Philippa Musoke

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

BACKGROUND 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. METHODS 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. FINDINGS 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. INTERPRETATION 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.

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

BACKGROUND 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 2mg/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, regimenB). 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, well-tolerated regimen has the potential to significantly decrease HIV-1 perinatal transmission in less-developed countries.

Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent Hiv-1 vertical transmission (hivnet 012)

ObjectiveTo examine the emergence and fading of NVP resistance (NVPR) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DesignWe examined NVPR in women and infants who received NVP in the HIVNET 012 clinical trial, including 41 out of 48 women with infected infants, 70 randomly-selected women with uninfected infants, and 33 out of 49 infected infants. MethodsPlasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. ResultsNVPR mutations were detected in 21 out of 111 (19%) women tested 6–8 weeks after delivery. The rate of NVPR was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVPR mutations faded from detection within 12–24 months in all 11 evaluable women. High baseline viral load and low baseline CD4 cell count were associated with development of NVPR. NVPR mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6–8 weeks of age. The most common NVPR mutation detected in infants was Y181C. Those mutations faded from detection by 12 months of age in all seven evaluable infants. Of nine evaluable infants with late HIV-1 infection, only one had evidence of NVPR. ConclusionsNVPR was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVPR mutations were detected in women versus infants. NVPR was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time.

Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa

BACKGROUND 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. METHODS 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. FINDINGS For universal treatment with 30% HIV-1 seroprevalence, the HIVNET 012 regimen would avert 603 cases of HIV-1 in babies, cost US

Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials.

83,333, and generate 15,862 DALYs. The associated cost-effectiveness ratios were

A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006)

138 per case averted or

Sensitive Drug-Resistance Assays Reveal Long-Term Persistence of HIV-1 Variants with the K103N Nevirapine (NVP) Resistance Mutation in Some Women and Infants after the Administration of Single-Dose NVP: HIVNET 012

5.25 per DALY. At 15% seroprevalence, the universal treatment option would cost

Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel

83,333 and avert 302 cases at

Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission

276 per case averted or

Antiretroviral treatment for children with peripartum nevirapine exposure

10.51 per DALY. For targeted treatment at 30% seroprevalence, HIVNET 012 would cost