Death rates of Zambians on ART underestimated up to ninefold

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People with HIV in Zambia were at least ten times more likely to die in the first two years after starting antiretroviral treatment (ART) than European patients, according to findings of a study which traced people lost from HIV care in Zambia. The researchers led by Charles B Holmes at the Centre for Infectious Disease Research in Zambia, Johns Hopkins University, Baltimore and Georgetown University, Washington DC, say that the national treatment programme had underestimated death rates by anywhere from 3-fold to 9-fold and that more investigation is needed of differences between facilities in referral of sicker patients for more advanced care.

Although the aim of antiretroviral treatment is to keep people alive, follow-up of people who drop out of treatment is often limited due to lack of resources and a lack of death registry information. This means that it is difficult to identify where treatment might be having less effect on mortality.

The study looked at 64 clinics in four provinces of Zambia. Patients in care for at least 24 months were eligible for inclusion in the study, including people who started antiretroviral therapy during that period (August 2013-July 2015). From this cohort, a random sample of patients lost to follow-up proportionate to the total number of people receiving care at each facility was selected for tracing. A loss to follow-up was defined as being more than 90 days late for an appointment.

Tracing was carried out by peer health workers in the community and by mobile phone. Health workers made three attempts to trace missing patients. If the patient had died health workers sought to establish the date of death, location and cause of death from family or close contacts.

The death rate exposed by tracing was compared to the death rate recorded at facilities, and also to the death rate recorded in a population study among people with HIV in Denmark, to provide a comparator from a health system with universal death registration.

The study population comprised 165,464 ART users, of which 64% were women, 56% received care at urban facilities and 32% had symptomatic HIV disease (WHO stage 3 or 4) at the time of antiretroviral treatment initiation. The median CD4 count at treatment initiation was 201 cells/mm3. Among those who had started treatment in the previous two years the median CD4 cell count at treatment initiation was 265 cells/mm3. 17% (28,111) of the study population were lost to follow-up. The random sample from the lost-to-follow-up group comprised 2,892 people.

Peer health workers traced three-quarters (75%) of the lost to follow-up sample. Of those traced, 19% (412) had died. Among those who had started antiretroviral treatment in the previous two years, 76% were traced and of these, 24% had died. As a result of tracing, the investigators calculated that the two-year incidence of death among people on antiretroviral treatment was 7%, and 8.3% among people who had started treatment within two years. In contrast, medical records showed that only 1.9%-2.1% had died. The vast majority of deaths (95%) were attributed to illness, suggesting that they were HIV-related.

The study found big variations between facilities in the death rate among new initiators (3.5-7.5 deaths per 100 person-years of follow-up). Furthermore, 57% of the deaths occurred in clinics and hospitals treating 15% of the entire population with HIV. Among new initiators, men, people with CD4 counts below 200 cells/mm3 and people with more advanced HIV disease were more likely to die after becoming lost to follow-up, but none of these factors predicted death in the sample as a whole.

The investigators warn that shifting patients who appear to be stable on treatment to less frequent clinic appointments, or to medication dispensing in the community, may be over-optimistic.

“Death rates remain unacceptably high even after 1 or more years of therapy, a time period when many might assume patients to be stable,” they write. “Persistent deaths after 2 years on treatment imply that a subset of patients is poorly adherent or retained […] effective support for adherence that is attuned to mitigating threats to adherence over time remains a crucial issue.”

The authors also warn that antiretroviral therapy cannot eliminate the risk of developing tuberculosis, so “rolling out isoniazid preventive therapy is a priority.”

Background: Survival represents the single most important indicator of successful HIV treatment. Routine monitoring fails to capture most deaths. As a result, both regional assessments of the impact of HIV services and identification of hotspots for improvement efforts are limited. We sought to assess true mortality on treatment, characterize the extent under-reporting of mortality in routine health information systems in Zambia, and identify drivers of mortality across sites and over time using a multistage, regionally representative sampling approach.
Methods and findings: We enumerated all HIV infected adults on antiretroviral therapy (ART) who visited any one of 64 facilities across 4 provinces in Zambia during the 24-month period from 1 August 2013 to 31 July 2015. We identified a probability sample of patients who were lost to follow-up through selecting facilities probability proportional to size and then a simple random sample of lost patients. Outcomes among patients lost to follow-up were incorporated into survival analysis and multivariate regression through probability weights. Of 165,464 individuals (64% female, median age 39 years (IQR 33–46), median CD4 201 cells/mm3 (IQR 111–312), the 2-year cumulative incidence of mortality increased from 1.9% (95% CI 1.7%–2.0%) to a corrected rate of 7.0% (95% CI 5.7%–8.4%) (all ART users) and from 2.1% (95% CI 1.8%–2.4%) to 8.3% (95% CI 6.1%–10.7%) (new ART users). Revised provincial mortality rates ranged from 3–9 times higher than naïve rates for new ART users and were lowest in Lusaka Province (4.6 per 100 person-years) and highest in Western Province (8.7 per 100 person-years) after correction. Corrected mortality rates varied markedly by clinic, with an IQR of 3.5 to 7.5 deaths per 100 person-years and a high of 13.4 deaths per 100 person-years among new ART users, even after adjustment for clinical (e.g., pretherapy CD4) and contextual (e.g., province and clinic size) factors. Mortality rates (all ART users) were highest year 1 after treatment at 4.6/100 person-years (95% CI 3.9–5.5), 2.9/100 person-years (95% CI 2.1–3.9) in year 2, and approximately 1.6% per year through 8 years on treatment. In multivariate analysis, patient-level factors including male sex and pretherapy CD4 levels and WHO stage were associated with higher mortality among new ART users, while male sex and HIV disclosure were associated with mortality among all ART users. In both cases, being late (>14 days late for appointment) or lost (>90 days late for an appointment) was associated with deaths. We were unable to ascertain the vital status of about one-quarter of those lost and selected for tracing and did not adjudicate causes of death.
Conclusions: HIV treatment in Zambia is not optimally effective. The high and sustained mortality rates and marked under-reporting of mortality at the provincial-level and unexplained heterogeneity between regions and sites suggest opportunities for the use of corrected mortality rates for quality improvement. A regionally representative sampling-based approach can bring gaps and opportunities for programs into clear epidemiological focus for local and global decision makers.

Charles B. Holmes, Izukanji Sikazwe, Kombatende Sikombe, Ingrid Eshun-Wilson, Nancy Czaicki, Laura K Beres, Njekwa Mukamba, Sandra Simbeza, Carolyn Bolton Moore, Cardinal Hantuba, Peter Mwaba, Caroline Phiri, Nancy Padian, David V Glidden, Elvin Geng

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