Conceived and designed the experiments: JH NE CM EG JM DB. Performed the experiments: NE AK CM. Analyzed the data: MS AT AL. Wrote the paper: MS AL AT DB. Revised and edited the manuscript: MS AL JH AK NE CM EG JM DB.
The authors have declared that no competing interests exist.
Many guidelines recommend adherence counseling prior to initiating antiretrovirals (ARVs), however the additional benefit of pre-therapy counseling visits on early adherence is not known. We sought to assess for a benefit of adherence counseling visits prior to ARV initiation versus adherence counseling during the early treatment period.
We performed a secondary analysis of data from a prospective cohort of HIV-infected patients in Mbarara, Uganda. Adults were enrolled upon initiation of ARVs. Our primary exposure of interest was ARV adherence counseling prior to initiating therapy (versus concurrent with initiation of therapy). Our outcomes of interest were: 1) average adherence >90% in first three months; 2) absence of treatment interruptions >72 hours in first three months; and 3) Viral load >400 copies/ml at the three month visit. We fit univariable and multivariable regression models, adjusted for predictors of ARV adherence, to estimate the association between additional pre-therapy counseling visits and our outcomes.
300 participants had records of counseling, of whom 231 (77%) completed visits prior to initiation of ARVs and 69 (23%) on or shortly after initiation. Median age was 33, 71% were female, and median CD4 was 133 cell/ml. Median 90-day adherence was 95%. Participants who completed pre-therapy counseling visits had longer delays from ARV eligibility to initiation (median 49 vs 14 days, p<0.01). In multivariable analyses, completing adherence counseling prior to ARV initiation was not associated with average adherence >90% (AOR 0.8, 95%CI 0.4–1.5), absence of treatment gaps (AOR 0.7, 95%CI 0.2–1.9), or HIV viremia (AOR 1.1, 95%CI 0.4–3.1).
Completion of adherence counseling visits prior to ARV therapy was not associated with higher adherence in this cohort of HIV-infected patients in Uganda. Because mortality and loss-to-follow-up remain high in the pre-ARV period, policy makers should reconsider whether counseling can be delivered with ARV initiation, especially in patients with advanced disease.
From 2005 through 2009, the number of people in low income countries taking HIV antiretroviral medications (ARVs) increased over 5-fold to 5.2 million
Adherence counseling is an important component of HIV care
All participants provided written informed consent to participate in the study, which was reviewed by the institutional ethics review committees of Mbarara University of Science and Technology, the Ugandan National Council for Science and Technology, Massachusetts General Hospital, and the University of California, San Francisco.
Study participants were members of the Uganda AIDS Rural Treatment Outcomes study (UARTO), a prospective cohort designed to measure predictors of ARV adherence in rural Uganda. HIV-infected patients older than 17 years who are initiating ARVs at the Immune Suppression Syndrome Clinic (ISS) of Mbarara Regional Referral Hospital were eligible for enrollment. An electronic medical record documented all clinic encounters.
Participants were enrolled on the day of ARV initiation. Blood draws for CD4 count and viral load were performed at baseline and every 3 months. Medication adherence was measured with Medication Event Monitoring System (MEMS) electronic pill bottle monitors (Aardex Group, Sion, Switzerland).
Pre-adherence counseling was defined as any counseling session entitled or including “ARV Counseling” which occurred prior to the date of ARV initiation. Trained counselors perform all ARV counseling visits, which are characterized by 20-minute sessions covering dosing schedule, drug toxicities, importance of adherence including prevention of resistance, and management of missed doses. Patients who received their first episode of ARV counseling on the day of ARV initiation were not considered to have had pre-adherence counseling, as they did not require extra patient visits. Counseling was measured by review of the electronic medical record for ARV counseling visits after 2007, when counseling forms were introduced in the clinical practice. For patients with no record of ARV-adherence counseling in the electronic medical record, we performed chart review to minimize the probability of misallocation bias.
We measured time delay to ARV initiation as the time from ARV eligibility to first receipt of ARVs. Eligibility for ARVs was defined as the date of first CD4 count result below 250, the threshold for initiation in Uganda during the study period. For patients who did not have a CD4 result prior to initiation, we defined time of ARV eligibility as the date of their first counseling session.
We measured adherence over 3 months because most patients in both groups received counseling around the time of initiation, and studies have found that the effect of adherence education declines with time
Demographic and clinical characteristics were summarized by presence or absence of pre-treatment adherence counseling. Comparisons of summary characteristics across the two groups were made with chi-square testing for categorical variables and non-parametric Mann-Whitney tests for continuous variables. For binary outcomes, we performed logistic regression to detect an association between the outcome and presence or absence of pre-adherence counseling. All analyses were done using univariable modeling and again with multivariable modeling adjusted for known predictors of adherence including age, sex, travel time, employment status, socioeconomic status as measured by an asset ownership index
A total of 300 of 521 total participants in the UARTO study enrolled after 2007 and had records of adherence counseling in the chart or electronic database. Two hundred thirty-one participants (77%) received adherence counseling prior to the initiation of ARVs. Of the remaining 69 patients, 88% received adherence counseling on the day of initiation. The median age of the cohort was 33 years (IQR 28–40), 71% were female, and median baseline CD4 count was 133 cell/microL (IQR 93–203). Median 90-day adherence in the cohort was 95% (IQR 85–98%), and 66% had adherence greater than 90%. There were no significant differences between those who received pre-treatment counseling and those who did not in terms of gender, age, baseline CD4, socioeconomic status, time travel to clinic, employment, history of opportunistic infection, or depression (
Characteristic | Completed Pre-TherapyAdeherence Counseling(n = 231) | No Pre-Therapy AdherenceCounseling(n = 69) | p-value |
Any Adherence Counseling (%) | 100 | 88.4 | <0.01 |
Percent Female (%) | 73.2 | 62.3 | 0.08 |
Age (median, IQR) | 33 (27–39) | 33 (30–40) | 0.29 |
Baseline CD4 (%) | 0.26 | ||
<100 | 31.2 | 23.2 | |
100–249 | 54.1 | 65.2 | |
≥250 | 14.6 | 11.6 | |
Period of ARV Initiation (%) | <0.01 | ||
Prior to 2008 | 44.6 | 71.0 | |
During or after 2008 | 55.4 | 29.0 | |
Asset Index Quartile | 0.81 | ||
1 | 26.6 | 26.1 | |
2 | 27.1 | 23.2 | |
3 | 24.9 | 30.4 | |
4 | 21.4 | 20.3 | |
Hours in Travel to Clinic (%) | 0.80 | ||
<1 hour | 58.4 | 55.1 | |
1–2 hours | 31.2 | 31.2 | |
>2 hours | 10.4 | 13.0 | |
Unemployed at baseline (%) | 32.0 | 20.6 | 0.07 |
Every History of OpportunisticInfection (%) | 41.7 | 45.6 | 0.57 |
AUDIT-C Alcohol Use Screen Positive | 15.6 | 29.9 | 0.01 |
Hopkins Symptoms ChecklistDepression Score >1.75 (%) | 28.7 | 33.8 | 0.41 |
Days from ARV Eligibility toInitiation (median, IQR) | 49 (27–83) | 14 (0–75) | <0.01 |
Days from ARV Eligibility to Initiationif CD4<100 (median, IQR) | 41 (27–69); n = 72 | 21 (0–50); n = 16 | 0.04 |
Average ARV Adherence first3 months of Therapy | 94.8 | 95.6 | 0.81 |
Average ARV Adherence >90%in first 3 months of Therapy (%) | 64.3 | 72.1 | 0.26 |
Any ARV Treatment Gaps >72 hoursin first 3 months of Therapy (%) | 11.7 | 7.3 | 0.29 |
Viral Load >400 copies/ml at3 month Follow-up Visit (%) | 9.7 | 9.5 | 0.97 |
Participants who completed adherence counseling visits prior to therapy had significantly longer delays from ARV eligibility to initiation (median 49 vs 14 days, p<0.01). This was also true in the subset of patients with baseline CD4 counts <100 cells (median 41 vs. 21 days, p = 0.04).
In univariable analyses, completing pre-therapy adherence counseling was not associated with average adherence >90% (OR 0.7, 95%CI 0.4–1.3), absence of treatment gaps >72 hours (OR 0.6, 95% CI 0.2–1.6), or HIV viremia (OR 1.0, 95%CI 0.4–2.7). The lack of association for these outcomes persisted in multivariable models adjusted for other predictors of adherence (
Univariable Analyses | Multivariable Analyses |
|||
Adherence Measure | Measure of Association |
95% CI | Measure of Association |
95% CI |
Average Adherence >90% | OR = 0.69 | 0.37–1.31 | AOR = 0.78 | 0.40–1.54 |
Absence of treatment gaps >72 hours | OR = 0.59 | 0.22–1.60 | AOR = 0.67 | 0.23–1.91 |
Persistnet Viremia >400 copies/ml | OR = 1.01 | 0.39–2.66 | AOR = 1.13 | 0.41–3.12 |
OR: odds ratio for odds of outcome if completed pre-ARV counseling vs no pre-therapy counseling. AOR: adjusted odds ratio for odds of outcome if completed pre-therapy counseling vs no pre-therapy counseling.
Multivariable analysis adjusted for age, sex, time travel to from clinic, asset index quartile, baseline CD4 count, year of ARV initiation and history of opportunistic infection.
Patients initiating ARVs in this cohort in rural Uganda achieved high levels of adherence and viral suppression regardless of whether they received additional adherence counseling visits prior to ARV initiation or adherence counseling at the time of ARV initiation. Compared to adherence counseling delivered concurrent with ARV initiation, adherence counseling prior to ARV initiation was associated with significant delays in initiation therapy. Because this was a prospective study that enrolled participants at the time of ARV initiation, lost to follow-up could not be measured in the pre-treatment period. Multiple other studies have documented high rates of mortality and losses to follow up among eligible patients who have not initiated ARVs. At the ISS Clinic in Mbarara, approximately 30% of ARV-eligible patients during the period 2007-2009 failed to initiate ARVs within one year
When asked, patients often cite transportation costs as a primary reason for difficulty engaging in care
Most national HIV guidelines in sub-Saharan Africa recommend some form of adherence counseling prior to initiation of ARVs in eligible patients. Of the 11 countries in the region with adult HIV infection prevalence >5% and publically available treatment guidelines, six (Botswana, Lesotho, Mozambique, Namibia, Tanzania, and Uganda) state that ARVs should be withheld from patients who have not completed counseling visits
Multiple studies have shown benefit from adherence counseling
While our study leverages objective adherence monitoring in a prototypical sub-Saharan African clinic serving a rural population, our sample is small, was derived from a single clinic, and was only powered to detect a large effect size of pre-therapy counseling on early treatment adherence. Though it is very unlikely that pre-treatment counseling has a large effect on early treatment adherence, further study of this intervention will be important to evaluate for potentially important modest effects. The absence of randomized adherence counseling may introduce uncontrolled confounders despite inclusion of known predictors of adherence in our multivariate regression model. A randomized control trial comparing ARV adherence counseling prior to versus concurrent with initiation of therapy would corroborate these findings.
The high level of adherence seen in this study is characteristic of many sub-Sahara African treatment settings
Our findings suggest that counseling at the time of ARV initiation is associated with excellent adherence and that additional adherence counseling visits prior to therapy might have at most a modest additional effect on early adherence. Counseling for both adherence and other health-related issues is a crucial aspect of HIV care and should be promoted throughout the care of the patient. However adherence counseling should not delay ARV initiation in patients with advanced disease, given high rates of death and attrition in the ARV eligibility period.