How to Start PrEP: Pills, Shots, and What to Expect

Starting PrEP typically involves a visit with a healthcare provider, a set of baseline lab tests, and a prescription you can sometimes walk out with the same day. The process is faster than most people expect, but the choices have expanded beyond a single daily pill. You now pick between two oral medications or a long-acting injection, and the option that fits your life best depends on factors worth understanding before that first appointment.

Your First Visit and Baseline Tests

Before you receive a PrEP prescription, a provider needs to confirm two things: that you are HIV-negative right now, and that your kidneys and liver can handle the medication. An HIV test is critical because starting PrEP while unknowingly infected creates a risk of drug resistance. If someone already has HIV and takes a two-drug PrEP regimen rather than a full treatment regimen, the virus can develop mutations that make future treatment harder.

Beyond the HIV test, expect bloodwork checking kidney function and screening for hepatitis B, since one of PrEP’s active ingredients also suppresses hepatitis B, and stopping abruptly could cause a flare. Most providers also run a standard panel for other sexually transmitted infections at baseline. These visits typically happen every three months once you are on PrEP, establishing a routine that doubles as regular STI screening.

Some clinics and community health centers now offer same-day PrEP starts, where you get tested and walk out with a prescription if results allow it. A pilot program at a nonclinical testing center found that the vast majority of patients evaluated for PrEP received a prescription the same day, and most filled it within a week.¹ The bottleneck often is not getting the prescription but returning for follow-up: in that same program, fewer than half of people who filled their prescription attended their initial clinical appointment within six weeks. If you start PrEP, building in those quarterly check-ins from the beginning matters.

The Two Oral PrEP Pills

Two oral medications are approved for PrEP in the United States. The older one, a combination of tenofovir disoproxil fumarate and emtricitabine (commonly known by the brand name Truvada, though generics are now widely available), was the first PrEP drug approved and has the longest track record. The newer one pairs tenofovir alafenamide with emtricitabine (brand name Descovy) and delivers the active drug differently, resulting in lower kidney and bone exposure.

In practice, the safety differences between these two pills appear to have limited clinical significance for most people taking PrEP. A survey of over a thousand PrEP users found that among those who switched to the newer formulation, more than half did so because their doctor recommended it, and about a third cited a perception of improved safety as their reason.² That perception was driven in part by marketing, and while the newer formulation does show a somewhat gentler kidney and bone profile in clinical trials, the older version remains safe for the vast majority of users and is considerably cheaper now that generics are available.

One important distinction: the older formulation is approved for all adults at risk of HIV regardless of the type of sexual exposure, while the newer one is currently approved only for people at risk through receptive vaginal sex or any type of anal sex. If your primary exposure route is receptive vaginal sex and you want the newer formulation, it is an option, but the older generic version covers everyone and costs less.

On-Demand Dosing

Not everyone needs to take a pill every single day. An approach called event-driven or on-demand PrEP involves taking two pills before anticipated sex, one pill 24 hours later, and one more pill 24 hours after that. This “2-1-1” schedule has been studied primarily in men who have sex with men and is endorsed by the World Health Organization for that population. It is not currently recommended for vaginal sex exposure because the drug takes longer to reach protective concentrations in vaginal tissue.

A modeling study estimating optimal PrEP assignment found that on-demand dosing was best suited for roughly a third of men who have sex with men, primarily those whose daily adherence would otherwise be low. Among people with daily adherence below about 40%, on-demand dosing was the better-performing option in the vast majority of cases.³ If your sexual activity is infrequent or predictable enough to plan around, on-demand PrEP can dramatically reduce your pill burden while still providing strong protection.

Injectable PrEP With Cabotegravir

If pills are not your thing, injectable cabotegravir offers an alternative that removes daily adherence from the equation entirely. The dosing schedule starts with two monthly injections, then shifts to one injection every two months after that.⁴ The injections are given in the gluteal muscle at a clinic, so you do need to show up in person on schedule.

Retention is where injectable PrEP shows a real advantage. In a comparative study in Zambia, half of oral PrEP users discontinued during follow-up compared to only 7% of those on the injectable, giving oral PrEP users more than double the hazard of discontinuation.⁵ Simulation modeling for Los Angeles County found that if injectable PrEP retention reaches published estimates, widespread adoption could reduce HIV incidence by as much as 45% among the most affected populations.⁶

The catch is that retention still matters. When injectable PrEP retention is low, modeling shows HIV incidence can actually increase compared to oral PrEP, because the bimonthly visit schedule becomes a cliff: miss an appointment and you drop off entirely, whereas a person on oral PrEP who misses a few pills might still have some protection.⁶ The injectable works brilliantly if you keep your appointments. If your life makes regular clinic visits difficult, oral PrEP with imperfect daily adherence may actually serve you better.

What Side Effects to Expect

The side effects differ depending on which form of PrEP you choose, but across the board they tend to be mild and manageable for most people.

With oral PrEP, the most common early complaints are nausea, headache, and stomach upset, sometimes called “start-up syndrome.” These typically fade within the first few weeks. The more meaningful long-term concern with the older tenofovir formulation involves modest effects on bone density and kidney function. Across multiple studies, tenofovir-based regimens led to roughly 1 to 3% more bone mineral density loss compared to non-tenofovir regimens, a small but measurable effect that generally reverses after stopping the drug.⁷ Kidney effects are similarly uncommon in real-world use. In a large Italian cohort followed for four years, twenty cases of kidney toxicity were recorded, and only one led to PrEP being stopped.⁸ The quarterly blood work your provider orders is designed to catch any changes early.

For injectable cabotegravir, the dominant side effect is pain, firmness, or swelling at the injection site. Most people experience some injection site reaction, but these tend to decrease over time, and few people in clinical trials stopped the injectable because of them. Weight gain has also been flagged as a possible association with cabotegravir, though the data remain mixed.⁹

PrEP and Gender-Affirming Hormone Therapy

Transgender people on hormone therapy sometimes worry that PrEP and their hormones will interfere with each other. The short answer is that PrEP is expected to be effective and safe regardless of gender-affirming hormone use.¹⁰

The longer answer involves some nuance for transgender women on feminizing hormones. Small studies have found that plasma levels of tenofovir can be somewhat lower in transgender women on estrogen, with reductions on the order of 12 to 27% compared to cisgender men.¹¹ That sounds alarming, but the drug levels that actually matter for protection are the concentrations inside cells, not in plasma, and those intracellular concentrations appear to be similar between transgender women on hormones and cisgender men.¹⁰ A study in Brazilian transgender women also found no meaningful difference in drug levels between those on feminizing hormones and those not on hormones, and no participant in that analysis acquired HIV during the study.¹²

For transgender men on testosterone, there is no evidence that masculinizing hormones reduce PrEP drug levels, and PrEP does not alter hormone levels in either direction. No interactions between feminizing hormones and injectable cabotegravir have been demonstrated either, making the injectable a solid option for transgender women who want to avoid any lingering uncertainty about oral drug absorption.¹⁰

PrEP During Pregnancy and Breastfeeding

People who become pregnant while on PrEP, or who want to start PrEP during pregnancy, face a valid question about fetal and infant safety. The evidence so far is reassuring. A systematic review of completed studies found no differences in pregnancy or birth outcomes associated with PrEP use.¹³ Current guidelines in many countries support continuing oral PrEP during pregnancy when the person remains at ongoing risk of HIV, with the rationale that preventing HIV acquisition during pregnancy protects both parent and child.

During breastfeeding, small amounts of tenofovir can pass into breast milk, but the levels are low and the available data consistently show no harm to infants. The potential risk is considered outweighed by the HIV prevention benefit, which includes indirectly protecting the infant by keeping the breastfeeding parent HIV-negative.¹⁴ Injectable cabotegravir has less data in pregnancy and breastfeeding, so oral PrEP remains the standard recommendation for these situations.

Navigating Cost and Insurance

Cost is the single biggest reason people stop PrEP or never start it. The relationship between out-of-pocket cost and abandonment is steep and well-documented: abandonment rates sit around 5.5% when PrEP costs nothing out of pocket but climb to nearly 43% when costs exceed $500. Even a small jump from zero to $10 out of pocket doubles the abandonment rate. And people who abandon their PrEP prescriptions go on to be diagnosed with HIV at two to three times the rate of those who fill them.¹⁵

People who have stopped PrEP in the past year consistently report more cost and insurance challenges than people who stay on it, suggesting that these barriers are not just theoretical obstacles but active reasons people fall off.¹⁶ If you face high costs, manufacturer assistance programs, copay cards, and local health department funding can close the gap. Qualitative research with PrEP users found that many described these assistance programs as the only reason they could afford to stay on PrEP.¹⁷ Generic versions of the older oral formulation have also brought monthly costs down considerably, and the injectable, while more expensive per dose, may be covered differently depending on your plan.

The policy landscape around PrEP coverage is unstable. Legal challenges to mandatory no-cost-sharing provisions could increase out-of-pocket costs for many users, and modeling suggests this could substantially increase PrEP abandonment and HIV rates.¹⁵ It is worth asking your provider or pharmacist about current assistance options before assuming you cannot afford PrEP.

What Happens When You Stop Injectable PrEP

Stopping oral PrEP is straightforward: you stop taking the pill, the drug clears your system within days to a couple of weeks, and you lose protection accordingly. Stopping injectable cabotegravir is a different story, and it is one of the more important things to understand before choosing the shot.

Cabotegravir is designed to release slowly from the injection site, which is what allows it to work for two months at a time. But that same slow release creates a long drug “tail” after your final injection, meaning detectable levels of the drug linger in your body for months or even years. In one study, about a quarter of men and nearly two-thirds of women still had detectable cabotegravir at a year after their last injection, and modeling suggests some women could have detectable levels for up to four years.¹⁸

The concern is that during this tail period, drug levels are too low to prevent HIV acquisition but high enough to pressure the virus into developing resistance mutations if you do acquire it. This would compromise not just cabotegravir but potentially an entire class of drugs used for HIV treatment.¹⁹ In practice, the clinical trials have been somewhat reassuring: no cases of cabotegravir resistance were linked to the tail period in one major trial, though a handful of breakthrough infections during active treatment did show resistance.¹⁸

If you decide to stop injectable PrEP, most guidelines recommend bridging to oral PrEP for a period after your last injection to maintain full protection while the drug clears. Discuss a stopping plan with your provider before you discontinue; just not showing up for your next injection and hoping for the best is the worst approach.

Why Adherence Shapes Everything

PrEP’s real-world effectiveness depends almost entirely on whether people actually take it. The drug itself is remarkably effective when used correctly, but trials where adherence was poor showed little benefit, a pattern that has been consistent across low- and high-income settings alike.²⁰ In one real-world study using a digital health tool, about a third of oral PrEP users reported missing at least one dose per week in the first three months.²¹

This is one reason the injectable option has generated so much excitement: it decouples protection from daily behavior. But the quarterly clinic visits PrEP requires serve a second purpose beyond medication management. Regular screening catches other STIs that PrEP does nothing to prevent. PrEP use may increase STI acquisition through changes in sexual behavior, but that effect can be counterbalanced by the increased STI screening that happens at regular PrEP visits.²² In other words, those check-in appointments are earning their keep twice over.

If an HIV breakthrough does occur despite PrEP use, the management approach depends on the circumstances. When HIV is acquired before PrEP starts, the risk of drug resistance is highest. When infection happens after PrEP initiation with good adherence, breakthroughs are extremely rare and typically involve already resistant strains. With poor adherence, infection is more likely but resistance is uncommon because drug pressure is insufficient to drive mutations. Regardless of the pathway, guidelines recommend upgrading to a full three-drug treatment regimen immediately while waiting for resistance test results.²³

Twice-Yearly Injections on the Horizon

The PrEP landscape is about to shift again. Lenacapavir, a drug given as a subcutaneous injection just twice a year, has shown extraordinary results in late-stage trials. In a study of over five thousand cisgender women in sub-Saharan Africa, zero HIV infections occurred among those receiving lenacapavir over the follow-up period, compared to background incidence of about 2.4 per 100 person-years in the screened population.²⁴ A companion trial in men and gender-diverse persons found a similar pattern: HIV incidence of 0.10 per 100 person-years with lenacapavir compared to 2.37 per 100 person-years as background incidence, representing a greater than 95% reduction.²⁵

A twice-yearly injection would reduce clinic visits further, which could reach people who find even bimonthly appointments difficult to maintain. Regulatory review is underway in multiple countries, and if approved, lenacapavir would represent the longest interval between doses of any PrEP option, turning HIV prevention into something closer to a semiannual health maintenance task than a daily commitment or bimonthly appointment.