New surveillance model to improve HIV treatment strategies

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A study that seeks to better ascertain HIV mortality rates in Zambia could provide a model for improved national and regional surveillance approaches, and ultimately, more effective HIV treatment strategies.

Survival represents the most important indicator of successful HIV treatment, according to the researchers. According to UNAIDS, Aids-related deaths have fallen by 50% since 2005 – largely due to the successes of national HIV programmes with support from PEPFAR and the Global Fund. Yet, because routine monitoring and evaluation fails to systematically capture most deaths, it can be challenging to accurately assess the impact of HIV services and to identify where improvement is most needed, the researchers say.

The Better Information for Health in Zambia (BetterInfo) study begins to examine HIV survival rates in Zambia. The work was conducted by a team of researchers co-led by Dr Charles Holmes, faculty co-director of Georgetown University Medical Centre’s Centre for Global Health and Quality, and visiting associate professor at Georgetown’s School of Medicine. Holmes led the work along with Dr Izukanji Sikazwe, CEO of the Centre for Infectious Research in Zambia (CIDRZ) and Dr Elvin Geng, of the University of California – San Francisco. Holmes, who previously led CIDRZ, also serves as associate professor of international health at the Johns Hopkins University Bloomberg School of Public Health and associate professor of medicine at the Johns Hopkins University School of Medicine.

The research was conducted in Zambia through a partnership with CIDRZ and the Zambian Ministry of Health, in close collaboration with numerous local and global academic centres and researchers.

The research group set out to provide a more accurate representation of site – and regional – level mortality among people on HIV therapy in Zambia by characterising the extent of under-reporting of mortality and the variability in data collection and use, and to assess the broader impact this might have on treatment programs and outcomes.

The group applied a multistage sampling-based approach – which they say is a novel methodology in this context – to obtain regionally representative mortality estimates in four Zambian provinces (Lusaka, Southern, Eastern, and Western). The estimates were also sufficiently precise to quantify variation in death rates among clinic sites.

They looked at a sample population of more than 160,000 patients who had visited government-operated HIV treatment sites in these provinces to determine: the magnitude of deaths of those who were taking antiretroviral therapy (ART); when deaths occurred; which groups are at highest risk of death; and whether these factors differ by region, facility, or other variables.

They also traced patients who were lost to follow-up to ascertain their status, and then used this information to create a corrected regional survival estimate as well as corrected site-specific mortality estimates.

The BetterInfo study concluded that mortality is substantially under-reported in routine provincial programme data – by as much as three- to nine-fold – among HIV-infected individuals starting ART, leading to a change in the ranking of provinces by mortality rates.

At the site-level, “corrected” mortality rates were found to be up to 23-fold higher among those on ART. The study also found unexpectedly high variability from site to site in reported mortality rates, ranging from less than 1 death per 100 person-years to up to 13.4 deaths per 100-person years over a two-year period.

“Even as we strive to reduce new HIV infections and end the HIV pandemic as a public health threat, we must not lose sight of premature deaths occurring amongst people living with HIV who are on treatment,” Holmes says. “HIV treatment is not a ‘set it and forget it’ proposition – deaths often occur outside of the health system and are therefore ‘silent’ events that are unknown to those providing or managing care.

“We believe our scalable approach, which builds on and extends earlier sampling methods, provides actionable data to clinic, provincial and national decision-makers to ensure the HIV programme in Zambia is able to become more patient-centred and impactful,” he says.

Based on the findings, certain prevailing assumptions that underlie HIV programmes may need to be re-examined. For example, the researchers say it has been assumed that most patients on treatment for longer periods of time will be more stable than those just starting treatment. However, the study data suggest that time on therapy alone may not be a reliable marker of stability, a finding that will have implications for delivery strategies recommending less health system interaction for patients considered clinically stable.

In addition, approximately 50% of deaths among those newly starting ART occurred relatively shortly after a recent clinic visit, suggesting even greater need for attention to diagnostic services and clinical vigilance for potential co-existing illnesses.

Overall, the authors seek to encourage national- and global-level policy makers to investigate and address the root causes of underestimated and highly variable mortality rates so they can refocus their quality improvement efforts and strengthen HIV programmes.

“These data from the BetterInfo study have provided new targets for quality improvement efforts, and we look forward to further evidence as it emerges that will enable us to support the strongest possible national HIV program in Zambia,” says CIDRZ’s Sikazwe. “We recommend that others consider the application of similar large-scale surveillance methodologies in order to better understand their programme outcomes, and we are excited to facilitate broader adoption through the forthcoming release of a “BetterInfo” toolkit and other materials.”

Holmes adds, “We believe our study also highlights the critical need for investments in vital status registries and data systems to enable better visibility into patient outcomes. These investments are critical not just for the HIV response, but for broader efforts to combat chronic conditions such non-communicable diseases and achieve universal health coverage.”

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

Georgetown University Medical Centre material
PLOS Medicine abstract

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