CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study

Background In patients with HIV, immune reconstitution after antiretroviral therapy (ART) is often incomplete. We assessed the probability of patients reaching a CD4/CD8 ratio of 1 or more after the start of ART and its association with the onset of non-AIDS-defining events and death.Methods We did an analysis of the ICONA cohort, which recruited treatment-naive patients with HIV in Italy. We included participants in the cohort who started ART, reached an undetectable viral load (≤80 copies per mL), and had a CD4/CD8 ratio of less than 0·8 at the time of an undetectable viral load. We defined ratio normalisation in patients as two consecutive values of 1 or more. We used Kaplan-Meier curves to estimate the cumulative probability of ratio normalisation. We then used Poisson regression models to identify factors independently associated with normalisation and with progression to non-AIDS-defining events or death.Findings We included 3236 participants, enrolled between Jan 22, 1997 and Feb 25, 2013. At the start of ART, median CD4/CD8 ratio in our population was 0·39 (range 0·26–0·55). 458 (14%) patients reached a CD4/CD8 ratio of 1 or more; the estimated probability of normalisation was 4·4% (95% CI 3·7–5·2) by 1 year from baseline, 11·5% (10·2–13·0) by 2 years, and 29·4% (26·7–32·4) by 5 years. Factors associated with normalisation were high pre-ART CD4 cell counts, a high CD4/CD8 ratio at baseline, and negative cytomegalovirus serological findings. The incidence rate of non-AIDS-defining events for patients with a CD4/CD8 ratio of less than 0·30 (4·2 per 100 patient years, 95% CI 3·4–5·3) was double that for those with a ratio of 0·30–0·45 (2·3, 2·1–2·5) or more than 0·45 (2·2, 1·7–2·9). A ratio of less than 0·30 was independently associated with an increased risk of non-AIDS-defining events or death compared with one of more than 0·45.Interpretation Few patients had normalised CD4/CD8 ratios, even though they had viral suppression. Low ratios were associated with increased risk of serious events and deaths. The CD4/CD8 ratio could be used by clinicians to identity patients at risk of non-AIDS-related events. Funding AbbVie, Bristol Myers-Squibb, Gilead, Jannsen, Merck Sharp & Dohme, ViiV Italy.IntroductionLife expectancy of patients with HIV infection who are taking antiretroviral therapy (ART) is similar but not equal to that of uninfected individuals.1 The main factor affecting the prognosis of patients with HIV infection is onset of non-AIDS-defining events, the most severe and most common of which are liver diseases, cardiovascular events, renal impairment, and cancers.2 Whether patients with HIV have a higher incidence of these events than do people without HIV is unknown. Increased risk might result from the lifestyles of individuals with HIV (eg, intravenous drug use or smoking) or to HIV infection itself possibly leading to a state of immune dysregulation not fully controlled by ART and fuelled by several disorders such as low-level residual HIV replication or continuous cytomegalovirus-specific immune stimu-lation and damage in the gut mucosal immunity.3,4Moreover, in many patients, immune reconstitution after ART is often either quantitatively or qualitatively incomplete. Although CD4 cell count is the most important predictive factor for clinical progression to AIDS, cell counts do not predict immune activation and risk of non-AIDS-defined events.5,6 These events are becoming more common, and surrogate markers for use in clinical settings are urgently needed to identify patients at risk. In patients without HIV infection, a CD4/CD8 ratio of less than 1 is linked to immune senescence and to all-cause mortality.7–9 In ART-naive patients with HIV who have a CD4 countof more than 200 cells per μL, a low CD4 percentage and a low CD4/CD8 ratio before the start of ART are predictive of the risk of clinical progression.10Moreover, CD4/CD8 ratio is independently associated with T-cell activation11 and with markers of age-associated disease such as carotid intima–media thickness, arterial stiffness, estimated glomerular filtration rate, muscle wasting, and sarcopenia.12 Finally, and most importantly, in two case-control studies in HIV-infected RNA-undetectable patients treated with ART, CD4/CD8 ratio was independently associated with serious non-AIDS events or mortality.13,14Lancet HIV 2015 Published OnlineFebruary 6, 2015 http://dx.doi.org/10.1016/S2352-3018(15)00006-5See Online/Commenthttp://dx.doi.org/10.1016/PII*Members listed at the end of the paperClinic of Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy(C Mussini MD); National Institute for Infectious Diseases, Rome, Italy(P Lorenzini Dr Stat, E Nicastri MD, A Antinori MD); Department of Infection and Population, Health Division of Population Health, University College London, London, UK (A Cozzi-Lepri PhD); Department of Infectious Diseases, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy (Prof G Lapadula MD, Andrea Gori MD); Clinic of Infectious Diseases, Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy (G Marchetti MD, Prof A d’Arminio Monforte MD); Clinic of Infectious Diseases, Catholic University, Rome, Italy(A Cingolani MD); and Department of Public Health and Infectious Disease, Sapienza University of Rome, Polo Pontino, Italy(M Lichtner MD)Correspondence to: Dr Cristina Mussini, Clinic of Infectious Diseases, University Hospital, Modena 41124, Italy cristina.mussini@unimore.itThis version saved: 11:33, 03-Feb-15THELANCETHIV-D-14-00074R1S2352-3018(15)00006-5Embargo: February 6, 2015—00:0 1 [GMT]LR14tlhiv007