Characteristics and clinical outcomes of patients presenting with advanced HIV disease in the “treat all” era: a retrospective cohort study from rural Rwanda

In 2016, the World Health Organization’s (WHO) guidelines changed from antiretroviral treatment (ART) initiation based on CD4 count thresholds to a “treat all” strategy in which patients are eligible to initiate ART regardless of their CD4 count [1]. Studies have shown clear benefits of starting ART while patients are still asymptomatic [1‐4]. The “treat all strategy” was designed to be accompanied with widespread access to HIV testing and was hypothesized to allow patients to benefit from early ART initiation through a variety of mechanisms, including providing ethical justification and personal motivation for routine asymptomatic testing, reducing stigma surrounding HIV, simplifying pre-initiation clinical procedures, and minimizing pre-ART loss to follow-up [5‐8]. However, evidence from different African countries suggests a significant prevalence of advanced HIV among ART patients presenting for care even in the treat all era [9‐11]. Despite efforts to scale up ART coverage over the past decade, in 2020 only 73% of the people living with HIV had access to ART and 680,000 people died from AIDS-related illness [12].

In Rwanda, the national HIV program has successfully decentralized access to free HIV services and by 2013 had created a national network of over 450 health facilities, almost all of which (97%) offered HIV testing and the vast majority of which (89%) offered ART with no cost required from patients [13]. In July 2016, Rwanda adopted the “treat all” strategy [14]. Subsequently, Rwanda has reached two of the three 2020 UNAIDs 90–90–90 targets, with 83.8% of people who live with HIV knowing their status, 97.5% of those who know their status being on ART treatment and 90.1% of those on treatment being virally suppressed [15]. However, in Rwanda, little is known about HIV positive patients presenting with advanced HIV since the start of “treat all”. This study aims to estimate the prevalence of patients presenting for treatment with advanced HIV after the start of the treat all era (July 2016 to July 2018) within health facilities in three rural Rwandan districts and compare clinical outcomes among patents presenting with and without advanced HIV.

Of the 1129 patients aged 15 years or older who enrolled in care for HIV at a PIH-IMB supported site between July 2016 and July 2018, 957 participants had data on baseline CD4 or WHO stage. Among these 957 patients, 105 (11.0%) presented with advanced HIV and 852 (89.0%) presented with non-advanced HIV (Table 1). Advanced HIV patients were more likely than non-advanced to be found in Burera district (46.7% vs. 22.4%). Older age was significantly associated with advanced HIV disease, with 39.0% of advanced HIV patients being ≥ 45 compared to 19.0% of non-advanced. There were no statistically significant differences in sex or distance to health facility between the two groups. Compared to non-advanced HIV patients, advanced HIV patients were more likely to be underweight (BMI < 18.5, 20.9%. vs 9.6%) and to be severely underweight (BMI < 16, 8.6% vs 1.5%). As expected, based on our definition of advanced HIV, most advanced HIV were classified as WHO stage 3 or 4 (56.2%) and 58.1% had baseline CD4 count < 200 cells/mm³. Although the majority (51.6%) of non-advanced HIV were identified through VCT or PMTCT, only 20.0% of advanced HIV were identified through these venues.

When comparing patients with and without advanced HIV, there were no statistically significant differences in initiating ART within 14 days, receipt of a viral load test within 9 months or viral suppression at first test (Table 2). However, in both groups less than 70% of patients-initiated care within two weeks of enrollment and less that 50% received an initial viral load test within 9 months of treatment. Patients presenting with advanced HIV were more likely to experience treatment failure in the first 12 months (21.9% vs 14.2%, p = 0.037) and to experience death in their first 12 months (9.5% vs 1.5%, p < 0.001). By 18 months, only the cumulative incidence of death remained different between the two groups (10.5% vs 1.9%, p < 0.001). There was no association between presenting with advanced HIV and loss to follow-up or virologic failure at 12 or 18 months (Table 2).

Patients presenting with advanced HIV had a significantly shorter time to first viral load test according to the log-rank test (Fig. 1a, p = 0.001) and the unadjusted Cox proportional hazards model (Table 3, HR = 1.5, 95% CI: 1.2, 2.0, p = 0.001), however, this association did not persist after adjustment for confounders. Similarly, advanced HIV was associated with shorter time to viral suppression in the log-rank test (Fig. 1b, p = 0.039) and the unadjusted Cox proportional hazards model (HR = 1.3, 95% CI: 1.0, 1.7, p = 0.040), but not after adjusting for confounders. However, patients presenting with advanced HIV had a much higher incidence of death in the log-rank test (Fig. 1c, p < 0.001) and the unadjusted Cox proportional hazards model (HR = 5.3, 95% CI: 2.5, 11.2, p < 0.001). This association persisted adjusting for demographic characteristics (aHR = 4.4, 95% CI: 1.9, 10.2, p < 0.001) and after adding BMI and method of enrollment to the model (aHR = 4.8, 95% CI: 2.0, 11.6, p = 0.001). Treatment failure was not associated with advanced HIV in the unadjusted in a log-rank test analyses (Fig. 1d, p < 0.245) but became significant after adjusting for demographic characteristics (aHR = 1.7, 95% CI: 1.1, 2.5, p = 0.017) and after adding BMI and method of enrollment to the model (aHR = 1.9, 95% CI: 1.2, 3.0, p = 0.005). When we allowed for the hazard ratio for the association between treatment failure and advanced HIV to vary over time, we observed that patients with advanced HIV experienced elevated rates of treatment failure in the first six of enrollment. However, by 9 months, the association between presenting with advanced HIV and treatment failure was no longer significant (Fig. 2).

Among patients presenting for care in PIH/IMB-supported health facilities between July 2016 and July 2018, 11.0% presented with advanced HIV. As has been reported elsewhere, older age and low BMI were associated with advanced HIV [21‐24], although we did not observe the expected associations between presenting with advanced HIV and either male sex or distance to the health facility. In our study, Burera district had the highest proportion of patients with advanced HIV. The Butaro district hospital, located in Burera, is Rwanda’s main cancer referral hospital and provides treatment for many cancers associated with HIV, such as HPV-related cancers or Hodgkin’s lymphoma [25]. For example, previous research in Butaro revealed that over 30% of cervical cancer patients had HIV as comorbidity [26]. We hypothesize that the higher prevalence of patients with advanced HIV in Burera may indicate that many patients who develop HIV-related cancers as a result of living with advanced HIV are referred to Burera for cancer treatment and subsequently diagnosed with HIV.

The percentage of patients presenting with advanced HIV is lower than what has previously been reported by other researchers in Africa since the adoption of treat all, including in Senegal (71%), South Africa (22%-26%) and Botswana (24.7%) [9, 11, 27]. Although the prevalence of advanced HIV was lower in this study than reported in the literature, possibly due to Rwanda’s highly decentralized HIV services, patients presenting with advanced HIV still experienced death at approximately 4 times the rate for those without advanced HIV, translating a 12-month cumulative incidence of death of 9.5% and an 18-month cumulative incidence of death of 10.5%. Comparable risks of death among patients with advanced HIV were observed prior to the initiation of treat all in Uganda, Zimbabwe, Malawi, and Kenya [28]. Collectively, these studies and many others indicate patients with advanced HIV disease remain a vulnerable population in the treat all era [29, 30]. In our study, the prevalence of advanced HIV was relatively low, 11 out of 27 deaths (41%) occurred among those with advanced HIV. Providing targeted support to patients presenting with advanced HIV, particularly during the first 6-months of treatment when the risk of death, loss to follow-up or virologic failure is especially high, could substantially reduce HIV-related mortality.

Surprisingly, in our unadjusted analyses we observed time to viral load testing and viral suppression were faster among patients presenting with advanced HIV. This finding is likely the result of selection bias due to competing risks of death as death was associated with advanced HIV and because death was substantially more likely to occur among patients with advanced HIV in the first six months of treatment. Consequently, the sickest advanced HIV patients would have exited the cohort through death before becoming eligible for viral load testing. However, this association did not persist after adjusting for confounders, and ultimately our results suggest that patients with advanced HIV who survive and remain and treatment experience similar virologic outcomes as patients without advanced HIV. However, in both groups we observed suboptimal adherence to Rwanda’s national guidelines: Less than 70% of patients initiated care within two weeks of enrollment and less than 50% received their initial viral load test within 9 months of treatment. It was reported that newly-diagnosed PLWH in Rwanda, initiating ART rapidly under Treat All presents logistical and emotional challenges despite the perceived benefits [31] and viral load suppression was less among patients with a pre-ART CD4 count less than 200 cells/mm³ [32]. In general, these finding could be an indication of poor quality of care which need to be investigated further and addressed.

Our findings suggest multiple opportunities to improve HIV services. First, although Rwanda has decentralized HIV testing, there is a need to increase patient engagement with existing HIV testing services, which could include strategies such as expanded self-testing options, provision of HIV tests through the workplace or at the community, and increasing community awareness of that Undetectable = Untransmitable (“U = U)” among others [33]. Second, there is need to address barrier that prevent patients, both with and without advanced HIV, from initiating ART in the first 14 days. Previous research in Rwanda suggests that enhanced, trauma-informed counseling and stigma-reduction interventions could better support patients to initiate ART in a timely manner [31]. Third, we observed substantial missingness of baseline CD4 count information. However, CD4 remains an important biomarker for HIV patients’ management and care, and universal pre-ART CD4 count testing is needed to ensure an accurate diagnosis of those with advanced HIV disease [34]. Third, after patients presenting with advanced HIV are identified, they should receive the WHO-recommended package of care, including rapid ART initiation, screening for tuberculosis and cryptococcal meningitis, preemptive fluconazole treatment as well as cotrimoxazole and isoniazid prophylaxis [35, 36]. Fourth, psychosocial support, including food packages and Community-based Accompaniment (CBA), which had been previously been demonstrated to improve patient outcome at PIH/IMB-supported sites [37, 38] but were largely discontinued following the adoption of treat all, should be automatically expanded to those with advanced HIV. This targeted support should persist for the first 6 months of treatment, when the patients are at highest risk of treatment failure. Finally, there is need for further research to identify whether there are specific causes of death that could be prevented among late presenters.

Our study had some limitations: First, we used routinely collected data from EMR and some variable of interest, including cause of death and markers of socioeconomic status, were commonly missing from the EMR. Due COVID-related movement restrictions, we were unable to supplement the EMR with data from patients’ chart. In particular, missing CD4 and WHO stage information led us to use a definition of non-advanced HIV that was vulnerable to misclassification. We would have expected this bias would be expected to underestimate the true prevalence of advanced HIV disease and bias associations between advanced HIV disease and poor clinical outcomes towards the null. However, missing data could have also caused us to underreport timely ART initiation or timely viral load testing and over-report loss to follow-up. Second, our time-to-event analyses for death does not account for potential competing risks due to loss to follow-up, which is likely associated with death. If loss to follow-up were associated with advanced HIV, the analyses for these outcomes could have underestimated the associated between death and advanced HIV. However, we did not observe any associations between advanced HIV and loss to follow-up. Furthermore, the composite outcome of treatment failure included, viral suppression, death, and loss to follow-up, and is consequently not vulnerable to bias from competing events. Similarly, our time-to-event analyses for time to viral testing and time to viral suppression do not account for the competing risks of death, which, as previously discussed, could account for the surprising finding that time to viral load testing and viral suppression were faster among patients presenting with advanced HIV. Third, our analysis focuses on three rural districts that receive substantial support from an international NGO, so our results might not be generalizable elsewhere in the country. However, because of the additional support provided to these facilities, we would generally expect better HIV-related outcomes, including lower proportion of patients presenting for care with advanced HIV and lower rates of death and treatment failure, than in other rural Rwandan settings, suggesting this problem could be more widespread elsewhere.

Despite adoption of the treat all, presentation for care with advanced HIV disease is still common in Rwanda and is still associated with poor treatment outcome. There is need for enhanced sensitization around the benefit of early HIV testing and availability of ART for all. In addition, patients presenting with advanced HIV may require additional support improve their treatment outcomes. More studies are needed to identify the specific causes of death among late presenters to help identity and prevent common causes of deaths.