Marc Lallemant

Mother-Child Transmission of HIV-1 and Infant Survival in Brazzaville, Congo

The aim of this study was to compare the probability of survival of infants born to anti-HIV-1-positive and anti-HIV-1-negative mothers. One thousand, eight hundred and thirty-three pregnant women, recruited sequentially in two mother-child clinics in Brazzaville, were screened for anti-HIV-1 (by enzyme-linked immunosorbent assay with confirmation by Western blot). Each seropositive mother (71 out of 1833, 3.9%) was matched for age, presumed date of delivery and place of residence with two seronegative mothers. Sixty-four babies born to anti-HIV-1-positive mothers and 130 control babies born to anti-HIV-1-negative mothers were followed up for 12-22 months (mean, 18 months). The probabilities of survival were estimated by the Kaplan-Meier method. At birth, the two groups of babies did not differ with regard to rate of stillbirths, gestational age, sex ratio and weight. Among babies born to seropositive mothers, the probability of survival was 0.87 (s.d. 0.04) at 3 months, 0.71 (s.d. 0.06) at 6 months, 0.68 (s.d. 0.06) at 9 months and 0.61 (s.d. 0.06) at 12.5 months. In the controls the probability of survival was 0.98 (s.d. 0.01) at 3 months and 0.97 (s.d. 0.02) at 12 months. The excess of mortality in the babies born to anti-HIV-1-positive mothers is highly significant (P less than 0.001). The deaths occurred more frequently and earlier than in similar cohort studies performed in developed countries.

Bacillus Calmette—guérin immunization in infants born to Hiv-1-seropositive mothers

During the prospective follow-up of 64 babies at risk for perinatal HIV-1 infection because their mothers were seropositive, and of 130 control babies whose mothers were seronegative, we studied the occurrence of complications of bacillus Calmette-Guérin (BCG) immunization and its ability to induce cutaneous reactivity to tuberculin. Babies born both to HIV-1-positive and HIV-1-negative mothers received BCG immunization during their first month of life according to the Expanded Programme on Immunization (EPI) recommendations. Local and regional complications of BCG vaccine were looked for at 3, 6 and 9 months after inoculation. A tuberculin skin test was performed at 6 or 9 months of age. Most babies born to HIV-1-positive mothers were later classified as infected or uninfected according to their clinical condition and/or serological status at 18 months of age. The mean duration of the follow-up was 36 months (range 30-40 months). No chronic or deep ulcerations at the site of injection or disseminated forms of BCG infection were observed. The frequency of BCG-related lymphadenitis in the group of HIV-1-infected children (24%) did not differ significantly from the group of uninfected children (19%; Fisher test: P = 0.73). In contrast, the tuberculin skin test responses were positive less often in the group of HIV-1-infected children (33%) than in the uninfected group (83%; Fisher test: P = 0.007). Because BCG vaccine appears to be safe--even when given to perinatally infected babies--continuation of the BCG immunization policies of the EPI is justified, especially in view of the growing incidence of tuberculosis as a complication of HIV infection.

Revisiting the Role of Neutralizing Antibodies in Mother-to-Child Transmission of HIV-1

We analyzed the association between mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) and maternal neutralizing antibodies to heterologous primary isolates of various HIV-1 clades, to test the hypothesis that protective antibodies are those with broad neutralizing activity. Our study sample included 90 Thai women for whom the timing of HIV-1 transmission (in utero or intrapartum) was known. The statistical analysis included a conditional logistic-regression model to control for both plasma viral load and duration of zidovudine prophylaxis. The higher the titer of neutralizing antibodies to a heterologous strain of the same clade, the lower the rate of MTCT of HIV-1. More specifically, high levels of neutralizing antibodies to the MBA (CRF01_AE) strain were associated with low intrapartum transmission of HIV-1. This suggested that such heterologous neutralizing antibodies may be involved in the natural prevention of late perinatal HIV transmission. These data are consistent with the hypothesis that the use of some antibodies might help to prevent perinatal HIV transmission, through passive immunoprophylaxis. Moreover, the study of humoral factors associated with MTCT of HIV-1 may identify correlates of protection that should help in the design of efficient HIV/acquired immunodeficiency syndrome vaccines.

Long-Term Survival of HIV-Infected Children Receiving Antiretroviral Therapy in Thailand: A 5-Year Observational Cohort Study

BACKGROUND There are scarce data on the long-term survival of human immunodeficiency virus (HIV)-infected children receiving antiretroviral therapy (ART) in lower-middle income countries beyond 2 years of follow-up. METHODS Previously untreated children who initiated ART on meeting immunological and/or clinical criteria were followed in a prospective cohort in Thailand. The probability of survival up to 5 years from initiation was estimated using Kaplan-Meier methods, and factors associated with mortality were assessed using Cox regression analyses. RESULTS Five hundred seventy-eight children received ART; of these, 111 (19.2%) were followed since birth. At start of ART (baseline), the median age was 6.7 years, 128 children (22%) were aged <2 years, and the median CD4 cell percentage was 7%. Median duration of follow-up was 53 months; 42 children (7%) died, and 38 (7%) were lost to follow-up. Age <12 months, low CD4 cell percentage, and low weight-for-height z score at ART initiation were independently associated with mortality (P < .001). The probability of survival among infants aged <12 months at baseline was 84.3% at 1 year and 76.7% at 5 years of ART, compared with 95.7% and 94.8%, respectively, among children aged ≥1 year. Low CD4 cell percentage and wasting at baseline had a strong association with mortality among older children but weak or no association among infants. CONCLUSIONS Children who initiated ART as infants after meeting immunological and/or clinical criteria had a high risk of mortality which persisted beyond the first year of therapy. Among older children, those with severe wasting or low CD4 cell percentage at treatment initiation were at high risk of mortality during the first 6 months of therapy. These findings support the scale-up of early HIV diagnosis and immediate treatment in infants, before advanced disease progression in older children.

Maternal antibody response at delivery and perinatal transmission of human immunodeficiency virus type 1 in African women

Prospective cohort studies indicate that 13-45% of human immunodeficiency virus type 1 (HIV-1)-infected pregnant women transmit the virus to their infants. Although factors that influence perinatal transmission are not well understood, drug and immunotherapy trials to interrupt transmission are underway. The identification of women most at risk is essential for prevention, counselling, and medical intervention. We assessed 70 HIV-1-infected pregnant women enrolled in a prospective study of perinatal transmission in Brazzaville, Congo. The relations between maternal health status, antibody levels to selected HIV-1 structural antigens at delivery, and infant outcome were explored. Independent of clinical stage, higher maternal antibody titres to peptides corresponding to the V3 region of gp120 and the immunodominant domain of gp41 were correlated with a higher risk of perinatal transmission. In a logistic regression model, the predicted risk of transmission for symptom-free women whose antibody titres to V3 and gp41 were lowest was 0.02, whereas it was 0.88 for symptomatic women whose antibody titres to V3 and TMSP18 were highest. These associations may give new insight into the mechanisms of perinatal transmission and they may also provide a powerful means of identifying women who would most benefit from intervention trials to halt perinatal transmission.

Early HIV-1 diagnosis using in-house real-time PCR amplification on dried blood spots for infants in remote and resource-limited settings.

Background:In resource-limited settings, most perinatally HIV-1-infected infants do not receive timely antiretroviral therapy because early HIV-1 diagnosis is not available or affordable. Objective:To assess the performance of a low-cost in-house real-time polymerase chain reaction (PCR) assay to detect HIV-1 DNA in infant dried blood spots (DBS). Methods:One thousand three hundred nineteen DBS collected throughout Thailand from non-breast-fed infants born to HIV-1-infected mothers were shipped at room temperature to a central laboratory.In-house real-time DNA PCR results were compared with Roche Amplicor HIV-1 DNA test (Version 1.5) results. In addition, we verified the Roche test performance on DBS sampled from 1218 other infants using as reference HIV serology result at 18 months of age. Results:Real-time DNA PCR and Roche DNA PCR results were 100% concordant. Compared with HIV serology results, the Roche test sensitivity was 98.6% (95% confidence interval: 92.6% to 100.0%) and its specificity at 4 months of age was 99.7% (95% confidence interval: 99.2% to 99.9%). Conclusions:In-house real-time PCR performed as well as the Roche test in detecting HIV-1 DNA on DBS in Thailand. Combined use of DBS and real-time PCR assays is a reliable and affordable tool to expand access to early HIV-1 diagnosis in remote and resource-limited settings, enabling timely treatment for HIV-1-infected infants.

Mother-to-child transmission of HIV-1 in Congo central Africa.

ObjectiveTo assess the risk of mother-to-child transmission of HIV-1 in a central African population and to study maternal factors associated with perinatal transmission. DesignProspective cohort study of infants born to HIV-1-positive women and controls born to HIV-1-negative women enrolled sequentially in two prenatal clinics and one maternity hospital in Brazzaville, Congo. Subjects and methodsA total of 118 exposed and 208 control infants were followed from birth for at least 2 years. Assessment of infection in children and computation of transmission rate were made according to the European Economic Community/World Health Organization Ghent guidelines (1992). ResultsThe transmission rate was 40.4% [95% confidence interval (Cl), 30.7–50.1]. Maternal age, parity, history of adverse pregnancy outcome or history of deceased children were not associated with transmission. However, independently, women whose relationship with their infants father was less than 1 year, or women who had symptoms of HIV-1 during pregnancy had an increased risk of transmission [adjusted odds ratios, 11.1 (95% Cl, 2.4–50.2) and 10.3 (95% Cl, 2.9–37.1), respectively]. ConclusionThe transmission rate observed in Congo is in the upper range of the rates reported in Africa. The uneven distribution of cofactors for perinatal transmission, such as the presence of symptoms of HIV disease during pregnancy, may explain some of the variation observed across studies.

Assessing Resistance Costs of Antiretroviral Therapies via Measures of Future Drug Options

The emergence of drug-resistant human immunodeficiency virus (HIV) type 1 in the setting of antiretroviral therapy failure limits the number of drugs available for use in subsequent therapy regimens. To quantify the relative HIV-1-resistance costs associated with various antiretroviral therapy strategies, we developed 2 related measures of future drug options (FDOs) by use of rule-based genotype-interpretation systems. The FDO1 metric assesses the number of drug classes that remain useful; the FDO2 metric assesses the number of drug classes that remain useful and the number of active drugs within each class. Application of these methods is illustrated with data from a randomized study of 3 therapy regimens in nucleoside analog-experienced patients. Each therapy regimen resulted in a unique pattern of drug-resistance (and cross-resistance) mutations. The regimen with the highest virologic failure rate preserved greater future drug options. Quantification of future drug options as an outcome of antiretroviral therapy trials may complement traditional clinical, virologic, and immunologic end points, thereby providing novel insights.

Ethics of placebo-controlled trials of zidovudine to prevent the perinatal transmission of HIV in the Third World.

This letter responds to an article claiming that placebo-controlled trials of antiretroviral agents to reduce perinatal transmission of HIV in developing countries are unethical. The authors note that even if most of the arguments put forth in the article are discounted randomization in such trials raises various problems and a less traumatic observational methodology can be used to assess the efficacy of a prophylactic strategy. This methodology would examine members of the numerous cohorts that have been established around the world in developing and developed countries to determine the epidemiology of mother-child transmission of HIV. These studies have revealed transmission rates of 20-30% in Africa (with breast feeding) and 15-25% in industrialized countries (with bottle feeding). Treating all informed volunteer members of cohorts where a stable transmission rate has been established would allow the effects of treatment to be assessed. Such an observation would be a continuous observation of the transmission rate not a historical one. This observation would also provide comparisons between treated mothers and those who were not treated for any reason during the same period. The larger margin of error that would be encountered in this type of approach (as compared to a placebo-controlled trial) could be reduced by comparing reproducibility of results in additional cohorts.

Influence of CYP2B6 polymorphisms on the persistence of plasma nevirapine concentrations following a single intra-partum dose for the prevention of mother to child transmission in HIV-infected Thai women

OBJECTIVES To investigate the association of single nucleotide polymorphisms (SNPs) with nevirapine concentrations following intra-partum single-dose nevirapine. METHODS Plasma and DNA samples were obtained from 330 HIV-infected Thai women who received intra-partum single-dose nevirapine in the PHPT-2 clinical trial to prevent perinatal HIV transmission. Nine SNPs within CYP2B6, CYP3A4 and ABCB1 were genotyped by real-time PCR. Nevirapine plasma concentrations were determined by HPLC and used in a population pharmacokinetic analysis. RESULTS Higher nevirapine exposure was observed in women carrying the CYP2B6 516G>T polymorphism, but this did not reach statistical significance (P = 0.054). The TGATC CYP2B6 haplotype (g.3003T, 516G, 785A, g.18492T and g.21563C) was associated with increased nevirapine clearance and lower exposure (P = 0.0029). The median time for nevirapine concentrations to reach 10 ng/mL post-partum (nevirapine IC(50) for HIV-1) was 14 days [interquartile range (IQR, 14-18)] for TGATC homozygotes, 16 days (14-20) for TGATC heterozygotes and 18 days (14-20) for non-TGATC homozygotes (P = 0.020). CONCLUSIONS The CYP2B6 516G>T impact on nevirapine concentrations was less pronounced after intra-partum single-dose nevirapine than reported under steady-state conditions, perhaps due to lack of enzyme auto-induction at the time of dosing. Although the TGATC CYP2B6 haplotype may shorten the persistence of nevirapine post-partum, its practical implications for the prevention of HIV transmission or selection of resistance mutations are likely limited.