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Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial
Clinical Microbiology and Infection xxx (2017) 1e8
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Original article
Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial J.R. Blanco 1, *, y, B. Alejos 2, y, S. Moreno 3 ~ o, La Rioja, Spain Department of Infectious Diseases, Hospital San PedrodCIBIR, Logron Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain 3) de Henares University, Instituto Ramo n y Cajal, Alcala n y Cajal de Investigacio n Sanitaria (IRYCIS), Department of Infectious Diseases, Hospital Ramo Madrid, Spain 1) 2)
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 August 2017 Received in revised form 19 November 2017 Accepted 20 November 2017 Available online xxx
Objectives: CD4/CD8 ratio and CD4þ T-cell percentage (CD4%) predicts the risk of AIDS and non-AIDS events. Multiple T-cell marker recovery (MTMR) has been proposed as the most complete level of immune reconstitution. We quantified differences in the CD4/CD8 ratio, CD4% recovery and MTMR after starting HIV-1 treatment with dolutegravir/abacavir/lamivudine vs. efavirenz (EFV)/tenofovir (TDF)/ emtricitabine (FTC). Methods: Exploratory post hoc analysis of the SINGLE study, a randomized double-blind, clinical trial. Percentage differences and corresponding precision based on 95% confidence intervals, and p values were calculated for CD4/CD8 ratio normalization, CD4% normalization and the achievement of MTMR. Cox models taking into account competing risks were used to estimate subehazard ratios when comparing the times to normalization of the CD4/CD8 ratio and the CD4% by treatment arm. Results: Data from 833 participants were analysed (414 in the dolutegravir/abacavir/lamivudine arm). There were no statistically significant differences in the proportion of patients who reached a CD4/CD8 ratio 0.5 at weeks 48 and 96. However, at week 96, the proportion of patients with a CD4/CD8 ratio 1 was higher in the EFV-TDF-FTC group (difference, 11.70; 95% confidence interval, 4.49e18.91; p 0.002). The decrease from baseline in CD8þ cell count was consistently greater in the EFV-TDF-FTC arm. Analysis of CD4þ percentages showed no significant differences during the study. The proportion of patients attaining a MTMR was higher in the EFV-TDF-FTC group, although the difference was only statistically significant at week 96 (p 0.001). Conclusions: EFV-TDF-FTC showed significantly greater increases in CD4/CD8 ratio 1.0 or MTMR beyond treatment week 96. Additional studies are necessary to better understand the impact of these findings. J.R. Blanco, Clin Microbiol Infect 2017;▪:1 © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
~o Handling editor: J. Rodriguez-Ban Keywords: Antiretroviral therapy CD4 percentage CD4 T-cell count CD4/CD8 ratio dolutegravir efavirenz
Introduction Although antiretroviral therapy (ART) can induce sustained virologic suppression that increases CD4 T-cell count [1], complete recovery of the immune system is difficult to achieve [2,3]. In addition to the CD4 T-cell count, the CD4/CD8 ratio has become an
* Corresponding author: J.-R. Blanco, Department of Infectious Diseases, Hospital ~ o, La Rioja, Spain. San PedrodCIBIR, Logron E-mail address: [email protected] (J.R. Blanco). y The first two authors contributed equally to this article, and both should be considered first author.
important measure of immune recovery because it predicts AIDS and non-AIDS events and/or mortality independently of CD4 T-cell count [4e12]. Besides absolute CD4 T-cell count and CD4/CD8 ratio, the CD4 T-cell percentage (CD4%) also predicts the risk of AIDS and non-AIDS events [5,13e16]. Although a single marker may be easier to use, combinations including the CD4% could provide more robust information regarding immune system restoration [17]. Because few data exist about the influence of ART on the CD4/ CD8 ratio, the CD4%, and multiple T-cell marker recovery (MTMR) (CD4 T cells >500/mm3 plus CD4% >29% plus CD4/CD8 ratio >1) [17], we conducted a study to evaluate data from the SINGLE study [18,19]. This study showed that the combination of dolutegravir
https://doi.org/10.1016/j.cmi.2017.11.016 1198-743X/© 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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J.R. Blanco et al. / Clinical Microbiology and Infection xxx (2017) 1e8
(DTG) with abacavir (ABC) and lamivudine (3TC) was statistically superior to the standard-of-care fixed-dose combination of efavirenz (EFV) and tenofovir (TDF) disoproxil fumarate/emtricitabine (FTC) in HIV-1enaive patients (Lake et al., ‘Cardiovascular biomarkers after switch to ABC-DTG-3TC: the STRIIVING Study,’ paper presented at the Conference on Retroviruses and Opportunistic Infections, 2016). This superiority of DTG-ABC-3TC arm remained until study completion at week 144 [19]. The main objectives of this study were to quantify the differences in the CD4/CD8 ratio and the CD4% recovery, and to determine the percentage of patients who experienced MTMR [17] after starting treatment with DTG-ABC-3TC or EFV-TDF-FTC. Methods The SINGLE clinical trial has been described elsewhere [18,19]. Briefly, SINGLE was a multicentre, randomized, double-blind, noninferiority study involving treatment-naive HIV-infected participants. The study was designed to assess the safety and efficacy of DTG-ABC-3TC provided once daily compared to fixed-dose EFVTDF-FTC provided once daily. The primary analysis occurred at week 48. After the week 48 visit, participants continued to receive blinded treatment until week 96. On completion of the week 96 visit, all the participants were offered the opportunity to continue the treatment until week 144 in an open-label fashion. The CD8þ Tcell count was determined only until week 96, so the CD4/CD8 ratio could be measured until week 96, but not at week 144. We have performed an exploratory post hoc analysis in the full SINGLE study, not included in the preregistered analysis plan. Approval by the applicable ethics committee was obtained at participating centres in accordance with international standards. Participants provided written informed consent before any study-specific procedures were performed. On the basis of the criteria described in the Supplementary Material, we assessed three different primary immunologic outcomes: (a) the achievement of CD4/CD8 ratio normalization at cutoffs of 0.5 and 1, (b) the achievement of CD4% normalization at a cutoff of 29% and (c) the achievement of MTMR. An exploratory post hoc analysis was performed in the intention-to-treat population. The primary approach for handling missing data was the observed-cases approach. In this approach, only cases with available data for a particular time point are included, which enables evaluation of immunologic normalization without confounding by discontinuations or lack of observation. Balance in the treatment group for the main baseline covariates was assessed by the nonparametric Mann-Whitney U test or the chi-squared test as appropriate. Percentage differences (EFV-TDF-FTC vs. DTG-ABC-3TC) were calculated for (a) CD4/CD8 ratio normalization (0.5 and 1) at week 48 and week 96, (b) the achievement of CD4% normalization (29%) at week 48, week 96 and week 144 and (c) the achievement of MTMR at weeks 48 and 96. Logistic regression models were used to estimate odds ratios for the impact of treatment group on the immunologic outcomes previously described. To evaluate the impact of the cutoff selection, we also used linear regression to calculate differences in the mean changes. A sensitivity analysis was performed to evaluate the impact of missing datadonly cases with available data for a particular time point includeddconsidering time to CD4/CD8 ratio normalization, time to CD4% normalization and time to achievement of MTMR as end points. We used the multiple decrement method to calculate the cumulative incidence [20] of the end points and a proportional hazards model on the subdistribution hazard [21,22] to estimate subehazard ratios for the effect treatment group, treating deaths before the end point of interest as competing events in every model.
We performed multivariable regression models to analyse the impact of DTG and EFV on the immunologic outcomes previously described after adjustment for potential confounders. Details of the multivariable regression modelling are described in the Supplementary Material. All statistical analyses were performed by Stata 14.0 (StataCorp, College Station, TX, USA). Results A total of 833 participants were randomized and received at least one dose of DTG-ABC-3TC (n ¼ 414) or EFV-TDF-FTC (n ¼ 419). Demographic and disease characteristics at baseline were well balanced. Median age was 35 years (range, 18e85 years), and there was a high representation of participants who were male (84%) and white (68%). HIV RNA was >100 000 copies/mL in 32% of the subjects, and the CD4þ T-cell count was <200 cells/mm3 in 14%. Median percentage and absolute CD4þ T-cell count was 22% (range, 16e27%) and 338 cells/mm3 (range, 246e436 cells/mm3), respectively. Median CD4/CD8 ratio was 0.38 (0.26e0.54) Other baseline immunologic characteristics are presented in Supplementary Table S1. Differences by treatment group were not observed. Discontinuations due to adverse events were higher in the EFVTDF-FTC arm, whereas the numbers of participants who were lost to follow-up, withdrew consent, exhibited protocol deviations or were excluded at the investigators' discretion were similar between arms, as previously described [18]. The proportion of subjects with missing data during the window used for end point calculations was similar in both treatment arms. Change from baseline in CD4þ cell counts was consistently greater in the DTG-ABC-3TC arm than in the EFV-TDF-FTC arm (week 48: 267 cells/mm3 vs. 208 cells/ mm3; p < 0.001; week 96: 325 cells/mm3 vs. 281 cells/mm3; p 0.004; week 144: 378 cells/mm3 vs. 332 cells/mm3 15.6 to 78.2 cells/mm3; p 0.003) [18,19]. The proportions of patients attaining CD4/CD8 ratio normalization with EFV-TDF-FTC or DTG-ABC-3TC treatment at the cutoffs of 0.5 and 1 are shown in Fig. 1. There were no statistically significant differences in the proportion of patients who reached a CD4þ/ CD8þ ratio 0.5 at week 48 and week 96. However, at week 96, the proportion of patients with a CD4/CD8 ratio 1 was 38.8% in the EFV-TDF-FTC group and 27.1% in the DTG-ABC-3TC group (difference, 11.70; 95% confidence interval (CI), (4.49; 18.91); p 0.002; adjusted odds ratio, 2.112; 95% CI (1.402; 3.182); p < 0.001). A difference between treatment groups was also observed in the mean change from baseline at week 96 (adjusted difference, 0.074; 95% CI (0.030; 0.118); p 0.001), but not at week 48 (adjusted difference, 0.024; 95% CI (0.011; 0.060); p 0.182). The decrease in CD8 cell count from baseline was consistently greater in the EFV-TDF-FTC arm than in the DTG-ABC-3TC arm at both week 48 (148.272 cells/mm3 vs. 53.677 cells/mm3; adjusted difference (95% CI) 99.574 (142.997; 56.151) cells/mm3 (p < 0.001)) and week 96 (187.275 cells/mm3 vs. 82.683 cells/ mm3; adjusted difference (95% CI) 105.027 ((152.372; 57.683 cells/mm3 (p < 0.001)). The proportions of patients attaining CD4% normalization are shown in Fig. 2. No significant differences were observed during the study. However, the patients in the EFV-TDF-FTC treatment group showed a higher mean increase at week 48 (adjusted difference, 1.147; 95% CI (0.371; 1.923); p 0.004), week 96, 1.941; 95% CI (1.064; 2.818); p < 0.001) and week 144 (1.885; 95% CI (0.943; 2.827); p < 0.001). The proportion of patients attaining a CD4 T-cell count >500/ mm3 plus a CD4% >29% plus a CD4/CD8 ratio >1 was higher in the EFV-TDF-FTC group than in the DTG-ABC-3TC group at week 48 (72/340 (21.18%) vs. 64/367 (17.44%)) and week 96 (102/307 (33.22%) vs. 84/340 (24.71%)), although the difference was only
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
J.R. Blanco et al. / Clinical Microbiology and Infection xxx (2017) 1e8
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Fig. 1. CD4þ/CD8þ ratio normalization differences by treatment group. (A) Proportion of participants with CD4/CD8 ratio 0.5. (B) Proportion of participants with CD4/CD8 ratio 1. ABC, abacavir; BL, baseline; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; 3TC, lamivudine; TDF, tenofovir.
statistically significant at week 96 (difference, 8.52; 95% CI (1.53; 15.50); p 0.017; adjusted odds ratio, 1.802; 95% CI (1.171; 2.772); p 0.007) (Table 1). The sensitivity analysis including the time to normalization of the CD4/CD8 ratio and the CD4% produced results that were concordant with the other approaches (Figs. 3e5). We observed a significantly shorter time to CD4/CD8 ratio normalization at a cutoff of 1 in the EFV-TDF-FTC group compared to the DTG-ABC-3TC group (adjusted subehazard ratios, 1.365; 95% CI (1.056; 1.763); p 0.017). These findings were not reproduced when using a CD4/CD8 ratio cutoff of 0.5 and a CD4% normalization cutoff of 29%. However, differences in time to MTMR achievement were not found
after adjusting for potential confounders (adjusted subehazard ratios, 1.090; 95% CI (0.830; 1.430); p 0.536). Results from crude and multivariable regression models are showed in Supplementary Tables S2, S3 and S4. Discussion The SINGLE study showed that more than 78% of patients treated with EFV-TDF-FTC or DTG-ABC-3TC had a CD4/CD8 ratio 0.5 by week 48, and this percentage continued increasing through week 96 (>84% for both therapeutic options). The clinical interpretation of CD4/CD8 ratio cutoff point is still controversial,
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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100
4
Proportion of participants with %CD4 >=29% EFV-TDF-FTC 217/270 (80.37%)
228/309
80
(73.79%) 223/344 (64.83%)
252/313 (80.51%)
60
246/344
DTG-ABC-3TC
(71.51%) 221/369
40
(59.89%) Difference in normalization Week 48, 4.93 (95% CI-2.17; 12.04) P=0.174 Week 96, 2.27 (95% CI-4.57; 9.12) P=0.515 Week 144 -0.14 (95% CI-6.60; 6.32) P=0.966
20
96/419 (22.91%) 74/414 (17.87%) BL 4
12
24
48
72
Week
96
120
144
Fig. 2. CD4þ percentage normalization differences by treatment group. ABC, abacavir; BL, baseline; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; 3TC, lamivudine; TDF, tenofovir.
Table 1 MTMR differences by treatment group Time
EFV-TDF-FTC
DTG-ABC-3TC
Treatment difference
n/N
No. patients with MTMR
n/N
No. patients with MTMR
%
95% CI
Baseline Week 48 Week 96
417/419 340/419 307/419
3 (0.72%) 72 (21.18%) 102 (33.22%)
411/414 367/414 340/414
1 (0.24%) 64 (17.44%) 84 (24.71%)
0.48 3.74 8.52
0.47, 1.42 2.09, 9.56 1.53, 15.50
p
0.320 0.208 0.017
MTMR ¼ ((CD4þ T cells >500/mm3) þ (CD4þ >29%) þ (CD4þ/CD8þ >1)). ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; MTMR, multiple T-cell marker recovery; 3TC, lamivudine; TDF, tenofovir.
although it is agreed that higher CD4/CD8 ratios are better. Several reports have shown that a lower CD4/CD8 ratio is associated with, among other things, an increased risk of AIDS events and AIDSrelated death [8], or an increased risk of coronary artery disease [16]. A CD4/CD8 ratio cutoff <0.5 has been proposed to identify patients who require intensive cancer prevention or screening strategies [12]. In our study, both EFV and DTG helped patients experience CD4/CD8 ratio 0.5. Regarding the CD4/CD8 ratio cutoff of 1.0, more than 20% of patients treated with any therapeutic option were above the cutoff by week 48, and this percentage continued to increase through week 96. However, at week 96, the ratio was significantly greater in those treated with EFV-TDF-FTC (38.8% vs. 27.1%). Although a ratio of <1 in seronegative patients has been associated with immunosenescence and mortality [23e25], its implications for HIV-infected patients is unknown. One reason for failure to normalize the CD4/CD8 ratio is a high CD8 T-cell count at baseline [26] or persistently elevated CD8 T cells [7,27]. Although the causes are not well known, these factors may reflect persistent virus replication, chronic inflammation or the intrinsic properties of CD8 T cells [27e29]. However, when surrogate markers of inflammation, immunoactivation or senescence have been evaluated in an attempt to understand CD4/CD8 ratio recovery, no differences have been observed [30,31]. In our study, the high percentage of patients in the EFV-TDF-FTC group who had CD4/CD8 ratio 1.0 was due to the substantial decrease in CD8 Tcell count from baseline.
To date, few studies have evaluated the impact of different classes of ART on CD4/CD8 ratio normalization, and those available are controversial. While some authors have not observed an association between ART and CD4/CD8 ratio normalization [26], others have found a better performance of TDF compared to maraviroc [31], and of TDF-FTCecontaining regimens compared to ABC3TCecontaining regimens [8,32], although differences disappeared in some cases after adjustments. In relation to the third drug used, there are similar discrepancies. While no differences have been observed in CD4/CD8 ratio normalization after comparing EFV and the most frequently used boosted protease inhibitor in some observational studies [8,26,32], others have observed higher increases in the mean CD4/CD8 ratio with nonnucleoside reverse transcriptase inhibitore vs. protease inhibitorebased regimens in an adjusted model [33]. However, receiving therapy with other nonnucleoside reverse transcriptase inhibitors different from EFV showed a significantly lower CD4/CD8 ratio recovery after performing adjusted analysis [32]. In a French study [34], there was no evidence that any type of ART affected CD4/CD8 ratio normalization when the treatment was coded as the main regimen. However, when integrase inhibitor was evaluated as an individual regimen, it was strongly associated with CD4/CD8 ratio normalization (odds ratio 7.67) [34]. Raltegravir has also been associated with an increased CD4/CD8 ratio in two studies where patients were switched to or received an intensified dose of this drug [35,36]. Finally, Serrano-Villar et al. [37] analysed CD4þ/CD8þ ratios in the
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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(a) CD4/CD8 ≥0.5 .9 Adjusted sub-hazard ratio* sHR: 0.973 (95% CI: 0.794; 1.193) P=0.795
.75 .6 .45 .3 .15 0 0 4
12
24
48
96
104
Weeks from baseline EFV-TDF-FTC
DTG-ABC-3TC
(b) CD4/CD8 ≥1 .9 Adjusted sub-hazard ratio* sHR: 1.365 (95% CI: 1.056; 1.763) P=0.017
.75 .6 .45 .3 .15 0 0 4
12
24
48
96 102
Weeks from baseline EFV-TDF-FTC
DTG-ABC-3TC
Fig. 3. Cumulative incidence plot of time to CD4/CD8 ratio normalization. (A) CD4/CD8 ratio 0.5. (B) CD4/CD8 ratio 1. sHR, EFV-TDF-FTC compared to DTG-ABC-3TC. *Adjusted by baseline CD4/CD8 ratio, baseline percentage CD4, baseline CD4, baseline CD8 baseline virus load, hepatitis C, HIV risk category, age and sex. ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; sHR, subehazard ratio; 3TC, lamivudine; TDF, tenofovir.
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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J.R. Blanco et al. / Clinical Microbiology and Infection xxx (2017) 1e8
.9 .75 .6 .45 Adjusted sub-hazard ratio* sHR: 0.974 (95% CI: 0.825; 1.150) P=0.757
.3 .15 0 0 4 12
24
48
96
144
Weeks from baseline EFV-TDF-FTC
DTG-ABC-3TC
Fig. 4. Cumulative incidence plot of time to CD4 percentage normalization (CD4% 0.29). sHR, EFV-TDF-FTC compared to DTG-ABC-3TC. *Adjusted by baseline CD4/CD8 ratio, baseline percentage CD4, baseline CD4, baseline CD8 baseline virus load, hepatitis C, HIV risk category, age and sex. ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; sHR, subehazard ratio; 3TC, lamivudine; TDF, tenofovir.
.75
.6 Adjusted sub-hazard ratio* sHR: 1.090 (95% CI: 0.830; 1.430) P=0.536
.45
.3
.15
0 0 4
12
24
48
96 104
Weeks from baseline EFV-TDF-FTC
DTG-ABC-3TC
Fig. 5. Cumulative incidence plot of MTMR. MTMR ¼ ((CD4þ T cells >500/mm3) þ (CD4þ >29%) þ (CD4þ/CD8þ >1)). sHR, EFV-TDF-FTC compared to DTG-ABC-3TC. *Adjusted by baseline CD4/CD8 ratio, baseline percentage CD4, baseline CD4, baseline CD8 baseline virus load, hepatitis C, HIV risk category, age and sex. ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; MTMR, multiple T-cell marker recovery; sHR, subehazard ratio; 3TC, lamivudine; TDF, tenofovir.
STARMRK study, a double-blind randomised controlled trial of raltegravir-based vs. EFV-based combination therapy in treatmentnaive patients, and found that raltegravir was associated with higher rates of CD4/CD8 ratio normalization at a cutoff of >0.4. This finding was not reproduced for other CD4/CD8 ratio cutoffs (>1,
>1.5 and >2.0). Unlike our analysis, the authors used a different cutoff (0.4) and used a linear mixed model to define the CD4/CD8 ratio response. According to the available data of the SINGLE study, it is not possible to attribute the improvement of CD4/CD8 ratio 1 at week
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
J.R. Blanco et al. / Clinical Microbiology and Infection xxx (2017) 1e8
96 to one of the backbone drugs, the third drug, or both [32], or to be better explained by virologic efficacy or higher CD4 cell recovery. In fact, change from baseline in CD4 T-cell counts was consistently greater in the DTG-ABC-3TC arm at week 48 (p < 0.001) [18], week 96 (p 0.004) and week 144 (p 0.003) [19]. As in other studies, the differential impact appears to be on the CD8þ T-cell count. Hypotheses to explain differences on this impact are currently lacking and deserve further research. It has been suggested that the CD4% is another independent predictive factor of AIDS progression [14]. Indeed, early HIV RNA decay has been associated with a greater increase in CD4% change from baseline to week 96 (Tsoukas et al., ‘Association between early virologic response and immunologic outcomes in raltegravirtreated patients,’ paper presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2010). However, although integrase inhibitors can more quickly reduce HIV virus load than other therapeutic options, no differences were observed in our study when comparing EFV-TDF-FTC and DTGABC-3TC. To our knowledge, no studies have evaluated the roles of different types of ART in recovery or the associated clinical implications. In relation to MTMR, it could be that a robust predictor of immune recovery because reconstitution of absolute CD4 T-cell counts does not always reflect normalization of T-cell homeostasis [17]. In our study, MTMR was always higher in patients treated with EFV, but the difference was only statistically significant at week 96. To date, no studies have evaluated the roles of different types of ART in recovery or the associated clinical implications. Our study has some limitations. First, we did not analyse variables related to reduced immunologic recovery such as cytomegalovirus serology [8,38]. However, the role of cytomegalovirus coinfection is controversial, with some studies reporting involvement at a low CD4/CD8 ratio [30] and others indicating an association with a suboptimal CD4/CD8 ratio [8,38]. Second, this is a post hoc analysis. However, these analyses are common in large multicentre clinical trials and as a result of the development of data registries [37,39,40]. Indeed, post hoc analyses of data can generate scientific hypotheses that could be studied in future randomized studies and might explore unanticipated gaps in study design [41]. Third, despite the potential benefit of applying mixed models to study continuous outcomes trajectories over time, the linear regression approach presented also valid results and an easier interpretation. Therefore, for the sake of simplicity, results from the linear models were presented. However, this study has important strengths, such as its methodology (a randomized, double-blind clinical trial) and the fact that determinations were carried out in centres of reference, avoiding differences in procedures and techniques. In conclusion, our results suggest that although DTG-ABC-3TC produced significantly greater increases in CD4þ T-cell count than EFV-TDF-FTC, analyses of other immune recovery markers supported EFV beyond treatment week 96. Additional studies are necessary to better understand the impact of these findings. Studies comparing different integrase inhibitors to other antiretroviral regimens in terms of CD4/CD8 ratio, CD4% and MTMR recovery and the associated clinical consequences are also needed. Moreover, given the potential clinical significance of the findings, evaluation of the CD4/CD8 ratio and other parameters should be included in clinical trials that evaluate new antiretroviral drugs. Acknowledgements We gratefully acknowledge all of the SINGLE study participants. We also acknowledge the additional members of the SINGLE study team who contributed to this study.
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Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.cmi.2017.11.016.
Transparency declaration Funded in part by the SPANISH AIDS Research Network (RIS) (RD16/0025/0001, RD16/0025/0036 and RD16CIII/0002/0006) and as part of the Plan Nacional RþDþI, cofinanced by ISCIIIe n General de Evaluacio n y el Fondo Europeo de DesarSubdireccio rollo Regional (FEDER). All authors report no conflicts of interest relevant to this article.
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Original article
Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial J.R. Blanco 1, *, y, B. Alejos 2, y, S. Moreno 3 ~ o, La Rioja, Spain Department of Infectious Diseases, Hospital San PedrodCIBIR, Logron Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain 3) de Henares University, Instituto Ramo n y Cajal, Alcala n y Cajal de Investigacio n Sanitaria (IRYCIS), Department of Infectious Diseases, Hospital Ramo Madrid, Spain 1) 2)
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 August 2017 Received in revised form 19 November 2017 Accepted 20 November 2017 Available online xxx
Objectives: CD4/CD8 ratio and CD4þ T-cell percentage (CD4%) predicts the risk of AIDS and non-AIDS events. Multiple T-cell marker recovery (MTMR) has been proposed as the most complete level of immune reconstitution. We quantified differences in the CD4/CD8 ratio, CD4% recovery and MTMR after starting HIV-1 treatment with dolutegravir/abacavir/lamivudine vs. efavirenz (EFV)/tenofovir (TDF)/ emtricitabine (FTC). Methods: Exploratory post hoc analysis of the SINGLE study, a randomized double-blind, clinical trial. Percentage differences and corresponding precision based on 95% confidence intervals, and p values were calculated for CD4/CD8 ratio normalization, CD4% normalization and the achievement of MTMR. Cox models taking into account competing risks were used to estimate subehazard ratios when comparing the times to normalization of the CD4/CD8 ratio and the CD4% by treatment arm. Results: Data from 833 participants were analysed (414 in the dolutegravir/abacavir/lamivudine arm). There were no statistically significant differences in the proportion of patients who reached a CD4/CD8 ratio 0.5 at weeks 48 and 96. However, at week 96, the proportion of patients with a CD4/CD8 ratio 1 was higher in the EFV-TDF-FTC group (difference, 11.70; 95% confidence interval, 4.49e18.91; p 0.002). The decrease from baseline in CD8þ cell count was consistently greater in the EFV-TDF-FTC arm. Analysis of CD4þ percentages showed no significant differences during the study. The proportion of patients attaining a MTMR was higher in the EFV-TDF-FTC group, although the difference was only statistically significant at week 96 (p 0.001). Conclusions: EFV-TDF-FTC showed significantly greater increases in CD4/CD8 ratio 1.0 or MTMR beyond treatment week 96. Additional studies are necessary to better understand the impact of these findings. J.R. Blanco, Clin Microbiol Infect 2017;▪:1 © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
~o Handling editor: J. Rodriguez-Ban Keywords: Antiretroviral therapy CD4 percentage CD4 T-cell count CD4/CD8 ratio dolutegravir efavirenz
Introduction Although antiretroviral therapy (ART) can induce sustained virologic suppression that increases CD4 T-cell count [1], complete recovery of the immune system is difficult to achieve [2,3]. In addition to the CD4 T-cell count, the CD4/CD8 ratio has become an
* Corresponding author: J.-R. Blanco, Department of Infectious Diseases, Hospital ~ o, La Rioja, Spain. San PedrodCIBIR, Logron E-mail address: [email protected] (J.R. Blanco). y The first two authors contributed equally to this article, and both should be considered first author.
important measure of immune recovery because it predicts AIDS and non-AIDS events and/or mortality independently of CD4 T-cell count [4e12]. Besides absolute CD4 T-cell count and CD4/CD8 ratio, the CD4 T-cell percentage (CD4%) also predicts the risk of AIDS and non-AIDS events [5,13e16]. Although a single marker may be easier to use, combinations including the CD4% could provide more robust information regarding immune system restoration [17]. Because few data exist about the influence of ART on the CD4/ CD8 ratio, the CD4%, and multiple T-cell marker recovery (MTMR) (CD4 T cells >500/mm3 plus CD4% >29% plus CD4/CD8 ratio >1) [17], we conducted a study to evaluate data from the SINGLE study [18,19]. This study showed that the combination of dolutegravir
https://doi.org/10.1016/j.cmi.2017.11.016 1198-743X/© 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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(DTG) with abacavir (ABC) and lamivudine (3TC) was statistically superior to the standard-of-care fixed-dose combination of efavirenz (EFV) and tenofovir (TDF) disoproxil fumarate/emtricitabine (FTC) in HIV-1enaive patients (Lake et al., ‘Cardiovascular biomarkers after switch to ABC-DTG-3TC: the STRIIVING Study,’ paper presented at the Conference on Retroviruses and Opportunistic Infections, 2016). This superiority of DTG-ABC-3TC arm remained until study completion at week 144 [19]. The main objectives of this study were to quantify the differences in the CD4/CD8 ratio and the CD4% recovery, and to determine the percentage of patients who experienced MTMR [17] after starting treatment with DTG-ABC-3TC or EFV-TDF-FTC. Methods The SINGLE clinical trial has been described elsewhere [18,19]. Briefly, SINGLE was a multicentre, randomized, double-blind, noninferiority study involving treatment-naive HIV-infected participants. The study was designed to assess the safety and efficacy of DTG-ABC-3TC provided once daily compared to fixed-dose EFVTDF-FTC provided once daily. The primary analysis occurred at week 48. After the week 48 visit, participants continued to receive blinded treatment until week 96. On completion of the week 96 visit, all the participants were offered the opportunity to continue the treatment until week 144 in an open-label fashion. The CD8þ Tcell count was determined only until week 96, so the CD4/CD8 ratio could be measured until week 96, but not at week 144. We have performed an exploratory post hoc analysis in the full SINGLE study, not included in the preregistered analysis plan. Approval by the applicable ethics committee was obtained at participating centres in accordance with international standards. Participants provided written informed consent before any study-specific procedures were performed. On the basis of the criteria described in the Supplementary Material, we assessed three different primary immunologic outcomes: (a) the achievement of CD4/CD8 ratio normalization at cutoffs of 0.5 and 1, (b) the achievement of CD4% normalization at a cutoff of 29% and (c) the achievement of MTMR. An exploratory post hoc analysis was performed in the intention-to-treat population. The primary approach for handling missing data was the observed-cases approach. In this approach, only cases with available data for a particular time point are included, which enables evaluation of immunologic normalization without confounding by discontinuations or lack of observation. Balance in the treatment group for the main baseline covariates was assessed by the nonparametric Mann-Whitney U test or the chi-squared test as appropriate. Percentage differences (EFV-TDF-FTC vs. DTG-ABC-3TC) were calculated for (a) CD4/CD8 ratio normalization (0.5 and 1) at week 48 and week 96, (b) the achievement of CD4% normalization (29%) at week 48, week 96 and week 144 and (c) the achievement of MTMR at weeks 48 and 96. Logistic regression models were used to estimate odds ratios for the impact of treatment group on the immunologic outcomes previously described. To evaluate the impact of the cutoff selection, we also used linear regression to calculate differences in the mean changes. A sensitivity analysis was performed to evaluate the impact of missing datadonly cases with available data for a particular time point includeddconsidering time to CD4/CD8 ratio normalization, time to CD4% normalization and time to achievement of MTMR as end points. We used the multiple decrement method to calculate the cumulative incidence [20] of the end points and a proportional hazards model on the subdistribution hazard [21,22] to estimate subehazard ratios for the effect treatment group, treating deaths before the end point of interest as competing events in every model.
We performed multivariable regression models to analyse the impact of DTG and EFV on the immunologic outcomes previously described after adjustment for potential confounders. Details of the multivariable regression modelling are described in the Supplementary Material. All statistical analyses were performed by Stata 14.0 (StataCorp, College Station, TX, USA). Results A total of 833 participants were randomized and received at least one dose of DTG-ABC-3TC (n ¼ 414) or EFV-TDF-FTC (n ¼ 419). Demographic and disease characteristics at baseline were well balanced. Median age was 35 years (range, 18e85 years), and there was a high representation of participants who were male (84%) and white (68%). HIV RNA was >100 000 copies/mL in 32% of the subjects, and the CD4þ T-cell count was <200 cells/mm3 in 14%. Median percentage and absolute CD4þ T-cell count was 22% (range, 16e27%) and 338 cells/mm3 (range, 246e436 cells/mm3), respectively. Median CD4/CD8 ratio was 0.38 (0.26e0.54) Other baseline immunologic characteristics are presented in Supplementary Table S1. Differences by treatment group were not observed. Discontinuations due to adverse events were higher in the EFVTDF-FTC arm, whereas the numbers of participants who were lost to follow-up, withdrew consent, exhibited protocol deviations or were excluded at the investigators' discretion were similar between arms, as previously described [18]. The proportion of subjects with missing data during the window used for end point calculations was similar in both treatment arms. Change from baseline in CD4þ cell counts was consistently greater in the DTG-ABC-3TC arm than in the EFV-TDF-FTC arm (week 48: 267 cells/mm3 vs. 208 cells/ mm3; p < 0.001; week 96: 325 cells/mm3 vs. 281 cells/mm3; p 0.004; week 144: 378 cells/mm3 vs. 332 cells/mm3 15.6 to 78.2 cells/mm3; p 0.003) [18,19]. The proportions of patients attaining CD4/CD8 ratio normalization with EFV-TDF-FTC or DTG-ABC-3TC treatment at the cutoffs of 0.5 and 1 are shown in Fig. 1. There were no statistically significant differences in the proportion of patients who reached a CD4þ/ CD8þ ratio 0.5 at week 48 and week 96. However, at week 96, the proportion of patients with a CD4/CD8 ratio 1 was 38.8% in the EFV-TDF-FTC group and 27.1% in the DTG-ABC-3TC group (difference, 11.70; 95% confidence interval (CI), (4.49; 18.91); p 0.002; adjusted odds ratio, 2.112; 95% CI (1.402; 3.182); p < 0.001). A difference between treatment groups was also observed in the mean change from baseline at week 96 (adjusted difference, 0.074; 95% CI (0.030; 0.118); p 0.001), but not at week 48 (adjusted difference, 0.024; 95% CI (0.011; 0.060); p 0.182). The decrease in CD8 cell count from baseline was consistently greater in the EFV-TDF-FTC arm than in the DTG-ABC-3TC arm at both week 48 (148.272 cells/mm3 vs. 53.677 cells/mm3; adjusted difference (95% CI) 99.574 (142.997; 56.151) cells/mm3 (p < 0.001)) and week 96 (187.275 cells/mm3 vs. 82.683 cells/ mm3; adjusted difference (95% CI) 105.027 ((152.372; 57.683 cells/mm3 (p < 0.001)). The proportions of patients attaining CD4% normalization are shown in Fig. 2. No significant differences were observed during the study. However, the patients in the EFV-TDF-FTC treatment group showed a higher mean increase at week 48 (adjusted difference, 1.147; 95% CI (0.371; 1.923); p 0.004), week 96, 1.941; 95% CI (1.064; 2.818); p < 0.001) and week 144 (1.885; 95% CI (0.943; 2.827); p < 0.001). The proportion of patients attaining a CD4 T-cell count >500/ mm3 plus a CD4% >29% plus a CD4/CD8 ratio >1 was higher in the EFV-TDF-FTC group than in the DTG-ABC-3TC group at week 48 (72/340 (21.18%) vs. 64/367 (17.44%)) and week 96 (102/307 (33.22%) vs. 84/340 (24.71%)), although the difference was only
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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Fig. 1. CD4þ/CD8þ ratio normalization differences by treatment group. (A) Proportion of participants with CD4/CD8 ratio 0.5. (B) Proportion of participants with CD4/CD8 ratio 1. ABC, abacavir; BL, baseline; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; 3TC, lamivudine; TDF, tenofovir.
statistically significant at week 96 (difference, 8.52; 95% CI (1.53; 15.50); p 0.017; adjusted odds ratio, 1.802; 95% CI (1.171; 2.772); p 0.007) (Table 1). The sensitivity analysis including the time to normalization of the CD4/CD8 ratio and the CD4% produced results that were concordant with the other approaches (Figs. 3e5). We observed a significantly shorter time to CD4/CD8 ratio normalization at a cutoff of 1 in the EFV-TDF-FTC group compared to the DTG-ABC-3TC group (adjusted subehazard ratios, 1.365; 95% CI (1.056; 1.763); p 0.017). These findings were not reproduced when using a CD4/CD8 ratio cutoff of 0.5 and a CD4% normalization cutoff of 29%. However, differences in time to MTMR achievement were not found
after adjusting for potential confounders (adjusted subehazard ratios, 1.090; 95% CI (0.830; 1.430); p 0.536). Results from crude and multivariable regression models are showed in Supplementary Tables S2, S3 and S4. Discussion The SINGLE study showed that more than 78% of patients treated with EFV-TDF-FTC or DTG-ABC-3TC had a CD4/CD8 ratio 0.5 by week 48, and this percentage continued increasing through week 96 (>84% for both therapeutic options). The clinical interpretation of CD4/CD8 ratio cutoff point is still controversial,
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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100
4
Proportion of participants with %CD4 >=29% EFV-TDF-FTC 217/270 (80.37%)
228/309
80
(73.79%) 223/344 (64.83%)
252/313 (80.51%)
60
246/344
DTG-ABC-3TC
(71.51%) 221/369
40
(59.89%) Difference in normalization Week 48, 4.93 (95% CI-2.17; 12.04) P=0.174 Week 96, 2.27 (95% CI-4.57; 9.12) P=0.515 Week 144 -0.14 (95% CI-6.60; 6.32) P=0.966
20
96/419 (22.91%) 74/414 (17.87%) BL 4
12
24
48
72
Week
96
120
144
Fig. 2. CD4þ percentage normalization differences by treatment group. ABC, abacavir; BL, baseline; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; 3TC, lamivudine; TDF, tenofovir.
Table 1 MTMR differences by treatment group Time
EFV-TDF-FTC
DTG-ABC-3TC
Treatment difference
n/N
No. patients with MTMR
n/N
No. patients with MTMR
%
95% CI
Baseline Week 48 Week 96
417/419 340/419 307/419
3 (0.72%) 72 (21.18%) 102 (33.22%)
411/414 367/414 340/414
1 (0.24%) 64 (17.44%) 84 (24.71%)
0.48 3.74 8.52
0.47, 1.42 2.09, 9.56 1.53, 15.50
p
0.320 0.208 0.017
MTMR ¼ ((CD4þ T cells >500/mm3) þ (CD4þ >29%) þ (CD4þ/CD8þ >1)). ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; MTMR, multiple T-cell marker recovery; 3TC, lamivudine; TDF, tenofovir.
although it is agreed that higher CD4/CD8 ratios are better. Several reports have shown that a lower CD4/CD8 ratio is associated with, among other things, an increased risk of AIDS events and AIDSrelated death [8], or an increased risk of coronary artery disease [16]. A CD4/CD8 ratio cutoff <0.5 has been proposed to identify patients who require intensive cancer prevention or screening strategies [12]. In our study, both EFV and DTG helped patients experience CD4/CD8 ratio 0.5. Regarding the CD4/CD8 ratio cutoff of 1.0, more than 20% of patients treated with any therapeutic option were above the cutoff by week 48, and this percentage continued to increase through week 96. However, at week 96, the ratio was significantly greater in those treated with EFV-TDF-FTC (38.8% vs. 27.1%). Although a ratio of <1 in seronegative patients has been associated with immunosenescence and mortality [23e25], its implications for HIV-infected patients is unknown. One reason for failure to normalize the CD4/CD8 ratio is a high CD8 T-cell count at baseline [26] or persistently elevated CD8 T cells [7,27]. Although the causes are not well known, these factors may reflect persistent virus replication, chronic inflammation or the intrinsic properties of CD8 T cells [27e29]. However, when surrogate markers of inflammation, immunoactivation or senescence have been evaluated in an attempt to understand CD4/CD8 ratio recovery, no differences have been observed [30,31]. In our study, the high percentage of patients in the EFV-TDF-FTC group who had CD4/CD8 ratio 1.0 was due to the substantial decrease in CD8 Tcell count from baseline.
To date, few studies have evaluated the impact of different classes of ART on CD4/CD8 ratio normalization, and those available are controversial. While some authors have not observed an association between ART and CD4/CD8 ratio normalization [26], others have found a better performance of TDF compared to maraviroc [31], and of TDF-FTCecontaining regimens compared to ABC3TCecontaining regimens [8,32], although differences disappeared in some cases after adjustments. In relation to the third drug used, there are similar discrepancies. While no differences have been observed in CD4/CD8 ratio normalization after comparing EFV and the most frequently used boosted protease inhibitor in some observational studies [8,26,32], others have observed higher increases in the mean CD4/CD8 ratio with nonnucleoside reverse transcriptase inhibitore vs. protease inhibitorebased regimens in an adjusted model [33]. However, receiving therapy with other nonnucleoside reverse transcriptase inhibitors different from EFV showed a significantly lower CD4/CD8 ratio recovery after performing adjusted analysis [32]. In a French study [34], there was no evidence that any type of ART affected CD4/CD8 ratio normalization when the treatment was coded as the main regimen. However, when integrase inhibitor was evaluated as an individual regimen, it was strongly associated with CD4/CD8 ratio normalization (odds ratio 7.67) [34]. Raltegravir has also been associated with an increased CD4/CD8 ratio in two studies where patients were switched to or received an intensified dose of this drug [35,36]. Finally, Serrano-Villar et al. [37] analysed CD4þ/CD8þ ratios in the
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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(a) CD4/CD8 ≥0.5 .9 Adjusted sub-hazard ratio* sHR: 0.973 (95% CI: 0.794; 1.193) P=0.795
.75 .6 .45 .3 .15 0 0 4
12
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Weeks from baseline EFV-TDF-FTC
DTG-ABC-3TC
(b) CD4/CD8 ≥1 .9 Adjusted sub-hazard ratio* sHR: 1.365 (95% CI: 1.056; 1.763) P=0.017
.75 .6 .45 .3 .15 0 0 4
12
24
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96 102
Weeks from baseline EFV-TDF-FTC
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Fig. 3. Cumulative incidence plot of time to CD4/CD8 ratio normalization. (A) CD4/CD8 ratio 0.5. (B) CD4/CD8 ratio 1. sHR, EFV-TDF-FTC compared to DTG-ABC-3TC. *Adjusted by baseline CD4/CD8 ratio, baseline percentage CD4, baseline CD4, baseline CD8 baseline virus load, hepatitis C, HIV risk category, age and sex. ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; sHR, subehazard ratio; 3TC, lamivudine; TDF, tenofovir.
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
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J.R. Blanco et al. / Clinical Microbiology and Infection xxx (2017) 1e8
.9 .75 .6 .45 Adjusted sub-hazard ratio* sHR: 0.974 (95% CI: 0.825; 1.150) P=0.757
.3 .15 0 0 4 12
24
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Weeks from baseline EFV-TDF-FTC
DTG-ABC-3TC
Fig. 4. Cumulative incidence plot of time to CD4 percentage normalization (CD4% 0.29). sHR, EFV-TDF-FTC compared to DTG-ABC-3TC. *Adjusted by baseline CD4/CD8 ratio, baseline percentage CD4, baseline CD4, baseline CD8 baseline virus load, hepatitis C, HIV risk category, age and sex. ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; sHR, subehazard ratio; 3TC, lamivudine; TDF, tenofovir.
.75
.6 Adjusted sub-hazard ratio* sHR: 1.090 (95% CI: 0.830; 1.430) P=0.536
.45
.3
.15
0 0 4
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96 104
Weeks from baseline EFV-TDF-FTC
DTG-ABC-3TC
Fig. 5. Cumulative incidence plot of MTMR. MTMR ¼ ((CD4þ T cells >500/mm3) þ (CD4þ >29%) þ (CD4þ/CD8þ >1)). sHR, EFV-TDF-FTC compared to DTG-ABC-3TC. *Adjusted by baseline CD4/CD8 ratio, baseline percentage CD4, baseline CD4, baseline CD8 baseline virus load, hepatitis C, HIV risk category, age and sex. ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; MTMR, multiple T-cell marker recovery; sHR, subehazard ratio; 3TC, lamivudine; TDF, tenofovir.
STARMRK study, a double-blind randomised controlled trial of raltegravir-based vs. EFV-based combination therapy in treatmentnaive patients, and found that raltegravir was associated with higher rates of CD4/CD8 ratio normalization at a cutoff of >0.4. This finding was not reproduced for other CD4/CD8 ratio cutoffs (>1,
>1.5 and >2.0). Unlike our analysis, the authors used a different cutoff (0.4) and used a linear mixed model to define the CD4/CD8 ratio response. According to the available data of the SINGLE study, it is not possible to attribute the improvement of CD4/CD8 ratio 1 at week
Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016
J.R. Blanco et al. / Clinical Microbiology and Infection xxx (2017) 1e8
96 to one of the backbone drugs, the third drug, or both [32], or to be better explained by virologic efficacy or higher CD4 cell recovery. In fact, change from baseline in CD4 T-cell counts was consistently greater in the DTG-ABC-3TC arm at week 48 (p < 0.001) [18], week 96 (p 0.004) and week 144 (p 0.003) [19]. As in other studies, the differential impact appears to be on the CD8þ T-cell count. Hypotheses to explain differences on this impact are currently lacking and deserve further research. It has been suggested that the CD4% is another independent predictive factor of AIDS progression [14]. Indeed, early HIV RNA decay has been associated with a greater increase in CD4% change from baseline to week 96 (Tsoukas et al., ‘Association between early virologic response and immunologic outcomes in raltegravirtreated patients,’ paper presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2010). However, although integrase inhibitors can more quickly reduce HIV virus load than other therapeutic options, no differences were observed in our study when comparing EFV-TDF-FTC and DTGABC-3TC. To our knowledge, no studies have evaluated the roles of different types of ART in recovery or the associated clinical implications. In relation to MTMR, it could be that a robust predictor of immune recovery because reconstitution of absolute CD4 T-cell counts does not always reflect normalization of T-cell homeostasis [17]. In our study, MTMR was always higher in patients treated with EFV, but the difference was only statistically significant at week 96. To date, no studies have evaluated the roles of different types of ART in recovery or the associated clinical implications. Our study has some limitations. First, we did not analyse variables related to reduced immunologic recovery such as cytomegalovirus serology [8,38]. However, the role of cytomegalovirus coinfection is controversial, with some studies reporting involvement at a low CD4/CD8 ratio [30] and others indicating an association with a suboptimal CD4/CD8 ratio [8,38]. Second, this is a post hoc analysis. However, these analyses are common in large multicentre clinical trials and as a result of the development of data registries [37,39,40]. Indeed, post hoc analyses of data can generate scientific hypotheses that could be studied in future randomized studies and might explore unanticipated gaps in study design [41]. Third, despite the potential benefit of applying mixed models to study continuous outcomes trajectories over time, the linear regression approach presented also valid results and an easier interpretation. Therefore, for the sake of simplicity, results from the linear models were presented. However, this study has important strengths, such as its methodology (a randomized, double-blind clinical trial) and the fact that determinations were carried out in centres of reference, avoiding differences in procedures and techniques. In conclusion, our results suggest that although DTG-ABC-3TC produced significantly greater increases in CD4þ T-cell count than EFV-TDF-FTC, analyses of other immune recovery markers supported EFV beyond treatment week 96. Additional studies are necessary to better understand the impact of these findings. Studies comparing different integrase inhibitors to other antiretroviral regimens in terms of CD4/CD8 ratio, CD4% and MTMR recovery and the associated clinical consequences are also needed. Moreover, given the potential clinical significance of the findings, evaluation of the CD4/CD8 ratio and other parameters should be included in clinical trials that evaluate new antiretroviral drugs. Acknowledgements We gratefully acknowledge all of the SINGLE study participants. We also acknowledge the additional members of the SINGLE study team who contributed to this study.
7
Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.cmi.2017.11.016.
Transparency declaration Funded in part by the SPANISH AIDS Research Network (RIS) (RD16/0025/0001, RD16/0025/0036 and RD16CIII/0002/0006) and as part of the Plan Nacional RþDþI, cofinanced by ISCIIIe n General de Evaluacio n y el Fondo Europeo de DesarSubdireccio rollo Regional (FEDER). All authors report no conflicts of interest relevant to this article.
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Please cite this article in press as: Blanco JR, et al., Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial, Clinical Microbiology and Infection (2017), https://doi.org/10.1016/j.cmi.2017.11.016