In July 2012, the US Food and Drug Administration (FDA) approved a once-daily, fixed-dose combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) for preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection. FTC/TDF, initially approved in 2004 to treat HIV in combination with other antiretroviral agents, became the first drug to be approved to prevent HIV infection in people who are at high risk for infection.¹ In May 2014, the US Public Health Service (USPHS) released a set of clinical practice guidelines for PrEP. ²

The FDA approved FTC/TDF for PrEP on the basis of 2 large, randomized, double-blind, placebo-controlled trials.^1,3,4

One, the iPrEX (Preexposure prophylaxis initiative) study, was conducted among 2499 HIV-negative men and transgender women who have sex with men. Participants received FTC/TDF or placebo once daily along with HIV testing, risk-reduction counseling, condoms, and treatment for sexually transmitted infections (STIs). After a median 1.2 years of follow-up, 100 participants were found to have acquired HIV infection: 36 in the active prophylaxis group and 64 in the placebo group. This result amounted to a significant 44% reduction in the incidence of new HIV infections among the participants receiving PrEP.³ While demonstrating the efficacy of PrEP, the study also showed the importance of adherence to the regimen. That is, study participants in the active arm who became infected were found to have low levels of FTC/DTF in their blood.³

The other study, called Partners PrEP, was conducted among 4758 serodiscordant heterosexual couples (couples in which 1 partner was HIV-positive and the other was HIV-negative) in Kenya and Uganda. The HIV-negative partners in this study received FTC/TDF, TDF alone, or placebo. A total of 82 of the HIV-negative partners became infected with HIV during the study. Compared with placebo, there was a 67% reduction in the incidence of infection among participants who received TDF alone, and a 75% reduction with FTC/TDF. Both of these results were statistically significant.⁴

The 2014 USPHS guidelines are based on these studies plus a number of others. Among the most important were the TDF2 Study and the Bangkok Tenofovir Study.⁵

The TDF2 Study evaluated PrEP in heterosexual men and women in Botswana. The 1219 participants (48% women, 52% men) were randomly assigned to FTC/TDF or placebo with monthly follow-up and prevention services including HIV testing, risk-reduction and adherence counseling, and management of STIs, as well as monitoring for potential drug side effects. Compared with placebo, PrEP reduced the risk of HIV infection by 62%. Again, efficacy correlated strongly with adherence as measured by drug levels.⁶

The Bangkok Tenofovir Study evaluated PrEP among a group of injection drug users (IDUs) in Thailand, a population that had not previously been studied as candidates for PrEP. The 2413 participants were assigned to receive either TDF or placebo along with monthly HIV testing, risk-reduction and adherence counseling, and safety assessments, and were offered condoms and methadone treatment. Compared with placebo, TDF reduced the risk of HIV infection by 49%. Once again, efficacy was correlated with adherence: among patients with detectable TDF in their blood, the reduction in risk of HIV infection was 74%.⁷

The USPHS guidelines are based on the premise that daily oral PrEP with FTC/TDF has been proven safe and effective at reducing the risk of becoming infected with HIV through sex with an infected partner. The guidelines recommend PrEP as 1 prevention option for sexually active adults who are at high risk for HIV infection based on their sexual practices. This includes gay and bisexual men, heterosexual men and women, and members of serodiscordant couples. The guidelines note that the safety and efficacy of PrEP for adolescents has not been fully characterized, so clinicians should weigh the risks and benefits of PrEP in counseling adolescent patients.²

Before prescribing PrEP to an eligible patient, clinicians must rule out current HIV infection. PrEP should be prescribed for daily use; the USPHS does not recommend PrEP for so-called coitally-timed or other noncontinuous use. Once a patient has initiated PrEP, the prescribing physician should test for HIV infection at least every 3 months. It is important for patients who acquire HIV infection while on PrEP to discontinue the medication, as the 2-drug FTC/TDF regimen is not sufficient treatment for HIV infection and its continued use may lead to viral resistance to 1 or both drugs.²

Before patients initiate PrEP, clinicians should assess renal function and test for hepatitis B virus (HBV) infection. Impaired renal function and loss of bone mineral density are potential safety concerns with the use of FTC/TDF. It is also important for clinicians to know if a patient is co-infected with HBV as FTC/TDF can be used to combat HBV, and discontinuation of HBV therapy may not be advisable. Clinicians should not prescribe FTC/TDF to any person with an estimated creatinine clearance rate (CrCL) of < 60 mL/min. In patients on PrEP, clinicians should assess renal function at least every 6 months so that patients who develop renal failure do not continue to take PrEP.²

As reflected in the clinical trial data, a high level of adherence is important for the success of PrEP but was not always achieved by participants in trials. Consequently, patients on PrEP should be encouraged to use PrEP in combination with other effective prevention methods (including condoms) and should be provided with access to such methods (directly by the prescribing clinician or via referral to appropriate risk-reduction services).²

Finally, a French study termed Ipergay has shown the success of an approach termed “PrEP on demand,” in which individuals at risk for acquisition of HIV were prescribed FTC/TDF only on the day of anticipated sexual relations and for 2 days thereafter instead of every day. The advantage of the latter approach is that it may lower the side effects associated with FTC/TDF since some patients would be taking fewer pills that once daily. This would also help reduce costs.⁸ As previously mentioned, however, the USPHS does not sanction this approach.

The complete USPHS Clinical Practice Guidelines for PrEP and A Clinical Provider’s Supplement are available online.The supplement includes a patient checklist to help maximize the benefit of PrEP and informational patient handouts. It also includes a risk measurement tool for MSM, allowing physicians to identify those patients at highest risk for HIV infection for whom PrEP may be indicated. Information about adherence and risk-reduction counseling is also provided, as well as information on administrative and billing codes for PrEP-related services.