Antoine Chéret1, Georges Nembot2, Adeline Mélard3, Caroline Lascoux4, Laurence Slama5, Patrick Miailhes6, Patrick Yeni7, Sylvie Abel8, Véronique Avettand-Fenoel3, Alain Venet9, Marie-Laure Chaix3, Jean-Michel Molina10, Christine Katlama11, Cécile Goujard12, Catherine Tamalet13, François Raffi14, Alain Lafeuillade15, Jacques Reynes16, Isabelle Ravaux17, Bruno Hoën18, Jean-François Delfraissy19, Laurence Meyer2, Christine Rouzioux3. 1. EA 7327, Paris Descartes University - Sorbonne Paris Cité, Paris, France; Infectious Diseases Department, Tourcoing Hospital, Tourcoing, France; Internal Medicine Department, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France. Electronic address: antoinecheret@free.fr. 2. INSERM U1018, Faculty of Medicine, Paris-Sud University, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France. 3. EA 7327, Paris Descartes University - Sorbonne Paris Cité, Paris, France; Virology Laboratory, AP-HP, Necker Hospital, Paris, France. 4. Infectious Diseases Department, AP-HP, Saint-Louis Hospital, Paris, France. 5. Infectious Diseases Department, AP-HP, Tenon Hospital, Paris, France. 6. Infectious Diseases Department, Croix Rousse Hospital, Lyon, France. 7. Infectious Diseases Department, AP-HP, Bichat Claude-Bernard Hospital, Paris, France. 8. Infectious Diseases Department, CHU de Fort de France, Martinique, France. 9. INSERM U1012, Faculty of Medicine, Paris-Sud University, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France. 10. Infectious Diseases Department, AP-HP, Saint-Louis Hospital, Paris, France; INSERM U941, University of Paris Diderot, Paris, France. 11. Infectious Diseases Department, AP-HP, La Pitié-Salpêtrière Hospital, Paris, France. 12. Internal Medicine Department, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France; INSERM U1018, Faculty of Medicine, Paris-Sud University, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France. 13. Virology Laboratory, AP-HM, La Timone Hospital, Marseille, France. 14. Collège des Universitaires des Maladies Infectieuses et Tropicales (CMIT), Paris, France. 15. Infectious Diseases Department, Font-Pré Hospital, Toulon, France. 16. Infectious Diseases Department, Gui de Chauliac Hospital, Montpellier, France. 17. Infectious Diseases Department, AP-HM, La Timone Hospital, Marseille, France. 18. Infectious Diseases Department, CHU Ricou Hospital, Pointe à Pître, France. 19. Internal Medicine Department, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
Abstract
BACKGROUND: Early combination antiretroviral therapy (cART) initiation at the time of primary HIV-1 infection could restrict the establishment of HIV reservoirs. We aimed to assess the effect of a cART regimen intensified with raltegravir and maraviroc, compared with standard triple-drug cART, on HIV-DNA load. METHODS: In this randomised, open-label, phase 3 trial, we recruited patients from hospitals across France. Inclusion criteria were primary HIV-1 infection (an incomplete HIV-1 western blot and detectable plasma HIV-RNA), with either symptoms or a CD4+ cell count below 500 cells per μL. Patients were randomly assigned (1:1) to an intensive, five-drug cART regimen (raltegravir 400 mg and maraviroc 150 mg twice daily, and a fixed-dose combination of tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) or a standard triple-drug cART regimen (tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) using a predefined randomised list generated by randomly selected variable block sizes. The primary endpoint was the median number of HIV-DNA copies per 10(6) peripheral blood mononuclear cells (PBMC) at month 24, analysed in the modified intention-to-treat population, defined as all patients who started their assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01033760. FINDINGS:Between April 26, 2010, and July 13, 2011, 110 patients were enrolled, of whom 92 were randomly assigned and 90 started treatment (45 in each treatment group). Six (13%) patients in the intensive cART group and two (4%) in the standard cART group discontinued before month 24. At month 24, HIV-DNA loads were similar between groups (2·35 [IQR 2·05-2·50] log₁₀ per 10(6) PBMC in the intensive cART group vs 2·25 [1·71-2·55] in the standard cART group; p=0·21). Eight grade 3-4 clinical adverse events were reported in seven patients in the intensive cART group and seven grade 3-4 clinical adverse events were reported in seven patients in the standard cART group. Three serious clinical adverse events occurred: two (pancreatitis and lipodystrophy) in the standard cART group, which were regarded as treatment related, and one event (suicide attempt) in the intensive cART group that was unrelated to treatment. INTERPRETATION: After 24 months, cART intensified with raltegravir and maraviroc did not have a greater effect on HIV blood reservoirs than did standard cART. These results should help to design future trials of treatments aiming to decrease the HIV reservoir in patients with primary HIV-1 infection. FUNDING: Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Laboratories.
RCT Entities:
BACKGROUND: Early combination antiretroviral therapy (cART) initiation at the time of primary HIV-1 infection could restrict the establishment of HIV reservoirs. We aimed to assess the effect of a cART regimen intensified with raltegravir and maraviroc, compared with standard triple-drug cART, on HIV-DNA load. METHODS: In this randomised, open-label, phase 3 trial, we recruited patients from hospitals across France. Inclusion criteria were primary HIV-1 infection (an incomplete HIV-1 western blot and detectable plasma HIV-RNA), with either symptoms or a CD4+ cell count below 500 cells per μL. Patients were randomly assigned (1:1) to an intensive, five-drug cART regimen (raltegravir 400 mg and maraviroc 150 mg twice daily, and a fixed-dose combination of tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) or a standard triple-drug cART regimen (tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) using a predefined randomised list generated by randomly selected variable block sizes. The primary endpoint was the median number of HIV-DNA copies per 10(6) peripheral blood mononuclear cells (PBMC) at month 24, analysed in the modified intention-to-treat population, defined as all patients who started their assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01033760. FINDINGS: Between April 26, 2010, and July 13, 2011, 110 patients were enrolled, of whom 92 were randomly assigned and 90 started treatment (45 in each treatment group). Six (13%) patients in the intensive cART group and two (4%) in the standard cART group discontinued before month 24. At month 24, HIV-DNA loads were similar between groups (2·35 [IQR 2·05-2·50] log₁₀ per 10(6) PBMC in the intensive cART group vs 2·25 [1·71-2·55] in the standard cART group; p=0·21). Eight grade 3-4 clinical adverse events were reported in seven patients in the intensive cART group and seven grade 3-4 clinical adverse events were reported in seven patients in the standard cART group. Three serious clinical adverse events occurred: two (pancreatitis and lipodystrophy) in the standard cART group, which were regarded as treatment related, and one event (suicide attempt) in the intensive cART group that was unrelated to treatment. INTERPRETATION: After 24 months, cART intensified with raltegravir and maraviroc did not have a greater effect on HIV blood reservoirs than did standard cART. These results should help to design future trials of treatments aiming to decrease the HIV reservoir in patients with primary HIV-1 infection. FUNDING: Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Laboratories.
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