Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment
Lapadula, Giuseppea; Cozzi-Lepri, Alessandrob; Marchetti, Giuliad; Antinori, Andreac; Chiodera, Alessandroe; Nicastri, Emanuelec; Parruti, Giustinof; Galli, Massimog; Gori, Andreaa; Monforte, Antonella d’Arminiod; for the ICONA Foundation Study
aClinic of Infectious Diseases, ‘San Gerardo de’ Tintori’ Hospital, Monza, Italy
bDepartment of Infection and Population Health, Division of Population Health, Hampstead Campus, University College London, UK
cIstituto Nazionale per le Malattie Infettive, Rome
dClinic of Infectious Diseases, ‘San Paolo’ Hospital, University of Milan
eClinic of Infectious Diseases, Hospital of Macerata
fClinic of Infectious Diseases, ‘Spirito Santo’ Hospital, Pescara
gClinic of Infectious Diseases, ‘Luigi Sacco’ Hospital, University of Milan, Italy.
Correspondence to Giuseppe Lapadula, MD, PhD, Clinic of Infectious Diseases, ‘San Gerardo de’ Tintori’ Hospital, Monza, Italy. E-mail: email@example.com
Received 14 August, 2012
Revised 12 November, 2012
Accepted 16 November, 2012
This work has been presented in part at the 19th Conference on Retroviruses and Opportunistic Infections, Seattle, March 5th–8th 2012. Abstract 641.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).
Background: It is unclear whether lack of immunological response despite viral suppression and relatively preserved CD4+ T-cell count is associated with increased risk of AIDS or severe non-AIDS events.
Methods: Patients initiating first combination antiretroviral therapy (cART) were studied from first viral load 80 copies/ml or less up to AIDS, serious non-AIDS events (malignancies, severe infections, acute kidney injury, cardiovascular events, liver decompensation) or death. Follow-up was right censored if viral load was more than 500. Immunological nonresponse (INR) was defined as current CD4+ cell count less than 120% pre-cART. A Poisson regression analysis was used to investigate the association between INR and the outcome.
Results: Three thousand, three hundred and seventy-eight patients were followed for a median of 32 months (interquartile range: 15–67). Two hundred and twenty-two events (32 deaths, 39 AIDS-defining events, 48 malignancies, 32 severe infections, 47 acute kidney injuries, 12 cardiovascular events, 12 other nonfatal events) were observed. The rate of clinical events among INR and immunological responders was 4.41 [95% confidence interval (CI) 3.38–5.74] and 1.84 (95% CI 1.58–2.15) per 100 person years of follow-up, respectively, accounting for a crude rate ratio of 2.39 (95% CI 1.77–3.25; P < 0.001). INR remained an independent predictor of clinical progression after adjusting for baseline characteristics, including pre-cART CD4+ cell count (adjusted rate ratio 2.93; 95% CI 2.06–4.16, P < 0.001) or current CD4+ cell count (adjusted rate ratio 1.94; 95% CI 1.39–2.72, P < 0.001). The association did not vary by pre-cART CD4+ cell counts (P for interaction = 0.93)
Conclusion: INR are at higher risk of severe clinical events than responders. The association was consistent across different CD4+ cell counts at cART initiation and was only partially explained by current CD4+ cell count. INR could be a marker of immune system malfunctioning, not completely captured by absolute CD4+ cell count.
A dramatic improvement in terms of AIDS-related morbidity and mortality has been demonstrated since the introduction of combination antiretroviral therapy (cART) . Such benefit is correlated with the suppression of HIV plasma replication and the increase of CD4+ T-cell count. Nonetheless, a variable proportion of patients, ranging from 6 to 20%, commonly referred to as ‘immunological nonresponders’ (INR), fail to achieve a significant immune recovery despite virological response to treatment [2–7]. It has been shown that INR have a higher risk of AIDS progression [5,8,9], non-AIDS-related morbidity  and, ultimately, death [6,10,11] than people with clinically significant CD4+ T-cell count recover on cART.
In most of these previous analyses, however, the definition of INR was based on the absolute value of people's current CD4+ cell count and it is, therefore, difficult to understand from the results of these analyses whether the observed increased risk (e.g. in patients with a current CD4+ cell count <200 cells/μl despite suppressed viral load) was indeed due to the current low level of CD4+ cell count or other factors affecting the chance of immune recovery. In addition, it remains unclear whether in people with conserved CD4+ cell count (e.g. >200 cells/μl) at time of cART initiation, lack of CD4+ cell count response despite complete virological suppression is still associated with increased risk of clinical disease.
In this analysis we aimed at assessing whether lack of immune-recovery during virological successful cART was associated with the risk of clinical progression (a composite outcome including both AIDS and serious non-AIDS events as well as all-cause mortality), after accounting for the current value of CD4+ T-cell count, and to assess whether lack of immune-recovery was associated to clinical progression also among patients with relatively preserved CD4+ T-cell count (i.e. >200 cells/μl) at the time of cART initiation.
HIV-1-infected patients from the Italian Cohort of Antiretroviral-Naive Patients (Icona) Foundation Study who had initiated their first cART regimen (i.e. including ≥3 antiretroviral drugs) after 1 January 1996 were included in this analysis. All data recorded in the database up to 31 May 2012 were used. Patients had to be at least 18 years old, started cART when they were naive to antiretrovirals and had achieved viral suppression below 80 copies/ml on at least one measurement after starting their first cART.
A detailed description of the Icona Foundation Study has been described elsewhere  In brief, it is a prospective study of 9313 HIV-infected patients, naive to antiretrovirals, recruited in 71 Italian clinical sites, 50 of which still provide new enrolments and updated follow-up of the persons enrolled. Data of the patients enrolled (including CD4+ cell counts, viral load, clinical and treatment information) are collected prospectively at clinical sites at least on a 6 months basis. All patients signed consent forms to participate to the Icona Foundation Study, in accordance with the ethical standards of the committee on human experimentation and the Helsinki Declaration (1983 revision). The present analysis includes follow-up data reported to the database up to the end of October 2012.
Outcome and immunological response definitions
The outcome of interest was a composite endpoint including a number of components: death for any causes, occurrence of AIDS-related opportunistic infection or neoplasm (as defined by the Center for Disease Control and Prevention 1993 classification ) and occurrence of serious non-AIDS-defining events, whichever came first. Serious non-AIDS defining events included the following: any non-AIDS-defining malignancy; severe non-AIDS defining infections (i.e. infections that are potentially life threatening or require intravenous antibiotic: sepsis, episodic pneumonia, endocarditis, meningitis, encephalitis, bacterial arthritis/ostemyelitis pyelonephritis, cholangitis/cholecystitis, peritonitis); cardiovascular events (acute myocardial infarction, coronary disease requiring invasive procedures, congestive heart failure, stroke); hepatic events (decompensated cirrhosis, i.e. variceal bleeding, porto-systemic encephalopathy, refractory ascites, hepatorenal syndrome); acute kidney injury (defined as confirmed estimated glomerular filtrate rate <60 ml/min using Modification of Diet in Renal Disease formula ) or kidney failure requiring dialysis or renal transplantation; other severe non-AIDS events (pancreatitis, nonvariceal gastrointestinal bleeding, pulmonary thromboembolism).
At the time of the first viral load 80 copies/ml or less after starting the first cART regimen (baseline for this analysis), patients were defined to be at risk of a component of the serious non-AIDS-defining endpoint, if they have never experienced an event belonging to that component prior to baseline. Thus, for example, an episode of cancer that occurred after baseline only counted as an event if the person was never diagnosed with cancer prior to baseline. Conversely, patients with predisposing conditions, such as atherosclerotic coronary disease not determining myocardial infarction or compensated liver disease without prior decompensation, were still considered to be at risk of myocardial infarction or liver decompensation, respectively.
Similarly, patients were defined to be at risk of the AIDS-defining endpoint if they have never experienced that particular AIDS-related opportunistic infection or neoplasm before. Recurrent conditions were treated as competing risks and people were not removed from the risk set if they did developed that condition.
Follow-up accrued from the date of the first viral load 80 copies/ml or less after cART initiation up to the date of an event, of the last measured viral load or the estimated time of rebound more than 200 copies/ml whichever occurred first. Viral rebound was estimated at the time of the first of two consecutive values more than 200 copies/ml after baseline.
Patients were defined as INR if their current CD4+ T-cell count was less than 120% pre-cART level, despite suppression of HIV replication. An increase of at least 20% from pre-cART level was considered to represent an actual CD4 cell count variation, as smaller variation may reflect physiological and/or laboratory variability [15–17]. Nonetheless, different definitions of INR (i.e. current CD4+ cell count <100 or <150% than pre-cART level) were also explored.
The incidence rate of the composite outcome was calculated as number of events recorded after baseline and person years of follow-up (PYFU) and expressed as rate per 100 PYFU, with 95% confidence intervals (CI).
A Poisson regression analysis was used to investigate the association between INR and the risk of developing outcome by calculation of unadjusted and adjusted relative rates. A number of factors, considered as potential confounders, were included in the multivariable models and are listed in the Results section. Two separate adjustments were shown: a first model controlling for the CD4+ T-cell count at cART initiation and a second model including the same covariates as the first model but replacing the baseline CD4+ T-cell count with the most recent CD4+ cell count value. Because one of our main hypotheses was to test whether the risk of INR versus non-INR was elevated even in persons starting cART with a conserved CD4+ cell count, we stratified the analysis according to baseline CD4+ cell count (using the cut-off previously used in the literature of 200, 350 and 500 cells/μl). In addition, we formally tested whether the association between INR and outcome varied according to these baseline CD4+ cell count groups by formally including an interaction term in the Poisson regression models. A sensitivity analysis including only patients who had achieved viral load 80 copies/ml or less within the first year of cART was conducted.
Eventually, in a sensitivity analysis, number of events and PYFU observed during episodes of viral suppression which occurred after the first episode were added. In other words, people who experienced virological rebound to their first episode were allowed to re-enter the analysis and contribute events and PYFU after reachieving viral suppression 80 copies/ml or less on their newly started regimen.
All analyses were repeated after excluding the AIDS component from the outcome-defining events.
Three thousand, three hundred and seventy-eight patients were included in this analysis and observed over a median follow-up of 32 months [interquartile range (IQR): 15–67 months]. Among them, 1130 (33.5%), 1157 (34.2%), 647 (19.2%) and 444 (13.1%) patients had initiated cART when their CD4+ T-cell count was 0–200, 201–350, 351–500 and more than 500 cells/μl, respectively. Patients who had initiated cART in the lowest CD4+ cell count strata were more likely to report heterosexual intercourses as risk factor for HIV acquisition (43.9 and 38.1% among those with ≤200 and >500 CD4+/μl, respectively). More than one-third (39%) of the patients with pre-cART CD4+ cell count 200 cells/μl or less had already experienced an AIDS-defining illness, whereas the proportion was much lower among those with higher CD4+ T-cell count before cART initiation (6.2, 4.5 and 6.8% among those whose pre-cART CD4+ cell count was 201–350, 351–500 or >500 cells/μl, respectively). First-line regimens including protease inhibitor, either alone or in combination with low-dose ritonavir as booster (boosted protease inhibitor), were the most frequently prescribed (35 and 25.1%, respectively), whereas regimens containing nonnucleoside reverse transcriptase inhibitors (NNRTI) were used in 34% of patients. Of note, use of boosted protease inhibitor was more frequent among patients with low compared with those with high CD4+ cell counts (31.7 and 13.7% among those with ≤200 and >500 CD4+/μl, respectively). All characteristics of the patients are shown in Table 1.
At cART initiation, 222 new events were observed, of whom 39 (17.6%) were AIDS-related, 151 (8%) were severe non-AIDS-defining events and 32 (14.4%) were deaths, none of whom was considered to be due to an AIDS-defining event. Patients were followed up for a total of 10 344 years for an overall incidence of clinical progression of 2.1 (95% CI 1.9–2.4) events per 100 PYFU. The median CD4+ T-cell count at event in those who developed one was 404/μl (245, 429, 546 and 566 cells/μl among those with pre-cART CD4+ cell count of <200, 201–350, 351–500 and >500, respectively).
Table 2 represents the distribution of AIDS-defining events, non-AIDS-defining events and causes of death.
Immunological nonresponders and risk of severe events
Table 3 shows the overall number of events observed, the PYFU and the overall rates among INR and immunological responders after stratification by baseline CD4+ cell count groups. The rate ratios of developing the outcome comparing INR with non-INR from fitting the univariable and multivariable Poisson regression analyses are also shown.
Overall, the incidence rate of events was associated with pre-cART CD4+ cell count (the lower the CD4+ cell count, the higher the risk). Incidence was 2.7 (95% CI 2.2–3.3), 2.0 (95% CI 1.6–2.5), 1.3 (95% CI 0.1–1.9) and 1.5 (95% CI 0.9–2.3) per 100 PYFU, among patients starting with 0–200, 201–350, 351–500 and >500 CD4+/μl, respectively.
Nonetheless, in the unadjusted analysis the incidence rates among INR [4.41 (95% CI 3.38–5.74) events per 100 PYFU] were significantly higher than among immunological responders [1.84 (95% CI 1.58–2.14) events per 100 PYFU], with a crude ratio of 2.39 (95% CI 1.77–3.25; P < 0.001). Immunological nonresponse was confirmed to be an independent predictor of clinical progression (adjusted rate ratio 2.93; 95% CI 2.06–4.16, P < 0.001) in a multivariable model adjusted for baseline characteristics of the patients (age, sex, nationality, mode of HIV transmission, previous AIDS diagnosis, baseline hepatitis coinfection status, calendar year of starting cART, CD4 cell count, CD8 cell count and viral load at starting cART and class of cART started). Interestingly, INR remained independently associated with a higher risk of risk of developing the defined outcome also after adjustment for current CD4+ T-cell count (adjusted rate ratio 1.94; 95% CI 1.39–2.72, P < 0.001, Table 3)
The rate ratios of developing the outcome, comparing INR with immunological responders, were not significantly different across different pre-cART CD4+ cell counts, either considered on a linear scale (P value for interaction = 0.93) or stratified as less than or at least 200 cells/μl (P value for interaction = 0.54), thus, suggesting that the association between INR and the risk of clinical progression did not vary according to pre-cART degree of immune deficiency.
The impact of current CD4+ cell count on the risk of progression was evaluated after stratification by pre-cART CD4+ T-cell counts. Among patients with pre-cART CD4+ cell counts 200 cells/μl or less, a CD4+ cell count between 201 and 350 was associated with a significant reduction of the risk of clinical progression (versus remaining in the same stratum of ≤200, rate ratio 0.43; 95% CI 0.26–0.72; P = 0.001). Further increases in current CD4+ cell count were associated with a significantly higher protective effect (e.g. when current CD4+ cell count was 350–500/μl versus remaining 200 or less rate ratio 0.33; 95% CI 0.19–0.58; P < 0.001 or when current CD4+ cell count >500/μl rate ratio 0.24; 95% CI 0.14–0.43; P < 0.001). Among patients who had initiated cART with 201–350 CD4+/μl, a trend towards a decrease in the risk of progression was observed among those who had increased their CD4+ T-cell count to 351–500 cells/μl (rate ratio 0.68; 95% CI 0.35–1.32; P = 0.26) and a significantly lower risk was observed among those with more than 500 cells/μl (rate ratio 0.32; 95% CI 0.17–0.63; P < 0.001). Similarly, an increase from pre-cART CD4+ cell count of 351–500 to more than 500/μl led to a significant reduction in the risk of progression (rate ratio 0.47; 95%CI 0.27–0.84; P = 0.01). Among those with pre-cART CD4+ more than 500 cells/μl, the risk seemed to be stable across different current CD4+ T-cell counts. However, the power of this analysis was insufficient to draw conclusions.
Rates of the defined outcome were fairly stable over time, although there was a slight tendency to decrease with longer duration of viral suppression. For instance, among immunological responders rates decreased from 2.7 (95% CI 1.87–3.88) 0–6 months after achieving viral suppression to 1.6 (95% CI 1.28–1.92) after more than 18 months of viral suppression. Similarly, among INR rates after 0–6 and more than 18 months of viral suppression were 5.02 (95% CI 3.12–8.07) and 3.66 (95% CI 2.33–5.73), respectively. Figure 1 shows rate ratios in INR versus immunological responder group, 6 monthly from baseline.
Other covariates which were found to be independently associated with the risk of severe clinical events were: age (rate ratio 1.51 per 10 years older; 95% CI 1.31–1.75; P < 0.001), non-Italian nationality (rate ratio 1.76 versus Italians; 95% CI 1.06–2.91; P = 0.027), HIV acquisition through injection of drugs (RR 1.54 versus heterosexual contacts; 95% CI 1.03–2.32; P = 0.036), coinfection with hepatitis B/C viruses (rate ratio 1.59 versus HIV mono-infected; 95% CI 1.03–2.44; P = 0.036), baseline CD4 cell count (rate ratio 0.90 per 100 cells/μl higher; 95% CI 0.82–0.98; P = 0.012) and cART including boosted protease inhibitor (rate ratio 2.05 versus NNRTI; 95% CI 1.39–3.03; P < 0.001).
The results of the sensitivity analyses were consistent with those of the main analysis. INR was associated with risk of clinical progression, independently of possible confounders (including current CD4+ cell count), either in the analysis restricted to patients who achieved virological suppression within 1 year of cART (adjusted rate ratio 1.64; 95% CI 1.09–2.45; P = 0.017) or in the analysis adding episodes of viral suppression which occurred after the first one (adjusted rate ratio 1.93; 95% CI 1.42–2.63; P < 0.001).
When we repeated the analyses after excluding AIDS events from our composite outcomes, results were also similar (See Table 4). Of note, as expected, the overall rate for those with baseline CD4 cell count in the 0–200 range was considerably lower in this analysis: 79 events per 3813 PYFU (2.1; 95% CI 1.6–2.6 per 100 PYFU).
When alternative definitions of INR (current CD4+ cell count <100% or <150% than pre-cART level) were used, the results were consistent with those of the main analysis (see Supplementary Tables S1 to S4, http://links.lww.com/QAD/A281).
In this population of previously antiretroviral-naive patients, who had initiated cART at various CD4+ T-cell counts and had achieved complete suppression of viral replication, immunological nonresponse (defined as a CD4+ cell count below 120% of pre-cART level) was associated with a two-fold to three-fold increased risk of developing the defined outcome. Not surprisingly, more than 80% of the observed outcomes were non-AIDS related serious events or deaths, thus, confirming that non-AIDS events may occur more frequently than AIDS events, particularly among patients with relatively preserved CD4+ cell counts, and that such events are associated with a significant morbidity and mortality [18–20].
Previous studies demonstrated that patients with immunological nonresponse despite virological suppression are at higher risk of AIDS progression and death than those with concordant viro-immunological response [5,6,8,9,11]. Nonetheless, the overall incidence rate of new AIDS-defining events among patients with suppressed HIV replication was shown to be low, irrespective of the individual CD4+ T-cell count, and the estimated increase in risk of developing AIDS observed among INR was suggested to be somehow negligible . Although our study confirms that the absolute risk of AIDS-defining event is low, the high burden of severe non AIDS-defining illnesses demonstrates the vulnerability of those with an ineffective immune-restoration and underlines the need for improved strategies aimed at reverting this condition.
Previous studies failed to demonstrate an independent association between the occurrence of non AIDS-defining diseases and the degree of immunological recovery . By converse, in our study INR was associated with risk of severe non-AIDS disease independently of age, sex and other confounders. The reason for this association is not easily explainable and, given the composite nature of the outcome, it is likely to be multifactorial. A persistent immunesuppression, as documented by a reduced CD4+ T-cell count, could justify an increased susceptibility to severe non-AIDS-defining infections. Similarly, impairment in the ability of the immune system to detect and destroy neoplastic cells is a possible explanation for the association between CD4+ T-cell count and non-AIDS-related malignancies . Moreover, persistent immune-activation and inflammation are typically increased among INR [22–25] and this could explain the increased susceptibility of these patients to certain non-AIDS-defining complications, such as cardiovascular disease or malignancies. In fact, it is well known that inflammatory mechanisms have a fundamental role in mediating atherogenesis  and that T-cell activation among HIV-infected patients is associated with arterial disease . Persistent immune-activation is also likely to influence the risk of cancerogenesis, providing the optimal environment for the development of malignancy . The exact mechanisms underlying HIV-associated immune-activation are still debated and include direct effect of residual HIV replication, co-infection with other pathogens (such as cytomegalovirus), nonantigen-specific bystander activation of immune cells and inflammatory response due to translocation of microbial products across damaged intestinal barrier. In particular, microbial translocation has been associated with failure in CD4+ cell count reconstitution [29,30] and has been shown to predict clinical progression independently of CD4+ cell count . Its possible role in increasing the risk of non-AIDS-defining severe morbidity and mortality merits further investigation.
Non-AIDS-related events observed in our patient population – that include malignancies, cardiovascular events, decline in renal function, liver failure and severe infections – are amongst the most frequent clinical conditions described in older patients and this may suggest an earlier aging process in INR. An accelerated aging of the immune system (immunosenescence) has been described in HIV infection and it does not seem to be substantially reverted by cART . One hypothesis is that INR experience immune-reconstitution which is sufficient to give control over opportunistic infections, but not to prevent the onset of degenerative clinical conditions and, ultimately, of age-associated end-organ disease. Consistently with this hypothesis, immunosenescence has been implicated in the pathogenesis of cardiovascular diseases and other non-AIDS comorbidities in the context of treated HIV infection [27,32–34].
Taken all together, these findings suggest that INR could benefit from an attentive monitoring and a more aggressive preventive approach in order to prevent non-AIDS-related complications. In our cohort, a two-fold increased risk of developing the defined outcome among INR was already detectable over the first 6 months of follow-up. This suggests that CD4 cell count variation from pre-cART levels should be monitored as early as 6 months after achieving viral suppression.
Further studies are needed to assess whether treatment targeting immune-activation and inflammation may prevent non-AIDS-related morbidity and mortality among HIV-positive patients with sub-optimal immune-recovery after cART.
A strength of our study is that results were adjusted for CD4+ T-cell count, either measured before cART initiation or updated at the latest time point.
Whereas previous studies had demonstrated an increased risk only among patients who had initiated treatment with low CD4+ cell count [7,35], in our cohort the association between INR and the outcome was consistent across different strata of pre-cART CD4+ T-cell counts (although the absolute risk of clinical progression was higher for patients with <200 CD4+/μl).
The value of current CD4+ T-cell count was confirmed as an important factor associated with clinical progression, even for CD4+ cell counts more than 200 cells/μl, and a low current CD4+ cell count partially explained the higher morbidity among INR. Nonetheless, immunological nonresponders had a higher risk of clinical progression, independently from current CD4+ cell count. Therefore, the lack of CD4+ cell count restoration despite cART emerged as a marker of immune system malfunctioning, not completely captured by absolute CD4+ cell count value. Possible underlying mechanisms that may have influenced the worst outcome include selective loss of naive CD4+ T-cell subset , imbalance of immunoregulatory mechanisms , persistently accelerated lymphocyte apoptosis , defects in T-cell maturation profile and inefficient T-helper function . Eventually, although all patients in our study had suppressed viral replication, it cannot be ruled out that INR was an indirect marker of persistent low-copy viral replication and/or reduced adherence to treatment [4,40].
Whatever the explanation of the increased frailty of this patient population, our findings suggest that using absolute CD4+ cell count as the sole prognostic marker of the outcome of HIV-infected patients with suppressed viral replication and not considering CD4+ cell count variation could be misleading. Further studies are needed to address the role of immune biomarkers other than (or in addition to) CD4+ cell count to identify those patients who have the highest risk of clinical progression.
It is unclear whether achieving a specific CD4+ cell count threshold minimizes the risk of clinical progression. In our study, increasing CD4+ cell count to more than 500 cells/μl was associated with a significant decrease in such risk. This finding is consistent with a previous study, demonstrating that mortality among patients with more than 500 CD4+/μl and prolonged suppression of HIV replication was the same as for the general population . These results indirectly support the indication for starting cART as soon as CD4+ cell counts drop below 500 cells/μl, thus, increasing the chance of restoring the CD4+ cell count value to above this threshold.
In any case, the definition of an immunological outcome, validated against clinical progression, is still needed, as it would be useful in guiding treatment management.
In conclusion, this study significantly adds to the growing body of evidence that HIV-infected patients have a higher than expected risk for a number of conditions commonly associated with aging also in the context of virologically suppressive cART, which has in turn led to the widespread assumption that HIV accelerates the aging process. Our finding that – irrespective of nadir CD4+ cell counts – poor CD4+ T-cell recovery predicts the onset of non-AIDS comorbidities provides an important epidemiological link between accelerated aging and treated HIV infection, offering a hint on where to further investigate possible pathogenetic insights.
Additional scientific efforts are needed to detail the immunological pathways that drive inefficient CD4+ cell count recovery and, in turn, increase clinical risk. Only by detailing the immunological gaps in these clinical settings, will it be possible to shape the most efficacious treatment approach.
Icona Foundation Study: Governing body: M. Moroni (Chair), G. Angarano, A. Antinori, G. Carosi, R. Cauda, A. d’Arminio Monforte, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, C.F. Perno, E. Sagnelli, P.L. Viale, F. Von Schlosser.
Scientific secretary: A. d’Arminio Monforte.
Steering committee: A. Ammassari, M. Andreoni, A. Antinori, C. Balotta, P. Bonfanti, S. Bonora, M. Borderi, M.R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, A. Cozzi-Lepri, A. d’Arminio Monforte, A. De Luca, M. Gargiulo, C. Gervasoni, E. Girardi, M. Lichtner, S. Lo Caputo, G. Madeddu, F. Maggiolo, S. Marcotullio, L. Monno, R. Murri, C. Mussini, M. Puoti, C. Torti.
Statistical and monitoring team: A. Cozzi-Lepri, I. Fanti, T. Formenti.
Participating physicians and centers. Italy M. Montroni, A. Giacometti, A. Costantini, A. Riva (Ancona); U. Tirelli, F. Martellotta (Aviano- PN); G. Angarano, L. Monno, N. Ladisa, (Bari); F. Suter, F. Maggiolo (Bergamo); PL: Viale, G. Verucchi, B. Piergentili, (Bologna); G. Carosi, G. Cristini, C. Torti, C. Minardi, D. Bertelli (Brescia); T. Quirino, C. Abeli (Busto Arsizio); P.E. Manconi, P. Piano (Cagliari); J. Vecchiet, K. Falasca (Chieti); G. Carnevale, S. Lorenzotti (Cremona); L. Sighinolfi, D. Segala (Ferrara); F. Leoncini, F. Mazzotta, M. Pozzi, S. Lo Caputo (Firenze); G. Cassola, G. Viscoli, A. Alessandrini, R. Piscopo, G. Mazzarello (Genova); C. Mastroianni, V. Belvisi (Latina); P. Bonfanti, C. Molteni (Lecco); A. Chiodera, P. Castelli (Macerata); M. Galli, A. Lazzarin, G. Rizzardini, M. Puoti, A. d’Arminio Monforte, A.L. Ridolfo, A. Foschi, A. Castagna, S. Salpietro, S. Merli, L. Carenzi, M.C. Moioli, P. Cicconi, T. Formenti (Milano); R. Esposito, C. Mussini (Modena); A. Gori, G. Lapadula, M. Longoni (Monza), N. Abrescia, A. Chirianni, M. De Marco, (Napoli); C. Ferrari, R. Borghi (Parma); F. Baldelli, B. Belfiori (Perugia); G. Parruti, F. Sozio (Pescara); G. Magnani, M.A. Ursitti (Reggio Emilia); M. Arlotti, P. Ortolani (Rimini); R. Cauda, M. Andreoni, A. Antinori, G. Antonucci, P. Narciso, V. Tozzi, V. Vullo, A. De Luca, M. Zaccarelli, L. Gallo, R. Acinapura, P. De Longis, L. Ceccarelli, R. Libertone, M.P. Trotta, A. Miccoli, (Roma); A.M. Cattelan (Rovigo); M.S. Mura, G. Madeddu (Sassari); P. Caramello, G. Di Perri, G.C. Orofino, M. Sciandra (Torino); E. Raise, F. Ebo (Venezia); G. Pellizzer, D. Buonfrate (Vicenza).
Authors’ contribution: G.L. conceived and designed the study, interpreted the results and drafted the manuscript; A.C.L. contributed in the study design, performed the statistical analysis and critically revised the manuscript; G.M., A.A., A.G. and A.dA.M. contributed in data interpretation, collected the data and critically revised the manuscript; A.C., E.N., G.P. and M.G. collected the data and critically revised the manuscript.
Funding: This work was supported in part by Italian Ministry of Health, ‘CCM’ and ‘Progetto AIDS’.
The Icona Foundation Study is supported by unrestricted educational grants of Abbott, Bristol-Myers Squibb, Gilead.
Conflicts of interest
The authors do not have any associations that might pose a conflict of interest.
1. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators
. N Engl J Med
2. Marimoutou C, Chene G, Mercie P, Neau D, Farbos S, Morlat P, et al. Prognostic factors of combined viral load and CD4+ cell count responses under triple antiretroviral therapy, Aquitaine cohort, 1996–1998
. J Acquir Immune Defic Syndr
3. Dronda F, Moreno S, Moreno A, Casado JL, Perez-Elias MJ, Antela A. Long-term outcomes among antiretroviral-naive human immunodeficiency virus-infected patients with small increases in CD4+ cell counts after successful virologic suppression
. Clin Infect Dis
4. Moore DM, Hogg RS, Yip B, Wood E, Tyndall M, Braitstein P, et al. Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy
. J Acquir Immune Defic Syndr
5. Tan R, Westfall AO, Willig JH, Mugavero MJ, Saag MS, Kaslow RA, et al. Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy
. J Acquir Immune Defic Syndr
6. Loutfy MR, Genebat M, Moore D, Raboud J, Chan K, Antoniou T, et al. A CD4+ cell count <200 cells per cubic millimeter at 2 years after initiation of combination antiretroviral therapy is associated with increased mortality in HIV-infected individuals with viral suppression
. J Acquir Immune Defic Syndr
7. van Lelyveld SF, Gras L, Kesselring A, Zhang S, De WF, Wensing AM, et al. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort
8. Grabar S, Le MV, Goujard C, Leport C, Kazatchkine MD, Costagliola D, et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy
. Ann Intern Med
9. Zoufaly A, an der HM, Kollan C, Bogner JR, Fatkenheuer G, Wasmuth JC, et al. Clinical outcome of HIV-infected patients with discordant virological and immunological response to antiretroviral therapy
. J Infect Dis
10. Gutierrez F, Padilla S, Masia M, Iribarren JA, Moreno S, Viciana P, et al. Patients’ characteristics and clinical implications of suboptimal CD4 T-cell gains after 1 year of successful antiretroviral therapy
. Curr HIV Res
11. Engsig FN, Gerstoft J, Kronborg G, Larsen CS, Pedersen G, Roge B, et al. Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: a cohort study
. BMC Infect Dis
12. D’Arminio MA, Cozzi-Lepri A, Castagna A, Antinori A, De LA, Mussini C, et al. Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and hepatitis C virus with or without liver cirrhosis
. Clin Infect Dis
13. Center for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults.MMWR Recomm Rep
14. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate
. Ann Intern Med
15. Lopez A, Caragol I, Candeias J, Villamor N, Echaniz P, Ortuno F, et al. Enumeration of CD4(+) T-cells in the peripheral blood of HIV-infected patients: an interlaboratory study of the FACSCount system
16. Raboud JM, Haley L, Montaner JS, Murphy C, Januszewska M, Schechter MT. Quantification of the variation due to laboratory and physiologic sources in CD4 lymphocyte counts of clinically stable HIV-infected individuals
. J Acquir Immune Defic Syndr Hum Retrovirol
1995; 10 (Suppl 2):S67–S73.
17. Whitby L, Granger V, Storie I, Goodfellow K, Sawle A, Reilly JT, et al. Quality control of CD4+ T-lymphocyte enumeration: results from the last 9 years of the United Kingdom National External Quality Assessment Scheme for Immune Monitoring (1993–2001)
18. Lau B, Gange SJ, Moore RD. Risk of non-AIDS-related mortality may exceed risk of AIDS-related mortality among individuals enrolling into care with CD4+ counts greater than 200 cells/mm3
. J Acquir Immune Defic Syndr
19. Mocroft A, Reiss P, Gasiorowski J, Ledergerber B, Kowalska J, Chiesi A, et al. Serious fatal and nonfatal non-AIDS-defining illnesses in Europe
. J Acquir Immune Defic Syndr
20. Neuhaus J, Angus B, Kowalska JD, La RA, Sampson J, Wentworth D, et al. Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV
21. Prosperi MC, Cozzi-Lepri A, Castagna A, Mussini C, Murri R, Giacometti A, et al. Incidence of malignancies in HIV-infected patients and prognostic role of current CD4 cell count: evidence from a large Italian cohort study
. Clin Infect Dis
22. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy
. J Infect Dis
23. Marchetti G, Gori A, Casabianca A, Magnani M, Franzetti F, Clerici M, et al. Comparative analysis of T-cell turnover and homeostatic parameters in HIV-infected patients with discordant immune-virological responses to HAART
24. Massanella M, Negredo E, Perez-Alvarez N, Puig J, Ruiz-Hernandez R, Bofill M, et al. CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART
25. Hunt PW, Cao HL, Muzoora C, Ssewanyana I, Bennett J, Emenyonu N, et al. Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy
26. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis
27. Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, et al. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women
. J Infect Dis
28. Dalgleish AG, O’Byrne KJ. Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer
. Adv Cancer Res
29. Marchetti G, Bellistri GM, Borghi E, Tincati C, Ferramosca S, La FM, et al. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy
30. Merlini E, Bai F, Bellistri GM, Tincati C, D’Arminio MA, Marchetti G. Evidence for polymicrobic flora translocating in peripheral blood of HIV-infected patients with poor immune response to antiretroviral therapy
. PLoS One
31. Marchetti G, Cozzi-Lepri A, Merlini E, Bellistri GM, Castagna A, Galli M, et al. Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count
32. Deeks SG. HIV infection, inflammation, immunosenescence, and aging
. Annu Rev Med
33. Appay V, Almeida JR, Sauce D, Autran B, Papagno L. Accelerated immune senescence and HIV-1 infection
. Exp Gerontol
34. Tincati C, Bellistri GM, Casana M, Merlini E, Comi L, Bai F, et al. CD8+ hyperactivation and senescence correlate with early carotid intima-media thickness in HIV+ patients with no cardiovascular disease
. J Acquir Immune Defic Syndr
35. Baker JV, Peng G, Rapkin J, Krason D, Reilly C, Cavert WP, et al. Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non-AIDS diseases
. J Acquir Immune Defic Syndr
36. Benveniste O, Flahault A, Rollot F, Elbim C, Estaquier J, Pedron B, et al. Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1-infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads
. J Infect Dis
37. Marziali M, De SW, Carello R, Leti W, Esposito A, Isgro A, et al. T-cell homeostasis alteration in HIV-1 infected subjects with low CD4 T-cell count despite undetectable virus load during HAART
38. Pitrak DL, Bolanos J, Hershow R, Novak RM. Discordant CD4 T lymphocyte responses to antiretroviral therapy for HIV infection are associated with ex-vivo rates of apoptosis
39. Marchetti G, Gazzola L, Trabattoni D, Bai F, Ancona G, Ferraris L, et al. Skewed T-cell maturation and function in HIV-infected patients failing CD4+ recovery upon long-term virologically suppressive HAART
40. Mavigner M, Delobel P, Cazabat M, Dubois M, L’faqihi-Olive FE, Raymond S, et al. HIV-1 residual viremia correlates with persistent T-cell activation in poor immunological responders to combination antiretroviral therapy
. PLoS One
41. Lewden C, Chene G, Morlat P, Raffi F, Dupon M, Dellamonica P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population
. J Acquir Immune Defic Syndr
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cardiovascular; HIV; immunological non responder; malignancies; non-AIDS defining event
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