JAIDS Journal of Acquired Immune Deficiency Syndromes:
Uncontrolled Viral Replication as a Risk Factor for Non-AIDS Severe Clinical Events in HIV-Infected Patients on Long-Term Antiretroviral Therapy: APROCO/COPILOTE (ANRS CO8) Cohort Study
Ferry, Tristan MD, PhD*; Raffi, François MD, PhD†; Collin-Filleul, Fidéline MD, PhD‡; Dupon, Michel§; Dellamonica, Pierre MD, PhD‖; Waldner, Anne MD¶; Strady, Christophe MD, PhD#; Chêne, Geneviève MD, PhD‡; Leport, Catherine MD, PhD**; Moing, Vincent Le MD, PhD††; and the ANRS CO8 (APROCO-COPILOTE) Study Group
From the *Service de Maladies Infectieuses et Tropicales, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Université Claude Bernard Lyon 1, Lyon, France; †Service de Maladies Infectieuses, Hôpital de l'Hotel-Dieu, CHU de Nantes, Nantes, France; ‡INSERM U897, Université Victor Segalen 2, Bordeaux, France; §Service de Maladies Infectieuses (B), Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France; ∥Service de Maladies Infectieuses, L'Archet 1, CHU de Nice, Université de Nice Sophia Antipolis, Nice, France; ¶Service de Maladies Infectieuses, CHU de Dijon, Dijon, France; #Service de Maladies Infectieuses, CHU de Reims, Reims, France; **Denis Diderot-Paris 7 University, Site Xavier Bichat-Laboratoire de Recherche en Pathologie Infectieuse, Paris, France; and ††Service des Maladies Infectieuses et Tropicales, Hôpital Gui de Chauliac, CHU de Montpellier, UMR 145, Université Montpellier 1, Montpellier, France.
Received for publication August 28, 2008; accepted December 17, 2008.
Meetings at which parts of the data were presented: This work was partially presented as a poster (H-1722) at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2007, Chicago, IL.
All authors have no conflict of interest to declare.
Correspondence to: Dr. Vincent Le Moing, MD, PhD, Service des Maladies Infectieuses et Tropicales, Hôpital Gui de Chauliac, CHU de Montpellier, 2 av Emile Bertin Sans, 34000 Montpellier, France (email: email@example.com).
Objective: To determine risk factor for non-AIDS severe clinical events in HIV-infected patients on long-term combination antiretroviral therapy (cART).
Methods: A validation committee reviewed each severe clinical event that occurred in the APROCO/COPILOTE (ANRS CO8) cohort that enrolled 1281 patients in 1997-1999 at the initiation of cART containing protease inhibitor. Probability of the occurrence of a first non-AIDS, cART-related, and AIDS-defining event was estimated, and potential determinants were studied using Cox regression models.
Results: During a median follow-up of 7.3 years, the incidence of non-AIDS events was higher than that of cART-related and AIDS-defining events (10.5, 3.6, and 2.6 per 100 patient-years, respectively). Bacterial (mainly airway) infections were the most frequent non-AIDS events (23.4%) followed by non-AIDS-defining malignancies and cardiovascular events (both 9.5%). Factors independently associated with the occurrence of a first non-AIDS event were age >60 years [hazard ratio (HR) 2.1; 95% confidence interval (CI): 1.3 to 3.2] and CD4 <100 cells per milliliter (HR 2.5; 95% CI: 1.8 to 3.6) but also plasma HIV RNA >4 log10 copies per milliliter at the time of the event (HR 1.9; 95% CI: 1.5 to 2.5).
Conclusion: Optimization and permanent continuation of long-term antiretroviral therapy in HIV-infected patients is the best strategy to prevent or reduce the occurrence of non-AIDS severe morbidity.
The use of combination antiretroviral therapy (cART) in industrialized countries has dramatically decreased mortality in HIV-infected patients since 1996, mainly due to the reduction of occurrence of AIDS-defining illnesses.1,2 Cohort studies revealed that in the early (1996-1999) and the late (2000-2007) cART eras, the proportion of deaths attributable to non-AIDS diseases such as non-AIDS-defining malignances, cardiovascular diseases, or liver failure has increased.3 In France, the analysis of the underlying causes of death distribution in 964 HIV-infected patients (78% of patients were under cART) in 2000 revealed that the proportion of AIDS and non-AIDS causes of death became similar.4
As HIV-infected persons live longer, they are increasingly more likely to develop non-HIV-related diseases and changes in morbidity have also been observed in the cART era.5,6 The spectrum of non-AIDS morbidity is currently poorly described, as in most cohorts, only AIDS events and particular illnesses such as adverse drug reactions, cardiovascular diseases, or cancer are systematically recorded. As a consequence, data on the incidence and determinants of non-AIDS events in patients on long-term cART are sparse. Factors responsible for non-AIDS morbidity in the HIV population may first be similar to factors responsible for morbidity in the general population. Second, it has been hypothesized that parameters related to the HIV disease may also have a role in the occurrence of non-AIDS morbidity, as recent studies based on a CD4+ count-guided interruption of antiretroviral treatment revealed that uncontrolled HIV viral load (that occurred in the intermittent antiretroviral therapy group) was associated with an increased incidence of severe bacterial infections and cardiovascular, renal, or hepatic complications.7,8
The aim of this study was (1) to describe the spectrum of non-AIDS severe clinical events in a large, multicenter, prospective cohort of HIV-infected patients receiving long-term cART, (2) to compare their incidence with that of AIDS-defining events and cART adverse reactions, and (3) to determine which factors (including factors associated with the HIV infection such as uncontrolled HIV viral replication) are independently associated with the occurrence of these events.
PATIENTS AND METHODS
The APROCO/COPILOTE (ANRS CO8) cohort study is a prospective observational cohort study ongoing in 47 clinical centers in France, which aims to describe the virological, immunological, and clinical effects of cART in the context of routine care. A total of 1281 HIV-1-infected patients naive of protease inhibitor (PI) were enrolled from May 1997 to June 1999 at the initiation of a PI-containing regimen. Standardized clinical and biological data were collected at baseline, after 1 and 4 months (M1 and M4, respectively) of PI therapy, and then every 4 months. During the follow-up, all clinical and laboratory events considered as severe were also prospectively recorded. An event was considered to be severe when it required hospitalization or an extension of hospitalization, when it led to a life-threatening condition (grade 3 or the grade 4 of the standardized classification of the Agence Nationale de Recherche sur le Sida, available at: http://www.isped.u-bordeaux2.fr/RECHERCHE/GETSI/GRILLES_GRAVITE/FR-GETSI-ANRS-EP11-GRILLE-ANRS.htm), or when it led to death. For all severe events, the following data were collected: clinical data, diagnosis, outcome, and modification of treatment. An event was defined as an AIDS-defining event according to the 1993 Centers for Disease Control and Prevention classification (ocular toxoplasmosis, visceral leishmaniasis, microsporidiosis, and Castleman disease were also considered as AIDS-defining diseases). The following events were defined as solely cART related: lipodystrophy, symptomatic liver enzyme elevation, or dyslipidemia considered as related to cART by the Events Validation Committee; rash or hypersensitivity reaction in patients treated with abacavir or nevirapine; pancreatitis or lactic acidosis in patients treated with a nucleoside reverse transcriptase inhibitor; anemia in patients treated with zidovudine; and indinavir-related nephrolithiasis. All other severe events were classified as severe non-AIDS events. Asymptomatic biological events (such as asymptomatic elevated liver or pancreatic enzyme levels and asymptomatic hematological or endocrinometabolic disorders) and pregnancy-related events were excluded from the analysis.
As we considered that the full initial response to cART occurred after a median time of 4 months, patients who died or who were lost to follow-up at M4 were excluded from this study. Probability of the occurrence of a first non-AIDS, a first cART-related, and a first AIDS-defining event was estimated using the Kaplan-Meier product-limit method. Time to an event was calculated in days from the date of cART initiation.
For the description of non-AIDS events and the analysis of potential determinants of the occurrence of the first event during long-term cART, we selected only non-AIDS events that occurred after the initial response to cART (after M4). Potential determinants of the occurrence of the first non-AIDS event, the first bacterial infection, and the first non-AIDS-related cancer were studied using Cox proportional hazards regression models. Plasma HIV RNA and CD4+ cell count recorded during follow-up were treated as time-dependent variables. To look for a potential bias due to interruption of cART immediately before the occurrence of the event, sensitivity analyses were done using a 15-day lag for time-dependent HIV RNA. The cutoff values for transformation of continuous variables into categorical variables and the log transformation of variables retained for regression models were those associated with maximal likelihood in the univariate analyses using the Akaike information criterion. Variables with a P value <0.25 were included in the initial multivariate models. A backward procedure retaining only significant variables (P ≤ 0.05) was then used to yield final multivariate models. All statistical analyses were performed using SAS software, version 9.0 (SAS Institute, Inc, Cary, NC).
Among the 1281 patients enrolled in the APROCO cohort study, 50 patients, who did not have at least 4 months of follow-up, were excluded. Among the 1231 patients included in this study, 949 were men (77.1%) with a median age of 36 years [interquartile range (IQR), 31.9-42.5]. Four hundred eighty (39%) belonged to the “men who have sex with men” transmission risk group, and 195 (15.9%) had presumably been infected through injecting drug use. Five hundred fifty-five patients (44.7%) were antiretroviral naive before initiating their PI-containing regimen. Two hundred eighty-two of them (22.9%) had anti-hepatitis C virus (HCV) antibodies and 59 (4.8%) had a hepatitis B surface antigenemia. At baseline, the median CD4+ cell count was 279 cells per milliliter (IQR, 128-425 cells/mL) and the median plasma HIV RNA level was 4.5 log10 copies per milliliter (IQR, 3.7-5.2 log10 copies/mL). Four hundred twelve patients (33.5%) defined themselves as nonsmokers in a self-administered questionnaire at baseline. Median and total follow-up were 7.3 years (IQR, 4.3-8.5 years) and 7664 patient-years, respectively.
At the time of analysis, 44% of patients were still receiving a PI-containing regimen, whereas 45% of patients had switched to cART without a PI and 6% of patients were on treatment interruption (Fig. 1).
We recorded 801 severe non-AIDS clinical events in 428 patients (incidence of 10.5 per 100 patient-years), 275 severe cART-related clinical events in 232 patients (incidence of 3.6 per 100 patient-years), and 198 AIDS-defining events in 126 patients (incidence of 2.6 per 100 patient-years). The estimated probabilities of developing after 7 years of follow-up a non-AIDS event, a cART-related event, and an AIDS-defining event were, respectively, 35.7%, 17%, and 8.5% (Fig. 2).
Focusing on non-AIDS events that occurred after the full initial response to cART, 713 of the 801 severe non-AIDS events were retrieved. These severe clinical events were very diverse. The most frequent one being bacterial infections (23.4%) followed by non-AIDS-defining malignancies (9.5%) and cardiovascular (9.5%), psychiatric (8.6%), and neurological (5.9%) events (Table 1). Severe clinical events due to complication of cirrhosis were not frequent, totalizing 13 events (1.8%). The univariate and multivariate analyses are detailed in Table 2. The following variables were independently associated with a higher risk of a first non-AIDS event: age >60 years [hazard ratio (HR), 2.1; 95% confidence interval (CI): 1.3 to 3.2], HCV coinfection (HR, 1.7; 95% CI: 1.4 to 2.1), CD4+ cell count <100 cells per milliliter (HR, 2.5; 95% CI: 1.8 to 3.6), and plasma HIV viral load >4 log10 copies per milliliter (HR, 1.9; 95% CI: 1.5 to 2.5) at the time of the event (Table 2). Analyses using a 15-day lag for time-dependent HIV RNA showed very similar results for the association between plasma HIV RNA and occurrence of a non-AIDS event (data not shown). Except for age, factors associated with bacterial infections were identical to those associated with all other types of non-AIDS events with a stronger association between virological failure and occurrence of an event (Table 3). The only factor significantly associated with the occurrence of a non-AIDS-defining cancer was age >60 years, and there was a trend to a lower incidence of cancer in patients with most recent CD4 >500 cells per milliliter (Table 4).
In this large cohort of unselected HIV-infected patients who were PI naive at the initiation of cART and followed for more than 7 years, a high frequency of non-AIDS events was observed. Non-AIDS events appeared as the most frequent clinical events, respectively, 3-fold and 4-fold more frequent than cART-related and AIDS-defining events. Among these non-AIDS events, it was noteworthy that occurrence of a first non-AIDS-defining bacterial infection was strongly associated with an uncontrolled viral load.
The use of cART has completely changed the natural history of HIV infection and the spectrum of morbidity and mortality in the HIV-infected population.2 From an acute-subacute disease almost invariably progressing to AIDS and death with occurrence of highly lethal opportunistic infections, HIV infection became a controllable chronic infection with a life expectancy approximating that of the general population when the CD4 cell count is maintained at >500 cells per milliliter.9 Thus, HIV-infected patients live older on cART, and these patients are now exposed to development of non-AIDS-defining illnesses that may be the consequence of multiple factors, related or not related (age and comorbidities) to HIV infection.5,10
In our study, age >60 years was an independent risk factor for developing non-AIDS events and particularly non-AIDS cancers. Aging is associated with immune dysfunction also called immunosenescence (decline of both innate and adaptive immune responses with age) that may, besides other risk factors, explain the increasing risk of infection and cancer with age.11 The recent Strategies for Management of Antiretroviral Therapy (SMART) study well established the increase of age as a risk factor for non-AIDS cancers in the HIV-infected population.12
The level of CD4 cell count is known as a strong prognostic factor for the occurrence of opportunistic AIDS-defining diseases in the HIV population.13 In our study, a CD4 cell count <100 cells per milliliter was also an independent factor for the occurrence of a first non-AIDS event, particularly bacterial infections that were the most frequent non-AIDS events. In the pre-cART era, bacterial pneumonia was already known as a frequent HIV-associated respiratory infection in individuals with HIV and recurrent pneumonia, often associated with a low CD4 cell count, is classified as an AIDS-defining event. In the same way, there was a trend toward an association between the level of CD4 cell count <500 cells per milliliter and the occurrence of a first event in relation with a non-AIDS cancer that was the second cause of non-AIDS events in our study. Non-AIDS-defining malignancies became a major cause of death among HIV-infected patients in industrialized nations in the cART era, and some non-AIDS-defining malignancies have been found with a higher frequency among HIV-infected patients as compared with the general population.14,15 The relationship between the level of CD4 cell count and the incidence of non-AIDS cancers is unclear and debated and may be different when considering particular types of cancer.14-16 Many data now support the role of immune suppression in the development of non-AIDS-defining malignancies.12,17 Moreover, in a recent study, the duration of exposure to a low CD4 cell count was associated with a higher risk of both AIDS-defining and non-AIDS-defining cancers.18 Finally, Lewden et al4 recently showed that the mortality of patients with a patent CD4 restoration (CD4+ cell count ≥500 cells/mL) reached the level of the general population 6 years and more after the initiation of cART. In this study, in patients who spent time with a CD4+ cell count between 350 and 499 cells per milliliter, mortality remained higher than in the general population, indicating that intermediate level of CD4 may provide immunological conditions for developing fatal clinical events. Our study and the data from a recent study performed in the Aquitaine cohort suggest that the survival advantage conferred by complete restoration of CD4+ cell count >500 per cubic millimeter may be related to protection against the development of non-AIDS-defining cancers.18
Immunosuppression not directly related to the level of the CD4 cell count may also be observed in HIV-infected patients. Unlike classical opportunistic infections, the risk of bacterial infections (especially bacterial pneumonia) depends to a lesser degree on the level of CD4+ cell count as bacterial infections can occur within all CD4+ cell strata.19 Emerging data from both humans and monkeys suggest that the recovery of CD4+ T cells in peripheral blood during the treatment of HIV infection could be associated with a persistent immunosuppressive status.19 First, during chronic HIV infection, cART induces the increase of peripheral CD4+ cells but may not completely restore the CD4+ T-cell repertoire and may fail to limit the destruction of the CD4+ memory compartment at the mucosal surface. This may lead to a substantial reduction in the CD4 function and immunologic resources, particularly at tissue-environment interfaces (such as the airway and digestive tract), that may facilitate the occurrence of bacterial infections (such as pneumonia) or non-AIDS cancers (such as lung and digestive cancers).19
Our observation that uncontrolled HIV replication per se may be an independent factor associated with the occurrence of non-AIDS events and particularly bacterial infections has not been previously reported. Indeed, indirect arguments were provided by studies based on a CD4+ count-guided interruption of antiretroviral treatment, as patients interrupting cART were at a higher risk for developing non-AIDS events than patients with continuous cART therapy whatever their CD4+ cell count.7,8,12 Uncontrolled HIV replication per se may induce a state of immunosuppression independent of the CD4 cell count but this has not been clearly demonstrated. In the SMART study, it was noteworthy that authors also recorded a higher risk for developing other complications, such as cardiovascular diseases, raising questions about the contribution of uncontrolled HIV replication to short-term vascular risk.8 The potential underlying mechanism of such an association remains to be determined, but the inflammatory response of the host against the viral replication leading to the endothelial dysfunction and hypercoagulable status is a hypothesis.20
Occurrence of non-AIDS cancers in the HIV population may be due to a particular exposition to carcinogens. Smoking is a well-known carcinogen (and also contribute to occurrence of bacterial pneumonia and ischemic cardiovascular events), and HIV-infected patients typically use tobacco more heavily than the general population.21 SMART study well established the increase of smoking as risk factors for non-AIDS cancers in the HIV-infected population.12 In our study, it is noteworthy that we recorded a high number of digestive tumors, such as colorectal adenocarcinoma, that are less smoking related than other cancers such as lung and head and neck cancers. This particularity and also the lack of power due to the low number of non-AIDS cancer-related events may explain the absence of association between smoking and cancers in our study. Our population may be also exposed to other carcinogens. First, HIV itself may have an oncogenic role, as the tat gene product can modulate the expression of certain proto-oncogenes in tumor cell lines in vitro.22 Finally, it is not excluded that cART may have a carcinogenic effect during a long-term exposition.23
Neuropsychiatric disorders (that may preexist before the HIV infection) represent almost 15% of all non-AIDS events in our study, and depression was the most common one. As it has been demonstrated that depression was independently associated with nonadherence, association between neuropsychiatric disorder and uncontrolled viral load may be partly due to nonadherence.24 However, it is not excluded that uncontrolled HIV replication may be partly responsible for neuropsychiatric disorders as HIV could be responsible for dementia and encephalopathy. Moreover, HCV-related cognitive impairment has been described (and supported by molecular virological studies of postmortem brain tissue), and HIV and HCV coinfection may have a synergic effect on the central nervous system function.25 The occurrence of neuropsychiatric disorders could also be related with characteristics of the population as they are particularly frequent in injection drug users.
Finally, we observed few complication of cirrhosis in this cohort, whereas 22.9% and 4.8% of our patients were coinfected with HCV and hepatitis B virus, respectively. This may be explained by the positive impact of cART on the natural course of both chronic hepatitis B and C. The relation we observed between HCV coinfection and morbidity may be more in relation with risky behaviors or socioeconomic conditions of this population.26
Our study has some limitations. First, our results were obtained from an observational study, with all its potential selection biases, and need to be confirmed by further and independent investigations. Second, non-AIDS events are very heterogeneous as they belong to very different classes of diseases such as bacterial infections, malignancies, or psychiatric illnesses, which may have various etiologies depending on the HIV-positive population, its way of living (including alcohol consumption that may be a confounding factor), and/or directly or indirectly on the HIV infection itself. Moreover, we did not use a control HIV-negative group with similar age, sex, and hepatitis C coinfection, which could allow to verify if the incidence of these events was more frequent than what could be expected. Finally, some of non-AIDS events such as cardiovascular events or liver diseases may be due, at least in part, to antiretroviral drugs as a causal relationship with therapy is suspected but has not been firmly established. On the other hand, the prolonged follow-up and the exhaustive and prospective recording, along with the scoring and categorization of all severe clinical events (ie, not only AIDS-defining and solely drug-related events), by an Events Validation Committee of clinician experts who assessed collegially each event are great strengths of our study. We were thus able to describe a representative spectrum of severe clinical events that occur in cART-treated HIV-infected patients within the context of a standard clinical practice in a developed European country.
In conclusion, non-AIDS events have become the most frequent severe clinical events in HIV-infected patients on long-term antiretroviral therapy. In our study, an age >60 years, a low CD4 cell count, and a moderate level of HIV replication were independently associated with the occurrence of non-AIDS events during the prolonged follow-up. Our results give further arguments against interruption of cART and underline the need to avoid virological rebound (also during salvage therapy), particularly in older patients and/or those with a low CD4 cell count. Optimization and permanent continuation of long-term antiretroviral therapy in HIV-infected patients is the best strategy to prevent or reduce the occurrence of non-AIDS severe morbidity.
APROCO-COPILOTE ANRS CO8 study group-Scientific Committee: Steering Committee: Principal Investigators: C. Leport and F. Raffi. Methodology: G. Chêne and R. Salamon. Social Sciences: J.-P. Moatti, J. Pierret, and B. Spire. Virology: F. Brun-Vézinet, H. Fleury, and B. Masquelier. Pharmacology: G. Peytavin and R. Garraffo. Other members: D. Costagliola, P. Dellamonica, C. Katlama, L. Meyer, D. Salmon, and A. Sobel. Events Validation Committee: L. Cuzin, M. Dupon, X. Duval, V. Le Moing, B. Marchou, T. May, P. Morlat, C. Rabaud, and A. Waldner-Combernoux. Project Coordination: F. Collin-Filleul. ANRS Representatives: Nadine Job-Spira and Marcia Trumeau. Observers: C. Perronne. Clinical Research Group: V. Le Moing and C. Lewden. Data Monitoring and Statistical Analysis: J. Biemar, S. Boucherit, A. D. Bouhnik, C. Brunet-François, M. P. Carrieri, F. Couturier, J. L. Ecobichon, V. Guiyedi, P. Kurkdji, S. Martiren, M. Préau, C. Protopopescu, C. Roy, J. Surzyn, A. Taieb, V. Villes, and C. Wallet. Promotion: Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS, Action Coordonnée n°7). Other Financial Supports: Collège des Universitaires de Maladies Infectieuses et Tropicales (CMIT ex APPIT) and Sidaction Ensemble contre le Sida, et laboratoires: Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, and Roche. Clinical Centers (coordinators): Amiens (Pr J. L. Schmit), Angers (Dr J. M. Chennebault), Belfort (Dr J. P. Faller), Besançon (Pr J. L. Dupond, Dr J. M. Estavoyer, and Dr Drobachef), Bobigny (Pr O. Bouchaud), Bordeaux (Pr M. Dupon, Pr Longy-Boursier, Pr P. Morlat, and Pr J. M. Ragnaud), Bourg-en-Bresse (Dr P. Granier), Brest (Pr M. Garré), Caen (Pr R. Verdon), Compiègne (Dr D. Merrien), Corbeil-Essonnes (Dr A. Devidas), Créteil (Pr A. Sobel), Dijon (Pr H. Portier), Garches (Pr C. Perronne), Lagny (Dr P. Lagarde), Libourne (Dr J. Ceccaldi), Lyon (Pr D. Peyramond), Meaux (Dr C. Allard), Montpellier (Pr J. Reynes), Nancy (Pr T. May), Nantes (Pr F. Raffi), Nice (Pr J. G. Fuzibet and Pr P. Dellamonica), Orléans (Dr P. Arsac), Paris (Pr E. Bouvet, Pr F. Bricaire, Pr P. Bergmann, Pr J. Cabane, Dr J. Monsonego, Pr P. M. Girard, Pr L. Guillevin, Pr S. Herson, Pr C. Leport, Pr M. C. Meyohas, Pr J. M. Molina, Pr G. Pialoux, and Pr D. Salmon), Poitiers (Pr B. Becq-Giraudon), Reims (Pr R. Jaussaud), Rennes (Pr C. Michelet), Saint-Etienne (Pr F. Lucht), Saint-Mandé (Pr T. Debord), Strasbourg (Pr J. M. Lang), Toulon (Dr J. P. De Jaureguiberry), Toulouse (Pr B. Marchou), and Tours (Pr J. M. Besnier).
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