Research Article: Estimating the real-world effects of expanding antiretroviral treatment eligibility: Evidence from a regression discontinuity analysis in Zambia

Date Published: June 5, 2018

Publisher: Public Library of Science

Author(s): Aaloke Mody, Izukanji Sikazwe, Nancy L. Czaicki, Mwanza Wa Mwanza, Theodora Savory, Kombatende Sikombe, Laura K. Beres, Paul Somwe, Monika Roy, Jake M. Pry, Nancy Padian, Carolyn Bolton-Moore, Charles B. Holmes, Elvin H. Geng, Marie-Louise Newell

Abstract: BackgroundAlthough randomized trials have established the clinical efficacy of treating all persons living with HIV (PLWHs), expanding treatment eligibility in the real world may have additional behavioral effects (e.g., changes in retention) or lead to unintended consequences (e.g., crowding out sicker patients owing to increased patient volume). Using a regression discontinuity design, we sought to assess the effects of a previous change to Zambia’s HIV treatment guidelines increasing the threshold for treatment eligibility from 350 to 500 cells/μL to anticipate effects of current global efforts to treat all PLWHs.Methods and findingsWe analyzed antiretroviral therapy (ART)-naïve adults who newly enrolled in HIV care in a network of 64 clinics operated by the Zambian Ministry of Health and supported by the Centre for Infectious Disease Research in Zambia (CIDRZ). Patients were restricted to those enrolling in a narrow window around the April 1, 2014 change to Zambian HIV treatment guidelines that raised the CD4 threshold for treatment from 350 to 500 cells/μL (i.e., August 1, 2013, to November 1, 2014). Clinical and sociodemographic data were obtained from an electronic medical record system used in routine care. We used a regression discontinuity design to estimate the effects of this change in treatment eligibility on ART initiation within 3 months of enrollment, retention in care at 6 months (defined as clinic attendance between 3 and 9 months after enrollment), and a composite of both ART initiation by 3 months and retention in care at 6 months in all new enrollees. We also performed an instrumental variable (IV) analysis to quantify the effect of actually initiating ART because of this guideline change on retention. Overall, 34,857 ART-naïve patients (39.1% male, median age 34 years [IQR 28–41], median CD4 268 cells/μL [IQR 134–430]) newly enrolled in HIV care during this period; 23,036 were analyzed after excluding patients around the threshold to allow for clinic-to-clinic variations in actual guideline uptake. In all newly enrolling patients, expanding the CD4 threshold for treatment from 350 to 500 cells/μL was associated with a 13.6% absolute increase in ART initiation within 3 months of enrollment (95% CI, 11.1%–16.2%), a 4.1% absolute increase in retention at 6 months (95% CI, 1.6%–6.7%), and a 10.8% absolute increase in the percentage of patients who initiated ART by 3 months and were retained at six months (95% CI, 8.1%–13.5%). These effects were greatest in patients who would have become newly eligible for ART with the change in guidelines: a 43.7% increase in ART initiation by 3 months (95% CI, 37.5%–49.9%), 13.6% increase in retention at six months (95% CI, 7.3%–20.0%), and a 35.5% increase in the percentage of patients on ART at 3 months and still in care at 6 months [95% CI, 29.2%–41.9%). We did not observe decreases in ART initiation or retention in patients not directly targeted by the guideline change. An IV analysis found that initiating ART in response to the guideline change led to a 37.9% (95% CI, 28.8%–46.9%) absolute increase in retention in care. Limitations of this study include uncertain generalizability under newer models of care, lack of laboratory data (e.g., viral load), inability to account for earlier stages in the HIV care cascade (e.g., HIV testing and linkage), and potential for misclassification of eligibility status or outcome.ConclusionsIn this study, guidelines raising the CD4 threshold for treatment from 350 to 500 cells/μL were associated with a rapid rise in ART initiation as well as enhanced retention among newly treatment-eligible patients, without negatively impacting patients with lower CD4 levels. These data suggest that health systems in Zambia and other high-prevalence settings could substantially enhance engagement even among those with high CD4 levels (i.e., above 500 cells/μL) by expanding treatment without undermining existing care standards.

Partial Text: Although randomized controlled trials (RCTs) have demonstrated that antiretroviral therapy (ART) in persons living with HIV (PLWHs), irrespective of CD4 levels, has broad clinical benefits, policies to expand HIV eligibility in the real world may have important additional effects that are not captured in the context of controlled trials. HPTN 052 first demonstrated in 2010 that treating the positive partner in a serodiscordant relationship reduces HIV transmission by as much as 96%. This was followed in 2015 by the INSIGHT START and TEMPRANO trials, which showed that immediate treatment reduced the incidence of serious AIDS-related events by 50%, even in patients with CD4 levels greater than 500 cells/μL [1–3]. Based on these trials, the World Health Organization (WHO) in 2015 recommended treatment for all individuals infected with HIV, irrespective of CD4 levels, and, over the last 2 years, national governments in high-prevalence regions are gradually adopting the treat-all approach as a cornerstone of HIV control programs [4,5]. Nevertheless, the public health impact of adopting a treat-all policy is still unknown, because it depends on the capacity of health systems to engage and absorb a new population as well as the behavior of these patients in routine healthcare settings [6].

Using a regression discontinuity design, we found that guidelines expanding ART eligibility improved ART initiation and retention in care in a large network of facilities in Zambia. These guidelines, which increased the CD4 threshold for treatment from 350 to 500 cells/μL and included all pregnant women, were associated with a 13.6% absolute increase in ART initiation within 3 months, a 4.1% increase in retention in care at 6 months, and a 10.8% increase in the percentage of newly enrolling ART-naïve patients on ART and still in care at 6 months. These effects were greatest in patients who became newly eligible for ART with the change in guidelines, with a 43.7% increase in ART initiation, a 13.6% increase in retention, and a 35.5% increase in the percentage of patients on ART and still in care at 6 months. Furthermore, we show that actually initiating ART led to a 37.9% increase in retention in care at 6 months; translated into a number needed to treat, this indicates that one episode of LTFU was averted for every 2.6 people initiated on ART because of these guideline changes. These results were robust to sensitivity analyses that varied model specifications, and, to the extent that this analysis meets the underlying assumptions of regression discontinuity and IV analyses, these findings indicate that expanding ART eligibility improves engagement in the population overall.

Source:

http://doi.org/10.1371/journal.pmed.1002574

 

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