Theodora Savory, Jake Pry, Monika Roy, Kombatende Sikombe, Nancy Czaicki, Paul Somwe, Nancy Padian, Carolyn Bolton-Moore, Charles B. Holmes, Elvin Geng, Mwanza Wa Mwanza, Aaloke Mody, Laura K. Beres, and Izukanji Sikazwe
Background Although 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 findings We 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. Conclusions In 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., In a regression discontinuity analysis, Aaloke Mody and colleagues assess the implications for treatment initiation and retention of expanded eligibility for antiretroviral therapy in Zambia., Author summary Why was this study done? Universal treatment with ART regardless of CD4 count (i.e., treat-all) is based on randomized controlled trials showing the biologic efficacy of ART, but the public impact of expanding ART eligibility also depends on the behavior of patients and the capacity of health systems to absorb an influx of new patients. Direct effects of expanding ART eligibility include increased ART initiation, but it may also indirectly affect patient behavior (i.e., retention) or create negative spillover effects through increased clinic congestion and crowding out of patients already eligible for ART. We leveraged a 2014 change to Zambia’s national ART guidelines that expanded ART eligibility to those with a CD4 between 350 and 500 cells/μL and pregnant or breastfeeding women to anticipate the effects of expanding treatment to those with CD4 above 500 cells/μL under treat-all. What did the researchers do and find? We used a regression discontinuity design to compare patients enrolling just before and after this 2014 change to Zambia’s national ART guidelines expanding the CD4 treatment threshold from 350 to 500 cells/μL to estimate the effects of the guideline change on ART initiation and retention in care in the entire patient population. Among 34,587 patients who newly enrolled in HIV care between August 1, 2013, and November 1, 2014, Zambia’s 2014 guideline change was associated with a 13.6% increase in the proportion initiating treatment within 3 months of enrollment, a 4.1% increase in retention in care at 6 months, and a 10.8% increase in the percentage of patients in care and on ART at 6 months in the entire clinic population. These effects were most pronounced in those patients who would have become newly eligible with the guideline, but ART initiation also increased without evidence of decreased retention in those who remained eligible as well as those who were not yet eligible for ART. We estimated that initiating ART in response to the change in guidelines led to a 37.9% increase in retention in care, indicating that 2.6 patients would need to be initiated on ART to prevent one episode of LTFU. What do these findings mean? Expanding ART eligibility to patients with higher CD4 counts in a real-world setting was associated with marked changes in patient behavior that were not observed in the more tightly controlled settings of randomized trials. Expanding treatment eligibility was associated with modest increases in ART initiation, overall retention in care, and the percentage of patients in care and on ART, without increasing clinic congestion or negatively impacting those who were already eligible for treatment before the 2014 guideline change (i.e., those with a CD4 less than 350 cells/μL at the time of enrollment). Adopting treat-all may lead to similar improvements in ART initiation and retention without associated negative effects; further research regarding the real-world effects of implementing treat-all is needed. Although expanding treatment eligibility improved ART initiation and retention in care, the overall HIV care cascade remained suboptimal. Further innovations in health systems are needed to increase early diagnosis and linkage and improve overall ART initiation and retention in care.