SUMMARY: HIV pre-exposure prophylaxis (PrEP) using once-daily oral tenofovir appeared safe and did not increase the likelihood of risky sexual behavior among men who have sex with men in 3 U.S. cities, researchers reported in a late-breaker presentation at the XVIII International Conference on AIDS (AIDS 2010) last week in Vienna. The study found no indication of significant safety issues including kidney problems or bone loss. None of the 7 men who became HIV infected during the 2-year follow-up period were taking tenofovir, but this analysis was not powered to determine effectiveness.

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Biomedical approaches to HIV prevention have become a mainstay of the field in recent years. As previously reported, investigators with the CAPRISA study last week presented the first evidence from a human trial indicating that a vaginal microbicide containing tenofovir -- the nucleotide reverse transcriptase inhibitor in the Viread, Truvada (tenofovir/emtricitabine), and Atripla (tenofovir/emtricitabine/efavirenz) pills -- can lower women's risk of HIV infection by 39%.

Later in the week, another group of researchers presented data from a study showing that tenofovir taken in pill form every day appears to be safe and acceptable as pre-exposure prophylaxis against HIV infection -- better known as PrEP -- and does not lead to "behavioral disinhibition," or increased propensity to engage in risky sex.

Lisa Grohskopf from the Centers for Disease Control and Prevention (CDC) and colleagues conducted a randomized double-blind trial (CDC-4323) to evaluate the clinical and behavioral safety of once-daily oral tenofovir among men who have sex with men (MSM) in Atlanta, Boston, and San Francisco.

Between February 2005 and July 2007, the study enrolled 400 initially HIV negative men who reported having anal sex with another man during the past year. Participants -- allocated into 4 study arms of 100 men each -- were randomly assigned to take either 300 mg oral tenofovir or placebo once-daily, starting either at the time of enrollment (and continuing for 4 years) or after a 9 month delay (and continuing for 15 months); 373 participants actually began their assigned treatment.

The participants had an average age of 39 years. Most (about 75%) were white, 15% were African-American (more in the placebo arm), 9% were Hispanic, and 4% were Asian/Pacific Islanders. On average, they had 4 male sexual partners in the past 3 months; about one-third in both arms reported unprotected sex during the same period and about 13% said they had high-risk sex (for example, unprotected sex with a partner known to be HIV positive).

Participants had quarterly study visits that included HIV testing, risk-reduction counseling, and assessment of adherence, acceptability, and biomedical and behavioral safety.

Researchers measured laboratory biomarkers of kidney function and bone health (creatinine and phosphate levels), and the San Francisco sites also assessed bone density using DEXA scans, since kidney impairment and bone loss are potential toxicities associated with tenofovir in some studies.

Results

	323 men completed the study, for a retention rate of 86%.
	7 participants became HIV positive during follow up:
	- 4 placebo recipients (including 1 who tested HIV negative at enrollment but was later found to have had acute infection in the "window period" before the test can measure enough antibodies); - 3 in the delayed treatment arm who seroconverted before starting tenofovir or placebo.
	The most common adverse events were diarrhea, back pain, headache, and depression; only back pain was significantly more common in the tenofovir group (13% vs 6%).
	Similar proportions of men in both groups (about 10%) experienced moderate or severe (grade 3-4) clinical events or laboratory abnormalities.
	27 serious adverse events occurred, 16 in the tenofovir group and 11 in the placebo group (not a statistically significant difference).
	Participants in both arms did not experience significant increases in creatinine from the baseline level, and no cases of grade 3-4 creatinine elevation were observed.
	No participants in the tenofovir group and about 3% in the placebo group developed serious hypophosphatemia, or low blood phosphate level (a possible sign of bone loss), but the difference did not reach significance.
	Among the San Francisco participants who underwent DEXA scans, about 4% of men taking tenofovir and 2% taking placebo experienced a decrease of more than 5% in hip or spine bone density, but again the difference again was not significant.
	Reported sexual risk behavior did not change significantly in either arm during the trial.

Based on these findings, the investigators concluded, "No significant biomedical safety issues were identified."

Importantly, this analysis was not designed to evaluate the effectiveness of tenofovir PrEP -- larger studies are underway for that purpose -- but oral tenofovir has been shown to reduce the risk of HIV acquisition in studies of monkeys. While none of the 7 men who became infected in this trial were taking tenofovir, the numbers were small enough that this outcome could have been due to chance.

The earliest (and furthest along) PrEP trials are studying tenofovir alone, while more recent trials are looking at the combination of tenofovir plus emtricitabine (Emtriva, also in the Truvada and Atripla coformulations), which appeared more effective than tenofovir monotherapy in animal studies. The first efficacy data is expected as soon as the end of this year.

Investigator affiliations: Centers for Disease Control and Prevention, Atlanta, GA; Northrop Grumman, Inc., Atlanta, GA; Fenway Community Health, Boston, MA; San Francisco Department of Public Health, San Francisco, CA; AIDS Research Consortium of Atlanta, Atlanta, GA.

7/30/10

Reference
L Grohskopf, R Gvetadze, S Pathak, and others. Preliminary analysis of biomedical data from the phase II clinical safety trial of tenofovir disoproxil fumarate (TDF) for HIV-1 pre-exposure prophylaxis (PrEP) among U.S. men who have sex with men (MSM). XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract FRLBC102.