicting [28,40,41,120]. However, studies of rectal microbicides and douches are underway, given the frequent use of topical lubricants by individuals who engage in receptive anal intercourse.

•Neutralizing antibodies – Two randomized trials of the broadly neutralizing antibody VRC01 given as infusions every eight weeks to women or cisgender men and transgender women did not show efficacy in preventing HIV infections [121]. However, among participants who became HIV infected, having an isolate that was readily neutralized in vitro was associated with significant protection. This finding has led to optimism that new antibodies that are more potent and/or broadly neutralizing and/or using combinations of antibodies might result in effective protection against HIV. Clinical trials are being conducted globally to examine combinations of neutralizing antibodies for safety and tolerability, and some combinations will ultimately be evaluated in efficacy trials [14,122,123].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV prevention".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Taking medicines to prevent HIV before exposure (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Candidates for PrEP – Pre-exposure prophylaxis (PrEP) with antiretroviral therapy (ART) is associated with marked reductions in HIV transmission in several populations. (See 'Determining PrEP eligibility' above.)

•We recommend PrEP for patients at the highest risk of acquiring HIV through sexual risk (table 3) (Grade 1A). (See 'Sexual risk' above.)

We also suggest PrEP for other individuals who are at increased risk for acquiring HIV through sexual risk behaviors, even if they are not in the highest risk category (table 3) (Grade 2B).

PrEP is generally not needed for persons who consistently engage in low-risk behaviors (eg, consistent condom use) and those who are in mutually monogamous relationships. (See 'Unclear risk' above.)

•In addition to persons with sexual risk, we suggest PrEP for persons who inject drugs and share needles/equipment (Grade 2B). PrEP should be initiated even in persons who are receiving treatment for their substance use. (See 'Injection drug use' above.)

●Evaluation prior to initiating treatment – HIV testing should be performed in all persons prior to initiating PrEP to confirm that the person does not have pre-existing infection. The approach to testing is described above. (See 'HIV testing' above.)

For those receiving an oral regimen, additional evaluation includes an assessment of kidney function, hepatitis B virus (HBV) status, history of bone disease, and lipids (table 8). (See 'Persons considering oral therapy' above.)

●Choice of agent – For persons initiating PrEP, we discuss the available agents (table 4). The best choice of regimen for any given patient is the one to which they can best adhere. (See 'Determining preference for oral versus injectable therapy' above.)

•Oral options include tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) and tenofovir alafenamide-emtricitabine (TAF-FTC). (See 'Oral therapy regimens' above.)

Once-daily TDF-FTC is the most widely studied regimen and has been evaluated in all patient populations. If taken as prescribed, TDF-FTC can reduce the risk of sexual HIV transmission by nearly 100 percent. However, TDF should be avoided in persons with reduced kidney function or osteoporosis. (See 'Available oral agents' above.)

Event-driven dosing of TDF-FTC or daily TAF-FTC are alternatives for persons who engage exclusively in anal sex. (See 'Alternative regimens' above.)

•Cabotegravir LA is a good choice for individuals who prefer injectable therapy and/or have contraindications to tenofovir-containing regimens. Cabotegravir is administered intragluteally every month for two months and then every two months thereafter. (See 'Injectable therapy' above.)

●Time to protection – Optimal protection after initiating PrEP appears to be about seven days for those engaging in anal sex. There is less data for protection during vaginal sex. (See 'Regimen selection' above.)

When initiating PrEP, persons should use an additional source of protection (eg, abstinence or condoms) for seven days (and up to 21 days for those engaging in vaginal sex).

For persons initiating TDF-FTC, protective levels may be achieved more quickly by taking a double dose on the first day, followed by daily dosing. Persons initiating cabotegravir may also achieve protection more quickly if they take TDF-FTC using this schedule for the first seven days, in addition to cabotegravir. There are no data on using a double dose of TAF-FTC.

●Patient Counseling – Clinicians should counsel patients about:

•The importance of taking PrEP as prescribed. There is a clear association between adherence to the drug regimen and decreasing HIV transmission. (See 'Medication adherence' above.)

•The signs and symptoms of acute HIV infection (eg, lymphadenopathy, fever, maculopapular eruption) (table 6) and the importance of seeking medical attention if symptoms develop. (See 'Symptoms of acute HIV' above.)

•Ways to reduce the risk of acquiring other sexually transmitted infections (STIs), such as consistent condom use, post-exposure prophylaxis with doxycycline, and immunizations (eg, vaccination against mpox and HBV). (See 'Reducing risk of other infections' above.)

●Monitoring on PrEP – Persons receiving PrEP should have regular follow-up and should be monitored for evidence of acute HIV, STIs, and toxicity to the regimen (table 9). (See 'Management on therapy' above.)

●Discontinuing PrEP – PrEP should ideally be continued as long as the risk of infection exists. However, some patients may want to discontinue PrEP even though they remain at risk for HIV. In this setting, PrEP should be continued for a period of time after their last sexual or drug-using encounter. The duration depends on the specific agent. (See 'Discontinuing PrEP' above.)

ACKNOWLEDGMENT — 

UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.