Philippe Msellati

International multicentre pooled analysis of late postnatal mother-to-child transmission of HIV-1 infection

BACKGROUND An understanding of the risk and timing of mother-to-child transmission of HIV-1 in the postnatal period is important for the development of public-health strategies. We aimed to estimate the rate and timing of late postnatal transmission of HIV-1. METHODS We did an international multicentre pooled analysis of individual data from prospective cohort studies of children followed-up from birth born to HIV-1-infected mothers. We enrolled all uninfected children confirmed by HIV-1-DNA PCR, HIV-1 serology, or both. Late postnatal transmission was taken to have occurred if a child later became infected. We calculated duration of follow-up for non-infected children from the time of negative diagnosis to the date of the last laboratory follow-up, or for infected children to the mid-point between the date of last negative and first positive results. We stratified the analysis for breastfeeding. FINDINGS Less than 5% of the 2807 children in four studies from industrialised countries (USA, Switzerland, France, and Europe) were breastfed and no HIV-1 infection was diagnosed. By contrast, late postnatal transmission occurred in 49 (5%) of 902 children in four cohorts from developing countries, in which breastfeeding was the norm (Rwanda [Butare and Kigali], Ivory Coast, Kenya), with an overall estimated risk of 3.2 per 100 child-years of breastfeeding follow-up (95% CI 3.1-3.8), with similar estimates in individual studies (p=0.10). Exact information on timing of infection and duration of breastfeeding was available for 20 of the 49 children with late postnatal transmission. We took transmission to have occurred midway between last negative and first positive HIV-1 tests. If breastfeeding had stopped at age 4 months transmission would have occurred in no infants, and in three if it had stopped at 6 months. INTERPRETATION Risk of late postnatal transmission is consistently shown to be substantial for breastfed children born to HIV-1-positive mothers. This risk should be balanced against the effect of early weaning on infant mortality and morbidity and maternal fertility.

Highly active antiretroviral therapies among HIV-1- infected children in Abidjan, Cote d'Ivoire

Objective: To describe the effect of highly active antiretroviral therapy (HAART) in HIV-1-infected African children. Study design: Observational ANRS 1244 cohort of 159 children with HIV between October 2000 and September 2002; 78 children (49%) receiving HAART were followed for a mean duration of 21 months. Methods: Weight-for-age Z-scores (WAZ), height-for-age Z-scores (HAZ), CD4 lymphocyte count and HIV-1 RNA viral load were measured before initiating HAART and every 6 months during treatment. Probability of survival and incidences of pneumonia and acute diarrhoea were calculated. Results: Values before and after 620 days of HAART, respectively, were −2.02 and −1.39 for mean WAZ, (P < 0.01); −2.03 and −1.83 for mean HAZ (P = 0.51); 0.07 and 0.025/child-month (P = 0.002) for incidence of pneumonia; and 0.12 and 0.048/child-month for incidence of acute diarrhoea (P < 0.001) (incidence changes statistically significant only in children < 6.5 years). Overall, the probability of survival under HAART was 72.8% at 24 months for children with < 5% CD4 cells versus 97.8% in children with ⩾ 5% (P < 0.01). At HAART initiation, median viral load and CD4 cell percentage were 5.41 log10 copies/ml and 7.7%, respectively. After 756 days of HAART, on average, 50% of patients had undetectable viral load and 10% had 2.4–3.0 log10 copies/ml. The median CD4 percentage was 22.5%. Conclusion: In resource-limited setting, it is possible to use HAART to treat African children. This treatment appears as effective as in developed countries.

Natural History of Human Immunodefiency Virus Type 1 Infection in Children: A Five-Year Prospective Study in Rwanda

Objective. To compare morbidity and mortality of human immunodeficiency virus type 1 (HIV-1)-infected and HIV-1-uninfected children and to identify predictors of acquired immunodeficiency syndrome (AIDS) and death among HIV-1-infected children in the context of a developing country. Design. Prospective cohort study. Setting. Maternal and child health clinic of the Centre Hospitalier de Kigali, Rwanda. Participants. Two hundred eighteen children born to HIV-1-seropositive mothers and 218 born to seronegative mothers of the same age and parity were enrolled at birth. Outcome Measures. Deaths, clinical AIDS, nonspecific HIV-related manifestations, and use of health care services. Results. Fifty-four infected and 347 uninfected children were followed up for a median of 27 and 51 months, respectively. With the exception of chronic cough, the risk of occurrence of nonspecific HIV-related conditions was 3 to 13 times higher in infected than in uninfected children. The recurrence rate and severity of these findings were increased systematically in infected infants. Estimated cumulative risk of developing AIDS was 28% and 35% at 2 and 5 years of age, respectively. Estimated risk of death among infected children at 2 and 5 years of age was 45% and 62%, respectively, a rate 21 times higher than in uninfected children. Median survival time after estimated infection was 12.4 months. Early infection, early onset of HIV-related conditions, failure to thrive, and generalized lymphadenopathy were associated with subsequent risk of death and/or AIDS, whereas lymphoid interstitial pneumonitis was predictive of a milder disease. Conclusions. In Africa, HIV-1-infected children develop disease manifestations early in life. Specific clinical findings are predictive of HIV-1 disease, AIDS stage, and death. Bimodal expression of HIV-1 pediatric disease is encountered in Africa, as in industrialized countries, but prognosis is poorer. human immunodeficiency virus infection, children, vertical transmission, natural history, Africa.

Impact of Hiv-1 Genetic Diversity on Plasma Hiv-1 Rna Quantification: Usefulness of the Agence Nationale de Recherches sur le Sida Second-generation Long Terminal Repeat-based Real-time Reverse Transcriptase Polymerase Chain Reaction Test

The high genetic diversity of HIV-1 has a major impact on the quantification of plasma HIV-1 RNA, representing an increasingly difficult challenge. A total of 898 plasma specimens positive for HIV-1 RNA by commercial assays (Amplicor v1.5; Roche Diagnostic Systems, Alameda, CA or Versant v3.0; Bayer Diagnostics, Emeryville, CA) were tested using the Agence Nationale de Recherches sur le SIDA second-generation (G2) real-time reverse transcriptase polymerase chain reaction (RT-PCR) test: 518 samples containing HIV-1 of known subtype, including 88 from 2 subtype panels and 430 harboring B (n = 266) and non-B (n = 164) group M HIV-1 subtypes from patients followed up in 2002 through 2005 at Necker Hospital (Paris, France), and 380 samples from 10 different countries (Argentina, Cambodia, Cameroon, Central African Republic, France, Ivory Coast, Madagascar, Morocco, Thailand, and Zimbabwe). HIV-1 RNA values obtained by G2 real-time PCR were highly correlated with those obtained by the Amplicor v1.5 for B and non-B subtypes (R2 = 0.892 and 0.892, respectively) and for samples from diverse countries (R2 = 0.867 and 0.893 for real-time PCR vs. Amplicor v1.5 and real-time PCR vs. Versant v3.0, respectively). Approximately 30% of specimens harboring non-B subtypes were underquantified by at least −0.51 log10 in Amplicor v1.5 versus 5% underquantified in G2 real-time PCR. Discrepant results were also obtained with subtype B samples (14% underquantified by Amplicor v1.5 vs. 7% by G2 real-time PCR). Similar percentages were observed when comparing results obtained with the G2 real-time PCR assay with those obtained using the Versant assay. Addressing HIV-1 diversity, continual monitoring of HIV-1 RNA assays, together with molecular epidemiology studies, is required to improve the accuracy of all HIV RNA assays.

Estimating the rate of mother-to-child transmission of HIV. Report of a workshop on methodological issues Ghent (Belgium) 17-20 February 1992.

PurposeIn the last 8 years, numerous cohort studies have been conducted to estimate the rate of mother-to-child transmission (MTCT) of HIV. Many of these have faced problems in data collection and analysis, making it difficult to compare transmission rates between studies. This workshop on methodological aspects of the study of MTCT of HIV-1 was held in Ghent (Belgium) in February 1992. Study selection and data extractionFourteen teams of investigators participated, representing studies from Central (five) and Eastern Africa (three), Europe (two), Haiti (one) and the United States (three). A critical evaluation of the projects was carried out, under four headings: (1) enrollment and follow-up procedures, (2) diagnostic criteria and case definitions, (3) measurement and comparison of MTCT rates and (4) determinants of transmission. Results of data analysisReported transmission rates ranged from 13 to 32% in industrialized countries and from 25 to 48% in developing countries. However, no direct comparisons could be made because methods of calculation differed from study to study. Based on this review, a common methodology was developed. Agreement was reached on definitions of HIV-related signs/symptoms, paediatric AIDS and HIV-related deaths. A classification system of children born to HIV-1-infected mothers according to their probable HIV infection status during the first 15 months of life, allowed the elaboration of a direct method of computation of the transmission rate and of an indirect method for studies with a comparison group of children born to HIV-seronegative mothers. This standardized approach was subsequently applied to selected data sets. ConclusionsThe methodology can now be applied to all studies with sufficient follow-up and comparisons made between transmission rates. This step is essential for assessing determinants of transmission and for the development of a common approach for the evaluation of interventions aimed at reducing or interrupting MTCT of HIV.

Net survival of perinatally and postnatally HIV-infected children: a pooled analysis of individual data from sub-Saharan Africa.

BACKGROUND Previously, HIV epidemic models have used a double Weibull curve to represent high initial and late mortality of HIV-infected children, without distinguishing timing of infection (peri- or post-natally). With more data on timing of infection, which may be associated with disease progression, a separate representation of children infected early and late was proposed. METHODS Paediatric survival post-HIV infection without anti-retroviral treatment was calculated using pooled data from 12 studies with known timing of HIV infection. Children were grouped into perinatally or post-natally infected. Net mortality was calculated using cause-deleted life tables to give survival as if HIV was the only competing cause of death. To extend the curve beyond the available data, children surviving beyond 2.5 years post infection were assumed to have the same survival as young adults. Double Weibull curves were fitted to both extended survival curves to represent survival of children infected perinatally or through breastfeeding. RESULTS Those children infected perinatally had a much higher risk of dying than those infected through breastfeeding, even allowing for background mortality. The final-fitted double Weibull curves gave 75% survival at 5 months after infection for perinatally infected, and 1.1 years for post-natally infected children. An estimated 25% of the early infected children would still be alive at 10.6 years compared with 16.9 years for those infected through breastfeeding. CONCLUSIONS The increase in available data has enabled separation of child mortality patterns by timing of infection allowing improvement and more flexibility in modelling of paediatric HIV infection and survival.

Growth of human immunodeficiency type 1-infected and uninfected children : a prospective cohort study in Kigali, Rwanda, 1988 to 1993

OBJECTIVE To compare the anthropometric characteristics of children with and without HIV-1 infection. METHODS In a prospective cohort study of 218 children born to HIV-1 seropositive mothers and 218 children born to HIV-1 seronegative mothers in Kigali, Rwanda, 3 groups were compared: infected children (n = 46); uninfected children born to seropositive mothers (n = 140); and uninfected children born to seronegative mothers (n = 207). Weight, height and head circumference were measured at birth, every 3 months during the first year of life and every 6 months thereafter. The weight-for-age, height-for-age, weight-for-height and head circumference-for-age mean z scores were calculated. RESULTS The weight-for-age, height-for-age and head circumference-for-age mean z scores were lower among HIV-infected children than among uninfected ones at each time period. The reduction in the weight-for-age mean z score was the greatest between 12 and 36 months. The reduction in the height-for-age mean z score of HIV-infected children was persistently below 2 SD after 9 months of age. On the other hand the weight-for-height mean z score was not consistently lower in HIV-infected children when compared with uninfected ones. The anthropometric characteristics of uninfected children born to seropositive mothers were similar to those of children born to seronegative mothers. CONCLUSIONS In this study HIV-infected children were more frequently stunted (low height-for-age) than uninfected ones. Wasting (low weight-for-height) was not common among HIV-infected children.

Children Who Acquire HIV Infection Perinatally Are at Higher Risk of Early Death than Those Acquiring Infection through Breastmilk: A Meta-Analysis

Background Assumptions about survival of HIV-infected children in Africa without antiretroviral therapy need to be updated to inform ongoing UNAIDS modelling of paediatric HIV epidemics among children. Improved estimates of infant survival by timing of HIV-infection (perinatally or postnatally) are thus needed. Methodology/Principal Findings A pooled analysis was conducted of individual data of all available intervention cohorts and randomized trials on prevention of HIV mother-to-child transmission in Africa. Studies were right-censored at the time of infant antiretroviral initiation. Overall mortality rate per 1000 child-years of follow-up was calculated by selected maternal and infant characteristics. The Kaplan-Meier method was used to estimate survival curves by childs HIV infection status and timing of HIV infection. Individual data from 12 studies were pooled, with 12,112 children of HIV-infected women. Mortality rates per 1,000 child-years follow-up were 39.3 and 381.6 for HIV-uninfected and infected children respectively. One year after acquisition of HIV infection, an estimated 26% postnatally and 52% perinatally infected children would have died; and 4% uninfected children by age 1 year. Mortality was independently associated with maternal death (adjusted hazard ratio 2.2, 95%CI 1.6–3.0), maternal CD4<350 cells/ml (1.4, 1.1–1.7), postnatal (3.1, 2.1–4.1) or peri-partum HIV-infection (12.4, 10.1–15.3). Conclusions/Results These results update previous work and inform future UNAIDS modelling by providing survival estimates for HIV-infected untreated African children by timing of infection. We highlight the urgent need for the prevention of peri-partum and postnatal transmission and timely assessment of HIV infection in infants to initiate antiretroviral care and support for HIV-infected children.

Genotypic human immunodeficiency virus type 1 drug resistance in highly active antiretroviral therapy-treated children in Abidjan, Côte d'Ivoire

Objective: To estimate the frequency of human immunodeficiency virus type 1 (HIV-1) displaying genotypic drug resistance in highly active antiretroviral therapy (HAART)-treated children in Abidjan. Methods: Among the 269 HIV-1-infected children enrolled in the ANRS 1278 prospective observational cohort between October 2000 and September 2003, 115 [median age, 6.35 years (range, 1.2–15)] required treatment and received HAART for at least 6 months. Treatment consisted of 2 nucleoside analogue reverse transcriptase inhibitors associated with nelfinavir (70.5%) or efavirenz (29.5%). Plasma HIV-1 RNA and CD4+ T cell counts were determined at baseline and every 6 months thereafter. Genotypic resistance tests were performed in cases of virologic failure (viral load ≥3 log10 copies/mL) after at least 6 months of HAART. Results: After a median of 10.2 months of HAART, 66% (76 of 115) of children were in virologic success. Most of these children were infected with CRF02 strains. Twenty-seven viruses displayed resistance to at least 1 antiretroviral drug (27 of 38, 71%). Thirteen, 9 and 5 children had viruses with resistance to 1, 2 or 3 of the drugs included in their regimen, respectively. Resistance to lamivudine and/or to non-nucleoside analogue reverse transcriptase inhibitors was frequent among the 38 children in virologic failure. The 90M, 46L, 88S or 54V mutations were found in 11 (38%) of the 29 children taking nelfinavir. The overall frequency of viruses showing genotypic resistance to at least 1 antiretroviral drug was 23% (27 of 115) among the treated children. Conclusion: These results are similar to what is generally observed in industrialized countries. Despite these encouraging results, efforts are needed to maximize the long-term efficiency of treatment and to minimize the risk of emergence of drug resistance in treated children.

Illness-related behaviour and utilization of oral health services among adult city-dwellers in Burkina Faso: evidence from a household survey

BackgroundIn sub-Saharan Africa, the availability and accessibility of oral health services are seriously constrained and the provision of essential oral care is limited. Reports from the region show a very low utilization of oral health care services, and visits to dental-care facilities are mostly undertaken for symptomatic reasons. The objectives of the present study were to describe the prevalence of oral symptoms among adults in Ouagadougou, capital city of Burkina Faso and the use of oral health services and self-medication in response to these symptoms and to measure the associations between predisposing, enabling and needs factors and decisions to seek oral health care.MethodsThe conceptual design of the study was derived from both the Andersen-Newman model of health care utilization and the conceptual framework of the WHO International Collaborative Study of Oral Health Outcomes. Data were obtained by two-stage stratified sampling through four areas representative of different stages of urbanization of Ouagadougou. The final study population comprised 3030 adults aged 15 years or over and the response rate was 65%.ResultsOverall, 28% of the respondents had experienced an oral health problem during the past 12 months; a high proportion (62%) reported pain or acute discomfort affecting daily life. In response to symptoms, only 28% used oral health facilities, 48% used self-medication and 24% sought no treatment at all. Multivariate analyses revealed that several socio-economic and socio-cultural factors such as religious affiliation, material living conditions and participation in a social network were significantly associated with the use of oral health care services by adults who had experienced oral health problems during the previous year.ConclusionThe proportion of people who have obtained oral health care is alarmingly low in Ouagadougou and self-medication appears to be an important alternative source of care for adult city-dwellers. Decision-makers in sub-Saharan countries must seek to ensure that access to essential oral health care is improved.