NRU :: Browsing by Author "Nakabiito, Clemensia"

Browsing by Author "Nakabiito, Clemensia"

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Analysis of HIV Diversity Using a High-Resolution Melting Assay
(AIDS research and human retroviruses, 2010) Towler, William I.; James, Maria M.; Ray, Stuart C.; Wang, Lei; Donnell, Deborah; Mwatha, Anthony; Guay, Laura; Nakabiito, Clemensia; Musoke, Philippa; Jackson, J. Brooks; Eshleman, Susan
HIV viruses are usually genetically homogeneous shortly after infection, and become more heterogeneous over time. We developed a high-resolution melting (HRM) assay to analyze HIV diversity without sequencing. Plasma samples from the HIVNET 012 trial were obtained from nine Ugandan mother–infant pairs. DNA amplified from the HIV gag region was analyzed to determine the number of degrees over which the DNA melted (HRM score). HRM gag DNA was also cloned and sequenced (50 clones/mother; 20 clones/infant). The median HRM score for infants (4.3, range 4.2–5.3) was higher than that for control plasmids (3.4, range 3.2–3.8, p < 0.001) and lower than that for mothers (5.7, range 4.4–7.7, p = 0.005, exact Wilcoxon rank sum test). The intraclass correlation coefficient reflecting assay reproducibility was 94% (95% CI: 89–98%). HRM scores were also compared to sequenced-based measures of HIV diversity; higher HRM scores were associated with higher genetic diversity (p < 0.001), complexity (p = 0.009), and Shannon entropy (p = 0.022), but not with length variation (p = 0.111). The HRM assay provides a novel, rapid method for assessing HIV diversity without sequencing. This assay could be applied to any region of the HIV genome or to other genetic systems that exhibit DNA diversity.
Analysis of HIV tropism in Ugandan infants
(Current HIV research, 2010) Church, Jessica D.; Huang, Wei; Mwatha, Anthony; Musoke, Philippa; Jackson, J. Brooks; Bagenda, Danstan; Omer, Saad B.; Donnell, Deborah; Nakabiito, Clemensia; Eure, Chineta; Guay, Laura A.; Taylor, Allan; Bakaki, Paul M.; Matovu, Flavia; McConnell, Michelle; Fowler, Mary Glenn; Eshleman, Susan H.
HIV-infected infants may have CXCR4-using (X4-tropic) HIV, CCR5-using (R5-tropic) HIV, or a mixture of R5-tropic and X4-tropic HIV (dual/mixed, DM HIV). The level of infectivity for R5 virus (R5-RLU) varies among HIV-infected infants. HIV tropism and R5-RLU were measured in samples from HIV-infected Ugandan infants using a commercial assay. DM HIV was detected in 7/72 (9.7%) infants at the time of HIV diagnosis (birth or 6–8 weeks of age, 4/15 (26.7%) with subtype D, 3/57 (5.3 %) with other subtypes, P=0.013). A transition from R5-tropic to DM HIV was observed in only two (6.7%) of 30 infants over 6–12 months. Six (85.7%) of seven infants with DM HIV died, compared to 21/67 (31.3%) infants with R5-tropic HIV (p=0.09). Higher R5- RLU at 6–8 weeks was not associated with decreased survival. Infants with in utero infection had a higher median R5-RLU than infants who were HIV-uninfected at birth (p=0.025).
Association of cord blood Nevirapine concentration with reported timing of dose and HIV-1 transmission
(Aids, 2006) Jackson, J. Brooks; Parsons, Teresa; Musoke, Philippa; Nakabiito, Clemensia; Donnell, Deborah; Fleming, Thomas; Mirochnick, Mark; Mofenson, Lynne; Fowler, Mary Glenn; Mmiro, Francis; Guay, Laura
Background: To correlate nevirapine presence and concentration in cord bloods of infants born to HIV-1 infected women with report of timing of dose and HIV-1 transmission at 6 weeks of age. Methods: All available cord blood samples from the infants of mothers enrolled in the HIVNET 012 trial who were randomly assigned to receive either nevirapine or zidovudine at the onset of labor were tested for a nevirapine concentration. Results: Nevirapine was detected in the cord blood of 244 of 259 (94%) infants whose mothers reported they took nevirapine in labor more than 1 h before delivery and in 12 of 13 (92%) infants whose mothers reported they took nevirapine less than 1 h before delivery. The median nevirapine cord blood concentration was 1238 ng/ml [interquartile range (IQR), 905–1474 ng/ml] and 122 ng/ml (IQR, 64–321 ng/ml) for women who reported taking nevirapine more or less than 1 h before delivery, respectively (P < 0.001). The median nevirapine cord blood concentration of infants who were HIV-1 negative at birth, but positive at 6–8 weeks of age (n ¼ 11), was 916 ng/ml (IQR, 737–1245 ng/ml) compared with 1192 ng/ml (IQR, 875–1471 ng/ml) for uninfected infants (n ¼ 236). Conclusions: Cord blood nevirapine concentration correlated well with report of nevirapine administration and timing of dose before delivery. The nevirapine cord blood concentration was modestly lower in infected infants, although the number of infants infected between birth and 6–8 weeks of age was small (n ¼ 11). The high adherence rate in the HIVNET 012 study supports the efficacy, simplicity and deliverability of this regimen.
Association of HIV Diversity and Survival in HIV-Infected Ugandan Infants
(PLoS One, 2011) James, Maria M.; Wang, Lei; Musoke, Philippa; Donnell, Deborah; Fogel, Jessica; Towler, William I.; Khaki, Leila; Nakabiito, Clemensia; Jackson, J. Brooks; Eshleman, Susan H.
Background: The level of viral diversity in an HIV-infected individual can change during the course of HIV infection, reflecting mutagenesis during viral replication and selection of viral variants by immune and other selective pressures. Differences in the level of viral diversity in HIV-infected infants may reflect differences in viral dynamics, immune responses, or other factors that may also influence HIV disease progression. We used a novel high resolution melting (HRM) assay to measure HIV diversity in Ugandan infants and examined the relationship between diversity and survival through 5 years of age. Methods: Plasma samples were obtained from 31 HIV-infected infants (HIVNET 012 trial). The HRM assay was used to measure diversity in two regions in the gag gene (Gag1 and Gag2) and one region in the pol gene (Pol). Results: HRM scores in all three regions increased with age from 6–8 weeks to 12–18 months (for Gag1: P = 0.005; for Gag2: P = 0.006; for Pol: P = 0.016). Higher HRM scores at 6–8 weeks of age (scores above the 75th percentile) were associated with an increased risk of death by 5 years of age (for Pol: P = 0.005; for Gag1/Gag2 (mean of two scores): P = 0.003; for Gag1/ Gag2/Pol (mean of three scores): P = 0.002). We did not find an association between HRM scores and other clinical and laboratory variables. Conclusions: Genetic diversity in HIV gag and pol measured using the HRM assay was typically low near birth and increased over time. Higher HIV diversity in these regions at 6–8 weeks of age was associated with a significantly increased risk of death by 5 years of age
Association of HIV Diversity and Survival in HIV-Infected Ugandan Infants
(PLoS One, 2011) James, Maria M.; Wang, Lei; Musoke, Philippa; Donnell, Deborah; Fogel, Jessica; Towler, William I.; Khaki, Leila; Nakabiito, Clemensia; Jackson, J. Brooks; Eshleman, Susan H.
The level of viral diversity in an HIV-infected individual can change during the course of HIV infection, reflecting mutagenesis during viral replication and selection of viral variants by immune and other selective pressures. Differences in the level of viral diversity in HIV-infected infants may reflect differences in viral dynamics, immune responses, or other factors that may also influence HIV disease progression. We used a novel high resolution melting (HRM) assay to measure HIV diversity in Ugandan infants and examined the relationship between diversity and survival through 5 years of age.Plasma samples were obtained from 31 HIV-infected infants (HIVNET 012 trial). The HRM assay was used to measure diversity in two regions in the gag gene (Gag1 and Gag2) and one region in the pol gene (Pol).HRM scores in all three regions increased with age from 6–8 weeks to 12–18 months (for Gag1: P = 0.005; for Gag2: P = 0.006; for Pol: P = 0.016). Higher HRM scores at 6–8 weeks of age (scores above the 75th percentile) were associated with an increased risk of death by 5 years of age (for Pol: P = 0.005; for Gag1/Gag2 (mean of two scores): P = 0.003; for Gag1/Gag2/Pol (mean of three scores): P = 0.002). We did not find an association between HRM scores and other clinical and laboratory variables.Genetic diversity in HIV gag and pol measured using the HRM assay was typically low near birth and increased over time. Higher HIV diversity in these regions at 6–8 weeks of age was associated with a significantly increased risk of death by 5 years of age.
Contraceptive Use and Pregnancy Incidence Among Women Participating in an HIV Prevention Trial
(Journal of Women's Health, 2017) Akello, Carolyne A; Bunge, Katherine E; Nakabiito, Clemensia; Mirembe, Brenda G; Fowler, Mary Glenn; Mishra, Anupam; Marrazzo, Jeanne; Chirenje, Zvavahera M; Celum, Connie; Balkus, Jennifer E
Background: Recent HIV prevention trials required use of effective contraceptive methods to fulfill eligibility for enrollment. We compared pregnancy rates in a subset of participants enrolled in the Microbicide Trials Network protocol (MTN-003), a randomized trial of chemoprophylaxis to prevent HIV acquisition among women aged 18–45 years who initiated depot medroxyprogesterone acetate (DMPA) or combined oral contraceptives (COCs) at enrollment, relative to those already using DMPA or COCs. Methods: Data were analyzed from MTN-003 participants from Uganda. Before enrollment, information on contraceptive type and initiation date was obtained. Urine pregnancy tests were performed at monthly follow-up visits. Cox proportional hazards models were used to compare pregnancy incidence among new users (initiated £60 days before enrollment) and established users (initiated >60 days before enrollment). Results: Of 322 women enrolled, 296 were COC or DMPA users, 82 (28%) were new users, and 214 (72%) were established users. Pregnancy incidence was higher among new contraceptive users compared to established users (20.70% vs. 10.55%; adjusted hazard ratio [HR] = 1.66; 95% confidence interval [95% CI] 0.93–2.96). Among DMPA users, pregnancy incidence was 10.20% in new users versus 3.48% in established users (HR= 2.56; 95% CI 0.86–7.65). Among new COC users, pregnancy incidence was 42.67% in new users versus 23.67% in established COC users (adjusted HR= 1.74; 95% CI 0.87–3.48). Conclusions: New contraceptive users, regardless of method, at the Uganda MTN-003 site had an increased pregnancy risk compared to established users, which may be due to contraceptive initiation primarily for trial eligibility. New users may benefit from intensive contraceptive counseling and additional contraceptive options, including longer acting reversible contraceptives.
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.
Ethical considerations for involving adolescents in biomedical HIV prevention research
(BMC Medical Ethics, 2021) Nakalega, Rita; Akello, Carolyne; Gati, Brenda; Nakabiito, Clemensia; Nolan, Monica; Kamira, Betty; Etima, Juliane; Nakyanzi, Teopista; Kemigisha, Doreen; Nanziri, Sophie C.; Nanyonga, Stella; Nambusi, Maria Janine; Mulumba, Emmie; Biira, Florence; Nabunya, Hadijah Kalule; Akasiima, Simon Afrika; Nansimbe, Joselyne; Maena, Joel; Babirye, Juliet Allen; Ngure, Kenneth; Mujugira, Andrew
Background: Involvement of adolescent girls in biomedical HIV research is essential to better understand efficacy and safety of new prevention interventions in this key population at high risk of HIV infection. However, there are many ethical issues to consider prior to engaging them in pivotal biomedical research. In Uganda, 16–17-year-old adolescents can access sexual and reproductive health services including for HIV or other sexually transmitted infections, contraception, and antenatal care without parental consent. In contrast, participation in HIV prevention research involving investigational new drugs requires adolescents to have parental or guardian consent. Thus, privacy and confidentiality concerns may deter adolescent participation. We describe community perspectives on ethical considerations for involving adolescent girls in the MTN 034 study in Uganda. Methods: From August 2017 to March 2018, we held five stakeholder engagement meetings in preparation for the MTN 034 study in Kampala, Uganda (NCT03593655): two with 140 community representatives, two with 125 adolescents, and one with 50 adolescents and parents. Discussions were moderated by the study team. Proceedings were documented by notetakers. Summary notes described community perspectives of adolescent participation in HIV research including convergent, divergent or minority views, challenges, and proposed solutions. Results: Most community members perceived parental or guardian consent as a principal barrier to study participation due to concerns about adolescent disclosure of pre-marital sex, which is a cultural taboo. Of 125 adolescent participants, 119 (95%) feared inadvertent disclosure of sexual activity to their parents. Community stakeholders identified the following critical considerations for ethical involvement of adolescents in HIV biomedical research: (1) involving key stakeholders in recruitment, (2) ensuring confidentiality of sensitive information about adolescent sexual activity, (3) informing adolescents about information to be disclosed to parents or guardians, (4) offering youth friendly services by appropriately trained staff, and (5) partnering with community youth organizations to maximize recruitment and retention. Conclusions: Stakeholder engagement with diverse community representatives prior to conducting adolescent HIV prevention research is critical to collectively shaping the research agenda, successfully recruiting and retaining
Expanded Phase I safety and acceptability study of 6% cellulose sulfate vaginal gel
(AIDS, 2005) Malonza, Isaac M.; Mirembe, Florence; Nakabiito, Clemensia; Odusoga, Lawrence O.; Osinupebi, Olubunmi A.; Hazari, Kamal; Chitlange, Shanta; Alia, Mohamed M.; Callahane, Marianne; Damme, Lut Van
An expanded Phase I trial was performed to assess the safety and acceptability of 6% cellulose sulfate gel (CS) in comparison with K-Y Jelly. Sexually abstinent (cohort I) and sexually active (cohort II) women in India, Nigeria and Uganda applied 3.5 ml of either 6% CS gel or K-Y Jelly for seven consecutive days. Safety was assessed by symptoms and signs (including colposcopy) of genital irritation, review of adverse events, and by changes in vaginal health as assessed by microscopy.
Impact of DSMB Outcomes on Participation in HIV Prevention Trials: The VOICE Study Experience in Kampala, Uganda
(AIDS Research and Human Retroviruses, 2014) Etima, Juliane; Nakyanzi, Teopista; Kabwigu, Samuel; Kiweewa, Flavia M.; Mirembe, Brenda G.; Akello, Carolyne A.; Rossi, Lisa; Nakabiito, Clemensia
Clinical trials are monitored and regulated by independent bodies to ensure participants’ safety and ethical conduct. Depending on study progress, these bodies may recommend a trial to continue as is, be modified or stopped. Six such reviews were conducted during the implementation of the VOICE study. We describe the impact of Data & Safety Monitoring Board (DSMB) recommendations on continued study participation in Kampala, Uganda, including retention, researchers’ motivation to continue the study, and community perceptions and attitudes about the study.
Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial
(The Lancet, 2003) Jackson, J. Brooks; Musoke, Philippa; Fleming, Thomas; Guay, Laura A.; Bagenda, Danstan; Allen, Melissa; Nakabiito, Clemensia; Sherman, Joseph; Bakaki, Paul; Owor, Maxensia; Ducar, Constance; Deseyve, Martina; Mwatha, Anthony; Emel, Lynda; Duefield, Corey; Mirochnick, Mark; Glenn Fowler, Mary; Mofenson, Lynne; Miotti, Paolo; Gigliotti, Maria; Bray, Dorothy; Mmiro, Francis
In 1999, we reported safety and efficacy data for short-course nevirapine from a Ugandan perinatal HIV-1 prevention trial when 496 babies were followed up to age 14–16 weeks. Safety and efficacy data are now presented for all babies followed up to 18 months of age. Methods From November, 1997, to April, 1999, HIV-1 infected pregnant women in Kampala, Uganda, were randomly assigned nevirapine (200 mg at labour onset and 2 mg/kg for babies within 72 h of birth; regimen A) or zidovudine (600 mg orally at labour onset and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily for babies for 7 days, regimen B). Infant HIV-1 testing was done at birth, age 6–8 and 14–16 weeks, and age 12 months by HIV-1 RNA PCR, and by HIV-1 antibody at 18 months. HIV-1 transmission and HIV-1-free survival were assessed using Kaplan-Meier analysis. We recorded adverse experiences through 6–8 weeks postpartum for mothers, and 18 months for babies. Efficacy analyses were by intention to treat. Findings We enrolled 645 mothers to the study: 313 were assigned regimen A, 313 regimen B, and 19 placebo. Eight mothers were lost to follow-up before delivery. 99% of babies were breastfed (median duration 9 months). Estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were 10·3% and 8·1% at birth (p=0·35); 20·0% and 11·8% by age 6–8 weeks (p=0·0063); 22·1% and 13·5% by age 14–16 weeks (p=0·0064); and 25·8% and 15·7% by age 18 months (p=0·0023). Nevirapine was associated with a 41% (95% CI 16–59) reduction in relative risk of transmission through to age 18 months. Both regimens were well-tolerated with few serious side-effects. Interpretation Intrapartum/neonatal nevirapine significantly lowered HIV-1 transmission risk in a breastfeeding population in Uganda compared with a short intrapartum/neonatal zidovudine regimen. The absolute 8·2% reduction in transmission at 6–8 weeks was sustained at age 18 months (10·1% [95% CI 3·5–16·6]). This simple, inexpensive, welltolerated regimen has the potential to significantly decrease HIV-1 perinatal transmission in less-developed countries.
Intrapartum And Neonatal Single-Dose Nevirapine Compared With Zidovudine For Prevention Of Mother-To-Child Transmission Of HIV-1 in Kampala, Uganda: HIVNET 012 Randomised Trial
(The Lancet, 1999) Guay, Laura A.; Musoke, Philippa; Fleming, Thomas; Bagenda, Danstan; Allen, Melissa; Nakabiito, Clemensia; Sherman, Joseph; Bakaki, Paul; Ducar, Constance; Deseyve, Martina; Emel, Lynda; Mirochnick, Mark; Fowler, Mary Glenn; Mofenson, Lynne; Miotti, Paolo; Dransfield, Kevin; Bray, Dorothy; Mmiro, Francis; Jackson, J. Brooks
The AIDS Clinical Trials Group protocol 076 zidovudine prophylaxis regimen for HIV-1-infected pregnant women and their babies has been associated with a significant decrease in vertical HIV-1 transmission in non-breastfeeding women in developed countries. We compared the safety and efficacy of short-course nevirapine or zidovudine during labour and the first week of life.From November, 1997, to April, 1999, we enrolled 626 HIV-1-infected pregnant women at Mulago Hospital in Kampala, Uganda. We randomly assigned mothers nevirapine 200 mg orally at onset of labour and 2 mg/kg to babies within 72 h of birth, or zidovudine 600 mg orally to the mother at onset of labour and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily to babies for 7 days after birth. We tested babies for HIV-1 infection at birth, 6–8 weeks, and 14–16 weeks by HIV-1 RNA PCR. We assessed HIV-1 transmission and HIV-1-free survival with Kaplan-Meier analysis.Nearly all babies (98·8%) were breastfed, and 95·6% were still breastfeeding at age 14–16 weeks. The estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were: 10·4% and 8·2% at birth (p=0·354); 21·3% and 11·9% by age 6–8 weeks (p=0·0027); and 25·1% and 13·1% by age 14–16 weeks (p=0·0006). The efficacy of nevirapine compared with zidovudine was 47% (95% CI 20–64) up to age 14–16 weeks. The two regimens were well tolerated and adverse events were similar in the two groups.Nevirapine lowered the risk of HIV-1 transmission during the first 14–16 weeks of life by nearly 50% in a breastfeeding population. This simple and inexpensive regimen could decrease mother-to-child HIV-1 transmission in less-developed countries.
Maximizing participant retention in a phase 2B HIV prevention trial in Kampala, Uganda: The MTN-003 (VOICE) Study
(HIV Clinical Trials, 2018) Wynne, Joshua; Muwawu, Rosemary; Mubiru, Michael C.; Kamira, Betty; Kemigisha, Doreen; Nakyanzi, Teopista; Kabwigu, Samuel; Nakabiito, Clemensia; Kiweewa Matovu, Flavia
The success of longitudinal trials depends greatly on using effective strategies to retain participants and ensure internal validity, maintain sufficient statistical power, and provide for the generalizability of study results. This paper describes the challenges and specific strategies used to retain participants in a Phase 2B safety and effectiveness study of daily oral and vaginal tenofovir formulations for the prevention of HIV-1 infection in the MTN-003 (VOICE) trial in Kampala, Uganda. Once enrolled, participants were seen every 28 days at the research site and their study product was re-filled. Challenges to retention included a mobile population, non-disclosure of study participation to spouse/family, and economic constraints. Strategies used to maintain high participation rates included the use of detailed locator information, a participant tracking database, regular HIV/STI testing, and the formation of close bonds between staff and subjects. We enrolled 322 women out of the 637 screened. The overall retention rate was 95% over a 3 year follow up period. Only 179 (3%) out of the 6124 expected visits were missed throughout study implementation. Reasons for missed visits included: participants thinking that they did not need frequent visits due to their HIV negative status, time constraints due to commercial sex work, and migration for better employment. With the implementation of multi-faceted comprehensive follow-up and retention strategies, we achieved very high retention rates in the MTN-003 study. This paper provides a blueprint for effective participant retention strategies for other longitudinal HIV prevention studies in resource-limited settings in Sub-Saharan Africa.
A Phase I/II Study Of The Safety And Pharmacokinetics Of Nevirapine In HIV-1-Infected Pregnant Ugandan Women And Their Neonates (HIVNET 006)
(Aids, 1999) Musoke, Philippa; Guay, Laura A.; Bagenda, Danstan; Mirochnick, Mark; Nakabiito, Clemensia; Fleming, Thomas; Elliott, Terry; Horton, Scott; Dransfield, Kevin; Pav, Joseph W.; Murarka, Amal; Allen, Melissa; Fowler, Mary Glenn; Mofenson, Lynne; Hom, David; Mmiro, Francis; Jackson, J. Brooks
To determine the safety, pharmacokinetics, tolerance, antiretroviral activity, and infant HIV infection status after giving a single dose of nevirapine to HIV-1-infected pregnant women during labor and their newborns during the first week of life.An open label phase I/II study.Tertiary care hospital, Kampala, Uganda.Nevirapine, 200mg, was given as a single dose during labor to 21 HIV-1-infected pregnant Ugandan women. In cohort 1, eight infants did not receive nevirapine whereas in cohort 2, 13 infants received a single dose of nevirapine, 2mg/kg, at 72h of age.The number and type of adverse events; nevirapine concentrations in the plasma and breast milk; maternal plasma HIV-1 RNA copy number before and up to 6 weeks after delivery; and HIV-1 infection status of the infants were monitored.Nevirapine was well tolerated by women and infants; no serious adverse events that were related to nevirapine were observed. Median nevirapine concentration in the women at delivery was 1623ng/ml (range 238-2356ng/ml); median cord/maternal blood ratio of 0.75 (0.37-0.93). The median half-life in women was 61.3h (27-90h) and the transplacental nevirapine half-life in infants who did not receive a neonatal dose was 54h. The median half-life after a single dose at 72h in infants was 46.5h. During the first week of life, the median colostrum/breast milk to maternal plasma nevirapine concentration was 60.5% (25-122%). The median nevirapine concentration in breast milk 1 week after delivery was 103ng/ml (25-309ng/ml). Plasma nevirapine concentrations were above 100ng/ml in all infants from both cohorts tested at age 7 days. Maternal HIV-1 RNA levels decreased by a median of 1.3 logs at 1 week postpartum, and returned to baseline by 6 weeks postpartum. Detectable plasma HIV-1 RNA was observed in one out of 22 (4.5%) infants at birth; three out of 21 (14%) at 6 weeks; and four out of 21 (19%) at 6 months of age.The administration of a single dose of nevirapine to women during labor and to their newborns at 72h was well tolerated and showed potent antiretroviral activity in the women at 1 week after dosing without rebound above baseline 6 weeks after a single dose. The nevirapine concentration was maintained above the target of 100ng/ml in infants at age 7 days, even in those infants not receiving a neonatal dose. This regimen has promise as prophylaxis against intrapartum and early breast milk transmission in a breastfeeding population.
Predictors of Early and Late Mother-to-Child Transmission of HIV in a Breastfeeding Population: HIV Network for Prevention Trials 012 Experience, Kampala, Uganda
(Journal of acquired immune deficiency syndromes, 2009) Mmiro, Francis A.; Aizire, Jim; Mwatha, Anthony K.; Eshleman, Susan H.; Donnell, Deborah; Fowler, Mary Glenn; Nakabiito, Clemensia; Musoke, Philippa M.; Jackson, J. Brooks; Guay, Laura A.
To determine the predictors for early versus later (breastfeeding) transmission of HIV-1.Secondary data analysis was performed on HIV Network for Prevention Trials 012, a completed randomized clinical trial assessing the relative efficacy of nevirapine (NVP) versus zidovudine in reducing mother-to-child transmission (MTCT) of HIV-1. We used Cox regression analysis to assess risk factors for MTCT. The ViroSeq HIV genotyping and a sensitive point mutation assay were used to detect NVP resistance mutations.In this subset analyses, 122 of 610 infants were HIV infected, of whom 99 (81.1%) were infected early (first positive polymerase chain reaction ≤56 days). Incidence of MTCT after 56 days was low [0.7% per month (95% confidence interval, CI: 0.4 to 1.0)], but continued through 18 months. In multivariate analyses, early MTCT “factors” included NVP versus zidovudine (hazard ratio (HR) = 0.57, 95% CI: 0.38 to 0.86), pre-entry maternal viral load (VL, HR = 1.76, 95% CI: 1.28 to 2.41), and CD4 cell count (HR = 1.16, 95% CI: 1.05 to 1.28). Maternal VL (6–8 weeks) was associated with late MTCT (HR = 3.66, 95% CI: 1.78 to 7.50), whereas maternal NVP resistance (6–8 weeks) was not.Maternal VL was the best predictor of both early and late transmission. Maternal NVP resistance at 6–8 weeks did not predict late transmission.
Predictors of unknown HIV serostatus at the time of labor and delivery in Kampala, Uganda
(International Journal of Gynecology & Obstetrics, 2014) Onongea, Sam; Karamagi, Charles; Nakabiito, Clemensia; Wandabwa, Julius; Mirembe, Florence; Rukundo, Godfrey Z.; Jennings, Larissa
To determine factors associated with an unknown HIV serostatus among pregnant women admitted in labor to Mulago Hospital, Kampala, Uganda. Methods—In total, 665 pregnant women admitted to Mulago Hospital were interviewed about their sociodemographic characteristics, obstetric history, access to prenatal care, fears regarding HIV testing, and knowledge about modes of mother-to child-transmission (MTCT). Knowledge of the HIV serostatus was assessed by self-report and verified by prenatal card review. Results—The prevalence of unknown HIV serostatus at the time of labor was 27.1%. Factors associated with an unknown HIV serostatus included high parity (odds ratio [OR] 1.9; 95% confidence interval [CI], 1.16–3.14), preterm delivery (OR 2.60; 95% CI, 1.06–6.34), prenatal care at a private clinic (OR 12.87; 95% CI, 5.68–29.14), residence more than 5 km from the nearest prenatal clinic (OR 2.86; 95% CI, 1.18–17.9), high knowledge about MTCT (OR 0.25; 95% CI, 0.07–0.86), and fears related to disclosing the test result to the partner (OR 3.60; 95% CI, 1.84–7.06). Conclusion—The high prevalence of unknown HIV serostatus among women in labor highlights the need to improve accessibility to HIV testing services early during pregnancy to be able to take advantage of antiretroviral therapy.
Prevalence of undetectable and suppressed viral load in HIV‑infected pregnant women initiating Option B+ in Uganda: an observational study nested within a randomized controlled trial
(Springer Nature, 2021) Gabagaya, Grace; Rukundo, Gordon; Amone, Alexander; Wavamunno, Priscilla; Namale‑Matovu, Joyce; Lubega, Irene; Nakabiito, Clemensia; Namukwaya, Zikulah; Nolan, Monica; Malamba, Samuel S.; King, Rachel; Homsy, Jaco ,; Glenn Fowler, Mary; Musoke, Philippa
Viral load (VL) testing is key in monitoring adherence to antiretroviral therapy (ART) and documenting HIV treatment response. As per HIV treatment guidelines in Uganda, the first VL test is recommended 6 months after initiation of ART. Undetectable VL (uVL) at ART initiation may be helpful in detecting elite controllers in the absence of previous ART use. We investigated viral suppression at ART initiation among a cohort of HIV-positive pregnant women enrolled in the Friends for Life Circles (FLC) for Option B+ randomized controlled trial (RCT). Methods: Pregnant women ≥ 18 years of age testing positive for HIV at their first antenatal care visit and starting on ART Option B+ as per the National PMTCT Program guidelines were enrolled into the FLC for Option B+ RCT in urban Kampala and rural Mityana districts of Uganda. Each participant had whole blood samples collected at enrolment to assess baseline VL. Plasma HIV-1 RNA was quantified using COBAS Ampliprep /COBAS Taqman. Baseline VL below 400 RNA copies/ml was considered as viral suppression while baseline VL below 20 RNA copies/ml was considered uVL. Results: The mean duration from the date of ART initiation to time of sample collection for baseline VL assessment was 4.4 days (SD 3.6). Of the 532 HIV-positive pregnant women enrolled in the FLC for Option B+ study and newly starting Option B+ without a self-reported history of prior ART use, 29 (5.5%) had uVL and 113 (21.4%) had suppressed VL at baseline. There was no association between participants’ age, gravidity, marital status, mean monthly income, educational level, disclosure of HIV status to partner, and uVL or viral suppression at baseline. However, nondisclosure of HIV status to any other person was associated with decreased odds of viral suppression at baseline (OR 0.640; 0.416–0.982). Conclusion: Twenty-one percent of HIV-positive Ugandan pregnant women initiating ART (Option B+) showed virological suppression at baseline and were presumed to be “elite controllers” or to have misreported being ART-naive.
Safety and Efficacy of HIV Hyperimmune Globulin (HIVIGLOB) for Prevention of Mother-to-Child HIV Transmission in HIV-1 infected Pregnant Women and their Infants in Kampala, Uganda (HIVIGLOB/NVP STUDY)
(Journal of acquired immune deficiency syndromes, 2011) Makumbi, Carolyne Onyango; Omer, Saad B.; Mubiru, Michael; Moulton, Lawrence H.; Nakabiito, Clemensia; Musoke, Philippa; Mmiro, Francis; Zwerski, Sheryl; Wigzell, Hans; Falksveden, Lars; Wahren, Britta; Antelman, Gretchen; Fowler, Mary Glenn; Guay, Laura; Jackson, J. Brooks
This phase III randomized clinical trial compared single dose nevirapine (sdNVP) plus HIV immunoglobulin (HIVIGLOB) to sdNVP alone for preventing maternal-to-child transmission (PMTCT) of HIV.Primary objectives were to determine rates of HIV infection among infants, and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants.Mother-infant pairs were randomized to receive 200mg of NVP to women in labor and 2mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240ml dose of HIVIGLOB given to women at 36-38 weeks gestation and a single intravenous 24ml dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6 and 12 months of age. Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm versus the sdNVP arm (18.7% vs.15.0%; RR =1.240 [95% CI: 0.833-1.846]; p= 0.290). Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively for mothers (18.9% vs. 19.3%; p= 0.91) and infants (62.6% vs. 59.5%; p=0.51), were not significantly different.Giving mother-infant pairs an infusion of peripartum HIV hyperimmunoglobulin in addition to sdNVP for PMTCT was as safe as sdNVP alone, but was no more effective than sdNVP alone in preventing HIV transmission.
Suboptimal Nevirapine Steady-State Pharmacokinetics During Intrapartum Compared With Postpartum in HIV-1–Seropositive Ugandan Women
(Journal of acquired immune deficiency syndromes, 2010) Lamorde, Mohammed; Byakika-Kibwika, Pauline; Okaba-Kayom, Violet; Flaherty, John P.; Boffito, Marta; Namakula, Rhoda; Ryan, Mairin; Nakabiito, Clemensia; Back, David J.; Khoo, Saye; Merry, Concepta; Scarsi, Kimberly K.
Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa. Methods: This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNAwas performed within 2weeks of each visit. Nevirapine C12 above 3000 ng/mLwas classified as optimal based on the suggested value for therapeutic drug monitoring.

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