Persistence of K103N-containing HIV-1 variants after single-dose nevirapine for prevention of HIV-1 mother-to-child transmission

K103N-containing human immunodeficiency virus (HIV)-1 variants are selected in some women who receive single-dose (SD) nevirapine (NVP) for prevention of HIV-1 mother-infant transmission. We examined the persistence of K103N in women who received SD NVP prophylaxis. K103N was detected using the LigAmp assay (assay cutoff, 0.5% K103N). K103N was detected at 6-8 weeks in 60 (41.7%) of 144 women. Fading (lack of detection) of K103N was documented in 16 women by 2 years, 43 women by 3 years, and 55 women by 4 and 5 years. Slower fading was independently associated with HIV-1 subtype (D>A) and higher pre-NVP viral load.     

Trial of oral fumagillin for the treatment of intestinal microsporidiosis in patients with HIV infection. ANRS 054 Study Group. Agence Nationale de Recherche sur le SIDA

OBJECTIVE: Intestinal microsporidiosis caused by Enterocytozoon bieneusi is a cause of chronic diarrhoea in patients with HIV infection for which there is no current therapy. This study was designed to assess the safety and efficacy of oral fumagillin in this infection. DESIGN: A dose-escalation trial. METHODS: Twenty-nine HIV-infected patients with E. bieneusi infection were consecutively enrolled in the trial. Oral doses of fumagillin were given to four groups of patients for 14 days: 10 mg/day (group 1), 20 mg/day (group 2), 40 mg/day (group 3), and 60 mg/day (group 4). Patients were seen at weeks 1, 2, 4 and 6 to assess safety and efficacy. Efficacy was assessed primarily by the clearance of microsporidia from stools and follow-up duodenal biopsies. RESULTS: Thirteen patients complained of abdominal cramps, vomiting or diarrhoea during the study, and three patients had fumagillin withdrawn because of adverse events. Thrombocytopenia, neutropenia and hyperlipasaemia were the most frequent biological adverse events. Twenty-one out of 29 patients transiently cleared microsporidia from their stools during the study. By week 6, however, all patients in groups 1, 2 and 3 had parasitic relapse. Interestingly, eight out of 11 (72%) patients treated with 60 mg/day (group 4) apparently cleared microsporidia from their gastrointestinal tract and gained weight. No parasitic relapse was documented in these eight patients during a mean follow-up of 11.5 months. CONCLUSION: Treatment with fumagillin at 60 mg/day for 14 days has promise as an effective oral treatment for E. bieneusi infections.     

Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1

We analyzed the development of nevirapine (NVP) resistance in human immunodeficiency virus type 1 (HIV-1)-infected Malawian infants who received regimens containing single-dose NVP (SD-NVP) for the prevention of mother-to-child transmission (MTCT) of HIV-1. All infants received SD-NVP, and some randomly received zidovudine (ZDV) as well. Mothers did or did not receive SD-NVP on the basis of when they arrived at the hospital for delivery. In infants 6-8 weeks of age, NVP resistance was less frequent when infants had received SD-NVP plus ZDV and mothers had not received SD-NVP than when infants had received SD-NVP alone and mothers had received SD-NVP (4/15 [27%] vs. 20/23 [87%]; P < .001). The risk of MTCT of HIV-1 was comparable with these regimens. Infant-only prophylaxis also eliminates the development of NVP resistance in mothers.     

Timing of maternal and neonatal dosing of nevirapine and the risk of mother-to-child transmission of HIV-1: HIVNET 024

OBJECTIVE: Despite a growing emphasis worldwide on complex and potent antiretroviral drug regimens for the prevention of mother-to-child transmission of HIV-1 (MTCT), two-dose nevirapine (NVP) prophylaxis remains an important choice in many settings. We analyzed data from a multicenter clinical trial to determine whether timing of maternal or infant NVP was associated with MTCT between delivery and 6 weeks of age (intrapartum/early postnatal transmission; I/EP). METHODS: HIVNET 024 was a placebo-controlled, double-blind trial of empiric antibiotics to reduce chorioamnionitis-associated MTCT. This secondary analysis used data collected in the original randomized trial. Enrolled women were instructed to self-administer NVP at labor onset; infants were to receive a dose within 72 h of birth. RESULTS: Data regarding 1491 mother-infant pairs were analyzed. The overall I/EP HIV-1 transmission rate was 8.1% at 6 weeks. Almost all women (93%) ingested NVP within 24 h of delivery; 90% of infants were given NVP within 48 h after delivery. Variations in mother or infant dose timing did not influence transmission rates, even when the combined pattern of both was taken into account through multivariate analysis. In the subset of women ingesting NVP or= 4 h). CONCLUSION: Variations in the timing of maternal and infant NVP doses (within reasonable proximity to delivery) do not appear to affect the risk of MTCT.     

Sociodemographic factors associated with participation by HIV-1-positive pregnant women in an intervention to prevent mother-to-child transmission of HIV in Cote d'Ivoire

Many HIV-1-seropositive women in Africa who are offered antiretroviral prophylaxis to prevent mother-to-child transmission (MTCT) of HIV do not begin interventions. Research on barriers to participation has not addressed the possible effects of women's sociocultural and economic circumstances. We examined these factors at an MTCT prevention programme in Abidjan, Cote d'Ivoire. We interviewed two groups of women after they had received HIV-positive test results and had been invited by the programme staff to return for monthly follow-up visits before beginning short-course zidovudine prophylaxis. Participants (n = 30) completed follow-up visits and prophylaxis. Non-participants (n = 27) refused or discontinued follow-up visits and did not begin zidovudine. Fewer non-participants had been born in Cote d'Ivoire (67% vs. 97%) or were Ivorian nationals (48% vs. 77%); they had lived in the country for less time (21 vs. 26 median years). They were less likely to be French-literate (37% vs. 77%), and more of them reported having had Koranic education only (18% vs. 0). They more often reported miscarriages, stillbirths, or infant deaths (69% vs. 33%), and had partners with low-ranked jobs (63% vs. 30%). Our findings suggest that the non-participants were more marginal socioculturally and economically in Ivorian society than participants. Greater attention to mitigating the effects of broader structural factors on women's participation in interventions may increase the effectiveness of MTCT prevention in Africa.     

Advances and research directions in the prevention of mother-to-child HIV-1 transmission

Although substantial progress has been made in preventing mother-to-child HIV-1 transmission in the past decade, critical research questions remain. Two perinatal epidemics now exist. In more-developed countries, integration of prenatal HIV-1 counselling and testing programmes into an existing antenatal infrastructure, availability of effective antiretroviral prophylaxis, and access to infant formula have resulted in new perinatal infections becoming rare. However, identification of missed prevention opportunities, the causes of prophylaxis failure, and the potential effects of in-utero antiretroviral exposure have become a priority. In less-developed countries, antenatal care is limited, testing programmes are almost non-existent, effective interventions remain unimplemented, and prevention of postnatal transmission through breastmilk while maintaining adequate infant nutrition is a major dilemma. The challenge for the next decade is to simultaneously address questions relevant to both epidemics while bridging the gap in prevention of perinatal transmission between more-developed and 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

A study was conducted to assess the safety and efficacy of short-course nevirapine compared with zidovudine given to women during labor and to neonates during the first week of life. 626 HIV-1 infected pregnant women attending the antenatal clinic from November 1997 to April 1999 at Mulago Hospital in Kampala, Uganda, were randomly given nevirapine or zidovudine. Infants were tested for HIV-1 infection at birth, at 6-8 weeks, and at 14-16 weeks. Findings revealed that the estimated risk of HIV-1 transmission in the zidovudine and nevirapine groups was 10.4% and 8.2%, respectively, at birth; 21.3% and 11.9%, by 6-8 weeks; and 25.1% and 13.1%, by 14-16 weeks. There was a 47% relative efficacy rate of the nevirapine regimen at 14-16 weeks compared to zidovudine. Based on the findings, nevirapine lowers the risk of HIV-1 transmission by nearly 50% during the first 14-16 weeks of life in breast-fed infants.     

Measurement of HIV-1 CRF02_AG-specific T cell responses indicates the dominance of a p24gag epitope in blood donors in Abidjan, Cote d'Ivoire

Characterization of human immunodeficiency virus (HIV)-1-specific immune responses against subtypes circulating in areas where the virus is endemic is critical for the design of candidate vaccines. In Cote d'Ivoire, the most prevalent HIV-1 subtype is CRF02_AG. We detected T cell responses to CRF02_AG consensus p24(gag) or protease peptides in 81% of HIV-1- or HIV-1/2-infected blood donors in Abidjan, Cote d'Ivoire. Both the magnitude and the breadth of interferon- gamma enzyme-linked immunospot responses were inversely correlated with plasma viral load. One frequently recognized peptide in p24(gag) was mapped to the optimal epitope (TPQDLNMML). Further studies of this epitope may be important for the development of HIV-1 vaccines for West Africa and West-Central Africa.     

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

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.     

Nevirapine resistance in women and infants after first versus repeated use of single-dose nevirapine for prevention of HIV-1 vertical transmission

Single-dose (SD) nevirapine (NVP) significantly reduces mother-to-child transmission of human immunodeficiency virus (HIV). We analyzed NVP resistance after receipt of SD NVP in 57 previously SD NVP-naive women, in 34 SD NVP-experienced women, and in 17 HIV-infected infants. The proportion of women infected with variants with resistance mutations, the types of mutations detected, and the frequency and level of K103N were similar in the two groups of women at 6 weeks and 6 months post partum. NVP resistance was detected in a similar proportion of infants born to SD NVP-naive versus SD NVP-experienced women. Repeated use of SD NVP to prevent HIV transmission does not appear to influence NVP resistance.     

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

OBJECTIVE: To examine the emergence and fading of NVP resistance (NVP(R)) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DESIGN: We examined NVP(R) 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. METHODS: Plasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. RESULTS: NVP(R) mutations were detected in 21 out of 111 (19%) women tested 6-8 weeks after delivery. The rate of NVP(R) was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVP(R) 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 NVP(R). NVP(R) mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6-8 weeks of age. The most common NVP(R) 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 NVP(R). CONCLUSIONS: NVP(R) was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVP(R) mutations were detected in women versus infants. NVP(R) was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time.     

Twin pregnancy as a risk factor for mother-to-child transmission of HIV-1: trends over 20 years

OBJECTIVE: We investigated whether twin pregnancies were at increased risk of mother-to-child HIV-1 transmission (MTCT), in comparison with singletons. METHODS: Among HIV-1 infected women enrolled in the French Perinatal HIV Cohort (n = 9262), we studied the association between twin deliveries and MTCT rate according to three time periods (pre-1994, 1994-1996, 1997-2004) and the effect of birth order. The mother was considered to have transmitted if at least one of the twins was infected. Univariate and multivariate analyses of risk factors for MTCT were performed for deliveries in the periods up to 1996. RESULTS: Overall, 2.1% (192/9262) of all the deliveries were twins. The rate of prematurity was greater in twins than in singletons (54% and 13%, respectively). Up to 1996 the rate of MTCT of HIV-1 was 28.3% (15/53) in twin pregnancies, versus 13.5% (414/3077) in singletons [odds ratio (OR), 2.5; 95% confidence interval (CI), 1.4-4.7; P = 0.002; adjusted OR, 2.3: 95% CI, 1.1-2.3; P = 0.03). In the period from 1997 to 2003, MTCT was low and did not differ between twins (1.0%) and singletons (1.8%; P = 1.0). Overall, the transmission rate for the first-born child was threefold that for the second-born child (14/164, 8.5% versus 4/164, 2.4%; P = 0.008). CONCLUSION: Twin pregnancies were at increased risk of transmission, but in the era of HAART this risk was reduced for twins, as well as singletons. Management of multiple pregnancies should take into account the risks of premature rupture of the membranes and preterm delivery.     

Reuse of single-dose nevirapine in subsequent pregnancies for the prevention of mother-to-child HIV transmission in Lusaka,Zambia: A cohort study

Background  

Single-dose nevirapine (SDNVP) for the prevention of mother-to-child HIV transmission (PMTCT) results in the selection of resistance mutants among HIV-infected mothers. The effects of these mutations on the efficacy of SDNVP use in a subsequent pregnancy are not well understood.