Back grey_arrow_rt.gif
 
 
Preexposure Chemoprophylaxis for HIV Prevention
in Men Who Have Sex with Men - pdf attached
 
 
  Download the PDF here
 
NEJM Nov 23 2010
 
The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In post hoc analyses, pill use on 90% or more of days was recorded at 49% of visits on which efficacy was 73% (95% CI, 41 to 88; P<0.001).
 
In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57).
 
Supplemental Introduction
Few concepts for the prevention of sexual HIV transmission have been rigorously proven: of 37 late-phase trials, only 6 have demonstrated a significant protective benefit.1,2 Tenofovir 1% vaginal gel had 39% efficacy in heterosexual women.2 All other successful prevention interventions were clinic-based and directly observed, including enhanced services for sexually transmitted infections (STIs),3 male circumcision,4-6 and a vaccine candidate.7 None of the successful interventions are known to be effective in men and transgender women who have sex with men (MSM), who carry a major burden of the global epidemic.8,9 Favorable characteristics of FTC/TDF for PrEP include the following: Both agents persist in active forms in the body for long periods of time, allowing for once daily dosing. Neither agent has interactions with anti-tuberculosis therapy, hormonal contraception, feminizing therapy, or anti- malarial agents. Both agents are used for treatment of HIV infection,10 for which they have a well- established safety profile, and are available in patented and generic formulations.
 
Supplemental Discussion
The most likely explanation for the high rate of undetectable drug in this study was low pill use. Poor drug absorption or rapid clearance are unlikely given that FTC and TDF plasma pharmacokinetics have been studied in diverse populations including HIV-negative volunteers and Hispanics, who made up much of the iPrEx study sample, and no unusual patterns of undetectable drug have been reported.19-21 The high concordance among positive and negative drug detection in plasma and cells and between FTC and TFV is also evidence against slow drug absorption or rapid clearance as causes for low drug levels. The intracellular assay used in this study was sensitive enough to detect drug for approximately 14 days after the last dose taken, assuming expected concentrations in stored viable specimens, which were used in this study, and the half-lives of 39h and 150h for FTC- TP and TFV-DP, respectively.16,18 The detection of intracellular TFV-DP in stored viable cell specimens has been compared against TFV detection in other sample types, such as plasma and hair, with >90% concordance.13
 
High reported adherence with low objective indicators of use have been reported in heterosexual women in a microbicide trial,22 as in this trial of MSM. Social desirability reporting bias may be higher in efficacy trials, which place a strong emphasis on perfect compliance: Strategies to allow comfort in accurate reporting are clearly needed.
 
Start-up symptoms could have contributed to drug interruptions that were not reported by the participants. Long-term adherence could be improved if peers or counselors provide reassurance that side effects will resolve after a few weeks.
 
Fewer participants in the FTC/TDF group were subsequently found to have pre-existing HIV infection at enrollment. FTC/TDF may have provided some post-exposure prophylactic benefit after enrollment. There was no evidence for delayed seroconversion in the FTC/TDF group in this trial. Occult infection and delayed seroconversion were not observed in non-human primates protected by PrEP regimens.23 Additional information about possible post-treatment manifestations of PrEP use will be available after all iPrEx participants stop study drug.
 
The optimum PrEP regimen has not been established. Non-human primate models suggest that combination FTC/TDF is more protective than TDF alone, although adding FTC to the regimen was associated with drug resistance while TDF alone was not.24 Clinical trials that include arms for both FTC/TDF and TDF alone are in progress (see www.avac.org). While the iPrEx study recommended once daily pill use to all participants, the levels of drug associated with protection could be achieved with less frequent dosing. Peri-intercourse use of a tenofovir 1% vaginal gel was efficacious for women.2 Whether peri-intercourse dosing of oral FTC/TDF is acceptable, feasible and effective in MSM warrants further study, as this approach would decrease pill requirements and costs and may decrease dose-related side effects.
 
This study of FTC/TDF PrEP in MSM is not generalizeable to other populations, like heterosexual men and women, and injection drug users who are being evaluated in other PrEP studies. These populations have different routes of exposure to HIV (penile, vaginal, and parenteral), special safety concerns related to pregnancy, and social circumstances that may make pill use easier or more difficult. FTC/TDF PrEP was more effective in those reporting unprotected rectal exposure at baseline in this study; more information about PrEP efficacy after penile exposure is needed, and trials in heterosexual men are underway in Africa (see www.avac.org).
 
PrEP is a behavioral intervention requiring that services be available and used. Both are well-known challenges in the prevention field. Cost-effectiveness is important, and is favored by efficacy in high- risk groups, minimal monitoring requirements to assure safety, rare adverse events, and activity in younger populations.25 The iPrEx study found greater efficacy in those reporting URAI at screening, the subgroup with the highest HIV incidence in the placebo arm. Finding safety and efficacy in young adult MSM, who comprised half of the iPrEx cohort, highlights important opportunities to protect people while social and behavioral skills are learned. Daily oral FTC/TDF PrEP was not associated with moderate or severe adverse events, confirming previous reports.26
 
Future research and program development should continue to build synergies between PrEP and other prevention strategies, including HIV testing and counseling, planning for sex, STI management, and HBV vaccination. Such mutually reinforced frameworks are needed to protect diverse communities from the spread of HIV and other diseases.

Safety
 
In testing for elevations in serum creatinine levels, there were 41 instances of elevations that were at least 1.1 times the upper limit of the normal range or more than 1.5 times the baseline level. Of these elevations, 26 (2%) were in the FTC-TDF group and 15 (1%) were in the placebo group (P=0.08). Two of these elevations increased in grade, accounting for a total of 43 creatinine adverse events (Table 2Table 2Adverse Events., and Table S9 in the Supplementary Appendix). Overall, 18 creatinine elevations (44%) remained in the normal range, and 36 (88%) were not confirmed on the next test. A total of 10 elevations led to discontinuation of a study drug (7 in the FTC-TDF group and 3 in the placebo group); study drugs were restarted in 9 subjects. Serum creatinine levels were elevated at more than one consecutive test in 5 subjects in the FTC-TDF group (<1%) and in none of the subjects in the placebo group. All elevations in the serum creatinine level resolved after the discontinuation of a study drug, within 4 weeks in 3 subjects, within 12 weeks in 1 subject, and within 20 weeks in 1 subject. Four of the subjects resumed taking FTC-TDF without recurrence of the elevation.
 
Moderate nausea (grade 2 and above) was reported more frequently in the FTC-TDF group than in the placebo group (22 vs. 10 events, P=0.04), as was unintentional weight loss of 5% or more (34 vs. 19 events, P=0.04) (for details, see Table S10 in the Supplementary Appendix).
 
 
 
 
  icon paper stack View Older Articles   Back to Top   www.natap.org