Browsing by Author "Brown, Elizabeth R."

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    Characterization of Nevirapine Resistance Mutations in Women With Subtype A Vs. D HIV-1 6–8 Weeks After Single-Dose Nevirapine (HIVNET 012)
    (JAIDS Journal of Acquired Immune Deficiency Syndromes, 2004) Eshleman, Susan H.; Guay, Laura A.; Mwatha, Anthony; Brown, Elizabeth R.; Cunningham, Shawn P.; Musoke, Philippa; Mmiro, Francis; Jackson, J. Brooks
    To compare the number and type of nevirapine (NVP) resistance mutations detected in Ugandan women with subtype A vs.D HIV-1 infection after single-dose NVP prophylaxis.In the HIVNET 012 trial, a higher rate of NVP resistance (NVPR) was seen in women with subtype D than A after single-dose NVP. In this study, the number and type of NVPR mutations detected 6–8 weeks after NVP were compared in women with subtypes A vs. D.Plasma samples were available for 282 (92%) of 306 women who received NVP in HIVNET 012. Samples were analyzed with the ViroSeq HIV-1 Genotyping System (Applied Biosystems, Foster City, CA). Subtyping was performed by phylogenetic analysis of pol region sequences. Results were obtained for 279 women, including 147 with subtype A, 98 with subtype D, 6 with subtype C, and 28 with recombinant HIV-1. NVPR mutations were detected in 70 (25%) of 279 women. NVPR was more common in women with subtype D vs. A (35.7 vs. 19%, P = 0.0035). Complex patterns of NVPR mutations were detected in both subtypes. Among women with NVPR, 43% of women with subtype A and 46% of women with subtype D had 2 NVPR mutations. The mean number and pattern of NVPR mutations detected in women with subtypes A and D were similar. This study confirms a higher rate of NVPR in women with subtype D than A and further defines the pattern of NVPR mutations that emerge 6–8 weeks after single-dose NVP prophylaxis in these subtypes.
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    Dapivirine vaginal ring use does not diminish the effectiveness of hormonal contraception
    (Journal of acquired immune deficiency syndromes, 2017) Balkus, Jennifer E.; Palanee-Phillips, Thesla; Reddy, Krishnaveni; Siva, Samantha; Harkoo, Ishana; Nakabiito, Clemensia; Kintu, Kenneth; Nair, Gonasangrie; Chappell, Catherine; Matovu Kiweewa, Flavia; Kabwigu, Samuel; Naidoo, Logashvari; Jeenarain, Nitesha; Marzinke, Mark; Soto-Torres, Lydia; Brown, Elizabeth R.; Baeten, Jared M.
    To evaluate the potential for a clinically relevant drug-drug interaction with concomitant use of a dapivirine vaginal ring, a novel antiretroviral-based HIV-1 prevention strategy, and hormonal contraception by examining contraceptive efficacies with and without dapivirine ring use. A secondary analysis of women participating in MTN-020/ASPIRE, a randomized, double-blind, placebo-controlled trial of the dapivirine vaginal ring for HIV-1 prevention. Methods: Use of a highly effective method of contraception was an eligibility criterion for study participation. Urine pregnancy tests were performed monthly. Pregnancy incidence by arm was calculated separately for each hormonal contraceptive method and compared using an Andersen-Gill proportional hazards model stratified by site and censored at HIV-1 infection. Of 2629 women enrolled, 2310 women returned for follow-up and reported using a hormonal contraceptive method at any point during study participation (1139 in the dapivirine arm, 1171 in the placebo arm). Pregnancy incidence in the dapivirine arm versus placebo among women using injectable depot medroxyprogesterone acetate was 0.43% vs. 0.54%, among women using injectable norethisterone enanthate was 1.15% vs. 0%, among women using hormonal implants was 0.22% vs. 0.69%, and among women using oral contraceptive pills was 32.26% vs. 28.01%. Pregnancy incidence did not differ by study arm for any of the hormonal contraceptive methods. Use of the dapivirine ring does not reduce the effectiveness of hormonal contraceptives for pregnancy prevention. Oral contraceptive pill use was associated with high pregnancy incidence, potentially due to poor pill adherence. Injectable and implantable methods were highly effective in preventing pregnancy.
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    Efficacy And Safety Of An Extended Nevirapine Regimen In Infant Children Of Breastfeeding Mothers With HIV-1 Infection For Prevention Of Postnatal HIV-1 Transmission (HPTN 046): A Randomised, Double-Blind, Placebo-Controlled Trial
    (The Lancet, 2012) Coovadia, Hoosen M.; Brown, Elizabeth R.; Fowler, Mary Glenn; Chipato, Tsungai; Moodley, Dhayendre; Manji, Karim; Musoke, Philippa; Chibanda, Lynda Stranix
    Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1 via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months.In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primary efficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412.Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1·1% (95% CI 0·3–1·8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2·4% (1·3–3·6) of controls (difference 1·3%, 95% CI 0–2·6), equating to a 54% reduction in transmission (p=0·049). However, mortality (1·2% for nevirapine vs 1·1% for placebo; p=0·81) and combined HIV infection and mortality rates (2·3% vs 3·2%; p=0·27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups.Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age.
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    Extended prophylaxis with nevirapine and cotrimoxazole among HIV-exposed uninfected infants is well tolerated
    (AIDS (London, England), 2012) Aizire, Jim; Fowler, Mary Glenn; Wang, Jing; Shetty, Avinash K.; Chibanda, Lynda Stranix; Kamateeka, Moreen; Brown, Elizabeth R.; Bolton, Steve G.; Musoke, Philippa M.; Coovadia, Hoosen
    Nevirapine and cotrimoxazole are associated with hematologic toxicities and skin-rash. Safety of their concurrent use for prophylaxis over extended periods among HIV-exposed uninfected infants has not been previously assessed.Secondary data analysis of the ‘HIV Prevention Trials Network-046 protocol’ (version 2.0), a phase-III, randomized, placebo-controlled trial that assessed efficacy and safety of nevirapine prophylaxis against breast milk transmission of HIV-1.Trial infants received 6-month study nevirapine/placebo, and standard-of-care peripartum single-dose nevirapine+/– zidovudine ‘tail’, and cotrimoxazole prophylaxis from 6 weeks through breastfeeding cessation. Adverse events were monitored using United States Division of AIDS Toxicity Tables (2004). Risk of neutropenia, anemia and skin-rash in the cotrimoxazole+nevirapine and the cotrimoxazole+placebo groups were compared using negative-binomial regression.Incidence of neutropenia and/or anemia, and skin-rash was highest during the first 6 weeks of life and declined, thereafter, regardless of study group. Time to first adverse event after 6 weeks was similar in cotrimoxazole+nevirapine and cotrimoxazole+placebo groups: hazard ratio (95% confidence interval) was 1.26 (0.96–1.66) for neutropenia and/or anemia (all grades), 1.27 (0.80–2.03) for neutropenia and/or anemia (grade ≥3) and 1.16 (0.46–2.90) for skin-rash (grade ≥2). There were no statistically significant differences in immediate (6 weeks–6 months) and long-term (6–12 months) adverse event risk among infants on cotrimoxazole+nevirapine versus cotrimoxazole+placebo.Extended nevirapine and cotrimoxazole prophylaxis through 6 months of age among HIV-exposed uninfected infants did not appear to increase the immediate or long-term risk of neutropenia, anemia or skin-rash. Concurrent use beyond 6 months, however, needs to be evaluated.
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    Implementation of a prospective pregnancy registry for antiretroviral based HIV prevention trials
    (HIV Clinical Trials, 2018) Mhlanga, Felix G.; Noguchi, Lisa; Balkus, Jennifer E.; Kabwigu, Samuel; Scheckter, Rachel; Piper, Jeanna; Watts, Heather; O’Rourke, Colin; Torjesen, Kristine; Brown, Elizabeth R.; Hillier, Sharon L.; Beigi, Richard
    Safety data on pregnancy and fetal outcomes among women in HIV prevention trials are urgently needed to inform use of effective antiretroviral agents for HIV prevention. We describe an effective, efficient, and novel method to prospectively collect perinatal safety data concurrent with on-going parent clinical trials. The Microbicide Trials Network (MTN)-016 study is a multinational prospective pregnancy exposure registry designed to capture pregnancy and neonatal outcomes. Studies currently contributing data to this registry included phase I and II safety trials with planned exposures to candidate HIV prevention agents, as well as phase IIB and III efficacy trials capturing data on pregnancy and infant outcomes following inadvertent fetal exposure during study participation. Results: To date, participants from two phase I studies and two effectiveness trials have participated in MTN- 016, resulting in 420 pregnant women and 381 infants enrolled. Infant retention has been high, with 329 of 381 (86%) infants completing the 12-month follow-up visit. In a research setting context, it is feasible to establish and implement a prospective, multinational HIV chemoprophylaxis pregnancy registry that will generate pregnancy exposure data in a robust fashion.
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    The Influence of Perceived Dapivirine Vaginal Ring Effectiveness on Social Disclosure and Ring Adherence
    (AIDS and Behavior, 2013) Stoner, Marie C. D.; Brown, Elizabeth R.; Palanee‑Phillips, Thesla; Mansoor, Leila E.; Tembo, Tchangani; Nair, Gonasagrie; Akello, Carolyne; Seyama, Linly; Jeenarain, Nitesha; Naidoo, Logashvari; Mgodi, Nyaradzo; Hunidzarira, Portia; Chitukuta, Miria; Straten, Ariane van der
    We analyzed data from 1428 users of the dapivirine vaginal ring, who participated in the MTN-020/ASPIRE phase III trial and subsequent open-label extension MTN-025/HOPE trial, to examine relationships between perceived ring protection, social disclosures, and self-reported ring adherence. In HOPE, 77% perceived the ring to be highly effective, and this view was associated with speaking: (a) to a greater number of people about the study, (b) with other participants, (c) to more people who were in favor of the ring, and (d) to more people whose opinions were valued. Reported adherence was not directly associated with perceived protection but was associated with disclosing to someone who was in favor of the ring. These findings suggest the importance of women’s internalized ideas about the protective benefits of the DVR in sharing information about the ring and the importance of social support on adherence
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    Total Lymphocyte Count: not a surrogate marker for risk of death in HIV infected Ugandan children
    (Journal of acquired immune deficiency syndromes, 2008) Musoke, Philippa M.; Young, Alicia M.; Owor, Maxensia A.; Lubega, Irene R.; Brown, Elizabeth R.; Mmiro, Francis A.; Mofenson, Lynne M.; Jackson, J. Brooks; Glenn Fowler, Mary; Guay, Laura A.
    To determine the utility of Total Lymphocyte Count (TLC) in predicting the 12 month mortality in HIV infected Ugandan children; to correlate TLC and CD4 cell %. Design—This is a retrospective data analysis of clinical and laboratory data collected prospectively on 128 HIV infected children in the HIVNET 012 trial. Methods—TLC and CD4 cell % measurements were obtained at birth, 14 weeks and 12, 24, 36, 48, and 60 months of age and assessed with respect to risk of death within 12 months. Results—Median TLC/ul (CD4 cell %) were 4150 (41%) at birth, 4900 (24%) at 12 months, 4300 (19%) at 24 months, 4150 (19 %) at 36 months, 4100 (18%) at 48 months and 3800 (20%) at 60 months. The highest risk of mortality within 12 months was 34–37% at birth and declined to 13– 15% at 24 months regardless of TLC measurement. The correlation between CD4 cell % and TLC was extremely low overall (r = 0.01). Conclusion—The TLC did not predict a risk of progression to death within 12 months and therefore TLC alone may not be a useful surrogate marker for determining those children in greatest need for antiretroviral therapy in HIV infected Ugandan children.