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1.  Disability Transitions and Health Expectancies among Adults 45 Years and Older in Malawi: A Cohort-Based Model 
PLoS Medicine  2013;10(5):e1001435.
Collin Payne and colleagues investigated development of disabilities and years expected to live with disabilities in participants 45 years and older participating in the Malawi Longitudinal Survey of Families and Health.
Please see later in the article for the Editors' Summary
Background
Falling fertility and increasing life expectancy contribute to a growing elderly population in sub-Saharan Africa (SSA); by 2060, persons aged 45 y and older are projected to be 25% of SSA's population, up from 10% in 2010. Aging in SSA is associated with unique challenges because of poverty and inadequate social supports. However, despite its importance for understanding the consequences of population aging, the evidence about the prevalence of disabilities and functional limitations due to poor physical health among older adults in SSA continues to be very limited.
Methods and Findings
Participants came from 2006, 2008, and 2010 waves of the Malawi Longitudinal Survey of Families and Health, a study of the rural population in Malawi. We investigate how poor physical health results in functional limitations that limit the day-to-day activities of individuals in domains relevant to this subsistence-agriculture context. These disabilities were parameterized based on questions from the SF-12 questionnaire about limitations in daily living activities. We estimated age-specific patterns of functional limitations and the transitions over time between different disability states using a discrete-time hazard model. The estimated transition rates were then used to calculate the first (to our knowledge) microdata-based health expectancies calculated for SSA. The risks of experiencing functional limitations due to poor physical health are high in this population, and the onset of disabilities happens early in life. Our analyses show that 45-y-old women can expect to spend 58% (95% CI, 55%–64%) of their remaining 28 y of life (95% CI, 25.7–33.5) with functional limitations; 45-y-old men can expect to live 41% (95% CI, 35%–46%) of their remaining 25.4 y (95% CI, 23.3–28.8) with such limitations. Disabilities related to functional limitations are shown to have a substantial negative effect on individuals' labor activities, and are negatively related to subjective well-being.
Conclusions
Individuals in this population experience a lengthy struggle with disabling conditions in adulthood, with high probabilities of remitting and relapsing between states of functional limitation. Given the strong association of disabilities with work efforts and subjective well-being, this research suggests that current national health policies and international donor-funded health programs in SSA inadequately target the physical health of mature and older adults.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The population of the world is getting older. In almost every country, the over-60 age group is growing faster than any other age group. In 2000, globally, there were about 605 million people aged 60 years or more; by 2050, 2 billion people will be in this age group. Much of this increase in the elderly population will be in low-income countries. In sub-Saharan Africa, for example, 10% of the population is currently aged 45 years or more, but by 2060, a quarter of the population will be so-called mature adults. In all countries, population aging is the result of women having fewer children (falling fertility) and people living longer (increasing life expectancy). Thus, population aging is a demographic transition, a change in birth and death rates. In low- and middle-income countries, population aging is occurring in parallel with an “epidemiological transition,” a shift from communicable (infectious) diseases to non-communicable diseases (for example, heart disease) as the primary causes of illness and death.
Why Was This Study Done?
Both the demographic and the epidemiological transition have public health implications for low-income countries. Good health is important for the independence and economic productivity of older people. Productive older people can help younger populations financially and physically, and help compensate for the limitations experienced by younger populations infected with HIV. Also, low-income countries lack social safety nets, so disabled older adults can be a burden on younger populations. Thus, the health of older individuals is important to the well-being of people of all ages. As populations age, low-income countries will need to invest in health care for mature and elderly adults and in disease prevention programs to prevent or delay the onset of non-communicable diseases, which can limit normal daily activities by causing disabilities. Before providing these services, national policy makers need to know the proportion of their population with disabilities, the functional limitations caused by poor physical health, and the health expectancies (the number of years a person can expect to be in good health) of older people in their country. In this cohort modeling study, the researchers estimate health expectancies and transition rates between different levels of disability among mature adults in Malawi, one of the world's poorest countries, using data collected by the Malawi Longitudinal Survey of Families and Health (MLSFH) on economic, social, and health conditions in a rural population. Because Malawi has shorter life expectancies and earlier onset of disability than wealthier countries, the authors considered individuals aged 45 and older as mature adults at risk for disability.
What Did the Researchers Do and Find?
The researchers categorized the participants in the 2006, 2008, and 2010 waves of the MLSFH into three levels of functional limitation (healthy, moderately limited, and severely limited) based on answers to questions in the SF-12 health survey questionnaire that ask about disabilities that limit daily activities that rural Malawians perform. The researchers estimated age–gender patterns of functional limitations and transition rates between different disability states using a discrete-time hazard model, and health expectancies by running a microsimulation to model the aging of synthetic cohorts with various starting ages but the same gender and functional limitation distributions as the study population. These analyses show that the chance of becoming physically disabled rises sharply with age, with 45-year-old women in rural Malawi expected to spend 58% of their estimated remaining 28 years with functional limitations, and 45-year-old men expected to live 41% of their remaining 25.4 years with functional limitations. Also, on average, a 45-year-old woman will spend 2.7 years with moderate functional limitation and 0.6 years with severe functional limitation before she reaches 55; for men the corresponding values are 1.6 and 0.4 years. Around 50% of moderately and 60%–80% of severely limited individuals stated that pain interfered quite a bit or extremely with their normal work during the past four weeks, suggesting that pain treatment may help reduce disability.
What Do These Findings Mean?
These findings suggest that mature adults in rural Malawi will have some degree of disability during much of their remaining lifetime. The risks of experiencing functional limitations are higher and the onset of persistent disabilities happens earlier in Malawi than in more developed contexts—the proportions of remaining life spent with severe limitations at age 45 in Malawi are comparable to those of 80-year-olds in the US. The accuracy of these findings is likely to be affected by assumptions made during modeling and by the quality of the data fed into the models. Nevertheless, these findings suggest that functional limitations, which have a negative effect on the labor activity of individuals, will become more prominent in Malawi (and probably other sub-Saharan countries) as the age composition of populations shifts over the coming years. Older populations in sub-Saharan Africa are not targeted well by health policies and programs at present. Consequently, these findings suggest that policy makers will need to ensure that additional financial resources are provided to improve health-care provision for aging individuals and to lessen the high rates of functional limitation and associated disabilities.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001435.
This study is further discussed in a PLoS Medicine Perspective by Andreas Stuck, et al.
The World Health Organization provides information on many aspects of aging (in several languages); the WHO Study on Global Ageing and Adult Health (SAGE) is compiling longitudinal information on the health and well-being of adult populations and the aging process
The United Nations Population Fund and HelpAge International publication Ageing in the Twenty-First Century is available
HelpAge International is an international nongovernmental organization that helps older people claim their rights, challenge discrimination, and overcome poverty, so that they can lead dignified, secure, and healthy lives
More information on the Malawi Longitudinal Study of Families and Health is available
doi:10.1371/journal.pmed.1001435
PMCID: PMC3646719  PMID: 23667343
2.  Donor Funding for Newborn Survival: An Analysis of Donor-Reported Data, 2002–2010 
PLoS Medicine  2012;9(10):e1001332.
With recent increases in development assistance money for maternal and child health, Catherine Pitt and colleagues examine whether foreign aid specifically for newborns has changed, whether it's on par with the burden of newborn deaths worldwide, and how such funding can be tracked.
Background
Neonatal mortality accounts for 43% of global under-five deaths and is decreasing more slowly than maternal or child mortality. Donor funding has increased for maternal, newborn, and child health (MNCH), but no analysis to date has disaggregated aid for newborns. We evaluated if and how aid flows for newborn care can be tracked, examined changes in the last decade, and considered methodological implications for tracking funding for specific population groups or diseases.
Methods and Findings
We critically reviewed and categorised previous analyses of aid to specific populations, diseases, or types of activities. We then developed and refined key terms related to newborn survival in seven languages and searched titles and descriptions of donor disbursement records in the Organisation for Economic Co-operation and Development's Creditor Reporting System database, 2002–2010. We compared results with the Countdown to 2015 database of aid for MNCH (2003–2008) and the search strategy used by the Institute for Health Metrics and Evaluation. Prior to 2005, key terms related to newborns were rare in disbursement records but their frequency increased markedly thereafter. Only two mentions were found of “stillbirth” and only nine references were found to “fetus” in any spelling variant or language. The total value of non-research disbursements mentioning any newborn search terms rose from US$38.4 million in 2002 to US$717.1 million in 2010 (constant 2010 US$). The value of non-research projects exclusively benefitting newborns fluctuated somewhat but remained low, at US$5.7 million in 2010. The United States and the United Nations Children's Fund (UNICEF) provided the largest value of non-research funding mentioning and exclusively benefitting newborns, respectively.
Conclusions
Donor attention to newborn survival has increased since 2002, but it appears unlikely that donor aid is commensurate with the 3.0 million newborn deaths and 2.7 million stillbirths each year. We recommend that those tracking funding for other specific population groups, diseases, or activities consider a key term search approach in the Creditor Reporting System along with a detailed review of their data, but that they develop their search terms and interpretations carefully, taking into account the limitations described.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 1990, 12 million children—most of them living in developing countries—died before they reached their fifth birthday. Faced with this largely avoidable loss of young lives, in 2000, world leaders set a target of reducing under-five mortality (deaths) to one-third of its 1990 level by 2015 as Millennium Development Goal 4 (MDG4); this goal, together with seven others, aims to eradicate extreme poverty globally. In recent years, progress towards reducing child mortality has accelerated but remains insufficient to achieve MDG4, in part, because progress towards reducing neonatal mortality—deaths during the first 28 days of life—has been particularly slow. Neonatal deaths now account for a greater proportion of global child deaths than in 1990—43% of the 7 million children who died before their fifth birthday in 2011 died during the neonatal period. The major causes of neonatal deaths are complications of preterm and term delivery and infections. Simple interventions such as improved hygiene at birth and advice on breastfeeding can substantially reduce neonatal deaths.
Why Was This Study Done?
To achieve MDG4, more must be done to prevent deaths among newborn babies. One reason that progress in reducing neonatal mortality is slow could be insufficient donor funding (aid) for newborn health. Previous analyses by, for example, Countdown to 2015 (which tracks coverage levels for health interventions that reduce maternal, newborn, and child mortality) indicate that donor funding has increased for maternal, newborn, and child health over the past decade, but how much of this aid directly benefits newborns is unknown. Here, the researchers develop a method for tracking aid flows for newborns and examine changes in this flow over the past decade by applying their new strategy to the Organisation for Economic Co-operation and Development (OECD) Creditor Reporting System (CRS) Aid Activity database. This database collects information about official development assistance for health given (disbursed) to developing countries by member countries of the OECD Development Assistance Committee, international organizations, and some private donors.
What Did the Researchers Do and Find?
The researchers developed a comprehensive set of search terms related to newborn survival by piloting it on the Countdown to 2015 official development assistance database, which covers the years 2003–2008. They then used their list of 24 key terms to search the CRS database from 2002 (the first year for which relatively complete disbursement data are available) to 2010 (the most recent year for which data are available) and classified each retrieved project according to whether its funding activities aimed to benefit newborns exclusively or to improve the health of other population groups as well. The researchers found that key terms related to newborns were rare in disbursement records before 2005 but that their frequency increased markedly thereafter. The total value of non-research disbursements (aid provided for programmatic or advocacy activities) that mentioned any newborn search terms increased from US$38.4 million in 2002 to US$717.1 million in 2010. The value of non-research projects that exclusively benefitted newborns fluctuated; in 2010, it was $US5.7 million. Finally, the US and United Nations Children's Fund (UNICEF) provided the largest value of non-research funding mentioning newborns and exclusively benefitting newborns, respectively.
What Do These Findings Mean?
These findings indicate that the value of aid disbursements mentioning newborns or an activity likely to benefit newborns increased 20-fold between 2002 and 2010 and constituted an increasing proportion of aid for maternal, newborn, and child health. Although this increase may partly reflect increased detail in aid disbursement reporting, it is also likely to reflect an increase in donor attention to newborn survival. The accuracy of these findings is likely to be affected by limitations in the search strategy and in the CRS database, which does not capture aid flows from emerging donors such as China or from many private foundations. Moreover, because these findings take no account of domestic expenditure, they do not provide a comprehensive estimate of the value of resources available in developing countries for newborn health. Nevertheless, investment in newborn survival is unlikely to be commensurate with global newborn mortality. Thus, an expansion of programmatic funding from donors as well as increased governmental support for newborn health in developing countries is urgently needed to catalyze the scale-up of cost-effective interventions to save newborn lives and to meet MDG4.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001332.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health, including the 2012 report of UN Inter-agency Group of Child Mortality Estimation; its Committing to Child Survival: a Promise Renewed webpage includes links to its 2012 progress report, to a video about progress made in reducing child deaths worldwide, and to stories about child survival in the field
The World Health Organization has information about Millennium Development Goal 4 and about maternal, newborn, child, and adolescent health (some information in several languages)
Countdown to 2015 provides additional information on maternal, newborn, and child survival, including its 2012 report Building a Future for Women and Children
The Healthy Newborn Network (HNN) is a community of more than 70 partner organizations addressing critical knowledge gaps for newborn health providing recent data on newborn survival and analyses of country programs
Information on and access to the Organisation for Economic Co-operation Development Creditor Reporting System Aid Activities database is available
Further information about the Millennium Development Goals is available
doi:10.1371/journal.pmed.1001332
PMCID: PMC3484125  PMID: 23118619
3.  Access To Essential Maternal Health Interventions and Human Rights Violations among Vulnerable Communities in Eastern Burma 
PLoS Medicine  2008;5(12):e242.
Background
Health indicators are poor and human rights violations are widespread in eastern Burma. Reproductive and maternal health indicators have not been measured in this setting but are necessary as part of an evaluation of a multi-ethnic pilot project exploring strategies to increase access to essential maternal health interventions. The goal of this study is to estimate coverage of maternal health services prior to this project and associations between exposure to human rights violations and access to such services.
Methods and Findings
Selected communities in the Shan, Mon, Karen, and Karenni regions of eastern Burma that were accessible to community-based organizations operating from Thailand were surveyed to estimate coverage of reproductive, maternal, and family planning services, and to assess exposure to household-level human rights violations within the pilot-project target population. Two-stage cluster sampling surveys among ever-married women of reproductive age (15–45 y) documented access to essential antenatal care interventions, skilled attendance at birth, postnatal care, and family planning services. Mid-upper arm circumference, hemoglobin by color scale, and Plasmodium falciparum parasitemia by rapid diagnostic dipstick were measured. Exposure to human rights violations in the prior 12 mo was recorded. Between September 2006 and January 2007, 2,914 surveys were conducted. Eighty-eight percent of women reported a home delivery for their last pregnancy (within previous 5 y). Skilled attendance at birth (5.1%), any (39.3%) or ≥ 4 (16.7%) antenatal visits, use of an insecticide-treated bed net (21.6%), and receipt of iron supplements (11.8%) were low. At the time of the survey, more than 60% of women had hemoglobin level estimates ≤ 11.0 g/dl and 7.2% were Pf positive. Unmet need for contraceptives exceeded 60%. Violations of rights were widely reported: 32.1% of Karenni households reported forced labor and 10% of Karen households had been forced to move. Among Karen households, odds of anemia were 1.51 (95% confidence interval [CI] 0.95–2.40) times higher among women reporting forced displacement, and 7.47 (95% CI 2.21–25.3) higher among those exposed to food security violations. The odds of receiving no antenatal care services were 5.94 (95% CI 2.23–15.8) times higher among those forcibly displaced.
Conclusions
Coverage of basic maternal health interventions is woefully inadequate in these selected populations and substantially lower than even the national estimates for Burma, among the lowest in the region. Considerable political, financial, and human resources are necessary to improve access to maternal health care in these communities.
Luke Mullany and colleagues examine access to essential maternal health interventions and human rights violations within vulnerable communities in eastern Burma.
Editors' Summary
Background.
After decades of military rule, Burma has one of the world's worst health-care systems and high levels of ill health. For example, maternal mortality (deaths among women from pregnancy-related causes) is around 360 per 100,000 live births in Burma, whereas in neighboring Thailand it is only 44 per 100,000 live births. Maternal health is even worse in the Shan, Karenni, Karen and Mon states in eastern Burma where ethnic conflicts and enforced village relocations have internally displaced more than half a million people. Here, maternal mortality is thought to be about 1000 per 100, 000 live births. In an effort to improve access to life-saving maternal health interventions in these states, Burmese community-based health organizations, the Johns Hopkins Center for Public Health and Human Rights and the Global Health Access Program in the USA, and the Mae Tao Clinic (a health-worker training center in Thailand) recently set up the Mobile Obstetric Maternal Health Workers (MOM) Project. In this pilot project, local health workers from 12 communities in eastern Burma received training in antenatal care, emergency obstetrics (the care of women during childbirth), blood transfusion, and family planning at the Mae Tao Clinic. Back in Burma, these maternal health workers trained additional local health workers and traditional birth attendants. All these individuals now provide maternal health care to their communities.
Why Was This Study Done?
The effectiveness of the MOM project can only be evaluated if accurate baseline information on women's access to maternal health-care services is available. This information is also needed to ensure the wise use of scarce health-care resources. However, very little is known about reproductive and maternal health in eastern Burma. In this study, the researchers analyze the information on women's access to reproductive and maternal health-care services that was collected during the initial field implementation stage of the MOM project. In addition, they analyze whether exposure to enforced village relocations and other human rights violations affect access to maternal health-care services.
What Did the Researchers Do and Find?
Trained survey workers asked nearly 3000 ever-married women of reproductive age in the selected communities about their access to antenatal and postnatal care, skilled birth attendants, and family planning. They measured each woman's mid-upper arm circumference (an indicator of nutritional status) and tested them for anemia (iron deficiency) and infection with malaria parasites (a common cause of anemia in tropical countries). Finally, they asked the women about any recent violations of their human rights such as forced labour or relocation. Nearly 90% of the women reported a home delivery for their last baby. A skilled attendant was present at only one in 20 births and only one in three women had any antenatal care. One third of the women received postnatal care and only a third said they had access to effective contraceptives. Few women had received iron supplements or had used insecticide-treated bednets to avoid malaria-carrying mosquitos. Consequently, more than half the women were anemic and 7.2% were infected with malaria parasites. Many women also showed signs of poor nutrition. Finally, human rights violations were widely reported by the women. In Karen, the region containing most of the study communities, forced relocation tripled the risk of women developing anemia and greatly decreased their chances of receiving any antenatal care.
What Do These Findings Mean?
These findings show that access to maternal health-care interventions is extremely limited and that poor nutrition, anemia, and malaria, all of which increase the risk of pregnancy complications, are widespread in the communities in the MOM project. Because these communities had some basic health services and access to training in Thailand before the project started, these results probably underestimate the lack of access to maternal health-care services in eastern Burma. Nevertheless, it is clear that considerable political, financial, and human resources will be needed to improve maternal health in this region. Finally, the findings also reveal a link between human rights violations and reduced access to maternal health-care services. Thus, the scale of human rights violations will need to be considered when evaluating programs designed to improve maternal health in Burma and in other places where there is ongoing conflict.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050242.
This research article is further discussed in a PLoS Medicine Perspective by Macaya Douoguih
The World Health Organization provides information on all aspects of health in Burma (in several languages)
The Mae Tao Clinic also provides general information about Burma and its health services
More information about the MOM project is available in a previous publication by the researchers
The Burma Campaign UK and Human Rights Watch both provide detailed information about human rights violations in Burma
The United Nations Population Fund provides information about safe motherhood and ongoing efforts to save mothers' lives around the world
doi:10.1371/journal.pmed.0050242
PMCID: PMC2605890  PMID: 19108601
4.  Prioritizing CD4 Count Monitoring in Response to ART in Resource-Constrained Settings: A Retrospective Application of Prediction-Based Classification 
PLoS Medicine  2012;9(4):e1001207.
Luis Montaner and colleagues retrospectively apply a potential capacity-saving CD4 count prediction tool to a cohort of HIV patients on antiretroviral therapy.
Background
Global programs of anti-HIV treatment depend on sustained laboratory capacity to assess treatment initiation thresholds and treatment response over time. Currently, there is no valid alternative to CD4 count testing for monitoring immunologic responses to treatment, but laboratory cost and capacity limit access to CD4 testing in resource-constrained settings. Thus, methods to prioritize patients for CD4 count testing could improve treatment monitoring by optimizing resource allocation.
Methods and Findings
Using a prospective cohort of HIV-infected patients (n = 1,956) monitored upon antiretroviral therapy initiation in seven clinical sites with distinct geographical and socio-economic settings, we retrospectively apply a novel prediction-based classification (PBC) modeling method. The model uses repeatedly measured biomarkers (white blood cell count and lymphocyte percent) to predict CD4+ T cell outcome through first-stage modeling and subsequent classification based on clinically relevant thresholds (CD4+ T cell count of 200 or 350 cells/µl). The algorithm correctly classified 90% (cross-validation estimate = 91.5%, standard deviation [SD] = 4.5%) of CD4 count measurements <200 cells/µl in the first year of follow-up; if laboratory testing is applied only to patients predicted to be below the 200-cells/µl threshold, we estimate a potential savings of 54.3% (SD = 4.2%) in CD4 testing capacity. A capacity savings of 34% (SD = 3.9%) is predicted using a CD4 threshold of 350 cells/µl. Similar results were obtained over the 3 y of follow-up available (n = 619). Limitations include a need for future economic healthcare outcome analysis, a need for assessment of extensibility beyond the 3-y observation time, and the need to assign a false positive threshold.
Conclusions
Our results support the use of PBC modeling as a triage point at the laboratory, lessening the need for laboratory-based CD4+ T cell count testing; implementation of this tool could help optimize the use of laboratory resources, directing CD4 testing towards higher-risk patients. However, further prospective studies and economic analyses are needed to demonstrate that the PBC model can be effectively applied in clinical settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed nearly 30 million people since 1981, and about 34 million people (most of them living in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte and one of the body's white blood cell types), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within ten years of infection. Then, in 1996, antiretroviral therapy (ART) became available, and for people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive, and for people living in developing countries, HIV/AIDS remained a fatal illness. In 2003, HIV was declared a global health emergency, and in 2006, the international community set itself the target of achieving universal access to ART by 2010. By the end of 2010, only 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving ART.
Why Was This Study Done?
One factor that has impeded progress towards universal ART coverage has been the limited availability of trained personnel and laboratory facilities in many developing countries. These resources are needed to determine when individuals should start ART—the World Health Organization currently recommends that people start ART when their CD4 count drops below 350 cells/µl—and to monitor treatment responses over time so that viral resistance to ART is quickly detected. Although a total lymphocyte count can be used as a surrogate measure to decide when to start treatment, repeated CD4 cell counts are the only way to monitor immunologic responses to treatment, a level of monitoring that is rarely sustainable in resource-constrained settings. A method that optimizes resource allocation by prioritizing who gets tested might be one way to improve treatment monitoring. In this study, the researchers applied a new tool for prioritizing laboratory-based CD4 cell count testing in resource-constrained settings to patient data that had been previously collected.
What Did the Researchers Do and Find?
The researchers fitted a mixed-effects statistical model to repeated CD4 count measurements from HIV-infected individuals from seven sites around the world (including some resource-limited sites). They then used model-derived estimates to apply a mathematical tool for predicting—from a CD4 count taken at the start of treatment, and white blood cell counts and lymphocyte percentage measurements taken later—whether CD4 counts would be above 200 cells/µl (the original threshold recommended for ART initiation) and 350 cells/µl (the current recommended threshold) for up to three years after ART initiation. The tool correctly classified 91.5% of the CD4 cell counts that were below 200 cells/µl in the first year of ART. With this threshold, the potential savings in CD4 testing capacity was 54.3%. With a CD4 count threshold of 350 cells/µl, the potential savings in testing capacity was 34%. The results over a three-year follow-up were similar. When applied to six representative HIV-positive individuals, the tool correctly predicted all the CD4 counts above 200 cells/µl, although some individuals who had a predicted CD4 count of less than 200 cells/µl actually had a CD4 count above this threshold. Thus, none of these individuals would have been exposed to an undetected dangerous CD4 count, but the application of the tool would have saved 57% of the CD4 laboratory tests done during the first year of ART.
What Do These Findings Mean?
These findings support the use of this new tool—the prediction-based classification (PBC) algorithm—for predicting a drop in CD4 count below a clinically meaningful threshold in HIV-infected individuals receiving ART. Further studies are now needed to demonstrate the feasibility, clinical effectiveness, and cost-effectiveness of this approach, to find out whether the tool can be used over extended periods of time, and to investigate whether the accuracy of its predictions can be improved by, for example, adding in periodic CD4 testing. Provided these studies confirm its early promise, the researchers suggest that the PBC algorithm could be used as a “triage” tool to direct available laboratory testing capacity to high-priority individuals (those likely to have a dangerously low CD4 count). By optimizing the use of limited laboratory resources in this and other ways, the PBC algorithm could therefore help to maintain and expand ART programs in low- and middle-income countries.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001207.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment (in several languages)
More information about universal access to HIV treatment, prevention, care, and support is available from UNAIDS
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001207
PMCID: PMC3328436  PMID: 22529752
5.  Early and Late Direct Costs in a Southern African Antiretroviral Treatment Programme: A Retrospective Cohort Analysis 
PLoS Medicine  2009;6(12):e1000189.
Gary Maartens and colleagues describe the direct heath care costs and identify the drivers of cost over time in an HIV managed care program in Southern Africa.
Background
There is a paucity of data on the health care costs of antiretroviral therapy (ART) programmes in Africa. Our objectives were to describe the direct heath care costs and establish the cost drivers over time in an HIV managed care programme in Southern Africa.
Methods/Findings
We analysed the direct costs of treating HIV-infected adults enrolled in the managed care programme from 3 years before starting non-nucleoside reverse transcriptase inhibitor-based ART up to 5 years afterwards. The CD4 cell count criterion for starting ART was <350 cells/µl. We explored associations between variables and mean total costs over time using a generalised linear model with a log-link function and a gamma distribution. Our cohort consisted of 10,735 patients (59.4% women) with 594,497 mo of follow up data (50.9% of months on ART). Median baseline CD4+ cell count and viral load were 125 cells/µl and 5.16 log10 copies/ml respectively. There was a peak in costs in the period around ART initiation (from 4 mo before until 4 mo after starting ART) driven largely by hospitalisation, following which costs plateaued for 5 years. The variables associated with changes in mean total costs varied with time. Key early associations with higher costs were low baseline CD4+ cell count, high baseline HIV viral load, and shorter duration in HIV care prior to starting ART; whilst later associations with higher costs were lower ART adherence, switching to protease inhibitor-based ART, and starting ART at an older age.
Conclusions
Drivers of mean total costs changed considerably over time. Starting ART at higher CD4 counts or longer pre-ART care should reduce early costs. Monitoring ART adherence and interventions to improve it should reduce later costs. Cost models of ART should take into account these time-dependent cost drivers, and include costs before starting ART.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 30 million people (22 million people in sub-Saharan Africa alone) are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, on average HIV-positive people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART; combinations of powerful antiretroviral drugs) was developed. For people living in affluent, developed countries HIV/AIDS became a chronic, treatable condition, but for the millions of HIV-infected people living in low- and middle-income countries, effective treatment was unavailable and HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global health emergency and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2008, of the 9.5 million people in need of ART in low- and middle-income countries, more than 4 million people were receiving treatment.
Why Was This Study Done?
Good progress is being made towards achieving universal access to ART, partly because the cost of antiretroviral drugs has plummeted in developing countries. But the provision of antiretroviral drugs is not the only direct cost associated with ART. General practitioner, specialist, and maternity-related care for patients receiving ART, hospital accommodation when necessary, and the investigations that are needed to monitor the progress of HIV infection such as CD4 cell counts and viral load measurements all incur considerable costs. To use their limited resources effectively, public-health officials in developing countries need to know as much as possible about the direct costs of HIV health care but few studies have investigated these costs, particularly those incurred before an individual starts taking ART. In this study, the researchers explore health care costs in a South African private-sector HIV/AIDS program and examine the variables that drive the costs of HIV health care around the time of ART initiation and during later phases of ART.
What Did the Researchers Do and Find?
The researchers analyzed the direct costs of treating more than 100,000 HIV-infected adults enrolled in a private HIV care program in South Africa from 3 years before they started ART until up to 5 years after ART initiation; within this program, individuals began to receive ART when their CD4 cell count fell below 350 cells/µl of blood. The researchers found a peak in direct health costs from 4 months before to 4 months after starting ART (the “peri-ART” period), which was driven mainly by hospital costs. After the peri-ART period, costs dropped (although not to the levels seen before this period) and stabilized at an intermediate level for the next 5 years. Detailed statistical analyses suggest that the key variables associated with higher costs in the peri-ART period were a low baseline CD4 cell count, a high baseline HIV viral load, and a shorter time in HIV care before ART initiation. The key variable associated with higher costs later in ART was lower adherence to the drug therapy. That is, costs were higher among patients who did not take their antiretroviral drugs regularly.
What Do These Findings Mean?
This study involved patients enrolled in a private health care program in which the criteria for initiating ART differed somewhat from those recommended by the World Health Organization for ART initiation in resource-limited settings. Thus, the absolute mean total costs calculated by the researchers are unlikely to be generalizable to public HIV care systems in South Africa and in other resource-poor settings. However, the finding that the drivers of mean total costs change considerably over time may be generalizable and provides some useful information for public-health planners that can now be tested in other, more resource-limited patient populations. In particular, the findings of this study suggest that the high early costs of ART programs could be reduced by starting ART at higher CD4 cell counts or by providing longer pre-ART care. In addition, the findings suggest that monitoring ART adherence and introducing interventions to improve ART adherence could reduce the later direct costs of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000189.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Africa, and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including the September 2009 progress report (in English and French)
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS epidemic
doi:10.1371/journal.pmed.1000189
PMCID: PMC2777319  PMID: 19956658
6.  Patient Retention in Antiretroviral Therapy Programs in Sub-Saharan Africa: A Systematic Review 
PLoS Medicine  2007;4(10):e298.
Background
Long-term retention of patients in Africa's rapidly expanding antiretroviral therapy (ART) programs for HIV/AIDS is essential for these programs' success but has received relatively little attention. In this paper we present a systematic review of patient retention in ART programs in sub-Saharan Africa.
Methods and Findings
We searched Medline, other literature databases, conference abstracts, publications archives, and the “gray literature” (project reports available online) between 2000 and 2007 for reports on the proportion of adult patients retained (i.e., remaining in care and on ART) after 6 mo or longer in sub-Saharan African, non-research ART programs, with and without donor support. Estimated retention rates at 6, 12, and 24 mo were calculated and plotted for each program. Retention was also estimated using Kaplan-Meier curves. In sensitivity analyses we considered best-case, worst-case, and midpoint scenarios for retention at 2 y; the best-case scenario assumed no further attrition beyond that reported, while the worst-case scenario assumed that attrition would continue in a linear fashion. We reviewed 32 publications reporting on 33 patient cohorts (74,192 patients, 13 countries). For all studies, the weighted average follow-up period reported was 9.9 mo, after which 77.5% of patients were retained. Loss to follow-up and death accounted for 56% and 40% of attrition, respectively. Weighted mean retention rates as reported were 79.1%, 75.0% and 61.6 % at 6, 12, and 24 mo, respectively. Of those reporting 24 mo of follow-up, the best program retained 85% of patients and the worst retained 46%. Attrition was higher in studies with shorter reporting periods, leading to monthly weighted mean attrition rates of 3.3%/mo, 1.9%/mo, and 1.6%/month for studies reporting to 6, 12, and 24 months, respectively, and suggesting that overall patient retention may be overestimated in the published reports. In sensitivity analyses, estimated retention rates ranged from 24% in the worse case to 77% in the best case at the end of 2 y, with a plausible midpoint scenario of 50%.
Conclusions
Since the inception of large-scale ART access early in this decade, ART programs in Africa have retained about 60% of their patients at the end of 2 y. Loss to follow-up is the major cause of attrition, followed by death. Better patient tracing procedures, better understanding of loss to follow-up, and earlier initiation of ART to reduce mortality are needed if retention is to be improved. Retention varies widely across programs, and programs that have achieved higher retention rates can serve as models for future improvements.
Almost half of people entering African HIV treatment programs were lost to follow-up or died within two years, according to this systematic review by Sydney Rosen and colleagues.
Editors' Summary
Background.
About 25 million people in sub-Saharan Africa are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Every year, about three million more people become infected with HIV and 2 million die from AIDS in this region, where the pandemic has reduced life expectancy, orphaned many children, and reversed economic growth. Since 1996, HIV-positive people living in wealthier parts of the world have had access to cocktails of antiretroviral drugs that hold HIV in check and allow them to live relatively normal, healthy lives. But these drugs are expensive and it is only in the past five years that antiretroviral therapy (ART) programs have been initiated in sub-Saharan Africa, often with international support.
Why Was This Study Done?
For ART to work, HIV-infected individuals whose immune systems have been damaged by the virus have to take antiretroviral drugs regularly for the rest of their lives. If people take ART irregularly or stop taking their medications they may become sicker or die, or the viruses they carry may become resistant to antiretroviral drugs. Several studies have looked at how well patients on ART stick to their day-to-day medication schedules, but how long patients stay in treatment programs, which they must do to prevent illness and death from AIDS, has received little attention. In this study the researchers reviewed reports of whether patients stay in treatment in ART programs in sub-Saharan Africa, and also looked at the reasons why they drop out.
What Did the Researchers Do and Find?
The researchers identified 32 scientific reports published or presented at meetings between 2000 and 2007 that gave details of the proportion of adult patients retained (alive and receiving ART) in ART treatment programs (not including research studies) in 13 countries in sub-Saharan Africa. The average follow-up time of the programs (adjusted for number of patients in each) was 9.9 months. At this time, 77.5% of the patients were retained on average. Of the patients not retained, just under half had died and half had been lost to follow up. That is, they had missed clinic visits or had not picked up their medication. Estimated average retention rates at 6, 12, and 24 months were 79.08%, 75% and 61.6%, respectively; retention rates reported at 24 months ranged between 46% and 85% of patients. Finally, using sensitivity analysis (a technique that can estimate best- and worst-case possibilities), the researchers estimated that actual retention in ART programs after 2 years probably lies between one-quarter and three-quarters of patients.
What Do These Findings Mean?
These results show that roughly half of people starting HIV treatment programs in Africa are no longer receiving treatment after two years. The overall success rates of African treatment programs may actually be even lower, if one takes into account that programs with very low retention may be unlikely to publish their results. This study therefore indicates that a worrying number of patients in sub-Saharan Africa who need ART are lost from treatment programs. Because many of these patients are lost because they die from AIDS, one way to improve retention might be to start treating people with ART earlier, before they become seriously ill from HIV. Better efforts to find out exactly why patients drop out of programs (for example, the cost of drugs and/or of transport to clinics) might reduce the number of patients lost to follow up. The researchers also suggest that ART programs with very high retention rates might serve as models to improve retention rates in other programs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040298.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite is a regional page on sub-Saharan Africa from the University of California, San Francisco
Information is provided by the US Centers for Disease Control and Prevention on the US President's Emergency Plan for AIDS Relief in various countries and regions
Avert is an international AIDS charity that provides information on HIV and AIDS in Africa
Aidsmap is an international AIDS organization that summarizes research about HIV/AIDS and reports news (in English, Spanish, Portuguese, French, and Russian)
doi:10.1371/journal.pmed.0040298
PMCID: PMC2020494  PMID: 17941716
7.  Public-Health and Individual Approaches to Antiretroviral Therapy: Township South Africa and Switzerland Compared 
PLoS Medicine  2008;5(7):e148.
Background
The provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland.
Methods and Findings
We analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/μl in South Africa and 204 cells/μl in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%–97%) in South Africa and 96% (94%–97%) in Switzerland, and 26% (22%–29%) and 27% (24%–31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95% CI 1.81–19.2) during months 1–3 and 1.77 (0.90–3.50) during months 4–24.
Conclusions
Compared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.
Comparing HIV treatment in Switzerland, where drug selection is individualized, and South Africa, where a programmatic approach is used, Matthias Egger and colleagues find similar virologic outcomes over two years.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since the first reported case in 1981, and more than 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, highly active antiretroviral therapy (HAART)—a combination of several antiretroviral drugs—was developed. Now, in resource-rich countries, clinicians provide individually tailored care for HIV-infected people by prescribing combinations of antiretroviral drugs chosen from more than 20 approved medicines. The approach to treatment of HIV in developed countries typically also includes frequent monitoring of the amount of virus in patients' blood (viral load), viral resistance testing (to see whether any viruses are resistant to specific antiretroviral drugs), and regular CD4 cell counts (an indication of immune-system health). Since the implementation of these interventions, the health and life expectancy of people with HIV has improved dramatically in these countries.
Why Was This Study Done?
The history of HIV care in resource-poor countries has been very different. Initially, these countries could not afford to provide HAART for their populations. In 2003, however, governments, international agencies, and funding bodies began to implement plans to increase HAART coverage in developing countries. By December 2006, more than a quarter of the HIV-infected people in low- and middle-income countries who urgently needed treatment were receiving HAART. However, instead of individualized treatment, HAART programs in developing countries follow a public-health approach developed by the World Health Organization. That is, drug regimens, clinical decision-making, and clinical and laboratory monitoring are all standardized. This public-health approach takes into account the realities of under-resourced health systems, but is it as effective as the individualized approach? The researchers addressed this question by comparing virologic responses (the effect of treatment on the viral load), changes to first-line (initial) therapy, and deaths in patients receiving HAART in South Africa (public-health approach) and in Switzerland (individualized approach).
What Did the Researchers Do and Find?
The researchers analyzed data collected since 2001 from more than 2,000 patients enrolled in HAART programs in two townships (Gugulethu and Khayelitsha) in Cape Town, South Africa, and from more than 1,000 patients enrolled in the Swiss HIV Cohort Study, a nationwide study of HIV-infected people. The patients in South Africa, who had a lower starting CD4 cell count and were more likely to have advanced AIDS than the patients in Switzerland, started their treatment for HIV infection with one of four first-line therapies, and about a quarter changed to a second-line therapy during the study. By contrast, 36 first-line regimens were used in Switzerland and half the patients changed to a different regimen. Despite these differences, the viral load was greatly reduced within a year in virtually all the patients and viral rebound (an increased viral load after a low measurement) developed within 2 years in a quarter of the patients in both countries. However, more patients died in South Africa than in Switzerland, particularly during the first 3 months of therapy.
What Do These Findings Mean?
These findings suggest that the public-health approach to HAART practiced in South Africa is as effective in terms of virologic outcomes as the individualized approach practiced in Switzerland. This is reassuring because it suggests that “antiretroviral anarchy” (the unregulated use of antiretroviral drugs, interruptions in drug supplies, and the lack of treatment monitoring), which is likely to lead to the emergence of viral resistance, is not happening in South Africa as some experts feared it might. Thus, these findings support the continued rollout of the public-health approach to HAART in resource-poor countries. Conversely, they also suggest that a more standardized approach to HAART could be taken in Switzerland (and in other industrialized countries) without compromising its effectiveness. Finally, the higher mortality in South Africa than in Switzerland, which partly reflects the many patients in South Africa in desperate need of HAART and their more advanced disease at the start of therapy, suggests that HIV-infected patients in South Africa and in other resource-limited countries would benefit from earlier initiation of therapy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050148.
The World Health Organization provides information about universal access to HIV treatment (in several languages) and on its recommendations for a public-health approach to antiretroviral therapy for HIV infection
More details on the Swiss HIV Cohort Study and on the studies in Gugulethu and Khayelitsha are available
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including detailed information about antiretroviral therapy and links to treatment guidelines for various countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS around the world and on providing AIDS drug treatment for millions
doi:10.1371/journal.pmed.0050148
PMCID: PMC2443185  PMID: 18613745
8.  Sex-Specific Differences in Hemodialysis Prevalence and Practices and the Male-to-Female Mortality Rate: The Dialysis Outcomes and Practice Patterns Study (DOPPS) 
PLoS Medicine  2014;11(10):e1001750.
In this study, Port and colleagues describe hemodialysis prevalence and patient characteristics by sex, compare men-to-women mortality rate with data from the general population, and evaluate sex interactions with mortality. The results show that women's survival advantage was markedly diminished in hemodialysis patients.
Please see later in the article for the Editors' Summary
Background
A comprehensive analysis of sex-specific differences in the characteristics, treatment, and outcomes of individuals with end-stage renal disease undergoing dialysis might reveal treatment inequalities and targets to improve sex-specific patient care. Here we describe hemodialysis prevalence and patient characteristics by sex, compare the adult male-to-female mortality rate with data from the general population, and evaluate sex interactions with mortality.
Methods and Findings
We assessed the Human Mortality Database and 206,374 patients receiving hemodialysis from 12 countries (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the UK, and the US) participating in the international, prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) between June 1996 and March 2012. Among 35,964 sampled DOPPS patients with full data collection, we studied patient characteristics (descriptively) and mortality (via Cox regression) by sex. In all age groups, more men than women were on hemodialysis (59% versus 41% overall), with large differences observed between countries. The average estimated glomerular filtration rate at hemodialysis initiation was higher in men than women. The male-to-female mortality rate ratio in the general population varied from 1.5 to 2.6 for age groups <75 y, but in hemodialysis patients was close to one. Compared to women, men were younger (mean = 61.9±standard deviation 14.6 versus 63.1±14.5 y), were less frequently obese, were more frequently married and recipients of a kidney transplant, more frequently had coronary artery disease, and were less frequently depressed. Interaction analyses showed that the mortality risk associated with several comorbidities and hemodialysis catheter use was lower for men (hazard ratio [HR] = 1.11) than women (HR = 1.33, interaction p<0.001). This study is limited by its inability to establish causality for the observed sex-specific differences and does not provide information about patients not treated with dialysis or dying prior to a planned start of dialysis.
Conclusions
Women's survival advantage was markedly diminished in hemodialysis patients. The finding that fewer women than men were being treated with dialysis for end-stage renal disease merits detailed further study, as the large discrepancies in sex-specific hemodialysis prevalence by country and age group are likely explained by factors beyond biology. Modifiable variables, such as catheter use, showing significant sex interactions suggest interventional targeting.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Throughout life, the kidneys filter waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. Chronic kidney disease—an increasingly common condition globally—gradually destroys the kidney's filtration units (the nephrons). As the nephrons stop working, the rate at which the blood is filtered (the glomerular filtration rate) decreases, and waste products build up in the blood, eventually leading to life-threatening end-stage kidney (renal) disease. Symptoms of chronic kidney disease, which rarely occur until the disease is advanced, include tiredness, swollen feet and ankles, and frequent urination, particularly at night. Chronic kidney disease cannot be cured, but its progression can be slowed by controlling diabetes and other conditions that contribute to its development. End-stage kidney disease is treated by regular hemodialysis (a process in which blood is cleaned by passing it through a filtration machine) or by kidney transplantation.
Why Was This Study Done?
Like many other long-term conditions, the prevalence (the proportion of the population that has a specific disease) of chronic kidney disease and of end-stage renal disease, and treatment outcomes for these conditions, may differ between men and women. Some of these sex-specific differences may arise because of sex-specific differences in normal biological functions. Other sex-specific differences may be related to sex-specific differences in patient care or in patient awareness of chronic kidney disease. A comprehensive analysis of sex-specific differences among individuals with end-stage renal disease might identify both treatment inequalities and ways to improve sex-specific care. Here, in the Dialysis Outcomes and Practice Patterns Study (DOPPS), the researchers investigate sex-specific differences in the prevalence and practices of hemodialysis and in the characteristics of patients undergoing hemodialysis, and investigate the adult male-to-female mortality (death) rate among patients undergoing hemodialysis. The DOPPS is a prospective cohort study that is investigating the characteristics, treatment, and outcomes of adult patients undergoing hemodialysis in representative facilities in 19 countries (12 countries were available for analysis at the time of the current study).
What Did the Researchers Do and Find?
To investigate sex-specific differences in hemodialysis prevalence, the researchers compared data from the Human Mortality Database, which provides detailed population and mortality data for 37 countries, with data collected by the DOPPS. Forty-one percent of DOPPS patients were women, compared to 52% of the general population in 12 of the DOPPS countries. Next, the researchers used data collected from a randomly selected subgroup of patients to examine sex-specific differences in patient characteristics and mortality. The average estimated glomerular filtration rate at hemodialysis initiation was higher in men than women. Moreover, men were more frequently recipients of a kidney transplant than women. Notably, although in the general population in a given age group women were less likely to die than men, among hemodialysis patients, women were as likely to die as men. Finally, the researchers investigated which patient characteristics were associated with the largest sex-specific differences in mortality risk. The use of a hemodialysis catheter (a tube that is inserted into a patient's vein to transfer their blood into the hemodialysis machine) was associated with a lower mortality risk in men than in women.
What Do These Findings Mean?
These findings show that, among patients treated with hemodialysis for end-stage renal disease, women differ from men in many ways. Although some of these sex-specific differences may be related to biology, others may be related to patient care and to patient awareness of chronic kidney disease. Because this is an observational study, these findings cannot prove that the reported differences in hemodialysis prevalence, treatment, and mortality are actually caused by being a man or a woman. Importantly, however, these findings suggest that hemodialysis may abolish the survival advantage that women have over men in the general population and that fewer women than men are being treated for end-stage-renal disease, even though chronic kidney disease is more common in women than in men. Finally, the finding that the use of hemodialysis catheters for access to veins is associated with a higher mortality risk among women than among men suggests that, where possible, women should be offered a surgical process called arteriovenous fistula placement, which is recommended for access to veins during long-term hemodialysis but which may, in the past, have been underused in women.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001750.
More information about the DOPPS program is available
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease and about hemodialysis, including some personal stories
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease and about hemodialysis (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers, including information and personal stories about hemodialysis
World Kidney Day, a joint initiative between the International Society of Nephrology and the International Federation of Kidney Foundations, aims to raise awareness about kidneys and kidney disease
MedlinePlus has pages about chronic kidney disease and about hemodialysis
doi:10.1371/journal.pmed.1001750
PMCID: PMC4211675  PMID: 25350533
9.  Packaging Health Services When Resources Are Limited: The Example of a Cervical Cancer Screening Visit 
PLoS Medicine  2006;3(11):e434.
Background
Increasing evidence supporting the value of screening women for cervical cancer once in their lifetime, coupled with mounting interest in scaling up successful screening demonstration projects, present challenges to public health decision makers seeking to take full advantage of the single-visit opportunity to provide additional services. We present an analytic framework for packaging multiple interventions during a single point of contact, explicitly taking into account a budget and scarce human resources, constraints acknowledged as significant obstacles for provision of health services in poor countries.
Methods and Findings
We developed a binary integer programming (IP) model capable of identifying an optimal package of health services to be provided during a single visit for a particular target population. Inputs to the IP model are derived using state-transition models, which compute lifetime costs and health benefits associated with each intervention. In a simplified example of a single lifetime cervical cancer screening visit, we identified packages of interventions among six diseases that maximized disability-adjusted life years (DALYs) averted subject to budget and human resource constraints in four resource-poor regions. Data were obtained from regional reports and surveys from the World Health Organization, international databases, the published literature, and expert opinion. With only a budget constraint, interventions for depression and iron deficiency anemia were packaged with cervical cancer screening, while the more costly breast cancer and cardiovascular disease interventions were not. Including personnel constraints resulted in shifting of interventions included in the package, not only across diseases but also between low- and high-intensity intervention options within diseases.
Conclusions
The results of our example suggest several key themes: Packaging other interventions during a one-time visit has the potential to increase health gains; the shortage of personnel represents a real-world constraint that can impact the optimal package of services; and the shortage of different types of personnel may influence the contents of the package of services. Our methods provide a general framework to enhance a decision maker's ability to simultaneously consider costs, benefits, and important nonmonetary constraints. We encourage analysts working on real-world problems to shift from considering costs and benefits of interventions for a single disease to exploring what synergies might be achievable by thinking across disease burdens.
Jane Kim and colleagues analyzed the possible ways that multiple health interventions might be packaged together during a single visit, taking into account scarce financial and human resources.
Editors' Summary
Background.
Public health decision makers in developed and developing countries are exploring the idea of providing packages of health checks at specific times during a person's lifetime to detect and/or prevent life-threatening diseases such as diabetes, heart problems, and some cancers. Bundling together tests for different diseases has advantages for both health-care systems and patients. It can save time and money for both parties and, by associating health checks with life events such as childbirth, it can take advantage of a valuable opportunity to check on the overall health of individuals who may otherwise rarely visit a doctor. But money and other resources (for example, nurses to measure blood pressure) are always limited, even in wealthy countries, so decision makers have to assess the likely costs and benefits of packages of interventions before putting them into action.
Why Was This Study Done?
Recent evidence suggests that women in developing countries would benefit from a once-in-a-lifetime screen for cervical cancer, a leading cause of cancer death for this population. If such a screening strategy for cervical cancer were introduced, it might provide a good opportunity to offer women other health checks, but it is unclear which interventions should be packaged together. In this study, the researchers have developed an analytic framework to identify an optimal package of health services to offer to women attending a clinic for their lifetime cervical cancer screen. Their model takes into account monetary limitations and possible shortages in trained personnel to do the health checks, and balances these constraints against the likely health benefits for the women.
What Did the Researchers Do and Find?
The researchers developed a “mathematical programming” model to identify an optimal package of health services to be provided during a single visit. They then used their model to estimate the average costs and health outcomes per woman of various combinations of health interventions for 35- to 40-year-old women living in four regions of the world with high adult death rates. The researchers chose breast cancer, cardiovascular disease, depression, anemia caused by iron deficiency, and sexually transmitted diseases as health conditions to be checked in addition to cervical cancer during the single visit. They considered two ways—one cheap in terms of money and people; the other more expensive but often more effective—of checking for or dealing with each potential health problem. When they set a realistic budgetary constraint (based on the annual health budget of the poorest countries and a single health check per woman in the two decades following her reproductive years), the optimal health package generated by the model for all four regions included cervical cancer screening done by testing for human papillomavirus (an effective but complex test), treatment for depression, and screening or treatment for anemia. When a 50% shortage in general (for example, nurses) and specialized (for example, doctors) personnel time was also included, the health benefits of the package were maximized by using a simpler test for cervical cancer and by treating anemia but not depression; this freed up resources in some regions to screen for breast cancer or cardiovascular disease.
What Do These Findings Mean?
The model described by the researchers provides a way to explore the potential advantages of delivering a package of health interventions to individuals in a single visit. Like all mathematical models, its conclusions rely heavily on the data used in its construction. Indeed, the researchers stress that, because they did not have full data on the effectiveness of each intervention and made many other assumptions, their results on their own cannot be used to make policy decisions. Nevertheless, their results clearly show that the packaging of multiple health services during a single visit has great potential to maximize health gains, provided the right interventions are chosen. Most importantly, their analysis shows that in the real world the shortage of personnel, which has been ignored in previous analyses even though it is a major problem in many developing countries, will affect which health conditions and specific interventions should be bundled together to provide the greatest impact on public health.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030434.g001.
The World Health Organization has information on choosing cost-effective health interventions and on human resources for health
The American Cancer Society offers patient information on cervical cancer
The Alliance for Cervical Cancer Prevention includes information about cervical cancer prevention programs in developing countries
doi:10.1371/journal.pmed.0030434
PMCID: PMC1635742  PMID: 17105337
10.  A new donor system for the patients with thalassemia: “Blood mother and blood father” 
Background:
Donor recruitment programs differ in countries depending on local conditions and causes. Regularly voluntary blood donation rate should be 5% of the population but it is extremely low in Turkey. In 1998, “Thalassemia flowers don’t fade” campaigning was started to get regular voluntary blood for patients with thalassemia. We would like to present results of our campaigning.
Materials and Methods:
The Thalassemia center was established in Antalya on the 1st June 1994 by Ministry of Health, Turkey, because the incidence of thalassemia is very high in the Antalya region. A total of 388 patients with thalassemia were followed up regularly in the center. The annually blood requirement was approximately 5000 units per year. In 1998, a new program of blood donation for patients with thalassemia called “BLOOD MOTHER and BLOOD FATHER” was started with the support of Governor of Antalya and health management system in Antalya.
Results:
Between year 1998 and 2006, a total 3000 voluntary blood donors between age 18 and 65 years, of which 2160 males (72%) and 840 were females (28%), had participated in this program.
Conclusion:
“Blood Mother and Blood Father” campaign was successful donor recruitment program for thalassemic care. After 2006, this program is now adopted and run by Turkish Red Crescent and Thalassemia Federation of Turkey for all thalassemics in Turkey.
doi:10.4103/0973-6247.67036
PMCID: PMC2937286  PMID: 20859510
Donors; thalassemia
11.  Impact of Antiretroviral Therapy on Incidence of Pregnancy among HIV-Infected Women in Sub-Saharan Africa: A Cohort Study 
PLoS Medicine  2010;7(2):e1000229.
A multicountry cohort study in sub-Saharan Africa by Landon Myer and colleagues reveals higher pregnancy rates in HIV-infected women on antiretroviral therapy (ART).
Background
With the rapid expansion of antiretroviral therapy (ART) services in sub-Saharan Africa there is growing recognition of the importance of fertility and childbearing among HIV-infected women. However there are few data on whether ART initiation influences pregnancy rates.
Methods and Findings
We analyzed data from the Mother-to-Child Transmission-Plus (MTCT-Plus) Initiative, a multicountry HIV care and treatment program for women, children, and families. From 11 programs in seven African countries, women were enrolled into care regardless of HIV disease stage and followed at regular intervals; ART was initiated according to national guidelines on the basis of immunological and/or clinical criteria. Standardized forms were used to collect sociodemographic and clinical data, including incident pregnancies. Overall 589 incident pregnancies were observed among the 4,531 women included in this analysis (pregnancy incidence, 7.8/100 person-years [PY]). The rate of new pregnancies was significantly higher among women receiving ART (9.0/100 PY) compared to women not on ART (6.5/100 PY) (adjusted hazard ratio, 1.74; 95% confidence interval, 1.19–2.54). Other factors independently associated with increased risk of incident pregnancy included younger age, lower educational attainment, being married or cohabiting, having a male partner enrolled into the program, failure to use nonbarrier contraception, and higher CD4 cell counts.
Conclusions
ART use is associated with significantly higher pregnancy rates among HIV-infected women in sub-Saharan Africa. While the possible behavioral or biomedical mechanisms that may underlie this association require further investigation, these data highlight the importance of pregnancy planning and management as a critical but neglected component of HIV care and treatment services.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Human immunodeficiency virus (HIV) causes Acquired Immunodeficiency Syndrome (AIDS), which is a major global cause of disease and death. More than 33 million people around the world are infected with HIV, with nearly 5,500 dying daily from HIV and AIDS-related complications. HIV/AIDS is especially problematic in sub-Saharan Africa, where it is the leading cause of death. There is no cure for HIV/AIDS, but medicines known as “antiretroviral therapy” (ART) can prolong life and reduce complications in patients infected with HIV. 97% of patients with HIV/AIDS live in low- and middle-income countries. According to the World Health Organization, nearly 10 million of these patients need ART. As patients' access to treatment is often hindered by the high cost and low availability of ART, global health efforts have focused on promoting ART use in resource-limited nations. Such efforts also increase awareness of how HIV is spread (contact with blood or semen, in sexual intercourse, sharing needles, or from mother to child during childbirth). ART reduces, but does not remove, the chance of a mother's passing HIV to her child during birth.
Why Was This Study Done?
By the end of 2007, 3 million HIV-infected patients in poor countries were receiving ART. Many of those treated with ART are young women of child-bearing age. Childbirth is an important means of spreading HIV in sub-Saharan Africa, where 60% of all HIV patients are women. This study questions whether the improved health and life expectancy that results from treatment with ART affects pregnancy rates of HIV-infected patients. The study explores this question in seven African countries, by examining the rates of pregnancy in HIV-infected women before and after they started ART.
What Did the Researchers Do and Find?
The authors looked at the records of 4,531 HIV-infected women enrolled in the Mother-to-Child-Transmission-Plus (MTCT-Plus) Initiative in seven African countries. MTCT -Plus, begun in 2002, is a family-centered treatment program that offers regular checkups, blood tests, counseling, and ART treatment (if appropriate) to women and their families. At each checkup, women's CD4+ cell counts and World Health Organization guidelines were used to determine their eligibility for starting ART. Over a 4-year period, nearly a third of the women starting ART experienced a pregnancy: 244 pregnancies occurred in the “pre-ART” group (women not receiving ART) compared to 345 pregnancies in the “on-ART” group (women receiving ART). The chance of pregnancy increased over time in the on-ART group to almost 80% greater than the pre-ART group, while remaining relatively low and constant in the pre-ART group. The authors noted that, as expected, other factors also increased the chances of pregnancy, including younger age, lower educational status, and use of nonbarrier contraception such as injectable hormones.
What Do These Findings Mean?
This study suggests that starting ART is associated with higher pregnancy rates in sub-Saharan Africa, nearly doubling the chances of a woman becoming pregnant. The reasons for this link are unclear. One possible explanation is behavioral: women receiving ART may feel more motivated to have children as their health and quality of life improve. However, the study did not examine how pregnancy desires and sexual activity of women changed while on ART, and cannot discern why ART is linked to increased pregnancy. By using pregnancy data gathered from patient questionnaires rather than laboratory tests, the study is limited by the possibility of inaccurate patient reporting. Understanding how pregnancy rates vary in HIV-infected women receiving ART helps support the formation of responsive, effective HIV programs. Female HIV patients of child-bearing age, who form the majority of patients receiving ART in sub-Saharan Africa, would benefit from programs that combine starting HIV treatment with ART with education and contraception counseling and pregnancy-related care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000229.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of articles and other sources of information about the primary care of adolescents with HIV
A UNAIDS 2008 report is available on the global AIDS epidemic
The International Planned Parenthood Foundation provides information on sexual and reproductive health and HIV
The International Center for AIDS Care and Treatment Programs at the Columbia University Mailman School of Public health provides information to assist HIV care and treatment programs in resource-limited settings
doi:10.1371/journal.pmed.1000229
PMCID: PMC2817715  PMID: 20161723
12.  Mini-Incision Living Donors Nephrectomy Using Anterior Muscle-Splitting Approach with Hybrid Technique 
Background: Significant morbidity is associated with standard open flank living donor nephrectomy. Laparoscopic donor nephrectomy is criticized for a steep learning curve and a tendency to avoid the right kidney. The anterior muscle-splitting technique uses principles or advantages of an open extraperitoneal approach with minimal morbidity and the advantageous muscle-splitting (instead of cutting) procedure.
Objective: To compare mini-incision laparoscopic instrument-assisted (MILIA) live donor nephrectomy using a muscle-splitting technique to the standard open-flank donor nephrectomy (ODN) approach for efficacy and safety.
Methods: MILIA living donor nephrectomies were performed in 119 donors and compared to a cohort of open-flank nephrectomy donors (n=38) from the same center. Both donor groups were matched for body mass index as well as other personal characteristics.
Results: The mean donor age was 35 (range: 18–60) years. The right kidney was procured in 28% of cases. The majority of donors were female (58%) and Caucasian (60%). No differences were observed between MILIA and ODN donors for the age, gender and ethnicity. However, MILIA donors experienced a longer mean±SD operative time (234±47 vs. 197±33 min, p<0.0001) but a shorter hospital stay (4±1 vs. 6±3 days for the ODN group, p<0.0001) and less intraoperative blood loss (215±180 vs. 331±397 mL, p<0.02). No difference was found in the number of units of blood transfused (0.13±0.6 vs. 0.34±1.0 units, p=0.13). Right-sided kidneys were almost equally harvested in both groups (29% of MILIA donors vs. 26% of ODN donors). Post-operatively, MILIA donors had a significantly lower mean pain scores at one week and one month after surgery (p<0.001). They showed significant better post-operative recovery—earlier stopping of pain medications and restoration of other preoperative activities. Moreover, they were better satisfied with their scar appearance. Scores on the short form-36 quality of life questionnaire were comparable for both groups.
Conclusion: MILIA is a viable option as an alternative for pure laparoscopic donor nephrectomy. MILIA appears to be as safe as open donor nephrectomy and may provide advantages over ODN, such as smaller incision, shorter hospital stay, and less incisional pain. Patient recovery and satisfaction after MILIA are excellent. This technique avoids the possibility of adhesive intestinal obstruction and also improves handling of major complications (e.g., bleeding) of laparoscopic donor nephrectomy. Utilization of this hybrid technique is particularly feasible on smaller (BMI<24 kg/m2) and medium-sized (BMI<28 kg/m2) donors. We believe that this technique should be adopted by centers that have limited advanced laparoscopic surgical experience and also it could be used selectively for the right donor nephrectomies, even in centers performing hand assisted donor nephrectomies by including a small patch of inferior vena cava for a better quality of right donor kidney during transplantation.
PMCID: PMC4089213  PMID: 25013560
Transplant; kidney; laparotomy; laparoscopy; nephrectomy
13.  Electrocardiographic Abnormalities in Trypanosoma cruzi Seropositive and Seronegative Former Blood Donors 
Background
Blood donor screening leads to large numbers of new diagnoses of Trypanosoma cruzi infection, with most donors in the asymptomatic chronic indeterminate form. Information on electrocardiogram (ECG) findings in infected blood donors is lacking and may help in counseling and recognizing those with more severe disease.
Objectives
To assess the frequency of ECG abnormalities in T.cruzi seropositive relative to seronegative blood donors, and to recognize ECG abnormalities associated with left ventricular dysfunction.
Methods
The study retrospectively enrolled 499 seropositive blood donors in São Paulo and Montes Claros, Brazil, and 483 seronegative control donors matched by site, gender, age, and year of blood donation. All subjects underwent a health clinical evaluation, ECG, and echocardiogram (Echo). ECG and Echo were reviewed blindly by centralized reading centers. Left ventricular (LV) dysfunction was defined as LV ejection fraction (EF)<0.50%.
Results
Right bundle branch block and left anterior fascicular block, isolated or in association, were more frequently found in seropositive cases (p<0.0001). Both QRS and QTc duration were associated with LVEF values (correlation coefficients −0.159,p<0.0003, and −0.142,p = 0.002) and showed a moderate accuracy in the detection of reduced LVEF (area under the ROC curve: 0.778 and 0.790, both p<0.0001). Several ECG abnormalities were more commonly found in seropositive donors with depressed LVEF, including rhythm disorders (frequent supraventricular ectopic beats, atrial fibrillation or flutter and pacemaker), intraventricular blocks (right bundle branch block and left anterior fascicular block) and ischemic abnormalities (possible old myocardial infarction and major and minor ST abnormalities). ECG was sensitive (92%) for recognition of seropositive donors with depressed LVEF and had a high negative predictive value (99%) for ruling out LV dysfunction.
Conclusions
ECG abnormalities are more frequent in seropositive than in seronegative blood donors. Several ECG abnormalities may help the recognition of seropositive cases with reduced LVEF who warrant careful follow-up and treatment.
Author Summary
Chagas disease (ChD), caused by the protozoa Trypanosoma cruzi, is endemic in most Latin America countries and may be transmitted via blood transfusions. Cardiac disease is a major feature of chronically infected patients and may be lethal. Universal blood bank screening for ChD has been established in most Latin American countries, as well as in non-endemic countries with large immigrant populations, including the United States, Canada, Spain and Portugal. Blood donor screening leads to large numbers of new diagnoses of chronic T. cruzi infection. Counseling these individuals should address the recognition of those with more severe disease that deserve to be rigorously evaluated by experienced cardiologists and treated more promptly. The electrocardiogram is an important exam that can help in the recognition of cardiac disease and the evaluation of prognosis in ChD patients, but its role in blood donors has not been studied. The authors describe some electrocardiographic abnormalities that are typical of the infected blood donors, as well ECG abnormalities that help in the identification of those with severe cardiac involvement. These results may guide the evaluations of patients with incidentally detected T. cruzi infection from blood bank testing or public health screening.
doi:10.1371/journal.pntd.0002078
PMCID: PMC3585012  PMID: 23469305
14.  Left Ventricular Assist Devices 
Executive Summary
Objective
The objective of this health technology policy assessment was to determine the effectiveness and cost-effectiveness of using implantable ventricular assist devices in the treatment of end-stage heart failure.
Heart Failure
Heart failure is a complex syndrome that impairs the ability of the heart to maintain adequate blood circulation, resulting in multiorgan abnormalities and, eventually, death. In the period of 1994 to 1997, 38,702 individuals in Ontario had a first hospital admission for heart failure. Despite reported improvement in survival, the five-year mortality rate for heart failure is about 50%.
For patients with end-stage heart failure that does not respond to medical therapy, surgical treatment or traditional circulatory assist devices, heart transplantation (in appropriate patients) is the only treatment that provides significant patient benefit.
Heart Transplant in Ontario
With a shortage in the supply of donor hearts, patients are waiting longer for a heart transplant and may die before a donor heart is available. From 1999 to 2003, 55 to 74 people received a heart transplant in Ontario each year. Another 12 to 21 people died while waiting for a suitable donor heart. Of these, 1 to 5 deaths occurred in people under 18 years old. The rate-limiting factor in heart transplant is the supply of donor hearts. Without an increase in available donor hearts, attempts at prolonging the life of some patients on the transplant wait list could have a harmful effect on other patients that are being pushed down the waiting list (knock on effect).
LVAD Technology
Ventricular assist devices [VADs] have been developed to provide circulatory assistance to patients with end-stage heart failure. These are small pumps that usually assist the damaged left ventricle [LVADs] and may be situated within the body (intracorporeal] or outside the body [extracorporeal). Some of these devices were designed for use in the right ventricle [RVAD] or both ventricles (bi-ventricular).
LVADs have been mainly used as a “bridge-to-transplant” for patients on a transplant waiting list. As well, they have been used as a “bridge-to-recovery” in acute heart failure, but this experience is limited. There has been an increasing interest in using LVAD as a permanent (destination) therapy.
Review of LVAD by the Medical Advisory Secretariat
The Medical Advisory Secretariat’s review included a descriptive synthesis of findings from five systematic reviews and 60 reports published between January 2000 and December 2003. Additional information was obtained through consultation and by searching the websites of Health Canada, the United Network of Organ Sharing, Organ Donation Ontario, and LVAD manufacturers.
Summary of Findings
Safety and Effectiveness
Previous HTAs and current Level 3 evidence from prospective non-randomized controlled studies showed that when compared to optimal medical therapy, LVAD support significantly improved the pre-transplant survival rates of heart transplant candidates waiting for a suitable donor heart (71% for LVAD and 36% for medical therapy). Pre-transplant survival rates reported ranged from 58% to 90% (median 74%). Improved transplant rates were also reported for people who received pre-transplant LVAD support (e.g. 67% for LVAD vs 33% for medical therapy). Reported transplant rates for LVAD patients ranged from 39% to 90% (median 71%).
Patient’s age greater than 60 years and pre-existing conditions of respiratory failure associated with septicemia, ventilation, and right heart failure were independent risk factors for mortality after the LVAD implantation.
LVAD support was shown to improve the New York Heart Association [NYHA)] functional classification and quality of life of patients waiting for heart transplant. LVAD also enabled approximately 41% - 49% of patients to be discharged from hospitals and wait for a heart transplant at home. However, over 50% of the discharged patients required re-hospitalization due to adverse events.
Post-transplant survival rates for LVAD-bridged patients were similar to or better than the survival rates of patients bridged by medical therapy.
LVAD support has been associated with serious adverse events, including infection (median 53%, range 6%–72%), bleeding (8.6%–48%, median 35%), thromboembolism (5%–37%), neurologic disorders (7%–28%), right ventricular failure (11%–26%), organ dysfunction (5%–50%) and hemolysis (6%–20%). Bleeding tends to occur in the first few post-implant days and is rare thereafter. It is fatal in 2%–7% of patients. Infection and thromboembolism occurred throughout the duration of the implant, though their frequency tended to diminish with time. Device malfunction has been identified as one of the major complications. Fatalities directly attributable to the devices were about 1% in short-term LVAD use. However, mechanical failure was the second most frequent cause of death in patients on prolonged LVAD support. Malfunctions were mainly associated with the external components, and often could be replaced by backed up components.
LVAD has been used as a bridge-to-recovery in patients suffering from acute cardiogenic shock due to cardiomyopathy, myocarditis or cardiotomy. The survival rates were reported to be lower than in bridge-to-transplant (median 26%). Some of the bridge-to-recovery patients (14%–75%) required a heart transplant or remained on prolonged LVAD support. According to an expert in the field, experience with LVAD as a bridge-to-recovery technology has been more favourable in Germany than in North America, where it is not regarded as a major indication since evidence for its effectiveness in this setting is limited.
LVAD has also been explored as a destination therapy. A small, randomized, controlled trial (level 2 evidence) showed that LVAD significantly increased the 1-year survival rate of patients with end-stage heart failure but were not eligible for a heart transplant (51% LVAD vs 25% for medical therapy). However, improved survival was associated with adverse events 2.35 times higher than medically treated patients and a higher hospital re-admission rate. The 2-year survival rate on LVAD decreased to 23%, although it was still significantly better compared to patients on medical therapy (8%). The leading causes of deaths were sepsis (41%) and device failure (17%).
The FDA has given conditional approval for the permanent use of HeartMate SNAP VE LVAS in patients with end-stage heart failure who are not eligible for heart transplantation, although the long-term effect of this application is not known.
In Canada, four LVAD systems have been licensed for bridge-to-transplant only. The use of LVAD support raises ethical issues because of the implications of potential explantation that could be perceived as a withdrawal of life support.
Potential Impact on the Transplant Waiting List
With the shortage of donor hearts for adults, LVAD support probably would not increase the number of patients who receive a heart transplant. If LVAD supported candidates are prioritized for urgent heart transplant, there will be a knock on effect as other transplant candidates without LVAD support would be pushed down, resulting in longer wait, deterioration in health status and die before a suitable donor heart becomes available.
Under the current policy for allocating donor hearts in Ontario, patients on LVAD support would be downgraded to Status 3 with a lower priority to receive a transplant. This would likely result in an expansion of the transplant waiting list with an increasing number of patients on prolonged LVAD support, which is not consistent with the indication of LVAD use approved by Health Canada.
There is indication in the United Kingdom that LVAD support in conjunction with an urgent transplant listing in the pediatric population may decrease the number of deaths on the waiting list without a harmful knock-on effect on other transplant candidates.
Conclusion
LVAD support as a bridge-to-transplant has been shown to improve the survival rate, functional status and quality of life of patients on the heart transplant waiting list. However, due to the shortage of donor hearts and the current heart transplant algorithm, LVAD support for transplant candidates of all age groups would likely result in an expansion of the waiting list and prolonged use of LVAD with significant budget implications but without increasing the number of heart transplants. Limited level 4 evidence showed that LVAD support in children yielded survival rates comparable to those in the adult population. The introduction of LVAD in the pediatric population would be more cost-effective and might not have a negative effect on the transplant waiting list.
PMCID: PMC3387736  PMID: 23074453
15.  Correcting Mortality for Loss to Follow-Up: A Nomogram Applied to Antiretroviral Treatment Programmes in Sub-Saharan Africa 
PLoS Medicine  2011;8(1):e1000390.
Matthias Egger and colleagues present a nomogram and a web-based calculator to correct estimates of program-level mortality for loss to follow-up, for use in antiretroviral treatment programs.
Background
The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART.
Methods and Findings
We developed a nomogram to correct mortality estimates for loss to follow-up, based on the fact that mortality of all patients starting ART in a treatment programme is a weighted average of mortality among patients lost to follow-up and patients remaining in care. The nomogram gives a correction factor based on the percentage of patients lost to follow-up at a given point in time, and the estimated ratio of mortality between patients lost and not lost to follow-up. The mortality observed among patients retained in care is then multiplied by the correction factor to obtain an estimate of programme-level mortality that takes all deaths into account. A web calculator directly calculates the corrected, programme-level mortality with 95% confidence intervals (CIs). We applied the method to 11 ART programmes in sub-Saharan Africa. Patients retained in care had a mortality at 1 year of 1.4% to 12.0%; loss to follow-up ranged from 2.8% to 28.7%; and the correction factor from 1.2 to 8.0. The absolute difference between uncorrected and corrected mortality at 1 year ranged from 1.6% to 9.8%, and was above 5% in four programmes. The largest difference in mortality was in a programme with 28.7% of patients lost to follow-up at 1 year.
Conclusions
The amount of bias in mortality estimates can be large in ART programmes with substantial loss to follow-up. Programmes should routinely report mortality among patients retained in care and the proportion of patients lost. A simple nomogram can then be used to estimate mortality among all patients who started ART, for a range of plausible mortality rates among patients lost to follow-up.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed more than 25 million people since 1981 and about 33 million people (30 million of them in low- and middle-income countries) are now infected with HIV, which causes AIDS. HIV destroys immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART) became available. For people living in affluent, developed countries, HIV/AIDS became a chronic condition, but for people living in low- and middle-income countries, ART was prohibitively expensive and HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global health emergency and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2009, 5.25 million of the 14.6 million people in low- and middle-income countries who needed ART (36%) were receiving it.
Why Was This Study Done?
ART program managers in developing countries need to monitor the effectiveness of their programs to ensure that their limited resources are used wisely. In particular, they need accurate records of the death (mortality) rates in their programs. However, in resource-limited countries, many patients drop out of ART programs. In sub-Saharan Africa, for example, only about 60% of patients are retained in ART programs 2 years after starting therapy. In many programs, it is not known how many of the patients lost to follow-up subsequently die, but it is known that mortality is higher among these patients than among those who remain in care. Thus, in programs with high dropout rates and poor ascertainment of death in patients lost to follow-up, estimates of the mortality of all patients starting ART are underestimates. In this study, the researchers develop a simple nomogram (a graphical method for finding the value of a third variable from the values of two other variables) to correct estimates of program-level mortality for loss to follow-up.
What Did the Researchers Do and Find?
The researchers' nomogram uses the percentage of patients lost to follow and the estimated ratio of mortality between patients lost and not lost to follow-up to provide a correction factor that converts mortality among patients remaining in care to mortality among all the patients in a program. The researchers first applied their nomogram to the Academic Model Providing Access to Healthcare (AMPATH), a large ART program in Kenya. They used data collected by outreach teams to estimate mortality among the 40.5% of patients lost to follow-up at two AMPATH sites between 1 January 2005 and 31 January 2007. The uncorrected estimate of mortality over this period was 2.8%, whereas the corrected estimate obtained using the nomogram was 9.4%. The researchers then applied their nomogram to 11 other African ART programs. This time, the researchers used a statistical model to provide estimates of mortality among patients lost to follow-up. Mortality among patients retained in care was 1.4% to 12.0% at 1 year; loss to follow-up ranged from 2.8% to 28.7%. The nomogram provided a correction value for mortality among all patients in the ART program of 1.2 to 8.0, which resulted in absolute differences between uncorrected and corrected mortality of 1.6% to 9.8%. The largest absolute difference was in the program with the largest percentage of patients lost to follow-up.
What Do These Findings Mean?
These findings indicate that, in ART programs where a large percentage of patients are lost to follow-up, program-level mortality estimates based on the mortality among patients retained in the program can be substantial underestimates. This bias needs to be taken into account when comparing the effectiveness of different programs, so the researchers recommend that all programs routinely report mortality among patients retained in care and the proportion of patients lost to follow-up. The nomogram developed by the researchers can then be used to estimate mortality among all patients who started ART using a range of plausible mortality rates among patients lost to follow-up. To help program managers make use of the nomogram, the researchers provide a user-friendly web calculator based on the nomogram on the International epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa website.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000390.
This study is further discussed in a PLoS Medicine Perspective by Gregory Bisson
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Africa, and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including the 2010 progress report (in English, French and Spanish)
The International epidemiologic Databases to Evaluate Aids (IeDEA) Southern Africa website provides access to a calculator for correcting overall program-specific mortality for loss to follow-up
doi:10.1371/journal.pmed.1000390
PMCID: PMC3022522  PMID: 21267057
16.  Description of 3,180 Courses of Chelation with Dimercaptosuccinic Acid in Children ≤5 y with Severe Lead Poisoning in Zamfara, Northern Nigeria: A Retrospective Analysis of Programme Data 
PLoS Medicine  2014;11(10):e1001739.
Jane Greig and colleagues from the medical humanitarian organization Médecins Sans Frontières describe the use of the oral chelating agent dimercaptosuccinic acid (DMSA) in several thousand young children with severe lead poisoning as a result of an environmental disaster in Zamfara, northern Nigeria.
Please see later in the article for the Editors' Summary
Background
In 2010, Médecins Sans Frontières (MSF) discovered extensive lead poisoning impacting several thousand children in rural northern Nigeria. An estimated 400 fatalities had occurred over 3 mo. The US Centers for Disease Control and Prevention (CDC) confirmed widespread contamination from lead-rich ore being processed for gold, and environmental management was begun. MSF commenced a medical management programme that included treatment with the oral chelating agent 2,3-dimercaptosuccinic acid (DMSA, succimer). Here we describe and evaluate the changes in venous blood lead level (VBLL) associated with DMSA treatment in the largest cohort of children ≤5 y of age with severe paediatric lead intoxication reported to date to our knowledge.
Methods and Findings
In a retrospective analysis of programme data, we describe change in VBLL after DMSA treatment courses in a cohort of 1,156 children ≤5 y of age who underwent between one and 15 courses of chelation treatment. Courses of DMSA of 19 or 28 d duration administered to children with VBLL ≥ 45 µg/dl were included. Impact of DMSA was calculated as end-course VBLL as a percentage of pre-course VBLL (ECP). Mixed model regression with nested random effects was used to evaluate the relative associations of covariates with ECP. Of 3,180 treatment courses administered, 36% and 6% of courses commenced with VBLL ≥ 80 µg/dl and ≥ 120 µg/dl, respectively. Overall mean ECP was 74.5% (95% CI 69.7%–79.7%); among 159 inpatient courses, ECP was 47.7% (95% CI 39.7%–57.3%). ECP after 19-d courses (n = 2,262) was lower in older children, first-ever courses, courses with a longer interval since a previous course, courses with more directly observed doses, and courses with higher pre-course VBLLs. Low haemoglobin was associated with higher ECP. Twenty children aged ≤5 y who commenced chelation died during the period studied, with lead poisoning a primary factor in six deaths. Monitoring of alanine transaminase (ALT), creatinine, and full blood count revealed moderate ALT elevation in <2.5% of courses. No clinically severe adverse drug effects were observed, and no laboratory findings required discontinuation of treatment. Limitations include that this was a retrospective analysis of clinical data, and unmeasured variables related to environmental exposures could not be accounted for.
Conclusions
Oral DMSA was a pharmacodynamically effective chelating agent for the treatment of severe childhood lead poisoning in a resource-limited setting. Re-exposure to lead, despite efforts to remediate the environment, and non-adherence may have influenced the impact of outpatient treatment.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lead, a toxic metal that occurs naturally in the earth's crust, is now present throughout the environment because of human activities. For many years, lead was added to paint and gasoline and used in solder for water pipes. In addition, the mining, smelting, and refining of some metallic ores releases lead into the environment. Inhalation of contaminated air, consumption of contaminated food and water, and contact with dust that contains lead raises venous blood lead levels (VBLLs) and causes many health problems, particularly in children. Children who ingest large amounts of lead can develop anemia, muscle weakness, kidney damage, and life-threatening encephalopathy (brain swelling). Although fatal lead poisoning is now rare in resource-rich countries, it nevertheless remains a major global health problem. Over a three-month period in early 2010, for example, about 400 young children died in Zamfara State, Nigeria, from unexplained, intractable fits. By May 2010, it was clear that recently expanded gold mining had caused widespread environmental lead contamination in the region, and an environmental management program was begun to reduce lead levels in the surface soils.
Why Was This Study Done?
In response to the lead poisoning outbreak, the not-for-profit organization Médecins Sans Frontières (MSF) began a medical management program to reduce VBLLs that included treatment with the oral chelation agent dimercaptosuccinic acid (DMSA). Chelation agents bind metal ions and facilitate their removal from the body, thereby reducing the likelihood of lead moving from the blood to the brain. Lead encephalopathy has been commonly treated by injecting another chelator called CaNa2EDTA, but the discovery of more than 1,000 cases of childhood lead poisoning in rural villages in Nigeria meant that MSF needed a chelation approach that could be applied rapidly in a remote resource-limited setting. Additionally, although CaNa2EDTA has been in common use for severe lead poisoning for longer than DMSA, and is commonly recommended in guidelines, the evidence base does not support one treatment as superior. Here, in a retrospective analysis of MSF program data, the researchers evaluate the changes in VBLLs before and after courses of oral DMSA treatment in children aged five years and below living in Zamfara to gain new insights into this understudied treatment for severe childhood lead poisoning.
What Did the Researchers Do and Find?
The researchers measured VBLLs before and after treatment with DMSA in 1,156 children (inpatient and outpatient) with high amounts of lead in their blood who underwent one or more courses of chelation treatment lasting 19 or 28 days by calculating each child's end-course VBLL as a percentage of the child's pre-course VBLL (ECP). Considering all the treatment courses given between June 2010 and June 2011, the mean (average) ECP was 74.5%. That is, on average, VBLLs measured at the end of treatment courses were reduced by a quarter compared to VBLLs at the start of treatment courses. Among 159 inpatient courses of DMSA, the ECP was 47.7% (a halving of pre-course VBLLs). The ECP after 19-day courses was lower in older children, after first-ever courses, after courses with a longer interval since a previous course, after courses that included more directly observed doses (DMSA given in the presence of a health-care worker), and in children with higher pre-course VBLLs. Nine of the children included in this analysis died during the study period; lead poisoning was probably involved in three of these deaths. Importantly, no clinically severe adverse effects related to DMSA were seen during the study period, and no laboratory findings were recorded that required treatment discontinuation.
What Do These Findings Mean?
Because many changes were made to the treatment given to the affected children in Zamfara during the study period and because no information is presented here on clinical outcomes, these findings cannot be used to reach any definitive conclusions about the effectiveness or safety of oral DMSA as a treatment for lead poisoning in young children. However, these findings show that chelation was associated with a large reduction in the death rate among probable or suspected cases of childhood lead poisoning in Zamfara and provide new information about oral chelation that may help agencies such as MSF provide urgent treatment for lead poisoning in resource-limited settings where intravenous chelation is not feasible. Moreover, the finding of a lower ECP after inpatient treatment courses compared to after outpatient courses suggests that re-exposure to lead and non-adherence to treatment may have influenced the impact of outpatient treatments. Thus, it is essential that medical management of lead poisoning in resource-limited settings be accompanied by environmental remediation and that efforts are made to support adherence to treatment in the community by implementing directly observed treatment wherever possible.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001739.
A related PLOS ONE Research Article by Greig et al. provides information about the association between VBLLs and neurological features in children affected by the acute lead poisoning outbreak in Zamfara
MSF provides information about the lead poisoning crisis in Zamfara State
Human Rights Watch, an international organization that works to uphold human dignity and advance the cause of human rights for all, also provides information about lead poisoning in Zamfara State, including photographs and a video
Tox Town, an interactive site about environmental health concerns from the US National Library of Medicine, provides information on exposure to lead (in English and Spanish)
The US Environmental Protection Agency provides information on lead and lead poisoning (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about lead in the environment and about its lead poisoning prevention program
MedlinePlus provides a list of links to further information about lead poisoning (in English and Spanish)
doi:10.1371/journal.pmed.1001739
PMCID: PMC4188566  PMID: 25291378
17.  The ethical approach to AIDS: a bibliographical review. 
Journal of Medical Ethics  1990;16(1):14-27.
This bibliographical study involved first the exploitation of four data-banks: Medline, CNRS, Bioethics and AIDS, with the following key words (in conjunction with AIDS): ethics, human rights, confidentiality, legislation, jurisprudence. A total of 412 references were listed between 1983 and the end of 1987. Examination of the quantitative increase of articles over these years shows that, while references to AIDS and/or HIV infection--referred to as 'AIDS' for brevity--increased by about one third per year, the number of papers treating ethical problems linked to AIDS doubled each year. This increase makes it clear that these problems are important and pressing, that they are evolving rapidly and can be given no easy solution. After reading and analysis of accessible articles in readily comprehensible languages, the different themes can be classified in two categories: 1: Measures intended to protect society (starting with the most coercive); quarantine and isolation; discriminatory measures concerning specific groups; non-respect of the confidential nature of medical information; application of the penal code; screening; obligatory declaration and registration; testing of blood given by donors; vaccination and medical innovations, therapeutic assays; information, education. 2. Measures intended to protect the individual: fundamental rights of the patient: his/her right to confidentiality, to information and to treatment; civil rights: civil liberty, right to education, right to work, etc...; rights of the healthy individual: right of those in contact with the patients, safety of hospital staff, of those receiving blood-transfusions, etc... The legislation adopted in the various countries and the main opinions to be found in these articles are listed and analysed, and for each particular theme it is possible to refer to a list of the 232 most important articles. While the debate seems to concentrate on the conflict between the right of society to protect itself against the spread of infection and the 'civil' rights of the infected minorities, our conclusion tends to reduce this antagonism, showing that, particularly as far as the confidential nature of medical information is concerned, measures intended to protect the individual also protect society.
PMCID: PMC1375860  PMID: 2181139
18.  Temporal trends in hepatitis B and C infection in family blood donors from interior Sindh, Pakistan 
Background
Hepatitis B (HBV) and C (HCV) infections are a serious global and national public health problem. Earlier studies have reported increasing rates of hepatitis infection in Pakistan, particularly in rural areas. Pakistan has no active surveillance program to monitor trends of these infections. The objective of this study was to verify this trend in blood donors from the rural Sindh area of the country.
Methods
The study analysed the data of blood donors of interior Sindh who donated blood at JPMC blood bank from January 1, 2004 to September 15, 2007. HBsAg status was determined by using HBsAg Serodia kit and antibodies to HCV using the Detect HCV ™ V.3 Kit. Samples repeatedly reactive for HBsAg or anti-HCV were considered positive for HBV or HCV infection respectively.
Results
The overall seroprevalence of HBV infection among donors was 6.2 % (95% CI 5.5%–6.9%) and did not change significantly over the study period. Overall seroprevalence of HBV infection in literate blood donors was 5.7 %(95% CI 4.7%–6.8%). Prevalence decreased significantly in this group over the study period (p = 0.05). No other significant trends in seroprevalence of HBV infection were seen in the stratified analyses.
The overall seroprevalence of HCV among donors was 7.5% (95% CI 6.8%–8.3%) and increased significantly over the study period from 7.2% (95% CI 5.8%–8.7%) in 2004 to 8.9% (95% CI 7.4%–10.6%) in 2007 (p = 0.02). Significant increase in seroprevalence was particularly seen in literate (p = 0.03), non–first time (p = 0.01) and Sindhi speaking (p = 0.01) donors.
Conclusion
Our study finds a steady increase in the prevalence of HCV infection in blood donors from interior Sindh between 2004 and 2007. On the contrary, decreasing prevalence of HBV was found, particularly in literate blood donors. There may be a need to have rural community-based epidemiological studies to identify the determinants of the spread of HCV infection and also those that are limiting the spread of HBV infection particularly in the literate blood donor population.
doi:10.1186/1471-2334-8-43
PMCID: PMC2329620  PMID: 18402660
19.  Evolution of Antiretroviral Drug Costs in Brazil in the Context of Free and Universal Access to AIDS Treatment  
PLoS Medicine  2007;4(11):e305.
Background
Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil's AIDS treatment program has been cited widely as the developing world's largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART) for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs), procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005.
Methods and Findings
We compared Brazil's ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil's reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir–ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil's locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil's locally produced generics totaled US$110 million from 2001 to 2005.
Conclusions
Despite Brazil's more costly generic ARVs, the net result of ARV price changes has been a cost savings of approximately US$1 billion since 2001. HAART costs have nevertheless risen steeply as Brazil has scaled up treatment. These trends may foreshadow future AIDS treatment cost trends in other developing countries as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available. The specific application of the Brazilian model to other countries will depend, however, on the strength of their health systems, intellectual property regulations, epidemiological profiles, AIDS treatment guidelines, and differing capacities to produce drugs locally.
Amy Nunn and colleagues analyze the cost of antiretroviral drugs in Brazil between 2001 and 2005 and discuss the implications for HIV treatment in other developing countries.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed 29 million people since the first case occurred in 1981 and an estimated 40 million people live with HIV/AIDS today. AIDS is caused by the human immunodeficiency virus (HIV), which destroys the immune system. Infected individuals are consequently very susceptible to other infections. Early in the AIDS epidemic, most HIV-positive individuals died within a few years of becoming infected. Then, in 1996, highly active antiretroviral therapy (HAART)—a cocktail of antiretroviral drugs (ARVs)—was developed. For people who could afford HAART (which holds HIV infections in check), AIDS became a chronic disease. People who start HAART must keep taking it or their illness will progress.
Unfortunately, few people in low- and middle-income countries could afford these expensive drugs. In 2001, ARV prices fell in developing countries as AIDS activists and developing country governments challenged pharmaceutical companies about ARV prices, pharmaceutical companies set tiered prices for the low- and middle-income countries and more generic (inexpensive copies of brand-named drugs) ARVs became available. In 2003, the lack of access to HIV/AIDS treatment was declared a global health emergency. Governments, international organizations, and funding bodies began to set targets and provide funds to increase access to HAART in developing countries. By 2007, over 2 million people in low- and middle-income countries had access to HAART, but another 5 million remain in urgent need of drugs for treatment.
Why Was This Study Done?
In 1995, many countries in the world signed the World Trade Organization (WTO) Trade-Related Aspects of Intellectual Property (TRIPS) agreement, which requires countries to acknowledge intellectual property rights for many products, including pharmaceuticals. In 1996, Brazil became the first developing country to commit to and implement policies to provide free and universal access to HAART. Since then, Brazil's successful AIDS treatment program has become a model for the developing world, and 180,000 Brazilians were receiving HAART at the end of 2006. However, as a WTO member that signed on to the TRIPS agreement, Brazil was required to recognize the intellectual property rights of pharmaceutical companies' patented ARVs. As Brazil scaled up treatment in the late 1990s, the cost of treating AIDS patients rose quickly and the country took controversial public policy steps to reduce the cost of providing HAART to people living with HIV/AIDS. Brazil produces several non-patented ARVs locally, and since 2001 has challenged multinational pharmaceutical companies about the prices of patented ARVs. To induce price reductions for patented ARVs, Brazil has threatened to issue compulsory licenses (which under WTO terms allow countries facing a health emergency to produce patented drugs without consent of the company holding the patent). Brazil also recently issued a compulsory license for one ARV.
Although world leaders have set a target of universal access to HAART by 2010, little is known about the long-term costs of AIDS treatment in developing countries. In this study, the researchers have investigated how and why the costs of ARVs changed in Brazil between 2001 and 2005 and discuss the relevance of the Brazilian model for AIDS treatment for other resource-limited settings.
What Did the Researchers Do and Find?
The researchers analyzed the prices for each ARV recommended in Brazil's therapeutic guidelines for adults and estimated the changes in purchase quantities for each between 2001 and 2005. These changes likely stem from the growing number of options in Brazil's treatment guidelines, the steadily rising number of patients commencing treatment, and patients' shifts to second- and third-line treatments when their HIV infection became resistant to first-line drugs or they developed side effects. The researchers report that the generic drugs produced in Brazil were generally more expensive than similar drugs made elsewhere, but Brazil's negotiated drug prices for many patented ARVs were lower than elsewhere. Overall, total annual drug expenditure on ARVs doubled between 2001 and 2005, reaching US$414 million in 2005. Because many drug prices fell sharply as a result of declining patented drug prices over the study period, this increase was mainly attributable to increases in drug quantities purchased. If these quantities had stayed constant, the total annual cost would have increased by only $7 million, to $211 million. Conversely, without the decrease in the price of patented drugs, Brazil would have spent $952 million annually by 2005. If Brazil had enjoyed the lowest global prices for generic medicines, the total costs per year in 2005 would have been $367 million, or nearly $50 million less than the costs Brazil actually realized.
What Do These Findings Mean?
These findings tease out the many factors—clinical, commercial, and political—that affected the total costs of the Brazilian AIDS treatment program between 2001 and 2005.
Brazil's ability to produce generic drugs facilitated Brazil's price negotiations for patented drugs. Although Brazil saved approximately US$1 billion over the study period as a result of declining prices for patented medicines, the cost of producing generic drugs locally has risen while the prices for generic drugs have fallen elsewhere. Brazil's recent decision to import a generic ARV using a compulsory license suggests that the Brazilian model for AIDS treatment continues to evolve.
Questions remain about the precise causes of year-to-year cost trends in Brazil because, for example, the researchers did not have full data on when patients switched from first-line to second- or third-line drugs. The observed steep rise in costs from 2004 to 2005 in particular warrants further analysis. In addition, the findings may not be generalizable to countries with different policies on HIV/AIDS treatment, different access to generic drugs, or different bargaining power with multinational drug companies. Nevertheless, the trends this study highlights provide important information about how AIDS treatment costs are likely to evolve in other developing countries as efforts are made to provide universal access to life-saving ARVs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040305.
Information from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information from the US Centers for Disease Control and Prevention on global HIV/AIDS topics (in English and Spanish)
HIV InSite, comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California San Francisco
Information from Avert, an international AIDS charity, on HIV and AIDS in Brazil and on HIV/AIDS treatment and care, including universal access to ARVs
Progress towards universal access to HIV/AIDS treatment, the latest report from the World Health Organization (available in several languages)
The National STD and AIDS Program of Brazil
doi:10.1371/journal.pmed.0040305
PMCID: PMC2071936  PMID: 18001145
20.  Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study 
PLoS Medicine  2012;9(9):e1001304.
Morna Cornell and colleagues investigate differences in mortality for HIV-positive men and women on antiretroviral therapy in South Africa.
Background
Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.
Methods and Findings
Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population.
Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22–1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12–1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86–1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located.
Conclusions
HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
About 34 million people (most living in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that keep HIV in check—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive and, for people living in poorer countries, HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global emergency, and governments and international agencies began to implement plans to increase ART coverage in resource-limited countries. Since then, ART programs in these countries have grown rapidly. In South Africa, for example, about 52% of the 3.14 million adults in need of ART were receiving an ART regimen recommended by the World Health Organization by the end of 2010.
Why Was This Study Done?
The outcomes of ART programs in resource-limited countries need to be evaluated thoroughly so that these programs can be optimized. One area of concern to ART providers is that of gender differences in survival among patients receiving treatment. In sub-Saharan Africa, for example, men are more likely to die than women while receiving ART. This gender difference in mortality may arise because men initiating ART in many African ART programs have more advanced HIV disease than women (early ART initiation is associated with better outcomes than late initiation) or because men are more likely to be lost to follow-up than women (failure to continue treatment is associated with death). Other possible explanations for gender differentials in mortality on ART include gender differences in immunologic and virologic responses to treatment (increased numbers of immune system cells and reduced amounts of virus in the blood, respectively). In this multicenter cohort study, the researchers examine the size of, and risk factors for, gender differences in mortality on ART in South Africa by examining data collected from adults starting ART at International Epidemiologic Databases to Evaluate AIDS South Africa (IeDEA-SA) collaboration sites.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 46,201 ART-naïve adults who started ART between 2002 and 2009 in eight IeDEA-SA ART programs. At ART initiation, men had a lower CD4 count on average and were more likely to have advanced HIV disease than women. During the study, after allowing for factors likely to affect mortality such as HIV disease stage at initiation, men on ART had a 31% higher risk of dying than women. Men were more likely to be lost to follow-up than women, but men and women who were lost to follow-up were equally likely to die. Women had a slightly better immunological response to ART than men but virologic suppression was similar in both genders. Importantly, in analyses of mortality limited to individuals who were virologically suppressed at 12 months and to patients who had a good immunological response to ART, men still had a higher risk of death than women. However, the gender differences in mortality on ART were smaller than the gender differences in age-standardized mortality in the HIV-negative South African population.
What Do These Findings Mean?
These analyses show that among South African patients initiating ART between 2002 and 2009, men were more likely to die than women but that this gender difference in mortality on ART cannot be completely explained by gender differences in baseline characteristics, loss to follow-up, or virologic and/or immunologic responses. Instead, the observed gender differences in mortality can best be explained by background gender differences in mortality in the whole South African population. Because substantial amounts of data were missing in this study (for example, HIV disease stage was not available for all the patients), these findings need to be interpreted cautiously. Moreover, similar studies need to be done in other settings to investigate whether they are generalizable to the South African national ART program and to other countries. If confirmed, however, these findings suggest that the root causes of gender differences in mortality on ART may be unrelated to HIV/AIDS or to the characteristics of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001304.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information on the treatment of HIV/AIDS in South Africa is available from the Southern African HIV Clinicians Society
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, and on HIV/AIDS in South Africa (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in several languages); its 2010 ART guidelines can be downloaded
Information about the IeDEA-SA collaboration is available
The Treatment Action Campaign provides information on antiretroviral therapy and South African HIV statistics
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
doi:10.1371/journal.pmed.1001304
PMCID: PMC3433409  PMID: 22973181
21.  Measuring Under-Five Mortality: Validation of New Low-Cost Methods 
PLoS Medicine  2010;7(4):e1000253.
n/a
Background
There has been increasing interest in measuring under-five mortality as a health indicator and as a critical measure of human development. In countries with complete vital registration systems that capture all births and deaths, under-five mortality can be directly calculated. In the absence of a complete vital registration system, however, child mortality must be estimated using surveys that ask women to report the births and deaths of their children. Two survey methods exist for capturing this information: summary birth histories and complete birth histories. A summary birth history requires a minimum of only two questions: how many live births has each mother had and how many of them have survived. Indirect methods are then applied using the information from these two questions and the age of the mother to estimate under-five mortality going back in time prior to the survey. Estimates generated from complete birth histories are viewed as the most accurate when surveys are required to estimate under-five mortality, especially for the most recent time periods. However, it is much more costly and labor intensive to collect these detailed data, especially for the purpose of generating small area estimates. As a result, there is a demand for improvement of the methods employing summary birth history data to produce more accurate as well as subnational estimates of child mortality.
Methods and Findings
We used data from 166 Demographic and Health Surveys (DHS) to develop new empirically based methods of estimating under-five mortality using children ever born and children dead data. We then validated them using both in- and out-of-sample analyses. We developed a range of methods on the basis of three dimensions of the problem: (1) approximating the average length of exposure to mortality from a mother's set of children using either maternal age or time since first birth; (2) using cohort and period measures of the fraction of children ever born that are dead; and (3) capturing country and regional variation in the age pattern of fertility and mortality. We focused on improving estimates in the most recent time periods prior to a survey where the traditional indirect methods fail. In addition, all of our methods incorporated uncertainty. Validated against under-five estimates generated from complete birth histories, our methods outperformed the standard indirect method by an average of 43.7% (95% confidence interval [CI] 41.2–45.2). In the 5 y prior to the survey, the new methods resulted in a 53.3% (95% CI 51.3–55.2) improvement. To illustrate the value of this method for local area estimation, we applied our new methods to an analysis of summary birth histories in the 1990, 2000, and 2005 Mexican censuses, generating subnational estimates of under-five mortality for each of 233 jurisdictions.
Conclusions
The new methods significantly improve the estimation of under-five mortality using summary birth history data. In areas without vital registration data, summary birth histories can provide accurate estimates of child mortality. Because only two questions are required of a female respondent to generate these data, they can easily be included in existing survey programs as well as routine censuses of the population. With the wider application of these methods to census data, countries now have the means to generate estimates for subnational areas and population subgroups, important for measuring and addressing health inequalities and developing local policy to improve child survival.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 8 million children die before their fifth birthdays. Most of these deaths occur in developing countries, and most are the result of diseases or combinations of diseases that could have been prevented or treated. Measles, for example, is a major killer in low-income countries and undernutrition contributes to one-third of childhood deaths. Faced with this largely avoidable loss of young lives, in 1990, the United Nations' World Summit for Children pledged to improve the survival of children. Later, in 2000, world leaders set a target of reducing child mortality to one-third of its 1990 level by 2015 as Millennium Development Goal 4. This goal, together with seven others, is designed to alleviate extreme poverty by 2015. In 2006, for the first time since mortality records began, annual deaths among children under five fell below 10 million as a result of public-health programs such as the Measles Initiative, which has reduced global measles mortality by more than two-thirds by vaccinating 500 million children, and the Nothing but Nets campaign, which distributed insecticide-treated antimalaria nets in Africa.
Why Was This Study Done?
Although global under-five mortality is declining, it is unlikely that Millennium Development Goal 4 will be reached by 2015. Indeed, in some countries, little or no progress is being made toward this goal. To improve progress and to monitor the effects of public-health interventions, accurate, up-to-date estimates of national and subnational child mortality rates are essential. In developed countries, vital registration systems—records of all births and deaths—mean that under-five mortality rates can be directly calculated. But many developing countries lack vital registration systems, and child mortality has to be estimated using data collected in surveys. In “complete birth history” surveys, mothers are asked numerous questions about each living child and each dead child. Such surveys can be used to estimate under-five mortality accurately for recent time periods but they are expensive and time-consuming. By contrast, in “summary birth history” surveys, each mother is simply asked how many live births she had and how many of her children have survived. Under-five mortality can be indirectly calculated from this information and the age of the mother, but the current methods for making this calculation cannot provide reliable estimates of under-five mortality more recently than 3 years before the survey. In this study, therefore, the researchers develop methods for estimating more recent under-five mortality rates from summary birth histories.
What Did the Researchers Do and Find?
The researchers used data about all children born and dead children extracted from 169 Demographic and Health Surveys (DHS; a project started in 1984 to help developing countries collect data on health and population trends) covering 70 countries to develop four new methods to estimate under-five mortality. They tested these new methods and a method that combined all four approaches by comparing the estimates of under-five mortality provided by these methods and the standard indirect method to the estimates obtained from an analysis of the complete birth data in the DHS. The new methods all outperformed the standard indirect method, particularly for the most recent 5 years. The researchers also used their new methods to generate estimates of under-five mortality for each of the 233 jurisdictions in Mexico from summary birth histories collected in the 1990, 2000, and 2005 Mexico censuses. The overall trends of these subnational estimates, they report, mirrored those obtained from vital registration data.
What Do These Findings Mean?
These findings suggest that application of the new methods developed by the researchers could significantly improve the accuracy of estimates of under-five mortality based on summary birth history data. The researchers warn that although their methods can provide accurate estimates of recent under-five mortality, they might not capture rapid fluctuations in mortality such as those that occur during wars. However, they suggest, the two questions needed to generate the data required to apply these new methods could easily be included in existing survey programs and in routine censuses. Consequently, systematic application of the methods proposed in this study should provide policy makers with the information about levels, recent trends, and inequalities in child mortality that they need to accelerate efforts to reduce the global toll of childhood deaths.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000253.
This study and two related PLoS Medicine Research Articles by Obermeyer et al and by Murray et al are further discussed in a PLoS Medicine Perspective by Mathers and Boerma
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health (some information in several languages)
Further information about the Millennium Development Goals is available
The World Health Organization also has information about Millennium Development Goal 4 and provides estimates of child mortality rates
Information is also available about the Demographic and Health Surveys
doi:10.1371/journal.pmed.1000253
PMCID: PMC2854123  PMID: 20405055
22.  Male Circumcision at Different Ages in Rwanda: A Cost-Effectiveness Study 
PLoS Medicine  2010;7(1):e1000211.
Agnes Binagwaho and colleagues predict that circumcision of newborn boys would be effective and cost-saving as a long-term strategy to prevent HIV in Rwanda.
Background
There is strong evidence showing that male circumcision (MC) reduces HIV infection and other sexually transmitted infections (STIs). In Rwanda, where adult HIV prevalence is 3%, MC is not a traditional practice. The Rwanda National AIDS Commission modelled cost and effects of MC at different ages to inform policy and programmatic decisions in relation to introducing MC. This study was necessary because the MC debate in Southern Africa has focused primarily on MC for adults. Further, this is the first time, to our knowledge, that a cost-effectiveness study on MC has been carried out in a country where HIV prevalence is below 5%.
Methods and Findings
A cost-effectiveness model was developed and applied to three hypothetical cohorts in Rwanda: newborns, adolescents, and adult men. Effectiveness was defined as the number of HIV infections averted, and was calculated as the product of the number of people susceptible to HIV infection in the cohort, the HIV incidence rate at different ages, and the protective effect of MC; discounted back to the year of circumcision and summed over the life expectancy of the circumcised person. Direct costs were based on interviews with experienced health care providers to determine inputs involved in the procedure (from consumables to staff time) and related prices. Other costs included training, patient counselling, treatment of adverse events, and promotion campaigns, and they were adjusted for the averted lifetime cost of health care (antiretroviral therapy [ART], opportunistic infection [OI], laboratory tests). One-way sensitivity analysis was performed by varying the main inputs of the model, and thresholds were calculated at which each intervention is no longer cost-saving and at which an intervention costs more than one gross domestic product (GDP) per capita per life-year gained. Results: Neonatal MC is less expensive than adolescent and adult MC (US$15 instead of US$59 per procedure) and is cost-saving (the cost-effectiveness ratio is negative), even though savings from infant circumcision will be realized later in time. The cost per infection averted is US$3,932 for adolescent MC and US$4,949 for adult MC. Results for infant MC appear robust. Infant MC remains highly cost-effective across a reasonable range of variation in the base case scenario. Adolescent MC is highly cost-effective for the base case scenario but this high cost-effectiveness is not robust to small changes in the input variables. Adult MC is neither cost-saving nor highly cost-effective when considering only the direct benefit for the circumcised man.
Conclusions
The study suggests that Rwanda should be simultaneously scaling up circumcision across a broad range of age groups, with high priority to the very young. Infant MC can be integrated into existing health services (i.e., neonatal visits and vaccination sessions) and over time has better potential than adolescent and adult circumcision to achieve the very high coverage of the population required for maximal reduction of HIV incidence. In the presence of infant MC, adolescent and adult MC would evolve into a “catch-up” campaign that would be needed at the start of the program but would eventually become superfluous.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981 and more than 31 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. There is no cure for HIV/AIDS and no vaccine against HIV infection. Consequently, prevention of HIV transmission is extremely important. HIV is most often spread through unprotected sex with an infected partner. Individuals can reduce their risk of HIV infection, therefore, by abstaining from sex, by having one or a few sexual partners, and by always using a male or female condom. In addition, male circumcision—the removal of the foreskin, the loose fold of skin that covers the head of penis—can halve HIV transmission rates to men resulting from sex with women. Thus, as part of its HIV prevention strategy, the World Health Organization (WHO) recommends that male circumcision programs be scaled up in countries where there is a generalized HIV epidemic and where few men are circumcised.
Why Was This Study Done?
One such country is Rwanda. Here, 3% of the adult population is infected with HIV but only 15% of men are circumcised—worldwide, about 30% of men are circumcised. Demand for circumcision is increasing in Rwanda but, before policy makers introduce a country-wide male circumcision program, they need to identify the most cost-effective way to increase circumcision rates. In particular, they need to decide the age at which circumcision should be offered. Circumcision soon after birth (neonatal circumcision) is quick and simple and rarely causes any complications. Circumcision of adolescents and adults is more complex and has a higher complication rate. Although several studies have investigated the cost-effectiveness (the balance between the clinical and financial costs of a medical intervention and its benefits) of circumcision in adult men, little is known about its cost-effectiveness in newborn boys. In this study, which is one of several studies on male circumcision being organized by the National AIDS Control Commission in Rwanda, the researchers model the cost-effectiveness of circumcision at different ages.
What Did the Researchers Do and Find?
The researchers developed a simple cost-effectiveness model and applied it to three hypothetical groups of Rwandans: newborn boys, adolescent boys, and adult men. For their model, the researchers calculated the effectiveness of male circumcision (the number of HIV infections averted) by estimating the reduction in the annual number of new HIV infections over time. They obtained estimates of the costs of circumcision (including the costs of consumables, staff time, and treatment of complications) from health care providers and adjusted these costs for the money saved through not needing to treat HIV in males in whom circumcision prevented infection. Using their model, the researchers estimate that each neonatal male circumcision would cost US$15 whereas each adolescent or adult male circumcision would cost US$59. Neonatal male circumcision, they report, would be cost-saving. That is, over a lifetime, neonatal male circumcision would save more money than it costs. Finally, using the WHO definition of cost-effectiveness (for a cost-effective intervention, the additional cost incurred to gain one year of life must be less than a country's per capita gross domestic product), the researchers estimate that, although adolescent circumcision would be highly cost-effective, circumcision of adult men would only be potentially cost-effective (but would likely prove cost-effective if the additional infections that would occur from men to their partners without a circumcision program were also taken into account).
What Do These Findings Mean?
As with all modeling studies, the accuracy of these findings depends on the many assumptions included in the model. However, the findings suggest that male circumcision for infants for the prevention of HIV infection later in life is highly cost-effective and likely to be cost-saving and that circumcision for adolescents is cost-effective. The researchers suggest, therefore, that policy makers in Rwanda and in countries with similar HIV infection and circumcision rates should scale up male circumcision programs across all age groups, with high priority being given to the very young. If infants are routinely circumcised, they suggest, circumcision of adolescent and adult males would become a “catch-up” campaign that would be needed at the start of the program but that would become superfluous over time. Such an approach would represent a switch from managing the HIV epidemic as an emergency towards focusing on sustainable, long-term solutions to this major public-health problem.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000211.
This study is further discussed in a PLoS Medicine Perspective by Seth Kalichman
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information is available from the Joint United Nations Programme on HIV/AIDS (UNAIDS) on HIV infection and AIDS and on male circumcision in relation to HIV and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV and AIDS in Africa, and on circumcision and HIV (some information in English and Spanish)
More information about male circumcision is available from the Clearinghouse on Male Circumcision
The National AIDS Control Commission of Rwanda provides detailed information about HIV/AIDS in Rwanda (in English and French)
doi:10.1371/journal.pmed.1000211
PMCID: PMC2808207  PMID: 20098721
23.  Retention in HIV Care between Testing and Treatment in Sub-Saharan Africa: A Systematic Review 
PLoS Medicine  2011;8(7):e1001056.
In this systematic review, Sydney Rosen and Matthew Fox find that less than one-third of patients who tested positive for HIV, but were not eligible for antiretroviral therapy (ART) when diagnosed, were retained in pre-ART care continuously.
Background
Improving the outcomes of HIV/AIDS treatment programs in resource-limited settings requires successful linkage of patients testing positive for HIV to pre–antiretroviral therapy (ART) care and retention in pre-ART care until ART initiation. We conducted a systematic review of pre-ART retention in care in Africa.
Methods and Findings
We searched PubMed, ISI Web of Knowledge, conference abstracts, and reference lists for reports on the proportion of adult patients retained between any two points between testing positive for HIV and initiating ART in sub-Saharan African HIV/AIDS care programs. Results were categorized as Stage 1 (from HIV testing to receipt of CD4 count results or clinical staging), Stage 2 (from staging to ART eligibility), or Stage 3 (from ART eligibility to ART initiation). Medians (ranges) were reported for the proportions of patients retained in each stage. We identified 28 eligible studies. The median proportion retained in Stage 1 was 59% (35%–88%); Stage 2, 46% (31%–95%); and Stage 3, 68% (14%–84%). Most studies reported on only one stage; none followed a cohort of patients through all three stages. Enrollment criteria, terminology, end points, follow-up, and outcomes varied widely and were often poorly defined, making aggregation of results difficult. Synthesis of findings from multiple studies suggests that fewer than one-third of patients testing positive for HIV and not yet eligible for ART when diagnosed are retained continuously in care, though this estimate should be regarded with caution because of review limitations.
Conclusions
Studies of retention in pre-ART care report substantial loss of patients at every step, starting with patients who do not return for their initial CD4 count results and ending with those who do not initiate ART despite eligibility. Better health information systems that allow patients to be tracked between service delivery points are needed to properly evaluate pre-ART loss to care, and researchers should attempt to standardize the terminology, definitions, and time periods reported.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since 1981, AIDS has killed more than 25 million people, and about 33 million people (mostly living in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. HIV gradually destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within ten years of infection. Then, in 1996, highly active antiretroviral therapy (ART) became available, and, for people living in developed countries, HIV infection became a chronic condition. Unfortunately, ART was extremely expensive, and HIV/AIDS remained a fatal illness for people living in developing countries. In 2003, governments, international agencies, and funding bodies began to implement plans to increase ART coverage in resource-limited countries. By the end of 2009, about a third of the people in these countries who needed ART (HIV-positive people whose CD4 count had dropped so low that they could not fight other infections) were receiving treatment.
Why Was This Study Done?
Unfortunately, many HIV-positive people in resource-limited countries who receive ART still do not have a normal life expectancy, often because they start ART when they have a very low CD4 count. ART is more successful if it is started before the CD4 count falls far below 350 cells/mm3 of blood, the threshold recommended by the World Health Organization for ART initiation. Thus, if the outcomes of HIV/AIDS programs in resource-limited settings are to be improved, all individuals testing positive for HIV must receive continuous pre-ART care that includes regular CD4 counts to ensure that ART is initiated as soon as they become eligible for treatment. Before interventions can be developed to achieve this aim, it is necessary to understand where and when patients are lost to pre-ART care. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers investigate the retention of HIV-positive adults in pre-ART care in sub-Saharan Africa.
What Did the Researchers Do and Find?
The researchers identified 28 studies that included data on the proportion of adult patients retained between any two time points between testing positive for HIV and starting ART in HIV/AIDS care programs in sub-Saharan Africa. They defined three stages of pre-ART care: Stage 1, the interval between testing positive for HIV and receiving CD4 count results or being clinically assessed; Stage 2, the interval between enrollment in pre-ART care and the determination of eligibility for ART; and Stage 3, the interval between being deemed eligible for ART and treatment initiation. A median of 59% of patients were retained in Stage 1 of pre-ART care, 46% were retained in Stage 2, and 68% were retained in Stage 3. Retention rates in each stage differed greatly between studies—between 14% and 84% for Stage 3 pre-ART care, for example. Because the enrollment criteria and other characteristics of the identified studies varied widely and were often poorly defined, it was hard to combine study results. Nevertheless, the researchers estimate that, taking all the studies together, less than one-third of patients testing positive for HIV but not eligible for ART when diagnosed were retained in pre-ART care continuously.
What Do These Findings Mean?
These findings suggest that there is a substantial loss of HIV-positive patients at every stage of pre-ART care in sub-Saharan Africa. Thus, some patients receiving a positive HIV test never return for the results of their initial CD4 count, some disappear between having an initial CD4 count and becoming eligible for ART, and others fail to initiate ART after having been found eligible for treatment. Because only a few studies were identified (half of which were undertaken in South Africa) and because the quality and design of some of these studies were suboptimal, the findings of this systematic review must be treated with caution. In particular, the estimate of the overall loss of patients during pre-ART care is likely to be imprecise. The researchers call, therefore, for the implementation of better health information systems that would allow patients to be tracked between service delivery points as a way to improve the evaluation and understanding of the loss of HIV-positive patients to pre-ART care in resource-limited countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001056.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, on HIV and AIDS in Africa and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including the 2010 progress report (in English, French and Spanish); its 2010 ART guidelines can be downloaded (in several languages)
The International AIDS Economics Network posts information about economic, social, and behavioral aspects of HIV care and treatment
Up-to-date research findings about HIV care and treatment are summarized by NAM/aidsmap
doi:10.1371/journal.pmed.1001056
PMCID: PMC3139665  PMID: 21811403
24.  Health and Human Rights in Chin State, Western Burma: A Population-Based Assessment Using Multistaged Household Cluster Sampling 
PLoS Medicine  2011;8(2):e1001007.
Sollom and colleagues report the findings from a household survey study carried out in Western Burma; they report a high prevalence of human rights violations such as forced labor, food theft, forced displacement, beatings, and ethnic persecution.
Background
The Chin State of Burma (also known as Myanmar) is an isolated ethnic minority area with poor health outcomes and reports of food insecurity and human rights violations. We report on a population-based assessment of health and human rights in Chin State. We sought to quantify reported human rights violations in Chin State and associations between these reported violations and health status at the household level.
Methods and Findings
Multistaged household cluster sampling was done. Heads of household were interviewed on demographics, access to health care, health status, food insecurity, forced displacement, forced labor, and other human rights violations during the preceding 12 months. Ratios of the prevalence of household hunger comparing exposed and unexposed to each reported violation were estimated using binomial regression, and 95% confidence intervals (CIs) were constructed. Multivariate models were done to adjust for possible confounders. Overall, 91.9% of households (95% CI 89.7%–94.1%) reported forced labor in the past 12 months. Forty-three percent of households met FANTA-2 (Food and Nutrition Technical Assistance II project) definitions for moderate to severe household hunger. Common violations reported were food theft, livestock theft or killing, forced displacement, beatings and torture, detentions, disappearances, and religious and ethnic persecution. Self reporting of multiple rights abuses was independently associated with household hunger.
Conclusions
Our findings indicate widespread self-reports of human rights violations. The nature and extent of these violations may warrant investigation by the United Nations or International Criminal Court.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
More than 60 years after the adoption of the Universal Declaration of Human Rights, thousands of people around the world are still deprived of their basic human rights—life, liberty, and security of person. In many countries, people live in fear of arbitrary arrest and detention, torture, forced labor, religious and ethnic persecution, forced displacement, and murder. In addition, ongoing conflicts and despotic governments deprive them of the ability to grow sufficient food (resulting in food insecurity) and deny them access to essential health care. In Burma, for example, the military junta, which seized power in 1962, frequently confiscates land unlawfully, demands forced labor, and uses violence against anyone who protests. Burma is also one of the world's poorest countries in terms of health indicators. Its average life expectancy is 54 years, its maternal mortality rate (380 deaths among women from pregnancy-related causes per 100,000 live births) is nearly ten times higher than that of neighboring Thailand, and its under-five death rate (122/1000 live births) is twice that of nearby countries. Moreover, nearly half of Burmese children under 5 are stunted, and a third of young children are underweight, indicators of malnutrition in a country that, on paper, has a food surplus.
Why Was This Study Done?
Investigators are increasingly using population-based methods to quantify the associations between human rights violations and health outcomes. In eastern Burma, for example, population-based research has recently revealed a link between human rights violations and reduced access to maternal health-care services. In this study, the researchers undertake a population-based assessment of health and human rights in Chin State, an ethnic minority area in western Burma where multiple reports of human rights abuses have been documented and from which thousands of people have fled. In particular, the researchers investigate correlations between household hunger and household experiences of human rights violations—food security in Chin State is affected by periodic expansions of rat populations that devastate crop yields, by farmers being forced by the government to grow an inedible oil crop (jatropha), and by the Burmese military regularly stealing food and livestock.
What Did the Researchers Do and Find?
Local surveyors questioned the heads of randomly selected households in Chin State about their household's access to health care and its health status, and about forced labor and other human rights violations experienced by the household during the preceding 12 months. They also asked three standard questions about food availability, the answers to which were combined to provide a measure of household hunger. Of the 621 households interviewed, 91.9% reported at least one episode of a household member being forced to work in the preceding 12 months. The Burmese military imposed two-thirds of these forced labor demands. Other human rights violations reported included beating or torture (14.8% of households), religious or ethnic persecutions (14.1% of households), and detention or imprisonment of a family member (5.9% of households). Forty-three percent of the households met the US Agency for International Development Food and Nutrition Technical Assistance (FANTA) definition for moderate to severe household hunger, and human rights violations related to food insecurity were common. For example, more than half the households were forced to give up food out of fear of violence. A statistical analysis of these data indicated that the prevalence of household hunger was 6.51 times higher in households that had experienced three food-related human rights violations than in households that had not experienced such violations.
What Do These Findings Mean?
These findings quantify the extent to which the Chin ethnic minority in Burma is subjected to multiple human rights violations and indicate the geographical spread of these abuses. Importantly, they show that the health impacts of human rights violations in Chin State are substantial. In addition, they suggest that the indirect health outcomes of human rights violations probably dwarf the mortality from direct killings. Although this study has some limitations (for example, surveyors had to work in secret and it was not safe for them to collect biological samples that could have given a more accurate indication of the health status of households than questions alone), these findings should encourage the international community to intensify its efforts to reduce human rights violations in Burma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001007.
The UN Universal Declaration of Human Rights is available in numerous languages
The Burma Campaign UK and Human Rights Watch provide detailed information about human rights violations in Burma (in several languages)
The World Health Organization provides information on health in Burma and on human rights (in several languages)
The Mae Tao clinic also provides general information about Burma and its health services (including some information in Thai)
A PLoS Medicine Research Article by Luke Mullany and colleagues provides data on human rights violations and maternal health in Burma
The Chin Human Rights Organization is working to protect and promote the rights of the Chin people
The Global Health Access Program (GHAP) provides information on health in Burma
FANTA works to improve nutrition and global food security policies
doi:10.1371/journal.pmed.1001007
PMCID: PMC3035608  PMID: 21346799
25.  The NHLBI Retrovirus Epidemiology Donor Studies (REDS and REDS-II): Twenty years of research to advance blood product safety and availability 
Transfusion medicine reviews  2012;26(4):281-304.e2.
The Retrovirus Epidemiology Donor Study (REDS), conducted from 1989–2001, and the Retrovirus Epidemiology Donor Study-II (REDS-II), conducted from 2004–2012, were National Heart Lung and Blood Institute (NHLBI) funded multicenter programs focused on improving blood safety and availability in the United States. REDS-II also included international study sites in Brazil and China. The three major research domains of REDS/REDS-II have been infectious disease risk evaluation, blood donation availability, and blood donor characterization. Both programs have made significant contributions to transfusion medicine research methodology by the use of mathematical modeling, large-scale donor surveys, innovative methods of repository sample storage, and establishing an infrastructure that responded to potential emerging blood safety threats such as XMRV. Blood safety studies have included protocols evaluating epidemiologic and/or laboratory aspects of HIV, HTLV I/II, HCV, HBV, WNV, CMV, HHV-8, B19V, malaria, CJD, influenza, and T. cruzi infections. Other analyses have characterized: blood donor demographics, motivations to donate, factors influencing donor return, behavioral risk factors, donors’ perception of the blood donation screening process, and aspects of donor deferral. In REDS-II, two large-scale blood donor protocols examined iron deficiency in donors and the prevalence of leukocyte antibodies. This review describes the major study results from over 150 peer-reviewed articles published by these two REDS programs. In 2011, a new seven year program, the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III), was launched. REDS-III expands beyond donor-based research to include studies of blood transfusion recipients in the hospital setting, and adds a third country, South Africa, to the international program.
doi:10.1016/j.tmrv.2012.04.004
PMCID: PMC3448800  PMID: 22633182
blood safety; transfusion-transmitted infections; blood availability; blood donors

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