Impact of peer support on virologic failure in HIV-infected patients on antiretroviral therapy - a cluster randomized controlled trial in Vietnam

Quang Ninh province is located along northeastern Vietnam with a population of 1.1 million and an area of 6100 km². Quang Ninh has 14 cities/districts, in which Ha Long City is the biggest (20 communes, 221,000 habitants). It is also home to the famous World Heritage Site, Ha Long Bay. Coal mining, fisheries, and tourism are the main industries.

HIV prevalence in Quang Ninh was about 1%, of which 55% of PLHIV were IDUs (reported by Provincial AIDS Committee-2006). Patients were recruited from four outpatient clinics (OPC): Ha Long CDC-LifeGap clinic, located in the provincial hospital in Ha Long City and supported by PEPFAR which has more resources, and three Global Fund supported clinics (Uong Bi, Ha Long Health Center and Yen Hung). These were the only clinics in the districts and hence there was a low risk for selection bias from both patients and the project.

The cluster randomized controlled trial “Directly Observed Therapy for Antiretrovirals” (DOTARV), registration number NCT01433601 was carried out in 4 districts/cities (Ha Long, Uong Bi, Dong Trieu, Yen Hung). The reasons for choosing these 4 districts/cities were: (i) community based care was not available, (ii) these were adjacent districts, and (iii) each had high HIV prevalence. To minimize contamination (that the effect of peer support to patients in the intervention group would also influence the control groups due to personal relationships among patients in intervention and control group), the unit of randomization and analysis was the cluster (commune).

This trial was conducted between July 2007 through November 2011, with 2 years of patient recruitment and 2 years of follow-up.

According to the National Guidelines (2005) [22], HIV-infected individuals were eligible to be registered for free at an ART clinic if they: i) were confirmed HIV positive, ii) possessed valid civil registration information (home address and telephone), iii) had a family member who could act as a supporter, and iv) agreed to enroll and to be followed up in the ART program. Each clinic was staffed with two medical doctors, one adherence counselor, one reception nurse, one phlebotomy nurse, one pharmacist, and one volunteer who was a person living with HIV (PLHIV). The staff were trained on basic and advanced HIV care and treatment and certified by Ministry of Health.

All registered patients received a set standard of care, co-trimoxazole prophylaxis, and were assessed at baseline for socio-economic situations. They were also evaluated clinically, undergoing WHO HIV clinical staging, as well as screening for tuberculosis (TB), viral hepatitis B and C, and opportunistic infections (OIs). Their CD4 counts were taken, and those who were eligible for ART (clinical stage 4 with CD4 count <200 cells/μl or clinical stage 3 with CD4 count <350 cells/μl) were put on the waiting list for ART and selected on a “first come, first served” basis. Patients diagnosed with OIs were treated by OI medications. If TB was diagnosed, patients were referred to the provincial TB hospital in Ha Long City. They were initiated on ART after receiving two months of intensive TB treatment. Every month, a range of 15 to 20 patients per clinic, from both groups, were selected, based on the “first come, first served” recruitment list, to attend a pre-ART readiness training on both an individual and group basis. Each clinic received a quota of patients that were planned to initiate ART stipulated by the local health authorities. The training included HIV basics, stigma and discrimination, positive living, transmission prevention, ART regimens and treatment adherence. A family member also attended the training and became an adherence supporter for the patient. ARV drugs were provided in pre-packed dosage form for convenience and to promote adherence. The first-line ARV regimens included two nucleoside reverse transcriptase inhibitors (NRTIs): stavudine (d4T) or zidovudine (AZT) plus lamivudine (3TC) combined with one non-nucleoside reverse transcriptase inhibitor NNRTI: nevirapine (NVP) or efavirenz (EFV). All care and medications were provided free of charge.

Patients who participated in the study were selected from the pre-ART waiting list. All patients fulfilling the criteria and planned for ART were asked for their consent to take part in the trial. The patients were informed about the trial by study doctors. The patients, if they agreed to participate, signed the informed consent form. Study doctors would assign patients to either the intervention group or the control group based on the commune where they were living from one of a total of 71 communes in 4 districts. The ratio for intervention: control communes was 36:35 (1:1). The clusters in all four districts were randomized by a statistician who was not involved in the study and were matched according to the following criteria (i) urban vs. rural (official registration, based on population density), (ii) vicinity to the clinic (more or less than 5 km), and (iii) population (more or less than 25,000). The randomization of matched clusters was through a computer software by a statistician not directly involved in the project with no local acquaintance. This study followed an open label cluster randomized controlled trial design.

The peer-support intervention strategy was home-based adherence counseling conducted by peer supporters who were HIV-infected individuals on ART and nominated by fellow patients and health care staff at each clinic site. The qualifications needed for peer-supporters were (i) social ability, (ii) good ART adherence for at least 6 months, (iii) high school graduation, (iv) willingness to participate in the study and (v) passed the qualifying test after the training. The OPC’s and local health authorities proposed candidates that fulfilled the selection criteria’s. The proportion of the peer-supporters to the number of recruited patients living in each district was about 1:20, meaning that one supporter would support a maximum of 20 patients. The peer-supporters received 1-week’s training conducted by project researchers on basic HIV care and support, communication and counseling skills, and the process for completing the adherence checklist form. Two 1-week refresher trainings were provided yearly throughout the study.

The standard support performed by peer-supporters included home-based visits and completion of the adherence checklist form, in which patients were asked about their wellbeing, OI and adverse drug reaction (ADR) signs and symptoms, the times at which they took the pills, any doses missed for last 4 days, barriers to adherence, and pill count. If an incomplete adherence was reported, the peer supporter would counsel and discuss with the patients and family supporters how to improve the adherence.

The initial schedule of support was twice a week in the first 2 months, then once a week when patients’ adherence passed assessments. Additional visits were provided if patients were sick or had a serious ADR or a history of poor adherence. A telephone call was used to arrange a 15- to 30-min appointment place in advance between peer supporters and patients to minimize wasting time or to ensure confidentiality for patients who feared disclosure of their HIV status to others in their surroundings. Due to the associated stigma, the supporters did not wear a work outfit for home visits to minimize the patient’s fear of stigma developing from others in their surroundings. Before being recruited for the study, patients were made aware that being a part of the study would require them to disclose their HIV status. They were warned about the possibility of stigmatization. If patients were not comfortable with that possibility or if they experienced any harm during the study, patients would choose not to be a part of the study. This was monitored during the OPC visits. To ensure satisfactory work by the peer supporters, bi-weekly supervision of peer-support activities was conducted by a peer-support group leader in each district. Monthly supervision meetings of peer-support activities were performed by project researchers.

Patients in both intervention and control groups received a set standard of care and treatment according to the National Guidelines [22] including pre-ART initiation, which consisted of three ART adherence training sessions in both individual and group settings. Health checks, blood sampling and drug dispensations were carried out on a monthly basis at the OPC. Selfreported adherence for the last-4-day period was assessed quarterly by an adherence counseling staff member. CD4 counts were run at baseline and every 6 months by using the Partec CyFlow® system in Uong Bi hospital and the Becton Dickinson® system in Quang Ninh provincial hospital.

The Exavir™ Load, an enzyme-linked immune-sorbent assay (ELISA)-based VL quantification test (Cavidi AB, Uppsala, Sweden [23, 24]), was used in Vietnam for the first time to monitor the virologic outcomes for all participants every 6 months for 24 months of the study. The detection limits range from 200 to 410,000 copies/ml [25]. Details on the laboratory procedures of ExaVir Load assay were reported in an earlier publication [26].

CD4 counts were run at baseline and every 6 months by the Partec CyFlow® in Uong Bi hospital and the Becton Dickinson® in Quang Ninh provincial hospital.

In both the intervention and control groups, patients were assessed by health care staff at the clinic for adherence every 3 months using an adherence checklist modified from the contextualized Adult AIDS Clinical Trials Group (AACTG) adherence instrument [27]. In this checklist, patients self-reported any OI and ADR symptoms, whether they had missed any doses during the last 4 days, or if they had incorrectly measured their pill-count.

Virologic failure was defined as either (i) primary virologic failure if VL >1000 copies/ml after 6 months of ART initiation or (ii) secondary virologic failure if VL was undetectable (<200 copies/ml) after 6 months of ART initiation and then became >1000 copies/ml at any time point during the follow-up. Virologic failure patients were reported to the attending medical doctors and adherence counselors in their respective clinics. Then a follow-up VL test was repeated after at least one month but within 3 months of the initial virologic failure. If VL remained >1000 copies/ml, the patient was then reported to an OPC doctor and flagged for a confirmatory PCR VL. According to VGHADT (2009) [17], patients were eligible for switching to second-line therapy if they meet the criteria of clinical or immunologic failure and, if available, they have been confirmed to have a PCR VL >5000 copies/ml. Additionally, patients with detectable viral load in the intervention group received an intensive adherence counseling support by the peer supporters through the provision of two to three home visits per week.

The primary endpoint was the risk of virologic failure during 24 months of follow-up.

The secondary endpoint was the time course of CD4 cell counts over the period of 24 months of follow up.

Data were collected as follows: i) socio-economic situation at baseline, ii) clinical and laboratory data at baseline and follow-up visits every 6 months, (iii) self-reported adherence form was administered by health staff every 3 months, and (iv) ART adherence forms completed by peer supporters.

Patients were allocated to the intervention group according to a randomization of clusters (communes) where patients lived. Sample size for cluster randomized trial was calculated by using formulas in [28]. Assuming the baseline figure for virologic failure risk in the intervention group equal to 5%, and equal to 15% in the control group, a power of 80%, the significance level of the two-sided alpha 0.05, a randomization ratio of 1 (intervention):1 (control), an estimation of intraclass coefficient equal to 0.1, a number of clusters in each group equal to 35 and adding 30% for lost-to-follow-up, the minimum needed sample size was 638 patients (about 319 patients per study arm).

Intention-to-treat analysis was used to calculate virologic failure risk.

Mean, median and standard deviation were used for summarizing numerical variables, frequencies, and percentages for the categorical variables.

Chi-square tests were performed to compare intervention and control groups for demographic and clinical characteristics at baseline.

Crude relative risks (RR) at 6, 12, 18, and 24 months were calculated to assess the relationship between virologic failure and intervention/control groups at different time points.

Kaplan-Meier curves were produced, together with a log-rank test, to compare time to virologic failure between control and intervention group. Cox proportional hazards frailty model, adjusting for potential confounders, was used to analyze the hazard rate among the intervention and control groups, taking into account the clustered nature of the data. Schoenfeld residuals were used for checking the proportional hazard assumptions; no timedependent variables were considered.

CD4 count trends over time were analyzed using a mixed-effects model with a polynomial function of time in the fixed component. Due to the hierarchical structure of the data, random effects of clusters (communes, individual and measurement) were incorporated into the model. Square-root transformation was used for the CD4 count approximating a normal distribution [29].

Once the data was collected, the models were adjusted for the following variables: randomized groups (control vs intervention); age (≥35 vs <35 years); gender (male vs female); WHO clinical stage (stage 1 and 2 vs stage 3 and 4); baseline VL (≥100,000 copies/ml vs <100,000 copies/ml) and baseline CD4 counts (≥100 cells/μl vs <100 cells/μl); ART-naïve status (yes vs no); history of IDU (yes vs no); TB history (yes vs no); history of OIs (yes vs no); having an HIV-infected family member (yes vs no); receiving ART in Halong CDC clinic (yes vs no), changed ART regimen (yes vs no); and incomplete adherence (yes vs no). Since there was a significant difference between the groups receiving ART in Halong CDC clinic, it was especially important to adjust for this difference.