The initiation of antiretroviral treatment (ART) based on a 2-drug regimen (2DR) with dolutegravir (DTG) plus lamivudine (3TC) has demonstrated non-inferior efficacy and a similar tolerability profile than the 3DR based on the combination of DTG plus tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) (1). However, further information is warranted about possible differentiating factors.

Analyzing the effect of therapeutic strategies on the CD4/CD8 ratio is clinically relevant. The persistence of high levels of circulating CD8+ T-cells or a low CD4/CD8 ratio translates into immunosenescence and heightened immune activation (2) and has been associated with an excess risk of non-AIDS comorbidities and higher all-cause mortality in people living with HIV (PLHIV) receiving ART (2–4). On the other hand, patients with a normal CD4/CD8 ratio (>1) show levels of immune activation and immunosenescence similar to those observed in the non-HIV-infected population. For these reasons, the CD4/CD8 ratio has been established as a marker of immune recovery in people receiving ART and, therefore, as an important prognostic marker. Some (5), but not all (6), clinical guidelines already recommend monitoring the CD4/CD8 ratio as a better predictor of adverse outcomes than the CD4+ T-cell count.

Accumulating evidence suggests that integrase strand-transfer inhibitors (INSTI)-based initial ART results in greater CD4/CD8 ratio recovery compared to non-nucleoside reverse transcriptase (NNRTI) or protease inhibitors (PI)-based ART, with a greater effect during the first year of therapy (3, 7). However, it is unknown whether the treatment initiation with INSTI-based 2DR has a different impact on the CD4/CD8 ratio recovery compared to INSTI-based 3DR. Some studies have been performed in the switch setting and usually group different drug combinations within the 2DR, many based on protease inhibitors (8–11). Hence, we show here the effects of initial INSTI-based 2DR versus 3DR in a large prospective cohort of ART-naïve PLHIV.

Of the 3,318 individuals who started BIC or DTG-based ART (675 and 2,643, respectively) after June 30^th, 2015, 326 initiated dual therapy with DTG plus 3TC. Table 1 summarizes the characteristics of the matched individuals included in each of the three analyses for cutoffs of 0.5, 1.0, and 1.5 (485, 805, and 924 participants, respectively). The distribution of covariates was similar in the three models. Overall, the study sample was representative of a medium-aged population (median age 37 years) with a higher representation of men (88%) and a median CD4/CD8 ratio around 0.30. No participant presented virological failure during follow-up. Appendix Table S1 shows the baseline characteristics of the individuals not included in the analyses because they were not matched, CD4/CD8 information was missing, or the CD4/CD8 ratio was above the cutoff point at baseline.

At 48 weeks, 45% of participants achieved a CD4/CD8 ratio >0.5, 15% achieved a ratio >1.0, and 6% achieved a ratio >1.5 ( Figure 1 ). After matching according to the covariates of interest, GEE models yielded a similar risk of reaching a CD4/CD8 ratio >0.5 (OR 1.00, 95% CI 0.67 - 1.50), CD4/CD8 >1.0 (OR 1.03, 95% CI 0.68 - 1.58), and CD4/CD8 >1.5 (OR 0.86, 95% CI 0.48 - 1.54) between both treatment strategies ( Appendix Table S2 ). Figure 1 shows Kaplan-Meier survival plots of estimated overall CD4/CD8 normalization at cut-offs of 0.5, 1.0, and 1.5. There were no differences between 2DR and 3DR in the incidence ratio of CD4/CD8 ratio normalization at 0.5, 1.0 and 1.5 cut-offs ( Appendix Table S3 ).

In this observational study of a prospective cohort of ART-naïve PLHIV, we found similar CD4/CD8 ratio recovery rates at 48 weeks between 2DR with DTG plus 3TC and 3DR based on DTG or BIC, measured at three different cutoff points (0.5, 1 and 1.5).

Persistently low CD4/CD8 ratios during ART have been strongly associated with morbidity and mortality in PLHIV (2). Therefore, given that the design of clinical trials evaluating the development of non-AIDS comorbidities according to the ART strategy is unlikely, evaluation of the effect of therapies on surrogate markers, such as the CD4/CD8 ratio, is justified.

The current interest in the study of the CD4/CD8 ratio is reflected in the different works that evaluate the evolution of this marker according to baseline predictors (12–14), and the impact achieved on this outcome with both pharmacological (15) and non-pharmacological strategies (16). Although data are showing a greater benefit in terms of CD4/CD8 ratio recovery after ART initiation with INSTI-based regimens, there are still little data on the different impact of starting 2DR vs. 3DR on this biomarker, and the vast majority have focused on the switch setting (8–11). Given the recent approval of the combination of DTG plus 3TC in the naïve patient, there is no data yet on the impact of this strategy on the recovery of this marker. Studies that have evaluated the effects of simplifying from 3DR to 2DR on the CD4/CD8 ratio included different antiretroviral classes and have yielded mixed results. While some studies have found no differences in the evolution of this marker after changing from 3DR to 2DR (8), others have reported both a possible worsening (9) and an improvement (10) in the CD4/CD8 ratio after simplification.

Previous work on this cohort showed a greater effect of INSTI-based 3DR initiation on the CD4/CD8 ratio during the first year, with significant differences in the trajectories of ratio recovery between different ART groups (7). However, because inflammation is slow to change in virologically suppressed individuals (17), further analyses will be needed to assess the impact of these different therapeutic strategies on CD4/CD8 ratio recovery in the longer term (18).

Given the large sample size and prospective nature of the CoRIS cohort, we were able to select matched participants according to the main determinants of ART choice. In addition, we mitigated the potential bias of different follow-up periods among participants by including participants on modern antiretroviral regimens, limited from the start of 2DR use in the second semester of 2015.

As in any observational study, residual confounding may have affected our study due to differences between dual and triple ART initiators. Therefore, we performed a rigorous matching of factors that could confound the causal effect of both treatment strategies on CD4/CD8 ratio normalization. After the matching process, we found a consistent pattern of similarity between groups, evidencing their exchangeability. However, we could only assess differences only after 48 weeks of ART, so next studies should evaluate potential differences that might become apparent after a longer follow-up.

This study found no differences in CD4/CD8 ratio recovery rates during the first 48 weeks after ART initiation with 2DR or 3DR INSTI-based therapies. Evaluating the effect of different therapeutic interventions on CD4/CD8 ratio changes will help decision-making as persistently low CD4/CD8 ratios despite optimal HIV-RNA suppression have been associated with a worse prognosis in PLHIV.

The data analyzed in this study is subject to the following licenses/restrictions: Data cannot be shared due to ethical restrictions. The data can be requested upon a substantiated request with a research protocol to Carlos III Health Research Institute. Requests to access these datasets should be directed to proyectoscoris@isciii.es.

The studies involving human participants were reviewed and approved by Institutional Review Board of the Carlos III Health Institute and Ethics Committee at University Hospital Ramón y Cajal (ceic.hrc@salud.madrid.org). The patients/participants provided their written informed consent to participate in this study.

JM-S: Conceptualization-Equal, Data curation-Equal, Formal analysis-Equal, Investigation-Equal, Methodology-Equal, Writing – original draft-Equal; RR: Investigation-Equal, Validation-Equal, Writing – review and editing-Equal; EM: Investigation-Equal, Writing – review and editing-Equal; MS-C: Investigation-Equal, Writing – review and editing-Equal; AMu: Formal analysis-Equal, Methodology-Equal, Writing – review and editing-Equal; LL-C: Investigation-Equal, Writing – review and editing-Equal; JB: Investigation-Equal, Writing – review and editing-Equal; JP: Investigation-Equal, Writing – review and editing-Equal; ÁMe: Methodology-Equal, Writing – review and editing-Equal; SC: Investigation-Equal, Writing – review and editing-Equal; SM: Investigation-Equal, Supervision-Equal, Validation-Equal, Writing – review and editing-Equal; SS-V: Conceptualization-Equal, Investigation-Equal, Methodology-Equal, Project administration-Equal, Supervision-Equal, Validation-Equal, Writing – review and editing-Equal. All authors contributed to the article and approved the submitted version.

This work was supported by the Spanish AIDS Research Network (RIS) through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006), Instituto de Salud Carlos III projects AC17/00019, PI18/00154, COV20/00349, and ICI20/00058, and co-financed by ISCIII- Subdirección General de Evaluación and by Fondo Europeo de Desarrollo Regional (FEDER). The funders had no role in the study design, data analysis, or in the interpretation of the results.

JM-S reports personal fees from ViiV Healthcare, Janssen Cilag, Gilead Sciences, and MSD and non-financial support from ViiV Healthcare, Jannsen Cilag, and Gilead Sciences, outside the submitted work. SS-V reports personal fees from ViiV Healthcare, Janssen Cilag, Gilead Sciences, and MSD as well as non-financial support from ViiV Healthcare and Gilead Sciences and research grants from MSD and Gilead Sciences, outside the submitted work. SM reports grants, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from Gilead, outside the submitted work.

MS-C reports personal fees and non-financial support from Gilead Sciences and MSD, outside the submitted work. JRB has carried out consulting work for AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare and has received compensation for lectures from AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare, as well as grants and payments for the development of educational presentations for Gilead Sciences, Bristol Myers Squibb and ViiV Healthcare.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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