Browsing by Author "Mmiro, Francis"

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    Analysis of Nevirapine (NVP) Resistance in Ugandan Infants Who Were HIV Infected Despite Receiving Single-Dose (SD) NVP versus SD NVP Plus Daily NVP Up to 6 Weeks of Age to Prevent HIV Vertical Transmission
    (The Journal of infectious disease, 2010) Church, Jessica D.; Omer, Saad B.; Guay, Laura A.; Huang, Wei; Lidstrom, Jessica; Musoke, Philippa; Mmiro, Francis; Jackson, J. Brooks; Eshleman, Susan H.
    Background. Single-dose nevirapine (SD NVP) at birth plus NVP prophylaxis for the infant up to 6 weeks of age is superior to SD NVPalone for prevention of vertical transmission of human immunodeficiency virus (HIV) through breastfeeding. We analyzed NVP resistance in HIV-infected Ugandan infants who received either SD NVP or extended NVP prophylaxis. Methods. We tested plasma HIV by using a genotyping assay (ViroSeq; Celera Diagnostics), a phenotypic resistance assay (PhenoSense; Monogram Biosciences), and sensitive point mutation assay (LigAmp, for K103N, Y181C, and G190A). Results. When infants were 6 weeks old, ViroSeq detected NVP resistance in a higher proportion of infants in the extended NVP arm than in the SD NVP arm (21 of 25 [84%] vs. 12 of 24 [50%]; P = .01). Similar results were obtained with LigAmp and PhenoSense. In both study arms, infants who were HIV infected at birth frequently had NVP resistance detected. In contrast, infants in the extended NVP arm who were HIV infected after birth were more likely to have resistance detected at 6 weeks, compared with infants in the SD NVP arm. The use of extended NVP prophylaxis was also associated with detection of NVP resistance by ViroSeq at 6 months (7 of 7 [100%] infants in the extended NVP arm had resistance detected, compared with 1 of 6 [16.7%] infants in the SD NVP arm; P = .005). Conclusions. The use of extended NVP prophylaxis was associated with increased selection for and persistence of NVP resistance in HIV-infected Ugandan infants.
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    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.
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    Associations of Chemokine Receptor Polymorphisms With HIV-1 Mother-to-Child Transmission in Sub-Saharan Africa: Possible Modulation of Genetic Effects by Antiretrovirals
    (Journal of acquired immune deficiency syndromes, 1999) Singh, Kumud K.; Hughes, Michael D.; Chen, Jie; Phiri, Kelesitse; Rousseau, Christine; Kuhn, Louise; Coutsoudis, Anna; Jackson, J. Brooks; Guay, Laura A.; Musoke, Philippa; Mmiro, Francis; Semba, Richard D.; Spector, Stephen A.
    Background—HIV-1 mother-to-child transmission (MTCT) remains an important route of infection in sub-Saharan Africa. Methods—Genetic variants in CCR5 promoter, CCR2, CX3CR1, and Stromal cell-derived factor-1 (SDF-1) genes were determined in 980 infants from sub-Saharan Africa using real-time polymerase chain reaction to determine association with MTCT. Results—In antiretroviral-naive mother–infant pairs (n = 637), CCR5 promoter polymorphisms at positions 59029: A allele vs. G/G [odds ratio (OR): 1.61, 95% confidence interval (CI): 1.04 to 2.48; P = 0.032] and 59356: T allele vs. C/C (OR: 0.63, 95% CI: 0.41 to 0.96; P = 0.033) and CCR2-180: G allele vs. A/A (OR: 3.32, 95% CI: 1.13 to 9.73; P = 0.029) were associated with risk of MTCT. Treatment of HIV-1–infected mothers and infants with single-dose nevirapine or perinatal zidovudine altered but did not eliminate the association of genetic variants with MTCT. Conclusions—CCR5 promoter, CCR2, and CX3CR1 polymorphisms were associated with risk of MTCT likely through their role as an HIV-1 coreceptor or by modulating the early immune response. genetics may continue to alter MTCT when short-course interventions that only partially suppress virus are used. These findings will need to be confirmed in validation cohorts with a large number of infected infants.
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    Associations of Chemokine Receptor Polymorphisms With HIV-1 Mother-to-Child Transmission in Sub-Saharan Africa: Possible Modulation of Genetic Effects by Antiretrovirals
    (Journal of acquired immune deficiency syndromes, 2008) Singh, Kumud K.; Hughes, Michael D.; Chen, Jie; Phiri, Kelesitse; Rousseau, Christine; Kuhn, Louise; Coutsoudis, Anna; Jackson, J. Brooks; Guay, Laura A.; Musoke, Philippa; Mmiro, Francis; Semba, Richard D.; Spector, Stephen A.
    HIV-1 mother-to-child transmission (MTCT) remains an important route of infection in sub-Saharan Africa.Genetic variants in CCR5 promoter, CCR2, CX3CR1, and Stromal cell-derived factor-1 (SDF-1) genes were determined in 980 infants from sub-Saharan Africa using real-time polymerase chain reaction to determine association with MTCT.In antiretroviral-naive mother–infant pairs (n = 637), CCR5 promoter polymorphisms at positions 59029: A allele vs. G/G [odds ratio (OR): 1.61, 95% confidence interval (CI): 1.04 to 2.48; P = 0.032] and 59356: T allele vs. C/C (OR: 0.63, 95% CI: 0.41 to 0.96; P = 0.033) and CCR2-180: G allele vs. A/A (OR: 3.32, 95% CI: 1.13 to 9.73; P = 0.029) were associated with risk of MTCT. Treatment of HIV-1–infected mothers and infants with single-dose nevirapine or perinatal zidovudine altered but did not eliminate the association of genetic variants with MTCT.CCR5 promoter, CCR2, and CX3CR1 polymorphisms were associated with risk of MTCT likely through their role as an HIV-1 coreceptor or by modulating the early immune response. Host genetics may continue to alter MTCT when short-course interventions that only partially suppress virus are used. These findings will need to be confirmed in validation cohorts with a large number of infected infants.
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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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    Comparison of HIV-1 Mother-to-Child Transmission After Single-Dose Nevirapine Prophylaxis Among African Women With Subtypes A, C, and D
    (JAIDS Journal of Acquired Immune Deficiency Syndromes, 2006) Eshleman, Susan; Church, Jessica; Guay, Laura A.; Mwatha, Anthony; Fiscus, Susan A.; Mmiro, Francis; Musoke, Philippa; Kumwenda, Newton; Jackson, J. Brooks; Taha, Taha E.; Hoover, Donald R.
    The HIVNET 012 trial in Uganda showed that mother-to-child transmission (MTCT) of HIV-1 can be prevented by providing pregnant women and their infants with a single dose (SD) of the antiretroviral drug, nevirapine (NVP).1,2 Safety and efficacy of 1- or 2-dose NVP prophylaxis for prevention of MTCT have been documented in other studies. We have shown that NVP resistance emerges in some women after SD NVP prophylaxis3 and that the portion of women with NVP resistance is influenced by HIV-1 subtype.4 At 6 to 8 weeks after SD NVP, NVP resistance was more common in women with subtype C (69.2%) than in women with subtype D (36.1%, P < 0.0001) or subtype A (19.4%, P < 0.0001).4 Selection of NVP-resistant HIV-1 variants in women after NVP dosing could theoretically lower the efficacy of NVP prophylaxis for prevention of HIV transmission by breast-feeding in the first few weeks after birth. In the HIVNET 012 trial, most women were infected with HIV-1 subtype A or D. Risk of MTCT was slightly (but not statistically) higher in women with subtype D.5 In this report, we combined data from the HIVNET 012 and NVAZ trials6 to compare the risk of MTCT in women with subtype C to the risk of MTCT in women with subtypes A and D in the setting of SD NVP prophylaxis.
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    Coreceptor Tropism in Human Immunodeficiency Virus Type 1 Subtype D: High Prevalence of CXCR4 Tropism and Heterogeneous Composition of Viral Populations
    (Journal of virology, 2007) Huang, Wei; Eshleman, Susan H.; Toma, Jonathan; Fransen, Signe; Stawiski, Eric; Paxinos, Ellen E.; Whitcomb, Jeannette M.; Young, Alicia M.; Donnell, Deborah; Mmiro, Francis; Musoke, Philippa; Guay, Laura A.; Jackson, J. Brooks; Parkin, Neil T.; Petropoulos, Christos J.
    In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from ∼20% in early infection to ∼50% in advanced disease. Coreceptor use by non-subtype B HIV is less well characterized. We studied coreceptor tropism of subtype A and D HIV-1 collected from 68 pregnant, antiretroviral drug-naive Ugandan women (HIVNET 012 trial). None of 33 subtype A or 10 A/D-recombinant viruses used the CXCR4 coreceptor. In contrast, nine (36%) of 25 subtype D viruses used both CXCR4 and CCR5 coreceptors. Clonal analyses of the nine subtype D samples with dual or mixed tropism revealed heterogeneous viral populations comprised of X4-, R5-, and dual-tropic HIV-1 variants. In five of the six samples with dual-tropic strains, V3 loop sequences of dual-tropic clones were identical to those of cocirculating R5-tropic clones, indicating the presence of CXCR4 tropism determinants outside of the V3 loop. These dual-tropic variants with R5-tropic-like V3 loops, which we designated “dual-R,” use CCR5 much more efficiently than CXCR4, in contrast to dual-tropic clones with X4-tropic-like V3 loops (“dual-X”). These observations have implications for pathogenesis and treatment of subtype D-infected individuals, for the association between V3 sequence and coreceptor tropism phenotype, and for understanding potential mechanisms of evolution from exclusive CCR5 use to efficient CXCR4 use by subtype D HIV-1.
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    Coreceptor Tropism in Human Immunodeficiency Virus Type 1 Subtype D: High Prevalence of CXCR4 Tropism and Heterogeneous Composition of Viral Populations
    (Journal of virology, 2007) Huang, Wei; Eshleman, Susan H.; Toma, Jonathan; Fransen, Signe; Stawiski, Eric; Paxinos, Ellen E.; Whitcomb, Jeannette M.; Young, Alicia M.; Donnell, Deborah; Mmiro, Francis; Musoke, Philippa; Guay, Laura A.; Jackson, Brooks; Parkin, Neil T.; Petropoulos, Christos J.
    In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from 20% in early infection to 50% in advanced disease. Coreceptor use by non-subtype B HIV is less well characterized. We studied coreceptor tropism of subtype A and D HIV-1 collected from 68 pregnant, antiretroviral drug-naive Ugandan women (HIVNET 012 trial). None of 33 subtype A or 10 A/D-recombinant viruses used the CXCR4 coreceptor. In contrast, nine (36%) of 25 subtype D viruses used both CXCR4 and CCR5 coreceptors. Clonal analyses of the nine subtype D samples with dual or mixed tropism revealed heterogeneous viral populations comprised of X4-, R5-, and dual-tropic HIV-1 variants. In five of the six samples with dual-tropic strains, V3 loop sequences of dual-tropic clones were identical to those of cocirculating R5-tropic clones, indicating the presence of CXCR4 tropism determinants outside of the V3 loop. These dual-tropic variants with R5-tropic-like V3 loops, which we designated “dual-R,” use CCR5 much more efficiently than CXCR4, in contrast to dual-tropic clones with X4-tropic-like V3 loops (“dual-X”). These observations have implications for pathogenesis and treatment of subtype D-infected individuals, for the association between V3 sequence and coreceptor tropism phenotype, and for understanding potential mechanisms of evolution from exclusive CCR5 use to efficient CXCR4 use by subtype D HIV-1.
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    Cost Effectiveness Of Single-Dose Nevirapine Regimen For Mothers And Babies To Decrease Vertical HIV-1 Transmission In Sub-Saharan Africa
    (The Lancet, 1999) Marseille, Elliot; Kahn, James G.; Mmiro, Francis; Guay, Laura; Musoke, Philippa; Fowler, Mary Glenn; Jackson, J. Brooks
    Identification of economical interventions to decrease HIV-1 transmission to children is an urgent public-health priority in sub-Saharan Africa. We assessed the cost effectiveness of the HIVNET 012 nevirapine regimen.We assessed cost effectiveness in a hypothetical cohort of 20 000 pregnant women in sub-Saharan Africa. Our main outcome measures were programme cost, paediatric HIV-1 cases averted, cost per case averted, and cost per disability-adjusted life-year (DALY). We compared HIVNET 012 with other short-course antiretroviral regimens. We also compared two implementation strategies: counselling and HIV-1 testing before treatment (targeted treatment), or nevirapine for all pregnant women (universal treatment, no counselling and testing). We did univariate and multivariate sensitivity analyses.For universal treatment with 30% HIV-1 seroprevalence, the HIVNET 012 regimen would avert 603 cases of HIV-1 in babies, cost US$83 333, and generate 15 862 DALYs. The associated cost-effectiveness ratios were $138 per case averted or $5·25 per DALY. At 15% seroprevalence, the universal treatment option would cost $83 333 and avert 302 cases at $276 per case averted or $10·51 per DALY. For targeted treatment at 30% seroprevalence, HIVNET 012 would cost $141 922 and avert 476 cases at $298 per case averted or $11·29 per DALY. With seroprevalence higher than 3·0% for universal and 4·5% for targeted treatment, the HIVNET 012 regimen was likely to be as cost effective as other public-health interventions. The cost effectiveness of HIVNET 012 was robust under a wide range of parameters in the sensitivity analysis.The HIVNET 012 regimen can be highly cost-effective in high seroprevalence settings. In lower seroprevalence areas, when multidose regimens are not cost effective, nevirapine therapy could have a major public-health impact at a reasonable cost.
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    Early Weaning of HIV-Exposed Uninfected Infants and Risk of Serious Gastroenteritis: Findings from Two Perinatal HIV Prevention Trials in Kampala, Uganda
    (Journal of acquired immune deficiency syndromes, 2010) Makumbi, Carolyne Onyango; Bagenda, Danstan; Mwatha, Antony; Omer, Saad B.; Musoke, Philippa; Mmiro, Francis; Zwerski, Sheryl L.; Kateera, Brenda Asiimwe; Musisi, Maria; Fowler, Mary Glenn; Jackson, J. Brooks; Guay, Laura A.
    To assess serious gastroenteritis risk and mortality associated with early cessation of breastfeeding in infants enrolled in two prevention-of-maternal-to-child-HIV-transmission trials in Uganda.We used hazard rates to evaluate serious gastroenteritis events by month of age and mortality among HIV-exposed uninfected infants enrolled in the HIVNET 012 (1997-2001) and HIVIGLOB/NVP (2004-2007) trials. HIV-infected mothers were counseled using local infant feeding guidelines current at the time.Breastfeeding cessation occurred earlier in HIVIGLOB/NVP compared to HIVNET 012 (median 4.0 vs. 9.3 months, p<0.001). Rates of serious gastroenteritis were higher in HIVIGLOB/NVP (8.0/1000 child-months) compared to HIVNET 012 (3.1/1000 child-months; p < 0.001). Serious gastroenteritis events also peaked earlier at 3-4 and 7-8 months (16.2/1000 and 15.0/1000 child-months, respectively) compared to HIVNET 012 at 9 to10 months (20.8/1000 child-months). All cause-infant mortality did not statistically differ between the HIVIGLOB/NVP and the HIVNET 012 trials [3.2/1000 versus 2.0/1000 child-months respectively, (p=0.10)]Early breastfeeding cessation seen in the HIVIGLOB/NVP trial was associated with increased risk of serious gastroenteritis among HIV-exposed uninfected infants when compared to later breastfeeding cessation in the HIVNET 012 trial. Testing interventions which could decrease HIV transmission through breastfeeding and allow safe breastfeeding into the second year of life are urgently needed.
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    Effect Of Periodic Vitamin A Supplementation On Mortality And Morbidity Of Human Immunodeficiency Virus–Infected Children In Uganda: A Controlled Clinical Trial
    (Nutrition, 2005) Semba, Richard D.; Ndugwa, Christopher; Perry, Robert T.; Clark, Tamara D.; Jackson, J. Brooks; Melikian, George; Tielsch, James; Mmiro, Francis; F.R.C.O.G.
    We investigated whether vitamin A supplementation would decrease mortality and morbidity rates in children infected with the human immunodeficiency virus (HIV).We conducted a randomized, double-blind, placebo-controlled clinical trial at Mulago Hospital, a large hospital that serves the urban and semiurban populations of Kampala, Uganda. One hundred eighty-one HIV-infected children were enrolled at 6 mo and randomized to receive vitamin A supplementation, 60 mg retinol equivalent, or placebo every 3 mo from ages 15 to 36 mo. Morbidity was assessed through a 7-d morbidity history every 3 mo, and vital events were measured. Children received daily trimethoprim-sulfamethoxazole prophylactic therapy.After age 15 mo, children were followed for a median of 17.8 mo (interquartile range = 11.1 to 21.0 mo). The trial was stopped when there was a new policy to implement a program of mass supplementation of vitamin A in the country. Mortality rates among 87 children in the vitamin A group and 94 children in the control group were 20.6% and 32.9%, respectively, yielding a relative risk of 0.54 (95% confidence interval, 0.30 to 0.98; P = 0.044) after adjusting for baseline weight-for-height Z score. Children who received vitamin A had lower modified point prevalences of persistent cough (odds ratio, 0.47; 95% confidence interval, 0.23 to 0.96; P = 0.038) and chronic diarrhea (odds ratio, 0.48; 95% confidence interval, 0.19 to 1.18; P = 0.11) and a shorter duration of ear discharge (P = 0.03). Vitamin A supplementation had no significant effect on modified point prevalences of fever, ear discharge, bloody stools, or hospitalizations.Vitamin A supplementation decreases mortality rate in HIV-infected children and should be considered in the care for these children in developing countries.
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    Genetic Linkage of Nevirapine Resistance Mutations in HIV Type 1 Seven Days after Single-Dose Nevirapine
    (AIDS Research & Human Retroviruses, 2005) Jones, Dana; Parkin, Neil; Hudelson, Sarah E.; Guay, Laura A.; Musoke, Philippa; Mmiro, Francis; Jackson, J. Brooks; Eshleman, Susan H.
    The HIVNET 012 trial in Uganda demonstrated that a regimen of single-dose nevirapine (NVP) can prevent HIV-1 mother-to-child transmission. Previous studies show that HIV-1 with one or more NVP resistance (NVPR) mutations can be selected in many women as early as 7 days after single-dose NVP. We evaluated the genetic linkage of NVPR mutations in plasma from women in HIVNET 012 collected 7 days after single-dose NVP administration. The HIV-1 pol region was amplified and cloned from 20 plasma samples (16 with NVPR mutations detected by population sequencing and 4 with no NVPR mutations detected), and 10 clones from each sample were sequenced. Up to five different NVPR mutations were detected in clones from a single sample. K103N and Y181C were the most common mutations detected. Clones with two genetically linked mutations were detected in four samples. Different combinations of NVPR mutations were linked in individual clones, but none of the clones contained both K103N and Y181C. Further studies are needed to evaluate whether selection of minority variants with one or more NVPR mutations after single-dose NVP is clinically relevant.
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    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.
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    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.
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    Iron Deficiency Anemia Is Highly Prevalent among Human Immunodeficiency Virus–Infected and Uninfected Infants in Uganda
    (The Journal of nutrition, 2002) Totin, Dana; Ndugwa, Christopher; Mmiro, Francis; Perry, Robert T.; Jackson, J. Brooks; Semba, Richard D.
    Although anemia is a common finding among human immunodeficiency (HIV)-infected infants in sub-Saharan Africa, the factors contributing to the pathogenesis of anemia have not been well characterized. We sought to characterize the relative contribution of iron deficiency and chronic disease to the anemia among infants. Hemoglobin, ferritin, erythropoietin, tumor necrosis factor-α (TNF-α), neopterin, CD4+ lymphocyte count and plasma HIV load were measured in 165 HIV-infected and 39 uninfected 9-mo-old infants seen in an outpatient pediatric clinic in Kampala, Uganda. Among HIV-infected and uninfected infants, the prevalence of anemia (hemoglobin < 110 g/L) was 90.9 and 76.9%, respectively (P = 0.015), and the prevalence of iron deficiency anemia (hemoglobin < 110 g/L and ferritin < 12 μg/L) was 44.3 and 45.4%, respectively (P = 0.92). The relatively higher prevalence of anemia among HIV-infected infants was attributed to the anemia of chronic disease. Among infants with and without iron deficiency, the fitted regression line was log10 plasma erythropoietin = 2.86 − 0.016 · hemoglobin, and log10 plasma erythropoietin = 4.11 − 0.028 · hemoglobin, respectively, with a difference in the slope of the regression lines between log10 erythropoietin and hemoglobin among infants with and without iron deficiency (P = 0.049). Infants in Uganda have an extremely high prevalence of anemia, and nearly half of the anemia is due to iron deficiency. The erythropoietin response to anemia appears to be upregulated among infants with iron deficiency.
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    Long Term Follow-up of Children in the HIVNET 012 Perinatal HIV Prevention Trial: Five-Year Growth and Survival
    (Journal of acquired immune deficiency syndromes, 2013) Owor, Maxensia; Mwatha, Anthony; Donnell, Deborah; Musoke, Philippa; Mmiro, Francis; Allen, Melissa; Jackson, J. Brooks; Fowler, Mary Glenn; Laura A; Guay, Laura A.
    To describe five year growth, survival and long-term safety among children exposed to nevirapine or zidovudine in an African perinatal prevention trial, HIVNET 012.All study children who were alive at eighteen months of age were eligible for an extended follow-up study. Children whose families consented were enrolled and evaluated every six months from 24 to 60 months. At each visit, history, physical exam and growth measures were taken. From these measurements Z scores based on World Health Organization (WHO) standards were computed. Serious adverse event data were collected. Data from the initial and extended follow-up cohorts were included in the analysis.528 study children were alive at age 18 months, and 491 (426 HIV uninfected; 65 infected) were enrolled into the follow-up study. Both exposed but uninfected children and HIV infected children were substantially below WHO growth standards for weight and height. Head circumference Z scores for uninfected children were comparable to WHO norms. Five-year survival rates were 93% for uninfected children versus 43% for infected children. Long-term safety and growth outcomes in the two study arms were similar.Both infected and uninfected children in the five-year HIVNET 012 follow-up showed poor height and weight growth outcomes, underscoring the need for early nutritional interventions to improve long-term growth of all infants born to HIV-infected women in resource limited settings. Likewise, the low five year survival among HIV infected children support the importance of early initiation of antiretroviral therapy. Both peripartum nevirapine and zidovudine were safe.
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    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.
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    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.