Among CASG participants, incidence of death after ART initiation was 0.3% at 2 years and 1.4% at 4 years, whereas LTFU incidence was 2.9% at 2 years and 10.1% at 4 years. After controlling for confounders (all variables listed in Table 5), and introducing CASG participation as a time-varying covariate to avoid survivor bias, compared with nonparticipation in CASG, CASG participation was associated with 35% lower LTFU rates [AHR 0.65, 95% confidence interval (CI), 0.46–0.91], but similar mortality (Table 5). In sensitivity analyses, restricting the cohort to the 128,364 enrollees starting ART during 2010–2013 at only those 69 clinics offering CASG programs, CASG participation was associated with 55% reduced LTFU rates (AHR 0.45, 95% CI: 0.32 to 0.64), but similar mortality (See Table, Supplemental Digital Content 5, http://links.lww.com/QAI/A924).
In multivariable analysis, compared with nonpregnant females, males had higher LTFU and mortality, and pregnant females had higher LTFU but lower mortality (Table 5).
In multivariable analysis, compared to patients with CD4 <50/μL at ART initiation, patients with CD4 counts between 50/μL and 500/μL had 7%–15% lower LTFU (Table 5). However, LTFU rates were similar between those with CD4 <50/μL (23.9/100 person-years) and CD4 >500/μL (32.0/100 person-years). In contrast, compared to patients with CD4 <50 μL, all patients with higher CD4 counts had 36%–54% lower mortality (Table 5). Other markers of advanced disease (ie, advanced WHO stage and low weight at ART initiation) were predictive of both LTFU and mortality (Table 5).
Compared with zidovudine-containing regimens, stavudine-containing regimens had 48% higher mortality, but similar LTFU. Compared with nevirapine-containing regimens, efavirenz-containing regimens had 9% higher LTFU but similar mortality, whereas protease inhibitor-containing regimens had 29% higher LTFU but similar mortality. AHRs derived using the multiple imputation approach were similar to AHRs derived using a complete case analysis approach (See Table, Supplemental Digital Content 6, http://links.lww.com/QAI/A925).
With a cohort size of 306,335, this is the largest single-country cohort of adult ART enrollees described to date.26 The analysis is timely in that it exemplifies a key success (ie, declines in observed ART mortality rates), a key challenge for the future (ie, increases in observed LTFU rates), and a potential partial solution to address the problem of increasing LTFU (ie, ART distribution through CASG). Other notable findings include the high 6-month LTFU among Option B+ enrollees with CD4 >350 cells per microliter and WHO stage I/II at ART initiation and the high LTFU rates among patients starting ART with CD4 >500 cells per microliter. Both these findings have implications for Mozambique as it begins to pilot test-and-treat in 2016.
Given the association between patient characteristics at ART initiation and outcomes, understanding patient characteristics and changes over time is important for program managers. The increasing female-to-male ART enrollee ratio from 1.2 to 2.7 during 2004–2013 was probably due to scale-up of HTC at ANC and Option B+ initiation in 2013 and is not explained by slight increases in population-level female-to-male ratios among PLHIV (from 1.43 to 1.49).28,29 As discussed in depth separately,29 increased ART enrollment among men is needed to reduce disproportionately high HIV-related morbidity and mortality among men30 and reduce HIV incidence among their sexual partners.29 Increases in median CD4 count at ART initiation, and declining prevalence of WHO stage IV, similar to other reports,5,31–33 probably reflect expanded HTC, ART access, and ART eligibility. Expanding ART access and ART eligibility are also reflected in the remarkable declines in time from HIV diagnosis to ART initiation during 2004–2013. However, more rapid average annual increases in median baseline CD4 for nonpregnant females (9.1 cells·μL−1·yr−1) and pregnant females (25.3 cells·μL−1·yr−1) compared with males (6.4 cells·μL−1·yr−1) suggest ART access increased more rapidly for females than males. This highlights the importance of ANC HTC and Option B+ as gateways to early ART for females, and the need to identify gateways that work for men.34
Due to stavudine-induced severe adverse events, WHO recommended stavudine phase-out in 2009.35 Mozambique responded rapidly with significant declines in first-line stavudine prescription during 2009–2010, and by 2013, only 7% of adults started stavudine-containing first-line regimens. This study contributes new evidence that, compared with zidovudine, first-line stavudine-containing regimens carry mortality risk.26,35 Complete stavudine phase-out is required, especially since costs of tenofovir and zidovudine have declined substantially.36
By including CASG participation as a time-varying covariate and controlling for confounders, this is the first attempt to quantify effect of CASG participation on LTFU rates and the first nation-wide report of CASG outcomes.9,10 This analysis complements a separately described propensity score-matched cohort analysis; both analytic approaches observed a statistically significant LTFU reduction associated with CASG participation. For both analytic approaches, a limitation is that agreeing to join a CASG might be correlated with better health-seeking behavior, which might result in better retention regardless of CASG participation.9 For example, CASG participants had a longer median time from HIV diagnosis to ART initiation, which might suggest they sought HIV testing earlier than nonparticipants, a possible indicator of health-seeking behavior. However, considering that CASG scale-up carries other benefits for the ART program, including decongestion of ART facilities and reduced burden on providers,9,46 and appears to be highly preferred by most CASG participants,46 these findings warrant continued CASG scale-up. Since these data were analyzed, CASG scale-up has continued and by April 2016, about 64,932 (8%) of all 802,659 patients were enrolled in CASGs nation-wide.
Notably, CASG participants were more commonly unemployed and uneducated than nonparticipants, which might indicate that CASG participation is more attractive for patients with fewer financial resources.9,10 This makes intuitive sense since key patient benefits of CASG participation, as reported by CASG participants, are the cost- and time-savings associated with biannual rather than monthly clinic attendance.46 Low male uptake of CASG warrants further research. Offering male-only CASGs might improve male participation in CASG.47 Alternately, other service delivery models that emphasize privacy might be preferred by some stable male patients.48 Possible reasons for lower LTFU following CASG participation include reduced patient transport costs, reduced patient time at the clinic, increased patient accountability, and improved social support.10 Given the shortage of healthcare workers, task-shifting to patients might be a cornerstone of future ART expansion and sustained ART coverage in Mozambique and similar LMIC.10,49–53
Strengths of the analysis include the large cohort size, number of clinics included (170), duration of observation (10 years), and proportion of Mozambique's adult ART population captured (67%). As with all observational studies, some associations might be confounded by unmeasured confounders. For example, the association between efavirenz use and LTFU might be confounded by higher likelihood of prescribing efavirenz-based regimens to TB co-infected enrollees.26 Other limitations include the fact that findings are limited to clinics with EPTS and the possibility that missing covariate data introduced nondifferential measurement error. In addition, despite MOH-recommended tracing efforts, reported LTFU rates are probably overestimates and observed mortality rates underestimates because of incomplete death documentation.27
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