Many studies have found an association between a higher CD4+ cell count at the initiation of combined antiretroviral therapy (cART) and a higher probability of CD4+ recovery for HIV-1-positive individuals [1–6]. Most published data comes from people living with HIV (PLHIV) who initiated cART before 2010. Since then, cART guidelines have evolved. The START trial showed the benefits of early initiation  and there is now a consensus on the necessity of treating PLHIV as soon as possible, regardless of the CD4+ cell count [8,9].
Moreover, integrase inhibitors (INI), authorized since 2007 in Europe and recommended as a first-line regimen since 2014 in Europe, as well as in the United States, and since 2016 in France [10–12], are associated with faster virologic suppression [13,14]. The impact of such faster virologic suppression on CD4+ recovery is still unclear, with some studies showing no difference between regimens with or without INI [13,15], whereas a meta-analysis reported that CD4+ cell count increase was higher, with a mean difference between 18 and 23 cells/μl after 48 weeks on INI-based cART (including dolutegravir, raltegravir, or cobicistat-boosted elvitegravir) relative to standard-dose efavirenz . The clinical relevance of the CD4+/CD8+ ratio is also of increasing interest . For example, a post hoc subgroup analysis of the START trial found that the benefits of starting treatment when CD4+ cell counts are above 500 cells/μl, were higher for individuals with a CD4+/CD8+ ratio less than 0.5 . However, very few studies have analyzed the association of the CD4+/CD8+ ratio with CD4+ recovery .
Here, we sought to estimate the CD4+ recovery rate at least 500 cells/μl and identify associated factors, using a competing-risk approach, among PLHIV, with a CD4+ cell count less than 500 cells/μl, who initiated cART between 2006 and 2014 and achieved virologic control. We particularly analyzed the association with the CD4+/CD8+ ratio and time to virologic suppression.
Study design and population
The French Hospital Database on HIV (FHDH-ANRS CO4) is a hospital-based multicentre open cohort with inclusion ongoing since 1989 . The number of clinical centres has recently increased and currently stands at 125. The FHDH inclusion criteria are HIV-1 or HIV-2 infection and written informed consent. Clinical, biological, and therapeutic data are collected from medical records, using specialized software. The FHDH was approved by the French data protection authority (Commission Nationale de l’Informatique et des Libertés).
Participants from the FHDH were eligible for this study if they were infected by HIV-1, antiretroviral (ARV) naïve, at least 15 years old, with a CD4+ cell count less than 500 cells/μl and HIV-1 viral load at least 50 copies/ml when initiating cART between January 2006 and December 2014. Participants starting on a ritonavir-boosted protease inhibitor (PI/r) monotherapy, dual therapy, triple combination, including two nucleoside reverse-transcriptase inhibitors (NRTI) and either a PI/r, or a nonnucleoside reverse-transcriptase inhibitor (NNRTI), or an integrase inhibitor (INI), or a combination with more than three antiretroviral drugs were eligible. Moreover, they had to have two consecutive viral loads less than 50 copies/ml after initiation, with at least one within 9 months and two CD4+ cell counts measured after the date of virologic control, which is achieved when two consecutive viral loads less than 50 copies/ml are measured. In addition to these criteria, we selected individuals with at least one CD4+/CD8+ ratio within 6 months prior to cART initiation, measured in a centre in which CD8+ cell counts were available in 70% or more of cases when CD4+ cell counts were available, to avoid a selection bias. We did not take into account this last criterion in a sensitivity analysis to assess whether our results on other variables were robust in a larger population.
CD4+ recovery was defined as two successive CD4+ cell counts at least 500 cells/μl, with a minimum of 1 month between the two assessments, the date of recovery being defined as the date of the second value. We used a competing-risk approach to estimate the cumulative incidence of CD4+ recovery, starting from the date of virologic control up to 6 years. We considered the events ‘virologic failure,’ ‘loss to follow-up’ and ‘death’ as competing events. Virologic failure was defined as two consecutive viral loads at least 50 copies/ml or one viral load at least 50 copies/ml followed by a treatment switch, the date of virologic failure being the date of the second viral load at least 50 copies/ml or the date of treatment switch. Individuals were considered to be lost to follow-up when there were 18 months or more between their last follow-up visit and the last database update in the centre in which they were followed. As virologic failure was considered as a competing event, individuals contributed in the analysis only for the period in which they had sustained virologic control. Individuals who did not achieve CD4+ recovery or did not experience a competing event were censored at the date of their last follow-up visit or after 6 years of follow-up, whichever came first.
The following characteristics, evaluated at cART initiation, were assessed in univariable and multivariable competing-risk regression models for their association with CD4+ recovery, using sHR: age (15–29, 30–39, 40–49, 50–59 and ≥60 years), HIV exposure group combined with sex and geographical origin [(MSM), other men from sub-Saharan Africa (SSA), other men, women from SSA, other women], past or current hepatitis C virus (HCV) infection (PCR or antibody-positive), HBs antigen, AIDS-defining events, primary HIV infection at cART initiation, CD4+ cell count (<100, ≥100 and <200, ≥200 and <350, ≥350 and <500 cells/μl), CD4+/CD8+ ratio (<0.30, ≥0.30 and <0.50, ≥0.50 and <0.75, ≥0.75 and <1.00, ≥1.00), HIV-1 viral load (≤5000, >5000 and ≤30 000, >30 000 and ≤100 000, >100 000 and ≤500 000, >500 000 copies/ml), period of cART initiation (2006–2008, 2009–2011, 2012–2014), type of first cART (one PI/r, dual therapy, two NRTIs with one PI/r, two NRTIs with one NNRTI, two NRTIs with one INI, four antiretroviral drugs or more), and time to viral load suppression, defined as the time, in months, since cART initiation to the first viral load less than 50 copies/ml of two consecutive measurements. The date of primary HIV infection was estimated as the presumed date of infection as reported in the medical record, the date of primary infection as reported in the medical record, or the midpoint between a negative and a positive test for HIV-1 infection, depending on available information . Missing values for HCV infection (15.6% of the individuals) or HBs antigen (16% of the individuals) were assumed to be negative. All analyses were performed using SAS statistical software, version 9.4 (SAS Institute, Cary, North Carolina, USA).
Flow chart and study population
From the 23 188 naïve HIV-1-infected individuals enrolled in the FHDH who initiated cART between January 2006 and December 2014 at the age of 15 years or more, 8431 fulfilled the inclusion criteria except for the CD4+/CD8+ ratio. Among them, 6050 individuals met this additional criterion (Fig. 1).
The characteristics of the study population are described in Table 1. Overall, participants enrolled in the study were mainly men (66%) and approximately one-third originated from SSA. At cART initiation, the median age (interquartile range, IQR) was 38.6 (31.8–46.4) years, median HIV-1 viral load 52 257 (15 200–154 783) copies/ml, median CD4+ cell count 275 (169–359) cells/μl, and median CD4+/CD8+ ratio 0.30 (0.18–0.46). After cART initiation, the median time to the first, the second and the third viral load measurements were, respectively, 1.2 months (IQR: 0.9–1.8), 3.1 months (IQR: 2.1–4.4), and 5.5 months (IQR: 3.5–6.8), the median time to viral load suppression 3.9 months (IQR: 2.7–5.7), and the median follow-up time since virologic control 14.2 months (IQR: 7.9–29.7).
The cumulative incidences at 6 years of follow-up for the competing events ‘death,’ ‘virologic failure’ and ‘loss to follow-up’ were 0.1% (95% CI 0.0–0.2), 12.8% (95% CI 11.9–13.8), and 5.3% (95% CI 4.7–6.0), respectively. For CD4+ recovery, the cumulative incidence reached 69.7% (95% CI 68.3–71.0) after 6 years of follow-up (Fig. 2). Finally, only 12.1% of individuals with sustained virologic control, neither dead nor lost to follow-up, did not achieve CD4+ recovery by 6 years. The cumulative incidence for CD4+ recovery varied, depending on the CD4+ cell count at cART initiation, from 30.0% (95% CI 26.1–34.0) for CD4+ less than 100 cells/μl, to 92% (95% CI 90.3–93.4) for CD4+ between 350 and 500 cells/μl (Fig. 3a). There was also a difference depending on the CD4+/CD8+ ratio. Given the shorter follow-up time for individuals who initiated with a ratio at least 1.00, we report cumulative incidences at 5 years, which ranged from 53.7% (95% CI 51.6–55.7) for individuals initiating with a ratio less than 0.3, to 89.6% (95% CI 80.1–94.7) for those initiating with a ratio at least 1.00 (Fig. 3b).
Factors associated with CD4+ recovery
In multivariable analysis, age at cART initiation was associated with CD4+ recovery, with individuals older than 60 years having a lower probability of CD4+ recovery than those aged between 15 and 29 years (sHR: 0.67). MSM and women not from SSA had a higher probability of CD4+ recovery than other men not from SSA (sHR: 1.12 and 1.14), whereas women and other men from SSA had a lower probability (sHR: 0.68 and 0.88). Women not from SSA had a higher probability of CD4+ recovery than those from SSA (sHR: 1.30; 95% CI 1.15–1.48). Individuals with hepatitis B or C co-infections or AIDS at cART initiation had a lower probability of CD4+ recovery, the sHR being 0.85 for HCV-infected individuals, 0.77 for individuals with HBs antigen, and 0.82 for individuals with AIDS.
The CD4+ cell count at cART initiation was strongly associated with a higher probability of CD4+ recovery. The sHR for individuals with CD4+ cell counts between 350 and 500 cells/μl was 9.64 compared with those with CD4+ cell counts less than 100 cells/μl at cART initiation. A higher CD4+/CD8+ ratio at cART initiation was also independently associated with a higher probability of CD4+ recovery. The sHR for individuals with a CD4+/CD8+ ratio at least 1.00 was 1.67 compared with those with a CD4+/CD8+ ratio less than 0.30 at cART initiation. In univariable analysis, a higher HIV-1 viral load was associated with a lower probability of CD4+ recovery, but in multivariable analysis, the adjustment on CD4+ cell count reversed the trend, a higher HIV-1 viral load at cART initiation was independently associated with a higher probability of CD4+ recovery. The sHR was 1.97 for individuals with a viral load greater than 500 000 copies/ml compared with those with a viral load 5000 or less at cART initiation. However, the time to viral load suppression was not associated with CD4+ recovery.
The period of first treatment was not associated with CD4+ recovery. Starting with a triple combination that included two NRTIs and one NNRTI instead of two NRTIs and one PI/r was associated with a lower probability of CD4+ recovery, with a sHR of 0.89. On the other hand, there was no difference when initiating with another treatment, including an INI-based regimen. In the sensitivity analysis, which excluded the CD4+/CD8+ ratio, the study population had similar characteristics to those of the population of the main study (Supplemental Table 1, https://links.lww.com/QAD/B358). The results were close to those of the main analysis.
In this study, the probability of achieving CD4+ recovery after 6 years of sustained virologic control for PLHIV who initiated cART between 2006 and 2014 was 69.7%. The main factors associated with CD4+ recovery were the CD4+ cell count at cART initiation and, to a lesser extent, the CD4+/CD8+ ratio. A higher viral load at initiation was also associated with a higher likelihood of CD4+ recovery, but no association with the time to virologic suppression was observed.
A strength of our study was the use of competing-risk analysis, which permits a nonbiased estimation of cumulative incidences by taking into account virologic failure, death, and loss to follow-up as competing events. Not all centres could provide CD8+ data. Thus, we could not include all of them in our analysis to avoid a possible selection bias. However, we found similar CD4+ recovery rates and similar associations in a sensitivity analysis that included all centres.
It is difficult to directly compare our results on CD4+ recovery rate with those of other studies. First, none of them used a competing-risk approach, overestimating the CD4+ recovery rates. More generally, methodologies were different between studies: the criteria for the evaluation of CD4+ recovery, choice of censoring virologic failure or not, or different selection criteria for the study population. Moreover, for most, the period of antiretroviral treatment initiation was earlier, with less effective treatments and different guidelines on when to start.
All studies have found that the CD4+ cell count at initiation is a major factor of CD4+ recovery [1–6], as ours. A higher CD4+ cell count at initiation was associated with a higher probability of CD4+ recovery. A higher CD4+/CD8+ ratio was also associated with higher probability of recovery, independently of CD4+ cell count. This result is consistent with a previous study by Rosado-Sánchez et al.. They found that, among individuals who started cART with a CD4+ cell count less than 200 cells/μl, those with a lower ratio were less likely to reach 250 CD4+ cells/μl after 24 months of successful therapy. It is noteworthy that a CD4+/CD8+ ratio below 0.3, here associated with a lower probability of CD4+ cell recovery, has also been associated with increased risk of non-AIDS-defining event and death . The CD4+/CD8+ ratio is a surrogate marker of T-cell compartment balance, reflecting both CD4+ T-cell recovery and CD8+ T-cell activation, expansion, and senescence . The persistence of immune activation in virally suppressed individuals impairs reconstitution of the immune system, inducing fibrosis of lymphoid tissue, with collagen deposition limiting access to the survival factor IL-7 and perpetuating CD4+ cell depletion . Thus, chronic immune activation under ART was associated with suboptimal CD4+ cell gains . However, we previously reported that less than 50% of individuals with suboptimal CD4+ cell recovery exhibited chronic CD8+ T-cell activation , highlighting that other factors probably account for low CD4+ cell recovery, including low thymic output  and the persistence of alterations of lymphopoiesis, despite ART-mediated viral suppression . Of note, the univariable sHR for CD4+/CD8+ ratio were largely attenuated by adjustment on CD4+ cell count in the multivariable analysis, whereas sHR for CD4+ cell count were less affected by adjustment on CD4+/CD8+ ratio.
The association of a higher viral load with a higher probability of CD4+ recovery has also been found in other studies [1,2,29]. Grabar et al. reported that an increase of the mean CD4+ cell count after the initiation of cART was significantly greater among individuals with a baseline viral load greater than 5 log copies/ml than among those with a baseline viral load less than 5 log copies/ml. This may be explained by the redistribution of memory CD4+ T cells after cART initiation, which were previously trapped in lymphoid tissue, a site of high viral replication and inflammation .
We found no significant association between the time from cART initiation to viral load suppression and the probability of CD4+ recovery. Previous work by Okulicz et al. found a significant association, but only in univariable analysis. No other study has tested for such an association. On the basis of our findings, there is no evidence of any benefit of more rapid virologic suppression on the probability of CD4+ recovery. Although INI-based regimens, which are known to reduce the time to virologic suppression [13,14], were found to be associated with a higher probability of CD4+ recovery in our univariable analysis, this association disappeared after adjustment. The INI in our study was mainly raltegravir (83%); the results might be different for other INIs. Moreover, only 311 individuals initiated with an INI-based regimen so this nonsignificant association could be explained by a lack of statistical power. INI-based regimens are also known to improve rate of virologic success, which could not be evaluated in our study, as we only selected individuals with virologic success. It is yet to be demonstrated whether such a better rate of virologic success is associated with a clinical benefit.
Other significant associations were moderate. Among men and among women, individuals from SSA had a lower probability of CD4+ recovery than others. Seng et al. also reported that CD4+ recovery was slower among SSA migrants than among French natives, even after adjustment for clinical, socioeconomic and biological determinants. An explanation could be a lower distribution of CD4+ among HIV-negative individuals in some African populations than in European populations . We found a lower probability of CD4+ recovery when individuals were hepatitis B virus (HBV)-infected. Few studies have tested for this factor [34–36], and none have found a significant association. We also found a negative association with HCV coinfection, for which no consensus has been found, as some studies reported the same results [29,34,36,37], whereas others reported no association [2,3]. Similarly, a previous AIDS-defining event at initiation was negatively associated with CD4+ recovery, in accordance with the study of Egger et al.. Finally, we found that individuals older than 60 years had a lower probability of CD4+ recovery. Previous studies have also shown that this population has a poorer immunological response [3,38], consistent with lower thymic function with age  and a smaller CD4+ cell count with increasing age .
Overall, this study confirms the necessity of early diagnosis and rapid treatment initiation, when the CD4+ count and the CD4+/CD8+ ratio are still high. Our results do not evidence a benefit of more rapid virologic suppression on CD4+ recovery.
The authors are grateful to all FHDH participants and research assistants, without whom this work would not have been possible. Members of FHDH-ANRS CO4 are listed at http://www.ccde.fr/main.php?main_file=fl-1171464013-677.html.
D.C., J.F.D., L.W. and M.M.K. designed the study; J.G., G.P., L.C., O.L., A.M., P.D.T., J.F.D. and L.W. included patients; H.R., J.M.L., M.M.K., and D.C. analyzed the data; H.R., M.M.K. and D.C. drafted the manuscript. All authors were involved in the interpretation of the data, did critical revision of the manuscript and approved its final version. H.R. and D.C. had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Conflicts of interest
J.G. reports research grants from Merck-Sharp & Dohme-Chibret (2015–2017), personal fees from Janssen-Cilag (2018), Merck-Sharp & Dohme-Chibret (2017–2018) and ViiV Healthcare (2017-2018) for French HIV advisory boards, from Merck-Sharp & Dohme-Chibret (2018) for travel/accommodations/meeting expenses, outside the submitted work. C.D. reports receiving financial support as an adviser for Gilead Sciences, Merck, Janssen and ViiV healthcare, and research grants from Merck and ViiV Healthcare, outside the submitted work. G.P. reports grants from Gilead (2017-2018), and personal fees for board or travel and congress accommodations from Janssen-Cilag, Merck-Sharp & Dohme-Chibret, Abbvie, Janssen and ViiVhealthcare (2011–2018), outside the submitted work. L.C. reports personal fees from ViiV Healthcare (2018) and MSD (2017) for travel/accommodations/meeting expenses, outside the submitted work. O.L. reports grants from MSD, GSK, Sanofi Pasteur, Janssen, Sanofi Pasteur MSD, personal fees for vaccine advisory boards from Pfizer, Sanofi Pasteur and Janssen (2016–2018), personal fees for consultancy from Innavirvax and Imaxio (2014–2016) outside the submitted work. P.D.T. reports fees for French HIV board from ViiV Healthcare (2016-18), fees for travel/accommodations/meeting expenses from Gilead Sc., Merck-Sharp-Dohme, ViiV Healthcare, (2014 to 2018), all outside the submitted work. L.W. reports personal fees from Janssen-Cilag (2017), Merck-Sharp & Dohme-Chibret (2015, 2016, 2017), Gilead (2016, 2017) and from Bristol Myers Squibb (2017) for lectures outside the submitted work. D.C. reports grants from Janssen-Cilag (2017-2018), Merck-Sharp & Dohme-Chibret (2015–2017), ViiV (2015), personal fees from Janssen-Cilag (2016, 2018) and Merck-Sharp & Dohme-Chibret (2015, 2017) for lectures, personal fees from ViiV (2015), for travel/accommodations/meeting expenses, personal fees from Gilead France from 2011 until December 2015 for French HIV board, personal fees from Innavirvax (2015 and 2016) and Merck Switzerland (2017) for consultancy, outside the submitted work. For the remaining authors none were declared.
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