Browsing by Author "Mofenson, Lynne"

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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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    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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    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.