Elsevier

The Lancet

Volume 385, Issue 9983, 30 May–5 June 2015, Pages 2173-2182
The Lancet

Articles
Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial

https://doi.org/10.1016/S0140-6736(15)60164-7Get rights and content

Summary

Background

Mortality in people in Africa with HIV infection starting antiretroviral therapy (ART) is high, particularly in those with advanced disease. We assessed the effect of a short period of community support to supplement clinic-based services combined with serum cryptococcal antigen screening.

Methods

We did an open-label, randomised controlled trial in six urban clinics in Dar es Salaam, Tanzania, and Lusaka, Zambia. From February, 2012, we enrolled eligible individuals with HIV infection (age ≥18 years, CD4 count of <200 cells per μL, ART naive) and randomly assigned them to either the standard clinic-based care supplemented with community support or standard clinic-based care alone, stratified by country and clinic, in permuted block sizes of ten. Clinic plus community support consisted of screening for serum cryptococcal antigen combined with antifungal therapy for patients testing antigen positive, weekly home visits for the first 4 weeks on ART by lay workers to provide support, and in Tanzania alone, re-screening for tuberculosis at 6–8 weeks after ART initiation. The primary endpoint was all-cause mortality at 12 months, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISCRTN 20410413.

Findings

Between Feb 9, 2012, and Sept 30, 2013, 1001 patients were randomly assigned to clinic plus community support and 998 to standard care. 89 (9%) of 1001 participants in the clinic plus community support group did not receive their assigned intervention, and 11 (1%) of 998 participants in the standard care group received a home visit or a cryptococcal antigen screen rather than only standard care. At 12 months, 25 (2%) of 1001 participants in the clinic plus community support group and 24 (2%) of 998 participants in the standard care group had been lost to follow-up, and were censored at their last visit for the primary analysis. At 12 months, 134 (13%) of 1001 participants in the clinic plus community support group had died compared with 180 (18%) of 998 in the standard care group. Mortality was 28% (95% CI 10–43) lower in the clinic plus community support group than in standard care group (p=0·004).

Interpretation

Screening and pre-emptive treatment for cryptococcal infection combined with a short initial period of adherence support after initiation of ART could substantially reduce mortality in HIV programmes in Africa.

Funding

European and Developing Countries Clinical Trials Partnership.

Introduction

About 10 million people in Africa are now receiving antiretroviral therapy (ART) for the treatment of HIV infection. Mortality in Africans during the first year of ART is higher than in Europeans, particularly during the first few months of treatment.1 Additionally, in Africa, mortality2, 3 and loss to follow-up4 are high during the pretreatment period between a patient's first presentation to clinic and ART initiation. About a third of Africans still begin ART with advanced disease,5, 6 and have a very high disease burden.

Tuberculosis and cryptococcal meningitis account for most deaths in people with HIV infection presenting at health facilities in Africa.7, 8, 9 For tuberculosis, the median diagnostic delay is about 2 months overall10 and diagnosis in people co-infected with HIV presenting with advanced HIV disease is particularly challenging.11 In autopsy studies, tuberculosis has been detected in more than 50% of adults with HIV infection.12 Cryptococcal meningitis occurs mostly in individuals with a CD4 count of less than 100 cells per μL13 and is associated with 25–50% mortality in clinical trials and well functioning clinical settings.9, 14 The mortality associated with cryptococcal meningitis has remained high in some settings despite increased access to ART.15, 16

The biggest challenge facing health-care delivery in Africa is the severe shortage of qualified health-care workers, particularly doctors.17 Findings of a cluster-randomised trial18 showed that home-based care delivered by trained lay workers was as effective as standard clinic-based care in a predominately rural setting where access to clinics was difficult.

In this trial, we assessed the effect of a short period of community-based support provided to individuals with HIV infection who presented at health centres with advanced disease combined with screening for cryptococcal meningitis, compared with standard care.

Section snippets

Study design and participants

This study was an open-label, randomised controlled trial that took place in six public clinics serving urban and peri-urban populations: three in Dar es Salaam, Tanzania, and three in Lusaka, Zambia.

Recruitment began in February, 2012, when consecutive individuals with HIV infection were invited to join the trial if they were older than 18 years, presented with a CD4 count of less than 100 cells per μL, lived in the trial clinic catchment population, were able to communicate with staff, and

Results

Between Feb 9, 2012, and Sept 30, 2013, 26 (1%) of 3186 patients assessed for eligibility declined to join the trial and 1999 (63%) of 3186 were eligible and randomly assigned to either clinic plus community support (n=1001) or standard care (n=998; figure 1). Each participant was followed up for up to 12 months; and the last follow-up ended on Sept 30, 2014. 89 (9%) of 1001 participants in the clinic plus community support group did not receive the intervention (ie, a cryptococcal antigen

Discussion

In this trial, just four short home visits by lay workers to provide adherence support combined with screening for cryptococcal meningitis led to a significant reduction in mortality in patients infected with HIV starting ART with advanced disease. Mortality was about 30% less than in individuals who did not receive this simple supportive package. These findings were robust to sensitivity analyses. The trial was large, done under real-life conditions, had a low loss to follow-up, and the

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