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Background: Although HIV program evaluations focusing on mortality on ART provide important evidence on treatment effectiveness, they do not asses overall HIV program performance because they exclude patients who are eligible but not started on ART for whatever reason. The objective of this study was to measure mortality that occurs both pre-ART and during ART among HIV-positive children enrolled in two HIV-programs in Cambodia., Methods: Retrospective cohort study on 1168 HIV-positive children <15 years old registered in two HIV-programs over a four-year period. Mortality rates were calculated for both children on treatment and children not started on ART., Results: Over half (53%) of children were 5 years or above and only 69(6%) were <18 months. Overall, 9% (105/1168) of children died since the set-up of the programs. By the end of the observation period, 66(14.5%) patients not on ART had died compared to 39(5.5%) of those under treatment, and 100(22%) who did not start ART were lost-to-follow-up compared to 13(2%) on ART. 66/105 (62.8%) of all in-program deaths occurred before starting ART, of which 56% (37/66) and 79% (52/66) occurred within 3 and 6 months of enrollment respectively. Mortality rate ratio between children not on ART and children on ART was 4.1 (95%CI: 2.7-6.2) (P < 0.001). The most common contributing cause of death in first 3 months of treatment and in first 3 months of program enrollment was tuberculosis. 41/52 (79%) children who died within 6 months of enrollment had met the ART eligibility criteria before death., Conclusion: HIV-positive children experienced a high mortality and loss-to-follow-up rates before starting ART. These program outcomes may be improved by a more timely ART initiation. Measuring overall in-program mortality as opposed to only mortality on ART is recommended in order to more accurately evaluate pediatric HIV-programs performance.

Humanitarian agencies are increasingly engaged in research in conflict and post-conflict settings. This is justified by the need to improve the quality of assistance provided in these settings and to collect evidence of the highest standard to inform advocacy and policy change. The instability of conflict-affected areas, and the heightened vulnerability of populations caught in conflict, calls for careful consideration of the research methods employed, the levels of evidence sought, and ethical requirements. Special attention needs to be placed on the feasibility and necessity of doing research in conflict-settings, and the harm-benefit ratio for potential research participants.

Objectives: To report on the cumulative proportion of deaths occurring within 3 months of starting antiretroviral treatment (ART) and to identify factors associated with such deaths, among adults at primary health centres in a rural district of Malawi., Methods: Retrospective cohort study: from June 2006 to April 2008, deaths occurring over a 3-month period were determined and risk factors examined., Results: A total of 2316 adults (706 men and 1610 women; median age 35 years) were included in the analysis and followed up for a total of 1588 person-years (PY); 277 (12%) people died, of whom 206 (74%) people died within 3 months of initiating ART (cumulative incidence: 13.0; 95% confidence interval: 11.3-14.8 per 100 PY of follow-up). Significant risk factors associated with early deaths included male sex, WHO stage 4 disease, oesophageal or persistent oral candidiasis and unexplained presumed or measured weight loss >10%. One in every 3 patients who either died or was lost to follow up had unexplained weight loss >10%, and survival in this group was significantly different from patients without this condition., Conclusions: Seven in 10 individuals initiating ART at primary health centres die early. Specific groups of patients are at higher risk of such mortality and should receive priority attention, care and support.

The vital signs of pulse rate, blood pressure, temperature and respiratory rate are the 'nub' of individual patient management. At the programmatic level, vital signs could also be used to monitor the burden and treatment outcome of chronic disease. Case detection and treatment outcome constitute the vital signs of tuberculosis control within the WHO's 'DOTS' framework, and similar vital signs could be adapted and used for management of chronic diseases. The numbers of new patients started on therapy in each month or quarter (new incident cases) are sensitive indicators for programme performance and access to services. Using similar reporting cycles, treatment outcomes for all patients can be assessed, the vital signs being: alive and retained on therapy at the respective facility; died; stopped therapy; lost to follow-up; and transferred out to another facility. Retention on treatment constitutes the prevalent number of cases, the burden of disease, and this provides important strategic information for rational drug forecasting and logistic planning. If case numbers and outcomes of chronic diseases were measured reliably and consistently as part of an integrated programmatic approach, this would strengthen the ability of resource-poor countries to monitor and assess their response to these growing epidemics.

This cohort study was conducted amongst female patients manifesting lipoatrophy while receiving stavudine-containing first-line antiretroviral treatment regimens at two urban health centres in Rwanda. The objectives were to assess weight evolution after stavudine substitution and to describe any significant difference in weight evolution when zidovudine or tenofovir/abacavir was used for substitution. All adult patients on stavudine-containing first-line regimens who developed lipoatrophy (diagnosed using a lipodystrophy case definition study-based questionnaire) and whose treatment regimen was changed were included (n=114). In the most severe cases stavudine was replaced with tenofovir or abacavir (n=39), and in the remainder with zidovudine (n=75). For patients changed to zidovudine a progressive weight loss was seen, while those on tenofovir/abacavir showed a progressive weight increase from six months. The between-group difference in weight evolution was significant from nine months (difference at 12 months: 2.3 kg, P=0.02). These differences were confirmed by follow-up lipoatrophy scores. In multivariate analysis, substitution with tenofovir/abacavir remained significantly associated with weight gain. This is the first study in Africa assessing weight gain as a proxy for recovery after stavudine substitution due to lipoatrophy, providing supporting evidence that tenofovir/abacavir is superior to zidovudine. The weight loss with zidovudine might justify earlier substitution and access to better alternatives like tenofovir/abacavir.

Co-trimoxazole (trimethoprim-sulfamethoxazole) is a widely available antibiotic that substantially reduces HIV-related morbidity and mortality in both adults and children. Prophylaxis with co-trimoxazole is a recommended intervention of proven benefit that could serve not only as an initial step towards improving paediatric care in young children with limited access to antiretroviral treatment, but also as an important complement to antiretroviral therapy in resource-limited settings. Despite co-trimoxazole's known clinical benefits, the potential operational benefits, and favourable recommendations by WHO, UNAIDS, and UNICEF, its routine use in developing countries--particularly sub-Saharan Africa--has remained limited. Out of an estimated 4 million children in need of co-trimoxazole prophylaxis (HIV-exposed and HIV-infected), only 4% are currently receiving this intervention. We discuss some of the major barriers preventing the scale-up of co-trimoxazole prophylaxis for children in countries with a high prevalence of HIV and propose specific actions required to tackle these challenges.

This study was conducted among individuals placed on WHO-recommended first-line antiretroviral therapy (ART) at two urban health centres in Kigali, Rwanda, in order to determine (a) the overall prevalence of lipodystrophy and (b) the risk factors for lipoatropy. Consecutive individuals on ART for >1 year were systematically subjected to a standardised case definition-based questionnaire and clinical assessment. Of a total of 409 individuals, 370 (90%) were on an ART regimen containing stavudine (d4T), whilst the rest were receiving a zidovudine (AZT)-containing regimen. Lipodystrophy was apparent in 140 individuals (34%), of whom 40 (9.8%) had isolated lipoatrophy, 20 (4.9%) had isolated lipohypertrophy and 80 (19.6%) had mixed patterns. Fifty-six percent of patients reported the effects as disturbing. The prevalence of lipoatrophy was more than three times higher when taking d4T compared with AZT-containing regimens (31.4% vs. 10.3%). Being female, d4T-based ART, baseline body mass index >or=25 kg/m(2) or baseline CD4 count >or=150 cells/microl and increasing duration of ART were all significantly associated with lipoatrophy. Lipoatrophy appears to be an important long-term complication of WHO-recommended first-line ART regimens. These data highlight the urgent need for access to more affordable and less toxic ART regimens in resource-limited settings.

A study of 568 children aged <5 years who commenced nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in resource-limited settings revealed good early outcomes. After 12 months of antiretroviral therapy, survival probability was 0.89 (95% confidence interval, 0.86-0.92), with no significant difference among children stratified on the basis of baseline immunological levels; 62% attained a CD4 cell percentage >25%, and 7% continued to have a CD4 cell percentage <15%.

Background: A study was conducted among newly registered HIV-positive tuberculosis (TB) patients systematically offered anti-retroviral treatment (ART) in a district hospital in rural Malawi in order to a) determine the acceptance of ART b) conduct a geographic mapping of those placed on ART and c) examine the association between "cost of transport" and ART acceptance., Methodology/principal Findings: A retrospective cross-sectional analysis was performed on routine program data for the period of February 2003 to July 2004. Standardized registers and patient cards were used to gather data. The place of residence was used to determine road distances to the Thyolo district hospital. Cost of transport from different parts of the district was based on the known cost for public transport to the road-stop closest to the patient's residence. Of 1,290 newly registered TB patients, 1,003(78%) underwent HIV-testing of whom 770 (77%) were HIV-positive. 742 of these individuals (pulmonary TB = 607; extra-pulmonary TB = 135) were considered eligible for ART of whom only 101(13.6%) accepted ART. Cost of transport to the hospital ART site was significantly associated with ART acceptance and there was a linear trend in association between cost and ART acceptance (chi(2) for trend = 25.4, P<0.001). Individuals who had to pay 50 Malawi Kwacha (1 United States Dollar = 100 Malawi Kwacha, MW) or less for a one-way trip to the Thyolo hospital were four times more likely to accept ART than those who had to pay over 100 MW (Adjusted Odds ratio = 4.0, 95% confidence interval: 2.0-8.1, P<0.001)., Conclusions/significance: ART acceptance among TB patients in a rural district in Malawi is low and associated with cost of transport to the centralized hospital based ART site. Decentralizing the ART offer from the hospital to health centers that are closer to home communities would be an essential step towards reducing the overall cost and burden of travel.

Objectives: Among adults started on antiretroviral treatment (ART) in a rural district hospital (a) to determine the cumulative proportion of deaths that occur within 3 and 6 months of starting ART, and (b) to identify risk factors that may be associated with such mortality., Design and Setting: A cross-sectional analytical study set in Thyolo district, Malawi., Methods: Over a 2-year period (April 2003 to April 2005) mortality within the first 3 and 6 months of starting ART was determined and risk factors were examined., Results: A total of 1507 individuals (517 men and 990 women), whose median age was 35 years were included in the study. There were a total of 190 (12.6%) deaths on ART of which 116 (61%) occurred within the first 3 months (very early mortality) and 150 (79%) during the first 6 months of initiating ART. Significant risk factors associated with such mortality included WHO stage IV disease, a baseline CD4 cell count under 50 cells/mul and increasing grades of malnutrition. A linear trend in mortality was observed with increasing grades of malnutrition (chi for trend = 96.1, P

Objectives: To (a) determine early treatment outcomes and (b) assess safety in children treated with adult fixed-dose combination (FDC) antiretroviral tablets., Setting: Sixteen Medecins Sans Frontieres (MSF) HIV programs in eight countries in resource-limited settings (RLS)., Methods: Analysis of routine program data gathered June 2001 to March 2005., Results: A total of 1184 children [median age, 7 years; inter-quartile range (IQR), 4.6-9.3] were treated with antiretroviral therapy (ART) of whom 616(52%) were male. At ART initiation, Centres for Disease Control stages N, A, B and C were 9, 14, 38 and 39%, respectively. Children were followed up for a median period of 6 months (IQR, 2-12 months). At 12 months the median CD4 percentage gain in children aged 18-59 months was 15% (IQR, 6-18%), and the percentage with CD4 gain < 15% was reduced from 85% at baseline to 11%. In those aged 60-156 months, median CD4 cell count gain was 275 cells/microl (IQR, 84-518 cells/microl), and the percentage with CD4 < 200 cells/mul reduced from 51% at baseline to 11%. Treatment outcomes included; 1012 (85%) alive and on ART, 36 (3%) deaths, 15 (1%) stopped ART, 89 (8%) lost to follow-up, and 31 (3%) with unknown outcomes. Overall probability of survival at 12 months was 0.87 (0.84-0.89). Side effects caused a change to alternative antiretroviral drugs in 26 (2%) but no deaths., Conclusions: Very satisfactory early outcomes can be achieved in children in RLS using generic adult FDC antiretroviral tablets. These findings strongly favour their use as an "interim solution" for scaling-up ART in children; however, more appropriate pediatric antiretroviral drugs remain urgently needed.

Background: HAART reduces tuberculosis (TB) incidence in people living with HIV/AIDS but those starting HAART may develop active TB or subclinical TB may become apparent in the immune reconstitution inflammatory syndrome., Objective: To measure the incidence rate of notified TB in people receiving HAART in five HIV programmes occurring in low-resource countries with a high TB/HIV burden., Methods: A retrospective review in five Médecins Sans Frontières programmes (Cambodia, Thailand, Kenya, Malawi and Cameroon) allowed incidence rates of notified TB to be calculated based on follow-up time after HAART initiation., Result: Among 3151 patients analysed, 90% had a CD4 cell count of < 200 cells/mul. Median follow-up time ranged from 3.7 months in Thailand or Kenya to 11.1 months in Cambodia. Incidence rates were 7.6, 10.4, 17.6, 14.3 and 4.8/100 person-years for pulmonary TB and 12.7, 4.3, 6.9, 2.1 and 0/100 person-years for extra-pulmonary TB in the programmes in Cambodia, Thailand, Kenya, Malawi and Cameroon, respectively. Overall, 62.3% of pulmonary TB and 54.9% of extra-pulmonary TB were diagnosed within 3 months after HAART initiation., Conclusion: High incidence rates of notified TB under HAART in programmes held in poor-resource countries were observed; these were likely to include both undiagnosed prevalent TB at HAART initiation and subclinical TB developing during the immune reconstitution inflammatory syndrome. This raises operational issues concerning TB diagnosis and treatment of TB/HIV-coinfected patients and prompts for urgent TB and HIV care integration.

Background: The use fixed-dose combination (FDC) is a critical tool in improving HAART. Studies on the effectiveness of combined lamivudine, stavudine and nevirapine (3TC/d4T/NVP) are scarce., Objective: To analyse 6861 patients in a large observational cohort from 21 Médecins Sans Frontieres (MSF) HIV/AIDS programmes taking 3TC/d4T/NVP, with subcohort analyses of patients at 12 and 18 months of treatment., Methods: Survival was analysed using Kaplan-Meier method and factors associated with progression to death with Cox proportional hazard ratio., Results: Median baseline CD4 cell count at initiating of FDC was 89 cells/microl [interquartile range (IQR), 33-158]. The median follow-up time was 4.1 months (IQR, 1.9-7.3). The incidence rate of death during follow-up was 14.2/100 person-years [95% confidence interval (CI), 13.8-14.5]. Estimates of survival (excluding those lost to follow-up) were 0.93 (95% CI, 92-94) at 6 months (n = 2,231) and 0.90 (95% CI, 89-91) at 12 months (n = 472). Using a Cox model, the following factors were associated with death: male gender, symptomatic infection, body mass index < 18 kg/m and CD4 cell count 15-50 cells/microl or < 15 cells/microl. Subcohort analysis of 655 patients after 1 year of follow-up (M12 FDC cohort) revealed that 77% remained on HAART, 91% of these still on the FDC regimen; 5% discontinued the FDC because of drug intolerance. At 18 months, 77% of the patients remained on HAART., Conclusions: Positive outcomes for d4T/3TC/NVP are reported for up to 18 months in terms of efficacy and safety.

Medical AID organisations such as Médecins Sans Frontières receive several requests from individuals and international academic institutions to conduct research at their implementation sites in Africa. Do AID agencies have an ethical duty to comply with research requests? In this paper we respond to the views and constructed theories (albeit unfounded) of one such researcher, whose request to conduct research at one of our sites in the Democratic Republic of Congo was turned down.

With assistance from the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM), Malawi is scaling-up the delivery of antiretroviral (ARV) therapy to HIV-positive eligible patients. The country has developed National ARV Treatment Guidelines, which emphasize a structured and standardized approach for all aspects of ARV delivery, including monitoring and evaluation. Using the successful DOTS model adapted by National TB Control Programmes throughout the world, Malawi has developed a system of quarterly ARV cohort and cumulative ARV quarterly analyses. Thyolo district, in the southern region of Malawi, has been using this system since April 2003. This paper describes the standardized ARV treatment regimens and the treatment outcomes used in Thyolo to assess the impact of treatment, the registration and monitoring systems and how the cohort analyses are carried out. Data are presented for case registration and treatment outcome for the first quarterly cohort (April to June) and the combined cohorts (April to June and July to September). Such quarterly analyses may be useful for districts and Ministries of Health in assessing ARV delivery, although the burden of work involved in calculating the numbers may become large once ARV delivery systems have been established for several years.

Objectives: To assess the feasibility and effectiveness of voluntary counselling, HIV testing and adjunctive cotrimoxazole in reducing mortality in a cohort of tuberculosis (TB) patients registered under routine programme conditions in a rural district of Malawi., Design: 'Before' and 'after' cohort study using historical controls., Methods: Between 1 July 1999 and 30 June 2000 all TB patients were started on standardized anti-TB treatment, and offered voluntary counselling and HIV testing (VCT). Those found to be HIV-positive were offered cotrimoxazole at a dose of 480 mg twice daily, provided there were no contraindications. Side-effects were monitored clinically. End-of-treatment outcomes in this cohort (intervention group) were compared with a cohort registered between 1 July 1998 and 30 June 1999 in whom VCT and cotrimoxazole was not offered (control group)., Findings: A total of 1986 patients was registered in the study: 1061 in the intervention group and 925 in the control cohort. In the intervention group, 1019 (96%) patients were counselled pre-test, 964 (91%) underwent HIV testing and 938 (88%) were counselled post-test. The overall HIV-seroprevalence rate was 77%. A total of 693 patients were given cotrimoxazole of whom 14 (2%) manifested minor dermatological reactions. The adjusted relative risk of death in the intervention group compared with the control group was 0.81 (P < 0.001). The number needed to treat with VCT and adjunctive cotrimoxazole to prevent one death during anti-TB treatment was 12.5., Interpretation: This study shows that VCT and adjunctive cotrimoxazole is feasible, safe and reduces mortality rates in TB patients under routine programme conditions.

As part of a comprehensive human immunodeficiency virus (HIV) prevention strategy targeting high-risk groups, sexually transmitted infection (STI) clinics are offered to all prisoners in Thyolo district, southern Malawi. Prison inmates are not, however, allowed access to condoms as it is felt that such an intervention might encourage homosexuality which is illegal in Malawi. A study was conducted between January 2000 and December 2001 in order to determine the prevalence, incidence, and patterns of STIs among male inmates of 2 prisons in this rural district. A total of 4229 inmates were entered into the study during a 2-year period. Of these, 178 (4.2%) were diagnosed with an STI. This included 83 (46%) inmates with urethral discharge, 60 (34%) with genital ulcer disease (GUD), and 35 (20%) inmates with epididymo-orchitis. Fifty (28%) STIs were considered incident cases acquired within the prisons (incidence risk 12 cases/1000 inmates/year). GUD was the most common STI in this group comprising 52% of all STI. This study shows that a considerable proportion of STIs among inmates are acquired within prison. In a setting of same-sex inmates, this suggests inter-prisoner same-sex sexual activity. The findings have implications for HIV transmission and might help in developing more rational policies on STI control and condom access within Malawi prisons.