Cryptococcal antigen screening plus home visits reduces early mortality

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.

Mfinanga S, Chanda D, Kivuyo SL, Guinness L, Bottomley C, Simms V, Chijoka C, Masasi A, Kimaro G, Ngowi B, Kahwa A, Mwaba P, Harrison TS, Egwaga S, Jaffar S, REMSTART trial team. Lancet. 2015 Mar 9. pii: S0140-6736(15)60164-7. doi: 10.1016/S0140-6736(15)60164-7. [Epub ahead of print]

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 uL, 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.

Abstract access 

Editor’s notes: Despite the huge success of antiretroviral programme roll-out, early mortality among people initiating antiretroviral therapy (ART) in low- and middle-income countries remains high, and reducing early mortality is a priority. The risk of early mortality is highest among people with low CD4 counts. Although there has been an increase over calendar time in the median CD4 count at ART start, many people still start ART with low CD4 counts, and continue to be at high risk of death.

Cryptococcal disease is consistently identified at autopsy among HIV-positive people, although less commonly than tuberculosis and other lung infections. Cryptococcal disease is typically seen among individuals with very low CD4 counts, and has high case-fatality, for reasons including late presentation and suboptimal treatment and care. Among people with low CD4 counts, cryptococcal antigen can be detected in blood several weeks before cryptococcal disease becomes symptomatic. In 2011, the World Health Organization (WHO) issued rapid advice concerning prevention and treatment of cryptococcal meningitis in resource-constrained settings. This included a conditional recommendation (based on low-quality evidence) to screen individuals with CD4 counts below 100 cells per µl for cryptococcal antigen, followed by treatment either for cryptococcal meningitis, or with fluconazole for asymptomatic cryptococcal antigenaemia, as appropriate.

This trial is the first to provide evidence that this strategy can save lives. This was a pragmatic, individually randomised trial enrolling HIV-positive, ART-naïve people initially with CD4 counts below 100 cells per µl. Because of slow enrolment, inclusion criteria were later expanded to include people with CD4 counts below 200 cells per µl. The programme had two components. The first involved screening for cryptococcal antigen with a point-of-care test using a finger prick blood sample, followed by management in line with WHO guidelines. The second was adherence support, with trained lay workers visiting participants at or near their homes weekly for the first four weeks. The lay workers delivered ART, provided adherence support and monitored for adverse events.

The reduction of mortality from 18% to 13% in the intervention arm is clearly important, but also intriguing in terms of identifying the “active ingredient”. This may be difficult in a pragmatic trial of a programme with more than one component. For example, there was no cryptococcal antigen testing in control arm participants. Thus we cannot assess precisely the reduction in mortality attributable to this component of the programme. The authors estimate that cryptococcal antigen screening and treatment contributed about half of the observed effect. This component is also interesting because in practice, implementation of the cryptococcal antigen “screen and treat” pathway in the trial was not exactly as per WHO guidelines. WHO guidelines recommend lumbar puncture for people who screen positive for cryptococcal antigen and have symptoms suggesting meningitis. However, in this trial 76% of people testing cryptococcal antigen positive refused lumbar puncture, similar to experience elsewhere. Despite the programme, 32% of people in the intervention arm who were cryptococcal antigen positive died. This suggests that the fluconazole that most people received may have been inadequate, and that alternatives to lumbar puncture are necessary to identify people at highest risk who would benefit from full treatment for cryptococcal meningitis with amphotericin B. Quantifying the cryptococcal antigen titre in blood might serve this purpose, and needs further investigation.

In a previous trial in Uganda, home-based ART care (monthly delivery of ART by lay workers) was as effective as clinic-based care, in terms of virologic failure. However, other programmes similarly aiming to provide support for individuals starting ART have been less successful. For example a recently-presented trial of health “navigators” who used mobile phones and text messages to help people living with HIV link to ART and, where relevant, TB treatment, did not reduce mortality at nine months. Supporting adherence and retention is clearly critical to the long-term success of ART programmes. The challenge is defining how to do this most effectively and sustainably.

As part of this trial, in both arms ART was intended to be started within four to seven days of the first visit where possible, substantially faster than was previously routine. All participants were asked to provide sputum for testing for tuberculosis with Xpert MTB/RIF, regardless of reported symptoms. Some 16% of participants were already on tuberculosis treatment at enrolment. A further 11% were newly-diagnosed with tuberculosis at enrolment, roughly half based on sputum smear or clinical features and half based on the Xpert MTB/RIF result. This emphasises the importance of routine investigation for tuberculosis among people presenting to start ART. In the United Republic of Tanzania, people not on tuberculosis treatment were rescreened with Xpert MTB/RIF six weeks after enrolment. A further 5% were found to have tuberculosis, highlighting the inadequate sensitivity of Xpert MTB/RIF on sputum in this group of people.

Overall this trial provides encouragement that early on-ART mortality among people with low CD4 counts can be reduced. This is achieved with targeted treatment of cryptococcal disease and home-based early adherence support, in the context of universal screening for tuberculosis and rapid ART initiation. Ongoing studies are investigating whether empirical treatment for tuberculosis will reduce early mortality among similar patient populations. These results together will help define the optimum package of care to minimise mortality among individuals presenting with low CD4 cell counts. At the same time, HIV testing needs to be promoted so that people living with HIV can start ART before reaching the stage of advanced disease where mortality is such a risk.

Avoid TB deaths
United Republic of Tanzania, Zambia
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