Strategies to prevent mother-to-child transmission of HIV

PURPOSE OF REVIEW: This review describes recent advances in the prevention of mother-to-child transmission, focusing on the use of antiretroviral treatment strategies in pregnancy, and discusses the emergence of viral resistance following the use of nevirapine to prevent mother-to-child transmission. RECENT FINDINGS: Mother-to-child transmission has been dramatically reduced in developed countries by the use of antiretroviral treatment and avoidance of breastfeeding. Highly active antiretroviral therapy use in pregnancy is recommended for women who require ongoing treatment, and, where available, is also very effective in reducing mother-to-child transmission in women with higher CD4 counts. The addition of a maternal and infant nevirapine dose to antenatal zidovudine can reduce transmission to below 5%, approximately half the transmission rate that can be achieved by single-dose nevirapine alone. The emergence of resistant virus following nevirapine use is a concern, occurring in up to 60% of mothers and 50% of infants following a single dose. Addition of zidovudine and lamivudine for 4-7 days postpartum can reduce the risk of resistance to 10%. SUMMARY: There is broad consensus on an approach to preventing mother-to-child transmission, which provides antiretroviral treatment in pregnancy and beyond to those women who need it, and an effective prophylactic regimen for those who do not yet need treatment, These regimens include highly active antiretroviral therapy, where available, a zidovudine-plus-nevirapine regimen in other settings, or nevirapine alone where this is all that is possible. More work is needed on the impact of nevirapine resistance and on reducing breast-milk transmission.     

Efavirenz replacement by immediate full-dose nevirapine is safe in HIV-1-infected patients in Cambodia

Background

Efavirenz is used for the antiretroviral treatment of HIV/tuberculosis‐coinfected patients in developing countries. A switch to nevirapine is regularly carried out because of the cost and side effects of efavirenz. Pharmacokinetic studies suggested that nevirapine should be initiated at full dose when used as a substitute for efavirenz.

Objectives

The aim of this study was to measure the cumulative incidence of adverse events (AEs) related to nevirapine in patients switched from efavirenz to immediate full‐dose nevirapine (FDN).

Methods

In 2001 an antiretroviral treatment programme was initiated with the first‐line regimen stavudine, lamivudine and efavirenz. In 2003, the fixed‐dose combination of stavudine, lamivudine and nevirapine was recommended. Thus, first‐line therapy was changed and FDN was initiated when patients were switched from efavirenz to nevirapine.

Results

Between April and December 2004, 394 patients were switched from efavirenz to FDN. The cumulative incidence of AEs related to nevirapine was 13.2% [95% confidence interval (CI) 10.2–16.7] and that of severe AEs was 8.9% (95% CI 6.5–11.9). In women the incidence of AEs was 17.6% (95% CI 12.1–24.3) and that of severe AEs was 12.2% (95% CI 7.7–18.2).

Conclusions

Our results indicate that an FDN switch from efavirenz does not appear to result in more AEs than when nevirapine is initiated with escalating doses. These data are particularly relevant in resource‐limited settings.     

Low risk of nevirapine resistance mutations in the prevention of mother-to-child transmission of HIV-1: Agence Nationale de Recherches sur le SIDA Ditrame Plus, Abidjan, Cote d'Ivoire

The frequency of resistance mutations was estimated in the cohort of Agence Nationale de Recherches sur le SIDA Ditrame Plus, a study that evaluated the combination of short-course zidovudine (ZDV) plus lamivudine (3TC) and single-dose nevirapine (SD-NVP) followed by 3 days of postpartum ZDV plus 3TC for the prevention of mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1). The frequency with which resistance mutations were detected in mothers at week 4 postpartum was 1.14% (95% confidence interval [CI], 0.03%-6.17%) for NVP and 8.33% (95% CI, 3.66%-15.76%) for 3TC. In multivariate analysis, 3TC resistance was associated with a longer duration of ZDV plus 3TC prepartum prophylaxis (P=.009). This regimen, which is feasible in resource-limited settings, prevents most peripartum HIV-1 transmission and minimizes the development of NVP resistance.     

Progress and emerging challenges in preventing mother-to-child transmission

There is a widening gulf between the effectiveness of interventions for preventing mother-to-child transmission (PMTCT) of HIV in sub-Saharan Africa and other regions of the world. Compared with long-course, triple antiretroviral regimens used in Brazil, Europe, and the United States, most countries in sub-Saharan Africa use a less effective regimen consisting of single-dose nevirapine (NVP). Furthermore, the documentation of unacceptable levels of resistance following this regimen makes it prudent to review current PMTCT strategies. Not only is it necessary to review the use of single-dose NVP for PMTCT, but efforts to minimize breast milk transmission of HIV should be enhanced. This review summarizes the programmatic and evidence-based reasons for adopting a standardized approach to long-course, triple-drug MTCT prophylaxis in sub-Saharan Africa. Antiretroviral treatment programs in resource-constrained settings have achieved similar levels of effectiveness as high-income countries, despite adopting standardized approaches to antiretroviral treatment. Similarly, in resource-constrained settings with adequate infrastructure and programmatic capacity, use of standardized, long-course, triple-drug regimens for MTCT prevention are likely to achieve levels of effectiveness seen in Brazil, Europe, and the United States.     

Reduction in mother-to-child transmission of HIV in Thailand, 2001-2003: Results from population-based surveillance in six provinces

BACKGROUND: In 2000, Thailand implemented a national program to prevent mother-to-child HIV transmission (PMTCT). OBJECTIVE: To describe the effectiveness of the prevention of mother-to-child HIV transmission program in Thailand. DESIGN AND METHODS: A register of HIV-exposed children at birth was created with follow-up of infection status. The register included children born to HIV-infected women between 1 January 2001 and 31 December 2003 at 84 public health hospitals in six provinces of Thailand. The main outcome measure was HIV infection in children. RESULTS: A total of 2200 children born to HIV-infected mothers were registered. Of these mother-infant pairs, 2105 (95.7%) received some antiretroviral prophylaxis, including 1358 (61.7%) who received the complete short-course zidovudine regimen during pregnancy and labor for the mother and after birth for the infant, with or without other antiretrovirals. HIV infection outcome was determined for 1667 (75.8%) children, of whom 158 [9.5%, 95% confidence interval (CI), 8.1-11.0%] were infected. Transmission risk was 6.8% (95% CI 5.2-8.9%) among 761 mother-infant pairs that received the complete zidovudine regimen alone, and 3.9% (95% CI, 2.2-6.6%) among 361 mother-infant pairs that received the complete zidovudine regimen combined with other antiretrovirals, usually nevirapine. The overall transmission risk from this cohort, including all antiretroviral prophylaxis combinations, is estimated to be 10.2%. CONCLUSIONS: The Thai national PMTCT program is effective in reducing mother-to-child transmission risk from the historical risk of 18.9-24.2%. The addition of nevirapine to short-course zidovudine beginning in 2004 may further improve program effectiveness in Thailand.     

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.     

Breast milk HIV-1 suppression and decreased transmission: a randomized trial comparing HIVNET 012 nevirapine versus short-course zidovudine

OBJECTIVE: To compare the effect of perinatal regimens of short-course nevirapine (HIVNET 012) and zidovudine [Thai-Centers for Disease Control and Prevention (CDC) regimen] on breast milk viral shedding and perinatal transmission during the first 6 weeks postpartum in a randomized clinical trial. DESIGN: Randomized clinical trial. METHODS: Pregnant HIV-1 seropositive women in Nairobi, Kenya who planned to breastfeed were randomized to HIVNET 012 or Thai-CDC regimens. Two to four breast milk samples were collected each week between delivery and 6 weeks postpartum. Breast milk HIV-1 RNA was quantified using the Gen-Probe TMA assay. Infants were tested for HIV-1 DNA at birth and 6 weeks. RESULTS: From March to October 2003, 76 women were enrolled and 795 breast milk samples were collected from 60 women who were randomized and followed after delivery. Between 3 and 21 days postpartum, nevirapine was associated with significantly greater suppression of breast milk log10 HIV-1 RNA: days 3 to 7 (1.98 versus 2.42, P = 0.1); days 8 to 14 (1.78 versus 2.48, P = 0.005); days 15 to 21 (1.90 versus 2.97, P = 0.003). At 6 weeks, the HIV-1 perinatal transmission rate was significantly lower among those who took nevirapine than zidovudine (6.8% versus 30.3%, P = 0.02). CONCLUSIONS: Compared to a peripartum zidovudine regimen, nevirapine was significantly more likely to decrease HIV-1 RNA in breast milk during the first week and through the third week postpartum following single-dose administration, and corresponded with decreased transmission risk at 6 weeks. Sustained breast milk HIV-1 suppression may contribute to the ability of nevirapine to decrease perinatal transmission of HIV-1.     

Cost-effectiveness analysis of infant feeding strategies to prevent mother-to-child transmission of HIV in South Africa

Despite increasing availability of perinatal interventions to prevent mother-to-child transmission (MTCT) of HIV in South Africa, MTCT remains high due to breastfeeding. To inform policy decisions in the country, cost-effectiveness of alternative infant-feeding interventions was conducted. Mathematical modelling was used to simulate post-natal transmission and mortality due to infant feeding in a hypothetical cohort of 1 000 HIV-exposed infants. Lifetime costs to the health system were calculated for each strategy. Interventions compared with current practice were: increasing coverage of extended nevirapine prophylaxis (ENP) to infants from 30% (base case) to 60% without changing current feeding practices; actively supporting breastfeeding with ENP to infants for 12 months; and actively supporting exclusive formula (replacement) feeding for 6 months. HIV-free survival at 24 months and disability-adjusted life years (DALYs) averted were estimated for typical rural and certain urban settings. Base-case analysis revealed that expanding coverage of nevirapine prophylaxis with breastfeeding is cost-saving and improves HIV-free survival. Changing feeding practices is beneficial, depending on context. Breastfeeding is dominant (less costly, more effective) in rural settings, whilst formula feeding is a dominant strategy in urban settings. Cost-effectiveness was most sensitive to proportion of women on lifelong antiretroviral therapy (ART) and infant mortality rate (IMR). When >55% of women are on ART, breastfeeding dominates in the urban settings modelled, whilst formula feeding is cost-effective in rural settings when IMR ≤ 45/1000. The study concludes that strategies to support breastfeeding are essential. Strengthening health systems is critical to ensure optimal nevirapine delivery during breastfeeding. A case can be made for formula feeding or breastfeeding in HIV-infected women in specific contexts.     

The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in human immunodeficiency virus type 1-infected persons

The steady-state pharmacokinetics of efavirenz and nevirapine, when used in combination to treat human immunodeficiency virus type 1 (HIV-1)-infected subjects, were investigated. HIV-1-infected persons who had used efavirenz (600 mg once daily) for > or =2 weeks were eligible for study inclusion. The plasma pharmacokinetics of efavirenz were determined over 24 h. Subsequently, nevirapine (400 mg once daily) was added to the regimen. After 4 weeks, the pharmacokinetics of efavirenz and nevirapine were assessed over 24 h. The differences between the pharmacokinetic parameters of efavirenz with and without nevirapine were analyzed, and the pharmacokinetics of nevirapine were compared with those in historical control patients. The exposure to efavirenz when combined with nevirapine was significantly decreased by 22% (area under the plasma concentration vs. time curve), 36% (minimum plasma concentration), and 17% (maximum plasma concentration). Nevirapine pharmacokinetics appear to be unaffected by coadministration of efavirenz, compared with data from historical control patients.     

170例HIV感染孕妇的妊娠结局分析

目的探讨并分析HIV感染孕妇的临床特征及妊娠结局。方法收集本院2007年1月—2018年11月期间HIV感染孕妇的流行病学资料,分析其流行病学特征以及妊娠结局。结果共纳入170例HIV感染孕妇,感染的主要方式为异性性传播。近3年诊治的HIV感染孕妇数量较前几年明显增多。孕妇的主要抗病毒方案为齐多夫定或替诺福韦+拉米夫定+洛匹那韦/利托那韦。婴儿主要抗病毒方案为齐多夫定或奈韦拉平。母婴阻断成功率100%。结论HIV感染孕妇数量呈上升趋势,及时对HIV感染孕妇进行规范系统的抗病毒治疗及对HIV暴露婴儿进行预防可有效阻断HIV母婴传播。     

The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals

OBJECTIVE: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. DESIGN: Open-label, randomized, cross-over study. METHODS: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Non-compartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC[24h]), and the maximal (Cmax) and minimal plasma concentration (Cmin), the time to Cmax (t(max)), the plasma elimination half-life (t1/2), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. RESULTS: The exposure to nevirapine, as measured by the AUC[24h], was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t1/2 Cl/F and V/F were not significantly different between the two dosing regimens (P > or = 0.08). However, Cmax and Cmin were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for Cmax and Cmin as measured for the once daily and twice daily regimens were 6.69 and 5.74 microg/ml, respectively (P = 0.03), and 2.88 and 3.73 microg/ml, respectively (P < 0.01). CONCLUSION: These data show that the daily exposure to nevirapine, as measured by the plasma AUC[24h], is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, Cmax and Cmin are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established.     

Prevention of mother-to-child transmission of HIV in Africa

HIV infection and mortality rates in African children are astoundingly high. Risk factors for mother-to-child transmission of HIV include maternal plasma viral load and breastfeeding. With regard to the latter, current data indicate that mixed feeding (breastfeeding with other oral foods and liquids) is associated with the greatest risk of transmission. Studies are under way to determine if exclusive breastfeeding with rapid early weaning can reduce transmission rates in the absence of exclusive formula feeding for all infants. Perinatal transmission rates have been dramatically reduced with the use of single-dose nevirapine, but this strategy protects only approximately 50% of infants, and more than 75% of women receiving nevirapine develop a major nevirapine resistance mutation. In developed areas of the world, antiretroviral therapy has reduced perinatal transmission by more than 90% compared with 1993 rates. Improved HIV-related care for HIV-infected women in Africa is needed to reduce rates of HIV infection in children and to prevent maternal mortality. This article summarizes a presentation by Sten H. Vermund, MD, PhD, at the International AIDS Society-USA course in Chicago in May 2004.     

Association of cord blood nevirapine concentration with reported timing of dose and HIV-1 transmission

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 = 11), was 916 ng/ml (IQR, 737-1245 ng/ml) compared with 1192 ng/ml (IQR, 875-1471 ng/ml) for uninfected infants (n = 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 = 11). The high adherence rate in the HIVNET 012 study supports the efficacy, simplicity and deliverability of this regimen.     

Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana

BACKGROUND: Single-dose nevirapine given to women and infants reduces mother-to-child HIV transmission, but nevirapine resistance develops in a large percentage of women. OBJECTIVE: To determine whether the maternal nevirapine dose could be eliminated in the setting of zidovudine prophylaxis. DESIGN, SETTING, AND PARTICIPANTS: A 2 x 2 factorial, randomized, clinical trial, with a double-blinded peripartum factor designed to assess the equivalence of maternal single-dose nevirapine versus placebo with respect to HIV transmission. A total of 709 HIV-infected pregnant women were randomized from four district hospitals in Botswana, resulting in 694 live first-born infants. HAART was available for women with AIDS. INTERVENTION: All women received a background of zidovudine from 34 weeks' gestation through delivery, and all infants received single-dose nevirapine at birth and zidovudine from birth through 1 month. Women were randomized to receive either single-dose nevirapine or placebo during labor. MAIN OUTCOME MEASURES: The primary endpoint was infant HIV infection by the 1-month visit. RESULTS: Of the 694 infants in this equivalence study, 15 (4.3%) of 345 in the maternal nevirapine arm were HIV infected by 1 month, versus 13 (3.7%) of 349 in the maternal placebo arm (95% confidence interval for difference, -2.4% to 3.8%), meeting pre-determined equivalence criteria. Nevirapine resistance at 1 month postpartum was detected in 45% of a random sample of women who received nevirapine. CONCLUSIONS: In the setting of maternal zidovudine and infant zidovudine plus single-dose nevirapine, infant HIV infection rates were similar whether women received single-dose nevirapine or placebo. This strategy avoids the potential for maternal nevirapine resistance.     

Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: week 24 results of a randomized controlled trial--PACTG 377. Pediatric AIDS Clinical Trials Group 377 Study Team

One hundred eighty-one antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children between 4 months and 17 years of age were randomly assigned to receive one of four combination regimens to evaluate the change in plasma HIV RNA, safety, and tolerance when changing antiretroviral therapy to a protease inhibitor-containing combination regimen. All four regimens contained stavudine; in addition children received nevirapine plus ritonavir, lamivudine plus nelfinavir, nevirapine plus nelfinavir, or lamivudine plus nevirapine plus nelfinavir. Twelve additional children chose to receive stavudine plus lamivudine plus nelfinavir, with nelfinavir given bid, rather than tid as for the main regimens. Overall, 51% (89/176; 95% CI 43-58%) of the children on the randomized portion of the study had an HIV RNA response (< or =400 copies/ml) on at least two of the three HIV RNA determinations taken at Weeks 8, 12, and 16. At Week 24 the proportion of children with an HIV RNA response still on initial therapy was 47% (83/176; 95% CI 40-55%) and ranged from 41 to 61% for the four randomized treatment arms. Rash was frequently seen (27%) on the treatment arms containing nevirapine. At Week 24 64% (7/11, 95% CI 31-89%) of the children on the bid nelfinavir combination regimen were still on initial therapy with an HIV RNA response as compared with 46% (23/50; 95% CI 32-61%) on the corresponding tid nelfinavir combination regimen. A change in antiretroviral therapy to a protease inhibitor-containing regimen was associated with a virological response rate of approximately 50% for this patient population.     

African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine

BACKGROUND: Individuals with more copies of CCL3L1 (CCR5 ligand) than their population median have been found to be less susceptible to HIV infection. We investigated whether maternal or infant CCL3L1 gene copy numbers are associated with perinatal HIV transmission when single-dose nevirapine is given for prevention. METHOD: A nested case-control study was undertaken combining data from four cohorts including 849 HIV-infected mothers and their infants followed prospectively in Johannesburg, South Africa. Access to antiretroviral drugs for the prevention of perinatal transmission differed across the cohorts. Maternal and infant CCL3L1 gene copy numbers per diploid genome (pdg) were determined by real-time polymerase chain reaction for 79 out of 83 transmitting pairs ( approximately 10% transmission rate) and 235 randomly selected non-transmitting pairs. RESULTS: Higher numbers of infant, but not maternal, CCL3L1 gene copies were associated with reduced HIV transmission (P = 0.004) overall, but the association was attenuated if mothers took single-dose nevirapine or if the maternal viral load was low. Maternal nevirapine was also associated with reduced spontaneously released CCL3 (P = 0.007) and phytohemagglutinin-stimulated CCL3 (P = 0.005) production in cord blood mononuclear cells from uninfected infants. CONCLUSION: We observed a strong association between higher infant CCL3L1 gene copies and reduced susceptibility to HIV in the absence of maternal nevirapine. We also observed a reduction in newborn CCL3 production with nevirapine exposure. Taken together, we hypothesize that nevirapine may have direct or indirect effects that partly modify the role of the CCR5 ligand CCL3 in HIV transmission, obscuring the relationship between this genetic marker and perinatal HIV transmission.     

Human immunodeficiency virus type 1 mother-to-child transmission and prevention: successes and controversies

The World Health Organization (WHO) and United Nations Programme on HIV/AIDS (UNAIDS) estimated that an additional 370 000 new human immunodeficiency virus type 1 (HIV-1) infections occurred in children in 2009, mainly through mother-to-child transmission (MTCT). Intrapartum transmission contributes to approximately 20-25% of infections, in utero transmission to 5-10% and postnatal transmission to an additional 10-15% of cases. MTCT accounts for only a few hundred infected newborns in those countries in which services are established for voluntary counselling and testing of pregnant women, and a supply of antiretroviral drugs is available throughout pregnancy with recommendations for elective Caesarean section and avoidance of breastfeeding. The single-dose nevirapine regimen has provided the momentum to initiate MTCT programmes in many resource-limited countries; however, regimens using a combination of antiretroviral drugs are needed also to effectively reduce transmission via breastfeeding.