Milly Marston

Time from HIV seroconversion to death: a collaborative analysis of eight studies in six low and middle-income countries before highly active antiretroviral therapy.

Objectives:To estimate survival patterns after HIV infection in adults in low and middle-income countries. Design:An analysis of pooled data from eight different studies in six countries. Methods:HIV seroconverters were included from eight studies (three population-based, two occupational, and three clinic cohorts) if they were at least 15 years of age, and had no more than 4 years between the last HIV-negative and subsequent HIV-positive test. Four strata were defined: East African cohorts; South African miners cohort; Thai cohorts; Haitian clinic cohort. Kaplan–Meier functions were used to estimate survival patterns, and Weibull distributions were used to model and extend survival estimates. Analyses examined the effect of site, age, and sex on survival. Results:From 3823 eligible seroconverters, 1079 deaths were observed in 19 671 person-years of follow-up. Survival times varied by age and by study site. Adjusting to age 25–29 years at seroconversion, the median survival was longer in South African miners: 11.6 years [95% confidence interval (CI) 9.8–13.7] and East African cohorts: 11.1 years (95% CI 8.7–14.2) than in Haiti: 8.3 years (95% CI 3.2–21.4) and Thailand: 7.5 years (95% CI 5.4–10.4). Survival was similar for men and women, after adjustment for age at seroconversion and site. Conclusion:Without antiretroviral therapy, overall survival after HIV infection in African cohorts was similar to survival in high-income countries, with a similar pattern of faster progression at older ages at seroconversion. Survival appears to be significantly worse in Thailand where other, unmeasured factors may affect progression.

HIV and Mortality of Mothers and Children: Evidence From Cohort Studies in Uganda, Tanzania, and Malawi

Background: The steady decline in child mortality observed in most African countries through the 1960s, 1970s, and 1980s has stalled in many countries in the 1990s because of the AIDS epidemic. However, the census and household survey data that generally are used to produce estimates of child mortality do not permit precise measures of the adverse effect of HIV on child mortality. Methods: To calculate excess risks of child mortality as the result of maternal HIV status, we used pooled data from 3 longitudinal community-based studies that classified births by the mothers HIV status. We also estimated excess risks of child death caused by increased mortality among mothers. The joint effects of maternal HIV status and maternal survival were quantified using multivariate techniques in a survival analysis. Results: Our analysis shows that the excess risk of death associated with having an HIV-positive mother is 2.9 (95% confidence interval = 2.3–3.6), and this effect lasts throughout childhood. The excess risk associated with a maternal death is 3.9 (2.8–5.5) in the 2-year period centered on the mothers death, with children of both infected and uninfected mothers experiencing higher mortality risks at this time. Conclusion: HIV impacts on child mortality directly through transmission of the virus to newborns by infected mothers and indirectly through higher child mortality rates associated with a maternal death.

The effects of high HIV prevalence on orphanhood and living arrangements of children in Malawi, Tanzania, and South Africa

Using longitudinal data from three demographic surveillance systems (DSS) and a retrospective cohort study, we estimate levels and trends in the prevalence and incidence of orphanhood in South Africa, Tanzania, and Malawi in the period 1988–2004. The prevalence of maternal, paternal, and double orphans rose in all three populations. In South Africa—where the HIV epidemic started later, has been very severe, and has not yet stabilized—the incidence of orphanhood among children is double that of the other populations. The living arrangements of children vary considerably between the populations, particularly in relation to fathers. Patterns of marriage, migration, and adult mortality influence the living and care arrangements of orphans and non-orphans. DSS data provide new insights into the impact of adult mortality on children, challenging several widely held assumptions. For example, we find no evidence that the prevalence of child-headed households is significant or has increased in the three study areas.

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.

Estimating the net effect of HIV on child mortality in African populations affected by generalized HIV epidemics

Summary:For a given prevalence, HIV has a relatively higher impact on child mortality when mortality from other causes is low. To project the effect of the epidemic on child mortality, it is necessary to estimate a realistic schedule of “net” age-specific mortality rates that would operate if HIV were the only cause of child death observable. We assume that this net pattern would be independent of mortality from other causes. We used African studies that measured the survival of HIV-infected children (direct data) or survival of children of HIV-infected mothers (indirect data). We developed a mathematic procedure to estimate the mortality of infected children from indirect data sources and obtained net HIV mortality patterns for each study population. The net age-specific HIV mortality pattern for infected children can be described by a double Weibull curve fitted to empiric data; this gives a functional representation of age-specific mortality rates that decline after infancy and rise in the preteens. The fitted curve that we would expect if HIV were the only effective cause of death shows 67% net survival at 1 year and 39% at 5 years. The curve also predicts 13% net survival at 10 years using constraints based on survival of infected adults.

Projecting the demographic impact of AIDS and the number of people in need of treatment: updates to the Spectrum projection package

Background: In the Joint United Nations Programme on HIV/AIDS (UNAIDS) approach to HIV and AIDS estimates, estimates of adult prevalence produced by the Estimation and Projection Package (EPP) or the Workbook are transferred to Spectrum to estimate the consequences of the HIV/AIDS epidemic, including the number of people living with HIV by age and sex, new infections, AIDS deaths, AIDS orphans, treatment needs, and the impact of treatment on survival. Methods: The UNAIDS Reference Group on Estimates, Models and Projections recommends updates to the methodology and assumptions based on the latest research findings and international policy and programme guidelines. The latest update to Spectrum has been used in the 2005 round of global estimates. Results: Several new features have been added to Spectrum in the past two years. New patterns of the age distribution of prevalence over time are based on the latest survey data. A more detailed treatment of mother to child transmission of HIV is now based on information about current breastfeeding practices, treatment options offered to prevent mother to child transmission (PMTCT), infant feeding options, and the percentage or number of pregnant women accessing PMTCT services. A new section on child survival includes the effects of cotrimoxazole and ART on child survival. Projections can now be calibrated with national survey data. A new set of outputs is provided for all adults over the age of 15 in addition to the traditional 15–49 age group. New outputs are now available to show plausibility bounds and regional estimates for key indicators. Conclusions: The latest update to the Spectrum program is intended to incorporate the latest research findings and provide new outputs needed by national and international planners.

Effect of HIV infection on pregnancy-related mortality in sub-Saharan Africa: secondary analyses of pooled community-based data from the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA)

Summary Background Model-based estimates of the global proportions of maternal deaths that are in HIV-infected women range from 7% to 21%, and the effects of HIV on the risk of maternal death is highly uncertain. We used longitudinal data from the Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA) network to estimate the excess mortality associated with HIV during pregnancy and the post-partum period in sub-Saharan Africa. Methods The ALPHA network pooled data gathered between June, 1989 and April, 2012 in six community-based studies in eastern and southern Africa with HIV serological surveillance and verbal-autopsy reporting. Deaths occurring during pregnancy and up to 42 days post partum were defined as pregnancy related. Pregnant or post-partum person-years were calculated for HIV-infected and HIV-uninfected women, and HIV-infected to HIV-uninfected mortality rate ratios and HIV-attributable rates were compared between pregnant or post-partum women and women who were not pregnant or post partum. Findings 138 074 women aged 15–49 years contributed 636 213 person-years of observation. 49 568 women had 86 963 pregnancies. 6760 of these women died, 235 of them during pregnancy or the post-partum period. Mean prevalence of HIV infection across all person-years in the pooled data was 17·2% (95% CI 17·0–17·3), but 60 of 118 (50·8%) of the women of known HIV status who died during pregnancy or post partum were HIV infected. The mortality rate ratio of HIV-infected to HIV-uninfected women was 20·5 (18·9–22·4) in women who were not pregnant or post partum and 8·2 (5·7–11·8) in pregnant or post-partum women. Excess mortality attributable to HIV was 51·8 (47·8–53·8) per 1000 person-years in women who were not pregnant or post partum and 11·8 (8·4–15·3) per 1000 person-years in pregnant or post-partum women. Interpretation HIV-infected pregnant or post-partum women had around eight times higher mortality than did their HIV-uninfected counterparts. On the basis of this estimate, we predict that roughly 24% of deaths in pregnant or post-partum women are attributable to HIV in sub-Saharan Africa, suggesting that safe motherhood programmes should pay special attention to the needs of HIV-infected pregnant or post-partum women. Funding Wellcome Trust, Health Metrics Network (WHO).

Updates to the Spectrum/Estimation and Projection Package (EPP) model to estimate HIV trends for adults and children

Background The Spectrum and Estimation and Projection Package (EPP) programs are used to estimate key HIV indicators based on HIV surveillance and surveys, programme statistics and epidemic patterns. These indicators include the number of people living with HIV, new infections, AIDS deaths, AIDS orphans, the number of adults and children needing treatment, the need for preventing mother to child transmission (PMTCT) and the impact of antiretroviral treatment on survival. Methods The Joint United Nations Programme on HIV and AIDS (UNAIDS) Reference Group on Estimates, Models and Projections regularly reviews new data and information needs and recommends updates to the methodology and assumptions used in Spectrum. The latest updates described here were used in the 2011 round of global estimates. Results Spectrum and EPP have now been combined into one software package to enhance ease of use and ensure consistent data and assumptions for the curve fitting and indicator estimations. Major enhancements to the methods include a new adult model that tracks the HIV+ population by CD4 count; new patterns describing child survival by time of infection (perinatally, <6 months, 7–12 months and 12+ months after birth); a more detailed estimate of mother-to-child transmission that includes differential transmission rates by CD4 count of the mother, the effects of incident infections and new prophylaxis options; and new procedures to estimate uncertainty ranges around regional estimates. Conclusions The revised model and software facilitate the preparation of new HIV estimates and use new data to address emerging needs for better information on need for treatment among adults and 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.

HIV impact on mother and Child mortality in rural Tanzania

Child mortality in Tanzania rose from 137 per 1000 in 1992-1996 to 147 per 1000 in 1995-1999. Impact of HIV on child mortality is analyzed in a longitudinal community-based study in Kisesa ward, Mwanza region. HIV data on 4273 mothers from 3 rounds of serologic testing are linked to survival information for 6049 children born between 1994 and 2001, contributing 10,002 person-years of observation and 584 child deaths. Impacts of maternal survival and HIV status on child mortality are assessed using hazard analysis. Infant mortality for children of HIV-positive mothers was 158 per 1000 live births compared with 79 per 1000 for children of uninfected mothers; by age 5, child mortality risks were 270 per 1000 live births and 135 per 1000, respectively. Fifty-one deaths were observed among child-bearing women, 14 to HIV-positive mothers. Infant mortality among children whose mothers died was 489 per 1000 live births compared with 84 per 1000 for children of surviving mothers. Maternal death effects were statistically independent of HIV status. Allowing for age, sex, twinning, birth interval, maternal education, and residence, the child death hazard ratio for maternal HIV infection was 2.3 (1.7-3.3); hazard ratio associated with maternal death was 4.8 (2.7-8.4). The HIV-attributable fraction of infant mortality is 8.3% in a population in which prevalence among women giving birth is around 6.2%.