Two-Year Death and Loss to Follow-Up Outcomes by Source of Referral to HIV Care for HIV-Infected Patients Initiating Antiretroviral Therapy in Rural Mozambique

Introduction

Following the rapid scale-up of combination antiretroviral therapy (cART) for HIV, programs throughout Africa have received additional resources from donors and governments to improve testing and linkage to care, most notably from the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) and from the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund). Earlier testing and treatment and long-term retention in care improve patient outcomes and reduce HIV transmission (i.e., treatment as prevention). ^{1 –4} Mozambique has one of the world's worst HIV epidemics, with an estimated national HIV prevalence of 11.5% and 1.4 million persons living with HIV in 2009, the most recent year for estimation. ⁵ Referral sites to HIV care in Mozambique identify patients in all disease stages, from early asymptomatic disease to near-death conditions. ⁶ Treatment scale-up efforts should give consideration to sources of referral as the entry point to HIV services as patients may require modified provision of care and support.

As a PEPFAR implementing partner, our group sought to describe the magnitude of loss to follow-up (LTFU) and death during the first 2 years of cART, and their association with types of referral sites. By establishing the risk of LTFU and/or mortality by the source of referral, quality improvement interventions may be appropriately tailored to improve HIV care and treatment program retention. We used data from 5 years of cART scale-up in Mozambique's rural Zambézia Province to assess these clinical outcomes.

Materials and Methods

Results

Our study includes 7,615 HIV-infected patients who initiated antiretroviral therapy in 10 districts of Zambézia Province in Mozambique during the study period (Table 1). The cohort was 61% female with a median (interquartile range, IQR) age of 30 years (25–38). The median (IQR) BMI was 19.6 kg/m² (17.8–21.6). World Health Organization (WHO) stage, CD4⁺ count, and hemoglobin were collected from 90 days before to 14 days after cART initiation and were incomplete for 39%, 44%, and 60% of patients. The median (IQR) CD4⁺ cell counts were 179 cells/μl (98–269) and 61% of patients were symptomatic at the WHO Stage III or IV classification.

The sources of referral to HIV care included VCT centers (51%), general outpatient clinic (21%), PMTCT programs (8%), medical inpatients at health facilities (3%), tuberculosis service (2%), laboratories/blood banks (1%), and transfer from other HIV care program (<1%). The source of referral may have been marked as “other” if the code was not available on the paper clinical record form; this indication was selected for 14% of patients (equally selected for both men and women). The source of referral was missing completely for 10% of patients. The source of referral was balanced across sex with the exception of PMTCT where 537 women and only 14 men were referred. VCT was consistently the largest source of referral over time (Fig. 1). General outpatient clinic as a source of referral saw a steady decrease and VCT an increase beginning October 2010 (Fig. 1). Patient characteristics were different by source of referral to HIV care (Table 2). In addition to capturing primarily women, PMTCT captured a younger patient population. Patients referred as medical inpatients or from tuberculosis services had more advanced stage disease. Patients referred from PMTCT and VCT had higher median CD4⁺ cell counts. Patients referred by general outpatient clinic or PMTCT were in care for an average of 2–3 months prior to ART initiation compared to 3–4 weeks for medical inpatients and VCT referrals (Table 2).

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FIG. 1.

Quarterly trends in source of referral to HIV care among patients starting treatment, Zambézia, Mozambique 2006–2011.

The cumulative incidence of 2-year LTFU (accounting for death as a competing risk), per Mozambique's definition as no effective clinical contact within 60 days after the last scheduled medication pickup, was 38.1% (95% CI: 36.9–39.3%). The cumulative incidence of LTFU was lower when applying two definitions from the literature. The cumulative incidence of LTFU using the “universal” definition ¹⁴ was 30.7% (95% CI: 29.6–31.9%) at 2 years. The cumulative incidence of LTFU using the “reference” definition ¹⁵ was 31.0% (95% CI: 29.8–32.1%) at 2 years. The 2-year probability of death was 14.2% (95% CI: 13.2–15.1%) and the probability of death/LTFU was 49.7% (95% CI: 48.4–50.9%). There was evidence that 2-year probabilities of death, cumulative LTFU, and death or LTFU were different by source of referral (Fig. 2, p<0.001 for all). Patients referred while they were medical inpatients or during antenatal care (PMTCT) had the highest and lowest probabilities of death, respectively. Patients referred by a general outpatient clinic had the lowest cumulative incidence of LTFU. Unadjusted hazard ratios (95% CI) for mortality in 2 years following treatment initiation by referral site with VCT as referent category were as follows: medical inpatient 2.68 (1.97–3.64), general outpatient clinic 1.42 (1.12–1.80), tuberculosis service 1.30 (0.79–2.13), and PMTCT 0.35 (0.22–0.55).

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FIG. 2.

Two year outcomes by referral to HIV care and treatment, Zambézia, Mozambique 2006–2011. Subfigures demonstrate the following: cumulative incidence of loss to follow-up (LTFU) (A), probability of death (B), and probability of death or LTFU at 24 months for each source of referral to HIV care (C). Mozambican national guidelines define LTFU as no effective clinical contact within 60 days after the last scheduled medication pickup.

Table 3 reports adjusted hazard ratios for LTFU using Cox regression and censoring at date of death for those who died in the first 2 years following treatment initiation. After controlling for other variables, the referral site remained strongly associated with LTFU during the first 2 years (p<0.001). Compared with VCT, patients referred from medical inpatient, tuberculosis care, and PMTCT had 43%, 50%, and 34% higher rates of LTFU, respectively. Other factors associated with a higher hazard of LTFU were male sex, younger age, more advanced stage of diseases, and more recent year of cART initiation.

Adjusted hazard ratios for mortality in 2 years following treatment initiation are given in Table 3. Adjusting for demographics and health status, the source of referral to HIV care remained associated with the hazard of death (p<0.001), such that hazard ratios (95% CI) for 2-year mortality with VCT as referent were medical inpatient 1.87 (1.36–2.48), general outpatient clinic 1.44 (1.11–1.85), and antenatal care 0.69 (0.43–1.11). Male sex and younger age were also associated with a higher hazard of death, as were standard measures of poor patient health including low BMI, low hemoglobin, low CD4 count, and advanced WHO stage.

With respect to the combined endpoint of mortality and LTFU, the source of referral to HIV care remained associated with 2-year retention after adjusting for demographics and health status indicators (p<0.001). Compared with VCT, hazards of 2-year mortality/LTFU were medical inpatient 1.60 (1.34–1.91), general outpatient clinic 1.17 (1.02–1.33), tuberculosis care 1.38 (1.08–1.75), and antenatal care 1.24 (1.06–1.44). Reduced and increased risk factors from all three models (LTFU, mortality, and mortality/LTFU) were generally similar with the exception of PMTCT as protective for mortality and a risk factor for LTFU and the combined endpoint.

Discussion

The source of referral in rural Mozambique was highly predictive of LTFU, mortality, and mortality/LTFU. Patients who were referred from an inpatient medical facility or general outpatient clinic had higher risks of mortality and LTFU even after controlling for standard indicators of patient health. Patients referred to care from these sites generally have more advanced HIV disease, as evidenced by higher WHO stage and lower BMI, hemoglobin, and CD4 count at cART initiation. There are likely other unmeasured attributes in these referral populations that are also associated with poorer health and subsequently higher risks of mortality and LTFU, and understanding these attributes may lead to interventions that target patient populations at the source of referral.

Obviously, HIV testing should occur before people become symptomatic. Clinical implications of late presentation include more opportunistic infections, concurrent illnesses, high short-term mortality, higher cost of care, and cART resistance. ¹⁸ The clinical implications for patients who return to care after being LTFU are similar: higher mortality, more opportunistic infections, and increased risk of HIV transmission. ⁴ With evidence that patients referred in medical inpatient facilities, tuberculosis care, and PMTCT have a higher incidence of LTFU than VCT, programs aimed at increasing retention may benefit from targeting these patient populations with more focused counseling and/or social support. These findings have important implications for planning and targeting strategies to retain newly enrolled HIV-infected patients in HIV care and treatment.

Patients in PMTCT are generally diagnosed earlier in disease progression (i.e., asymptomatic) and may not stay in care due to fear of stigma, discontinuation of cART postdelivery, and not feeling ill. ^19,20 Owing to new WHO recommendations for Option B+, the lifelong administration of cART for all HIV-infected women diagnosed during pregnancy, our findings of a lower risk of death and rates of LTFU similar to the overall program among women referred from antenatal care (PMTCT) is of interest to policymakers. ²¹ The observed LTFU in antenatal care is less affected by unrecorded mortality and is more likely the result of disengagement from care. Our results suggest that this PMTCT referral population at high risk for LTFU may require assistance, such as active case finding, health systems navigation, and increased HIV counseling or social support. ²²

Sex differences in mortality and LTFU may be due to delayed HIV testing and social support, and interventions could be targeted at the source of referral. Men were found to have both a higher hazard of LTFU (AHR: 1.58) and death (AHR: 1.65) compared to women. Partners of women in PMTCT were typically referred to VCT for testing rather than testing at the PMTCT site. Beginning in 2012, FGH is currently piloting a program that employs “male champions” and traditional birth attendants to provide community-based HIV education services to pregnant women and their partners, while providing education to the wider community about the importance of male partner support during pregnancy. As a result, couples counseling has increased in early 2013, resulting in higher rates of HIV testing and ART acceptance among pregnant women and their partners with antenatal care as the source of referral. The “male champion” pilot program is an example of an intervention that may be targeted at the source of referral to improve outcomes and reduce gender disparities.

In early 2011, FGH began quality improvement activities to improve counseling and testing at the clinics that resulted from health worker referral. Prior to this initiative the uptake of PITC was inconsistent within clinics and across clinics. Poor uptake was mainly due to health worker overload and practices in which clinicians at the various sectors would send their patients to the VCT for testing rather than perform the tests themselves due to time constraints. This likely resulted in an artificial elevation in the number of referrals to HIV care from VCT (as displayed in Fig. 1) when in reality the process of identification of patients in need of HIV testing was initiated in the inpatient services, tuberculosis services, general outpatient clinics, and PMTCT services. This indirect referral likely results in further delays to HIV testing among those motivated enough to follow up on provider recommendations, which affects the composition of the VCT group. With VCT as the referent in all models, there is the potential to bias results toward the null because the group contains individuals who would have been referred elsewhere had the provider consistently initiated testing.

The major strength of our study is the large cohort of adults initiating therapy during 5 years of ART scale-up in a rural, sub-Saharan African setting. The quality of the data recorded is good with routine audits and daily, onsite electronic data entry, though missing data are still common.

The limitations of this study include over 30% undocumented information on major health status indicators at ART initiation. Since a complete case analysis would drop 86% of the patients, multiple imputation (using patient characteristics to predict missing values and properly incorporating missing-data uncertainty) was necessary to avoid substantial loss of power. Multiple imputation assumes that after accounting for patient characteristics, whether or not a variable is missing is independent of patient outcomes. ²³ This assumption may be unrealistic in our setting, and therefore imputation models may not fully adjust estimates of association between the source of referral and patient outcomes.

The referral site is recorded at the first HIV care visit and there is no way of validating whether the documented source is accurate (i.e., no referral system). Because patients enter the database through enrollment into care, we are unable to account for potential selection bias that might result from differential rates of linkage to care by referral site. In Fig. 1, the low proportions of non-VCT source of referral in the last quarters among cART initiators suggest that there may be a lag between non-VCT HIV entry into HIV care and cART initiation (i.e., more outpatient consults and PMTCT referrals enrolled during quarters 17–20 have not yet initiated therapy). The temporal trend in which LTFU rates increased during rapid scale-up may indicate an increasingly constrained health system and has been observed in other cohorts from resource-limited settings. ^{24 –26} Additionally, patients who initiated ART earlier in the program scale-up had a longer window of opportunity to reengage into care.

Mortality and LTFU are all too common among HIV-infected adults in rural Mozambique. Of study patients fortunate to receive testing and counseling and who enter care, only half were alive and remained in the program 2 years hence. We do not think that we are overestimating this much ^27,28 since there are very few alternative sources of ART care other than these PEPFAR-supported venues. Furthermore, the mobility of rural subsistence farmers and fishermen and families is low in this region, in contrast to circumstances during the civil war. ^29,30 Estimates and figures of mortality make an assumption of noninformative censoring—that patients LTFU had an incidence of death similar to patients not LTFU. Such an assumption is dubious for our rural Mozambican cohort. Instead of correcting mortality estimates for this bias using some common techniques (e.g., inverse probability censor weighting or nomogram-correction for 1 year mortality ^31,32 ), we present estimates for the combined endpoint of mortality/LTFU that serves as a crude sensitivity analysis. Because of the high rates of LTFU, hazard ratios for mortality/LTFU more closely resemble the results for LTFU in magnitude, although results were generally similar across mortality and LTFU Cox regression models.

We do not presume a causal effect of referral site on 2-year mortality, and so we expect that unmeasured confounding may explain the residual association after covariate adjustment. Unmeasured confounding would be of great interest in explaining why the referral source remains associated with 2-year outcomes. Important confounders mentioned in this discussion that are not measured in our cohort include but are not limited to duration of symptoms, fear of stigma, comorbidities, cART adherence, psychosocial support, traditional medicine use, and satisfaction with the health facility. Future research needs to explore unmeasured attributes among these patient populations that lead to poor treatment outcomes.

We believe that PEPFAR-supported initiatives in the least well-capacitated regions of rural Africa will need many more years of capacity building, health care worker training, and shifting of health care adherence norms before we can expect self-sustaining programs that do not have high mortality and LTFU rates. ³³ That source of referral was associated with mortality and LTFU after adjusting for sociodemographic characteristics, clinical status at treatment initiation, location, and date of cART initiation suggests that (1) additional unmeasured factors are influential, and (2) interventions targeted at increasing retention may benefit from targeting patient populations, based on the source of referral, with more focused counseling and/or social support.