Raziya Bobat

Antiretroviral treatment for children with peripartum nevirapine exposure

BACKGROUND Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown. METHODS We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. RESULTS A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events. CONCLUSIONS Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.).

Safety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: a randomised double-blind placebo-controlled trial

BACKGROUND Zinc deficiency is associated with impaired immune function and an increased risk of infection. Supplementation can decrease the incidence of diarrhoea and pneumonia in children in resource-poor countries. However, in children with HIV-1 infection, the safety of zinc supplementation is uncertain. We aimed to assess the role of zinc in HIV-1 replication before mass zinc supplementation is recommended in regions of high HIV-1 prevalence. METHODS We did a randomised double-blind placebo-controlled equivalence trial of zinc supplementation at Greys Hospital in Pietermaritzburg, South Africa. 96 children with HIV-1 infection were randomly assigned to receive 10 mg of elemental zinc as sulphate or placebo daily for 6 months. Baseline measurements of plasma HIV-1 viral load and the percentage of CD4+ T lymphocytes were established at two study visits before randomisation, and measurements were repeated 3, 6, and 9 months after the start of supplementation. The primary outcome measure was plasma HIV-1 viral load. Analysis was per protocol. FINDINGS The mean log(10) HIV-1 viral load was 5.4 (SD 0.61) for the placebo group and 5.4 (SD 0.66) for the zinc-supplemented group 6 months after supplementation began (difference 0.0002, 95% CI -0.27 to 0.27). 3 months after supplementation ended, the corresponding values were 5.5 (SD 0.77) and 5.4 (SD 0.61), a difference of 0.05 (-0.24 to 0.35). The mean percentage of CD4+ T lymphocytes and median haemoglobin concentrations were also similar between the two groups after zinc supplementation. Two deaths occurred in the zinc supplementation group and seven in the placebo group (p=0.1). Children given zinc supplementation were less likely to get watery diarrhoea than those given placebo. Watery diarrhoea was diagnosed at 30 (7.4%) of 407 clinic visits in the zinc-supplemented group versus 65 (14.5%) of 447 visits in the placebo group (p=0.001). INTERPRETATION Zinc supplementation of HIV-1-infected children does not result in an increase in plasma HIV-1 viral load and could reduce morbidity caused by diarrhoea. RELEVANCE TO PRACTICE Programmes to enhance zinc intake in deficient populations with a high prevalence of HIV-1 infection can be implemented without concern for adverse effects on HIV-1 replication. In view of the reductions in diarrhoea and pneumonia morbidity, zinc supplementation should be used as adjunct therapy for children with HIV-1 infection.

Nevirapine versus Ritonavir-Boosted Lopinavir for HIV-Infected Children

BACKGROUND Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06). CONCLUSIONS Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

Breastfeeding by HIV-1-infected women and outcome in their infants: a cohort study from Durban South Africa.

Background:Women in developing countries have the difficult choice of balancing the risk of transmitting HIV through breast milk against the substantial benefits of breastfeeding. It is not known, however, whether the benefits of breastfeeding are the same when the mother is HIV-infected. Therefore, we examined the impact of breastfeeding on infections, growth and mortality in the infants of HIV-1-infected women. Methods:Infants of HIV-1-positive women were followed from birth and at each visit they were examined, growth parameters were recorded and notes were made of feeding method, and of current and interim illnesses. Results:Of the 43 HIV-infected and 90 non-infected infants for whom feeding data were available, 36 infants (27%) were exclusively breastfed, 76 (57%) received mixed feeding, and 21 (16%) received formula only. The HIV transmission rate was 39% in those exclusively breastfed, 24% in those fed exclusively on formula and 32% in those receiving mixed feeding [relative risk (RR), 7.39; 95% confidence interval (CI), 1.67–32.6 between the exclusive breast and formula only groups]. There was a stepwise increase in the transmission rate with duration of exclusive breastfeeding of 1, 2, and 3 months (45%, 64%, and 75%, respectively). Of the infected infants, seven (50%) exclusively breastfed, 13 (51%) of those on mixed feeds and none on formula only developed AIDS; exclusively breastfed infants had a slower rate of progression to AIDS (mean age, 7.5 months versus 5.0 months, P= 0.2242) than those on mixed feeds. Mortality (which occurred in the infected infants only) was 19% in the exclusively breastfed infants; 13% in those on mixed feeds and 0% in those exclusively formula-fed. The frequency of failure to thrive and episodes of diarrhoea and pneumonia were not significantly different between the three groups in both the infected and non-infected infants. Conclusions:Exclusive breastfeeding by HIV-infected women does not appear to protect their infants against common childhood illnesses and failure to thrive, nor does it significantly delay progression to AIDS. The implication of the trend towards differential mortality rates according to feeding groups is uncertain and requires further investigation.

Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children

BACKGROUND The dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infected children and uninfected children exposed to HIV during the perinatal period. METHODS We randomly assigned 548 HIV-infected and 804 HIV-uninfected infants (91 to 120 days of age) to isoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infected children had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infected children and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfected children within 96 to 108 weeks after randomization. RESULTS Antiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P=0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P=0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups. CONCLUSIONS Primary isoniazid prophylaxis did not improve tuberculosis-disease-free survival among HIV-infected children or tuberculosis-infection-free survival among HIV-uninfected children immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infected children. (Funded by the National Institutes of Health and Secure the Future; ClinicalTrials.gov number, NCT00080119.).

Determinants of mother-to-child transmission of human immunodeficiency virus type 1 infection in a cohort from Durban, South Africa.

OBJECTIVES To determine the vertical transmission rate of HIV-1 infection and to assess the influence of maternal risk factors on transmission in infants born to HIV-1-infected black women in Durban. DESIGN A prospective, hospital-based cohort study conducted at King Edward VIII hospital, Durban. HIV-1-seropositive women were enrolled into the study, and their infants were followed up at regular intervals from birth to early childhood. The infection status of the children was classified and the transmission rate was computed according to the recommendations of the workshop held in Ghent, Belgium (1992). RESULTS The final cohort of 181 infants were classified as 48 infected, 93 not infected and 40 indeterminate. Clearance of maternal antibodies was achieved by 12 months of age in virtually all infants who became seronegative. The intermediate transmission rate was 34% (95% confidence interval, 26 to 42). Deliveries by cesarean section had significantly lower transmission (relative risk, 0.46; 95% confidence interval 0.23 to 0.91). Women with lower hemoglobin concentrations during pregnancy (< 10 g/dl) had an increased risk of transmission (relative risk, 1.99; 95% confidence interval, 1.18 to 3.34). Advanced maternal age, multiparity, positive syphilis serology, duration of ruptured membranes, preterm delivery and breast-feeding were not associated with an increased risk of transmission. CONCLUSIONS This study, the first from South Africa, has confirmed that the rate of vertical transmission of HIV-1 is as high as that reported from most African cohorts. Cesarean sections were protective against transmission, whereas low hemoglobin values values were associated with an increased risk of transmission. Twelve months could be used as the cutoff age for teh diagnosis of vertical infection using antibody tests.

Growth in early childhood in a cohort of children born to HIV-1-infected women from Durban, South Africa.

Summary This study describes growth in a cohort of black South African children born to HIV-1-infected women in Durban. Children born to HIV-1-seropositive women were followed up from birth to early childhood. At birth and at each visit, growth parameters were measured. Mean Z-scores were calculated for weight-for-length, weight-for-age and length-for-age and, if they were low, the children were regarded as wasted, malnourished or stunted, respectively. At the end of the study, there were 48 infected and 93 uninfected children. There were no significant differences between the two groups at birth. Thereafter, the infected group was found to have early and sustained low mean Z-scores for length-for-age and weight-forage but not for weight-for-length. The means reached significance at ages 3, 6 and 12 months for length and at 3, 6 and 9 months for weight. Infected children who died early had more severe stunting, wasting and malnutrition than infected children who survived. Infected children born to HIV-positive women have early and sustained stunting and are malnourished but not wasted. Children with rapidly progressive disease have both stunting and wasting and are more severely affected. Early nutritional intervention might help prevent early progression or death in HIV-infected children, particularly in developing countries without access to anti-retroviral therapy in state hospitals.

Human Immunodeficiency Virus-Specific CD8+ T-Cell Activity Is Detectable from Birth in the Majority of In Utero-Infected Infants

ABSTRACT Human immunodeficiency virus (HIV)-infected infants in sub-Saharan Africa typically progress to AIDS or death by 2 years of life in the absence of antiretroviral therapy. This rapid progression to HIV disease has been related to immaturity of the adaptive immune response in infants. We screened 740 infants born to HIV-infected mothers and tracked development and specificity of HIV-specific CD8+ T-cell responses in 63 HIV-infected infants identified using gamma interferon enzyme-linked immunospot assays and intracellular cytokine staining. Forty-four in utero-infected and 19 intrapartum-infected infants were compared to 45 chronically infected children >2 years of age. Seventy percent (14 of 20) in utero-infected infants tested within the first week of life demonstrated HIV-specific CD8+ T-cell responses. Gag, Pol, and Nef were the principally targeted regions in chronic pediatric infection. However, Env dominated the overall response in one-third (12/36) of the acutely infected infants, compared to only 2/45 (4%) of chronically infected children (P = 0.00083). Gag-specific CD4+ T-cell responses were minimal to undetectable in the first 6 months of pediatric infection. These data indicate that failure to control HIV replication in in utero-infected infants is not due to an inability to induce responses but instead suggest secondary failure of adaptive immunity in containing this infection. Moreover, the detection of virus-specific CD8+ T-cell responses in the first days of life in most in utero-infected infants is encouraging for HIV vaccine interventions in infants.

The early natural history of vertically transmitted HIV-1 infection in African children from Durban South Africa.

Forty-eight children with vertically transmitted HIV-1 infection and 93 uninfected infants were followed up at regular intervals from birth for a mean of 26 months. They were examined physically, growth and development were assessed and illnesses recorded. Seventy per cent of infected infants were symptomatic by 6 months. Relative risks in the infected infants were highest for lymphadenopathy (4.56; CI 2.7-7.7), failure to thrive (4.48; 2.57-7.81), and neurological abnormalities (3.32; 1.9-5.58). The most frequent findings were diarrhoea (78%), pneumonia (76%) and lymphadenopathy (70%). Thrush and pneumonia occurred early but declined over time, whereas diarrhoea and neurological abnormalities occurred later and increased in frequency. A diagnosis of AIDS was made in 44% of infected infants by 12 months of age. Mortality in infected infants was 35.4%, and 76% of deaths occurred within the 1st year. About two-thirds of HIV-infected infants survived into early childhood. In South African children with vertically acquired HIV-1 infection the onset of disease is early and deterioration to AIDS and death are rapid. Infected infants can be easily recognized clinically, the majority by 6 months of age.

Cesarean deliveries and maternal-infant HIV transmission : Results from a prospective study in South Africa

Data from a prospective study undertaken at an urban hospital in Durban, South Africa, were used to investigate associations between maternal-infant HIV transmission, mode of delivery, and specific circumstances of cesarean deliveries. A total of 141 children of HIV-infected women were followed until the children were 15 months of age to determine their HIV status. supplementary data were collected from obstetric records, masked to the HIV status of the children. In this African and predominantly breast-fed population, infants delivered vaginally were more likely to be infected (39.8% infected) than were infants delivered by cesarean section [22.9% infected; odds ratio (OR), 0.45; 95% confidence interval (CI), 0.20-0.99]. There were no significant differences between cesarean deliveries undertaken following prior rupture of membranes and those undertaken with membranes intact, but numbers for this comparison were small. Singleton cesarean deliveries without concurrent obstetric complications had lower rates of transmission than did vaginal deliveries (OR, 0.20; 95% CI, 0.04-0.94). These results suggest that certain intrapartum events may modify the risk of HIV transmission and highlight the importance of collecting more detailed intrapartum information in order to clarify the route by which mode of delivery may be associated with maternal-infant HIV transmission.