Gonzague Jourdain

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.

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.

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.

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.

Risk Factors for In Utero or Intrapartum Mother-to-Child Transmission of Human Immunodeficiency Virus Type 1 in Thailand

BACKGROUND The identification of risk factors for in utero and intrapartum transmission of human immunodeficiency virus type 1 (HIV-1) is crucial to the design and understanding of preventive interventions. METHODS The randomized Perinatal HIV Prevention Trial-1 enrolled 1437 pregnant women and their non-breast-fed infants, to compare the efficacy of various durations of zidovudine prophylaxis. Using univariate and multivariate logistic regression analyses, we studied the role that factors known or occurring at various times during gestation or delivery play in in utero and intrapartum transmission. RESULTS Variables independently associated with in utero transmission were HIV-1 load >35,000 copies/mL (adjusted odds ratio [AOR], 4.2) and delayed initiation of maternal zidovudine prophylaxis until >31.4 weeks gestation (AOR, 3.0). Variables associated with intrapartum transmission were HIV-1 load >10,000 copies/mL (AOR, 3.8 for 10,000-35,000 copies/mL and 7.1 for >35,000 copies/mL), induction of labor (AOR, 2.6), and premature labor with tocolysis (AOR, 15.1). CONCLUSIONS With the exception of very high HIV-1 load, risk factors for in utero transmission were different from those for intrapartum transmission. Optimal prophylactic interventions must address each of the major risk factors, with appropriate timing.

Predictors of 5-year mortality in HIV-infected adults starting highly active antiretroviral therapy in Thailand.

Objective:To estimate the early and long-term mortalities and associated risk factors in adults receiving highly active antiretroviral therapy (HAART) in Thailand. Design:A prospective observational cohort study. Methods:Previously untreated adults starting HAART in 2002–2009 were followed-up in 43 public hospitals. Kaplan–Meier probability of survival was estimated up to 5 years of therapy. Factors associated with early (⩽6 months) and long-term (>6 months) mortalities were assessed using Cox regression analyses. Results:A total of 1578 adults received HAART (74% women; median age, 33 years; CD4 cell count, 124/mL), with a median follow-up of 50 months (interquartile range, 41–66). Eighty-nine patients (6%) died (37 occurred ⩽6 months and 52 occurred >6 months) and 183 (12%) were lost to follow-up. Probability of survival [95% confidence interval (CI)] was 97.5% (96.7% to 98.2%) at 6 months, 96.6% (95.6% to 97.4%) at 1 year, and 93.5% (91.9% to 94.8%) at 5 years. Probability of being alive and on follow-up was 80.8% (78.5% to 82.8%) at 5 years. Early mortality was associated with anemia [adjusted hazard ratio (aHR) 3.6, 95% CI: 1.7 to 7.5] and low CD4 count (aHR 1.6, 95% CI: 1.1 to 2.2 per 50 cells decrease) at treatment initiation. Long-term mortality was associated with persistent anemia (aHR 4.9, 95% CI: 2.1 to 11.6), CD4 increase from baseline <50 cells per cubic millimeter (aHR 3.1, 95% CI: 1.6 to 5.7), and viral load >1000 copies per milliliter (aHR 2.8, 95% CI: 1.3 to 6.1) at 6 months of HAART; male gender; and calendar year of enrollment. Conclusions:Early mortality was associated with anemia and severe immunosuppression at initiation of therapy. Long-term mortality was associated with persistent anemia, CD4 count increase, and virological response at 6 months of therapy over baseline characteristics, highlighting the importance of laboratory monitoring.

Association between Detection of HIV-1 DNA Resistance Mutations by a Sensitive Assay at Initiation of Antiretroviral Therapy and Virologic Failure

BACKGROUND Antiretroviral therapy (ART) has become more available throughout the developing world during the past 5 years. The World Health Organization recommends nonnucleoside reverse-transcriptase inhibitor-based regimens as initial ART. However, their efficacy may be compromised by resistance mutations selected by single-dose nevirapine (sdNVP) used to prevent mother-to-child transmission of human immunodeficiency virus (HIV)-1. There is no simple and efficient method to detect such mutations at the initiation of ART. METHODS One hundred eighty-one women who were participating in a clinical trial to prevent mother-to-child transmission and who started NVP-ART after they had received sdNVP or a placebo were included in the study. One hundred copies of each patients HIV-1 DNA were tested for NVP-resistance point-mutations (K103N, Y181C, and G190A) with a sensitive oligonucleotide ligation assay that was able to detect mutants even at low concentrations (> or = 5% of the viral population). Virologic failure was defined as confirmed plasma HIV-1 RNA >50 copies/mL after 6 to 18 months of NVP-ART. RESULTS At initiation of NVP-ART, resistance mutations were identified in 38 (26%) of 148 participants given sdNVP (K103N in 19 [13%], Y181C in 8 [5%], G190A in 28 [19%], and > or = 2 mutations in 15 [10%]), at a median 9.3 months after receipt of sdNVP. The risk of virologic failure was 0.62 (95% confidence interval [CI], 0.46-0.77) in women with > or = 1% resistance mutation, compared with a risk of 0.25 (95% CI, 0.17-0.35) in those without detectable resistance mutations (P < .001). Failure was independently associated with resistance, an interval of <6 months between sdNVP and NVP-ART initiation, and a viral load higher than the median at NVP-ART initiation. CONCLUSIONS Access to simple and inexpensive assays to detect low concentrations of NVP-resistant HIV-1 DNA before the initiation of ART could help improve the outcome of first-line ART.

Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54–59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.