The Effect of Protease Inhibitor-Based Dual Antiretroviral Regimens on CD4/CD8 Ratio During the First Year of Therapy in ART-Naïve Patients With HIV-Infection

MI Figueroa; A Camiro-Zuñiga; PF Belaunzaran-Zamudio; J Sierra Madero; J Andrade Villanueva; JR Arribas; JR Lama; DM Cecchini; G Lopardo; B Crabtree-Ramírez; A Gun; P Patterson; VI Fink; OG Sued; P Cahn


HIV Medicine. 2021;22(4):254-261. 

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In this study, we observed no differences in the CD4/CD8 ratio recovery between HIV-infected, ARV-naïve adults starting combination therapy with either a boosted PI-based DT regime (3TC + bPI) or a standard, boosted-PI-based TT regimen during the first year after treatment initiation. In addition, DT was not associated to a lower likelihood of achieving a CD4/CD8 ratio > 1. People at higher risk of poor immune recovery, such as those older than 50 years starting ART, those with advanced immunosuppression, with high HIV RNA levels or receiving LPV/r-based regimens, showed similar CD4/CD8 ratio responses with either DT or TT, although these results should be interpreted with caution given the small number of patients included for subgroup analysis. Finally, higher baseline CD4 counts and HIV RNA levels were associated with an increased probability of achieving a CD4/CD8 ratio > 1.

To our knowledge, the impact of DT on the CD4/CD8 ratio recovery has not been evaluated before using randomized treatment allocation in prospective studies. Recently, in an observational, retrospective cohort study, virally suppressed patients receiving TT who were switched to DT or monotherapy for any clinically indicated reason were observed to have increased CD8 cell counts after switching as opposed to a group of apparently similar patients who switched to TT regimens. This effectively decreased their CD4/CD8 ratio after 1 and 2 years of treatment modification in people on DT.[20] While this observation raised reasonable concerns about the long-term effect of DT, these results are subject to unobserved confounders and strong selection biases, thus limiting its validity. For instance, clinically indicated ART regimen modifications on virally suppressed patients are usually a manoeuvre to manage adverse events and end-organ toxicities, and to simplify regimens in patients with comorbidities, which are more frequent at older ages.[21] All of the aforementioned conditions are also causally related to a poorer immune response.[22] Random treatment allocation and stringent inclusion criteria in clinical trials effectively deal with observed and unobserved confounding factors. Even though CD8 counts were slightly higher in the DT group near the beginning of our study, the differences eventually disappeared and proved to be statistically and clinically non-significant. The differences between the ICONA study and ours could be explained by the heterogeneity among the TT and DT groups in the ICONA cohort, different study populations, different study designs and more effective methods to account for confounding factors and selection bias in our study. While patients in the ICONA study were observed for a longer period, the differences in CD8 counts were observed even during the first year after switching. In summary, in this study, using random treatment group allocation, we found no evidence of a negative effect of immune recovery measured as CD4/CD8 ratio on ART-naïve people starting DT in comparison to TT.

An important limitation of our study was that 54% of the patients in the TT arm of the GARDEL study received ZDV as part of their ART regime, which has been previously linked to a lower absolute rise in CD4 counts after ART initiation.[23] Although absolute CD4 counts did not differ significantly amongst both groups, the lack of AZT in the DT group makes it difficult to make a direct comparison of its effect on CD4 counts.