Plct-02-05-09 1.9

Tenofovir Disoproxil Fumarate for Preventionof HIV Infection in Women: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial Leigh Peterson1*, Doug Taylor1, Ronald Roddy2, Ghiorghis Belai1, Pamela Phillips1, Kavita Nanda1, Robert Grant3,4, Edith Essie Kekawo Clarke5, Anderson Sama Doh6, Renee Ridzon7, Howard S. Jaffe8, 1 Family Health International, Durham, North Carolina, United States of America, 2 Duke Clinical Research Institute, Durham, North Carolina, United States of America, 3 University of California San Francisco, San Francisco, California, United States of America, 4 J. David Gladstone Institutes, San Francisco, California, United States of America, 5 Ghana Health Service, Ministry of Health, Accra, Ghana, 6 University of Yaounde´, Yaounde´, Cameroon, 7 Bill and Melinda Gates Foundation, Seattle, Washington, United States of America, 8 Gilead Sciences, Foster City, California, United States of America Objectives: The objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in Foundation to Family HealthInternational (FHI). The views expressed in this article do not necessarily reflectthose of FHI or the Bill and Melinda GatesFoundation. Gilead Sciences provided the Design: This was a phase 2, randomized, double-blind, placebo-controlled trial.
tenofovir disoproxil fumarate andplacebo pills used in the study. Analysisof drug resistance was supported byNational Institutes of Health grant RO1 Setting: The study was conducted between June 2004 and March 2006 in Tema, Ghana; AI062333. RR is with the Bill and Melinda Douala, Cameroon; and Ibadan, Nigeria.
Gates Foundation and HJ is with GileadSciences; both contributed to study Participants: We enrolled 936 HIV-negative women at high risk of HIV infection into this design, as well as writing/reviewing thepaper and the decision to submit it for publication. LP has access to all the dataand has responsibility for the accuracy ofthe manuscript.
Intervention: Participants were randomized 1:1 to once daily use of 300 mg of TDF orplacebo.
Competing Interests: HSJ is anemployee and shareholder of GileadSciences, which provided tenofovirdisoproxil fumarate and matching Outcome measures: The primary safety endpoints were grade 2 or higher serum creatinine placebo for the study. RR is with the Bill elevations (.2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine and Melinda Gates Foundation, whichfunded the study.
aminotransferase elevations (.170 U/l) for hepatic function, and grade 3 or 4 phosphorusabnormalities (,1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2.
Citation: Peterson L, Taylor D, Roddy R,Belai G, Phillips P, et al. (2007) Tenofovirdisoproxil fumarate for prevention of HIVinfection in women: A phase 2, double- Results: Study participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or trial. PLoS Clin Trials 2(5): e27. doi:10.
1371/journal.pctr.0020027 laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing tothe primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in Accepted: April 10, 2007Published: May 25, 2007 participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95%confidence interval ¼ 0.03–1.93), which did not achieve statistical significance. Owing to Copyright: Ó 2007 Peterson et al. This isan open-access article distributed under premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved.
Attribution License, which permitsunrestricted use, distribution, andreproduction in any medium, providedthe original author and source are Conclusion: Daily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study.
alanine aminotransferase; AST, aspartateaminotransferase; ELISA, enzyme-linkedimmunosorbent assay; FHI, Family HealthInternational; HBsAg, hepatitis B virussurface antigen; HBV, hepatitis B virus;OMT, oral mucosal transudate; PEP, post-exposure prophylaxis; SAE, seriousadverse event; TDF, tenofovir disoproxilfumarate * To whom correspondence should beaddressed. E-mail: [email protected] Background: The World Health Organization has estimated that in The HIV epidemic is continuing to grow worldwide [1].
2006 around 4.3 million people were newly infected with HIV. Infection Consistent and correct use of condoms is recommended for rates seem to be increasing in some countries, and there is an urgent prevention of sexually transmitted HIV, but often women are need to find safe and effective ways of preventing HIV from being unable to negotiate condom use with their male partners.
transmitted from one person to another. Many strategies for the Safe, effective, and easy to use methods of HIV prevention are prevention of HIV transmission between adults, such as use of urgently needed, especially for women.
condoms or changes to behavior, are not completely reliable, and Tenofovir disoproxil fumarate (TDF) [2], the orally women, in particular, may not always be able to negotiate condomuse. Additional strategies for reducing the risk of HIV transmission are bioavailable prodrug of tenofovir, is metabolized to a needed. One of these strategies is called ‘‘pre-exposure prophylaxis.’’ competitive inhibitor of viral reverse transcriptase. TDF was This strategy involves individuals who are at high risk of becoming selected for clinical development as a treatment for HIV infected with HIV taking antiviral drugs to prevent HIV infection. One infection because of its (1) potency against wild-type HIV and particular drug, tenofovir disoproxil fumarate, is currently approved as some nucleoside-resistant strains of HIV [3–6], (2) low a treatment for HIV infection, and is also being investigated as a strong potential of selecting for TDF-resistant mutants [7], (3) low candidate for pre-exposure prophylaxis. The research presented herereports on results of a trial carried out at three different sites in Ghana, likelihood of metabolic/mitochondrial toxicity [8], and (4) Cameroon, and Nigeria. In the trial, 936 women who were not infected pharmacologic profile supporting daily dosing [2]. TDF was with HIV but who were at high risk of becoming infected, were licensed for the treatment of established HIV-l infection by randomized to take tenofovir tablets daily or, alternatively, placebo the United States Federal Drug Administration in 2001, and tablets. The researchers planned to follow up with the women for 12 the European Commission issued a marketing authorization months, and the primary analysis for efficacy would focus on a in 2002 [9]. TDF has since been used worldwide for treatment comparison of the rate of new HIV infections between the two arms ofthe trial. Primary safety analyses included specific laboratory tests of HIV infection, accounting for nearly 500,000 patient-years carried out on blood samples that might point to abnormalities in liver or kidney function. Safety data were also collected throughout the trial, We investigated the safety and effectiveness of a daily dose and health problems that arose were classified as adverse events or of 300 mg of TDF in preventing HIV infection among women at high risk for infection based on the following rationale: (1)initial prevention studies in simian models have provided What this trial shows: Unfortunately, this trial was not completed asplanned. Two sites (Nigeria and Cameroon) were closed either before the support for both pre- and post-exposure efficacy of TDF in planned number of participants had been recruited or before all preventing retroviral infections [11–14]; (2) TDF has been participants had completed full follow-up. Therefore, not enough data shown to be safe in large numbers of HIV-infected persons were available from this trial to determine whether tenofovir reduced the [15,16]; (3) TDF is dosed conveniently once a day; (4) TDF has risk of HIV infection. Only two sites contributed data for the primary no known interactions with hormonal contraception [17]; (5) safety analyses, which looked at liver and kidney function. The a high barrier to resistance was seen in clinical trials of HIV researchers did not see any statistically significant differences in thesesafety endpoints between participants taking tenofovir and those taking treatment, with the primary mutation identified (K65R) placebo. There were also no statistically significant differences between resulting in a reduction of viral replication to almost half the treatment groups in the number of adverse events. The main efficacy that of wild-type [18]; and (6) the drug’s sponsor, Gilead analysis found two new HIV infections in the tenofovir group and six in Sciences, is supportive of investigating the potential use of the placebo group. Because only eight effectiveness endpoints were TDF as a preventive agent. Moreover, should it prove to be observed during this study, the difference in HIV incidence between effective for HIV prevention, Gilead Sciences has committed these groups was not statistically significant.
to making TDF available in resource-poor settings for public Strengths and limitations: A strength of this trial is that it was correctly health use, as they currently do for treatment of HIV, via no- designed to address the original objectives of the study, involving profit pricing and licensing agreements.
appropriate concealment of randomization and blinding of participantsand study staff to treatment assignment. The main limitation of thisstudy was the closure of two study sites, which meant that the study did not have sufficient power to assess differences between trial arms in the Study participants were recruited from areas within each city Contribution to the evidence: At the time this trial was completed, that were considered high HIV transmission areas, including there was no other evidence from randomized studies that evaluated markets, bars, and hotels. Although we did not specifically ask antiretroviral drugs for prevention of HIV infection. This trial cannot, as part of the clinical trial procedures if the participants were however, definitively address whether tenofovir reduces the risk of HIV sex workers, most exchanged sex for money. Special ethical infection among at-risk women or not. Ongoing and future trials are considerations were taken into account because of the essential in order to answer this question. The trial reported hereprovides important data on the safety of daily tenofovir among high-risk potential vulnerability of this population. We developed HIV-uninfected women; the safety data are encouraging and suggest strategies to protect the confidentiality and autonomy of the that tenofovir use is not associated with increased adverse events as participants, increase/ensure comprehension of the informed consent and research methods, and promote access toresources and services during and after the trial.
The Editorial Commentary is written by PLoS staff, based on the reports of the We enrolled HIV-antibody-negative women 18 to 35 y old academic editors and peer reviewers.
who were at risk of HIV infection by virtue of having anaverage of three or more coital acts per week and four ormore sexual partners per month. Participants had to bewilling to use the study drug as directed and participate for up to 12 mo of follow-up. Because TDF has been associated resistance testing in their communities, as well as antiretro- with rare episodes of renal disorders, increased liver enzymes, viral drug provision when needed. Immediately after a and hypophosphatemia, participants were also required to participant missed a scheduled follow-up appointment, study have adequate renal function (serum creatinine , 1.5 mg/dl), staff made up to three attempts to contact that participant liver function (aspartate aminotransferase [AST] and alanine and reschedule the clinic appointment (ideally to occur aminotransferase [ALT] , 43 U/l), and serum phosphorus within 1 wk of the original appointment).
(2.2 mg/dl) at their screening visit. Since no adequate andwell-controlled studies of TDF have been conducted in pregnant women, participants were not enrolled if pregnant The objective of this trial was to investigate the safety and or breastfeeding, or wishing to become pregnant during the preliminary effectiveness of a daily dose of 300 mg of TDF versus placebo in HIV-uninfected women.
During recruitment, study staff explained the general purpose of the study and the eligibility requirements. Ifeligible, women were referred to the study clinic at each of Protocol-defined primary safety endpoints included grade 2 the three study sites. At the screening visit, women completed or higher serum creatinine elevations (.2.0 mg/dl) for renal written informed consent, received HIV pretest and condom function, grade 3 or 4 AST or ALT elevations (.170 U/l) for counseling, and underwent oral mucosal transudate (OMT) hepatic function, and grade 3 or 4 phosphorus abnormalities rapid HIV testing. All participants received HIV post-test counseling, a physical and pelvic examination, urine preg- After the study began, the TDF prescribing information nancy tests, and assessment of hepatic and renal function.
was amended to reflect a concern that people with chronic Women with reactive OMT rapid HIV tests received ELISA to hepatitis B virus (HBV) infection are at risk of developing confirm HIV status. Potential participants were asked to reactivation (i.e., flares) of hepatic disease after stopping use return 4 wk after their screening visit to receive the results of of TDF. To monitor for potential flares, we amended our their hepatic and renal function tests and, if applicable, a protocol to add HBV surface antigen (HBsAg) testing for all confirmatory HIV test. At this second visit, participants enrolled participants at the time of product discontinuation, signed or marked a consent form for enrollment, received and ALT/AST monitoring for 3 mo after product discontin- HIV counseling, provided urine for pregnancy testing, and uation among HBsAg-positive participants. This amendment provided another OMT sample for HIV testing.
was implemented only at the Ghana site in August 2005, All participants provided written informed consent in their which was the only active study site (i.e., on drug) at the time.
preferred language. Illiterate participants were read the The effectiveness endpoint was infection with HIV-1 or informed consent forms verbatim in the presence of a HIV-2, measured by detecting antibodies in OMT (OraQuick witness, and provided a mark or thumbprint in lieu of ADVANCE Rapid HIV-1/2 Antibody Test, Orasure Technol- signature. The study protocol and informed consent forms ogies, http://www.orasure.com) and confirmed by an enzyme- were approved by the Ghana Health Service Ethical Review linked immunosorbent assay (ELISA) (Genetic Systems HIV-1/ Committee, Accra, Ghana; the National Ethics Review HIV-2 Plus O ELISA, Bio-Rad, http://www.bio-rad.com) or Committee, Ministry of Public Health, Yaounde´, Cameroon; Western blot (Genetic Systems HIV-1 Western Blot, BioRad) the University of Ibadan/University College Hospital Institu- from a finger prick or blood serum specimen. Discordant tional Review Board, Ibadan, Nigeria; and the Protection of results between the rapid antibody and the ELISA assays were Human Subjects Committee, Family Health International (FHI), Durham, North Carolina, United States.
At each monthly follow-up visit, participants underwent OMT HIV and pregnancy testing, adverse event (AE) assess- We designed the study to have 90% power to conclude with ment, risk reduction counseling, and study drug and condom 95% confidence that TDF reduced the rate of HIV infection re-supply. Clinic staff counseled participants to take one pill by 50% (i.e., power to obtain a one-sided 95% upper every day, distributed condoms, and emphasized that confidence limit for the rate ratio that is less than 0.5) if condoms should be used for all sexual contacts with all the true rate of reduction due to TDF was at least 83%. The partners because they were using a product of unknown or no planned sample size was 1,200 participants (400 per site), with effectiveness for preventing HIV. Participants responded to 12 mo of follow-up for each participant. Based on prior work structured questionnaires on their sexual behavior and their with high-risk women in Cameroon [19], we assumed that the experience taking the pills during the previous 30 d, and were HIV incidence rate in the placebo group would be no less reminded of study concepts discussed during the informed than five per 100 person-years, and that follow-up would be at consent process. At months 1, 3, 6, 9, 12, and as needed, least 80% at 12 mo. Under these assumptions, we expected participants underwent physical examination and blood was that we would reach the required number of incident HIV drawn for laboratory assessment of hepatic and renal infections (30) to achieve 90% power. Owing to premature function. We discontinued product use for any participant closures of the Cameroon and Nigeria study sites, however, who had a reactive rapid HIV or positive pregnancy test the planned person-years of follow-up and study power could result. Pregnant women were allowed to resume study drug not be achieved. Consequently, the primary effectiveness use after their pregnancy had ended, providing they were not analysis was revised to a traditional two-sided test of non-zero breastfeeding. Study staff at each study site referred and effectiveness at the 0.05 significance level. The decision to offered to escort participants who became infected with HIV change the primary effectiveness analysis was made by the during the study to HIV-related psychological, social, and project leader and statistician before unblinding the study.
medical services, such as viral load, CD4 level, and HIV For non-HIV safety outcomes, the planned sample size would have provided approximately 90% power to detect a records, when available, for serious adverse events (SAEs) doubling in the proportion of women experiencing any particular adverse reaction, if the proportion experiencingthe reaction in the placebo arm was 0.05 or more. However, due to early termination of the study in Cameroon and Participant Flow, Numbers Analyzed, and Baseline Nigeria, we had only approximately 70% power to detectsuch a difference.
CharacteristicsA total of 2,040 women were screened for inclusion in the study (Figure 1). The Ghana site completed planned enroll- A randomization manager not otherwise involved in the study ment (n ¼ 400) in December 2004. Routine follow-up developed a random allocation sequence using a permuted- procedures continued monthly for 1 y, after which 3 mo of block design stratified by site, with random block sizes of 12, off-product monitoring of liver function was continued for 18, and 32. A copy of the randomization list was sent to the the 56 HBsAg-positive participants. The Cameroon site manufacturer, who filled each drug bottle with a 30-d supply completed enrollment (n ¼ 400) in December 2004, before of TDF or placebo (12 bottles per randomization number).
the Ministry of Health suspended study drug distribution in Placebo tablets were identical to the TDF tablets in size, February 2005. In Nigeria, 136 of the planned 400 partic- shape, color, and taste. Each drug bottle was marked with a ipants were enrolled before site closure. Loss to follow-up was sequential randomization number, but no product identifier.
17.3% (19.2% in the TDF group and 15.4% in the placebo Participants, field study staff, monitors, statisticians, and group, p ¼ 0.11). Among these were 77 participants who never other FHI staff involved in the trial were blinded to drug returned after their enrollment visit and were therefore assignment. Study staff assigned each eligible participant the excluded from the primary safety and effectiveness analyses.
next sequential number, and gave her the first month’s supply No participants were discontinued from the study by the site of study drug after she had fully qualified for the study and investigator or study clinician because of an AE or abnormal signed or marked the enrollment consent form.
laboratory result. Participants enrolled into the TDF andplacebo groups were similar in important demographic Primary safety analyses were based on time to grade 2 orhigher abnormalities for creatinine or grade 3 or higher abnormalities for ALT, AST, and phosphorus, by site, using We enrolled participants into this study between June 2004 exact two-sided log-rank tests computed in StatXact Version and March 2005. The last participant visit occurred in Ghana 7 (Cytel, http://www.cytel.com). Because of irregularities in the in March 2006. In Cameroon, the Ministry of Health performance of the laboratory in Nigeria, data from that site suspended study drug distribution in February 2005 primarily were excluded from the primary safety analyses. The project in response to concerns about the standard of long-term leader and study statistician made this decision before post-trial care that could be guaranteed to seroconverters.
Participants continued to come to the clinic for off-product The primary effectiveness analysis was based on an exact laboratory, pregnancy, and HIV testing, and HIV prevention log-rank test of no difference in the distribution of HIV-free counseling and condom distribution until September 2005, at survival times, with data pooled across all three sites. Each which time the Cameroon site was closed. In Nigeria, because laboratory abnormality and HIV infection date was estimated of repeated noncompliance with the protocol that was not as the midpoint between the date of the first positive test resolved with staff retraining, enrollment was stopped in result and the previous, negative test date. A right censoring March 2005, and the site was closed thereafter.
time of 12 mo was applied in Ghana, corresponding to the treatment regimen. For all participants in Cameroon and During screening, participants reported an average of 12 Nigeria, the censoring date was the date of permanent coital acts per week with an average of 21 sexual partners in product withdrawal (4 February 2005 and 7 March 2005, the previous 30 d (including 11 new partners). During follow- respectively). Secondarily, exact confidence intervals for the up, participants reported an average of 15 coital acts per relative risk of HIV, laboratory abnormalities, and AEs within week, with an average of 14 sexual partners in the previous 30 system organ classes were computed under a Poisson d (six new partners). Self-reported condom use increased assumption for the event rates in each treatment group. All from 52% at screening (average across all sites during the last primary and secondary analyses were based on two-sided tests coital act prior to screening) to approximately 92% at the and conducted at the 0.05 significance level.
enrollment, month 3, month 6, and month 9 visits, to 95% at Protocol-specified interim safety analyses occurred in April the month 12 visit (for acts occurring during the last 7 d). The and December 2005. An independent Data Monitoring average condom use during the follow-up period was 92%.
Committee, with access to treatment assignments, reviewed The overall pregnancy rate during follow-up was 52 per 100 AEs and primary safety and effectiveness outcomes. The committee did not recommend changes in study proceduresafter either analysis.
FHI monitors (trained in Good Clinical Practice) visited the The amount of product used was estimated by subtracting the sites regularly to review study eligibility, informed consent, number of pills returned from the number dispensed, and protocol compliance, laboratory procedures, source docu- dividing this number by the total number of days in the ments, and AEs. We attempted to get original hospital effectiveness analysis. Based on this calculation, drug was used for no more than 69% of all study days (78% in a grade 3þ decrease in phosphorus (,1.5 mg/dl), which Cameroon, 68% in Ghana, and 50% in Nigeria). Excluding spontaneously resolved to normal within 3 mo (study product time off product due to pregnancy, drug was used for no was not withdrawn). No participants in either group had a more than 74% of study days. Missed/late clinic visits and grade 2þ creatinine elevation (.2.0 mg/dl). We did not find pregnancy were the principal documented reasons for time significant differences in laboratory abnormalities between treatment groups when the data were stratified by site,although significantly more grade 1 AST and phosphorus abnormalities occurred in Ghana than in Cameroon, and Hepatic and renal function. Analysis of hepatic and renal significantly more grade 1 creatinine abnormalities occurred function was restricted to data from Ghana and Cameroon, which resulted in 210.2 person-years of follow-up in the TDF Among the 56 participants who tested positive for HBsAg, group and 217.6 person-years in the placebo group. We did 23 were in the TDF group and 33 in the placebo group. The not find significant differences in the primary safety mean and median ALT and AST levels were not significantly endpoints between treatment groups (Table 2). Specifically, different between groups immediately before or after none of the 363 participants assigned to TDF in Ghana or discontinuation of study drug. Four ALT/AST abnormalities Cameroon had grade 3 or higher (.170 U/l) ALT or AST (none over grade 1 [.42 U/l]) occurred within 3 mo after elevations before product withdrawal, whereas two and three discontinuation of study drug in HBsAg-positive participants; of the 368 participants in the placebo group had grade 3þ one was in the TDF group and three were in the placebo ALT and AST elevations, respectively. The percentage of grade 1 or higher (.42 U/l) ALT and AST abnormalities was In Cameroon, study drug was stopped before the imple- greater in the TDF group, but the difference did not achieve mentation of the protocol amendment that included HBsAg statistical significance. One participant in the TDF group had testing. We therefore monitored liver function for several If have been pregnant, number of pregnancies Had any sexually transmitted infection in past 6 mo, n (%) months after product withdrawal in all participants, regard- participant by the site investigator or study clinician because less of HBV status. The mean and median ALT and AST levels of an AE or abnormal laboratory result.
were not significantly different between groups immediatelybefore or after discontinuation of study drug. Twenty ALT/ AST abnormalities occurred within 3 mo after discontinua- For the primary effectiveness analysis, women in Cameroon, tion of study drug; 14 were in the TDF group and six were in Ghana, and Nigeria contributed 232.6 person-years of follow- the placebo group. With the exception of one, all were grade up in the TDF group and 241.3 person-years in the placebo 1 or 2 events (i.e., less than 85 U/l). One participant (who Eight seroconversions occurred among participants while received TDF) had a grade 3 AST abnormality, which resolved receiving the study drug. Two HIV infections were diagnosed in participants randomized to TDF (rate ¼ 0.86 per 100 Adverse events. A total of 320 (75%) women in the TDF person-years) and six in participants receiving placebo (rate ¼ group and 310 (72%) women in the placebo group had at 2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% least one AE. The most frequently reported AEs (occurring in confidence interval ¼ 0.03–1.93; p ¼ 0.24). With the exception 5% of participants in either treatment group) are summar- of two participants (one randomized to TDF and one to ized in Table 3. There were no significant differences between placebo), all seroconversions were detected on or after the treatment groups for any AEs within system organ classes.
second monthly follow-up visit. Blood specimens were Similar results were obtained among HBsAg-positive partic- available from one of the two participants who seroconverted while on TDF; standard genotypic analysis revealed no Twenty–two SAEs were reported during the study (nine in evidence of drug resistance mutations. An additional six the TDF group and 13 in the placebo group) in 17 participants seroconverted after study drug was discontinued participants. The majority of the SAEs were hospitalizations in Cameroon (four had been randomized to TDF and two to due to malaria (nine events). No SAEs were considered related to study drug. Two deaths occurred in Cameroonduring the course of the study; both occurred approximately 5 mo after study drug dispensation was suspended. One wasdue to an unspecified condition with anemia (the participant had been randomized to placebo), and one was suspected to Our data provide an encouraging rationale for additional be related to an induced abortion (the participant had been research to evaluate oral antiretroviral drugs as prophylaxis randomized to TDF). Study drug was not discontinued in any against HIV infection. No significant differences in safety Table 2. Laboratory Abnormalities during Scheduled Follow-Up in Ghana and Cameroon patterns occurred among participants receiving daily oral access to information and medications. Furthermore, PEP or TDF compared with those receiving placebo, consistent with event-driven dosing is limited by the fact that failures can results seen in previous treatment studies [2].
occur when treatment is not initiated because the risk of the No randomized clinical studies have been completed to exposure is not recognized [23]. We address this limitation of evaluate the effectiveness of antiretroviral drugs as pre- or event-driven dosing in this study by recommending daily post-exposure prophylaxis against HIV infection. In a recent dosing for frequently exposed persons—a strategy referred to Cochrane review [20], only one case-control study of health- as pre-exposure prophylaxis. Because public health practice care workers after needlestick injury was identified. HIV- should be guided by evidence, especially in settings having infected workers had significantly lower odds of having taken competing demands for scarce public health resources, an zidovudine prophylaxis after exposure than those who did urgent need exists for antiviral prophylaxis for HIV to be not seroconvert (odds ratio ¼ 0.19, 95% confidence interval ¼ evaluated in randomized, placebo-controlled trials, as we 0.06–0.52) [21]. The effectiveness of antiviral prophylaxis report here. Further effectiveness studies in populations of after sexual exposure is not known [22]. Non-randomized women at high risk for acquiring HIV should proceed observations of post-exposure prophylaxis (PEP) are difficult to interpret because there could be underlying and uncon- The premature stopping of the study in Cameroon and trolled differences between those who seek and use PEP and Nigeria limited the amount of follow-up safety and effective- those who do not, including differences in behavior and ness data obtained in this study. Furthermore, AEs and Table 3. Selected Treatment-Emergent AEs Reported in 5% in Any Treatment Group (All Sites Combined) laboratory abnormalities in the TDF group may have been diluted by lower than expected product use due to missed We wish to acknowledge the study participants and study staff at visits, drug stoppage due to pregnancy, and other reasons for Virtual Access in Tema, Ghana, the Care and Health Program in non-use of study drug. The overall rate of HIV infection while Douala, Cameroon, and the University College Hospital Study Clinic women were on TDF or placebo in Ghana, Cameroon, and Nigeria was too low to demonstrate a reduction in risk forthose assigned to the TDF group.
TDF is active against HBV, and is recommended for treatment of HBV infection in Europe and by many experts LP, RR, RG, HSJ, and WC designed the study. GB was the Clinical [24–27]. Transaminase increases have been observed in up to Research Manager for this study. LP and PP monitored that the study 25% of patients stopping anti-HBV drugs after receiving was conducted per protocol, Good Clinical Practice, and FHI therapy for clinically important HBV infection, characterized Standard Operating Procedures. EEKC and ASD enrolled patientsand collected data or performed experiments for this study. RG by pre-treatment elevated ALT or AST or signs of liver helped design a protocol modification, did the resistance testing, fibrosis [28]. No flares of ALT or AST were observed among interpreted the results, and provided assistance to analyze the data.
those with HBV infection in this study, although our analysis DT analyzed the data. All authors contributed to writing the paper.
was limited to 23 TDF-treated women with reactive tests forHBsAg. The rate of HBV flares after withdrawing TDF may below among people with normal baseline liver tests and no signs or symptoms of advanced liver disease, such as the Joint United Nations Programme on HIV/AIDS (2006) Report on the global women enrolled here. Additional data on the use of TDF in AIDS epidemic 2006. Geneva: Joint United Nations Programme on HIV/ persons with circulating HBsAg are needed to confirm the AIDS. Available: http://www.unaids.org/en/HIV_data/2006GlobalReport/default.asp. Accessed 17 April 2007.
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