Durable Suppression of HIV-1 after Virologic Monitoring-Based Antiretroviral Adherence Counseling in Rakai, Uganda

Objectives HIV viral load is recommended for monitoring antiretroviral treatment and identifying treatment failure. We assessed the durability of viral suppression after viral load-triggered adherence counseling among patients with HIV viremia 6 months after ART initiation. Design Observational cohort enrolled in an antiretroviral treatment program in rural Uganda. Methods Participants who underwent routine viral load determination every 24 weeks and had at least 48 weeks of follow-up were included in this analysis. Patients with viral loads >400 copies/ml at 24 weeks of treatment were given additional adherence counseling, and all patients were followed to assess the duration of viral suppression and development of virologic failure. Results 1,841 participants initiating antiretroviral therapy were enrolled in the Rakai Health Sciences Program between June 2005 and June 2011 and were followed with viral load monitoring every 24 weeks. 148 (8%) of patients did not achieve viral suppression at 24 weeks and were given additional adherence counseling. 85 (60%) of these patients had undetectable viral loads at 48 weeks, with a median duration of viral suppression of 240 weeks (IQR 193-288 weeks). Failure to achieve an undetectable viral load at 48 weeks was associated with age <30 years and 24 week viral load >2,000 copies/ml in multivariate logistic regression analysis. Conclusions The majority of patients with persistent viremia who were provided adherence counseling achieved robust viral suppression for a median 4.6 years. Access to virologic monitoring and adherence counseling is a priority in resource-limited settings.


Introduction
Adherence to antiretroviral therapy (ART) is critical for successful treatment of HIV infection. Consistent ART use leads to viral suppression and dramatically reduced morbidity and mortality [1,2]. Additionally, virologic suppression reduces HIV transmission to the partners of infected individuals and can decrease incidence within communities [3,4]. However, achieving these benefits requires high levels of treatment adherence-generally estimated to be 90-95%which many patients find difficult to maintain [5][6][7][8]. Adherence may be improved through motivational patient counseling, involvement of peer treatment support, and text message reminder systems, but the resource requirements of these interventions may limit their implementation as the standard of care in large, resource-constrained programs [9][10][11]. Therefore, identifying patients at higher risk of poor adherence and subsequent treatment failure is a priority.
The best indicator of adherence and response to treatment is the virologic response [12]. Accordingly, the World Health Organization (WHO) and many national AIDS control programs have adopted guidelines recommending viral load testing 3 to 6 months after initiating ART and then at regular intervals thereafter [13]. While these viral load determinations are primarily performed to identify early treatment failure, recent studies have demonstrated that virologic monitoring may also help identify individuals with slow response to therapy who might benefit from early adherence interventions to avoid treatment failure [14]. Between 57-84% of patients in these studies achieve viral suppression or re-suppression after targeted adherence interventions; however, few studies have reported maintenance of suppression beyond 1 year of follow-up. The objective of this study was to determine whether patients in ART clinics in rural Rakai District, Uganda with slow initial virologic response to therapy maintained longterm viral suppression after targeted adherence interventions.

Methods
Rakai District, located in rural southwestern Uganda, has one of the highest HIV prevalences in Uganda. The Rakai Health Sciences Program (RHSP), funded by the President's Emergency Plan for AIDS Relief (PEPFAR), has provided free antiretroviral therapy (ART) since June, 2004 through mobile outreach clinics with biweekly visits to 16 regional health clinics. Starting in 2005, viral load monitoring was introduced to follow all patients on ART. Between June 2005 and June 2011, 2,365 ART-naïve adult (age 18 years or more) participants were enrolled in an open cohort and after ART initiation based on a CD4 cell count <250 cells/mm 3 or WHO stage IV disease. Initial treatment regimens consisted of two NRTIs (zidovudine or stavudine plus lamivudine) and nevirapine or efavirenz. Participants were seen weekly for the first month and then biweekly for 2 months followed by monthly follow-up appointments with adherence and HIV risk reduction counseling at all visits. HIV-1 viral load testing using the Roche Amplicor 1.5 Monitor assay (Roche Diagnostics, Indiana, USA) was used to monitor all ART clients every 24 weeks. Individualized adherence plans were developed for patients with a viral load >400 copies/μl at 24 weeks by a multi-disciplinary team composed of physicians, clinic officers, and counselors, with interventions including additional adherence counseling in a one-on-one session with clinicians, assignment of a peer treatment supporter, or in-depth psychosocial counseling interventions by specialized staff. Baseline characteristics were compared among early suppressors, late suppressors, and nonsuppressors using chi-square tests for categorical variables and analysis of variance for continuous variables. We assessed predictors of non-suppression by week 48 among n = 142 patients who failed to suppress by week 24 using stepwise logistic regression to estimate odds ratios associated with gender, age, baseline CD4 cell count, baseline WHO stage and 24 week viral load.
Stepwise regression entry criterion was set as p = 0.3 and stay criterion was set as p = 0.15. In order to calculate duration of virolgic suppression, we censored subjects at the time of their last available viral load result. All analyses were conducted using SAS version 9.2.
The study was approved by the Uganda Virus Research Institute Scientific and Ethics Committee, The Johns Hopkins University IRB and the Uganda National Council for Science and Technology.

Results
Between June, 2005 and June, 2011, 2,365 ART-naïve patients were initiated on ART (Fig 1). We included the 1,841 (77.8%) patients alive and in care at least 48 weeks after initiation in this analysis. Baseline characteristics according to virologic outcome categories are presented in Table 1. To summarize, median age among these patients was 33 years (IQR = 28-40) and 1220 (66.3%) were female. The proportion of patients initiated on a d4T-containing regimen was 19%, while 80% were initiated on a regimen containing 3TC/AZT. Median (IQR) for baseline CD4+ count was 186 (107-226), and for baseline HIV-1 viral load was 73426 (17417-234728). Thirty-eight (38%) of patients were WHO stage I at baseline, 37% stage II, 18% stage III and 6% stage IV. The overall prevalence of virologic failure at week 24 for the entire cohort was 9%. Of the 1,841 patients in care at 48 weeks included in this analysis, 1,699 (92%) had a 24 week viral load <400 copies/ml and were termed 'early suppressors.' The remaining 142 patients had a median viral load of 1020 copies/ml (IQR 543-2,974 copies/ml) at 24 weeks. These patients underwent additional adherence counseling and were continued on first-line therapy. At 48 weeks, 85 (60%) of these patients achieved a viral load <400 copies/ml and were termed 'late suppressors.' Fifty-seven (3%) patients included in this analysis never achieved viral suppression with first-line regimens and were termed "non-suppressors." Early suppressors, late suppressors, and non-suppressors differed significantly by age, baseline CD4 count, and WHO clinical stage at time of enrollment (Table 1), with early suppressors having a higher median CD4 count (188 copies/μl) and lower percentage of patients with stage IV disease (6%). There was no difference in gender, baseline viral load, or first-line ART regimen. Failure to achieve an undetectable viral load at 48 weeks was associated with age <30 years and 24 week viral load >2,000 copies/ml in multivariate logistic regression analysis ( Table 1).

Discussion
Viral load monitoring remains a critical component of HIV care, to evaluate treatment efficacy and provide early warnings of resistance and treatment failure [15]. This study demonstrates that early determination of viral load may help avoid downstream virologic failure with targeted adherence counseling. While the majority of patients in our cohort achieved suppressed viral loads by 24 weeks of treatment, a subset of patients with persistent viremia at this time point were provided further adherence support. Subsequently, the majority of these patients achieved viral suppression when retested 24 weeks later. These late suppressors were subsequently found to maintain suppressed viral loads for a median of 4.6 years, one of the longest follow-up terms reported in the literature. It is important to note that our findings may overestimate the effectiveness the counseling intervention, as those with virologic failure whom remained non-adherent to their medication may have been at greater risk of dying before reaching one year on treatment.
Our findings add to evidence supporting the importance of early viral load determination after ART initiation. In addition to allowing for earlier diagnosis of virologic failure [16], others have found viral load testing 6 months after ART initiation to be predictive of future virologic failure [12], HIV disease progression [17], and mortality [18,19]. Programs that employ viral load testing are also more likely to detect treatment failure earlier in therapy than programs relying on immunological or clinical monitoring, though no difference in mortality has been demonstrated between patients managed using CD4 counts or viral loads to determine treatment failure [20][21][22][23]. Reducing the duration of HIV viremia decreases the likelihood of developing viral resistance and achieving viral suppression [24,25].
The current study reinforces the utility of viral load testing to identify patients with persistent viremia who may benefit from further adherence counseling in order to avoid treatment failure. A recent systematic review found that programs employing such viral load-triggered adherence interventions were able to achieve substantial rates of viral suppression or re-suppression, though the percentage of patients achieving suppression varied considerably between studies [14]. A study from Thailand reported results similar to ours, with 92% of patients with persistent low-level viremia achieving viral suppression after additional adherence counseling [26]. However. Studies in Burkina Faso and Mali found that only one-third of patients receiving viral-load triggered adherence interventions were able to achieve undetectable viremia [27]. However, patients in these cohorts had been treated with ART for a mean of 23.7 months prior to their first viral load determination and were found to have high rates of resistance mutations. All patients in our cohort were monitored virologically from 6 months after ART initiation, and virologic failure rates were consistent with median values reported by other programs in resource-limited settings [28]. Notably, the longest period of follow-up after viral suppression reported in the review was 18 months [29]. Therefore our median duration of suppression after viral load-triggered adherence counseling of 4.6 years is unique and supports the value of early viral load monitoring in resource-limited settings. This study's retrospective design precludes strong causal inferences about the impact of adherence counseling on viral suppression in patients with persistent viremia. Indeed the high rates of initial suppression observed, as well as the success of our targeted adherence interventions, may in part reflect the effects of closely monitoring viral load itself, rather than the added counseling. Nevertheless, given the growing number of studies reporting an association between viral load-triggered adherence counseling and improved rates of subsequent suppression adds plausibility to the benefits of this intervention. Our findings from a large cohort of patients receiving ART support early viral load monitoring and targeted adherence programs in resource-limited settings.