Convergent ethical issues in HIV/AIDS,tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics,Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban,South Africa

Background  

Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB) and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges.     

Methods to estimate the number of orphans as a result of AIDS and other causes in Sub-Saharan Africa

OBJECTIVE: To derive methods to estimate and project the fraction of children orphaned by AIDS and other causes. METHODS: HIV/AIDS affects orphan numbers through increased adult and child mortality and reduced fertility of HIV-positive women. We extend an epidemiologic and demographic model used previously to estimate maternal orphans to paternal orphans. We account for the impact of HIV/AIDS on child survival by modeling the HIV status of the partners of men who die of AIDS or other causes based on data on the concordance of heterosexual partners. Subsequently, the proportion of orphans whose parents have both died is predicted by a regression model fitted to orphanhood data from 34 national demographic and health surveys (DHSs). The approach is illustrated with an application to Tanzania and compared with DHS estimates for the years 1992 and 1999. RESULTS: Projections of the number and age distribution of orphans using these methods agree with survey data for Tanzania. They show the rise in orphanhood over the last decade that has resulted from the HIV epidemic. CONCLUSIONS: The methods allow estimation of the numbers of children whose mother, father, or both parents have died for countries with generalized heterosexual HIV epidemics. These methods have been used to produce orphan estimates for high-prevalence countries published by Joint United Nations Program on HIV/AIDS, World Health Organization, United Nations Children's Fund, and US Agency for International Development in 2002 and 2004.     

Maternal disease stage and child undernutrition in relation to mortality among children born to HIV-infected women in Tanzania

OBJECTIVE: To examine whether maternal HIV disease stage during pregnancy and child malnutrition are associated with child mortality. DESIGN: Prospective cohort study in Tanzania. METHODS: Indicators of disease stage were assessed for 939 HIV-infected women during pregnancy and at delivery, and children's anthropometric status was obtained at scheduled monthly clinic visits after delivery. Children were followed up for survival status until 24 months after birth. RESULTS: Advanced maternal HIV disease during pregnancy (CD4 count <350 vs. >or=350 cells/mm) was associated with increased risk of child mortality through 24 months of age (hazard ratio [HR] = 1.74, 95% confidence interval [CI]: 1.32 to 2.30). CD4 count <350 cells/mm was also associated with an increased risk of death among children who remained HIV-negative during follow-up (HR = 2.00, 95% CI: 1.36 to 2.94). Low maternal hemoglobin concentration and child undernutrition were related to an increased risk of mortality in this cohort of children. CONCLUSIONS: Low maternal CD4 cell count during pregnancy is related to increased risk of mortality in children born to HIV-infected women. Care and treatment for HIV disease, including highly active antiretroviral therapy to pregnant women, could improve child survival. Prevention and treatment of undernutrition in children remain critical interventions in settings with high HIV prevalence.     

Perinatal transmission in developing countries: new developments,new challenges

In Africa, about 30% of all infants born to HIV-infected mothers become infected with HIV. About 4 million women of reproductive age in Africa are infected with HIV. Africa lacks HIV counseling and testing facilities. Family sizes are large. Asia has paid less attention to perinatal transmission than has Africa. Heterosexual transmission is also the predominant mode of HIV infection in Asia. Interventions that might prevent perinatal transmission have recently emerged. HIV/AIDS programs, maternal and child health (MCH) programs, and family planning providers must collaborate to reduce perinatal transmission. HIV/AIDS, MCH, and reproductive health specialists; women's health advocates; and pregnant women must discuss complex policy and ethics issues as they consider interventions. Women in developing countries familiar with their HIV status would arrive at more informed decisions about reproduction than those ignorant of their HIV status. Rapidly falling prices of HIV tests may mean access to testing for more women in developing countries. Availability of safe, effective contraception and abortion services would contribute to the success of counseling and testing to reduce the number of births at risk of perinatal transmission. In areas where infectious diseases and malnutrition cause most infant deaths, mothers should breast feed regardless of HIV status. In areas where this is not the case, mothers should use breast milk substitutes. Some evidence suggests that cesarean sections reduce the rate of perinatal transmission. Vaginal cleansing before and during labor may also reduce it. Since maternal vitamin A deficiency may facilitate perinatal transmission, vitamin A supplementation in pregnant women may reduce the risk of perinatal transmission. Administration of zidovudine to HIV-infected pregnant women reduced the risk of perinatal transmission by 67% in a recent clinical trial.     

Poverty and child mortality in different contexts: can Mozambique learn from the decline in mortality at the turn of the 19th century in Stockholm?

Child mortality has declined in many low-income countries. However, in Sub-Saharan Africa, childhood mortality is still a major public health problem, which is worsening with some countries experiencing new increases in mortality due to HIV /AIDS. This lack of success in reducing child mortality is not only due to HIV /AIDS, but also to high numbers of deaths in other causes of death such as diarrhoea, pneumonia and neonatal causes, for which there are effective curative and preventative interventions. One problem seems to be in the access, coverage and implementation of these interventions, particularly among the poorer sections of the population. A related problem is the interventions that sometimes, when implemented, take place in environments in which they can only be expected to have limited effects. On the other hand in many developed countries infant and child mortality declined as social and economic changes of modernisation took place. However, the mechanisms that did bring about the decline are still not well understood. This paper discuss whether analyses of the historical decline of mortality in industrialised countries could contribute to knowledge in reducing the high child mortality in poor countries today, based on studies of child mortality in different social contexts in Mozambique 1973-1997 and Stockholm 1878-1925.     

Enjeux politiques de l’évaluation à cinq ans du Fonds mondial de lutte contre le sida, la tuberculose et le paludisme

The Global Fund to fight HIV/AIDS, Tuberculosis and Malaria (GFATM) was founded in 2002 in the context of increased political and financial commitments towards health and development, in the aftermath of the Millennium Declaration, and on track to implement the Millennium Development Goals (MDGs). As of today, the institution has mobilized over 16 billion US dollars through its partnership, and spent over 8 billion dollars through 620 contracts in 140 countries for these three diseases. Principles at inception were to accelerate and expand HIV, TB, and Malaria prevention and awareness, care, and treatment related activities, in the poorest and the most affected countries worldwide, with a special emphasis on Africa, being the continent with the highest disease burden, especially with respect to HIV/AIDS and its dreadful social and economic consequences. In 2006, a Technical and Evaluation Reference Group was set up. This group responding to the GFATM Board in relation to the 5-year evaluation, defined the Terms of reference for the 5-year evaluation. Macro International, a firm based in Washington DC, was given the contract to conduct three studies over the period 2006–2009, looking at: (i) GFATM organizational effectiveness, (ii) partnerships at international and global levels, as well as systems effects, (iii) collective impact of the GFATM, the World Bank and (PEPFAR) funds on HIV, TB, and Malaria control. Twenty-five countries participated all together in the evaluation, out of which 18 in study area 3. Total budget for the evaluation amounted almost 17 million US dollars. This paper outlines: (i) the results of study areas 2 and 3 as well as the 5-year Evaluation Synthesis report, contents, and (ii) comments on the results and potential policy implications of the GFATM 5-year evaluation findings, as well as first responses prepared by the GF Secretariat shared at the GFATM Board meeting held in Ethiopia in November 2009. The evaluators raised the weaknesses of national health information systems, which limit the availability of reliable data and indicators that could be useful in assessing disease control impact as well as in monitoring the progress through management for result initiatives. Nevertheless, it can be shown that increased funding is linked to expansion of preventive interventions (including Voluntary Counseling and Testing (VCT) and preventing mother-to-child transmission (PMTCT)) as well as treatment (ARV) activities, the quality of which could be improved and better monitored. Especially in Eastern Africa, malaria control has improved significantly, benefiting from additional funding. Health systems’ weaknesses at district level, such as human resources, laboratory commodities, and medicine shortages, are major constraints to further expansion of services and impact of funds. Issues at stake are the following: (i) soundness of the GFATM assumptions at inception with respect to national disease control strategies, especially in relation to HIV prevention, (ii) whether it belongs to the GFATM to finance health systems strengthening to start with, (iii) GFATM systems effects, (iv) misfinancing in relation to disease burden, marginalized and vulnerable groups, (v) technical expertise identification, mobilization and financing, (vi) equity of access of funding, expertise and guidance, to francophone countries in Africa. Recommendations are made to bring the attention of the GFATM Board members prior to the Replenishment Conference to be prepared in March 2010 and held in October 2010.     

PEPFAR support for the scaling up of collaborative TB/HIV activities

The US President's Emergency Plan for AIDS Relief (PEPFAR) has supported a comprehensive package of care in which interventions to address HIV-related tuberculosis (TB) have received increased funding and support in recent years. PEPFAR's TB/HIV programming is based on the World Health Organization's 12-point policy for collaborative TB/HIV activities, which are integrated into PEPFAR annual guidance. PEPFAR implementing partners have provided crucial support to TB/HIV collaboration, and as a result, PEPFAR-supported countries in sub-Saharan Africa have made significant gains in HIV testing and counseling of TB patients and linkages to HIV care and treatment, intensified TB case finding, and TB infection control. PEPFAR's support of TB/HIV integration has also included significant investment in health systems, including improved laboratory services and educating and enlarging the workforce. The scale-up of antiretroviral therapy along with support of programs to increase HIV counseling and testing and improve linkage and retention in HIV care may have considerable impact on TB morbidity and mortality, if used synergistically with isoniazid preventive therapy, intensified case finding, and infection control. Issues to be addressed by future programming include accelerating implementation of isoniazid preventive therapy, increasing access and ensuring appropriate use of new TB diagnostics, supporting early initiation of antiretroviral therapy for HIV-infected TB patients, and strengthening systems to monitor and evaluate program implementation.     

Global transition in health

"Tempora mutantur et nos in illis" King Lothar I remarked by year 900 AD. What exactly changed in us over time, i.e. how patterns of the epidemiological transition in populations locally and globally might appear, was described by Omran in 1971 [1]. The effect of transition on health and diseases in populations was demonstrated by Frenkl et al in 1991 [2]. And which major public health problems following each other, and why, was underscored by LaPorte in 1995 [3]. In 2000, leaders of the world society decided to identify a range of common goals, the Millennium Development Goals (MDG), to be reached by year 2015. Many of the MDG are directly or indirectly related with the major health problems, particularly those hitting the poorest: lack of clean drinking water, unhealthy environment, high maternal mortality due to lack of care for the pregnant, and lack of control of major communicable, often fatal diseases like child diseases, malaria, HIV/AIDS and tuberculosis. It is remarkable that the specific chronic diseases of major public health relevance are in fact not mentioned in the MDG, even if these diseases increasingly are hitting populations in low- and middle-income societies, i.e. developing countries. The world community seems to prioritize the diseases that are most visible, and most often linked with poverty, namely the infectious diseases mentioned above, which together kill about 17 million people annually, often in combination with malnutrition, and the 0.6 million deaths related to birth and pregnancy. With the exception of HIV/AIDS, which also hit richer societies, these diseases of poverty have been under-prioritized regarding research as well. However, at the turn of the Millennium, the burden of "Western" non-communicable diseases was increasing fast in developing countries. And by 2025, the burden of non-communicable diseases is expected to have doubled globally, with half of the burden on developing countries. Therefore it may be rewarding to look backwards upon the three stages of Omran's original thesis on epidemiological transition, to understand life and death forwards, in a world in fast transition, cf. the Danish philosopher Soeren Kirkegaard: "it is true what philosophy tells us, that life must be understood backwards, while not forgetting the second sentence, that it must be lived forwards".     

Diagnosis of tuberculosis: urgent need to strengthen laboratory services

Tuberculosis (TB) is of great public health concern globally, and the impact is most felt in developing countries of Asia and Africa, where 95% of cases and 98% of deaths are attributable to the disease, The disease is poverty-driven and the situation is further worsened by absence of rapid diagnostic tools to facilitate early diagnosis of the illness, thus leading to widespread of the disease. While attention is being focused on the HIV/AIDS pandemic, little is being heard of TB, especially in the areas of laboratory diagnosis despite the fact that the disease is the commonest cause of death in people living with HIV/AIDS. The importance of a diagnostic laboratory in a TB control program cannot be overemphasized. Smear microscopy, which is the cornerstone of World Health Organization (WHO) 'DOTS' strategy for the treatment of TB, has many drawbacks among which is its inability to detect latent infection and the dependency of its sensitivity on a trained and motivated microscopist. Therefore, there is a need for a more reliable, sensitive and rapid diagnostic test to facilitate early diagnosis of cases and prompt initiation of therapy for a TB control program to have a meaningful impact in the community.     

Modulation of the immune response to Mycobacterium tuberculosis during malaria/M. tuberculosis co‐infection

Tuberculosis (TB) causes significant morbidity and mortality on a global scale. The African region has 24% of the world's TB cases. TB overlaps with other infectious diseases such as malaria and HIV, which are also highly prevalent in the African region. TB is a leading cause of death among HIV‐positive patients and co‐infection with HIV and TB has been described as a syndemic. In view of the overlapping epidemiology of these diseases, it is important to understand the dynamics of the immune response to TB in the context of co‐infection. We investigated the cytokine response to purified protein derivative (PPD) in peripheral blood mononuclear cells from TB patients co‐infected with HIV or malaria and compared it to that of malaria‐ and HIV‐free TB patients. A total of 231 subjects were recruited for this study and classified into six groups; untreated TB‐positive, TB positive subjects on TB drugs, TB‐ and HIV‐positive, TB‐ and malaria‐positive, latent TB and apparently healthy control subjects. Our results demonstrate maintenance of interferon (IFN)‐γ production in HIV and malaria co‐infected TB patients in spite of lower CD4 counts in the HIV‐infected cohort. Malaria co‐infection caused an increase in the production of the T helper type 2 (Th2)‐associated cytokine interleukin (IL)‐4 and the anti‐inflammatory cytokine IL‐10 in PPD‐stimulated cultures. These results suggest that malaria co‐infection diverts immune response against M. tuberculosis towards a Th‐2/anti‐inflammatory response which might have important consequences for disease progression.     

Africa's children and AIDS -- a continent in crisis. The devastation of the HIV / AIDS pandemic

AIDS is having a major impact upon child health. By mid-1996, UNAIDS estimated that worldwide there were 3 million HIV infections in children. Accordingly, infant mortality rates (IMRs) have increased due to AIDS, reversing declines which had been occurring in many countries over the last few decades. The IMR in 1996 would have been 51.7 per 1000 without AIDS; it is instead 72.8 with AIDS, 40% higher than expected. IMR is 30% higher than expected in Zambia and almost 20% higher in Kenya and Uganda. IMRs should grow considerably during the next decade as the epidemic spreads. Two-thirds of AIDS deaths among children occur among those aged 1-4 years, with countries in southern Africa being the most affected. With regard to life expectancy, many years of life will be lost due to the AIDS epidemic. AIDS has already led to widespread and marked reductions in life expectancy, with life expectancy for females being lower than that for males because women are infected with HIV and die at younger ages than men. Lower life expectancy will lead to an increase in the proportion of orphaned children. It is likely that at least 30 million children are living with HIV-positive parents, at risk of being orphaned in the next few years. The implications of the growing proportions of orphans and challenges in child health are considered.     

Global impact of human immunodeficiency virus and AIDS

This review provides information on the epidemiology, economic impact, and intervention strategies for the human immunodeficiency virus (HIV)/AIDS pandemic in developing countries. According to the World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) at the end of 1999, an estimated 34.3 million people were living with HIV/AIDS. Most of the people living with HIV, 95% of the global total, live in developing countries. Examples of the impact of HIV/AIDS in Africa, Asia, Latin America, the Caribbean, and the Newly Independent States provide insight into the demographics, modes of exposure, treatment and prevention options, and the economic effect of the epidemic on the global community. The epidemic in each region of the world is influenced by the specific risk factors that are associated with the spread of HIV/AIDS and the responses that have evolved to address it. These influences are important in developing HIV/AIDS policies and programs to effectively address the global pandemic.     

Ending pediatric AIDS and achieving a generation born HIV-free

In the 30 years of the AIDS pandemic, the devastating effects of HIV on infants and young children have often been overlooked and neglected. However, the ability to prevent mother-to-child transmission of HIV (PMTCT), or vertical transmission, has been one of the most significant prevention success stories in the global AIDS response. New HIV infections in children have been virtually eliminated in high-income countries and programmatic efforts have shifted to low-income and middle-income countries, particularly in sub-Saharan Africa, home to the vast majority of pediatric AIDS cases.Over the past decade, the dramatic scale-up of PMTCT programs has saved millions of lives and has provided a foundation for HIV prevention and care and treatment programs that are integrated within maternal and child health services. Although some countries in sub-Saharan Africa are now approaching universal PMTCT coverage, global access to PMTCT for HIV-positive pregnant women remains at nearly 50%. Recently, a new global plan has focused efforts and resources to keep HIV-positive mothers healthy and to virtually eliminate new pediatric infections by 2015.What programmatic and technical innovations will be necessary to overcome current service gaps and implementation barriers? How can countries continue the current momentum with sustainable locally-led programs that address the epidemic in women and children? And how can the vital perspectives of communities and people living with HIV help drive these efforts? Successfully addressing these and other issues will be key to ending HIV infections in children and creating an AIDS-free generation within the next decade.     

HIV/AIDS global prophylaxis in the light of decisions of the Big Eight

HIV/AIDS, tuberculosis and malaria are three main infection diseases of present time. In the world 6 million persons die from these diseases every year. The purpose for international community is to stop the spread of HIV/AIDS and to initiate tendency to reduce morbidity of HIV/AIDS and malaria. In the declaration on the summit in St. Petersburg (2006 year) the Big Eight proposed the main principles of global strategy in resistance to epidemics. The main commitments of Big Eight: To ensure worldwide access to complex programs of prophylaxis, treatment, care and support by 2010; To realize principles of triunuque approach in all countries; To struggle with increasing rate of HIV/AIDS spread among youth; To decrease discrimination of persons with HIV/AIDS.     

Impact of tuberculosis on HIV disease progression in persons with well-documented time of HIV seroconversion

Tuberculosis (TB) enhances HIV replication in vitro, but its impact on HIV progression at the population level is not established. Studies from industrialized and nonindustrialized countries show contradictory results as to whether TB accelerates HIV progression, although no studies have been conducted in persons with well-documented seroconversion times. Data from HIV seroconverters from 19 cohorts were analyzed to examine the effect of TB on HIV progression comparing persons with TB and persons without TB infected by HIV for the same length of time. TB and other AIDS-defining conditions (ADCs) were fitted as time-dependent covariates, adjusting for age, sex, transmission category, calendar year at risk, and cohort, using Cox proportional hazards models and allowing for late entry. Of 4398 seroconverters, 1294 (29%) developed AIDS. TB accounted for 72 (5.6%) of initial ADCs and for 105 (5.7%) of all ADCs. Survival from HIV seroconversion shows that compared with AIDS-free subjects, the risk of death associated with TB as an initial ADC (hazard ratio [HR] = 23.23, 95% CI: 14.60-36.96) does not differ from that associated with Kaposi sarcoma (HR = 23.47, 95% CI: 16.66-33.05) or esophageal candidiasis (OC)/Pneumocystis carinii pneumonia (PCP) (HR = 30.97, 95% CI: 24.38-39.34) but is lower than that for opportunistic infections other than TB, OC/PCP (HR = 46.83, 95% CI: 37.86-47.94) and high-grade non-Hodgkin lymphomas/invasive cervical carcinoma (HR = 92.71, 95% CI: 60.83-141.3). The lowest risk of death was seen, as expected, in AIDS-free subjects. HIV progression is not inherently faster in subjects who develop TB compared with other individuals with AIDS who have been infected by HIV for the same length of time in countries where TB treatment is widely available.     

Human immunodeficiency virus (HIV) and malaria interaction in sub-Saharan Africa: the collision of two Titans

HIV and malaria are among the leading causes of morbidity and mortality in sub-Saharan Africa, home to 10% of the world's population. An association between HIV and malaria is expected in theory, however, there is conflicting evidence regarding the impact of HIV infection on parasite loads. HIV-associated immunosuppression contributes to more frequent and more severe malaria and reduced efficacy of antimalarials in pregnant women and adults. These effects are modified by the endemicity and stability of malaria transmission. Co-infection with malaria and HIV in pregnant women is associated with anemia, low birth weight, and increased risk of infant mortality to a greater extent than infection with either disease alone. Studies investigating the impact of placental malaria on mother-to-child HIV-1 transmission continue to show conflicting results. This article attempts to review the pertinent information available about the interaction between HIV and malaria and information about chemoprophylaxis and treatment issues. Although much has been published in the last 10 years regarding the interaction of HIV and malaria in sub-Saharan Africa, we still need more information so as to understand the issues that will help us develop effective programs.     

Determinants of social inequalities in child mortality in Mozambique: what do we know? What could be done?

Health inequalities are no longer an issue only for developed countries. In recent years there is agreement that all countries present health inequalities regardless of their level of wealth. In low-income countries and especially in sub-Saharan Africa where the majority of the poor people live as well as their children, research on child health inequalities is still scarce. This review of evidence suggests that if Mozambique is to achieve the millennium development goals (MDGs) by 2015 further research on important determinants of disparities in child mortality is urgently needed.     

Surveillance sentinelle du VIH chez les femmes enceintes en Mauritanie entre 2001 et 2007

According to the 2008 report on global AIDS epidemic, 33 millions of people are living with HIV/AIDS. Subsaharian Africa is the most affected part of the world. The first case of AIDS in Mauritania was reported in 1987. The national prevalence of HIV/AIDS in the country is estimated at less than 1%. The HIV serosurveillance among pregnant women started in country in 2001. This work has focused on HIV sentinel surveillance among pregnant women in antenatal clinics, attending health centres in different wilayas (regions) of the country in order to assess evolution of prevalence between 2001 and 2007. An anonymous and non-correlated method is used for this survey. A questionnaire was administered and venous sampling made for eligible women. Analyses were performed with an algorithm based on two screening tests (ELISA) and another test for confirmation (New Lav Blot). Despite some disparities between the sites considered, the results have shown a low prevalence rate (between 0.1 and 1.48). The average prevalence of HIV infection samples collected increased from 0.57% [0.34–0.80] in 2001 to 0.61% [0.40–0.82] in 2007 with 95% confidence interval. Statistical analysis showed no significant changes between 2001 and 2007 at all these sites. HIV1 is the most frequent type with a proportion of 93.5% in 2007. After several years of classic HIV sentinel surveillance, and to better understand disparities between sites, we recommend a second generation sentinel surveillance (behavioural and serological) approach.     

Combining PMTCT with active case finding for tuberculosis

Tuberculosis (TB) is the preeminent manifestation of HIV infection and has become a leading cause of maternal mortality and morbidity in high HIV-prevalence settings. Active TB in pregnant women has potentially serious consequences for fetuses and newborns. In Soweto, South Africa, there is a more than 90% uptake of voluntary counseling and HIV testing during routine antenatal care, and almost one third of pregnant women are HIV-infected. The posttest counseling session of the prevention of mother-to-child transmission program provides an opportunity to screen HIV-infected pregnant women for TB. In this study, 370 HIV-infected pregnant women were screened for symptoms of active TB by lay counselors at the posttest counseling session. If symptomatic, they were referred to nurses who investigated them further. Eight women were found to have previously undiagnosed, smear-negative, culture-confirmed TB (2160/100,000). The mean CD4 count in those with active TB compared to those without TB was 276 x 10(6) cells per liter vs 447 x 10(6) cells per liter (P = 0.051). Symptoms most associated with active TB were hemoptysis and fever. We conclude that rates of TB in HIV-infected pregnant women are high, and screening for TB during routine antenatal care should be implemented in high HIV-prevalence settings.