Tenofovir for Pre-exposure Prophylaxis Appears Safe and Does Not Discourage
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.
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,
and Atripla (tenofovir/emtricitabine/efavirenz)
pills -- can lower women's risk of HIV infection by 39%.
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.
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.
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
men completed the study, for a retention rate of 86%.
participants became HIV positive during follow up:
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
in the delayed treatment arm who seroconverted before starting
tenofovir or placebo.
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%).
proportions of men in both groups (about 10%) experienced moderate
or severe (grade 3-4) clinical events or laboratory abnormalities.
serious adverse events occurred, 16 in the tenofovir group and 11
in the placebo group (not a statistically significant difference).
in both arms did not experience significant increases in creatinine
from the baseline level, and no cases of grade 3-4 creatinine elevation
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
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.
sexual risk behavior did not change significantly in either arm
during the trial.
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.
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.