Preexposure Prophylaxis for HIV Prevention

Etiology

HIV is a retrovirus that replicates primarily in CD4+ T cells and macrophages, resulting in an illness characterized by an acute phase, followed by a prolonged, generally asymptomatic infection, and then leads to acquired immunodeficiency syndrome with progressive destruction of the immune system as CD4+ cells are depleted.[16] The HIV viral load is exceptionally high during the acute phase of illness but rapidly decreases at the start of the latent period and then increases as the disease progresses. Due to the effectiveness of antiretroviral therapy, HIV infection is now widely seen as a manageable chronic disease. However, despite significant advancements in controlling the virus, the disease remains a significant global health concern fed by and contributing to inequities.[17] Prevention measures, including PrEP, are critical to decreasing the burden on patients, communities, and healthcare systems. 

The WHO and public health authorities in many countries recommend PrEP for anyone at high risk of acquiring HIV.[UNAIDS. Global Report. 2023] PrEP's key role in the prevention of HIV is based on several factors, including the long-term consequences of HIV infection despite the availability of excellent treatments, the limitations of the other approaches in preventing HIV, and the effectiveness and efficacy of PrEP. 

The WHO estimates that more than 630,000 people died from HIV-related causes in 2022.[WHO. HIV Data and Statistics. 2023] Thirty-nine million people are living with HIV, two-thirds of whom are in Africa. The CDC estimates that 1.2 million people in the United States had HIV at the end of 2021.[CDC. Basic Statistics. 2023] Long-term survival is possible with appropriate treatment but can come at a very high cost to the patient and healthcare system, particularly in resource-limited settings.[18] Those who survive, dependent on CD4+ count, may be at risk for new opportunistic or reactivated infections associated with high morbidity.[19] The use of highly active antiretroviral therapy can be associated with numerous adverse effects, drug interactions, and viral resistance to therapy. Many patients treated with protease inhibitors developed lipodystrophy and an increased risk for premature atherosclerosis.[20][21] Older, non-nucleoside reverse transcriptase inhibitors (NNRTI) such as efavirenz are associated with neuropsychiatric and neurological manifestations.[22] Newer generation antiretroviral classes such as integrase inhibitors or tenofovir alafenamide have far fewer adverse events reported than previous agents and are generally well tolerated—but may be associated with metabolic effects such as weight gain.[23]

Diversity of HIV prevention options is necessary to ensure suitable choices are available to all those at high risk of HIV transmission. Treatment as prevention is very effective worldwide in both resource-rich and resource-limited settings, with 0% of sexual transmission of HIV to sexual partners if antiretroviral therapy is taken consistently and the viral load is undetectable.[24][25] However, not everyone is aware they have HIV, can take HIV medications consistently, or even if they do, can achieve complete viral suppression.

Other measures, such as behavioral approaches, lower the risk of HIV. However, people have limits in their capacity to comply; no measures eliminate the risk.[25][26] Condoms are modestly effective in preventing HIV, other sexually transmitted infections, and pregnancy. A meta-analysis showed condoms reduce HIV transmission by more than 70% when used consistently by HIV-serodiscordant heterosexual couples.[27] However, many lack the ability to ensure consistent use, particularly women and girls.[WHO. Consolidated HIV Guidelines. 2021] A lack of knowledge of individual risk levels also decreases PrEP uptake, particularly among women and youths. Female condoms have the advantage of transferring decision-making to the female, yet the method lacks widespread acceptance and understanding.[28][29][43]

The advent of PrEP puts control into the hands of individuals who are unable or unwilling to prevent exposure to HIV through other methods and adds an extra layer of protection if other methods are already used; this is particularly important when vaccine development has experienced setbacks, with several candidate vaccines failing in phase 3 trials. There is still hope with new research into messenger ribonucleic acid vaccines, but a successful vaccine is at least several years away.[UNAIDS. Global Report. 2023]  

The use of antiretrovirals as PrEP is a less expensive, more straightforward, and more effective way to prevent HIV in higher-risk populations compared to treatment with antiretroviral therapy. Results from multiple large trials demonstrated the efficacy of oral PrEP in decreasing HIV transmission risk in people at high risk of acquiring HIV across sex, age, risk category, and study duration.[30][31][32][33] The risk of HIV is up to 92% lower for people who take oral PrEP consistently compared to those who take a placebo. The effectiveness of PrEP is significantly reduced if used inconsistently.[CDC. PrEP HIV Prevention in the US. 2021] The first long-acting injectable PrEP, cabotegravir, was approved in the United States in 2021. Men, women, and transgender women in the cabotegravir groups of 2 large studies had a 69% to 90% lower chance of contracting HIV through sexual transmission than those taking tenofovir disoproxil fumarate/emtricitabine.[34][35][36][CDC. PrEP HIV Prevention in the US. 2021] 

When targeted at individuals with risk factors for HIV acquisition at the partnership level, the use of PrEP as prescribed has a powerful influence on reducing incident HIV transmission at the population level. A 2022 mathematical modeling study estimates that 33% of HIV infections can be prevented in people aged 15 to 34, with 6% to 17% PrEP coverage if individual-level partnership dynamics are used to determine eligibility for PrEP.[37] If eligibility is determined based solely on risk groups, 46% PrEP coverage would be required to achieve the same reduction in HIV infections.

Most study results demonstrate that widespread changes in sexual behavior to more risky practices when taking PrEP, such as lack of condom use, do not occur.[38][39] However, perceived changes have been observed in some settings, including among adolescents and young people.[40][WHO. Consolidated HIV Guidelines. 2021] Randomized controlled trials likewise show no association of the use of PrEP with sexually transmitted infections, including syphilis, gonorrhea, and chlamydia.[30] Only an open-label trial in men who have sex with men showed an increased risk of chlamydia and syphilis but not gonorrhea. Three trials have demonstrated a lack of relationship between PrEP and herpes simplex virus infection.[30]  

Preexposure prophylaxis is significantly less costly than the treatment of HIV infection, both in terms of duration of use and per dose. The PrEP regimen is prescribed to high-risk individuals and is taken daily until the risk factors diminish, whereas antiretroviral therapy is taken for life by those who acquire HIV. Further, antiretroviral therapy consists of multiple, generally expensive drug combinations versus simpler and less costly options available for PrEP. The WHO defined being at "substantial risk" as anyone with greater than a 3 per 100 person-years risk of acquiring HIV in the absence of PrEP, the level above which PrEP was found to be cost-saving.[41] Below this level, PrEP may still be cost-effective. 

See the "Prognosis" section below for further information on the effectiveness of PrEP with varying adherence levels. See StatPearls' companion topic, "HIV and AIDS," for further information on HIV and the pathophysiology of HIV infection.

Epidemiology

HIV Incidence and Modes of Transmission

Globally, approximately 1.3 million people acquired HIV in 2022.[WHO. HIV Data and Statistics. 2023] The most significant numbers of infections occurred in Eastern and Southern Africa (500,000 infections), Asia and the Pacific (300,000), Eastern Europe and Central Asia (160,000), and Western and Central Africa (160,000).[UNAIDS. Global HIV Fact Sheet 2022. 2023]

Sexual transmissions account for the bulk of new infections in the United States and worldwide.[42] Receptive anal intercourse is the highest-risk sexual practice for HIV transmission, with approximately 138 infections per 10,000 exposures with an infected source, while insertive anal intercourse has an 11 in 10,000 exposure risk.[43][CDC. HIV Risk Behaviours. 2019] The risk of receptive and insertive vaginal intercourse is 8 and 4 per 10,000 exposures, respectively. Injection drug use currently represents the most significant risk of HIV transmission via the blood-borne route, with an estimated 63 infections for every 10,000 exposures from an infected source.  

The number of people acquiring HIV has decreased by 38% from 2010 to 2022, and the rates in children have decreased by 58%. The HIV acquisition rate in Africa has shown a remarkable 3-fold decline from 2010 to 2022, from 1.75 to 0.57 per 1000 population, with the most significant improvements in Eastern and Southern Africa.[WHO. HIV Data and Statistics. 2023] Heterosexual contact is the most common route of infection worldwide, corresponding to the large number of infections that occur via this route in Africa, where half of all new global infections occur.

In the United States, more than 36,000 people acquired HIV in 2021—the most recent year for which data are currently available. Newly diagnosed infections occur predominantly in adolescent and adult men, with men having sex with men accounting for 67% of all new HIV diagnoses, heterosexual contact accounting for 22%, and intravenous drug use for 7%.[CDC. Basic Statistics. 2023]

There remains much to be accomplished globally and in the United States to prevent HIV. The rates of new infections in Africa remain far higher than those experienced in the rest of the world, with 77% of all incident cases in sub-Saharan Africa occurring in adolescent girls and young women aged 15 to 24 years in 2022.[UNAIDS. Global HIV Fact Sheet 2022. 2023] The number and rates of new cases have increased in some regions; Eastern Europe and Central Asia, which has a sizeable HIV-positive population, experienced a 49% increase in new infections between 2010 and 2022.[UNAIDS. Global Report. 2023] However, the increase has been most remarkable in the Middle East and North Africa, with the lowest prevalence globally but the most significant increase in infections at 61% over the same period.

Key Populations

A broad range of people are at risk for acquiring HIV and should be informed of PrEP; UNAIDS and the WHO have identified priority at-risk populations targeted to receive PrEP: gay, bisexual, and transgender individuals; men who have sex with men (MSM); people who inject drugs; people who partake in occupational sex; and people incarcerated or in other closed settings.[UNAIDS. Global Report. 2023] Youth from these groups are particularly at risk.  

Globally, men who have sex with men face a prevalence of HIV that is 11 times higher than other members of society; this is disproportionately higher in low- and middle-income countries.[44][45][46] As the group with the highest rate of HIV in the United States and most countries in the world outside of Africa, MSM must be a global priority group for HIV prevention. MSM are at higher risk of acquiring HIV due to a higher prevalence in this population, high-risk sexual practices, and a higher risk of sexually transmitted infections, which increase the risk of HIV transmission.[45]

Eighty-five percent of gay and bisexual men without HIV in the United States are aware of PrEP, and only 25% use it.[CDC. HIV and Gay and Bisexual Men. 2021] However, inequalities exist across subpopulations. In the United States, Black/African American gay and bisexual men are the most affected by HIV in the United States, comprising 26% of all new HIV diagnoses and 37% of new diagnoses in gay and bisexual men in 2019.[CDC. HIV and Gay and Bisexual Men. 2021] Yet people in this group are often less aware of their HIV status and have lower awareness and use of PrEP as compared to other gay and bisexual men.[47][CDC. HIV and Gay and Bisexual Men. 2021]

Across the world, people who inject drugs have a prevalence of HIV that is 7 times higher than the rest of the population. Results from one study estimated the prevalence of HIV among people who inject drugs ranges from about 5% in Western Europe and North America to 14% to 17% in Asia and over 30% in Eastern Europe and Latin America.[UNAIDS. Global Report. 2023] An estimated 3.7 million people in the United States injected drugs in 2018—a number that increased sizeably within the 10 previous years.[48] In 2019, 1.6% of all high school students reported having injected drugs at least once.[CDC. Syringe Services Programs. 2023] Approximately 32% of all people who inject drugs in the United States share needles; almost half of those aged 18 to 24 reported sharing needles.[CDC. Syringe Services Programs. 2023] 

Those who partake in occupational sex practices have a prevalence of HIV that is 4 times higher than other members of society, and globally, they have up to 30 times greater risk for contracting HIV than other populations.[44][49][50][51] HIV prevalence is exceptionally high in some countries; for example, there is an estimated prevalence of 62% in South Africa, 50% in Zimbabwe, and 16% in Nigeria.[UNAIDS. Global Report. 2023] Even among those who partake in occupational sex practices, certain groups are at higher risk. European data show the prevalence of those involved in occupational sex who also inject drugs and those who are transgender to be higher than non-injecting and cisgender women in sex occupations. Younger individuals in the sex occupation population have a much lower prevalence of HIV and are an essential group for prevention efforts.[UNAIDS. Global Report. 2023] 

Worldwide, transgender people have a prevalence of HIV that is 14 times higher than the general population.[UNAIDS. Global Report. 2023] Where prevalence is known, the percentage of transgender people living with HIV varies significantly across regions. For example, in Western and Central Europe and North America, about 7.6% of transgender people live with HIV, as do about 14.7% in Latin America and 21.9% in Western and Central Africa. In the Caribbean region, only 2 countries reported HIV prevalence rates in key populations, showing a median HIV prevalence of 39.4% among transgender people—the highest of any at-risk group.[UNAIDS. Global Report. 2023] A CDC survey in 7 cities in the United States found that 43% of transgender women had HIV, with even higher rates among Black and Native American/Alaska Native transgender women.[52] People who have experienced gender-based violence have an increased risk of acquiring HIV; a median of 29% of transgender people have experienced sexual or physical violence in the past 12 months.[UNAIDS. Global Report. 2023] Transgender people living in prisons are 13 times more likely to be sexually assaulted than cisgender people in prisons. 

Young people (aged 15 to 24) from these risk groups are highly vulnerable to HIV acquisition; as an example, this age group comprises a quarter of all people newly infected with HIV in Asia and the Pacific in 2022.[UNAIDS. Global Report. 2023] Fortunately, the steepest drops in new HIV infections worldwide have been seen in young people aged 15 and 24 due to targeted programs. Rates of decline in youth are unequal in different regions. The rate in women and girls is declining more slowly than men and boys of the same age in sub-Saharan Africa, with the number of new infections in adolescent girls and young women per year decreasing by 53% from 2010 to 2022 and by 66% in adolescent boys and young men.[UNAIDS. Global Report. 2023] New infections in adolescent girls and young women account for 66% of all incident infections among people aged 15 and older in sub-Saharan Africa and 77% among those aged 14 to 24. Adolescent boys and young men are at risk in other areas. HIV prevalence in young MSM increased in Indonesia from 6% to 13% (2012 to 2019), 6% to 15% in Malaysia (2101 to 2022), and 3% to 11% in Vietnam from 2012 to 2022.[UNAIDS. Global Report. 2023]

Demand for and Use of Preexposure Prophylaxis

Studies show that many participants would like to use PrEP if it were readily available.[53][54][63] However, PrEP remains underutilized, with many barriers to implementation that require the efforts of the entire healthcare team and public health partners to mitigate. In 2022, more than 2.5 million people worldwide received PrEP at least once, far short of the 10 million person target, but a huge advance from 2019, when only 233,000 people were estimated to have received PrEP.[UNAIDS. Global Report. 2023] The greatest increases in the use of PrEP have occurred in Western and Southern Africa, where rates of HIV acquisition are the highest.[55] However, this progress is limited to a small number of countries. PrEP implementation is far behind the estimated need worldwide. Significant gaps exist in the provision of PrEP to key at-risk populations in low- and middle-income countries, particularly Asia and the Pacific, where a quarter of all new infections occurred in 2022.[56]

Overall, progress in HIV treatment and prevention in priority groups has stalled between 2010 and 2022—and has regressed in some areas. While those in sex occupations and their clients have experienced decreases in infections over this period, in some regions, MSM, transgender individuals, and people who inject drugs have not benefited equally from HIV prevention efforts. Globally, PrEP use among people from key populations remains very low, often under 5%.[UNAIDS. Global Report. 2023] This can be due to structural barriers from lack of awareness, availability of medications, or affordability to individual beliefs that they are not at risk or not a candidate for PrEP. 

Racial, ethnic, and other disparities play a role in low PrEP uptake. For example, in the United States in 2019, approximately 40% of persons eligible for PrEP are Black. Yet, the number of White people prescribed PrEP was about 5 times higher than the number of Black people.[52] The CDC estimated that 60.5% of eligible White people, 13.8% of eligible Hispanic/Latino people, and 7.9% of eligible Black people received PrEP. Women use PrEP less than men for the same indications, as do younger people aged 16 to 14 as compared to those older than 25.[52] See StatPearls' companion topic, "HIV Prevention," for further information on modes of transmission and populations at risk for HIV.

History and Physical

Conducting a careful and nonjudgmental sexual and drug use history and assessing for potential risks should be a routine part of clinical care. The history should focus on the risk of acquiring HIV and other sexual or blood-borne infections; this includes the frequency and type of sexual and drug use practices, use of preventive measures, sharing drug use equipment, number of sexual partners, HIV status of partner(s) if known, and whether their partner or partners are from a group with a higher prevalence of HIV. Symptoms of potential sexually transmitted infections should also be sought, as well as a history of hepatitis and hepatitis vaccination status. The clinician should ask about the possibility of pregnancy for all women and transgender men of reproductive age. The International Antiviral Society–USA recommends considering additional risks, such as partners who come from high-incidence areas and the use of nonprescription drugs and alcohol.[18]

All adults and adolescents who are sexually active or inject or inhale nonprescribed drugs who do not currently have HIV should be informed about HIV prevention measures, including PrEP.[19][18][WHO. HIV Factsheet. 2023] Risk and risk prevention measures exist along a continuum, and specific patient recommendations should be tailored to individual circumstances, considering the patient's preferences. Ideally, after the exclusion of active HIV, people identified to be at increased risk should be offered PrEP.[57][WHO. HIV Factsheet. 2023][CDC. PrEP Guidelines. 2021]

After deciding to prescribe PrEP, it is necessary to conduct a comprehensive patient history and a focused physical examination to determine the appropriate therapy, considering factors such as bone loss, renal failure, and cardiac risk factors, including smoking. Weight should be recorded, as PrEP is restricted to those weighing at least 35 kg (77 lb), and some therapies may induce weight gain. Baseline blood pressure should be measured to gauge future cardiovascular risk. A thorough personal and social history can identify potential barriers to adherence to treatment and the need for social or other ancillary supports.

Limited data exists on whether PrEP provides any additional benefit for people in a monogamous relationship with an HIV-positive partner who is on antiretroviral therapy and with an undetectable viral load—though observational evidence suggests there is minimal added benefit of PrEP in limiting HIV transmission in serodiscordant couples with suppressed viral loads. The partner's consistency of medication use and viral suppression and the patient's degree of certainty of these can help inform decisions regarding PrEP use.[52] To assist in risk assessment, local HIV prevalence estimates in the United States are available from AIDSVu or the CDC.  

Evaluation

HIV testing is the first step in the evaluation of any patient who requests PrEP or may be at risk for HIV. A documented negative HIV test within 7 days before initiating, reinitiating, or continuing PrEP is crucial. This precaution is necessary to mitigate the risk of inducing resistance if HIV is exposed to inadequate retroviral treatment, potentially limiting future treatment options.[20] Patient-reported or documented anonymous results should not be accepted.[CDC. PrEP Guidelines. 2021]

An antigen-antibody test is recommended for initial testing as these can detect HIV earlier than antibody tests.[59] Laboratory-based testing is preferred because these are the most sensitive, detecting HIV within 18 to 24 days after exposure. A rapid fingerstick antigen-antibody test can detect the virus 18 to 90 days after exposure and offer the advantage of immediate availability.[60][CDC. HIV Testing. 2022] Rapid oral fluid tests should not be used in PrEP due to decreased sensitivity for acute or recent infection compared to other options.

For people who have taken oral PrEP for postexposure prophylaxis in the last 3 months or cabotegravir in the last 12 months, both an antigen-antibody test and an HIV ribonucleic acid assay should be performed.[CDC. PrEP Guidelines. 2021] For those with exposure to a high-risk event in the last 4 weeks, such as a condom breaking during sex with an HIV-positive partner or sharing a drug needle, symptoms of acute HIV should be sought, a nucleic acid amplification test that can detect HIV within 10 to 33 days after exposure should be conducted. 

Once a decision to offer PrEP has been made, further testing is required to confirm HIV negativity and identify possible risk factors for complications. This testing should not delay the initiation of therapy in most circumstances, as this can increase the period of risk for HIV acquisition.[CDC. PrEP Guidelines. 2021]

• Laboratory-based HIV antigen-antibody test: Use this if the decision to start PrEP was based on a rapid or point-of-care HIV test. 
• Hepatitis B serology: This is ideally performed before initiation of therapy because tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is also used to treat hepatitis B virus (HBV); the presence of HBV would not exclude using TDF/FTC but would need to be evaluated separately for use. Sudden discontinuation of TDF/FTC can also cause a hepatitis flare.
• Hepatitis C serology: This is only for MSM, transgender women, and people who inject drugs.
• Sexually transmitted infection testing: Test using updated local guidelines for recommended assays; testing for syphilis, chlamydia, and gonorrhea should be included. 
• Renal function: Test renal function if oral PrEP is being considered due to the risk of proximal renal tubular disease associated with long-term TDF use.   
• Lipid profile: Test lipid levels if oral PrEP is being considered due to the possibility of weight gain and lipid abnormalities. 

DEXA (dual-emission x-ray absorption) scans for bone density are not recommended to initiate or monitor oral PrEP. For appropriate assessment and management, referral should be made for those with a history of fragility fractures or significant risk of fractures.[CDC. PrEP Guidelines. 2021]

See the section on "Treatment" below for further information on the timing of initiation of therapy and required monitoring while on PrEP.

Treatment / Management

Eligibility

Antiretroviral medications used as PrEP are highly effective in decreasing HIV acquisition. These medications should be offered based on clinical judgment to all high-risk individuals as defined by local, state, or country guidelines. While the WHO highlights the need for PrEP according to key populations, individual countries or other authorities develop guidelines based on country or local epidemiology, and clinicians make decisions based on local epidemiology and individual risk factors.

It is essential to consult the most recent guidelines when assisting patients in making decisions for PrEP as new indications and agents become available. The CDC updated its recommendations for the United States in 2021, and the ISA-USA Panel's Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults was updated in 2022.[18][CDC. PrEP Guidelines. 2021] In August 2023, the US Preventive Services Task Force (USPTF) published new recommendations for the use of antiretroviral agents in adults and adolescents with HIV based on an evidence report and systematic review of PrEP.[30] 

The CDC and USPSTF recommend PrEP be offered to people in the United States who have had anal or vaginal sex in the past 6 months and any of the following: a partner with HIV (especially if viral load is unknown or detectable), a bacterial sexual transmitted infection in the last 6 months, or a history of inconsistent or no condom use with sexual partner(s) whose HIV status is not known. PrEP should also be offered to people who inject drugs and who have an injecting partner with HIV or share injection equipment.[52][CDC. PrEP Guidelines. 2021] Gonorrhea, syphilis, and chlamydia infections in MSM and women correlate with the risk of HIV acquisition.[61][70][71] Due to many peoples' hesitation to share details of their sexual and drug use behaviors, PrEP should be provided to all patients who request it, regardless of known risk factors.[57] 

Treatment should not be withheld if a patient explicitly requests PrEP despite disclosing no risk factors. Patients may not disclose risk factors due, for example, to a fear of stigma or the lack of a trusting relationship with the practitioner.[52]

Choice of Medication

Three PrEP regimes are currently recommended in the United States: TDF/FTC, tenofovir alafenamide (TAF/FTC), and long-acting cabotegravir.[63][64] The choice of PrEP regime should be based on a discussion between the individual and clinician based on the person's risk factor profile, comorbid conditions, preference for oral or injectable medications, barriers to consistent adherence to medications, in addition to the adverse effect profile and cost of the medication if not covered through insurance or pharmaceutical-sponsored programs.[30] 

Oral PrEP can be taken as 1 tablet once a day of TDF/FTC (300 mg/200 mg, respectively) by all people at risk of acquiring HIV who weigh at least 35 kg and those who are pregnant or breastfeeding.[30] One tablet orally of TAF/FTC (25 mg/200 mg, respectively) daily is an equal alternative for cisgender men and others at risk who do not have receptive vaginal sex, including those at risk solely due to injection drug use. TAF/FTC is preferable to TDF for people in these populations with a creatinine clearance between 30 to 60 mL/min or known osteoporosis or osteopenia. TAF/emtricitabine is not indicated for women at risk of HIV via vaginal penetration, as no trial data are available for this population.[30] The effectiveness of TAF/FTC is non-inferior to TDF/FTC.[52]

TDF/FTC and TAF/FTC have been approved for use in adolescents at high risk of infection who weigh at least 35 kg. The effects of long-term bone health need to be considered in young men when considering initiation of PrEP and choice of medication. Pharmacodynamic studies suggest less bone loss with TAF/FTC.[CDC. PrEP Guidelines. 2021]

MSM who can identify high-risk sexual events at least 2 hours beforehand can take oral PrEP "on-demand."[30] Also known as episodic or "2:1:1", on-demand PrEP is taken as 2 tablets orally of TDF/FTC at least 2 hours, but up to 24 hours before the sexual encounter and then 1 tablet on each of the 2 days after the sexual encounter.[CDC. PrEP Guidelines. 2021] TAF/FTC cannot be used for episodic PrEP. Episodic PrEP is not indicated for people at risk of HIV from receptive vaginal or neovaginal sex or injection drug use due to the lack of studies in these populations. Episodic therapy must be used with caution in transgender women receiving gender-affirming therapy, as PrEP may take longer to reach adequate concentrations in rectal tissues to prevent HIV.[30] People who took 15 or fewer tablets with high adherence or 15 or more tablets per month had a decreased incidence of HIV compared to placebo, with 0 versus 9.2 events per 100 person-years and 0 versus 8.1 per 100 years, respectively.[30]

Cabotegravir, given as a 600-mg gluteal intramuscular injection every 2 months, can be used for the prevention of sexual transmission of HIV across populations, including those who inject drugs and are also at risk of acquiring HIV through sex, pregnant people, and youth.[30] Further, it may be particularly appropriate for people with renal disease, with difficulty adhering to oral PrEP, or who prefer receiving injections every 2 months rather than taking daily oral medication.[CDC. PrEP Guidelines. 2021]

Cabotegravir can be initiated with 30 mg of daily oral cabotegravir for 4 to 5 weeks before injection for those who have anxiety about adverse events, but it should not be prescribed as ongoing therapy. Oral initiation is not required as trials of cabotegravir have not demonstrated safety concerns.[CDC. PrEP Guidelines. 2021] Injection must be intragluteal as the pharmacokinetics in other administration sites are unknown. 

In 2021, the WHO additionally recommended the dapivirine vaginal ring for women at substantial risk of HIV infection as part of combination prevention approaches.[WHO. Consolidated HIV Guidelines. 2021] Versus placebo, African women at risk of HIV had a relative risk of HIV of 0.71, with an absolute risk reduction of -2.23% at 1.4 to 1.6 years.[52] The dapivirine vaginal ring is not approved by the Food and Drug Administration and is not available for use in the United States, but a 2022 randomized control trial of postmenopausal women in the United States showed high acceptability of the ring as a means of HIV prevention.[65]

Timing of Therapy

PrEP should be started as soon as possible for those at risk, including on the same day if the patient is willing and has no signs or symptoms of acute HIV, a documented negative HIV test result no more than 1 week prior, and no contraindicated medications or conditions. 

PrEP may need to be started later for reasons that may include the following circumstances:

• The patient needs additional time to make a decision.
• Additional HIV laboratory testing is required in the case of recent HIV PrEP or postexposure prophylaxis use. 
• Additional investigations and discussion for shared decision-making are required due to particular medical circumstances, such as renal or liver impairment, pregnancy, or breastfeeding.[CDC. PrEP Guidelines. 2021]

When initiation of treatment is delayed, options for safer sex and drug use practices should be reinforced, tests should be ordered, and plans for follow-up need to be made.

Ongoing Monitoring 

Ongoing monitoring is required to detect HIV infections, potential medication toxicities, and any changes in risk behavior that may indicate a need to change therapy. For patients on oral PrEP, laboratory and in-office testing is required before receiving each prescription refill, with frequency and recommendations dependent on patient characteristics.[CDC. PrEP Guidelines. 2021]

• An HIV antigen/antibody test is recommended every 3 months for all patients.
• Tests for syphilis, gonorrhea, and chlamydia are recommended every 6 months for all sexually active patients and every 3 months for MSM and transgender women. 
• A lipid panel is recommended every year for those on TAF/FTC.
• Creatinine clearance testing is recommended every 6 months for those on TDF. 
• Hep C serology testing is recommended yearly only for MSM, transgender women, and people who inject drugs. 

For patients on injectable cabotegravir, a negative nucleic acid amplification test is required 1 to 2 months after initiation of therapy and every 2 months before each injection. Regular sexually transmitted infection screening should also be performed every 6 months for heterosexually active women and men and every 4 months for MSM and transgender women.[CDC. PrEP Guidelines. 2021] 

Medication Adherence 

The individuals most at risk of HIV often have challenges with adhering to therapy due to multiple structural and systemic barriers, and loss to follow-up is common.[30] Barriers may include a lack or loss of insurance, exposure to abuse and violence, such as a partner throwing medications away, major stressful life events, the stigma of being at risk for HIV, discrimination, or other factors beyond the patient's control. For example, during the COVID-19 pandemic, decreased rates of prescription refills were observed, which may not be associated with changes in sexual behaviors.[66] Young adults experienced more barriers to accessing health services, and people who identify as Hispanic/Latin American, Black/African American, or other non-White identities or those who were on public health insurance had more lapses in PrEP.[66] Medical conditions such as mental health or substance use issues can also lead to decreased medication adherence.[67]

When a patient who takes oral PrEP presents, members of the interprofessional should pay close attention to the patient's adherence to therapy and potential barriers to adherence during every clinical visit, and collective problem-solving should be engaged to overcome the identified obstacles. Data from clinical trials and observational studies have demonstrated that adherence to therapy is essential to PrEP effectiveness. A pharmacokinetic study of oral PrEP estimated effectiveness to be 99% if doses are taken 7 days a week, 96% for 4 doses per week, and 76% for 2 doses per week.[CDC. PrEP Guidelines. 2021] While this suggests that 100% adherence is not required for benefit, optimal benefit is only achieved with high adherence rates. Also, lower levels of active metabolites of PrEP medications have been found in vaginal tissues as compared with colorectal tissues, strongly suggesting that greater adherence may be required for women taking PrEP. 

Patients receiving cabotegravir injections must be advised that if they discontinue medication, the gradually declining levels of cabotegravir raise the risk of developing a drug-resistant strain if HIV infection occurs at that time.[CDC. PrEP Guidelines. 2021] Therefore, individuals need to keep regular injection appointments. 

While adherence to therapy may be improved with intramuscular cabotegravir due to the simple bimonthly dosing schedule, patients may experience barriers similar to those encountered with oral PrEP due to the need for ongoing connection with healthcare services. Medication adherence requires an interdisciplinary team approach that identifies and addresses all adherence barriers.

Patients with Substance Use Disorders

People who inject drugs should be offered PrEP. In addition, efforts should be made to decrease or eliminate the risk of acquiring HIV through needle sharing by offering drug treatment and relapse prevention services. Medication-assisted treatment with buprenorphine, naltrexone, or methadone can be provided in the PrEP setting or by referral to a specialized clinic. If the patient is unable or not motivated to engage in drug treatment services, access to sterile injection equipment should be facilitated, where available and legal, through syringe services programs, prescriptions, or the purchase of needles without a prescription. Cognitive or behavioral counseling and referral to mental health or social services may also reduce high-risk practices.[CDC. PrEP Guidelines. 2021]  

See the "Deterrence and Patient Education" section below for further information on supporting medication adherence and the "Improving Healthcare Team Outcomes" section for program improvements and removing barriers to care. 

Differential Diagnosis

The possibility of prior acquisition of HIV is the crucial alternative diagnosis to consider when a person seeks or is considering PrEP. HIV testing is vital before initiating therapy, with a confirmatory nucleic acid amplification test required if a recent high-risk exposure is identified or acute HIV illness is suspected. HIV testing must also be performed before each prescription refill or injection.

Persons at risk for HIV often have other risks that may impact their health and should be considered as appropriate to the patient's medical and social history and clinical presentation. Other risks and suggested treatments include those listed below.

• Sexually transmitted infections: Seek signs or symptoms of sexually transmitted infections and risks, counsel to avoid risk of transmission, and repeat testing as needed.  
• Blood-borne infections or other complications of illicit drug use: Examine for signs and symptoms of cardiac or soft tissue infection. Counsel the patient on when to seek treatment and safer drug practices to avoid overdose and infection. Refer for drug use treatment if appropriate.
• Socioeconomic concerns: Seek indications of intimate partner violence, homelessness, stigma, or discrimination and refer the individual to the appropriate support channel as necessary.
• Mental health concerns: Mental health concerns may be a preexisting condition that has led to increased risk for HIV or be an ongoing barrier to optimal benefit from PrEP. Depending on the clinical presentation and PrEP healthcare team resources, counseling, medication treatment, or referral for care may be required.

Prognosis

While HIV is not curable, people who are infected can live long, healthy lives due to the advent of highly active antiretroviral therapies. The prognosis for individuals seeking prevention of HIV infection is excellent if treatment adherence can be maintained. The effectiveness of oral PrEP in preventing HIV acquisition during sexual contact is approximately 99% when medication is strictly adhered to; effectiveness is significantly decreased if adherence is not maintained.[CDC. PrEP Guidelines. 2021] Pooled analyses of results from large trials of TDF/FTC versus placebo showed a relative risk of HIV acquisition of 0.46 after 4 months to 4 years of follow-up.[68] After categorizing study outcomes based on PrEP adherence levels, the relative risk was 0.27 for studies with adherence of 70% or higher, 0.51 for studies with adherence between 40% and less than 70%, and 0.93 (95% CI .72-1.2).[52]

Complications

Adverse Events

Overall, tenofovir formulations are well tolerated by most individuals, with overall rates of any adverse event identical between the 2 formulations at 94%.[21] About 10% of patients starting oral PrEP experience what is known as a "startup syndrome," consisting of headache, nausea, and abdominal discomfort that usually resolves within the first month. The use of over-the-counter medications is recommended to treat these symptoms. Some patients on TAF/FTC report weight gain; appropriate lifestyle intervention measures should be recommended.[CDC. PrEP Guidelines. 2021]

The ATN 110 and 113 studies showed decreased bone density in young men taking TDF/FTC oral PrEP compared to placebo, with greater declines in those aged 15 to 19 than those aged 20 to 22.[22][23] While declines resolved during the 48 weeks after the studies were completed, declines were persistent in younger men.[21][CDC. PrEP Guidelines. 2021]

Serious adverse events are reported in about 7% of both formulations, with between 1.5% and 1.9% of patients needing to stop the medication due to adverse events. Rates of kidney adverse events, kidney adverse events leading to discontinuation of therapy, and fracture were the same.[71] Rarely, tenofovir-based medications can cause acute renal injury; patients should be advised of signs and symptoms and to follow up urgently with a physician. Given these precautions, guidelines recommend that tenofovir disoproxil is avoided when the estimated glomerular filtration rate (eGFR) is less than 60 mL/min/1.73 m², and TAF is avoided when the eGFR is less than 30 mL/min/1.73 m².[72][73]

Long-acting cabotegravir and TDF/FTC likewise demonstrated similar risks of serious adverse events. There were no differences between long-acting cabotegravir and TDF/FTC in serious kidney or liver adverse events, discontinuation of therapy due to liver events, or sexually transmitted infections.[35][64] Injection site reactions such as pain, tenderness, and induration were reported in 81.4% of patients receiving cabotegravir. Reactions were generally mild, disappeared within a few days, and occurred most frequently with the first 2 to 3 injections. These reactions can be managed with over-the-counter pain medications and hot compresses for 15 to 20 minutes after the injection.[30]

Potential for Drug Interactions

Recommended tenofovir formulations are known to interact with many drugs, including many often prescribed in conjunction with PrEP. TAF should not be coadministered with rifampicin, rifabutin, or rifapentin.[74] Tenofovir alafenamide should not be coadministered with St. John's Wort, as decreased TAF concentrations are possible due to greater P-glycoprotein manipulation than with TDF.[75][CDC. PrEP Guidelines. 2021]

By comparison, TDF interacts with several medications for which TAF data are unavailable.[CDC. PrEP Guidelines. 2021] When TDF is coadministered with some antiretrovirals, aminoglycosides, high-dose or multiple nonsteroidal anti-inflammatory drugs, and other medications that reduce renal function or compete for active renal tubular secretion, increased serum concentrations of TDF and these drugs may result.[75] Other acyclic nucleotide drugs, such as adefovir and cidofovir, should not be coadministered with TDF as serum concentrations of TDF may be increased and cause substantial nephrotoxicity. When TDF is taken with ledipasvir, sofosbuvir, velpatasvir, or voxilaprevir, this may result in increased serum concentrations of TDF.[76][77] These have no significant effect on TAF. Dose-related toxicities must be monitored when interactions may occur. 

No significant interactions have been found when TDF or TAF is coadministered with buprenorphine, methadone, or oral contraceptives, and no dosage adjustments are necessary.[78][79]

No studies on interactions with masculinizing hormones exist, and data are limited on feminizing hormones. Some study results suggest lower tenofovir concentrations in blood and rectal tissue with the concurrent use of feminizing hormones; however, this evidence is limited by small sample sizes and potential recall bias.[80][81][82] However, TDF is not known to affect levels of feminizing hormones. Data for TAF are currently unavailable.[CDC. PrEP Guidelines. 2021]

Cabotegravir should not be coadministered with rifampicin or rifapentin due to increased metabolism and significantly reduced levels of cabotegravir.[83][CDC. PrEP Guidelines. 2021] Rifabutin moderately increases the metabolism of cabotegravir and can be coadministered with caution. Until further data are available, carbamazepine, oxcarbazepine, phenytoin, and phenobarbital should not be coadministered with cabotegravir as these convulsants may lower cabotegravir levels. Hormonal contraceptives can safely be taken with cabotegravir, but data on coadministration with feminizing hormones are lacking.[CDC. PrEP Guidelines. 2021]

HIV Acquisition

Acquiring HIV infection while being prescribed PrEP mainly occurs due to nonadherence to medication by stopping, infrequently using, or stopping and starting treatment.[84] Socioeconomic disadvantage and a lack of awareness of the risks may contribute to nonadherence. Rarely, infection can occur despite high adherence because of exposure to a drug-resistant strain or simply because PrEP protection is not 100%.[CDC. PrEP Supplement. 2021]

When a follow-up test indicates possible HIV infection, a history should be taken, seeking signs and symptoms of acute HIV testing. Confirmatory testing is required unless the initial test was laboratory testing with confirmatory results already known. Diagnosis of HIV in patients on cabotegravir can be challenging due to cabotegravir's high potency and long half-life, resulting in repeat indeterminate or conflicting results, including those between qualitative and quantitative nucleic acid amplification test results.[CDC. PrEP Supplement. 2021]

PrEP may need to be stopped or augmented with additional antiretroviral medication while confirmatory laboratory testing is completed. Once a diagnosis of HIV is confirmed, draw appropriate specimens for evaluating HIV infection and initiate antiretroviral therapy. A case report form should be completed for submission to the local health department.[CDC. PrEP Supplement. 2021]

Consultation with an HIV specialist is available in the United States by calling the toll-free national PrEP hotline at 855-448-7737. See the StatPearls companion article "HIV and AIDS" for further treatment and management of HIV infection.