"…… This comparative analysis investigating a wide range of factors revealed that current alcohol use and a history of steroid use were strongly associated with the occurrence of AN….history of steroid use was independently associated with a high risk of AN…...even short courses of steroid treatment increased this risk substantially….the first line of prevention of this bone disorder in HIV-infected patients should be the cessation of alcohol consumption and the limitation of steroid prescription….Although it has been speculated that receipt of HAART is associated with the occurrence of AN, no association between this bone disorder and the receipt or duration of antiretroviral therapy has been observed in the present comparative study…….Hypertriglycemia or hypercholesterolemia were not found to be predisposing factors, as is described in the literature. In the present study, more case patients presented with high total cholesterol levels than did control subjects, and the number of case patients with hypertriglyceridemia was 5-fold greater than the number of control subjects with hypertriglyceridemia……." see author ‘Discussion Below’
Clinical Infectious Diseases April 2005;40:1188-1193
Reprints or correspondence: Dr. F. Dabis, ISPED, INSERM U593—Case 11, Université Victor Segalen Bordeaux 2, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France (francois.dabis@isped.u-bordeaux2.fr).
Sylvie Lawson-Ayayi,1,2 Fabrice Bonnet,1,2 Elise Bernardin,1 Jean-Marie Ragnaud,2 Denis Lacoste,2 Denis Malvy,2 Marie-Josée Blaizeau,2 Ghada Miremont-Salamé,3 Michel Dupon,2 Patrick Mercié,1,2 and François Dabis,1,2 for the Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA)a
1Institut National de la Santé et de la Recherche Médicale Unité 593, Institut de Santé Publique, d'Epidémiologie et de Développement, and 2Centre d'Information et de Soins de l'Immunodéficience Humaine, and 3Centre Régional de Pharmacovigilance, Département de Pharmacologie, Equipe d'Accueil 3676, Centre Hospitalo-Universitaire de Bordeaux, Bordeaux, France
Using a case-control study design, we studied the factors associated with HIV-related avascular necrosis (AN). During a 6-year period, 12 symptomatic AN cases were validated, and each case was individually matched with 3 control cases. A conditional logistic regression model showed that current alcohol consumption and a history of steroid use were the only factors associated with the occurrence of AN.
Since HAART was introduced and its use has become widespread in industrialized countries, rates of mortality and severe morbidity related to HIV infection have been drastically reduced. Although survival rates and quality of life have improved among HIV-infected individuals, adverse consequences of long-term exposure to antiretroviral regimens have emerged [1—4]. Particularly, metabolic complications have been diagnosed in HIV-infected patients who are treated with HAART, and they have been associated with the receipt of protease inhibitors (PIs) and nonnucleoside reverse-transcriptase inhibitors (NNRTIs) [5—8]. More recently, cases of avascular necrosis (AN), also referred to as osteonecrosis, have been reported [9—20], but few studies have reported an increased incidence of this severe bone disorder [3, 4]. The incidence of asymptomatic AN among HIV-infected patients was estimated to be 4.4%, through systematic screening with MRI [21]. The annual incidence of AN, whether symptomatic or not, in the general population has been estimated to be between 0.010% and 0.135% [15, 22—24]. Thus, the incidence of AN among HIV-infected adults has been found to be times greater than the incidence in the general population [15], which suggests that its occurrence is a consequence of or a complication of either HIV infection or receipt of HAART [25].
Several risk factors and conditions, such as hyperlipidemia, alcohol abuse, steroid use, pancreatitis, and underlying vascular diseases, have been postulated to be associated with AN [14, 26]. Case reports also have suggested that HIV infection and antiretroviral therapy, particularly HAART regimens, could also be risk factors for AN, independent of underlying comorbidities [17]; however, to our knowledge, no systematic study has been conducted thus far. We studied the main known and hypothesized risk factors for symptomatic cases of AN that were identified in a large cohort of HIV-infected patients.
Results. Through December 2002, a total of 12 symptomatic AN cases were identified and validated. Eleven of the 12 cases were in men. The median age of the case patients was 38.3 years (interquartile range [IQR], 36.2—45.2), and 9 case patients had received a diagnosis of AIDS. The median time since diagnosis of HIV infection was 10.4 years (IQR, 8.6—12.9). All case patients had been exposed to HAART (consisting of at least 3 antiretroviral drugs, including a PI or an NNRTI) before the occurrence of AN. Criteria used for matching had comparable values in the case and control groups at baseline: median ages were 38.3 years and 38.4 years, respectively (P = .83); median CD4+ cell counts at the time of diagnosis of HIV infection were 266.5 cells/mL and 272.0 cells/mL, respectively (P = .66); and median durations of HIV infection since the time of diagnosis were 123.0 months and 125.1 months, respectively (P = .94).
In univariate analyses, case patients were more likely than control subjects to be men who reported sex with men, to have fat accumulation, and to engage in regular or heavy alcohol use, according to physicians' reports. Neither receipt of a specific antiretroviral drug nor the duration of HAART was associated with AN. However, history of intravenous or oral course of steroid treatment was associated with AN occurrence at a borderline level of statistical significance.
In the multivariate analyses, the only adjusted matched OR (aOR) >1 was for alcohol consumption (P = .02). Statistical association appeared to be of borderline significance in the reduced model with regard to fat accumulation (P = .07) and receipt of efavirenz, ritonavir, or nelfinavir (P = .08, P = .05, and P = .09, respectively).
When all factors identified by the 2 initial multivariate analyses were combined in the final model, the risk of the occurrence of AN remained significantly associated with alcohol consumption (aOR, 20.48; 95% CI, 1.83—229.72; P = .01) and history of steroid use (aOR, 16.96; 95% CI, 1.20—239.12; P = .04), whereas fat accumulation failed to be associated with the occurrence of AN (aOR, 22.67; 95% CI, 0.69—745.95; P = .08).
Author Discussion
This comparative analysis investigating a wide range of factors revealed that current alcohol use and a history of steroid use were strongly associated with the occurrence of AN. The findings of the present study also provided a presumption of an association of AN with fat accumulation. The association of the occurrence of AN with receipt of HAART or the individual components of HAART was not confirmed. Despite the fact that a trend for association with AN was detected for receipt of individual drugs, receipt of PIs or NNRTIs , when considered as cumulative exposure before the diagnosis of AN, could not be identified as having an association with the occurrence of AN. Nevertheless, the role of antiretroviral therapy, if any, is probably limited, compared with the roles of steroid use and alcohol use.
Hypertriglycemia or hypercholesterolemia were not found to be predisposing factors, as is described in the literature [23, 28]. In the present study, more case patients presented with high total cholesterol levels than did control subjects, and the number of case patients with hypertriglyceridemia was 5-fold greater than the number of control subjects with hypertriglyceridemia (data not shown). The potential link between hyperlipidemia and AN supports the hypothesis that the use of PIs is implicated, through an increase of serum lipid levels, in the occurrence of AN [29]. Scribner et al. [22] have suggested that moderate hypertriglyceridemia is an independent risk factor for the occurrence of AN but that severe hypertriglyceridemia is more likely to be associated with AN by means of PI therapy.
Previous studies have concluded that HIV infection alone may be a risk factor for AN [28, 30]. Although it has been speculated that receipt of HAART is associated with the occurrence of AN [10], no association between this bone disorder and the receipt or duration of antiretroviral therapy has been observed in the present comparative study. This is possibly because antiretroviral therapy is widely used in hospital-based cohorts with unlimited access to care, as is the case in France. The lack of an association between the receipt of PIs and the occurrence of AN has been observed in other studies, as well [16, 21, 24, 31].
Steroid use and alcohol abuse are the most common risk factors associated with AN [26]. Indeed, in the present study, a history of steroid use was independently associated with a high risk of AN, and the association did persist when the analysis was adjusted for other variables. This result confirmed findings of previous case-control studies that reported an association between steroid use and the occurrence of AN but could not control for as many factors as we did in the present analysis [22, 31]. Miller et al. [21] indicated that even short courses of steroid treatment increased this risk substantially. In the present study, "alcohol use" was defined as the consumption of any combination of different types of alcohol (wine, beer, and cocktails). Because French consumers usually record a more regular intake of alcoholic beverages than do consumers elsewhere in the world, we considered regular or heavy drinkers to be the "high-exposure" category. The estimation of this risk factor by physicians from patients' self-reported behavior could have introduced a bias that is a common limitation of studies on alcohol intake. We could not investigate hereditary vascular diseases–in particular, the presence of antiphospholipid antibodies, which may contribute to the occurrence of AN, given its high prevalence among HIV-infected patients [32].
To our knowledge, the present analysis is the first to investigate the contribution of antiretroviral therapy to the occurrence of AN in detail and by use of a powerful comparative design, and the first to finally rule out its role. HIV-infected patients with asymptomatic cases of AN were not included in the present study, because of the system we used to find cases. Thus, we evaluated only symptomatic cases of AN, and our findings should not be extrapolated to all cases of AN. Because the limited number of cases may have affected the outcome of the present study, large, collaborative epidemiological studies are still needed to confirm our results and to fully evaluate the role of antiretroviral therapy in AN, symptomatic or not. Finally, the mechanisms that lead to AN in HIV-infected patients must also be determined. In the interim, the first line of prevention of this bone disorder in HIV-infected patients should be the cessation of alcohol consumption and the limitation of steroid prescription.
Patients and methods. We performed a case-control study nested within the Aquitaine Cohort [27]. The Aquitaine Cohort comprises patients enrolled through a hospital-based surveillance system of HIV infection in southwestern France. Beginning in 1987, adult inpatients and outpatients were enrolled prospectively in the present case-control study if they were referred by participating hospital wards, had confirmed HIV-1 infection and at least 1 follow-up visit after enrollment or a documented date of death after initial reporting, and provided informed consent. Follow-up is based on clinical practice; a standardized reporting form for epidemiological, clinical, biological, and therapeutic data is completed by physicians at the time of each hospital contact, which generally occur every 3 or 6 months or in the case of any intercurrent event.
All symptomatic cases of AN that were reported through December 2002 through either the cohort monitoring system or the pharmaco-epidemiology information system maintained by the Bordeaux University Hospital were systematically investigated. These 2 reporting systems allowed us to identify AN cases that had been diagnosed by physicians since the first AN case notification in 1997. Symptomatic AN cases were detected on the basis of clinical symptoms and confirmed by radiological or scintigraphical imaging. For each patient with a confirmed case, we randomly selected 3 control subjects from the Aquitaine Cohort database who showed no clinical evidence of AN and who could be matched on the basis of age (±3 years), time since the diagnosis of HIV infection (±2 years), CD4+ cell count at the time of diagnosis of HIV infection (i.e., <200 cells/mL, 200—349 cells/mL, 350—499 cells/mL, or ⩾500 cells/mL), and duration of follow-up after the diagnosis of HIV infection. Information on demographic characteristics, clinical data, biological values, and antiretroviral therapy use were retrieved from the database for case patients and control subjects and were systematically verified using clinical records for the purpose of the present study.
Association of the occurrence of AN with a given variable was estimated by the matched odds ratio (OR). A conditional logistic regression model was used to analyze the simultaneous effects of several independent factors. A variable was included in the multivariate model if it was associated with the occurrence of AN at a statistical significance of P < .25 in univariate analysis. Because of the small number of observations relative to the number of variables, 2 models were first developed: one model with demographic, clinical, and biological variables, and the other with variables relating to antiretroviral therapy. In each model, a backward stepwise procedure was applied to remove variables that were not significantly associated with the occurrence of AN. A forward selection was then applied for the robustness of the analysis. The variables that were retained in the 2 separate models were included in a final model. Models were fitted using STATA software, version 5.0 (Stata).
REFERENCES
1. Herman JS, Easterbrook PJ. The metabolic toxicities of antiretroviral therapy. Int J STD AIDS 2001; 12:555—62. First citation in article | PubMed
2. Powderly WG. Long-term exposure to lifelong therapies. J Acquir Immune Defic Syndr 2002; 29(Suppl 1):S28—40. First citation in article | PubMed
3. Gutierrez F, Padilla S, Ortega E, et al. Avascular necrosis of the bone in HIV-infected patients: incidence and associated factors. AIDS 2002; 16:481—3. First citation in article | PubMed
4. Keruly JC, Moore RD. Incidence and risk factors for avascular necrosis (AVN) in HIV-infected persons [abstract H-2]. In: Program and abstracts of the 10th Conference on Retrovirus and Opportunistic Infections (Boston). 2003. First citation in article
5. Fellay J, Boubaker K, Ledergerber B, et al. Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study. Lancet 2001; 358:1322—7. First citation in article | PubMed
6. Bonfanti P, Ricci E, Landonio S, et al. Predictors of protease inhibitor—associated adverse events. Biomed Pharmacother 2001; 55:321—3. First citation in article | PubMed
7. Bonnet F, Lawson-Ayayi S, Thiébaut R, et al. A cohort study of nevirapine tolerance in clinical practice: French Aquitaine Cohort, 1997—1999. Clin Infect Dis 2002; 35:1231—7. First citation in article | Full Text | PubMed
8. Montessori V, Press N, Harris M, Akagi L, Montaner JS. Adverse effects of antiretrovial therapy for HIV infection. CMAJ 2004; 170:229—38. First citation in article | PubMed
9. Olive A, Queralt C, Sirera G, Centelles M, Force L. Osteonecrosis and HIV infection: four more cases. J Rheumatol 1998; 25:1243—4. First citation in article | PubMed
10. Meyer D, Behrens G, Schmidt RE, Stoll M. Osteonecrosis of the femoral head in patients receiving HIV protease inhibitors. AIDS 1999; 13:1147—8. First citation in article | PubMed
11. Johns DG, Gill MJ. Avascular necrosis in HIV infection. AIDS 1999; 13:1997. First citation in article | PubMed
12. Blangy H, Loeuille D, Chary-Valckenaere I, Christian B, May T, Gillet P. Osteonecrosis of the femoral head in HIV-1 patients: four additional cases. AIDS 2000; 14:2214—5. First citation in article | PubMed
13. Roudière L, Viard JP. Ostenecrosis of the hip, lipodystrophy and antiretroviral treatment. AIDS 2000; 14:2056. First citation in article | PubMed
14. Wolfe CJ, Taylor-Butler KL. Avascular necrosis: a case history and literature review. Arch Fam Med 2000; 9:291—4. First citation in article | PubMed
15. Brown P, Crane L. Avascular necrosis of bone in patients with human immunodeficiency virus infection: report of 6 cases and review of the literature. Clin Infect Dis 2001; 32:1221—6. First citation in article | Full Text | PubMed
16. Gaughan DM, Mofenson LM, Hughes MD, Seage GR, Ciupak GL, Oleske JM. The Pediatric AIDS Clinical Trials Group. Osteonecrosis of the hip (Legg-Calvé-Perthes disease) in human immunodeficiency virus—infected children. Pediatrics 2002; 109:E74. First citation in article | PubMed
17. Bongiovanni M, Chiesa E, Riva A, D'Arminio Monforte A, Bini T. Avascular necrosis of the femoral head in a HIV-1 infected patient receiving lopinavir/ritonavir. Int J Antimicrob Agents 2003; 22:630—1. First citation in article | PubMed
18. Valencia ME, Barreiro P, Soriano V, Blanco F, Moreno V, Lahoz JG. Avascular necrosis in HIV-infected patients receiving antiretroviral treatment: study of 7 cases. HIV Clin Trials 2003; 4:132—6. First citation in article | PubMed
19. Gasiorowski J, Knysz B, Sokolska V, Gladysz A. Avascular necrosis of femoral heads in a man with HIV infection. Lancet Infect Dis 2003; 3:708. First citation in article | PubMed
20. Calza L, Manfredi R, Chiodo F. Osteonecrosis in HIV-infected patients and its correlation with highly active antiretroviral therapy (HAART) [in French]. Presse Med 2003; 32:595—8. First citation in article | PubMed
21. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002; 137:17—25. First citation in article | PubMed
22. Scribner A, Troia-Cancio PV, Cox BA, et al. Osteonecrosis in HIV: a case-control study. J Acquir Immune Defic Syndr 2000; 25:19—25. First citation in article | PubMed
23. Allison GT, Bostrom MP, Glesby MJ. Osteonecrosis in HIV disease: epidemiology, etiologies, and clinical management. AIDS 2003; 17:1—9. First citation in article | PubMed
24. Keruly JC, Chaisson RE, Moore RD. Increasing incidence of avascular necrosis of the hip in HIV-infected patients. J Acquir Immune Defic Syndr 2001; 28:101—2. First citation in article | PubMed
25. Monier P, McKown K, Bronze MS. Osteonecrosis complicating highly active antiretroviral therapy in patients infected with human immunodeficiency virus. Clin Infect Dis 2000; 31:1488—92. First citation in article | Full Text | PubMed
26. Blacksin MF, Kloser PC, Simon J. Avascular necrosis of bone in human immunodeficiency virus infected patients. Clin Imaging 1999; 23:314—8. First citation in article | PubMed
27. Marimoutou C, Chêne G, Dabis F, Lacoste D, Salamon R. Human immunodeficiency virus infection and AIDS in Aquitaine: 10 years' experience of a hospital information system, 1985—1995. Le Groupe d'Epidemiologie Clinique du SIDA en Aquitaine (GECSA) [in French]. Presse Med 1997; 26:703—10. First citation in article | PubMed
28. Ries MD, Barcohana B, Davidson A, Jergesen HE, Paiement GD. Association between human immunodeficiency virus and osteonecrosis of the femoral head. J Arthroplasty 2002; 17:135—9. First citation in article | PubMed
29. Bonfanti P, Grabbuti A, Carradori S, et al. Osteonecrosis in protease inhibitor—treated patients. Orthopedics 2001; 24:271—2. First citation in article | PubMed
30. Skiest DJ. Osteonecrosis in human imunodeficiency virus—infected patients may not be related to immune reconstitution. Clin Infect Dis 2001; 33:268—9. First citation in article | Full Text | PubMed
31. Glesby MJ, Hoover DR, Vaamonde CM. Osteonecrosis in patients infected with human immunodeficiency virus: a case-control study. J Infect Dis 2001; 184:519—23. First citation in article | Full Text | PubMed
32. Bonnet F, Pineau JJ, Taupin JL, et al. Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients. J Rheumatol 2003; 30:2005—10. First citation in article | PubMed
