Background:  Increased combination ART (cART) complexity is associated with lower adherence and, therefore, might lead to more frequent viral breakthrough. With this study, our intent was to assess the incidence of virological rebound according to cART complexity in persons with effectively controlled HIV infection.

Methods:  A total of 1873 ART-naïve participants in the ICoNA cohort with no evidence of virological failure prior to reaching HIV RNA <80 copies/mL were considered. Complexity was categorized as follows:  once-daily, twice-daily 2 to 5 pills/day, twice-daily 6 to 8 pills/day, twice-daily 9 to 12 pills/day, or twice-daily >12 pills/day. Virological rebound was defined as date of the first of 2 consecutive HIV RNA >400 copies/mL. Follow-up was considered from the date of first HIV RNA <80 copies/mL to date of virological rebound, death, or last clinic visit. Poisson regression model was used to assess the relation between virological rebound and cART complexity adjusting for age, sex, transmission route, CD4 and HIV RNA at start of cART, calendar year, years of cART, specific nucleoside reverse transcriptase inhibitor (NRTI) pairs, type of third drug, and whether the regimen complexity was switched since viral load <80 copies/mL.

Results:  Participants were characterized by:  female 30%; median age 36 years (IQR 32 to 41); transmission route­—injecting drug use 29%, homosexual 22%, heterosexual 41%; median CD4 and log₁₀ HIV RNA at start of cART were 267/mm³ (IQR 126 to 395) and 4.8 copies/mL (IQR, 4.2 to 5.2), respectively; and median time to HIV RNA <80 copies/mL was 6 months (IQR 3 to 11). Among a total 4.998 person-years of follow-up (once-daily, 248; twice-daily 2 to 5 pills/day,  2169; twice-daily 6 to 8 pills/day, 966; twice-daily 9 to 12 pills/day, 926; twice-daily >12 pills/day, 690), overall, 311 virological rebounds  were registered with an incidence rate of 6.2x100 person-years (95%CI 5.6 to 7.0). In the crude analysis, with increasing complexity, we observed rising incidence rates of virological rebound  x100 person-years:  once-daily, 1.6 (95%CI 0.4 to 4.1); twice-daily 2 to 5 pills/day, 4.7 (95%CI 3.8 to 5.7); twice-daily 6 to 8 pills/day, 6.4 (95%CI 4.9 to 8.2); twice-daily 9 to 12 pills/day, 7.3 (95%CI 5.7 to 9.3); and twice daily >12 pills/day, 11.0 (95%CI 8.7 to 13.8). At multivariate analysis, only the once-daily regimen showed a significantly different virological rebound rate (RR 0.25; 95%CI 0.08 to 0.79; p = 0.02) in respect to the twice-daily 6 to 8 pills/day group.

Conclusions: Our analysis suggests that, in persons with previously effectively controlled viremia, virological rebound rates appear to increase with greater cART complexity, based on the number of daily doses and pills. Systematic assessment of treatment burden due to complexity is imperative to allow for early identification of treatment fatigue and for adherence intervention.