Incomplete Antiretroviral Therapy Adherence Is Associated with Lower CD4-CD8 Ratio in Virally Suppressed Patients with HIV Infection in Mexico

Abstract

Suboptimal adherence to antiretroviral therapy (ART) in people with HIV, even during sustained viral suppression, is associated with persistent inflammation, immune activation, and coagulopathy. Persistently low CD4-CD8 Ratio has been also associated with residual inflammation, is a good predictor of increased risk of death and more widely available than inflammatory biomarkers. We tested the hypothesis that the CD4-CD8 Ratio is associated with ART adherence during periods of complete viral suppression. We used the Medication Possession Ratio based in pharmacy registries as measure of adherence and time-varying, routine care CD4 and CD8 measurements as outcome. We used a linear mixed model for longitudinal data, including fixed effects for sex, age, education, date of ART initiation, AIDS-related conditions, and baseline CD4 to model the outcome. In 988 adults with a median follow-up of 4.13 years, higher ART adherence was independently associated with a modest increase in CD4-CD8. For each increasing percentage point in adherence, the CD4-CD8 Ratio increased 0.000857 (95% confidence interval [CI] -0.000494 to 0.002209, p = .213731) in the first year after achieving viral suppression; 0.001057 (95% CI 0.000262-0.001853, p = .009160) in years 1 to 3; 0.000323 (95% CI -0.000448 to 0.001095, p = .411441) in years 3 to 5; and 0.000850 (95% CI 0.000272-0.001429, p = .003946) 5-10 years after achieving viral suppression. The magnitude of the effect of adherence over CD4-CD8 Ratios varied over time and by baseline CD4 count, with increasing adherence having a larger effect early after ART initiation in people with higher baseline CD4 (>500 cells/μL) and in later years in people with lower baseline CD4 count (≥200 cells/μL). Our findings expand on previous evidence suggesting that the benefits of optimal adherence to modern ART regimens goes beyond maintaining viral suppression. These results highlight the importance of including objective measurements of adherence as part of routine care, even in patients with complete HIV suppression over long-term follow-up.

Keywords: acquired immunodeficiency syndrome; adult; cohort studies; linear mixed models; pharmacy; sustained virologic response.

FIG. 1.

Patient selection for analysis. *VS = HIV viral load suppression.

FIG. 2.

Unadjusted predicted values in CD4-CD8 Ratio by ART adherence for different baseline CD4+ counts (colored lines in all panels) and periods of time after achieving viral suppression (1, 3, 5, and 10 years, in A–D). Footnote: Lines represent mean predictions and shades their 95% CI. Each fitted line and its 95% CI were independently estimated for each time partition and baseline CD4+ count category using the first LMM. Only data for adherence over 60% are plotted since these encompassed 98% of the ART adherence data. ART, antiretroviral therapy; CI, confidence interval; LMM, linear mixed model.

FIG. 3.

CD4-CD8 Ratio predicted changes by different values of suboptimal ART adherence on each period of observation after achieving viral suppression. The estimates have been obtained by using reference categories of male, the mean age of 34 at ART initiation, education equal or lower than 9 years, ART initiation in 2005–2007, no AIDS previous to enrollment in care, baseline CD4+ counts ≤200, and at the end of each period (1, 3, 5, and 10 years, respectively). Each line was independently estimated for each time partition.

FIG. 4.

Adjusted 1 predicted values in CD4-CD8 Ratio by ART adherence for different baseline CD4+ counts (colored lines in all panels) and periods of time after achieving viral suppression (1, 3, 5, and 10 years, in A–D). Adjusted for sex at birth, age at ART initiation, education, and period of ART initiation. Each plot was independently obtained by estimating the second LMM for each time partition (at the end of each period, i.e., 1, 3, 5, and 10 years), using reference categories of male, the mean age of 34 at ART initiation, education equal or lower than 9 years, ART initiation in 2005–2007, and no AIDS previous to enrollment in care. Lines represent mean predictions and shades their 95% CI. Only data for adherence over 60% are plotted since these encompassed 98% of the ART adherence data.