Elsevier

The Lancet HIV

Volume 2, Issue 3, March 2015, Pages e107-e116
The Lancet HIV

Articles
Estimation of mortality among HIV-infected people on antiretroviral treatment in east Africa: a sampling based approach in an observational, multisite, cohort study

https://doi.org/10.1016/S2352-3018(15)00002-8Get rights and content

Summary

Background

Mortality in HIV-infected people after initiation of antiretroviral treatment (ART) in resource-limited settings is an important measure of the effectiveness and comparative effectiveness of the global public health response. Substantial loss to follow-up precludes accurate accounting of deaths and limits our understanding of effectiveness. We aimed to provide a better understanding of mortality at scale and, by extension, the effectiveness and comparative effectiveness of public health ART treatment in east Africa.

Methods

In 14 clinics in five settings in Kenya, Uganda, and Tanzania, we intensively traced a sample of patients randomly selected using a random number generator, who were infected with HIV and on ART and who were lost to follow-up (>90 days late for last scheduled visit). We incorporated the vital status outcomes for these patients into analyses of the entire clinic population through probability-weighted survival analyses.

Findings

We followed 34 277 adults on ART from Mbarara and Kampala in Uganda, Eldoret, and Kisumu in Kenya, and Morogoro in Tanzania. The median age was 35 years (IQR 30–42), 11 628 (34%) were men, and median CD4 count count before therapy was 154 cells per μL (IQR 70–234). 5780 patients (17%) were lost to follow-up, 991 (17%) were selected for tracing between June 10, 2011, and Aug 27, 2012, and vital status was ascertained for 860 (87%). With incorporation of outcomes from the patients lost to follow-up, estimated 3 year mortality increased from 3·9% (95% CI 3·6–4·2) to 12·5% (11·8–13·3). The sample-corrected, unadjusted 3 year mortality across settings was lowest in Mbarara (7·2%) and highest in Morogoro (23·6%). After adjustment for age, sex, CD4 count before therapy, and WHO stage, the sample-corrected hazard ratio comparing the settings with highest and lowest mortalities was 2·2 (95% CI 1·5–3·4) and the risk difference for death at 3 years was 11% (95% CI 5·0–17·7).

Interpretation

A sampling-based approach is widely feasible and important to an understanding of mortality after initiation of ART. After adjustment for measured biological drivers, mortality differs substantially across settings despite delivery of a similar clinical package of treatment. Implementation research to understand the systems, community, and patients' behaviours driving these differences is urgently needed.

Funding

The US National Institutes of Health and President's Emergency Fund for AIDS Relief.

Introduction

Although worldwide investments in HIV/AIDS care and treatment have helped to deliver highly effective antiretroviral therapy to 13 million individuals (ART),1 an understanding of the effectiveness and comparative effectiveness across settings of this public health investment depends on our ability to assess survival after treatment initiation. Although the antiretroviral regimens routinely used in resource-limited settings have reliable and potent pharmacological ability to suppress HIV RNA replication, the actual attainment of viral control, restoration of health, and achievement of long-term survival in the real world is far less certain. To achieve optimum effectiveness, HIV drugs must be delivered by adequately staffed clinics with qualified and motivated providers, accompanied by clinical and laboratory monitoring and taken by engaged patients with high day-to-day adherence. Barriers to these behaviours are common: poverty is prevalent,2 transportation is unreliable,3 free drugs incur ancillary and opportunity costs (eg, loss of wages),4 provider burn-out and long waiting times are commonplace,5 and stigma and depression remain widespread.6 Quantification of mortality after ART initiation is therefore urgently needed to understand the effectiveness and comparative effectiveness of global HIV treatment programmes.

To date, however, uncertainty remains about mortality in HIV-infected patients after starting ART. Existing reports from programmatic settings7, 8, 9 likely miss many deaths because of loss to follow-up.10, 11, 12 For example, the Antiretroviral Therapy in Lower Income Countries (ART-LINC) cohorts reported mortality of 1·8–6·0% in 30 clinics in Africa at 1 year after ART initiation, but those researchers noted that these figures were related to how active follow-up (and therefore ascertainment) was at each site.13 By contrast, interval research cohorts or randomised trials of clinical interventions can show mortality more completely.14 These studies, however, select individuals who are willing and able to comply with research protocols and often offer special services (such as transportation). Finally, international agencies provide estimates of HIV mortality on treatment.15 These figures, however, come from models that rely, in turn, on inputs from epidemiological studies. Models also generally offer national figures and do not shed light on site-to-site variability needed to inform practice behaviours at the front lines of the response to HIV.

We have previously developed a sampling-based approach to obtain more valid estimates of mortality in real-world, clinic-based cohorts of HIV patients in treatment programmes in Africa.16, 17 This approach is based on identification of a numerically small but randomly selected sample of patients lost to follow-up, intensive searching for their outcomes in the community, and incorporation of these findings to correct estimates in the entire clinic population by use of a probability weight. Previous work has been done in single clinic sites.18, 19 In this paper, we apply this approach in a network of clinics in east Africa to better understand mortality at scale, and by extension, the effectiveness and comparative effectiveness of public health ART treatment in Africa.

Section snippets

Patients and setting

We assessed adult patients on ART in 14 clinics and five programmes in east Africa that operate in five locations: Mbarara, Uganda; Eldoret, Kenya; Kisumu, Kenya; Kampala, Uganda; and Morogoro, Tanzania. All programmes deliver a similar package of simplified and standardised care, which consists of a few first-line regimens based on non-nucleoside reverse-transcriptase inhibitors (NNRTIs), no assigned stable provider for patients, the absence of routine HIV RNA testing, and HIV genotype

Results

Overall, we assessed 34 277 adults on ART in 14 clinics in five different settings during 63 390 person-years and for an average of 1·85 years per person. The programme in Mbarara contributed 7515 patients from a single clinic site, Eldoret 15 568 from five sites, Kisumu 4261 from four sites; Kampala 3611 from three clinics, and Morogoro 3322 from one site. The median (IQR) age of patients was 35 years (30–42), 11 628 (34%) were men, median (IQR) CD4 count before therapy was 154 cells per μL

Discussion

In a network of clinics providing facility-based care in east Africa, accounting for outcomes among lost patients through a sampling based approach led to an increase of greater than 3 times the estimated 3 year mortality as compared with an estimate using only outcomes known to the clinic through routine practices. The resulting corrected mortality estimate of 12·5% is substantially higher than pooled estimates from Europe.28, 29 A comparison of the corrected mortality estimates across

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