Compensation of subjects for participation in biomedical research in resource - limited settings: a discussion of practices in Malawi.

BACKGROUND: Compensating participants of biomedical research is a common practice. However, its proximity with ethical concerns of coercion, undue influence, and exploitation, demand that participant compensation be regulated. The objective of this paper is to discuss the current regulations for compensation of research participants in Malawi and how they can be improved in relation to ethical concerns of coercion, undue influence, and exploitation. MAIN TEXT: In Malawi, national regulations recommend that research subjects be compensated with a stipend of US$10 per study visit. However, no guidance is provided on how this figure was determined and how it should be implemented. While necessary to prevent exploitation, the stipend may expose the very poor to undue influence. The stipend may also raise the cost of doing research disadvantaging local researchers and may have implications on studies where income stipend is the intervention under investigation. We recommend that development and implementation of guidelines of this importance involve interested parties such as the research community and patient groups. CONCLUSION: Compensating human research subjects is important but can also act as a barrier to voluntary participation and good research efforts. Deliberate measures need to be put in place to ensure fair compensation of research participants, avoid their exploitation and level the field for locally funded research

Outcomes and Diagnostic Processes in Outpatients with Presumptive Tuberculosis in Zomba District, Malawi.

BACKGROUND: In Malawi, outpatients who have presumptive tuberculosis (TB), i.e. fever, night sweats, weight loss and/or any-duration cough (HIV-infected) or cough of at least 2 weeks (HIV-uninfected), are registered in chronic cough registers. They should receive a diagnostic work-up with first-step provider-initiated HIV testing and sputum testing which includes XpertMTB/RIF, following a national algorithm introduced in 2012. METHODS: An operational study, in which we prospectively studied 6-month outcomes of adult outpatients who were registered in chronic cough registers in Zomba Central Hospital and Matawale peri-urban Health Center, between February and September 2013. We recorded implementation of the diagnostic protocol and outcomes at 6 months from registration. RESULTS: Of 348 patients enrolled, 165(47%) were male, median age was 40 years, 72(21%) had previous TB. At registration 154(44%) were known HIV-positive, 34(10%) HIV-negative (26 unconfirmed) and 160(46%) had unknown HIV status; 104(56%) patients with unknown/unconfirmed HIV status underwent HIV testing. At 6 months 191(55%) were HIV-positive, 87(25%) HIV-negative (26 unconfirmed) and 70(20%) still had unknown HIV status. Higher age and registration in Matawale were independently associated with remaining unknown HIV status after 6 months. 62% of patients had sputum tested, including XpertMTB/RIF, according to the algorithm. TB was diagnosed in 54(15%) patients. This was based on XpertMTB/RIF results in 8(15%) diagnosed cases. In 26(48%) TB was diagnosed on clinical grounds. Coverage of ART in HIV-positive patients was 89%. At 6 months, 236(68%) were asymptomatic, 48(14%) symptomatic, 25(7%) had been lost-to-follow-up and 39(11%) had died. Mortality among those HIV-positive, HIV-negative and with unknown HIV-status was 15%, 2% and 10%, respectively. Male gender, being HIV-positive-not-on-ART and not receiving antibiotics were independent risk factors for mortality. CONCLUSION: HIV prevalence among patients with presumptive TB was high (55%). One quarter was not HIV tested and mortality in this group was substantial (10%). The impact of XpertMTB/RIF on TB diagnosis was limited

Frequent malaria illness episodes in two Malawian patients on antiretroviral therapy soon after stopping cotrimoxazole preventive therapy

We describe two Malawian adults on successful antiretroviral therapy who experienced frequent malaria episodes after stopping cotrimoxazole prophylaxis. We argue that, in addition to stopping cotrimoxazole, diminished malaria immunity and drug interactions between efavirenz and artemether–lumefantrine may have played a causative role in the recurrent malaria our patients experienced

TSCQ study: a randomized, controlled, open-label trial of daily trimethoprim-sulfamethoxazole or weekly chloroquine among adults on antiretroviral therapy in Malawi: study protocol for a randomized controlled trial.

BACKGROUND: Before antiretroviral therapy (ART) became widely available in sub-Saharan Africa, several studies demonstrated that daily trimethoprim-sulfamethoxazole (TS) prophylaxis reduced morbidity and mortality among HIV-infected adults. As a result, the World Health Organization (WHO) recommended administering TS prophylaxis to this group. However, the applicability of the results to individuals taking ART and living in sub-Saharan Africa has not been definitively evaluated. This study aims to determine if TS prophylaxis benefits HIV-infected Malawian adults after a good response to ART. If TS prophylaxis does indeed show benefit, it is important to determine if this is due to its antibacterial and/or antimalarial properties. METHODS/DESIGN: A randomized, controlled, open-label, phase III trial of continued standard of care prophylaxis with daily trimethoprim-sulfamethoxazole (TS) compared to discontinuation of standard of care TS prophylaxis and starting weekly chloroquine (CQ) prophylaxis or discontinuation of standard of care TS prophylaxis. The study will randomize 1400-1500 HIV-infected adults (equally divided over the three study arms) with a nondetectable viral load and a CD4 count of 250/mm(3) or more from antiretroviral therapy clinics in Blantyre and Zomba. The expected rate of primary endpoint events of death and WHO stage 3 and 4 events is 6.8 per 100 person-years of follow-up in all participants. Assuming the number of events follows a Poisson distribution and average participant follow-up after 10 % loss to follow-up is 41.6 months, the study will have approximately 85 % power to rule out a reduction of 35 % or more in primary endpoint events in the TS or CQ arms compared to discontinuation of TS prophylaxis-i.e., to show that discontinuation of TS prophylaxis is noninferior to either TS or CQ, with a noninferiority margin of 35 %. Ethical and regulatory approvals were obtained from the University of Malawi College of Medicine Research Ethics Committee; the Malawi Pharmacy, Medicines and Poisons Board; and the University of Maryland Baltimore Institutional Review Board. DISCUSSION: The study began recruitment activities at the Ndirande site in November 2012. The sponsor agreed to extend and expand the study in early 2015, and a second site, Zomba, was added for recruitment and follow-up in mid-2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01650558 (registered on 6 July 2012). PROTOCOL VERSION: Letter of amendment #1 to the DAIDS-ES 10822 TSCQ Malawi Protocol, Version 4.0, 16 December 2014

Task shifting of triage to peer expert informal care providers at a tertiary referral HIV clinic in Malawi: a cross-sectional operational evaluation

Abstract Background HIV treatment models in Africa are labour intensive and require a high number of skilled staff. In this context, task-shifting is considered a feasible alternative for ART service delivery. In 2006, a lay health cadre of expert patients (EPs) at a tertiary referral HIV clinic in Zomba, Malawi was capacitated. There are few evaluations of EP program efficacy in this setting. Triage is the process of prioritizing patients in terms of the severity of their condition and ensures that no harmful delays occur to treatment and care. This study evaluates the safety of task-shifting triage, in an ambulatory low resource setting, to EPs. Methods As a quality improvement exercise in April 2010, formal triage training was conducted by adapting the World Health Organization Emergency Triage Assessment and Treatment Triage Module Guidelines. A cross sectional observation study was conducted 2 years after the intervention. Triage assessments performed by EPs were repeated by a clinical officer (gold standard) to assess sensitivities, specificities, positive and negative predictive values for EP triage scores. Proportions were calculated for categories of disposition by stratifying by EP and clinician triage scores. Results A total of 467 patients were triaged by 7 EPs and re-triaged by clinical officers. With combined triage scores for emergency and priority patients we report a sensitivity of 85% and specificity of 74% for the EP scoring, with a low positive predictive value (41%) and a high negative predictive value (96%). We calculate a serious miss rate of EP scoring (i.e. missed priority or emergency patients) as 2.2%. Admission rates to hospital were highest among those patients triaged as emergency cases either by the EP’s (21%) or the clinicians (83%). Fewer patients triaged as priority by either EPs (5%) or clinicians (15%) were admitted to hospital, however these patients had the highest prevalence of same day lab testing and/or specialty referral. Conclusions Our study provides reassurance that in the context of adequate training and ongoing supervision, task-shifting triage to lay health care workers does not necessarily lead to less accurate triaging. EPs have a tendency to be more conservative in over-triaging patients

Survival Outcomes in a Pediatric Antiretroviral Treatment Cohort in Southern Malawi

<div><p>Background</p><p>Pediatric uptake and outcomes in antiretroviral treatment (ART) programmes have lagged behind adult programmes. We describe outcomes from a population-based pediatric ART cohort in rural southern Malawi.</p><p>Methods</p><p>Data were analyzed on children who initiated ART from October/2003 –September/2011. Demographics and diagnoses were described and survival analyses conducted to assess the impact of age, presenting features at enrolment, and drug selection.</p><p>Results</p><p>The cohort consisted of 2203 children <15 years of age. Age at entry was <1 year for 219 (10%), 1–1.9 years for 343 (16%), 2–4.9 years for 584 (27%), and 5–15 years for 1057 (48%) patients. Initial clinical diagnoses of tuberculosis and wasting were documented for 409 (19%) and 523 (24%) patients, respectively. Median follow-up time was 1.5 years (range 0–8 years), with 3900 patient-years of follow-up. Over the period of observation, 134 patients (6%) died, 1324 (60%) remained in the cohort, 345 (16%) transferred out, and 387 (18%) defaulted. Infants <1 year of age accounted for 19% of deaths, with a 2.7-fold adjusted mortality hazard ratio relative to 5–15 year olds; median time to death was also shorter for infants (60 days) than older children (108 days). Survival analysis demonstrated younger age at ART initiation, more advanced HIV stage, and presence of tuberculosis to each be associated with shorter survival time. Among children <5 years, severe wasting (weight-for-height z-score </p><p>Conclusions</p><p>Cumulative incidence of mortality was 5.2%, 7.1% and 7.7% after 1, 3, and 5 years, respectively, with disproportionate mortality in infants <1 year of age and those presenting with tuberculosis. These findings reinforce the urgent need for early diagnosis and treatment in this population, but also demonstrate that provision of pediatric care in a rural setting can yield outcomes comparable to more resourced urban settings of poor countries.</p></div

Estimated point-wise cumulative incidence (95% confidence interval) of death, transfer out of cohort, and defaulting, based on competing risk models.

<p>Estimated point-wise cumulative incidence (95% confidence interval) of death, transfer out of cohort, and defaulting, based on competing risk models.</p

Additional file 1: of Task shifting of triage to peer expert informal care providers at a tertiary referral HIV clinic in Malawi: a cross-sectional operational evaluation

Work Aid for EP Triage Training. Description of data: A work aid summarizing the triage process and training for Expert Patients, modified from the WHO ETAT training. This work aid was also translated into Chichewa (the local language). (PPTX 99 kb

Estimated cumulative incidence curves with mortality, transfer out of cohort, and default as competing events.

<p>Estimated cumulative incidence curves with mortality, transfer out of cohort, and default as competing events.</p

Survival Outcomes in a Pediatric Antiretroviral Treatment Cohort in Southern Malawi - Fig 1

<p><b>Survival curves for the Z-OCS pediatric cohort (n = 2203) by (A) age at enrolment; (B) clinical stage at diagnosis; (C) clinical diagnosis of tuberculosis at enrolment; and (D) wasting (weight for-length/height <-3SD).</b> Survival analysis for wasting was restricted to patients <5 years of age.</p