CD4+T Lymphocyte Recovery in Individuals with Type 1 Human Immunodeficiency Virus Infection

The widespread use of highly active antiretroviral therapy (HAART) has substantially improved the prognosis of patients infected with type 1 human immunodeficiency virus (HIV-1). Shortly after the initiation of HAART, there is a rapid decline in the incidence of opportunistic infections related to a sharp rise in the peripheral CD4+ cell count [1]. The immune recovery in HIV-infected patients starting first-line HAART for the first time has been extensively studied. In most patients, after a rapid increase in the CD4+ cell count, during the first weeks of therapy, there is a more gradual increase until a normal level of CD4+ cell count is achieved [2]. The CD4+ cell count at baseline and the virologic response to HAART represent the most important predictive factors for the immune recovery [1]. In the Swiss HIV Cohort Study, Kaufmann et al [3] observed that approximately 70% of patients who started therapy with a CD4+ cell count of 300–400 cells/μL achieved of a CD4+ cell count of 500 cells/μL, whereas only 51% of patients with a baseline CD4+ cell count of 200–300 cells/mL and 40% of patients with a baseline CD4+ cell count of 100–200 cells/μL achieved the same endpoint over 4 years. More recently, Kelly et al [4] reported that 95% of patients starting therapy with a CD4+ cell count ≥300 cells/μL achieved a CD4+ cell count ≥500 cells/μL, whereas, only 44% of patients initiating therapy with a CD4+ cell count <100 cells/μL and 25% of patients starting therapy with a CD4+ cell count of 100–200 cells/μL showed a similar immunological response over a mean of 7.5 years. In this issue of the journal, Trotta et al [5] provide further evidence on the kinetics of CD4+ cell count recovery in HIV-infected patients who receive multiple HAART regimes after virological failure. In 3537 patients from a large Italian cohort contributing to 4498 episodes of viral suppression, the authors observed that the median time to achieve an increase in the CD4+ cell count of 1300 cells/μL was significantly associated with the number of previous virological failures ( P < .001, by long-rank test). They also showed that most of the increment was obtained in the first year of viral suppression (98 cells/μL), whereas much lower gains were observed thereafter: 45 cells/μL in the period 1–2 years and 16 cells/mL after the second year. This dynamic was independent of the number of previous virological failures, although the estimated annual increase was less pronounced in advanced therapeutic lines. The next logical passage would be to ask how this effect of the first year of HAART could be maximized and whether specific components of the HAART regimen could improve the immunological outcome. About this issue, contrasting data have been published. In a study analyzing the data from the Swiss HIV Cohort, Khanna et al [6] observed that, in previously naive HIV-infected patients, the increase in CD4+ cell count after 48 months of therapy was from 210 to 520 cells/μL in patients receiving an unboosted protease inhibitor (PI) regimen, from 220 to 475 cells/μL in patients treated with a nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based regimen, and from 168 to 511 cells/μL in patients starting a boosted PI-based regimen. According to these data, in the multivariate analysis, the treatment group did not affect the CD4+ cell count response. Similarly, Putido et al [7] did not observe any difference in the time needed to reach a CD4+ cell count 1200 cells/μL in patients starting either efavirenz or a PI plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs). In this issue of the journal, Trotta et al [5] report that the annual increase in CD4+ cell count varied according to specific antiretrovirals and was larger in patients receiving PIs (unboosted indinavir and ritonavir-boosted lopinavir), compared with patients receiving efavirenz, whereas the annual increase in CD4+ cell count was lower in those patients receiving nevirapine. Recently, the results of a controlled randomized trial (by the STARTMRK investigators) emphasized how the mean change in CD4+ cell count from baseline to week 48 was 189 cells/μL (95% confidence interval [CI], 174–204 cells/μL) for patients treated with the new integrase inhibitor raltegravir and 163 cells/μL (95% CI, 148–178 cells/μL) for patients receiving efavirenz. This difference (26 cells/μL [95% CI, 4–47 cells/μL]) was statistically significant ( P = .018) but was not confirmed in a subsequent analysis on data obtained after 96 weeks of treatment [8, 9]. In a systematic review on 53 trials, Bartlett et al [10] observed that the CD4+ cell count increases were significantly greater in ritonavir-boosted PI-treated patients (200 cells/μL) than in patients receiving a PI alone (179 cells/μL) or in patients receiving an NNRTI (173 cells/μL) or an NRTI (161 cells/μL). Importantly, the superior and statistically significant effect of a boosted PI-based HAART on the CD4+ cell count was also retained in multivariate analysis. There are several methodological limits that should be considered when analyzing these data. Most of the results, like those from Trotta et al [5], have been obtained from cohorts that have the advantage of offering enough great samples but that have the relevant limit that therapies are offered without a random choice. This implies a possible selection bias that could not be caught by adjustments used in the statistical analysis. As an example, it is highly plausible that the most patient-friendly regimens (eg, the NNRTI-based regimens), in terms of doses and number of pills, are preferentially offered to patients (such as intravenous drug users) thought to have a lower adherence rate. It has been confirmed by several studies that the lifestyle of a patient may highly influence the immunological outcome of HAART [11]. However, it may be expected that boosted PI-based HAART could be prescribed more frequently in patients with advanced HIV-1 infection and with higher viral loads, to take advantage of the greater genetic barrier of boosted PIs and to lower the risk of selecting for resistance-conferring viral mutations in the early phases of treatment. These patients often present a more compromised immunological status, and, consequently, the immune recovery may be slower or never equal to that observed in patients starting HAART with a higher CD4+ cell count nadir [12]. The controversial and long-debated question as to what is the best HAART to boost immune recovery does not find an answer in the study by Trotta et al [5]. Although some indications exist about the supposed superiority of PIs, the magnitudes of the differences as reported by Trotta et al [5] are small and raise concerns about their effective clinical relevance, especially for highly immunocompromised patients. Maybe, however, we are not asking the right question, and antiviral drugs (independent of the class they belong to) may not be the answer, or the only answer, for immunocompromised patients. The pathogenesis of immune deficiency in HIV-infected patients is complex, and some aspects of it are unknown. Recent studies on the gastrointestinal pathology in HIV-infected patients suggested an interesting and thrilling scenario for future therapeutic interventions. Brenchley et al [13] observed that CD4+ cell count depletion occurs predominantly in the gastrointestinal tract during all stages of HIV disease. The mucosal immune system contains the majority of the body's T cells. Early in its course, HIV infection induces enterocyte apoptosis, disruption of tight epithelial junctions, and lymphoid tissue fibrosis. As a consequence, the translocation of microbial products as lipopolysaccharide (LPS) is enhanced. These antigens act as a direct stimuli on the innate immune system through Toll-like receptors with a consequent activation of lymphocytes that are not specific for HIV. After starting HAART, LPS levels decrease, but they persist to higher levels compared with uninfected controls. HIV could therefore act as the first trigger in inducing the loss of immune cells, but through a systemic continuous immune activation, other antigens may contribute to maintaining a low immune response, even in patients with HAART-induced complete suppression of HIV replication. As a matter of fact, high-plasma LPS levels, detected in HAART-treated patients, were associated with a poorer immune recovery, which suggests that we need to go beyond the control of viral replication to restore immune functions (at least in some patients) [14]. Trotta et al [5] confirm that first-line HAART is “the best shot” we have, not just in virological terms but also in terms of boosting the immunological response. How to maximize this response remains an unanswered question. New understandings on the pathogenesis of HIV-related immune depletion suggest that HIV infection directly and indirectly causes damage to many immune compartments, and that a combination of such deleterious effects leads to immune failure and AIDS. Understanding this complex scenario can open up new therapeutic opportunities in which HAART is not the only component. Potential conflicts of interest. F.M. reports that he has served as a consultant on advisory boards for Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Roche, and Tibotec; has received lecture fees from Abbott, Bayer, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp and Dome, Roche; and has received research and educational grants from Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmith-Kline, Jansen-Cilag, and Roche; S.L.: no conflicts.