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1.  Delays in childhood immunization in a conflict area: a study from Sierra Leone during civil war 
Conflict and Health  2007;1:14.
Background
Sierra Leone has undergone a decade of civil war from 1991 to 2001. From this period few data on immunization coverage are available, and conflict-related delays in immunization according to the Expanded Programme on Immunization (EPI) schedule have not been investigated. We aimed to study delays in childhood immunization in the context of civil war in a Sierra Leonean community.
Methods
We conducted an immunization survey in Kissy Mess-Mess in the Greater Freetown area in 1998/99 using a two-stage sampling method. Based on immunization cards and verbal history we collected data on immunization for tuberculosis, diphtheria, tetanus, pertussis, polio, and measles by age group (0–8/9–11/12–23/24–35 months). We studied differences between age groups and explored temporal associations with war-related hostilities taking place in the community.
Results
We included 286 children who received 1690 vaccine doses; card retention was 87%. In 243 children (85%, 95% confidence interval (CI): 80–89%) immunization was up-to-date. In 161 of these children (56%, 95%CI: 50–62%) full age-appropriate immunization was achieved; in 82 (29%, 95%CI: 24–34%) immunization was not appropriate for age. In the remaining 43 children immunization was partial in 37 (13%, 95%CI: 9–17) and absent in 6 (2%, 95%CI: 1–5). Immunization status varied across age groups. In children aged 9–11 months the proportion with age-inappropriate (delayed) immunization was higher than in other age groups suggesting an association with war-related hostilities in the community.
Conclusion
Only about half of children under three years received full age-appropriate immunization. In children born during a period of increased hostilities, immunization was mostly inappropriate for age, but recommended immunizations were not completely abandoned. Missing or delayed immunization represents an additional threat to the health of children living in conflict areas.
doi:10.1186/1752-1505-1-14
PMCID: PMC2231345  PMID: 18067680
2.  Risk factors for incomplete vaccination and missed opportunity for immunization in rural Mozambique 
BMC Public Health  2008;8:161.
Background
Inadequate levels of immunization against childhood diseases remain a significant public health problem in resource-poor areas of the globe. Nonetheless, the reasons for incomplete vaccination and non-uptake of immunization services are poorly understood. This study aimed at finding out the reasons for non-vaccination and the magnitude of missed opportunities for vaccination in children less than two years of age in a rural area in southern Mozambique.
Methods
Mothers of children under two years of age (N = 668) were interviewed in a cross-sectional study. The Road-to-Health card was utilized to check for completeness and correctness of vaccination schedule as well as for identifying the appropriate use of all available opportunities for vaccination. The chi-square test and the logistic regression were used for statistical analysis.
Results
We found that 28.2% of the children had not completed the vaccination program by two years of age, 25.7% had experienced a missed opportunity for vaccination and 14.9% were incorrectly vaccinated. Reasons for incomplete vaccination were associated with accessibility to the vaccination sites, no schooling of mothers and children born at home or outside Mozambique.
Conclusion
Efforts to increase vaccination coverage should take into account factors that contribute to the incomplete vaccination status of children. Missed opportunities for vaccination and incorrect vaccination need to be avoided in order to increase the vaccine coverage for those clients that reach the health facility, specially in those countries where health services do not have 100% of coverage.
doi:10.1186/1471-2458-8-161
PMCID: PMC2405792  PMID: 18485194
3.  Factors associated with underimmunization at 3 months of age in four medically underserved areas. 
Public Health Reports  2004;119(5):479-485.
OBJECTIVE: Risk factors for underimmunization at 3 months of age are not well described. This study examines coverage rates and factors associated with under-immunization at 3 months of age in four medically underserved areas. METHODS: During 1997-1998, cross-sectional household surveys using a two-stage cluster sample design were conducted in four federally designated Health Professional Shortage Areas. Respondents were parents or caregivers of children ages 12-35 months: 847 from northern Manhattan, 843 from Detroit, 771 from San Diego, and 1,091 from rural Colorado. A child was considered up-to-date (UTD) with vaccinations at 3 months of age if documentation of receipt of diphtheria-tetanus-pertussis, polio, haemophilus influenzae type B, and hepatitis B vaccines was obtained from a provider or a hand-held vaccination card, or both. RESULTS: Household response rates ranged from 79% to 88% across sites. Vaccination coverage levels at 3 months of age varied across sites: 82.4% in northern Manhattan, 70.5% in Detroit, 82.3% in San Diego, and 75.8% in rural Colorado. Among children who were not UTD, the majority (65.7% to 71.5% per site) had missed vaccines due to missed opportunities. Factors associated with not being UTD varied by site and included having public or no insurance, >/=2 children living in the household, and the adult respondent being unmarried. At all sites, vaccination coverage among WIC enrollees was higher than coverage among children eligible for but not enrolled in WIC, but the association between UTD status and WIC enrollment was statistically significant for only one site and marginally significant for two other sites. CONCLUSIONS: Missed opportunities were a significant barrier to vaccinations, even at this early age. Practice-based strategies to reduce missed opportunities and prenatal WIC enrollment should be focused especially toward those at highest risk of underimmunization.
doi:10.1016/j.phr.2004.07.005
PMCID: PMC1497657  PMID: 15313111
4.  Evaluation of immunization coverage within the Expanded Program on Immunization in Kita Circle, Mali: a cross-sectional survey 
Background
In 1986, the Government of Mali launched its Expanded Program on Immunization (EPI) with the goal of vaccinating, within five years, 80% of all children under the age of five against six target diseases: diphtheria, tetanus, pertussis, poliomyelitis, tuberculosis, and measles. The Demographic and Health Survey carried out in 2001 revealed that, in Kita Circle, in the Kayes region, only 13% of children aged 12 to 23 months had received all the EPI vaccinations. A priority program was implemented in 2003 by the Regional Health Department in Kayes to improve EPI immunization coverage in this area.
Methods
A cross-sectional survey using Henderson's method (following the method used by the Demographic and Health Surveys) was carried out in July 2006 to determine the level of vaccination coverage among children aged 12 to 23 months in Kita Circle, after implementation of the priority program. Both vaccination cards and mothers' declarations (in cases where the mother cannot make the declaration, it is made by the person responsible for the child) were used to determine coverage.
Results
According to the vaccination cards, 59.9% [CI 95% (54.7-64.8)] of the children were fully vaccinated, while according to the mothers' declarations the rate was 74.1% [CI 95% (69.3-78.4)]. The drop-out rate between DTCP1 and DTCP3 was 5.5%, according to the vaccination cards. The rate of immunization coverage was higher among children whose mothers had received the anti-tetanus vaccine [OR = 2.1, CI 95% (1.44-3.28)]. However, our study found no difference associated with parents' knowledge about EPI diseases, distance from the health centre, or socio-economic status. Lack of information was one reason given for children not being vaccinated against the six EPI diseases.
Conclusion
Three years after the implementation of the priority program (which included decentralization, the active search for missing children, and deployment of health personnel, material and financial resources), our evaluation of the vaccination coverage rates shows that there is improvement in the EPI immunization coverage rate in Kita Circle. The design of our study did not, however, enable us to determine the extent to which different aspects of the program contributed to this increase in coverage. Efforts should nevertheless be continued, in order to reach the goal of 80% immunization coverage.
Abstract in French
See the full article online for a translation of this abstract in French.
doi:10.1186/1472-698X-9-S1-S13
PMCID: PMC3226232  PMID: 19828057
5.  Predicting Patterns of Long-Term CD4 Reconstitution in HIV-Infected Children Starting Antiretroviral Therapy in Sub-Saharan Africa: A Cohort-Based Modelling Study 
PLoS Medicine  2013;10(10):e1001542.
Using data from the ARROW trial, Joanna Lewis and colleagues investigate the CD4 cell count recovery profiles of children infected with HIV starting antiretroviral therapy in Sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery.
Methods and Findings
CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4–17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization–recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled.
Conclusions
Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.3 million children under 15 years old are infected with HIV, the virus that causes AIDS. More than 90% of these children live in sub-Saharan Africa, where nearly 600 children become infected with HIV every day, usually acquiring the virus from their mother during pregnancy, birth, or breastfeeding. HIV gradually reduces the numbers of CD4 lymphocytes in the immune system, leaving infected individuals susceptible to other infections. HIV infection can be kept in check but not cured with antiretroviral therapy (ART)—cocktails of drugs that have to be taken every day throughout life. ART reduces the amount of virus in the blood (viral load), which allows the immune system to recover (long-term immune reconstitution). Unfortunately, ART is very expensive, but concerted international efforts over the past decade mean that about a third of children who need ART are now receiving it, including half a million children in sub-Saharan Africa.
Why Was This Study Done?
World Health Organization (WHO) guidelines recommend initiation of ART at age-related CD4 cell count thresholds based on the risk of short-term disease progression. The guidelines recommend that all HIV-positive children under two years old begin ART as soon they receive a diagnosis of HIV infection. For children aged 2–5 years, ART initiation is recommended once the CD4 count drops below 750 cells/µl blood, whereas for older children the threshold for ART initiation is 350 CD4 cells/µl. Because of improved ART coverage, many more HIV-infected children now survive into adulthood than in the past. It is therefore important to know how the timing of ART initiation in childhood affects long-term immune reconstitution. Unfortunately, although several studies have examined the effect of ART on immune reconstitution in adults, the results of these studies cannot be extrapolated to children because of age-related differences in immune reconstitution. In this cohort-based modelling study, the researchers investigate long-term CD4 recovery in a cohort (group) of HIV-infected children initiating ART in Uganda and Zimbabwe, and present statistical models that predict patterns of long-term CD4 status based on age and CD4 count at ART initiation.
What Did the Researchers Do and Find?
To investigate long-term CD4 reconstitution in children, the researchers used CD4 counts collected during the ARROW trial, a study designed to investigate monitoring strategies during first-line ART in 1,206 HIV-positive children. In three-quarters of the children, CD4 reconstitution following ART initiation was asymptotic—CD4 counts increased rapidly immediately after ART initiation, then slowed before eventually reaching a constant level of about 80% of the CD4 count expected in an uninfected child of the same age. Using a nonlinear mixed-effects statistical model that fitted this pattern of immune reconstitution, the researchers predicted CD4 trajectories for children starting ART at different ages and with different CD4 counts. Higher long-term counts were predicted for children starting ART earlier and with higher CD4 counts. Thus, to achieve a CD4 count greater than 700 cells/µl at age 20 years, CD4 counts of at least 96 cells/µl, 130 cells/µl, and 557 cells/µl are needed for children aged two, five, and 12 years, respectively, when they initiate ART. Qualitatively distinct reconstitution patterns were seen in the remaining children in the study.
What Do These Findings Mean?
These findings suggest that young HIV-positive, ART-naïve children can achieve high CD4 counts in later life, provided ART is initiated as recommended in the current WHO guidelines. However, the recommended CD4 count thresholds for ART initiation are unlikely to maximize immune reconstitution in treatment-naïve children over ten years old. Rather, these findings suggest that ART initiation should be considered in these older children when their CD4 count is still high—even though they have a low risk of immediate disease progression—in order to achieve higher long-term CD4 levels. The omission of viral load measurements in the researchers' model may limit the accuracy of these findings. Moreover, although the predictions made by the model apply to children who will go on to experience asymptotic recovery, they are less relevant to those with different recovery profiles, who cannot currently be accurately identified. Further exploration of the immunological mechanisms underlying the CD4 recovery profiles described here should improve our understanding of the factors that determine the response of HIV-positive children to ART and provide information to guide the management of HIV infections in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001542.
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 and AIDS in Africa and on HIV infection in children (in English and Spanish)
The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the UNAIDS's 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children can be downloaded
Information about the ARROW trial is available
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001542
PMCID: PMC3812080  PMID: 24204216
6.  Incident HIV during Pregnancy and Postpartum and Risk of Mother-to-Child HIV Transmission: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(2):e1001608.
Alison Drake and colleagues conduct a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy and the postpartum period and to compare mother-to-child HIV transmission risk among women with incident versus chronic infection.
Please see later in the article for the Editors' Summary
Background
Women may have persistent risk of HIV acquisition during pregnancy and postpartum. Estimating risk of HIV during these periods is important to inform optimal prevention approaches. We performed a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy/postpartum and to compare mother-to-child HIV transmission (MTCT) risk among women with incident versus chronic infection.
Methods and Findings
We searched PubMed, Embase, and AIDS-related conference abstracts between January 1, 1980, and October 31, 2013, for articles and abstracts describing HIV acquisition during pregnancy/postpartum. The inclusion criterion was studies with data on recent HIV during pregnancy/postpartum. Random effects models were constructed to pool HIV incidence rates, cumulative HIV incidence, hazard ratios (HRs), or odds ratios (ORs) summarizing the association between pregnancy/postpartum status and HIV incidence, and MTCT risk and rates. Overall, 1,176 studies met the search criteria, of which 78 met the inclusion criterion, and 47 contributed data. Using data from 19 cohorts representing 22,803 total person-years, the pooled HIV incidence rate during pregnancy/postpartum was 3.8/100 person-years (95% CI 3.0–4.6): 4.7/100 person-years during pregnancy and 2.9/100 person-years postpartum (p = 0.18). Pooled cumulative HIV incidence was significantly higher in African than non-African countries (3.6% versus 0.3%, respectively; p<0.001). Risk of HIV was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6) than among non-pregnant/non-postpartum women in five studies with available data. In African cohorts, MTCT risk was significantly higher among women with incident versus chronic HIV infection in the postpartum period (OR 2.9, 95% CI 2.2–3.9) or in pregnancy/postpartum periods combined (OR 2.3, 95% CI 1.2–4.4). However, the small number of studies limited power to detect associations and sources of heterogeneity.
Conclusions
Pregnancy and the postpartum period are times of persistent HIV risk, at rates similar to “high risk” cohorts. MTCT risk was elevated among women with incident infections. Detection and prevention of incident HIV in pregnancy/postpartum should be prioritized, and is critical to decrease MTCT.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.4 million children younger than 15 years old (mostly living in sub-Saharan Africa) are infected with HIV, the virus that causes AIDS by gradually destroying immune system cells, thereby leaving infected individuals susceptible to other serious infections. In 2012 alone, 230,000 children (more than 700 every day) were newly infected with HIV. Most HIV infections among children are the result of mother-to-child HIV transmission (MTCT) during pregnancy, delivery, or breastfeeding. The rate of MTCT (and deaths among HIV-positive pregnant women from complications related to HIV infection) can be greatly reduced by testing women for HIV infection during pregnancy (antenatal HIV testing), treating HIV-positive women with antiretroviral drugs (ARVs, powerful drugs that control HIV replication and allow the immune system to recover) during pregnancy, delivery, and breastfeeding, and giving ARVs to their newborn babies.
Why Was This Study Done?
The World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have developed a global plan that aims to move towards eliminating new HIV infections among children by 2015 and towards keeping their mothers alive. To ensure the plan's success, the incidence of HIV (the number of new infections) among women and the rate of MTCT must be reduced by increasing ARV uptake by mothers and their infants for the prevention of MTCT. However, the risk of HIV infection among pregnant women and among women who have recently given birth (postpartum women) is poorly understood because, although guidelines recommend repeat HIV testing during late pregnancy or at delivery in settings where HIV infection is common, pregnant women are often tested only once for HIV infection. The lack of retesting represents a missed opportunity to identify pregnant and postpartum women who have recently acquired HIV and to prevent MTCT by initiating ARV therapy. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a study that uses statistical methods to combine the results of several studies), the researchers estimate maternal HIV incidence during pregnancy and the postpartum period, and compare the risk of MTCT among women with incident (new) and chronic (long-standing) HIV infection.
What Did the Researchers Do and Find?
The researchers identified 47 studies (35 undertaken in Africa) that examined recent HIV acquisition by women during pregnancy and the 12-month postpartum period. They used random effects statistical models to estimate the pooled HIV incidence rate and cumulative HIV incidence (the number of new infections per number of people at risk), and the association between pregnancy/postpartum status and HIV incidence and MTCT risk and rates. The pooled HIV incidence rate among pregnant/postpartum women estimated from 19 studies (all from sub-Saharan Africa) that reported HIV incidence rates was 3.8/100 person-years. The pooled cumulative HIV incidence was significantly higher in African countries than in non-African countries (3.6% and 0.3%, respectively; a “significant” difference is one that is unlikely to arise by chance). In the five studies that provided suitable data, the risk of HIV acquisition was similar in pregnant, postpartum, and non-pregnant/non-postpartum women. Finally, among African women, the risk of MTCT was 2.9-fold higher during the postpartum period among those who had recently acquired HIV than among those with chronic HIV infection, and 2.3-fold higher during the pregnancy/postpartum periods combined.
What Do These Findings Mean?
These results suggest that women living in regions where HIV infection is common are at high risk of acquiring HIV infection during pregnancy and the postpartum period and that mothers who acquire HIV during pregnancy or postpartum are more likely to pass the infection on to their offspring than mothers with chronic HIV infections. However, the small number of studies included in this meta-analysis and the use of heterogeneous research methodologies in these studies may limit the accuracy of these findings. Nevertheless, these findings have important implications for the global plan to eliminate HIV infections in children. First, they suggest that women living in regions where HIV infection is common should be offered repeat HIV testing (using sensitive methods to enhance early detection of infection) during pregnancy and in the postpartum period to detect incident HIV infections, and should be promptly referred to HIV care and treatment. Second, they suggest that prevention of HIV transmission during pregnancy and postpartum should be prioritized, for example, by counseling women about the need to use condoms to prevent transmission during this period of their lives.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001608.
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 children and HIV/AIDS and on the prevention of mother-to-child transmission of HIV (in English and Spanish)
The 2013 UNAIDS World AIDS Day Report provides information about the AIDS epidemic and efforts to halt it; the 2013 UNAIDS Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children; the UNAIDS Believe it. Do it website provides information about the campaign to support the UNAIDS global plan
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, NAM/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001608
PMCID: PMC3934828  PMID: 24586123
7.  Immunization Status of Children Admitted to a Tertiary-care Hospital of North India: Reasons for Partial Immunization or Non-immunization 
Reasons for the low coverage of immunization vary from logistic ones to those dependent on human behaviour. The study was planned to find out: (a) the immunization status of children admitted to a paediatric ward of tertiary-care hospital in Delhi, India and (b) reasons for partial immunization and non-immunization. Parents of 325 consecutively-admitted children aged 12–60 months were interviewed using a semi-structured questionnaire. A child who had missed any of the vaccines given under the national immunization programme till one year of age was classified as partially-immunized while those who had not received any vaccine up to 12 months of age or received only pulse polio vaccine were classified as non-immunized. Reasons for partial/non-immunization were recorded using open-ended questions. Of the 325 children (148 males, 177 females), 58 (17.84%) were completely immunized, 156 (48%) were partially immunized, and 111 (34.15%) were non-immunized. Mothers were the primary respondents in 84% of the cases. The immunization card was available with 31.3% of the patients. All 214 partially- or completely-immunized children received BCG, 207 received OPV/DPT1, 182 received OPV/DPT2, 180 received OPV/DPT3, and 115 received measles vaccines. Most (96%) received pulse polio immunization, including 98 of the 111 non-immunized children. The immunization status varied significantly (p<0.05) with sex, education of parents, urban/rural background, route and place of delivery. On logistic regression, place of delivery [odds ratio (OR): 2.3, 95% confidence interval (CI) 1.3–4.1], maternal education (OR=6.94, 95% CI 3.1–15.1), and religion (OR=1.75, 95% CI 1.2–3.1) were significant (p<0.05). The most common reasons for partial or non-immunization were: inadequate knowledge about immunization or subsequent dose (n=140, 52.4%); belief that vaccine has side-effects (n=77, 28.8%); lack of faith in immunization (n=58, 21.7%); or oral polio vaccine is the only vaccine required (n=56, 20.9%. Most (82.5%) children admitted to a tertiary-care hospital were partially immunized or non-immunized. The immunization status needs to be improved by education, increasing awareness, and counselling of parents and caregivers regarding immunizations and associated misconceptions as observed in the study.
PMCID: PMC2980896  PMID: 20635642
Child; Immunization; Vaccination; India
8.  Is Economic Growth Associated with Reduction in Child Undernutrition in India? 
PLoS Medicine  2011;8(3):e1000424.
An analysis of cross-sectional data from repeated household surveys in India, combined with data on economic growth, fails to find strong evidence that recent economic growth in India is associated with a reduction in child undernutrition.
Background
Economic growth is widely perceived as a major policy instrument in reducing childhood undernutrition in India. We assessed the association between changes in state per capita income and the risk of undernutrition among children in India.
Methods and Findings
Data for this analysis came from three cross-sectional waves of the National Family Health Survey (NFHS) conducted in 1992–93, 1998–99, and 2005–06 in India. The sample sizes in the three waves were 33,816, 30,383, and 28,876 children, respectively. After excluding observations missing on the child anthropometric measures and the independent variables included in the study, the analytic sample size was 28,066, 26,121, and 23,139, respectively, with a pooled sample size of 77,326 children. The proportion of missing data was 12%–20%. The outcomes were underweight, stunting, and wasting, defined as more than two standard deviations below the World Health Organization–determined median scores by age and gender. We also examined severe underweight, severe stunting, and severe wasting. The main exposure of interest was per capita income at the state level at each survey period measured as per capita net state domestic product measured in 2008 prices. We estimated fixed and random effects logistic models that accounted for the clustering of the data. In models that did not account for survey-period effects, there appeared to be an inverse association between state economic growth and risk of undernutrition among children. However, in models accounting for data structure related to repeated cross-sectional design through survey period effects, state economic growth was not associated with the risk of underweight (OR 1.01, 95% CI 0.98, 1.04), stunting (OR 1.02, 95% CI 0.99, 1.05), and wasting (OR 0.99, 95% CI 0.96, 1.02). Adjustment for demographic and socioeconomic covariates did not alter these estimates. Similar patterns were observed for severe undernutrition outcomes.
Conclusions
We failed to find consistent evidence that economic growth leads to reduction in childhood undernutrition in India. Direct investments in appropriate health interventions may be necessary to reduce childhood undernutrition in India.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Good nutrition during childhood is essential for health and survival. Undernourished children are more susceptible to infections and more likely to die from common ailments such as diarrhea than well-nourished children. Thus, globally, undernutrition contributes to more than a third of deaths among children under 5 years old. Experts use three physical measurements to determine whether a child is undernourished. An "underweight" child has a low weight for his or her age and gender when compared to the World Health Organization Child Growth Standards, which chart the growth of a reference population. A "stunted" child has a low height for his or her age; stunting is an indicator of chronic undernutrition. A "wasted" child has a low weight for his or her height; wasting is an indicator of acute undernutrition and often follows an earthquake, flood, or other emergency. The prevalence (how often a condition occurs within a population) of undernutrition is particularly high in India. Here, almost half of children under the age of 3 are underweight, about half are stunted, and a quarter are wasted.
Why Was This Study Done?
Although the prevalence of undernutrition in India is decreasing, progress is slow. Economic growth is widely regarded as the major way to reduce child undernutrition in India. Economic growth, the argument goes, will increase incomes, reduce poverty, and increase access to health services and nutrition. But some experts believe that better education for women and reduced household sizes might have a greater influence on child undernutrition than economic growth. And others believe that healthier, better fed populations lead to increased economic growth rather than the other way around. In this study, the researchers assess the association between economic growth and child undernutrition in India by analyzing the relationship between changes in per capita income in individual Indian states and the individual risk of undernutrition among children in India.
What Did the Researchers Do and Find?
For their analyses, the researchers used data on 77,326 Indian children that were collected in the 1992–93, 1998–99, and 2005–06 National Family Health Surveys; these surveys are part of the Demographic and Health Surveys, a project that collects health data in developing countries to aid health-system development. The researchers used eight "ecological" statistical models to investigate whether there was an association between underweight, stunting, or wasting and per capita income at the state level in each survey period; these ecological models assumed that the risk of undernutrition was the same for every child in a state. They also used 10 "multilevel" models to quantify the association between state-level growth and the individual-level risk of undernutrition. The multilevel models also took account of various combinations of additional factors likely to affect undernutrition (for example, mother's education and marital status). In five of the ecological models, there was no statistically significant association between state economic growth and average levels of child undernutrition at the state level (statistically significant associations are unlikely to have arisen by chance). Similarly, in eight of the multilevel models, there was no statistical evidence for an association between economic growth and undernutrition.
What Do These Findings Mean?
These findings provide little statistical support for the widely held assumption that there is an association between the risk of child undernutrition and economic growth in India. By contrast, a previous study that used data from 63 countries collected over 26 years did find evidence that national economic growth was inversely associated with the risk of child undernutrition. However, this study was an ecological study and did not, therefore, allow for the possibility that the risk of undernutrition might vary between children in one state and between states. Further, the target of inference in this study was "explaining" between-country differences, while the target of inference in this analysis was explaining within country differences over time. The researchers suggest several reasons why there might not be a clear association between economic growth and undernutrition in India. For example, they suggest, economic growth in India might have only benefitted privileged sections of society. Whether this or an alternative explanation accounts for the lack of an association, it seems likely that further reductions in the prevalence of child undernutrition in India (and possibly in other developing countries) will require direct investment in health and health-related programs; expecting economic growth to improve child undernutrition might not be a viable option after all.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000424.
The charity UNICEF, which protects the rights of children and young people around the world, provides detailed statistics on child undernutrition and on child nutrition and undernutrition in India
The WHO Child Growth Standards are available (in several languages)
More information on the Demographic and Health Surveys and on the Indian National Family Health Surveys is available
The United Nations Millennium Development Goals website provides information on ongoing world efforts to reduce hunger and child mortality
doi:10.1371/journal.pmed.1000424
PMCID: PMC3050933  PMID: 21408084
9.  Immunization coverage of 12–23 months old children and associated factors in Jigjiga District, Somali National Regional State, Ethiopia 
BMC Public Health  2014;14(1):865.
Background
Immunization coverage in Ethiopia is less than the herd immunity level desired to prevent the spread of eight target diseases targeted by the World Health Organization’s Expanded Program of Immunization. In particular, the Somali region of the country still has by far the lowest level of immunization coverage. The objective of this study was to measure the immunization coverage of 12–23 months old children and associated factors in the urban and rural areas of Jigjiga district.
Methods
A community based cross-sectional survey was conducted in 582 households with 12–23 months old children in two urban and four rural wards. The data were collected from mothers or caregivers through interviews based on pre-tested and structured questionnaires and from the review of vaccination cards. Data were processed using SPSS version 16. To identify factors associated with the immunization status of children, bivariate and multiple logistic regression analyses were worked out and the Hoshmer and Lemeshow’s goodness-of-fit was used to assess the fitness of multiple logistic regression model.
Results
Three–fourth (74.6%) of the children surveyed were ever vaccinated, whereas 36.6% were fully vaccinated. The immunization coverage rate from card assessment for Bacillus Calmette-Guérin was 41.8%, while for Oral Polio Vaccine Zero, Oral Polio Vaccine One /Pentavalent1, Oral Polio Vaccine Two /Pentavalent2, Oral Polio Vaccine Three /Pentavalent3, and measles were 10.4%, 41.1%, 33.9%, 27.5%, and 24.9%, respectively. Maternal literacy (AOR = 3.06, 95% CI = 1.64, 5.71), Tetanus Toxoid Vaccine (AOR = 2.43, 95% CI = 1.56, 3.77), place of delivery (AOR = 2.02, 95% CI = 1.24, 3.28), place of residence (AOR = 2.04, 95% CI = 1.33, 3.13), and household visits by health workers (AOR = 1.92, 95% CI = 1.17, 3.16), were found to be factors significantly associated with full immunization in the multivariate logistic regression analysis.
Conclusions
The overall immunization coverage was found to be low. Hence, to increase the immunization coverage and reduce the incidences of missed opportunity, delivery in the health institution should be promoted, the outreach activities of the health institutions should be strengthened and greater utilization of health services by mothers should be encouraged.
doi:10.1186/1471-2458-14-865
PMCID: PMC4158082  PMID: 25146502
Immunization coverage; Vaccination; Children; Ethiopia
10.  The impact of missed opportunities on seasonal influenza vaccination coverage for healthy young children 
Objective
To estimate the impact of missed opportunities on influenza vaccination coverage among 6 through 23 month old children who sought medical care during the 2004–2005 influenza season.
Design
Retrospective cohort study
Setting
Fifty two primary care practice sites located in Rochester New York, Nashville Tennessee and Cincinnati Ohio
Participants
Children 6 through 23 months of age
Methods/Outcome Measure
Charts were reviewed and data collected on influenza vaccinations, type of health care visit (well-child or other), and presence of illness symptoms. Missed opportunity was defined as a practice visit by an eligible child during influenza season, when vaccine was available, but during which the child did not receive an influenza vaccination. Vaccine was assumed to be available between the first and last dates influenza vaccination was recorded at that practice. Each child was classified as fully vaccinated, partially vaccinated or unvaccinated.
Results
Data were analyzed for 1724 children 6 through 23 months. Most children (62.0%) had at least one missed opportunity during this period. Among children with any missed opportunities, 12.8% were fully and 29.8% were partially vaccinated. Overall, 33.6% of missed opportunities occurred during well child visits and 66.4% during other types of visits; 75% occurred when no other vaccines were given. Eliminating all missed opportunities would have increased full vaccination coverage from 30.3% to 49.9%.
Conclusions
Missed opportunities for influenza vaccination are frequent. Reducing missed opportunities could significantly increase influenza vaccination rates and should be a goal in each practice.
doi:10.1097/PHH.0b013e31821831c3
PMCID: PMC3713481  PMID: 21964369
vaccination; child health services; influenza; human
11.  Toward an Understanding of Disengagement from HIV Treatment and Care in Sub-Saharan Africa: A Qualitative Study 
PLoS Medicine  2013;10(1):e1001369.
Norma Ware and colleagues conducted a large qualitative study among patients in HIV treatment programs in sub-Saharan Africa to investigate reasons for missed visits and provide an explanation for disengagement from care.
Background
The rollout of antiretroviral therapy in sub-Saharan Africa has brought lifesaving treatment to millions of HIV-infected individuals. Treatment is lifelong, however, and to continue to benefit, patients must remain in care. Despite this, systematic investigations of retention have repeatedly documented high rates of loss to follow-up from HIV treatment programs. This paper introduces an explanation for missed clinic visits and subsequent disengagement among patients enrolled in HIV treatment and care programs in Africa.
Methods and Findings
Eight-hundred-ninety patients enrolled in HIV treatment programs in Jos, Nigeria; Dar es Salaam, Tanzania; and Mbarara, Uganda who had extended absences from care were tracked for qualitative research interviews. Two-hundred-eighty-seven were located, and 91 took part in the study. Interview data were inductively analyzed to identify reasons for missed visits and to assemble them into a broader explanation of how missed visits may develop into disengagement. Findings reveal unintentional and intentional reasons for missing, along with reluctance to return to care following an absence. Disengagement is interpreted as a process through which missed visits and ensuing reluctance to return over time erode patients' subjective sense of connectedness to care.
Conclusions
Missed visits are inevitable over a lifelong course of HIV care. Efforts to prevent missed clinic visits combined with moves to minimize barriers to re-entry into care are more likely than either approach alone to keep missed visits from turning into long-term disengagement.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The human immunodeficiency virus (HIV) infects cells of the immune system, destroying or impairing their function. As the infection progresses, the immune system becomes weaker, and the affected person becomes more susceptible to life-threatening infections. Over the past three decades, 25 million people have died from HIV, and according to the World Health Organization, in 2011, there were roughly 34.2 million people living with HIV, over 60% of whom lived in sub-Saharan Africa. Although HIV cannot be cured, the virus can be suppressed by combination antiretroviral therapy (ART) consisting of three or more antiretroviral drugs. ART controls viral replication and strengthens the immune system, allowing the affected person to fight off infections. With ART, HIV can be managed as a chronic disease: people living with HIV can live healthy lives as long as they take antiretroviral drugs regularly for the rest of their lives.
Why Was This Study Done?
Unfortunately, poor retention in HIV programs is a huge problem: a large proportion—30%–60% in some settings in sub-Saharan Africa—of people starting ART, are lost to follow-up and stop taking treatment. Few studies have looked in depth at the reasons why people with HIV in sub-Saharan Africa miss clinic appointments or even stop coming altogether. So in this study in Tanzania, Uganda, and Nigeria, the researchers did a qualitative analysis from the patients' perspective on the reasons for missing clinic visits. Qualitative research can use information-gathering techniques, such as open-ended interviews, to develop an in-depth understanding of human behavior and the reasons behind such behavior.
What Did the Researchers Do and Find?
The researchers indentified people to interview by using “tracking lists” from HIV/AIDS care clinics in the three countries—patient tracking by clinical trackers is increasingly used as a way to contact patients who have missed clinic appointments. The researchers included people in the study who had been tracked and contacted by clinic trackers, had been absent from the clinic for three months or more, and gave consent to be re-contacted by the researchers. The researchers interviewed participants, using their local language, on several topics, including their experiences of care at the clinic and of tracking, and the circumstances of missed appointments. The detailed accounts were transcribed, and then the researchers categorized the reasons for missing appointments into intentional and unintentional reasons.
Eight-hundred-ninety patients in the three countries were tracked during the study period, but only 287 were located, of whom 91 participated in the study. Of the 91 participants, 76 were being prescribed ART, and 15 had not started treatment. The main unintentional reason for missing clinic visits was a conflicting demand on the patients' time, which was often unexpected and for complex reasons, such as caring for a dying relative, going to a funeral, or traveling to work. These reasons were often transient and changed over time. Intentional reasons were often related to dissatisfaction with the care received at the clinic, especially “the harsh treatment” they received from health workers, which typically referred to behavior perceived by patients to be rude. For example, participants reported being spoken to “roughly” or feeling that the clinic staff “didn't care.” Such behavior made patients feel hurt, humiliated, and angry, and reluctant to return to the clinic. The researchers found that, overall, disengagement from care appeared to be a process through which missed visits and subsequent reluctance to return over time eroded patients' sense of connectedness to care.
What Do These Findings Mean?
Absences from care will be inevitable over a lifetime course of treatment for HIV/AIDS. These findings indicate that absences may be unintentional as well as intentional, and that the reasons are complex and can change over time. Initial reasons for missing may disappear, leaving patients free, but reluctant, to return to care. Reasons for reluctance include shame at having been absent and the anticipation of a negative response to return from care providers. Patient education for ART initiation in sub-Saharan Africa often includes stern warnings about the lifelong commitment beginning ART represents. Paradoxically, educational efforts intended to maximize the benefits of ART for patients may be driving some away from care. Therefore, efforts to prevent missed clinic visits coupled with strategies to minimize any obstacles to coming back to care are necessary to keep patients' missed visits from turning into long-term disengagement from treatment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001369.
This study is further discussed in a PLOS Medicine Perspective by Edward Mills
The World Health Organization has the latest data on access to ART
The US National Institute of Allergy and Infectious Diseases has more information on types of ART, and also on adherence to treatment
The US Centers for Disease Control and Prevention has some information about interventions to help improve adherence
doi:10.1371/journal.pmed.1001369
PMCID: PMC3541407  PMID: 23341753
12.  Commercial Serological Tests for the Diagnosis of Active Pulmonary and Extrapulmonary Tuberculosis: An Updated Systematic Review and Meta-Analysis 
PLoS Medicine  2011;8(8):e1001062.
An up-to-date systematic review and meta-analysis by Karen Steingart and colleagues confirms that commercially available serological tests do not provide an accurate diagnosis of tuberculosis.
Background
Serological (antibody detection) tests for tuberculosis (TB) are widely used in developing countries. As part of a World Health Organization policy process, we performed an updated systematic review to assess the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary TB with a focus on the relevance of these tests in low- and middle-income countries.
Methods and Findings
We used methods recommended by the Cochrane Collaboration and GRADE approach for rating quality of evidence. In a previous review, we searched multiple databases for papers published from 1 January 1990 to 30 May 2006, and in this update, we add additional papers published from that period until 29 June 2010. We prespecified subgroups to address heterogeneity and summarized test performance using bivariate random effects meta-analysis. For pulmonary TB, we included 67 studies (48% from low- and middle-income countries) with 5,147 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (31% to 100%). For anda-TB IgG, the only test with enough studies for meta-analysis, pooled sensitivity was 76% (95% CI 63%–87%) in smear-positive (seven studies) and 59% (95% CI 10%–96%) in smear-negative (four studies) patients; pooled specificities were 92% (95% CI 74%–98%) and 91% (95% CI 79%–96%), respectively. Compared with ELISA (pooled sensitivity 60% [95% CI 6%–65%]; pooled specificity 98% [95% CI 96%–99%]), immunochromatographic tests yielded lower pooled sensitivity (53%, 95% CI 42%–64%) and comparable pooled specificity (98%, 95% CI 94%–99%). For extrapulmonary TB, we included 25 studies (40% from low- and middle-income countries) with 1,809 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (59% to 100%). Overall, quality of evidence was graded very low for studies of pulmonary and extrapulmonary TB.
Conclusions
Despite expansion of the literature since 2006, commercial serological tests continue to produce inconsistent and imprecise estimates of sensitivity and specificity. Quality of evidence remains very low. These data informed a recently published World Health Organization policy statement against serological tests.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year nearly 10 million people develop tuberculosis—a contagious bacterial infection—and about two million people die from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze. It usually infects the lungs (pulmonary tuberculosis) but can also infect the lymph nodes, bones, and other tissues (extrapulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Diagnostic tests for the disease include microscopic examination of sputum (mucus brought up from the lungs by coughing) for M. tuberculosis bacilli, chest radiography, mycobacterial culture (in which bacteriologists try to grow M. tuberculosis from sputum or tissue samples), and nucleic acid amplification tests (which detect the bacterium's genome in patient samples). Tuberculosis can usually be cured by taking several powerful drugs daily or several times a week for at least six months.
Why Was This Study Done?
Although efforts to control tuberculosis have advanced over the past decade, missed tuberculosis diagnoses and mismanaged tuberculosis continue to fuel the global epidemic. A missed diagnosis may lead to more severe illness and death, especially for people infected with both tuberculosis and HIV. Also, a missed diagnosis means that an untreated individual with pulmonary tuberculosis may remain infectious for longer, continuing to spread tuberculosis within the community Missed diagnoses are a particular problem in resource-limited countries where sputum microscopy and chest radiography often perform poorly and other diagnostic tests are too expensive and complex for routine use. Serological tests, which detect antibodies against M. tuberculosis in the blood (antibodies are proteins made by the immune system in response to infections), might provide a way to diagnose tuberculosis in resource-limited countries. Indeed, many serological tests for tuberculosis diagnosis are on sale in developing countries. However, because of doubts about the accuracy of these commercial tests, they are not recommended for use in routine practice. In this systematic review and meta-analysis, the researchers assess the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary tuberculosis. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers searched the literature for studies that evaluated serological tests for active tuberculosis published between 1990 and 2010. They used data from these studies to calculate each test's sensitivity (the proportion of patients with a positive serological test among patients with tuberculosis confirmed by a reference method; a high sensitivity indicates that the test detects most patients with tuberculosis) and specificity (the proportion of patients with a negative serological result among people without tuberculosis; a high specificity means the test gives few false-positive diagnoses). They also assessed the methodological quality of each study and rated the overall quality of the evidence. The researchers found 67 studies (half from low/middle-income countries) that evaluated serological tests for the diagnosis of pulmonary tuberculosis. The sensitivity of these tests varied between studies, ranging from 0% to 100%; their specificities ranged from 31% to 100%. For the anda-TB IgG test—the only test with sufficient studies for a meta-analysis—the pooled sensitivity from the relevant studies was 76% in smear-positive patients and 59% in smear-negative patients. The pooled specificities were 92% and 91%, respectively. The researchers found 25 studies (40% from low/middle-income countries) that evaluated serological tests for the diagnosis of extrapulmonary tuberculosis. Again, sensitivities and specificities for each test varied greatly between studies, ranging from 0% to 100% and 59% to 100%, respectively. Overall, for both pulmonary and extrapulmonary tuberculosis, the quality of evidence from the studies of the serological tests was graded very low.
What Do These Findings Mean?
This systematic review, which updates an analysis published in 2007, indicates that commercial serological tests do not provide an accurate diagnosis of tuberculosis. This finding confirms previous systematic reviews of the evidence, despite a recent expansion in the relevant literature. Moreover, the researchers' analysis indicates that the overall quality of the body of evidence on these tests remains poor. Many of the identified studies used unsatisfactory patient selection methods, for example. Clearly, there is a need for continued and improved research on existing serological tests and for research into new approaches to the serological diagnosis of tuberculosis. For now, though, based on these findings, cost-effectiveness data, and expert opinion, the World Health Organization has issued a recommendation against the use of currently available serological tests for the diagnosis of tuberculosis, while stressing the importance of continued research on these and other tests that could provide quick and accurate diagnosis of TB.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001062.
The World Health Organization provides information on all aspects of tuberculosis, including information on tuberculosis diagnostics on the Stop TB Partnership (some information is in several languages); the Strategic and Technical Advisory Group for Tuberculosis recommendations on tuberculosis diagnosis are available
The Web site Evidence-Based Tuberculosis Diagnosis (from Stop TB Partnership's New Diagnostics Working Group) provides access to several resources on TB diagnostics, including systematic reviews, guidelines, and training materials
The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the diagnosis of tuberculosis disease
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001062
PMCID: PMC3153457  PMID: 21857806
13.  Can Prenatal Malaria Exposure Produce an Immune Tolerant Phenotype?: A Prospective Birth Cohort Study in Kenya 
PLoS Medicine  2009;6(7):e1000116.
In a prospective cohort study of newborns residing in a malaria holoendemic area of Kenya, Christopher King and colleagues find a subset of children born to malaria-infected women who acquire a tolerant phenotype, which persists into childhood and is associated with increased susceptibility to malarial infection and anemia.
Background
Malaria in pregnancy can expose the fetus to malaria-infected erythrocytes or their soluble products, thereby stimulating T and B cell immune responses to malaria blood stage antigens. We hypothesized that fetal immune priming, or malaria exposure in the absence of priming (putative tolerance), affects the child's susceptibility to subsequent malaria infections.
Methods and Findings
We conducted a prospective birth cohort study of 586 newborns residing in a malaria-holoendemic area of Kenya who were examined biannually to age 3 years for malaria infection, and whose malaria-specific cellular and humoral immune responses were assessed. Newborns were classified as (i) sensitized (and thus exposed), as demonstrated by IFNγ, IL-2, IL-13, and/or IL-5 production by cord blood mononuclear cells (CBMCs) to malaria blood stage antigens, indicative of in utero priming (n = 246), (ii) exposed not sensitized (mother Plasmodium falciparum [Pf]+ and no CBMC production of IFNγ, IL-2, IL-13, and/or IL-5, n = 120), or (iii) not exposed (mother Pf−, no CBMC reactivity, n = 220). Exposed not sensitized children had evidence for prenatal immune experience demonstrated by increased IL-10 production and partial reversal of malaria antigen-specific hyporesponsiveness with IL-2+IL-15, indicative of immune tolerance. Relative risk data showed that the putatively tolerant children had a 1.61 (95% confidence interval [CI] 1.10–2.43; p = 0.024) and 1.34 (95% CI 0.95–1.87; p = 0.097) greater risk for malaria infection based on light microscopy (LM) or PCR diagnosis, respectively, compared to the not-exposed group, and a 1.41 (95%CI 0.97–2.07, p = 0.074) and 1.39 (95%CI 0.99–2.07, p = 0.053) greater risk of infection based on LM or PCR diagnosis, respectively, compared to the sensitized group. Putatively tolerant children had an average of 0.5 g/dl lower hemoglobin levels (p = 0.01) compared to the other two groups. Exposed not sensitized children also had 2- to 3-fold lower frequency of malaria antigen-driven IFNγ and/or IL-2 production (p<0.001) and higher IL-10 release (p<0.001) at 6-month follow-ups, when compared to sensitized and not-exposed children. Malaria blood stage–specific IgG antibody levels were similar among the three groups.
Conclusions
These results show that a subset of children exposed to malaria in utero acquire a tolerant phenotype to blood-stage antigens that persists into childhood and is associated with an increased susceptibility to malaria infection and anemia. This finding could have important implications for malaria vaccination of children residing in endemic areas.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Each year, Plasmodium falciparum, a mosquito-borne parasite, causes about 500 million cases of malaria and about one million people die as a result. Most of these deaths occur in young children in sub-Saharan Africa. Indeed, malaria accounts for a fifth of all childhood deaths in Africa, which makes it one of the most important childhood infectious diseases in this region. Very young children—those up to 6 months old—are relatively resistant to high-density parasitaemia and to clinical malaria, but children between 6 and 36 months old have an increased susceptibility to parasitaemia and to clinical malaria. Parasitaemia is the presence of P. falciparum parasites in the blood; a high density of blood-stage parasites causes the symptoms of clinical malaria (including high fever) and life-threatening organ damage and anemia (a lack of red blood cells).
Why Was This Study Done?
The age-dependent pattern of susceptibility to malaria suggests that young babies are protected by antibodies provided by their mothers, but that by 6 months old, when these antibodies have largely disappeared, babies have not yet fully developed their own anti-malaria immunity. However, little is known about the acquisition of anti-malaria immunity in infants, a process that needs to be understood in order to design effective vaccines for this age group. In particular, it is unclear how maternal malaria infection affects the acquisition of anti-malaria immunity. Malaria in pregnancy may expose the unborn child to malaria-infected red blood cells and to soluble malaria antigens (molecules that the immune system recognizes as foreign). This exposure could increase or decrease the child's immune responses to blood-stage malaria antigens and thus affect his/her ability to fight off malaria. In this study, the researchers investigated how prenatal malaria exposure affects anti-malaria immunity in young children and their susceptibility to subsequent malaria infections.
What Did the Researchers Do and Find?
The researchers determined which of 586 newborn babies enrolled into their study in an area of Kenya where malaria is very common had been exposed to P. falciparum before birth by looking for parasites in their mother's blood at delivery. They looked for malaria-specific immune responses in T cells (a type of immune system cell) in the newborn babies' cord blood by measuring the production of cytokines (molecules that either activate or inhibit the immune system) by these cells after exposure to malaria antigens. Finally, they examined the infants twice yearly for 3 years for malaria infection, malaria-specific immune responses, and anemia. The researchers classified the babies into three groups; cord blood cells of “sensitized” babies made activating cytokines in response to malaria antigens; cord blood cells of “exposed, not-sensitized” babies did not make activating cytokines but made an inhibitory cytokine (IL-10); and “not-exposed” babies were born to mothers with no P. falciparum infection at delivery. In their first 3 years of life, the exposed, not-sensitized group had a 60% greater risk of malaria infection (measured by counting parasites in their blood) than the unexposed group and a slightly higher risk of malaria infection than the sensitized group. They also had lower hemoglobulin levels (a sign of anemia) than the other babies. At age 6 months, the T cells of exposed, not-sensitized children were less likely to make activating cytokines in response to malaria antigens but made more IL-10 than the T cells of the other children; malaria-specific antibody levels were similar in the three groups.
What Do These Findings Mean?
These findings suggest that some children who are exposed to malaria before birth become “tolerant” to blood-stage malaria antigens. Exposure to malaria antigens before birth “tricks” their T cells into recognizing these antigens as self antigens. This immune tolerance, which persists into childhood, reduces the ability of the immune system to attack and destroy parasites and increases the susceptibility of these tolerant children to malaria infection. Why some children who are exposed to malaria before birth become tolerant while exposure to malaria antigens “primes” the immune system of other children to respond efficiently to these antigens is not clear. However, these findings could have important implications for the design of malaria vaccines for use in areas where children are often exposed to malaria before birth and for the design of strategies for the prevention of malaria during pregnancy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000116.
This study is further discussed in a PLoS Medicine Perspective by Lars Hviid
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy and on children and malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000116
PMCID: PMC2707618  PMID: 19636353
14.  Barriers to Provider-Initiated Testing and Counselling for Children in a High HIV Prevalence Setting: A Mixed Methods Study 
PLoS Medicine  2014;11(5):e1001649.
Rashida Ferrand and colleagues combine quantitative and qualitative methods to investigate HIV prevalence among older children receiving primary care in Harare, Zimbabwe, and reasons why providers did not pursue testing.
Please see later in the article for the Editors' Summary
Background
There is a substantial burden of HIV infection among older children in sub-Saharan Africa, the majority of whom are diagnosed after presentation with advanced disease. We investigated the provision and uptake of provider-initiated HIV testing and counselling (PITC) among children in primary health care facilities, and explored health care worker (HCW) perspectives on providing HIV testing to children.
Methods and Findings
Children aged 6 to 15 y attending six primary care clinics in Harare, Zimbabwe, were offered PITC, with guardian consent and child assent. The reasons why testing did not occur in eligible children were recorded, and factors associated with HCWs offering and children/guardians refusing HIV testing were investigated using multivariable logistic regression. Semi-structured interviews were conducted with clinic nurses and counsellors to explore these factors. Among 2,831 eligible children, 2,151 (76%) were offered PITC, of whom 1,534 (54.2%) consented to HIV testing. The main reasons HCWs gave for not offering PITC were the perceived unsuitability of the accompanying guardian to provide consent for HIV testing on behalf of the child and lack of availability of staff or HIV testing kits. Children who were asymptomatic, older, or attending with a male or a younger guardian had significantly lower odds of being offered HIV testing. Male guardians were less likely to consent to their child being tested. 82 (5.3%) children tested HIV-positive, with 95% linking to care. Of the 940 guardians who tested with the child, 186 (19.8%) were HIV-positive.
Conclusions
The HIV prevalence among children tested was high, highlighting the need for PITC. For PITC to be successfully implemented, clear legislation about consent and guardianship needs to be developed, and structural issues addressed. HCWs require training on counselling children and guardians, particularly male guardians, who are less likely to engage with health care services. Increased awareness of the risk of HIV infection in asymptomatic older children is needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over 3 million children globally are estimated to be living with HIV (the virus that causes AIDS). While HIV infection is most commonly spread through unprotected sex with an infected person, most HIV infections among children are the result of mother-to-child HIV transmission during pregnancy, delivery, or breastfeeding. Mother-to-child transmission can be prevented by administering antiretroviral therapy to mothers with HIV during pregnancy, delivery, and breast feeding, and to their newborn babies. According to a report by the Joint United Nations Programme on HIV/AIDS published in 2012, 92% of pregnant women with HIV were living in sub-Saharan Africa and just under 60% were receiving antiretroviral therapy. Consequently, sub-Saharan Africa is the region where most children infected with HIV live.
Why Was This Study Done?
If an opportunity to prevent mother-to-child transmission around the time of birth is missed, diagnosis of HIV infection in a child or adolescent is likely to depend on HIV testing in health care facilities. Health care provider–initiated HIV testing and counselling (PITC) for children is important in areas where HIV infection is common because earlier diagnosis allows children to benefit from care that can prevent the development of advanced HIV disease. Even if a child or adolescent appears to be in good health, access to care and antiretroviral therapy provides a health benefit to the individual over the long term. The administration of HIV testing (and counselling) to children relies not only on health care workers (HCWs) offering HIV testing but also on parents or guardians consenting for a child to be tested. However, more than 30% of children in countries with severe HIV epidemics are AIDS orphans, and economic conditions in these countries cause many adults to migrate for work, leaving children under the care of extended families. This study aimed to investigate the reasons for acceptance and rejection of PITC in primary health care settings in Harare, Zimbabwe. By exploring HCW perspectives on providing HIV testing to children and adolescents, the study also sought to gain insight into factors that could be hindering implementation of testing procedures.
What Did the Researchers Do and Find?
The researchers identified all children aged 6 to 15 years old at six primary care clinics in Harare, who were offered HIV testing as part of routine care between 22 January and 31 May 2013. Study fieldworkers collected data on numbers of child attendances, numbers offered testing, numbers who underwent HIV testing, and reasons why HIV testing did not occur. During the study 2,831 children attending the health clinics were eligible for PITC, and just over half (1,534, 54.2%) underwent HIV testing. Eighty-two children tested HIV-positive, and nearly all of them received counselling, medication, and follow-up care. HCWs offered the test to around 75% of those eligible. The most frequent explanation given by HCWs for a diagnostic test not being offered was that the child was accompanied by a guardian not appropriate for providing consent (401 occasions, 59%); Other reasons given were a lack of available counsellors or test kits and counsellors refusing to conduct the test. The likelihood of being offered the test was lower for children not exhibiting symptoms (such as persistent skin problems), older children, or those attending with a male or a younger guardian. In addition, over 100 guardians or parents provided consent but left before the child could be tested.
The researchers also conducted semi-structured interviews with 12 clinic nurses and counsellors (two from each clinic) to explore challenges to implementation of PITC. The researchers recorded the factors associated with testing not taking place, either when offered to eligible children or when HCWs declined to offer the test. The interviewees identified the frequent absence or unavailability of parents or legal guardians as an obstacle, and showed uncertainty or misconceptions around whether testing of the guardian was mandatory (versus recommended) and whether specifically a parent (if one was living) must provide consent. The interviews also revealed HCW concerns about the availability of adequate counselling and child services, and fears that a child might experience maltreatment if he or she tested positive. HCWs also noted long waiting times and test kits being out of stock as practical hindrances to testing.
What Do These Findings Mean?
Prevalence of HIV was high among the children tested, validating the need for PITC in sub-Saharan health care settings. Although 76% of eligible attendees were offered testing, the authors note that this is likely higher than in routine settings because the researchers were actively recording reasons for not offering testing and counselling, which may have encouraged heath care staff to offer PITC more often than usual. The researchers outline strategies that may improve PITC rates and testing acceptance for Zimbabwe and other sub-Saharan settings. These strategies include developing clear laws and guidance concerning guardianship and proxy consent when testing older children for HIV, training HCWs around these policies, strengthening legislation to address discrimination, and increasing public awareness about HIV infection in older children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001649.
This study is further discussed in a PLOS Medicine Perspective by Davies and Kalk
The Joint United Nations Programme on HIV/AIDS publishes an annual report on the global AIDS epidemic, which provides information on progress towards eliminating new HIV infections
The World Health Organization has more information on mother-to-child transmission of HIV
The World Health Organization's website also has information about treatment for children living with HIV
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001649
PMCID: PMC4035250  PMID: 24866209
15.  Collection of vaccination data in the German National Cohort 
Background
Data about the vaccination status of participants are required in epidemiological cohort studies whenever infection or immunity is considered as potential exposure or outcome. Within Pretest 2 of the German National Cohort (GNC) we therefore investigated the acceptance and feasibility of extracting vaccination status from vaccination certificates provided by the participants of the study.
Methods
This study was conducted in three study centers (Bremen, n = 73; Hamburg, n = 200; Hannover, n = 193). In order to test if an additional reminder would prevent participants from forgetting their vaccination certificates at home persons willing to participate in Pretest 2 were randomly assigned to one of three invitation groups (IG). About one third of the participants received either no further reminder (IG1), a reminder card together with the appointment letter (IG2) or a separate reminder card 4 days before the appointment (IG3). At the study center, vaccination data were scanned or copied and entered into a database using a unique identification number. Participants were also asked to fill in a short questionnaire to assess the completeness of the provided vaccination data. Additionally, in one of the three participating study centers, general practitioners (GP) were asked to provide vaccination data from their records following respective participants’ consent. Finally, we compared the influenza data from the vaccination certificates with the influenza data obtained from participants in Pretest 2 by use of a self-administered questionnaire (ID-Screen).
Results
Due to different starting dates of the study the intended reminder procedure was implemented only in Hamburg and Hannover. In Hamburg, significantly more vaccination certificates were submitted by the group which received the reminder card separately 4 days before the examination (IG3) compared to IG1 and IG2 (p = 0.04). In Hannover, in contrast, most vaccination certificates were brought by those who received the reminder card together with the appointment letter. Overall, the use of a reminder card had a positive but not significant effect as 89 % (185/209) of participants who received the reminder card submitted vaccination data versus 81 % (84/104) of participants who did not receive any reminder card (p = 0.06). Of all Pretest 2 participants in Hannover, 62 % (120/193) gave written consent for data collection by the GPs. In total, 114 practices were contacted of which 49 (43 %) sent vaccination data. All in all, 360 vaccination certificates with 5065 documented vaccinations were entered into a database, of which 4830 (95 %) were valid for analysis covering a period from 1946 to 2012. The comparison of influenza vaccination data from vaccination certificates to the remembered data from a self-completed questionnaire showed an agreement of data in 46 % (84/184) of cases (Kappa = 0.48). Influenza vaccinations were underreported in 4 % (7/170) of self-completed questionnaires.
Conclusion
The reliable documentation of vaccinations within the context of the GNC proved to be feasible and thus recommendable at a large scale within the GNC as participants showed high willingness and compliance in providing available vaccination documents. An additional validation by means of documents provided by physicians seems to be possible for more than a quarter of participants. In order to maximize the likelyhood of participants’ of bringing their vaccination certificates it would be sufficient to send a reminder card together with the appointment letter.
Electronic supplementary material
The online version of this article (doi: 10.1007/s00103-014-2050-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00103-014-2050-0
PMCID: PMC4210722  PMID: 25293888
Vaccination certificate; Vaccination data collection; Population-based study; Vaccination status; Impfpass; Impfdatenerhebung; Bevölkerungsbasierte Studie; Impfstatus
16.  Insensitivity of Paediatric HIV-1 Subtype C Viruses to Broadly Neutralising Monoclonal Antibodies Raised against Subtype B 
PLoS Medicine  2006;3(7):e255.
Background
A Phase I clinical trial has been proposed that uses neutralising monoclonal antibodies (MAbs) as passive immunoprophylaxis to prevent mother-to-child transmission of HIV-1 in South Africa. To assess the suitability of such an approach, we determined the sensitivity of paediatric HIV-1 subtype C viruses to the broadly neutralising MAbs IgG1b12, 2G12, 2F5, and 4E10.
Methods and Findings
The gp160 envelope genes from seven children with HIV-1 subtype C infection were cloned and used to construct Env-pseudotyped viruses that were tested in a single-cycle neutralisation assay. The epitopes defining three of these MAbs were determined from sequence analysis of the envelope genes. None of the seven HIV-1 subtype C pseudovirions was sensitive to 2G12 or 2F5, which correlated with the absence of crucial N-linked glycans that define the 2G12 epitope and substitutions of residues integral to the 2F5 epitope. Four viruses were sensitive to IgG1b12, and all seven viruses were sensitive to 4E10.
Conclusions
Only 4E10 showed significant activity against HIV-1 subtype C isolates, while 2G12 and 2F5 MAbs were ineffective and IgG1b12 was partly effective. It is therefore recommended that 2G12 and 2F5 MAbs not be used for passive immunization experiments in southern Africa and other regions where HIV-1 subtype C viruses predominate.
Editors' Summary
Background.
AIDS is caused by HIV. By killing the cells of the body's immune system, HIV infection makes people vulnerable to many potentially fatal bacterial and viral diseases. HIV is most commonly spread through unprotected sex with an infected partner but it can also pass from mother to child during late pregnancy or birth, or through breast milk. At least one in four infected women will transmit HIV to their babies if left untreated. But if infected women are treated with drugs that fight HIV—so-called antiretrovirals—during late pregnancy and if breastfeeding does not occur, only one to two babies in 100 will become infected with HIV. In addition, elective Caesarian section has been found to be protective against HIV infection. Implementation of this approach has greatly reduced mother-to-child transmission in developed countries, but most HIV-infected women live in developing countries where access to antiretrovirals is limited. In these cases, treatment of pregnant women (during pregnancy and delivery) and their newborn babies with a single dose of one antiretroviral drug, which can halve HIV transmission, is used, even though WHO/UNAIDS recommends simple antenatal, intrapartum, and postnatal antiretroviral regimens to achieve levels of less than 5% transmission in resource poor settings. These strategies will not have an impact on breastmilk transmission, which accounts for half the transmissions in these settings.
Why Was This Study Done?
One way to reduce breastmilk transmission of HIV might be by “passive immunization.” In this, newborn babies would be injected with HIV-specific antibodies—proteins that stick to molecules on the surface of HIV. Because the virus uses these molecules to invade the baby's immune cells, injected antibodies might stop HIV from the mother becoming established in her offspring. Four antibodies have been made in the laboratory—so-called human monoclonal antibodies—that bind to the surface of HIV subtype B, which is found mainly in Europe and North America, and stop HIV from killing human cells. However, most HIV isolated in Africa is subtype C, so in this study researchers have tested whether these antibodies prevent HIV subtype C killing cells grown in the laboratory. It is important, they argue, that antibodies should be shown to work outside the body before testing passive immunization in babies.
What Did the Researchers Do and Find?
The researchers isolated several subtype C viruses from babies born in Johannesburg, South Africa, and made artificial viruses (known as “pseudotyped” viruses) from them. These artificial viruses could then be used in tests to see whether the human monoclonal antibodies could prevent the viruses infecting human cells in a laboratory test, that is, whether the viruses were “sensitive” to the antibodies. All the viruses were insensitive to two of the antibodies (2G12 and 2F5), and the researchers show that this was because the viruses lacked the specific parts of the HIV surface molecules recognized by these antibodies. Four of the viruses were sensitive to an antibody called IgG1b12, and all were sensitive to antibody 4E10, albeit at high concentrations that might be difficult to achieve in people. Finally, the researchers report that the sensitivity of the viruses was not enhanced by using all four antibodies at the same time.
What Do These Findings Mean?
Given these results, the researchers warn against using 2G12 and 2F5 antibodies for passive immunization to prevent mother-to-child transmission, in particular postnatal transmission, in areas where most people are infected with HIV subtype C viruses. Furthermore, because animal studies have indicated that only combinations of at least three monoclonal antibodies with activity against HIV in laboratory tests provide complete protection against HIV infection, the researchers question whether any clinical trials on passive immunization should be started with currently available antibodies. Their doubts about such trials are heightened by observations that 4E10 and 2F5 react against antigens present on human cells, which might make them unsafe for use in people, although so far no adverse effects have been seen in adults treated with these antibodies. However, these experiments used an artificial laboratory-based assay and it's possible that these antibodies might kill HIV subtype C more effectively in people; other components of the immune system might help them deal with the virus. If clinical studies of these antibodies do go ahead, it is essential that the babies in these trials must be carefully monitored to ensure that the antibodies are safe, and they and their mothers should also be given access to optimal antiretroviral prophylaxis according to WHO/UNAIDS guidelines. In a related PLoS Medicine Perspective paper (http://dx.doi.org/10.1371/journal.pmed.0030259), Miroslaw Gorny1 and Susan Zolla-Pazner discuss the study further and stress the critical need to determine if passive immunization with such antibodies could decrease mother-to-child transmission of HIV, and if so what the best antibodies would be.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030255.
•  National Institute of Allergy and Infectious Diseases fact sheets on HIV infection and AIDS
•  US Department of Health and Human Services information on HIV/AIDS, including clinical guidelines and fact sheets on preventing transmission from mother to child
•  US Centers for Disease Control and Prevention information on HIV/AIDS, including pages on the prevention of mother-to-child transmission
•  MedlinePlus encyclopedia entry on HIV/AIDS
•  Preventing mother-to-child transmission of HIV Web page
Assessment of viruses from seven children with HIV-1 subtype C infection showed generally poor sensitivity to four monoclonal antibodies proposed for a trial of passive immunoprophylaxis to prevent mother-to-child transmission.
doi:10.1371/journal.pmed.0030255
PMCID: PMC1502151  PMID: 16834457
17.  Accuracy of epidemiological inferences based on publicly available information: retrospective comparative analysis of line lists of human cases infected with influenza A(H7N9) in China 
BMC Medicine  2014;12:88.
Background
Appropriate public health responses to infectious disease threats should be based on best-available evidence, which requires timely reliable data for appropriate analysis. During the early stages of epidemics, analysis of ‘line lists’ with detailed information on laboratory-confirmed cases can provide important insights into the epidemiology of a specific disease. The objective of the present study was to investigate the extent to which reliable epidemiologic inferences could be made from publicly-available epidemiologic data of human infection with influenza A(H7N9) virus.
Methods
We collated and compared six different line lists of laboratory-confirmed human cases of influenza A(H7N9) virus infection in the 2013 outbreak in China, including the official line list constructed by the Chinese Center for Disease Control and Prevention plus five other line lists by HealthMap, Virginia Tech, Bloomberg News, the University of Hong Kong and FluTrackers, based on publicly-available information. We characterized clinical severity and transmissibility of the outbreak, using line lists available at specific dates to estimate epidemiologic parameters, to replicate real-time inferences on the hospitalization fatality risk, and the impact of live poultry market closure.
Results
Demographic information was mostly complete (less than 10% missing for all variables) in different line lists, but there were more missing data on dates of hospitalization, discharge and health status (more than 10% missing for each variable). The estimated onset to hospitalization distributions were similar (median ranged from 4.6 to 5.6 days) for all line lists. Hospital fatality risk was consistently around 20% in the early phase of the epidemic for all line lists and approached the final estimate of 35% afterwards for the official line list only. Most of the line lists estimated >90% reduction in incidence rates after live poultry market closures in Shanghai, Nanjing and Hangzhou.
Conclusions
We demonstrated that analysis of publicly-available data on H7N9 permitted reliable assessment of transmissibility and geographical dispersion, while assessment of clinical severity was less straightforward. Our results highlight the potential value in constructing a minimum dataset with standardized format and definition, and regular updates of patient status. Such an approach could be particularly useful for diseases that spread across multiple countries.
doi:10.1186/1741-7015-12-88
PMCID: PMC4066833  PMID: 24885692
Epidemiological monitoring; Line list; Infectious disease outbreak; Influenza A virus; H7N9 subtype
18.  A systematic review of missed opportunities for improving tuberculosis and HIV/AIDS control in Sub-saharan Africa: what is still missed by health experts? 
In sub-Saharan Africa, HIV/AIDS and tuberculosis are major public health problems. In 2010, 64% of the 34 million of people infected with HIV were reported to be living in sub-Saharan Africa. Only 41% of eligible HIV-positive people had access to antiretroviral therapy (ART). Regarding tuberculosis, in 2010, the region had 12% of the world's population but reported 26% of the 8.8 million incident cases and 254000 tuberculosis-related deaths. This paper aims to review missed opportunities for improving HIV/AIDS and tuberculosis prevention and care. We conducted a systematic review in PubMed using the terms ‘missed’(Title) AND ‘opportunities’(Title). We included systematic review and original research articles done in sub-Saharan Africa on missed opportunities in HIV/AIDS and/or tuberculosis care. Missed opportunities for improving HIV/AIDS and/or tuberculosis care can be classified into five categories: i) patient and community; ii) health professional; iii) health facility; iv) local health system; and v) vertical programme (HIV/AIDS and/or tuberculosis control programmes). None of the reviewed studies identified any missed opportunities related to health system strengthening. Opportunities that are missed hamper tuberculosis and/or HIV/AIDS care in sub-Saharan Africa where health systems remain weak. What is still missing in the analysis of health experts is the acknowledgement that opportunities that are missed to strengthen health systems also undermine tuberculosis and HIV/AIDS prevention and care. Studying why these opportunities are missed will help to understand the rationales behind the missed opportunities, and customize adequate strategies to seize them and for effective diseases control.
doi:10.11604/pamj.2014.18.320.4066
PMCID: PMC4250026  PMID: 25478041
Missed opportunities; HIV/AIDS; tuberculosis; sub-Saharan Africa; health systems
19.  Antiretroviral Treatment and Prevention of Peripartum and Postnatal HIV Transmission in West Africa: Evaluation of a Two-Tiered Approach 
PLoS Medicine  2007;4(8):e257.
Background
Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long-term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to-child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens.
Methods and Findings
The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Côte d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged ≥ 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%–4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%–9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%–7.0%) at age week 4 wk and 11.7% (95% CI 7.5%–15.9%) at 12 mo.
Conclusions
This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health.
In an observational cohort study from Côte d'Ivoire, François Dabis and colleagues report on prevention of mother-to-child HIV transmission among women receiving antiretroviral therapy according to World Health Organization recommendations.
Editors' Summary
Background
Effective treatments are available to prevent AIDS in people who are infected with HIV, but not everyone with HIV needs to take medication. Usually, anti-HIV medication is recommended only for those whose immune systems have been significantly affected by the virus, as evidenced by symptoms or by the results of a blood test, the CD4 lymphocyte (“T cell”) count. Treating HIV usually requires a combination of three or more medications. These combinations (called HAART) must be taken every day, can cause complications, and can be expensive.
Worldwide, more than half a million children became infected with HIV each year. Most of these children acquire HIV from their mothers during pregnancy or around the time of birth. If a pregnant woman with HIV takes HAART, her chances of passing HIV to the baby are greatly reduced, but the possible side effects of HAART on the baby are not known. Also, most transmission of HIV from mothers to babies occurs in poor countries where supplies of HAART are limited. For these reasons, World Health Organization (WHO) does not recommend that every pregnant woman receive HAART to prevent HIV transmission to the baby, unless the woman needs HAART for her own health (for example if her T cells are low or she has severe symptoms of HIV infection). For pregnant women with HIV who do not need to take HAART for their own health, less complicated treatments, involving a short course of one or two HIV drugs, can be used to reduce the risk of passing HIV to the baby.
Why Was This Study Done?
The WHO recommendations for HAART in pregnancy are based on the best available evidence, but it is important to know how well they work in actual practice. The authors of this study were providing HIV treatment to pregnant women with HIV in West Africa through an established clinic program in Abidjan, Côte d'Ivoire, and wanted to see how well the WHO recommendations for HAART or short-course treatments, depending on the mother's condition, were working to protect babies from HIV infection.
What Did the Researchers Do and Find?
The researchers studied 250 HIV-infected pregnant women who received HIV medications in the Abidjan program between mid-2003 and mid-2005. In accordance with WHO guidelines, 107 women began HAART for their own health during pregnancy, and 143 women did not qualify for HAART but received other short course treatments (scARV) to prevent HIV transmission to their babies. The authors monitored mothers and babies for treatment side effects and tested the babies for HIV infection up to age 1 y.
They found that HAART was relatively safe during pregnancy, although babies born to women on HAART were more likely (26.3%) to have low birth weight than babies born to women who received scARV (12.4%). Also, 7.5% of women on HAART developed side effects requiring a change in their medications. Combining the results from HAART and scART groups, the chance of HIV transmission around the time of birth was 2.2%, increasing to 5.7% at age 1 y. (Three-quarters of the infants were breast-fed; safe water for mixing formula was not reliably available.) The study found no difference in risk of HIV infection between babies whose mothers received HAART and those whose mothers received scARV according to guidelines.
What Do These Findings Mean?
These results support the safety and effectiveness of the WHO two-tiered approach for preventing mother-to-child transmission. This study was not designed to compare HAART to scART directly, because the women who received HAART were the ones with more advanced HIV infection, which might have affected their babies in many ways.
Compared to earlier pregnancy studies of HAART in rich countries, this study of the WHO approach in West Africa showed similar success in protecting infants from HIV infection around the time of birth. Unfortunately, because formula feeding was not generally available in resource-limited settings, protection declined over the first year of life with breast-feeding, but some protection remained.
This study confirms that close monitoring of pregnant women on HAART is necessary, so that drugs can be changed if side effects develop. The study does not tell us whether using scARV in pregnancy might change the virus in ways that would make it more difficult to treat the same women with HAART later if they needed it. The reason for low birth weight in some babies born to mothers on HAART is unclear. It may be because the women who needed HAART had more severe health problems from their HIV, or it may be a result of the HAART itself.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040257.
World Health Organization has a page on prevention of mother-to-child transmission of HIV
“Women, Children, and HIV” is a resource site from the François Xavier Bagnoud Center and UCSF
The MTCT-Plus initiative at Columbia University supports the programs in Abidjan
doi:10.1371/journal.pmed.0040257
PMCID: PMC1949842  PMID: 17713983
20.  Risk Factors and Outcomes for Late Presentation for HIV-Positive Persons in Europe: Results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE) 
PLoS Medicine  2013;10(9):e1001510.
Amanda Mocroft and colleagues investigate risk factors and health outcomes associated with diagnosis at a late stage of infection in individuals across Europe.
Please see later in the article for the Editors' Summary
Background
Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality.
Methods and Findings
LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm3 or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95–0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19–20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55–12.43).
Conclusions
LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year about 2.5 million people become newly infected with HIV, the virus that causes AIDS. HIV can be transmitted through unprotected sex with an infected partner, from an HIV-positive mother to her unborn baby, or through injection of drugs. Most people do not become ill immediately after infection with HIV although some develop a short influenza-like illness. The next stage of the HIV infection, which may last up to 10 years, also has no major symptoms but, during this stage, HIV slowly destroys immune system cells, including CD4 cells, a type of lymphocyte. Eventually, when the immune system is unable to fight off infections by other disease-causing organisms, HIV-positive people develop AIDS-defining conditions—unusual viral, bacterial, and fungal infections and unusual tumors. Progression to AIDS occurs when any severe AIDS-defining condition is diagnosed, when the CD4 count in the blood falls below 200 cells/mm3, or when CD4 cells account for fewer than 15% of lymphocytes.
Why Was This Study Done?
People need to know they are HIV positive as soon as possible after they become infected because antiretroviral therapy, which controls but does not cure HIV infection, works best if it is initiated when people still have a relatively high CD4 count. Early diagnosis also reduces the risk of onward HIV transmission. However, 40%–60% of HIV-positive individuals in developed countries are not diagnosed until they have a low CD4 count or an AIDS-defining illness. Reasons for such late presentation include fear of discrimination or stigmatization, limited knowledge about HIV risk factors, testing, and treatment together with missed opportunities to offer an HIV test. Policy makers involved in national and international HIV control programs need detailed information about patterns of late presentation before they can make informed decisions about how to reduce this problem. In this study, therefore, the researchers use data collected by the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) to analyze trends in late presentation over time across Europe and in different groups of people at risk of HIV infection and to investigate the clinical consequences of late presentation.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 84,524 individuals participating in more than 20 observational studies that were undertaken in 35 European countries and that investigated outcomes among HIV-positive people. Nearly 54% of the participants were late presenters—individuals who had a CD4 count of less than 350 cells/mm3 or an AIDS-defining illness within 6 months of HIV diagnosis. Late presentation was highest among heterosexual males, in Southern European countries, and among people originating in Africa. Overall, late presentation decreased from 57.3% in 2000 to 51.7% in 2010/11. However, whereas late presentation decreased over time among men having sex with men in Central and Northern Europe, for example, it increased over time among female heterosexuals in Southern Europe. Finally, among the 8,000 individuals who developed a new AIDS-defining illness or died during follow-up, compared to non-late presentation, late presentation was associated with an increased incidence of AIDS/death in all regions of Europe during the first and second year after HIV diagnosis (but not in later years); the largest increase in incidence (13-fold) occurred during the first year after diagnosis in Southern Europe.
What Do These Findings Mean?
These findings indicate that, although late presentation with HIV infection has decreased in recent years, it remains an important issue across Europe and in all groups of people at risk of HIV infection. They also show that individuals presenting late have a worse clinical outlook, particularly in the first and second year after diagnosis compared to non-late presenters. Several aspects of the study design may affect the accuracy and usefulness of these findings, however. For example, some of the study participants recorded as late presenters may have been people who were aware of their HIV status but who chose not to seek care for HIV infection, or may have been seen in the health care system prior to HIV diagnosis without being offered an HIV test. Delayed entry into care and late presentation are likely to have different risk factors, a possibility that needs to be studied further. Despite this and other study limitations, these findings nevertheless suggest that HIV testing strategies that encourage early testing in all populations at risk, that ensure timely referrals, and that improve retention in care are required to further reduce the incidence of late presentation with HIV infection in Europe.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001510.
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 detailed information on the stages of HIV infection and on HIV and AIDS in Europe (in English and Spanish)
The HIV in Europe Initiative has information about strategies to improve earlier diagnosis and access to care in Europe
Information about COHERE, which was established in 2005 to conduct epidemiological research on the prognosis and outcome of HIV-infected people from across Europe, is available; more information on the consensus definition of late presentation used in this study is available through the HIV in Europe initiative
Patient stories about living with HIV/AIDS are available through Avert and through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001510
PMCID: PMC3796947  PMID: 24137103
21.  Measuring the Performance of Vaccination Programs Using Cross-Sectional Surveys: A Likelihood Framework and Retrospective Analysis 
PLoS Medicine  2011;8(10):e1001110.
Justin Lessler and colleagues describe a method that estimates the fraction of a population accessible to vaccination activities, and they apply it to measles vaccination in three African countries: Ghana, Madagascar, and Sierra Leone.
Background
The performance of routine and supplemental immunization activities is usually measured by the administrative method: dividing the number of doses distributed by the size of the target population. This method leads to coverage estimates that are sometimes impossible (e.g., vaccination of 102% of the target population), and are generally inconsistent with the proportion found to be vaccinated in Demographic and Health Surveys (DHS). We describe a method that estimates the fraction of the population accessible to vaccination activities, as well as within-campaign inefficiencies, thus providing a consistent estimate of vaccination coverage.
Methods and Findings
We developed a likelihood framework for estimating the effective coverage of vaccination programs using cross-sectional surveys of vaccine coverage combined with administrative data. We applied our method to measles vaccination in three African countries: Ghana, Madagascar, and Sierra Leone, using data from each country's most recent DHS survey and administrative coverage data reported to the World Health Organization. We estimate that 93% (95% CI: 91, 94) of the population in Ghana was ever covered by any measles vaccination activity, 77% (95% CI: 78, 81) in Madagascar, and 69% (95% CI: 67, 70) in Sierra Leone. “Within-activity” inefficiencies were estimated to be low in Ghana, and higher in Sierra Leone and Madagascar. Our model successfully fits age-specific vaccination coverage levels seen in DHS data, which differ markedly from those predicted by naïve extrapolation from country-reported and World Health Organization–adjusted vaccination coverage.
Conclusions
Combining administrative data with survey data substantially improves estimates of vaccination coverage. Estimates of the inefficiency of past vaccination activities and the proportion not covered by any activity allow us to more accurately predict the results of future activities and provide insight into the ways in which vaccination programs are failing to meet their goals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Immunization (vaccination) is a proven, cost-effective tool for controlling life-threatening infectious diseases. It provides protection against infectious diseases by priming the human immune system to respond quickly and efficiently to bacteria, viruses, and other disease-causing organisms (pathogens). Whenever the human body is exposed to a pathogen, the immune system—a network of cells, tissues, and organs—mounts an attack against the foreign invader. Importantly, the immune system “learns” from the encounter, and the next time the body is exposed to the same pathogen, the immune system responds much faster to the threat. Immunization exposes the body to a very small amount of a pathogen, thereby safely providing protection against subsequent infection. More than two billion deaths are averted every year through routine childhood immunization and supplemental immunization activities (mass vaccination campaigns designed to increase vaccination coverage where immunization goals have not been reached by routine vaccination). Indeed, these two types of vaccination activities have eliminated smallpox from the world and are close to doing the same for several other infectious diseases.
Why Was This Study Done?
To reduce deaths from infectious diseases even further, it is important to know the proportion of the population reached by vaccination activities. At present, countries report vaccination coverage to the World Health Organization (WHO) that is calculated by dividing the number of vaccine doses delivered during the activity by the size of the target population. However, estimates arrived at through this “administrative method” do not account for vaccine doses that were not actually delivered, and can only reflect a single vaccination activity, which prevents us from identifying populations that may be systematically missed by all vaccination activities (for example, children living in remote areas, or children whose parents refuse vaccination). Moreover, estimates of coverage obtained by the administrative method rarely agree with estimates obtained through cross-sectional surveys such as Demographic and Health Surveys (DHS), which are household surveys of family circumstances and health undertaken at a single time point. In this study, the researchers developed a method for measuring the performance of vaccination activities that estimates the fraction of the population accessible to these activities and within-activity inefficiencies. They then tested their method by applying it to measles vaccination in three African countries; before 1980, measles killed about 2.6 million children worldwide every year, but vaccination activities have reduced this death toll to about 164,000 per year.
What Did the Researchers Do and Find?
The researchers developed a set of formulae (a “likelihood framework”) to estimate the effective coverage of vaccination activities using data on vaccine coverage from cross-sectional surveys and administrative data. They then applied their method to measles vaccination in Ghana, Madagascar, and Sierra Leone using data obtained in each country's most recent DHS survey and administrative data reported to WHO. The researchers estimate that 93%, 77%, and 65% of the target populations in Ghana, Madagascar, and Sierra Leone, respectively, were ever covered by any vaccination activity, and that inefficiencies within vaccination activities were low for Ghana, but higher for Madagascar and Sierra Leone. Consequently, the researchers' estimates of vaccination activity coverage were substantially lower than the administrative estimates for Madagascar and Sierra Leone but only slightly lower than that for Ghana. Finally, the researchers' estimates of routine vaccination coverage were generally lower than WHO-adjusted estimates but broadly agreed with age-specific vaccination coverage levels from DHS surveys.
What Do These Findings Mean?
Although the accuracy of the estimates provided by this likelihood framework depends on the assumptions included in the framework and the quality of the data fed into it, these findings show that, by combining administrative data with survey data, estimates of vaccine coverage can be substantially improved. By providing estimates of both the inefficiency of past vaccination activities and the proportion of the target population inaccessible to any vaccination activity, this method should help public health experts predict the results of future activities and help them understand why some vaccination programs fail to meet their goals. Importantly, knowing both the size of the inaccessible population and the inefficiency level of past programs makes it possible to estimate the effect of providing additional doses of vaccine on vaccination coverage. Finally, the application of this new method might help individual countries understand how susceptibility to specific infectious diseases is building up in their population and enable them to avoid outbreaks similar to the measles outbreaks that have recently occurred in several African countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001080.
WHO provides information about immunization and details of its Expanded Program on Immunization and its Global Immunization Vision and Strategy; WHO Africa provides details about measles immunization in Africa; a photo story about mass measles vaccination in Côte d’Ivoire is available (some material in several languages)
The UK National Health Service Choices website provides information for members of the public about immunization
The Measles Initiative is a collaborative effort that aims to reduce global measles mortality through mass vaccination campaigns and by strengthening routine immunization; its website includes information on measles and measles vaccination, including photos and videos of vaccination activities
MedlinePlus provides links to additional resources about immunization and about measles (in English and Spanish)
The charity website Healthtalkonline has interviews with UK parents about their experience of immunizing their children
doi:10.1371/journal.pmed.1001110
PMCID: PMC3201935  PMID: 22039353
22.  Quality of antenatal care services at public health facilities of Bahir-Dar special zone, Northwest Ethiopia 
Background
Antenatal care (ANC) is one of the evidence based interventions to decrease the probability of bad health outcomes for mothers and their newborns. Effectiveness of antenatal care, however, relies on the quality of care provided during each antenatal care visit. Hence this study attempted to assess the quality of antenatal care services at public health facilities of Bahir-Dar special zone, North Western Ethiopia.
Methods
A facility based cross-sectional study employing both quantitative and qualitative methods was conducted from March to April 2010 in Bahir-Dar special zone, North Western Ethiopia. Quality of care was measured as a proportion of patients receiving recommended components of care. To measure the indicators, data was collected from 369 pregnant women who attended ANC clinics in eight public health facilities, during the data collection period. Data were collected through exit interviews with ANC attendees, observation during consultation, and in-depth interviews with health care providers.
Results
Pregnant mothers attending ANC clinics were found to receive only part of recommended care components. Venereal Disease Research Laboratory (VDRL) test, blood group and Rhesus factor tests were done only for 73 (19.8%) and 133 (36.0%) of the women, respectively. Moreover 236 (64.0%) of the mothers missed the opportunity of receiving iron/folic acid supplement during their ANC visit. Three hundred fifty five (96.2%) of the women received tetanus toxoid vaccine. And only 226 (61.2%) of the women had their conjunctiva checked for anemia. Lack of reagents partly explained the problems observed in the provision of recommended care components.
Conclusion
Almost half, 175 (47.7%) of the study women were not satisfied and a large proportion of mothers are missing opportunities to receive screening (like blood pressure and weight measurements) and preventive components of antenatal care (iron/folic acid supplementation). Therefore, efforts should be targeted to avoid missed opportunities by taking quality improvement measures including the fulfillment of all necessary resources.
doi:10.1186/1472-6963-13-443
PMCID: PMC4231347  PMID: 24161007
Antenatal care; Quality of health care; Public health facilities; Prenatal care
23.  Randomized controlled trial to improve childhood immunization adherence in rural Pakistan: redesigned immunization card and maternal education 
SUMMARY
OBJECTIVE
A substantial dropout from the first dose of diphtheria-tetanus-pertussis (DTP1) to the 3rd dose of DTP (DTP3) immunization has been recorded in Pakistan. We conducted a randomized controlled trial to assess the effects of providing substantially redesigned immunization card, center-based education, or both interventions together on DTP3 completion at six rural Expanded Programme on Immunization (EPI) centers in Pakistan.
METHODS
Mother-child units were enrolled at DTP1 and randomized to four study groups: redesigned card, center-based education, combined intervention, and standard care. Each child was followed-up for 90 days to record the dates of DTP2 and DTP3 visits. The study outcome was DTP3 completion by the end of follow-up period in each study group.
RESULTS
We enrolled 378 mother-child units in redesigned card group, 376 in center-based education group, 374 in combined intervention group, and 378 in standard care group. By the end of follow-up, 39% of children in standard care group completed DTP3. Compared to this, a significantly higher proportion of children completed DTP3 in redesigned card group (66%) (crude Risk Ratio [RR] = 1.7; 95% CI = 1.5, 2.0), center-based education group (61%) (RR = 1.5; 95% CI = 1.3, 1.8), and combined intervention group (67%) (RR = 1.7; 95% CI = 1.4, 2.0).
CONCLUSIONS
Improved immunization card alone, education to mothers alone, or both together were all effective in increasing follow-up immunization visits. The study underscores the potential of study interventions’ public health impact and necessitates their evaluation for complete EPI schedule at a large scale in the EPI system.
doi:10.1111/j.1365-3156.2010.02698.x
PMCID: PMC3763701  PMID: 21159080
24.  Prospects for Advancing Tuberculosis Control Efforts through Novel Therapies 
PLoS Medicine  2006;3(8):e273.
Background
Development of new, effective, and affordable tuberculosis (TB) therapies has been identified as a critical priority for global TB control. As new candidates emerge from the global TB drug pipeline, the potential impacts of novel, shorter regimens on TB incidence and mortality have not yet been examined.
Methods and Findings
We used a mathematical model of TB to evaluate the expected benefits of shortening the duration of effective chemotherapy for active pulmonary TB. First, we considered general relationships between treatment duration and TB dynamics. Next, as a specific example, we calibrated the model to reflect the current situation in the South-East Asia region. We found that even with continued and rapid progress in scaling up the World Health Organization's DOTS strategy of directly observed, short-course chemotherapy, the benefits of reducing treatment duration would be substantial. Compared to a baseline of continuing DOTS coverage at current levels, and with currently available tools, a 2-mo regimen introduced by 2012 could prevent around 20% (range 13%–28%) of new cases and 25% (range 19%–29%) of TB deaths in South-East Asia between 2012 and 2030. If effective treatment with existing drugs expands rapidly, overall incremental benefits of shorter regimens would be lower, but would remain considerable (13% [range 8%–19%] and 19% [range 15%–23%] reductions in incidence and mortality, respectively, between 2012 and 2030). A ten-year delay in the introduction of new drugs would erase nearly three-fourths of the total expected benefits in this region through 2030.
Conclusions
The introduction of new, shorter treatment regimens could dramatically accelerate the reductions in TB incidence and mortality that are expected under current regimens—with up to 2- or 3-fold increases in rates of decline if shorter regimens are accompanied by enhanced case detection. Continued progress in reducing the global TB burden will require a balanced approach to pursuing new technologies while promoting wider implementation of proven strategies.
Mathematical modeling suggests that new tuberculosis treatments that are shorter than the current 6-month standard regimen would lead to considerable reductions in incidence and mortality of TB, which remains the leading cause of global deaths.
Editors' Summary
Background.
One third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that is the main cause of tuberculosis (TB). In most people, the infection remains dormant, but every year eight million people develop active TB, usually in their lungs, and two million people die from the disease. For most of the second half of the 20th century, TB was in decline, particularly in developed countries, due to the availability of powerful antibiotics. Recently, however, global efforts to control TB have been set back by the HIV/AIDS epidemic—people with damaged immune systems are very susceptible to TB—and the emergence of antibiotic-resistant bacteria. In the 1990s, the World Health Organization (WHO) introduced DOTS as the recommended strategy for global TB control. Central to DOTS is “directly observed short-course chemotherapy.” To cure TB, several antibiotics have to be taken daily for 6 months. Patients must complete this treatment, even if they feel better sooner, to prevent relapse and the emergence of drug-resistant bacteria. The DOTS approach ensures that patients do this by having trained observers watch them swallow each dose of their medication for the entire 6-month period.
Why Was This Study Done?
This year, WHO and partners launched a renewed Global Plan to Stop TB, which aims to reduce, by 2015, the number of people who are sick with TB (disease prevalence) and the number of people who die each year from the disease (mortality) to half the 1990 levels. Because sick people often infect others, reducing disease prevalence will also reduce the number of new infections each year (disease incidence). The Global Plan to Stop TB includes a commitment to expand and intensify the DOTS strategy (in the year 2004, only around half of new active, infectious TB cases were detected under DOTS). The drug combinations currently used for DOTS consist of four or more different antibiotics, which have all been around and in use for many years. Recently, renewed effort has gone into the search for new TB treatments. Several candidate drugs have been identified and are now being tested, and scientists expect that some of them will be able to cure patients quicker than the current 6-month regimen. In this study, the researchers wanted to understand the potential benefits of such shorter treatments.
What Did the Researchers Do and Find?
The researchers developed a mathematical model that considers the acquisition, progression, diagnosis, and treatment of M. tuberculosis infection and its clinical consequences. They used the model to predict how changes in treatment duration might affect TB incidence, prevalence, and mortality. In the model, shorter treatment durations are connected to higher cure rates, as each additional month of treatment means more time to ensure that patients keep taking their medications, and more doses that might be missed. Since patients who drop out of treatment early can continue to infect other people, the model shows how a 2-month course of antibiotics will produce a quicker decline in the incidence of TB than a 6-month course by reducing these opportunities to infect others.
  The researchers then refined their model to include current conditions in South-East Asia, an area where DOTS is being scaled up and where one-third of all new TB cases occur. This “calibrated” model indicates that even if DOTS is scaled up as planned, shorter drug courses would still reduce TB incidence and deaths much quicker than a 6-month course. If, for example, a 2-month drug treatment were introduced by 2012, it might prevent 13% of the new cases and 19% of the TB deaths that would otherwise occur in South-East Asia between 2012 and 2030. These benefits might be even greater if the new drug regimen freed up resources to improve the systematic effort to detect new TB cases. On the other hand, delaying its implementation until 2022 would erase three-quarters of the predicted benefits.
What Do These Findings Mean?
Like all mathematical models, this one makes many assumptions that, if incorrect, will change the predictions. With this caveat, the study confirms that the planned scale-up of DOTS will greatly reduce TB incidence and mortality over the next few years. However, it also suggests that the impact of DOTS could be substantially improved by introducing shorter drug regimens. The earlier such shorter treatments become available, the greater their benefits would be. By reducing the opportunities for patients to default on their treatment and by shortening the period during which they can infect others, the researchers predict that the rate of decline in TB incidence and mortality could be up to three times higher for antibiotics that only have to be taken for 2 months compared with those that need to be taken for 6 months. But, they stress, strategies for reducing the global TB burden must strike a balance between pursuing new treatment and detection strategies and promoting wider implementation of proven strategies. And while there is hope that new shorter treatments will prove effective over the next few years, this will only become clear as candidates are rigorously tested.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030273.
• US National Institute of Allergy and Infectious Diseases patient fact sheet on TB
• US Centers for Disease Control and Prevention information for patients and professionals on TB
• MedlinePlus encyclopedia entry on TB
• NHS Direct Online patient information on TB from the UK National Health Service
• World Health Organization information on global TB control
• Global Alliance for TB Drug Development information on current initiatives to develop new TB drugs
• Wikipedia page on TB treatment (note that Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030273
PMCID: PMC1523376  PMID: 16866578
25.  Missed opportunities for earlier HIV testing and diagnosis at the health facilities of Dessie town, North East Ethiopia 
BMC Public Health  2010;10:362.
Background
For patients in all health-care settings HIV screening is recommended after the patient is notified that testing will be performed unless the patient declines. The nation's physicians and other health care providers should assume a much more active role in promoting HIV testing. The aim of this study was to investigate the extent to which missed opportunities for earlier HIV testing and diagnosis occur in the health facilities of north east Ethiopia.
Methods
A confidential client exit interview and medical record review was made on 427 clients who attended health facilities of Dessie town between November-December 2008. Data collection was done by counselors trained on Provider Initiated Counseling and Testing (PICT) and data collection tool included demographics, reason for visit to health facilities, HIV test initiation by service providers, clients self risk perception, clients willingness and acceptance of HIV test, HIV test result and review of client medical records.
Results
Among 427 clients, missed opportunities for HIV testing were found in 76.1% (325) of clients. HIV test initiation was made by data collecting counselors during interview period and 80.0% (260) of clients not initiated by service providers were found to be willing to have HIV test. Large number, 43.0% (112), of the willing clients actually tested for HIV. Of the tested clients, 13.4% (15) were found to be HIV positive. Most, 60% (9), of HIV positive clients who lost the opportunities of diagnosis felt themselves as having no risk for HIV infection. Missed opportunities for HIV diagnosis of 51.7% (15), overall HIV test acceptance rate of 36.5% (154) and positivity rate of 6.9% (29) were found.
Conclusions
The missed opportunities for earlier HIV test and diagnosis of patients attending health facilities were found to be high and frequent. Testing only clients with HIV risk misses large number of HIV positive patients. Asking clients' willingness for HIV testing should be conducted by all service providers irrespective of the clients' risk behaviors for HIV infection or the type of services they need.
doi:10.1186/1471-2458-10-362
PMCID: PMC2903520  PMID: 20573215

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