HIV prophylaxis

HIV Prophylaxis Successful Before and After Exposure CME/CE

News Author: Steven Fox
CME Author: Laurie Barclay, MD

Clinical Context

The main routes of HIV transmission include unprotected sexual activity, use of contaminated needles, and mother-to-child transmission during the peripartum period or through breast-feeding.

Evidence-based strategies to prevent HIV transmission include pharmacologic as well as nonpharmacologic therapies.

The objective of this review by Bogoch and colleagues was to describe evidence-based strategies for clinical practice regarding pharmacotherapy to prevent HIV transmission among people who have been exposed to the virus or who are at high risk for HIV infection in nonoccupational settings. The reviewers discuss postexposure prophylaxis, preexposure prophylaxis, and early initiation of antiretroviral therapy.

Study Synopsis and Perspective

Although treating people exposed to HIV soon after exposure is crucial, offering treatment to some especially high-risk people before potential exposure is an even newer approach that is showing promise, according to a review article focusing on strategies for preventing HIV infections in nonoccupational settings, published in the June issue of the Canadian Medical Association Journal.

"Although postexposure prophylaxis has a long history of success, newer methods such as pre-exposure prophylaxis and earlier treatment in the course of the infection ('treatment as prevention') are being implemented with some success," write Isaac Bogoch, MD, from the Division of Infectious Diseases, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; and the Division of Infectious Diseases, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, and colleagues.

During the past few years, a number of large randomized trials have been conducted, and the results of those studies have added considerably to what is known about effective pre- and postexposure treatment.

To help highlight those findings, this group of researchers conducted a review of the literature on those topics from January 1990 through April 2012.

The authors say they included trials with the highest level of evidence for each topic under consideration. When no controlled trials were available, they relied on observational studies.

Postexposure Prophylaxis

First, according to the review, the authors say evidence for nonoccupational postexposure prophylaxis is limited to only 1 case-control study and a few observational cohort studies.

The earliest evidence was extrapolated from a retrospective case-control study of healthcare workers who had been exposed to HIV via percutaneous injuries in their jobs (N Engl J Med. 1997;337:1485-1490). In that study, an 81% reduction in HIV seroconversion was seen using zidovudine monotherapy (odds ratio [OR] 0.19; 95% confidence interval [CI], 0.06 - 0.52).

Since that study, several observational studies have been conducted. One study (Clin Infect Dis. 2005;41:1507-1513) documented 7 seroconversions among 702 people (1.0%; 95% CI, 0.4 - 2) who had high-risk exposures (most often unprotected anal intercourse between men). Their HIV status was evaluated 12 weeks after being administered an antiretroviral regimen that began within 72 hours of their exposure. All of the men who seroconverted had engaged in receptive anal intercourse.

The authors say it appears some postexposure regimens are better tolerated than others, and therefore patients may be more likely to complete courses of therapy with those drugs.

For example, the authors write, 1 study that employed historical controls found that significantly more patients finished a 28-day course of postexposure therapy with the drug tenofovir, rather than zidovudine, mostly because of tenofovir's more favorable adverse effect profile (J Acquir Immune Defic Syndr. 2008;47:494-499).

The authors note that according to their review, postexposure treatment should be initiated within 72 hours after exposure and continued for 28 days, and therapy should be offered to anyone who has engaged in high-risk behaviors such as sharing needles or having unprotected sex with a person who is known to be HIV-positive.

The choice of which drugs to use for postexposure prophylaxis varies according to risk for exposure, the authors note. Two or 3 drugs are often combined, with 3-drug regimens recommended for patients with highest-risk exposure; for example, receptive anal intercourse or other mucosal exposure to people with detectable viral loads.

In theory, all classes of antiretroviral agents can be used for postexposure prophylaxis, the authors say, but in day-to-day practice, some are not as practical to use because of their potential for adverse effects. Those include nevirapine, abacavir, and efavirenz.

More commonly used antiretrovirals include the 2-drug regimen of tenofovir plus emtricitabine. If a third agent is to be added, the authors say, one of the protease inhibitors such as lopinavir, atazanavir, or darunavir, all of which can be boosted by ritonavir, may be good choices.

Once treatment has begun, patients should be followed up 2 weeks later with blood tests to check for renal or liver toxicity, and should be screened for HIV seroconversion at baseline, 6 weeks, 12 weeks, and 6 months.

Preexposure Prophylaxis

There have been several recent large trials for preexposure prophylaxis, some of which are showing significant success in preventing HIV transmission, the authors note.

The first, published in 2010 (N Engl J Med. 2010;363:2587-2599), was a randomized, placebo-controlled, double-blind study conducted among nearly 900 women in a high-HIV-prevalence area of Africa who used a topical vaginal microbicide no more than 12 hours before sex and again within 12 hours after.

That approach was shown to be 39% effective in preventing HIV infection. Incidence in the treatment group was 5.6 infections per 100 woman-years (95% CI, 4 - 7.7). Among women using the placebo, the incidence rate was 9.1 per 100 woman-years (95% CI, 6.9 - 11.7). Women who reported higher levels of adherence to the treatment also had less risk for infection.

In another study (Study to Assess the Role of Truvada in Preventing HIV Acquisition in Women), an international trial that was randomized and placebo controlled, investigators followed up 2499 gay or bisexual men and transgender women for a total of 3324 person-years and found that once-daily preexposure administration of combined emtricitabine and tenofovir led to a 44% relative reduction (95% CI, 15% - 63%) in HIV transmission. Once again, individuals who reported the highest rates of adherence to therapy demonstrated the least risk for HIV seroconversion.

In fact, study participants who reported having taken their medications more than 90% of the time showed a 73% reduction in risk (95% CI, 41% - 88%), the authors say.

Results in another trial that used the same 2-drug regimen were less encouraging. In that study, no significant difference in infection rates was seen. Investigators are continuing to look into why the results differed from the earlier study.

Unanswered Questions

The authors of the present study note that several unanswered questions remain regarding preexposure prophylaxis. Among them are which risk groups would derive the most benefit from such approaches, the relative efficacy of continuous therapy vs intermittent prophylaxis, and whether resistance to drugs will eventually develop in people receiving prophylactic therapy.

They conclude their review by stressing that probably the best method for stemming the spread of HIV is to effectively treat people who are already infected, as antiretroviral therapy reduces the concentration of virus in blood and in genital secretions.

The authors have disclosed no relevant financial relationships.

CMAJ. Published online May 28, 2012.

Study Highlights

• The reviewers searched Ovid MEDLINE from January 1990 to April 2012 and the Cochrane Library for pertinent English-language publications.
• Search terms were postexposure prophylaxis, preexposure prophylaxis, HIV transmission, PEP, PrEP, and antiretroviral therapy.
• Inclusion criteria were trials with the highest level of evidence for each topic under consideration and observational studies when no controlled trials were available.
• Evidence regarding nonoccupational postexposure prophylaxis is limited: 1 case-control study and several observational cohort studies.
• Data from these studies suggest that postexposure prophylaxis is effective, but there are no randomized, prospective data.
• Postexposure prophylaxis should be started as soon as possible within 72 hours of a suspected HIV exposure and continued for 28 days.
• Regimens for postexposure prophylaxis may include 300 mg of tenofovir and 200 mg of emtricitabine (a combination tablet is available for these medications), once daily for 28 days.
• Another regimen for postexposure prophylaxis is 150 mg of lamivudine and 300 mg of zidovudine (a combination tablet is available for these medications), twice daily for 28 days.
• If a third agent is needed for postexposure prophylaxis, options include 400 mg of raltegravir twice daily; 2 combination tablets of 400 mg of lopinavir/100 mg of ritonavir twice daily; 800 mg of darunavir plus 100 mg of ritonavir once daily; or 300 mg of atazanavir plus 100 mg of ritonavir once daily.
• Usual follow-up includes blood tests after 2 weeks to evaluate for renal or liver toxicity, and HIV screening at baseline, 6 weeks, 12 weeks, and 6 months.
• Patients should be advised to have only protected intercourse (oral, vaginal, and anal) at least until a 6-month HIV screening test result is confirmed to be negative.
• In certain high-risk populations, preexposure prophylaxis is a newer method that may be effective to prevent HIV transmission, and it may be considered in these patients after consulting guidelines.
• Among several recent large trials of preexposure prophylaxis, some have shown marked success in preventing HIV transmission.
• Controversies regarding preexposure prophylaxis include appropriate recipients, implementation, costs, the possibility for increased risk-taking behavior, the risk for viral resistance to antiretroviral drugs, and the potential for long-term adverse effects.
• All preexposure prophylaxis should be used as part of a more comprehensive plan for preventing HIV transmission.
• This plan should include counseling on safer sexual practices and condom use, testing for and treating other sexually transmitted infections, and male circumcision and needle exchange programs when appropriate.
• A suitable regimen for preexposure prophylaxis is 300 mg of tenofovir and 200 mg of emtricitabine, once daily, continued indefinitely.
• In patients who already have HIV infection, starting antiretroviral therapy early may effectively prevent HIV transmission in the community.

Clinical Implications

• A literature review on prophylaxis for HIV suggests that postexposure prophylaxis is effective, but randomized, prospective data are lacking. Postexposure prophylaxis should be started as soon as possible within 72 hours of a suspected HIV exposure and continued for 28 days.
• Among several recent large trials of preexposure prophylaxis for HIV, some have shown marked success in preventing HIV transmission. All preexposure prophylaxis should be used as part of a more comprehensive plan for preventing HIV transmission.