Bone demineralization is a common metabolic disorder in HIV-infected patients, with an incidence greater than in the general population of the same age and sex [1–4]. The increasing age of HIV-infected individuals, the virus itself and the presence of other concomitant factors such as low body weight and smoking are all factors that can contribute to the high prevalence of osteopenia and osteoporosis in this population . Several observational or cross-sectional studies have reported an increasing frequency of reduced bone mineral density (BMD) among HIV-infected patients receiving antiretroviral therapy (ART). Although an association between reduced BMD and protease inhibitors (PIs) has been suggested [4–12], a number of studies have not confirmed this association [1,2,11,13–22] or have suggested that other ART drugs such as tenofovir may be important etiologic agents . The causes of low BMD in HIV-infected patients remain uncertain in particular because many previous cross-sectional studies have not controlled for important confounders such as BMI . Some randomized trials have explored this issue and usually found little or no difference according to treatment composition, but they often used total BMD as the endpoint [25,26], although clinically it is more relevant to explore specific sites as the evolution in bone demineralization is not the same at all sites [27,28].
Given the small number of randomized studies evaluating the impact of different ART regimens on the evolution of BMD at specific sites in ART-naive patients, our objective was to evaluate the change in BMD at the hip and the lumbar spine in patients initiating ARTs in a substudy of the AIDS and Viral Hepatitis Research (ANRS) 121-Hippocampe Trial .
Patients and methods
Antiretroviral-naive HIV-infected patients enrolled between November 2003 and May 2004 in the Hippocampe-ANRS 121 , multicenter, open-label trial were randomized (2: 1: 1) into three treatment strategy arms: a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen [PI/r and nonnucleoside reverse transcriptase inhibitor (NNRTI)] (PIs, lopinavir/ritonavir or indinavir/ritonavir), an NRTI-containing regimen consisting of a PI/r and NRTIs or an NNRTI-containing regimen consisting of efavirenz or nevirapine and NRTIs. The main objective was to study the change in limb fat between baseline and week 96, as evaluated by dual-energy X-ray absorptiometry (DXA). The aim of this substudy was to compare the change in BMD when using one of these three ART regimens. The Institutional Review Board of Pitié-Salpêtrière Hospital approved the study protocol. All patients provided written informed consent. The ClinicalTrials.gov identifier was NCT00122668.
HIV-1 infected patients, at least 18 years of age and antiretroviral treatment-naive, were eligible if they had a CD4 cell count less than 350 cells/μl and a plasma HIV-RNA (pVL) more than 5000 copies/ml or pVL more than 100 000 copies/ml, regardless of the CD4 cell count. Exclusion criteria included any active AIDS-defining illness in the last 30 days, acute viral hepatitis, chronic hepatitis B or C requiring specific therapy, any cytotoxic chemotherapy, aspartate aminotransferase or alanine aminotransferase value, or both, serum creatinine concentration more than twice the upper limit of normal, haemoglobin level less than 8 g/dl, platelet count less than 20 000 cells/μl or an absolute neutrophil count less than 750 cells/μl, pregnancy or breastfeeding.
Prior to randomization, investigators had to select two NRTIs among available currently licensed antiretroviral drugs, except for stavudine and zalcitabine. They also selected which PI/r and NNRTI they would prescribe depending on randomization. Indinavir/ritonavir 400/100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily were the only PIs allowed; nevirapine and efavirenz were the only NNRTIs allowed. To account for the drug–drug interaction between the coadministered NNRTIs and PIs, indinavir/ritonavir and lopinavir/ritonavir were given at higher doses (600/100 and 533/133 mg twice daily, respectively) in the NRTI-sparing regimens.
The primary endpoints of the substudy were the change in BMD at lumbar spine and total hip between baseline and week 48, as evaluated by DEXA in a centralized reading center. All, but one, DEXA center participated in the substudy. Quality controls were performed on DEXA to verify the validity of imaging procedures. Only images that satisfied the quality control were considered. As GE-Lunar (Madison, Wisconsin, USA) and Hologic (Bedford, Massachusetts, USA) DEXA devices were used, the same device being always used for a given patient, the standardized BMD (sBMD, mg/cm2) was calculated . For GE-Lunar, the sBMD was 952.2 × BMD at the lumbar spine and 979 × BMD − 31 at the hip. For Hologic, the sBMD was 1075.5 × BMD at the lumbar spine and 1008 × BMD + 6 at the hip .
To evaluate the frequency of osteopenia and osteoporosis, the T-scores were calculated at each site using the appropriate reference curve of each device. The T-score is the difference between a patient's BMD and the mean BMD at time of peak bone mass among 30-year-old persons, divided by the standard deviation (SD) in the group accounting for sex. The WHO definition of osteoporosis is a T-score less than −2.5 SDs and of ostopenia a T-score between −2.5 and −1 SDs .
A planned interim analysis of Hippocampe demonstrated significantly lower treatment and virological responses with the NRTI-sparing strategy, resulting in premature study termination. At that time, all patients had completed week 48 evaluation . We report here percentage changes in sBMD between baseline and week 48.
We compared each PI/r-containing arm with the PI/r-sparing arm. The analyses were done with an intent-to-treat approach on available data. Variables were summarized using proportions for categorical variables, median and interquartile range (IQR) for continuous baseline characteristic variables and mean and SD for continuous variables used as endpoints. Percentage changes in sBMD at both sites between baseline and week 48 were compared using paired Wilcoxon test. The groups were compared using the Mann–Whitney test. Multivariable linear regression was used to assess the factors associated with the change in sBMD at the lumbar spine. The following variables were considered: age, sex, geographical origin, transmission group, time since HIV-1 diagnosis, baseline CD4 cell count, baseline plasma HIV RNA, baseline BMI, baseline and change in total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol between baseline and week 48, baseline and change in limb fat between baseline and week 48, smoking, alcohol consumption greater than 20 g per day and type of device (GE-Lunar or Hologic). We assessed whether age was better modelled as a continuous variable or as a three-class categorical variable according to terciles, using the Akaike criteria to select the best model. Variables with a P value less than 0.15 in the univariate analyses were retained for the backward multivariable model. All reported P values are two-tailed, with a significance level of 0.05. Analyses were performed with the SPSS software package version 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
Out of 117 patients enrolled in Hippocampe-ANRS 121, 18 patients with DEXA done in the nonparticipating DEXA center were not eligible for the substudy, and 71 of the remaining 99 had available DEXA at both baseline and week 48, 36 in the PI/r and NNRTI, 19 in the PI/r and NRTIs and 16 in the NNRTI and NRTIs arms. Overall, patients' baseline characteristics were well balanced between the three groups (Table 1). The median age was 40 years, 23% of the patients were women; the median BMI was 23 kg/m2 and 58% of patients were smokers. The median CD4 cell count was 219 cells/μl, and the median plasma HIV-1 RNA was 5.1 log10 copies/ml. In the NRTI-containing regimen arms, the NRTI backbone was mainly zidovudine and lamivudine (86%), one patient received tenofovir. At baseline, the median T-score was −0.14 (−0.98; 0.47) at lumbar spine and −0.01 (−0.88; 0.83) at total hip sites. Before starting ARTs, osteoporosis was present in 3% and osteopenia in 31% of patients.
At week 48, there was a significant reduction in sBMD at both sites regardless of the ART regimens, with a mean percentage change in sBMD from baseline of −4.1 ± 3.9% (mean ± SD) at lumbar spine and −2.8 ± 4.7% at hip (P = <0.001) (Fig. 1a). The decrease of sBMD at lumbar spine (Fig. 1b) was significantly greater in the PI/r and NNRTI group (−4.4 ± 3.4%) and in the PI/r and NRTIs group (−5.8 ± 4.5%) compared with the NNRTI and NRTIs group (−1.5 ± 2.9%) (PI/r and NNRTI versus NNRTI and NRTIs, P = 0.007 and PI/r and NRTIs versus NNRTI and NRTIs, P = 0.001). At hip, there was no difference between treatment arms.
In univariate analyses, treatment arms, age, geographical origin, plasma HIV-RNA, and change in total cholesterol and LDL cholesterol between week 48 and baseline were retained for multivariable analysis. In the final backward model, we found that the percentage decrease in sBMD at lumbar spine was greater in patients older than 35 years of age (−1.9 ± 0.9, P = 0.037) and with greater increase in total cholesterol (−1.1 ± 0.3 per mmol/l; P = 0.003). Treatment arms were also independent predictors of decrease in sBMD [as compared to the NNRTI and NRTIs arm, −1.9 ± 1.1 in the PI/r and NNRTI arm (P = 0.099) and −3.5 ± 1.2 in the PI/r and NRTIs arm (P = 0.005)].
In a group of HIV-1 infected, treatment-naive patients, with a median age of 40 years, a median BMI of 23 kg/m2 and a CD4 cell count of 219 cells/μl, we found 34% with osteopenia or osteoporosis. This high prevalence of osteopenia, already noted by others [20,23,25,26,32], could be explained by the chronic inflammation associated with HIV infection . HIV itself may have direct effects on osteoclast activity [33–35] and could contribute to a higher prevalence of osteopenia/osteoporosis in HIV-infected patients, either directly or through its impact on BMI .
In addition, this randomized study shows a significant reduction in sBMD at the hip and the lumbar spine sites after 1 year of treatment, whatever ART regimens were received. The decrease at lumbar spine after 1 year of ARTs was of a similar magnitude to the yearly decrease observed in women after menopause .
Moreover, at the lumbar spine, the decrease was significantly greater when patients received a PI/r-containing regimen, whereas no difference was evidenced at hip. A meta-analysis of cross-sectional studies has concluded that exposure to ARTs, especially those including PIs, leads to a greater reduction in BMD in HIV-infected patients . Furthermore, Jain et al. compared the effects of various PIs on bone resorption and found that some PIs, but not all, increase bone resorption. The effect of PI regimen could be explained by impact on osteoclast differentiation, exogenous hormone metabolism via inhibition of cytochrome activity or vitamin D metabolism or all . Although our study has a limited sample size, it is among the rare studies of BMD in HIV-infected patients, which are both randomized and evaluating changes during ART at specific sites. We did observe significant differences between treatment arms at week 48 at lumbar spine, but not at hip. Interestingly, such a difference between changes at lumbar spine and at hip was also observed in the Gilead study 903, comparing tenofovir and stavudine . As bone remodelling is more rapid for trabecular bone than for cortical bone , this may explain the difference between the results at 1 year at lumbar spine, in which there is mainly trabacular bone, and at hip with more cortical bone. This reinforces the importance of looking at specific sites, rather than the whole body BMD. For instance, Tebas et al., in the A5005s metabolic substudy of ACTG 384, showed that there was a statistical decrease in total bone mineral content at 48 weeks of 1.0% (IQR −3.6 to 1.2%, P < 0.01) in treatment-naive patients randomized to receive nelfinavir, efavirenz, or both drugs combined with zidovudine and lamivudine or didanosine and stavudine. Even though the decline in total bone mineral content in the efavirenz group was slightly less using a mixed-model analysis limited to participants remaining on original treatment, the difference between the nelfinavir and efavirenz groups did not reach statistical significance (P = 0.08). No effect of NRTI assignment (P = 0.60) was shown . The difference with our study can probably be explained by the measurement of whole-body BMD in the ACTG 384 study while we used measurements at specific sites. Brown et al. evaluated change in BMD at 96 weeks in treatment-naive patients randomized to receive either zidovudine/lamivudine and efavirenz or lopinavir/r for the first 24 weeks followed by lopinavir/r alone. They also found a significant decrease in whole-body BMD after 96 weeks, but no difference according to treatment. Here also, the measurement of whole-body BMD instead of specific sites may explain the discrepant results compared with ours. Alternatively, this difference may reflect differences in the rate of change depending on regimen as their results are at 96 weeks, whereas ours are at 48 weeks. Unfortunately, because of premature study termination, no data were available at 96 weeks in our study.
In our study, age more than 35 years was found as a predictor of change in sBMD after treatment initiation, with no difference between men and women, which may be due to a lack of power. Another predictor of change in sBMD was the change in total cholesterol independently of treatment arm. In the general population, BMD is correlated with serum lipids, negatively for HDL cholesterol and positively for triglycerides and LDL cholesterol . It has been reported already that oxidized lipids and hyperlipidaemia might inhibit osteoblastic differentiation . Recently, Wiercinska-Drapalo et al. found a significant negative association between BMD and serum total cholesterol concentrations. In the Hippocampe-ANRS 121 trial, we found that both change in total cholesterol and treatment arm were associated with a decrease in sBMD. Treatment regimens were heterogeneous within arms, with either lopinavir/r or indinavir/r in PI-containing arms and either efavirenz or nevirapine in NNRTI-containing arms. These drugs may have a different impact on change in cholesterol and, therefore, change in sBMD, which may explain why both treatment arms and changes in cholesterol predicted changes in sBMD in our study. This can also partly explain the difference between Brown et al.'s  study and our own, as in that study both evaluated drugs are known to be associated with large increase in cholesterol [43,44]. Of note, in subgroup analyses, we did not find any significant difference in change from baseline in sBMD between lopinavir and indinavir or between efavirenz and nevirapine, but our study was underpowered to detect any such differences. Although the difference between change in sBMD in the PI/r and NNRTI arm and the PI/r and NRTIs at lumbar spine did not reach statistical significance (−4.4 versus −5.8, P = 0.167), we cannot rule out a small effect of the NRTIs, and imbalance between PI/r used in each of the two PI/r arms is unlikely to play a significant role.
In our study, the BMD was impaired in 34% of patients before starting any ART, suggesting either a direct or an indirect role of HIV. After 1 year on combined antiretroviral treatment, the decrease was more pronounced with PI-containing regimens compared with non-PI regimens consisting of an NNRTI and two NRTIs. Follow-up of BMD is crucial in this infection, in which ART is assumed to be lifelong.
This study was presented at the 11th European AIDS Conference/EACS, 24–27 October 2007, Madrid, Spain (abstract #P9.7/12) and at the 15th Conference on Retroviruses and Opportunistic Infections, 3–6 February 2008, Boston, Massachusetts, USA (abstract #967).
We are thankful to all the patients who participated in the study. We also thank the nurses of the different centers who took care of the patients and all the investigators and contributors. A special thanks is given to Marie-Joseph Commoy.
The French National Agency for ANRS sponsored the trial and was involved in the study design. After approval of the protocol, the sponsor was not involved in the collection, analysis or interpretation of the data, writing of the report or the decision to submit the paper for publication. This study was registered with ClinicalTrials.gov, number NCT00122668.
Dominique Costagliola, Christine Katlama, Sami Kolta and Sylvie Rozenberg were involved in the conception and design of the substudy.
Claudine Duvivier, Jade Ghosn, Christine Katlama, Sami Kolta and Sylvie Rozenberg were responsible for the provision of study materials or patients.
Sami Kolta was a member of DEXA-centralized reading center.
Lambert Assoumou and Dominique Costagliola were responsible for statistical analysis.
Lambert Assoumou, Dominique Costagliola, Claudine Duvivier, Jade Ghosn, Christine Katlama, Sami Kolta, Robert L. Murphy and Sylvie Rozenberg were involved in interpretation of the data.
Lambert Assoumou, Dominique Costagliola, Claudine Duvivier, and Robert L. Murphy were responsible for drafting of the article.
Lambert Assoumou, Dominique Costagliola, Claudine Duvivier, Jade Ghosn, Christine Katlama, Sami Kolta, Robert L. Murphy and Sylvie Rozenberg did the critical revision of the article for important intellectual content and also final approval of the article.
The members of the Hippocampe study team are as follows:
The scientific committee comprised of: C. Duvivier, C. Katlama, V. Calvez, G. Peytavin, D. Costagliola, I. Beucler, E. Dion, F. Raffi, J.F. Delfraissy and M.J. Commoy.
The data and safety monitoring board comprised of: P. Massip, R. Garraffo, L. Mazetier, J. Izopet and G. Chêne.
The clinical centers with the respective members are as follows: C. Katlama, C. Duvivier and J. Ghosn, Hôpital Pitié-Salpétrière, Paris, Service des Maladies Infectieuses et Tropicales; J.M. Molina and A. Racheline, Hôpital Saint-Louis, Paris, Service des Maladies Infectieuses et Tropicales; B. Phung and J. Gerbe, Hôpital Bichat, Paris, Service des Maladies Infectieuses et Tropicales; P. Miailhes, B. Lebouche, K. Kouadjo and N. Benmakhlouf, Hôpital Hôtel Dieu, Lyon, Service d'Hépato-gastroentérologie; C. Goujard, A. Miquel, Y. Quetainmont and M.T. Rannou, Hôpital de Bicêtre, Le Kremlin Bicêtre, Service de Médecine Interne; A. Rami, V. Delcey, M. Drener and M. Parrinello, Hôpital Lariboisière, Paris, Service de Médecine Interne A; P. Galanaud, F. Boué and A.M. Delavalle, Hôpital Antoine Béclère, Clamart, Médecine Interne Immunologie Clinique; T. May, Hôpital de Brabois, Vandoeuvre les Nancy, Service des Maladies Infectieuses et Tropicales; C. Perronne, P. de Truchis and H. Berthé, Hôpital Raymond Poincaré, Garches, Service des Maladies Infectieuses et Tropicales; A. Simon, M. Bonmarchand, C. Brançon and H. Kouadio, Hôpital Pitié-Salpétrière, Paris, Service de Médecine Interne; B. Lefebvre, D. Bollens, J.L. Meynard and Z. Ouazene, Hôpital Saint Antoine, Paris, Service des Maladies Infectieuses et Tropicales; F. Raffi, Hôpital Hôtel Dieu, Nantes, Service des Maladies infectieuses; W. Rozenbaum, L. Slama and C. Chakvetaze, Hôpital Gustave Dron; Hôpital Tenon, Paris, Service des Maladies Infectieuses et Tropicales; J.P. Faller and P. Eglinger, Centre Hospitalier de Belfort, Belfort, Service de Réanimation et Maladies Infectieuses; A. Dos Santos, A. Tone, S. Pavel and F. Ajana, Tourcoing, Service Universitaire des Maladies Infectieuses et du Voyageur; J.P. Viard and L. Roudière, Hôpital Necker, Paris, Service des Maladies Infectieuses et Tropicales.
The DEXA scanning centers with the respective members are as follows: R. Inaoui, Hôpital Pitié-Salpétrière, Paris; E. de Kerviller, Hôpital Saint-Louis, Paris; G. Frielander and M. Essig, Hôpital Bichat, Paris; M.C. De Vernejoul, Hôpital Lariboisière, Paris; P. Delmas and F. Duboeuf, Hôpital Hôtel Dieu, Lyon; C. Vallée and R. Carlier, Hôpital Raymond Poincaré, Garches; J.M. Tubiana and A. Sebag, Hôpital Tenon, Paris; J.Y. Devaux and P. Delmaire, Hôpital Saint Antoine; M. Werhya, Hôpital de Brabois, Vandoeuvre les Nancy; Y. Maugars and J. Glemarec, Hôpital Hôtel Dieu, Nantes; X. Marchandise, Hôpital Gustave Dron, Tourcoing; P. Speich, Centre Hospitalier de Belfort, Belfort.
Lambert Assoumou and Sami Kolta declare no conflict of interest. Dominique Costagliola has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies including Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences, Glaxo-Smith-Kline, Janssen and Roche. Claudine Duvivier has received honoraria from Merck and travel grants from various pharmaceutical companies including Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Glaxo-Smith-Kline, Janssen, Merck and Roche. Jade Ghosn has received honoraria from Gilead Sciences and study grants from Abbott. Christine Katlama has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies including Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences, Merck, Roche and Tibotec. Robert L. Murphy has served as a consultant for or received grants from Abbott, Bristol-Myers Squibb and Gilead or both. Sylvie Rozenberg has received honoraria from Gilead Sciences.
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