Received 31 October 2013; returned 10 November 2013; revised 16 December 2013; accepted 19 December 2013

Transcription

1 J Antimicrob Chemother 2014; 69: doi: /jac/dkt536 Advance Access publication 16 February 2014 Maraviroc plus raltegravir failed to maintain virological suppression in HIV-infected patients with lipohypertrophy: results from the ROCnRAL ANRS 157 study Christine Katlama 1 3 *, Lambert Assoumou 1,2, Marc-Antoine Valantin 1 3, Cathia Soulié 1,2,4, Claudine Duvivier 5, Laetitia Chablais 1,2, Sami Kolta 6, Gilles Pialoux 7, Patrick Mercié 8, Anne Simon 2,3, Dominique Costagliola 1,2, Gilles Peytavin 9 and Anne-Genevieve Marcelin 1,2,4 on behalf of the ROCnRAL ANRS 157 Study Group 1 INSERM, UMRS 943, Paris F-75013, France; 2 UPMC Univ Paris 06, UMRS 943, Paris F-75013, France; 3 Department of Infectious Diseases, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; 4 Department of Virology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; 5 Department of Infectious Diseases, AP-HP, Necker Hospital, Paris, France; 6 Rheumatology Department, AP-HP, Paris-Descartes University, Cochin Hospital, Paris, France; 7 Department of Infectious Diseases, AP-HP, Tenon Hospital, Paris, France; 8 Department of Infectious Diseases, AP-HP, Bordeaux Hospital, Bordeaux, France; 9 Laboratory of Toxicology and Pharmacokinetics, AP-HP, Bichat-Claude Bernard Hospital, Paris, France *Corresponding author. Hôpital Pitié-Salpêtrière, Paris, France. Tel: ; Fax: ; christine.katlama@psl.aphp.fr Members are listed in the Acknowledgements section. Received 31 October 2013; returned 10 November 2013; revised 16 December 2013; accepted 19 December 2013 Background: Novel nucleoside reverse transcriptase inhibitor- and protease inhibitor-sparing strategies are needed in long-term-treated patients with lipohypertrophy. Given their potency and their excellent metabolic profile, maraviroc and raltegravir appear to be good candidates for such an approach. Methods: This single-arm study enrolled lipohypertrophic HIV-infected patients with suppressed viraemia and an R5 tropic virus in HIV DNA; they switched from suppressive antiretroviral treatment to maraviroc plus raltegravir. The primary endpoint was the proportion of patients with treatment success at week 24, defined as no virological failure or treatment discontinuation. To ensure a success rate of at least 80%, a maximum of 10 failures were allowed for 90 patients enrolled. ClinicalTrials.gov: NCT Results: A total of 44 patients were enrolled; their median age was 55 years, median nadir CD4 cell count was 210 cells/mm 3, median time on antiretroviral treatment was 15 years and median duration of viral suppression was 5.2 years. Seven patients failed maraviroc/raltegravir therapy: five had virological failure and two discontinued treatment due to serious adverse events (one had hepatitis B virus reactivation and one had hypersensitivity syndrome). At failure, raltegravir resistance mutations were detected in 3/5 patients and CXCR4 tropic virus in 2/5. Upon DSMB recommendation, the study was prematurely discontinued on 3 September Lipid profile and bone mineral density improved with a decrease from baseline values in total cholesterol ( mmol/l; P ¼ 0.001), low-density lipoprotein cholesterol ( mmol/l; P ¼ 0.039) and triglycerides ( mmol/L; P¼0.001) and an increase in total hip bone mineral density ( %; P¼0.013) Conclusions: In long-term-experienced patients, maraviroc/raltegravir therapy lacks virological robustness despite a benefit in lipid profile and bone density. Keywords: lipodystrophy, nucleoside reverse transcriptase inhibitors, protease inhibitors Introduction In the context of lifelong antiretroviral therapy to maintain HIV viral suppression, 1 the cumulative toxicity of antiretroviral drug therapy represents a major issue, particularly in ageing patients. Nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) are associated with long-term toxicity, such as bone and renal disorders, lipodystrophy and increased cardiovascular risk. 2 6 Integrase and CCR5 inhibitors are virologically highly potent and offer the advantage of an excellent safety and tolerability profile in the short term with limited metabolic disorders # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oup.com 1648

2 Raltegravir/maraviroc therapy in HIV-infected lipohypertrophic patients JAC Table 1. Baseline patient characteristics; total n¼44 Age (years), 55 (50 60) Male sex, n (%) 38 (86) Ethnicity, n (%) Caucasian 40 (91) sub-saharan African 4 (9) Transmission group, n (%) men who have sex with men 28 (64) heterosexual 11 (25) unknown/other 5 (11) Time since HIV diagnosis (years), 20 (14 24) Duration of antiretroviral treatment (years), 15 (13 19) Duration of suppressed HIV viraemia 5.2 ( ) (,50 copies/ml) (years), CD4 cell count nadir (cells/mm 3 ), 210 ( ) CD4 cell count (cells/mm 3 ), 635 ( ) CD8 cell count (cells/mm 3 ), 731 ( ) CD4/CD8 ratio, 0.9 ( ) Plasma viral load zenith (log 10 copies/ml), 4.8 ( ) HIV DNA in PBMCs (log 10 copies/10 6 PBMCs), 2.8 ( ) Viral tropism detection [FPR (%)], 52.8 ( ) CDC stage C, n (%) 9 (20) Antiretroviral treatment at screening, n (%) two NRTIs+PI/ritonavir 16 (36) two NRTIs+PI 5 (11) PI/ritonavir 9 (20) two NRTIs+NNRTI 5 (11) NNRTI+PI/ritonavir 2 (5) others 5 (11) Antiretroviral treatment daily dosing, n (%) once daily 27 (61) twice daily 17 (39) Total cholesterol (mmol/l), 5.2 ( ) Low-density lipoprotein cholesterol (mmol/l), 3.1 ( ) High-density lipoprotein cholesterol (mmol/l), 1.1 ( ) Triglycerides (mmol/l), 2.0 ( ) Fasting glycaemia (mmol/l), 5.2 ( ) Lipohypertrophy (% of patients) 100 abdomen 100 trunk 52 buffalo hump 32 Body mass index (kg/m 2 ), 26 (24 28) Trunk fat (kg), 13.7 ( ) T score, lumbar spine ( ) hip 0.05 ( ) NNRTI, non-nucleoside reverse transcriptase inhibitor; PBMC, peripheral blood mononuclear cell. In the search for an NRTI- and PI-sparing regimen that could be used in lipodystrophic patients, we designed the ROCnRAL- ANRS 157 study to evaluate whether the dual combination of maraviroc/raltegravir was able to maintain viral suppression and improve lipohypertrophy in a population of long-term chronically infected patients with suppressed viraemia and clinical lipohypertrophy. Patients and methods The ROCnRAL ANRS-157 study was a pilot Phase II, single-arm, multicentre clinical trial designed to evaluate the capacity of the raltegravir plus maraviroc combination to maintain HIV viraemia below 50 copies/ml over 24 weeks in HIV-1-infected patients with controlled viral load under antiretroviral treatment and clinical lipohypertrophy. The Institutional Review Board of Pitié-Salpêtrière Hospital approved the study protocol (ClinicalTrials.gov: NCT ). All patients provided written informed consent. The study population consisted of HIV-1-infected adults with clinical lipohypertrophy who had been under antiretroviral treatment for at least 5 years, were naive to raltegravir and maraviroc, had HIV RNA,200 copies/ml over the last 24 months and,50 copies/ml for at least 12 months, and had R5 tropism in HIV DNA and B or CRF02 virus. Patients with X4, dual X4/R5 or undetermined tropic virus, HIV-2 or active hepatitis B [hepatitis B surface antigen (HBsAg) positive] or hepatitis C (anti-hepatitis C virus positive) coinfections could not be enrolled. After enrolment, patients switched from their current antiretroviral treatment to the combination of raltegravir (Isentress w ) 400 mg twice a day and maraviroc (Celsentri w ) 300 mg twice a day. Clinical and biological evaluations were completed at baseline (week 0), weeks 4, 8, 12, 20 and 24, and every 8 weeks until week 48. HIV RNA was evaluated at each visit. The C min (12 h) raltegravir and maraviroc concentrations were considered adequate when they were.50 ng/ml. Viral tropism was determined using the Geno2Pheno algorithm [falsepositive rate (FPR) 20%] 13 on blood cellular DNA. A more conservative FPR (20%) was chosen rather than the usual 10% recommended by the ANRS to increase the chances of detecting sequences of X4-tropic viruses. Genotypic resistance testing was performed in case of virological failure ( updated September 2012). Bone mineral density (g/cm 2 ) was measured by DEXA scan at day 0 and week 48 and data were analysed centrally in a blinded manner. The primary endpoint was the proportion of patients with treatment success at week 24. Treatment success was defined as the absence of virological failure (two consecutive measurements of HIV-1 RNA.50 copies/ ml, taken 2 4 weeks apart) or any treatment modification or discontinuation. Patients with a single value of HIV-1 RNA.50 copies/ml and a missing second HIV-1 RNA value and patients with two or more consecutive missing HIV RNA values were considered as failures. The main secondary endpoints included drug safety, raltegravir and maraviroc plasma C trough (12 h) concentrations, resistance profile in case of virological failure, change in the amount of fat tissue, metabolic and bone mineral density parameters. Statistical considerations The objective of the study was to assess whether the maraviroc/raltegravir combination could achieve a treatment success rate of at least 80% at week 24 assuming an observed success rate of at least 92%. The sample size of 82 subjects would enable a statistical power of at least 90% using a one-sided x 2 test. The Data Safety Monitoring Board (DSMB) recommended (i) that patients with a CD4 nadir count,100 cells/mm 3 on 13 July 2012 should be excluded and (ii) the study should be stopped because 1649

3 Katlama et al. Table 2. Patients who discontinued the maraviroc/raltegravir combination due to virological failure Patient cart prior to entry Week 4 screening Baseline Virological failure self-reported adherence level duration of suppressed viraemia (years) CD4 cell count (cells/ mm 3 ) HIV DNA tropism and time of failure plasma HIV-1 viral load (copies/ml) drug C min (ng/ml) a integrase mutation HIV RNA tropism 1 TDF/FTC/EFV high (.99%) CCR5, B 2 DRV/r high (.99%) CCR5, B 3 TDF/FTC/DRV/r medium CCR5, B (80% 99%) 4 TDF/FTC/DRV/r medium CCR5, CRF02 (80% 99%) 5 TDF/FTC/EFV high (.99%) CCR5, B week RAL: 21 none CCR5 week MVC: 13 week RAL: 1960 Y143C CXCR4 week MVC: 160 week RAL 56 N155H CXCR4 week MVC 104 week RAL: 121 none CCR5 week MVC: 28 week RAL: 87 F121Y CCR5 week MVC: 105 TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; EFV, efavirenz; DRV/r, darunavir/ritonavir. a Raltegravir and maraviroc plasma C min 12 h target value: 50 ng/ml. of an excessive rate of treatment failure on 3 September A study termination visit was scheduled within 45 days and patients were advised to resume their prior antiretroviral treatment. The primary endpoint analysis was performed with an intentionto-treat approach. The 95% CI of the observed proportion of patients reaching the efficacy endpoint was calculated using a Kaplan Meier estimate. All reported P values were two-tailed, with a significance level of Analyses were performed with SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL, USA). Results Between 6 December 2011 and 10 August 2012, 101 patients were screened for the study; 53 were screen failures mainly for virological reasons [CXCR4 or undetermined tropism (21), non-b (7)]. Four discontinued the study following the DSMB recommendation because of CD4 cell nadir,100/mm 3. Overall, 44 patients were analysed. The median time between baseline and the closing visit was 19.4 weeks ( weeks). Baseline characteristics of the 44 patients are shown in Table 1. Patients were mainly male, in their mid-fifties with a median duration of 15 years of antiretroviral treatment. Between weeks 8 and 20, five patients experienced virological failure and two developed adverse events (Tables 2 and 3). The 24 week treatment success rate was estimated as 79% (95% CI 62% 89%). In two of the five virological failures, maraviroc and/or raltegravir C min values were low (,50 ng/ml), with no emergence of viral resistance. In the three remaining cases, viral resistance mutations emerged (Y143C- and CXCR4-using virus, N155H- and CXCR4-using virus, and F121Y). Resumption of the baseline antiretroviral regimen led to suppressed viraemia in all five patients. No change was observed in CD4 counts ( cells/mm 3, P¼0.492). At the closing visit, 22 out of 37 patients with treatment success decided to maintain maraviroc and raltegravir therapy. Eight serious adverse events occurred in six patients; in addition to the adverse events described for two patients in Table 3, these comprised ophthalmological disorder, grade 3 increase in g-glutamyl transferase, rash and death from chronic obstructive pulmonary disease. After a median time of 19.4 weeks, there were significant decreases from baseline values in total cholesterol ( mmol/l; P ¼ 0.001), low-density lipoprotein cholesterol ( mmol/L; P¼0.039) and triglycerides ( mmol/L; P¼0.001) in 37 evaluable patients. No significant changes were observed in body mass index (P¼0.649), limb fat (P¼0.128) and trunk fat (P¼0.058). In 24 evaluable men, over a median interval of 26 weeks (range weeks) between the two DEXA evaluations, the mean change in bone mineral density was 0.7%+2.9% (P ¼0.339) at the lumbar spine and 0.9%+1.5% (P¼0.013) at the hip, translating to a mean increase of 2.1%+3.4% per year (P¼0.009). Discussion This pilot study shows that, in a population of long-term-treated, ageing patients with lipohypertrophy, the combination of maraviroc/raltegravir given twice daily did not meet the protocol definition of acceptable virological efficacy. Indeed, only 79% (95% CI 62% 89%) of the patients maintained optimal viral suppression at week 24. Overall, 7 of the 44 enrolled patients out of 90 initially planned had to discontinue the maraviroc/raltegravir combination due to treatment failure, with five virological failures and two serious adverse events. The emergence of raltegravir resistance mutations in three out of five patients who failed virologically, with the concomitant emergence of CXCR4 virus detected in two of them, was a strong reason to discontinue the study prematurely. The rapid emergence of X4-tropic viruses in two patients raises the question of the failure to detect such viruses in total HIV DNA 1650

4 Raltegravir/maraviroc therapy in HIV-infected lipohypertrophic patients JAC Table 3. Patients who discontinued the maraviroc/raltegravir combination due to serious adverse events Patient Characteristics (week 4 screening) Serious adverse events Timing of serious adverse events 6 CCR5 tropism hepatitis B virus reactivation week 16 B AST/ALT.20 ULN (grade 4) cart prior to entry: ABC/3TC/ATV related to lamivudine discontinuation duration of suppressed viraemia: 6.2 years CD4 cell count: 716 cells/mm 3 HBsAg2, HBsAb2, HBcAb+ 7 CCR5 tropism cutaneous rash and diarrhoea week 4 CRF02 possibly related to raltegravir and maraviroc cart prior to entry: TDF/FTC/RTV duration of suppressed viraemia: 5.6 years CD4 cell count: 594 cells/mm 3 cart, combination antiretroviral therapy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBsAb, hepatitis B surface antibody; HBcAb, hepatitis B core antibody; TDF, tenofovir disoproxil fumarate; 3TC, lamuvidine; FTC, emtricitabine; ATV, atazanavir; RTV, ritonavir; ULN, upper limit of normal. despite the selection of an FPR of 20% rather than the usual 10%. Indeed, we cannot rule out difficulties in detecting X4 minority variants in these patients with a long duration of 15 years of therapy and a nadir CD4 around 200 cells/mm 3. Primary resistance to raltegravir and elvitegravir is rare and unlikely in this patient population. 14 One potential explanation for the unexpected observed failure rate could be a lack of treatment compliance in the elderly patients who had to switch from a once-daily to a twice-daily regimen, which may have increased the risk of missing dose intakes. 15 Not surprisingly, there was a trend towards a higher risk of virological failure with a level of adherence,80%. Drug drug interactions represent a potential cause of diminished antiviral potency. Maraviroc is a substrate of CYP3A4, whereas raltegravir is a substrate of UDP-glucuronyl transferase 1A1(UGT1A1),andbotharesubstratesofP-glycoprotein. 16,17 However, the pharmacokinetic substudy of the ROCnRAL trial (complete data not shown) confirmed the lack of a clinically relevant drug interaction between maraviroc and raltegravir. Approximately 95% of samples had free C min of maraviroc and raltegravir above the 10 and 15 ng/ml thresholds, respectively. In terms of the impact of the dual raltegravir maraviroc combination on fat tissue, keeping in mind the small number of patients and the short follow-up, we did not observe significant changes in terms of trunk and limb fat. However, there was a clear benefit in terms of reduction of total cholesterol, low-density lipoprotein cholesterol and triglycerides, as shown by previous studies. Interestingly, despite the short delay in NRTI and PI discontinuation (26 weeks) we observed an improvement in total hip bone mineral density, with a trend to a greater increase in patients with longer exposure to raltegravir/maraviroc. These data are in accordance with the SMART metabolic substudy, in which a significant increase in bone mineral density was observed in patients randomized to discontinue antiretroviral treatment, 18 and the reported bone toxicity of PI- and tenofovir-containing strategies. 19,20 In conclusion, the ROCnRAL-ANRS 157 study suggests that, in a population of long-term-treated ageing patients, maraviroc/ raltegravir dual therapy lacks virological robustness, resulting in the emergence of resistance mutations, and therefore cannot be recommended for further evaluation on a larger scale. Given the cumulative effects of HIV, ageing and long-term exposure to NRTIs and PIs, particularly with regard to the cardiovascular, bone and renal systems, the need for NRTI- and PI-free regimens has become more acute without wavering from the key principle of sustained virological control of HIV replication. Acknowledgements PresentedinpartattheTwentiethConferenceonRetrovirusesand Opportunistic Infections, Atlanta, GA, USA, 2013 (Abstract 566). We thank the investigators, study coordinators, site and data managers, and the patients for their contributions as well as ViiV Healthcare (France) and Merck Sharp & Dohme (France) for providing maraviroc and raltegravir, respectively, for this trial. Members of the ROCnRAL ANRS 157 Study Group Trial Chair: C. Katlama; Trial Co-chairs: A. Simon, M. A. Valantin; Trial Statisticians: L. Assoumou, D. Costagliola; Trial Virologists: C. Soulié, V.Calvez,A.G.Marcelin;TrialPharmacologist:G.Peytavin; Scientific Committee: C. Katlama, A. Simon, M. A. Valantin, L. Assoumou, D. Costagliola, L. Chablais, G. Peytavin, J. Capeau, J.-P. Bastard, S. Kolta, C. Soulié, V. Calvez, A. G. Marcelin, S. Couffin Cadiergues (ANRS), J. Saillard (ANRS), X. Rey-Coquais, F. Durand (Merck Sharp & Dohme Ltd), C. Lemarchand (ViiV Healthcare); Data Safety and Monitoring Board: L. Cuzin, J. P. Aboulker, H. Fisher and a special mention to Dr Bernard Masquelier. Participating centres and investigators (all in France) Hôpital St-Jacques (Besançon): B. Hoen, C. Haffner-Mauvais. Hôpital Necker (Paris): C. Duvivier, M. Shoai-Tehrani, F. Touam. Hôpital Bicêtre (Le Kremlin Bicêtre): A. Canestri, M.-J. Dulucq. Hôpital Tenon (Paris): G. Pialoux, J. Chas, N. Velazquez. Hôpital Henri-Mondor (Créteil): Y. Levy, C. Chesnel, S. Scerra, S. Dominguez. Hôpital Pitié-Salpètrière (Paris) Maladies Infectieuses: C. Katlama, M. A.Valantin,Y.Dudoit,P.Bourse, L. Schneider. Hôpital Pitié-Salpètrière (Paris) Médecine Interne: A. Simon, 1651

5 Katlama et al. C. Lupin. Hôpital Saint Louis (Paris) Maladies Infectieuses: J. M. Molina, D. Ponscarme. Hôpital St-Andre (Bordeaux) Médecine Interne: P. Morlat, S. Caldato. Hôpital St-Andre (Bordeaux) Maladies Infectieuses et Tropicales: P. Mercié, S. Caldato. Hôpital de la Croix Rousse (Lyon): L. Cotte, K. Koffi, C. Brochier, V. Thoirain. Hôpital Ste-Marguerite (Marseille): I. Poizot Martin, O. Faucher, P. Geneau de la Marliere, C. Debreux, A.-S. Ritleng. Hôpital Gui De Chauliac (Montpellier): J. Reynes, A. Makinson, C. Crisol. Hôpital A. Michallon (Grenoble): P. Leclercq, C. Blanc, S. Gerberon. Hôpital Gustave Dron (Tourcoing): A. Cheret, S. Bonne, M.-C. Marien. Hôpital de l hôtel Dieu (Nantes): F. Raffi, H. Hue. Funding This work was supported by the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS), France, as well as ViiV Healthcare (France) and Merck Sharp & Dohme (France), who provided maraviroc and raltegravir, respectively, for this trial. Transparency declarations C. K. has served on the advisory board for and has received lecture fees, travel expenses and payment of registration fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme and Tibotec. M.-A. V. has received lecture fees, travel expenses and payment of registration fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Roche and Tibotec. G. P. has served on the advisory board for and has received travel expenses and payment of registration fees from Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck Sharp & Dohme, Abbott and Janssen. A. S. has served on the advisory board for and has received travel grants and consultancy fees from Bristol-Myers Squibb, Gilead Sciences and Janssen- Cilag. D. C. has received travel grants, consultancy fees, honoraria and study grants from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme and Roche. A.-G. M. has served on the advisory board for and has received travel grants, consultancy fees, honoraria and study grants from Bristol- Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck Sharp & Dohme and Janssen-Cilag. L. A., C. S., C. D., L. C., S. K. and P. M.: none to declare. References 1 Phillips AN, Leen C, Wilson A et al. Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study. Lancet 2007; 370: Assoumou L, Katlama C, Viard JP et al. Changes in bone mineral density over a two-year period in HIV-1-infected men under cart with osteopenia. AIDS 2013; 27: Friis-Moller N, Reiss P, Sabin CA et al. 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