3 Newly Published PrEP Studies: Preexposure Prophylaxis for HIV Infection among African Women
Download the PDF here|
Download the PDF here
Lut Van Damme, M.D., Amy Corneli, Ph.D., Khatija Ahmed, M.Med., Kawango Agot, Ph.D., Johan Lombaard, M.B., Ch.B., Saidi Kapiga, M.D., Mookho Malahleha, M.B., Ch.B., Fredrick Owino, M.B., Ch.B., Rachel Manongi, M.D., Jacob Onyango, M.A., Lucky Temu, M.D., Modie Constance Monedi, Adv.Dip.Mid., Paul Mak'Oketch, B.Pharm., Mankalimeng Makanda, M.B., Ch.B., Ilse Reblin, B.Soc.Sc., Shumani Elsie Makatu, M.A., Lisa Saylor, B.A., Haddie Kiernan, B.S.N., Stella Kirkendale, M.P.H., Christina Wong, Ph.D., Robert Grant, M.D., Angela Kashuba, Pharm.D., Kavita Nanda, M.D., Justin Mandala, M.D., Katrien Fransen, M.S., Jennifer Deese, M.P.H., Tania Crucitti, Ph.D., Timothy D. Mastro, M.D., and Douglas Taylor, Ph.D. for the FEM-PrEP Study Group
NEJM July 11, 2012
Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others.
In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF-FTC in preventing HIV acquisition and to evaluate safety.
HIV infections occurred in 33 women in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF-FTC group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF-FTC group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the TDF-FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy.
Prophylaxis with TDF-FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low.
Recent studies have shown that daily oral preexposure prophylaxis with 300 mg of tenofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir, alone or in combination with 200 mg of emtricitabine (FTC) (TDF-FTC [Truvada], Gilead Sciences) can reduce the risk of sexually acquired human immunodeficiency virus (HIV) infection in men and women.1-3 Consequently, an advisory committee of the Food and Drug Administration recently recommended that the label indications for Truvada be changed to include HIV prevention.4
We report the primary results of the Preexposure Prophylaxis Trial for HIV Prevention among African Women (FEM-PrEP), a randomized, double-blind, placebo-controlled trial of once-daily oral TDF-FTC among high-risk women in Africa. The study was stopped early, on April 18, 2011, because of a lack of efficacy.
In this study, there was no significant reduction in HIV acquisition among women in the TDF-FTC group, as compared with the placebo group. Drug-level analyses revealed that less than 40% of the HIV-uninfected women had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. If such low adherence levels prevailed for the entire cohort, the trial was substantially underpowered to detect an effect of TDF-FTC on the risk of HIV acquisition. Although women in the TDF-FTC group had higher rates of some known side effects than those in the placebo group, the prevalence of these events was modest and consistent with the overall low adherence. However, the rate of adverse events might have been higher if the level of adherence had been higher.
Relatively low adherence levels were also observed in the case-control analysis in the Preexposure Prophylaxis Initiative study involving men who have sex with men,9 in which tenofovir was detected in 44% of the uninfected controls. This finding might indicate that TDF-FTC is more forgiving of imperfect use with rectal exposure to HIV than with vaginal exposure, possibly because of a difference in concentrations of the active metabolites in rectal and vaginal tissues after oral administration.10
In the Partners Preexposure Prophylaxis study,2,11 there was a highly significant protective effect of both TDF and TDF-FTC in the overall study population and among female participants. Among uninfected controls, drug-level analyses revealed adherence rates of 81% in the TDF-FTC group and 83% in the TDF group. Thus, if there are biologic differences between drug responses in men and those in women or between HIV exposure with vaginal and rectal sex, it appears that these differences may be overcome with high rates of adherence.
In the Vaginal and Oral Interventions to Control the Epidemic (VOICE, or MTN-003) trial among women,12 treatment with daily oral TDF was stopped early because of a lack of effectiveness, a finding that is similar to ours for TDF-FTC and that contrasts with the findings for both TDF and TDF-FTC in the Partners Preexposure Prophylaxis study. One of the hypotheses is that low adherence may have played a role. In the VOICE trial, participants continue to receive daily oral TDF-FTC.
It is important to understand why so many women came for the monthly visits and underwent frequent blood testing but did not take their pills. We hypothesize that the women's perception that they were at low risk for HIV infection may have contributed to the poor adherence. In addition, the high pregnancy rate among women receiving oral contraceptives may indicate difficulty with daily pill regimens. Understanding these issues and identifying characteristics predictive of high adherence will be important in developing strategies for adherence counseling for future studies and programs.
Self-reported behaviors and data regarding the prevalence of sexually transmitted infections do not suggest increased risk behavior among women in the TDF-FTC group. Although there were slightly higher rates of study-drug discontinuation owing to adverse events in the TDF-FTC group, the percentage of days on which women had a study drug available for use was high in the two groups.
There were no major safety concerns in the trial, although low adherence may have compromised our ability to identify a safety concern or an effect on the CD4+ T-cell count and viral load in participants with seroconversion. Five participants had HIV infections that were resistant to FTC, one of them in the placebo group. Among these five participants, one in the TDF-FTC group had not received the study drug for 48 weeks because of early toxicity, leaving three cases of resistant infection in the TDF-FTC group among participants who may have had access to the study drug around the time of acquiring the infection. Seroconversion was discovered in these three participants within 12 weeks after enrollment. Thus, despite intensive testing, we cannot definitively rule out the possibility that the participants were already infected at enrollment.
It has been suggested that the use of TDF-FTC may mask HIV infection by modifying the viral load and antibody production. However, the similarity in the rates of HIV infection in the two study groups after study-drug discontinuation is not consistent with this concern.
Although we suspect that the lack of efficacy of TDF-FTC in our study population was due to low adherence, biologic factors may also be involved. The protective effect of TDF-FTC might be diminished in the presence of a very high viral load in the infecting partner, as occurs in the acute phase of HIV infection. Another possible reason for the lack of efficacy of TDF-FTC is a high cytokine level. It has been reported that the effect of vaginal tenofovir 1% gel may be lower in women with an elevated vaginal cytokine profile.13
Our trial has several limitations. The low adherence impairs our ability to make clear conclusions regarding the effectiveness and safety of TDF-FTC in the study population. In addition, 13% of the participants were lost to follow-up. Although we were able to document that a third of these women had relocated outside the study area, the absence of HIV testing at the final visit means that we cannot rule out the possibility that a difference in rates of HIV acquisition existed between the two study groups among those who were lost to follow-up.
In conclusion, prophylaxis with TDF-FTC did not reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. However, we were unable to accurately assess the effect of TDF-FTC on HIV acquisition or safety because of low study-drug adherence, which may be an indication that a daily pill-taking regimen will be difficult for some populations. A better understanding of indicators of adherence among women at high risk for HIV infection is needed to ensure the effectiveness of future preexposure prophylaxis programs.
Recruitment and Follow-up
During the nearly 2-year recruitment period, 4163 women were screened and 2120 underwent randomization (Figure 1). Demographic characteristics and other baseline data were generally similar in the two groups (Table 1). The mean age was 24.2 years. Among the women who were tested at baseline, 5.7% had gonorrhea and 14.0% had chlamydial infection; 41.8% had bacterial vaginosis. Participants reported an average of 3.7 vaginal sex acts, 1.9 sex acts without a condom, and 1.0 sex partners in the 7 days before enrollment; 12.6% reported exchanging sex for money or gifts with a nonprimary partner in the previous 4 weeks. At enrollment, most participants were using an injectable contraceptive (66.1%) or oral contraceptive (30.1%) to meet the study requirement, with more use of oral contraceptives in the TDF-FTC group than in the placebo group (32.0% vs. 28.2%).
Among enrolled participants, 62 (2.9%) had no follow-up HIV testing; it was determined that 2 participants (1 in each study group) had preexisting HIV infection, leaving 2056 women who contributed 1407.4 person-years to the primary effectiveness analysis (Figure 1). A total of 266 women (12.5%) were lost to follow-up, with a determination that a third of these women had relocated without returning for a final visit. Another 113 women (5.3%) discontinued the study early (most for personal reasons unrelated to the study), leaving 1741 of 2120 women (82.1%) who contracted HIV infection or completed follow-up and were included in the primary end-point analysis.
Of the 68 HIV infections that occurred before the visit at 52 weeks (or the first visit after April 18, 2011), 33 occurred in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and 35 in the placebo group (incidence rate, 5.0 per 100 person-years), leading to an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval [CI], 0.59 to 1.52; P=0.81) (Table 2). A prespecified sensitivity analysis in which data were censored when the study drug was no longer available (i.e., owing to an interruption or a missed visit) also showed a between-group difference that was not significant (hazard ratio, 0.82; 95% CI, 0.49 to 1.36; P=0.44). When all HIV infections occurring after randomization (i.e., through week 8 after the regular study visit) were included in the analysis, there were 34 infections in the TDF-FTC group and 39 in the placebo group (hazard ratio, 0.87; 95% CI, 0.55 to 1.38; P=0.56). The estimated cumulative probability of infection at 12 months was 0.049 in the TDF-FTC group and 0.046 in the placebo group (Figure 2).
Less than 1% of women had grade 3 or higher hepatic abnormalities or grade 2 or higher creatinine abnormalities, with no significant differences between the two study groups (Table 3). Rates of grade 3 or higher phosphorus abnormalities were also similar in the two groups (4.4% in the TDF-FTC group and 3.9% in the placebo group, P=0.59). With respect to other prespecified safety end points, only the proportions of women with nausea (P=0.04), vomiting (P<0.001), and any alanine aminotransferase elevation (P=0.03) were significantly higher in the TDF-FTC group, with rates of vomiting and nausea more frequent in the first few months of follow-up. (Details regarding the safety analysis are provided in the Supplementary Appendix, available at NEJM.org.)
Less than 5% of women had hepatic or renal abnormalities requiring discontinuation of the study drug (Table S4 in the Supplementary Appendix), with a trend toward a significant between-group difference (4.7% in the TDF-FTC group vs. 3.0% in the placebo group, P=0.051).
There were 36 serious adverse events reported in the TDF-FTC group and 24 in the placebo group. (A complete list is provided in Table S2 in the Supplementary Appendix.) One participant in the TDF-FTC group was hospitalized with diarrhea and severe dehydration and later died. Another participant in the placebo group died of unknown causes several months after her last clinic visit. We were unable to obtain any additional details with respect to these two events.
The percentage of women with pregnancy-related adverse events was higher in the TDF-FTC group (P=0.04), but there were also 74 pregnancies in this group (incidence rate, 11.2 per 100 person-years), as compared with 51 in the placebo group (incidence rate, 7.5 per 100 person-years). In a preliminary analysis, there was no evidence of a difference between groups in rates of abortions or other potentially teratogenic effects. The between-group difference in pregnancy rates was not significant after adjustment for study site, age, and the imbalance in the use of oral contraceptives at baseline (hazard ratio, 1.32; P=0.13). Pregnancy rates were highest among participants who chose to use oral contraceptives at baseline (incidence rate, 29.0 per 100 person-years), with no significant difference between the two study groups.
Among participants in whom HIV infection was identified, there was no significant between-group difference in the mean CD4+ counts or log10 viral loads (Table 3). We did not observe any K65R or K70E mutations in reverse transcriptase, which cause resistance to tenofovir. Among women with HIV seroconversion, one in the placebo group and three in the TDF-FTC group were infected with a viral strain with a M184V mutation in reverse transcriptase; a fourth woman with a resistant infection in the TDF-FTC group had a viral strain with an M184I mutation. Both M184V and M184I mutations cause resistance to FTC. Phenotypic testing was successful in four of the five resistant infections and confirmed resistance to FTC.
At the time of study-drug discontinuation, 95% of participants reported that they had usually or always taken the assigned drug. Pill-count data were consistent with ingestion of the study drug on 88% of the days on which it was available to the participants. In contrast, drug-level testing revealed much lower levels of adherence. In prespecified analyses, we considered that 10 ng of tenofovir per milliliter in plasma was evidence that TDF had been taken within the previous 48 hours.8 Among women with seroconversion in the TDF-FTC group, the target plasma level of tenofovir (≥10 ng per milliliter) was identified in 7 of 27 women (26%) at the beginning of the infection window (excluding 6 women for whom the window started at enrollment), in 7 of 33 (21%) at the end of the window, and in 4 of 27 (15%) at both visits (Figure S2 in the Supplementary Appendix).
Among the uninfected control participants, the numbers of women with target-level tenofovir were somewhat higher: 27 of 78 women (35%) at the beginning of the infection window, 35 of 95 (37%) at the end of the window, and 19 of 78 (24%) at both visits. These differences were not significant after adjustment for age, unprotected sex, and use of injectable contraception (P=0.70 at the start of the infection window, P=0.13 at end of the window, and P=0.68 at both visits).
Risk Perception and Sexual Behavior
Most women perceived themselves to be at no or low risk for HIV infection in the coming month when asked at the baseline visit (70.0%) and at the last regular follow-up visit (74.8%). There was no evidence of increased HIV risk behavior during the trial, with modest but significant reductions in the numbers of partners (mean reduction, 0.14; P<0.001 by paired-data t-test), vaginal sex acts (mean reduction, 0.58; P<0.001), and sex acts without a condom (mean reduction, 0.46; P<0.001) reported by women at the last follow-up visit, as compared with 7 days before enrollment.
Fewer than half the study participants agreed to undergo a pelvic examination after randomization, so we were not able to confirm the self-reported data on risk behavior on the basis of data regarding sexually transmitted infections. Among participants who underwent testing at the final visit, there were no significant between-group differences in the prevalence of trichomoniasis (3.5% in the TDF-FTC group and 5.8% in the placebo group, P=0.20), candidiasis (15.2% and 15.2%, respectively; P=1.00), gonorrhea (4.9% and 3.2%, P=0.25), or chlamydial infection (13.3% and 12.0%, P=0.65).