Mark Mirochnick

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.

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

OBJECTIVE 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. DESIGN An open label phase I/II study. SETTING Tertiary care hospital, Kampala, Uganda. PATIENTS AND INTERVENTIONS Nevirapine, 200 mg, 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, 2 mg/kg, at 72 h of age. OUTCOMES 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. RESULTS 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 1623 ng/ml (range 238-2356 ng/ml); median cord/maternal blood ratio of 0.75 (0.37-0.93). The median half-life in women was 61.3 h (27-90 h) and the transplacental nevirapine half-life in infants who did not receive a neonatal dose was 54 h. The median half-life after a single dose at 72 h in infants was 46.5 h. 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 103 ng/ml (25-309 ng/ml). Plasma nevirapine concentrations were above 100 ng/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. CONCLUSION The administration of a single dose of nevirapine to women during labor and to their newborns at 72 h 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 100 ng/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.

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

ObjectiveA recent trial in Uganda demonstrated that a simple, inexpensive regimen of nevirapine (NVP) prophylaxis can dramatically reduce HIV-1 vertical transmission risk. In this regimen, women receive a single dose of NVP at the onset of labor and infants receive a single dose of NVP within 72 h of birth. The objective of this study was to determine whether HIV-1 variants with NVP resistance mutations were selected in Ugandan women who received this regimen in the Phase I/II trial HIVNET 006. MethodsReverse transcriptase (RT) sequences from plasma HIV-1 were analyzed from 15 women 6 weeks after NVP dosing. RT sequences from plasma collected prior to NVP dosing were also analyzed. ResultsThe K103N NVP resistance mutation was detected 6 weeks after NVP administration in three (20%) out of 15 women (95% confidence interval, 0–40%). Pre-dose samples were available from two of the three women; both pre-dose samples lacked the mutation. Other NVP resistance mutations were absent from all 15 women. Women with the K103N mutation had a longer median NVP elimination half-life, decreased median oral clearance, and increased median area under the concentration time curve than those without the mutation. An evaluable sample was obtained from one of these three women 33 months after delivery; the K103N mutation was not detected in that sample. ConclusionsThis preliminary study demonstrates that HIV-1 with the RT K103N mutation can be detected in some Ugandan women following a single dose of NVP. This suggests that non-nucleoside RT inhibitor resistance may be selected in some people by single dose NVP prophylaxis. Pharmacokinetic data suggested that a more prolonged exposure to NVP after dosing may favor selection of NVP-resistant HIV-1.

Pharmacokinetics of Nevirapine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

The safety, toxicity, and pharmacokinetics of intrapartum and early newborn nevirapine were evaluated in 17 human immunodeficiency virus type 1-infected women in labor and their newborns. No adverse effects of nevirapine were noted in any study mothers or infants. Following maternal dosing with 200 mg during labor, concentrations exceeding 100 ng/mL (10 times the in vitro IC50) were achieved in the newborns. Nevirapine elimination was prolonged in both mothers and infants, with median half-lives ranging from 36.8 to 65.7 h. Administration of 200 mg orally to the mothers in labor and of a single 2-mg/kg oral dose to the infants at 48-72 h after birth maintained serum concentrations in the infants > 100 ng/mL through 7 days of life.

Reduced lopinavir exposure during pregnancy.

Background:Optimal antiretroviral exposure during pregnancy is critical for prevention of mother-to-child HIV transmission and for maternal health. Pregnancy can alter antiretroviral pharmacokinetics. Our objective was to describe lopinavir/ritonavir (LPV/r) pharmacokinetics during pregnancy. Methods:We performed intensive steady-state 12-h pharmacokinetic profiles of lopinavir and ritonavir (three capsules: LPV 400 mg/r 100 mg) at 30–36 weeks gestation and 6–12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. We measured LPV and ritonavir by reverse-phase high-performance liquid chromatography. Target LPV area under concentration versus time curve (AUC) was ≥ 52 μg h/ml, the estimated 10th percentile LPV AUC in non-pregnant historical controls (mean AUC = 83 μg h/ml). Results:Seventeen women completed antepartum evaluations; average gestational age was 35 weeks. Geometric mean antepartum LPV AUC was 44.4 μg h/ml [90% confidence interval (CI), 38.7–50.9] and 12-h post-dose concentration (C12h) was 1.6 μg/ml (90% CI, 1.1–2.5). Twelve women completed postpartum evaluations; geometric mean LPV AUC was 65.2 μg h/ml (90% CI, 49.7–85.4) and C12h was 4.6 μg/ml (90% CI, 3.7–5.7). The geometric mean ratio of antepartum/postpartum LPV AUC was 0.72 (90% CI, 0.54–0.96). Fourteen of 17 (82%) pregnant and three of 12 (25%) postpartum women did not meet our target LPV AUC. The ratio of cord blood/maternal LPV concentration in ten paired detectable samples was 0.2 ± 0.13. Conclusions:LPV/r exposure during late pregnancy was lower compared to postpartum and compared to non-pregnant historical controls. Small amounts of lopinavir cross the placenta. The pharmacokinetics, safety, and effectiveness of increased LPV/r dosing during the third trimester of pregnancy should be investigated.

Pharmacokinetics of antiretrovirals in pregnant women

Antiretroviral treatment of HIV-infected pregnant women is widely used to prevent mother-to-child HIV transmission and as primary therapy of maternal HIV infection. The physiological changes associated with pregnancy have a large impact on drug disposition, and changes in antiretroviral pharmacokinetics during pregnancy must be understood for these drugs to be used safely and effectively in pregnant women.Zidovudine and didanosine, two of the nucleoside reverse transcriptase inhibitors, demonstrate an increase in clearance and decrease in area under the concentration-time curve during pregnancy. The clinical significance of these changes is unknown due to the lack of a clear relationship between plasma concentrations of nucleoside reverse transcriptase inhibitors and clinical effects. Pharmacokinetic parameters of lamivudine, stavudine and abacavir are not significantly changed during pregnancy. There are no data describing the effect of pregnancy on the pharmacokinetics of the other nucleoside/nucleotide analogues (zalcitabine, emtricitabine and tenofovir). Pregnancy does not appear to have a significant effect on the pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor nevirapine and there are no data describing the pharmacokinetics of the other non-nucleoside reverse transcriptase inhibitors (efavirenz and delavirdine) during pregnancy.Reduced plasma concentrations during pregnancy have been described for several of the protease inhibitors, including nelfinavir (with administration of 750mg three times daily), indinavir, saquinavir and Kaletra® (a co-formulation of lopinavir and ritonavir). Plasma concentrations equivalent to those in nonpregnant adults have been reported in pregnant women receiving nelfinavir at doses of 1250mg twice daily, and the addition of ritonavir to saquinavir greatly increases saquinavir exposure to therapeutic concentrations in pregnant women. No pregnancy pharmacokinetic data are available for the newer protease inhibitors atazanavir and fosamprenavir, or with other dual protease inhibitor combinations that include low dose ritonavir to boost concentrations of the coadministered protease inhibitor. Further investigations of antiretroviral pharmacology during pregnancy, including protein binding studies, are urgently needed.

Effect of training traditional birth attendants on neonatal mortality (Lufwanyama Neonatal Survival Project): randomised controlled study

Objective To determine whether training traditional birth attendants to manage several common perinatal conditions could reduce neonatal mortality in the setting of a resource poor country with limited access to healthcare. Design Prospective, cluster randomised and controlled effectiveness study. Setting Lufwanyama, an agrarian, poorly developed district located in the Copperbelt province, Zambia. All births carried out by study birth attendants occurred at mothers’ homes, in rural village settings. Participants 127 traditional birth attendants and mothers and their newborns (3559 infants delivered regardless of vital status) from Lufwanyama district. Interventions Using an unblinded design, birth attendants were cluster randomised to intervention or control groups. The intervention had two components: training in a modified version of the neonatal resuscitation protocol, and single dose amoxicillin coupled with facilitated referral of infants to a health centre. Control birth attendants continued their existing standard of care (basic obstetric skills and use of clean delivery kits). Main outcome measures The primary outcome was the proportion of liveborn infants who died by day 28 after birth, with rate ratios statistically adjusted for clustering. Secondary outcomes were mortality at different time points; and comparison of causes of death based on verbal autopsy data. Results Among 3497 deliveries with reliable information, mortality at day 28 after birth was 45% lower among liveborn infants delivered by intervention birth attendants than control birth attendants (rate ratio 0.55, 95% confidence interval 0.33 to 0.90). The greatest reductions in mortality were in the first 24 hours after birth: 7.8 deaths per 1000 live births for infants delivered by intervention birth attendants compared with 19.9 per 1000 for infants delivered by control birth attendants (0.40, 0.19 to 0.83). Deaths due to birth asphyxia were reduced by 63% among infants delivered by intervention birth attendants (0.37, 0.17 to 0.81) and by 81% within the first two days after birth (0.19, 0.07 to 0.52). Stillbirths and deaths from serious infection occurred at similar rates in both groups. Conclusions Training traditional birth attendants to manage common perinatal conditions significantly reduced neonatal mortality in a rural African setting. This approach has high potential to be applied to similar settings with dispersed rural populations. Trial registration Clinicaltrials.gov NCT00518856.

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.