PrEP Medication for HIV Prevention: Pills, Shots, and Rings

PrEP medication is any antiretroviral drug taken by HIV-negative people to prevent HIV infection before potential exposure. The most widely used form, a daily pill combining two antiretrovirals, reduces HIV risk by more than 90 percent when taken consistently. Since the U.S. Food and Drug Administration first approved this approach in 2012, the options have expanded from a single daily tablet to newer pills, injections given every two months, and even a twice-yearly shot now working through regulatory review. The science behind each option, how well it works, and who it works best for vary enough that the details matter.

How PrEP Pills Work

The original and still most common PrEP pill is a combination of two drugs: tenofovir disoproxil fumarate and emtricitabine, sold under the brand name Truvada. Both belong to a class of medications that mimic the building blocks HIV needs to copy itself. When they get inside cells lining the genital or rectal tissue, they convert into active forms that block the virus from establishing a foothold. These drugs were chosen for prevention partly because they have favorable dosing characteristics, few serious interactions with other medications or food, and a strong safety record built up over years of use in HIV treatment.¹

A second pill formulation, Descovy, pairs emtricitabine with a newer version of tenofovir called tenofovir alafenamide (TAF). Descovy is considered equally effective at preventing HIV and may cause slightly less impact on kidneys and bones, though the real-world difference for most healthy PrEP users appears clinically small.² One important caveat: Descovy’s approval for PrEP does not include receptive vaginal sex, because the relevant clinical trials enrolled only cisgender men and transgender women who have sex with men. That leaves the older Truvada formulation, or its now widely available generics, as the standard pill for cisgender women.

Efficacy of Daily Oral PrEP

The protection numbers that come out of clinical trials depend heavily on how reliably participants took their pills. In the landmark iPrEx trial among men who have sex with men, the overall reduction in HIV acquisition was about 44 percent compared to placebo. But that figure includes everyone randomized to the drug arm, including many who rarely took it. The Partners PrEP Study, which enrolled couples where one partner was HIV-positive, found reductions of about 67 percent with tenofovir alone and 75 percent with the tenofovir-emtricitabine combination.³ A separate trial among young heterosexual adults in Botswana reported a 62 percent reduction.⁴

Those headline numbers undersell the drug when people actually take it. In the Partners PrEP Study, participants who had measurable drug levels above a protective threshold saw an estimated 88 percent reduction with tenofovir alone and 91 percent with the combination pill.⁵ Across pivotal trials, the consistent finding is that people who stuck with the daily regimen achieved protection north of 90 percent. The gap between the modest intention-to-treat numbers and the near-total protection with good adherence is not a weakness of the drug; it is a reflection of how hard it can be to take a pill every day, especially in a trial lasting years.

Adherence Changes Everything

The relationship between how often you take PrEP and how well it protects you is not a gentle slope. Modeling work based on trial data suggests that with a long-acting drug profile and pills taken only half the days, expected protection ranges from roughly 34 to 60 percent depending on whether missed doses are clustered together or spread out randomly.⁶ Block patterns of non-adherence, where someone stops for a stretch and then restarts, are the most dangerous because drug levels drop below protective thresholds for extended windows.

For cisgender women, the math is a bit less forgiving. The active drug accumulates more slowly in vaginal tissue than in rectal tissue, so consistent dosing matters even more. Modeling estimates suggest that two pills per week reduces HIV risk for cisgender women by about 59 percent, four pills per week by about 84 percent, and seven pills per week by roughly 96 percent.⁷ This tissue-level difference helps explain why some early trials in African women showed disappointing results: adherence was low, and the drug concentrations needed to protect vaginal tissue require more consistent dosing than those needed for rectal tissue.⁸

Event-Based Dosing

Not everyone needs or wants to take a pill every day, especially people who have sex infrequently. An alternative called 2-1-1 dosing, also known as on-demand or event-driven PrEP, involves taking two pills between 2 and 24 hours before sex, then one pill 24 hours later and another pill 48 hours after that. In a study tracking real-world use of this approach, adherence to each component of the regimen was high: roughly 85 percent of users consistently took the pre-sex double dose, and about 90 percent remembered each of the follow-up single doses.⁹

This regimen is currently supported by guidelines for men who have sex with men and transgender women in many countries, but it is not recommended for cisgender women or for people exposed through injection drug use. The reason ties back to the tissue-distribution issue: rectal tissue achieves protective drug levels quickly with a loading dose, but vaginal tissue takes longer to reach those concentrations.

Injectable PrEP With Cabotegravir

The first injectable PrEP option, long-acting cabotegravir (sold as Apretude), is given as a shot in the gluteal muscle every two months after an initial loading phase. It works through an entirely different mechanism than the oral pills, blocking a viral enzyme called integrase rather than mimicking the building blocks the virus uses. In the HPTN 083 trial among cisgender men and transgender women who have sex with men, injectable cabotegravir cut HIV incidence by about 69 percent compared to daily oral PrEP during the blinded phase, and by about 65 percent in the first year after unblinding.¹⁰

A pooled analysis of efficacy trials found an overall 79 percent reduction in HIV risk with injectable cabotegravir compared to oral PrEP.¹¹ That comparison is against daily oral PrEP, not against no prevention at all, making the absolute protection level quite high. The injectable also appears safe and effective for transgender women specifically.¹² The main appeal is obvious: you do not have to remember a daily pill. The main drawback is equally obvious: you need to show up at a clinic every eight weeks.

Twice-Yearly Lenacapavir

The newest development in PrEP is lenacapavir, a drug that works by a novel mechanism, blocking the protein shell that surrounds the virus. It is given as a subcutaneous injection just twice a year. The PURPOSE 1 trial enrolled over 5,000 young cisgender women in South Africa and Uganda and found that none of the participants who received lenacapavir acquired HIV, compared to 16 new infections in the daily oral PrEP group.¹³

The PURPOSE 2 trial broadened the study population to include cisgender men, transgender women, and nonbinary individuals across the Americas, South Africa, and the Asia-Pacific region. Only two HIV infections occurred in the lenacapavir group, compared to nine in the oral PrEP group, and the background incidence in the screened population was about 2.4 per 100 person-years. The HIV incidence in the lenacapavir group was 0.10 per 100 person-years, a 96 percent reduction compared to daily oral PrEP.¹⁴ Pharmacokinetic modeling suggests that a single injection maintains protective drug levels for roughly 50 weeks in an average individual.¹⁵

The results are extraordinary enough that the real question is no longer whether the drug works, but whether it can be made accessible. Lenacapavir has a list price of roughly $28,000 per year in the United States, and without a regulatory mandate requiring insurers to cover it, many payers are already balking at the cost, especially given that generic daily oral PrEP is available for about $30 per month.¹⁶

The Dapivirine Vaginal Ring

For cisgender women, a silicone vaginal ring that slowly releases the antiretroviral dapivirine over a month offers a non-pill, non-injection alternative. Two pivotal placebo-controlled trials found reductions in HIV incidence of roughly 27 to 31 percent overall.¹⁷¹⁸ Those numbers are lower than what daily oral PrEP achieves, but they improve substantially with consistent use: women over 21, who were more adherent, saw protection as high as 56 percent in post hoc analysis.

An open-label extension study, where participants knew they were receiving the active ring, reported an HIV incidence about 62 percent lower than what would have been expected without the ring.¹⁹ The ring is approved for use in several sub-Saharan African countries and recommended by the World Health Organization as an additional prevention option for women who cannot or prefer not to use oral PrEP.

Side Effects and Routine Monitoring

Most people tolerate PrEP pills well. The most common complaints are gastrointestinal: mild to moderate nausea, sometimes vomiting or diarrhea, which usually resolve within the first few weeks. Monitoring during PrEP use typically involves checking kidney function, liver enzymes, and bone mineral density in people at risk, along with regular HIV testing to confirm the user remains negative.²⁰

The kidney and bone concerns are real but modest for most users. The older tenofovir formulation (TDF) can cause small, measurable decreases in bone mineral density that tend to stabilize after around 24 weeks of treatment and reverse after stopping the medication.²¹ That said, a large real-world analysis found that roughly four in five people prescribed oral PrEP had at least one pre-existing risk factor for kidney or bone problems, often related to age, other medications, or existing health conditions.²² This is why routine blood work is part of the PrEP care package, not an optional add-on.

For injectable cabotegravir, the main side effect is injection-site reactions: pain, swelling, or hardness at the injection site that can last several days. Systemic side effects are generally uncommon.

Drug Resistance

One of the early concerns about giving HIV medications to uninfected people was the possibility of breeding drug-resistant virus. The evidence from more than a decade of trials and real-world use is reassuring on this point: resistance selected by PrEP is rare and occurs almost exclusively in one specific scenario. When someone starts PrEP while unknowingly already infected with HIV during the acute phase, where a standard antibody test might not yet detect the virus, the partial drug exposure can select for resistant strains.²³

A meta-analysis across six PrEP trials found that people with undiagnosed acute HIV who were assigned to PrEP were about three times more likely to develop resistance mutations than those on placebo, with resistance to emtricitabine more common than resistance to tenofovir.²⁴ In the iPrEx trial specifically, the resistance mutations that were found occurred exclusively in participants exposed to the drug during undiagnosed acute infection, and no tenofovir-selected resistance was seen at all.²⁵ This is precisely why PrEP guidelines require an HIV test before starting and at every follow-up visit.

PrEP During Pregnancy and Breastfeeding

For women at ongoing risk of HIV, pregnancy is not a time to stop prevention. A systematic review and meta-analysis found no association between oral PrEP and preterm birth across randomized trials or observational studies, and no link to low birth weight, small-for-gestational-age infants, or neonatal death.²⁶ Longer-term follow-up of children with perinatal PrEP exposure has found no differences in growth, wasting, stunting, or social-emotional development out to 36 months compared to unexposed children.²⁷

Safety data on injectable cabotegravir and lenacapavir during pregnancy is still lacking, so the current evidence base applies to oral tenofovir-based regimens and, to a lesser extent, the dapivirine vaginal ring, which also showed no association with preterm birth or neonatal death in the available analyses.

PrEP and Gender-Affirming Hormones

Transgender people on hormone therapy sometimes worry that PrEP and hormones will interfere with each other. The research is encouraging on both directions of this question. Studies of the older tenofovir formulation with feminizing hormones show that while plasma tenofovir levels drop somewhat, the intracellular concentrations of the active drug form are not reduced, and PrEP efficacy is expected to be maintained. Masculinizing hormones do not meaningfully alter tenofovir concentrations. And no interactions have been demonstrated between gender-affirming hormones and either cabotegravir or the newer tenofovir alafenamide formulation.²⁸

Going the other direction, PrEP does not alter hormone levels. A study in young transgender women and transgender men found that estradiol and testosterone exposures did not significantly differ when participants were on daily PrEP compared to their baseline hormone levels.²⁹ In short, PrEP and hormones do not undermine each other.

Access Gaps and Cost Barriers

PrEP works brilliantly when people can get it and keep taking it, but access in the United States remains deeply unequal. An analysis of the first decade of PrEP uptake found that Black and Hispanic individuals, as well as women, used PrEP at rates far below what their share of new HIV diagnoses would call for. The gap between Black and White PrEP use relative to epidemic need grew in the early years after PrEP became available and persisted throughout the study period, never approaching an equitable ratio.³⁰

The arrival of generic oral PrEP has brought pill costs down dramatically, but newer options carry significant price tags. Cost-effectiveness modeling for injectable cabotegravir in a city like Atlanta found that even in the most favorable expansion scenarios, the drug would need to drop to roughly $2,800 per dose to remain cost-effective alongside generic oral alternatives.³¹ Without price reductions or policy changes, the most effective new prevention tools risk becoming available mainly to people with generous insurance, widening existing disparities.

Telehealth and Home Testing

One approach to closing access gaps is removing the need for in-person visits. Telehealth PrEP programs have expanded rapidly, and a systematic review of U.S.-based programs found consistently high acceptability among users, who described the services as easy to use and convenient.³² Some programs pair virtual visits with home specimen self-collection kits for routine lab monitoring. An evaluation of one such program in Iowa found that about 46 percent of clients chose home kits over visiting a lab. Kit users were more likely to complete STI screening swabs, though less likely to complete blood tests, partly because the finger-prick blood collection proved challenging for some users.³³

Brazil saw similar success during the COVID-19 pandemic, where teleconsultation and home delivery of self-testing kits were offered to existing PrEP users. Acceptability was high, and participants who had experienced teleconsultation rated it favorably enough that researchers concluded it could be maintained permanently as an option to improve retention.³⁴

STI Prevention and Doxycycline Post-Exposure Prophylaxis

PrEP prevents HIV, not other sexually transmitted infections. Because PrEP users are already engaged in regular clinical care, the visits create an opportunity to screen for and treat other STIs. Some clinics have begun integrating doxycycline post-exposure prophylaxis, sometimes called doxy-PEP, into PrEP services. This involves taking a dose of the antibiotic doxycycline after a potential STI exposure. Integrated programs have reported reductions in chlamydia and syphilis incidence of roughly 70 to 85 percent, though there are legitimate concerns about antibiotic resistance with widespread use, and ongoing stewardship is considered essential.³⁵

Multipurpose Prevention on the Horizon

Researchers have been working on products that combine HIV prevention with contraception or protection against other STIs in a single delivery system. Over two dozen candidates are in active development, spanning vaginal rings, gels, implants, and even microarray patches that could deliver both antiretroviral and contraceptive drugs simultaneously.³⁶ The appeal is practical: in settings where clinic visits are difficult and multiple health needs compete for attention, a single product addressing more than one concern could simplify care and improve adherence. None of these combination products have completed late-stage clinical trials yet, but they represent the direction that prevention research is heading, especially for women in resource-limited settings who bear a disproportionate burden of both HIV and unintended pregnancy.

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