Short cycle Antiretrovirals: on the road to treatment 4 days a week
Triple antiretroviral therapy taken just 4 days a week, instead of daily, kept plasma viral load below 50 copies/mL in 96 of 100 patients in the study ANRS 162-4D. Dr Pierre de Truchis (Hôpital Raymond Poincaré, Garches, France) will present these findings at AIDS 2016 in Durban, South Africa (18 to 22 July). A larger, randomized study, ANRS QUATUOR, will start in late 2016 in order to confirm these data over a longer period.
Simplification of treatment use is designed to lower rates of side effects and treatment costs, and to improve acceptability and adherence. It is important for people living with HIV, whose antiretroviral therapy is lifelong. This is why it is being studied in several trials worldwide. ANRS is assessing the value of reducing drug dosages or their frequency, and the value of sparing treatment options. In France, the ANRS 165 DARULIGHT trial is evaluating the benefits of halving the daily dose Darunavir ; ANRS 167 LAMIDOL is assessing combination therapy with Lamivudine and Dolutegravir, and ANRS 163 ETRAL is evaluating another combination therapy, Etravirine-Raltegravir. The ANRS 162-4D trial is studying the effect of limited frequency of antiretrovirals intake. Dr Pierre de Truchis (Hôpital Raymond Poincaré, Garches, France) presents the results of ANRS 162-4D in a poster at AIDS 2016 in Durban, South Africa (18 to 22 July).
The ICCARRE project headed by Professor Jacques Leibowitch (Infectious Diseases Department, Hôpital Raymond Poincaré, Garches, France) yielded encouraging results in patients whose treatment was reduced to 5 and then to 4 days a week, or even less for some patients (FASEB Journal, 2015).
To confirm these observations, in 2014 the ANRS started a prospective, multicenter, nonrandomized trial (ANRS 162-4D) run by Professor Christian Perronne (Hôpital Raymond Poincaré, Garches, France) in which patients received the same antiretroviral treatment regimen over 48 weeks. The aim was to assess whether treatment taken on 4 consecutive days a week by HIV-positive patients would keep plasma viral load below 50 copies/mL. The 100 patients had been taking triple antiretroviral therapy for an average of 5 years and their viral load had been undetectable for 4 years. Their combination therapy comprised 2 nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor.
The results presented in Durban are encouraging. After 48 weeks, 96% of patients were still on the 4 days a week regimen and had a viral load below 50 copies/mL. Only three patients had a detectable viral load at weeks 4, 12, and 40 (respectively, 785, 124, and 969 copies/mL). In these patients, viral load dropped below the detection threshold upon return to the 7 days a week treatment regimen, without appearance of resistance. One patient dropped out of the study at week 4.
These data were completed by a concomitant analysis of treatment adherence in a subgroup of patients using self-report questionnaires, assays of blood drug levels, and counting of drug doses taken using electronic pillboxes. Dr Pierre de Truchis noted that “The analysis of treatment adherence showed that the 4 times a week regimen was well adhered to and accepted by the patients. In over 90% of cases, drug intake matched the prescription.”
This innovative strategy now needs to be confirmed in a randomized trial comparing two groups of patients. This is the aim of ANRS QUATUOR, a trial which will be conducted in more patients over a longer period using more recent antiretrovirals such as integrase inhibitors, which are now the mainstay of treatment. Of 640 patients recruited in several hospital centers, half will receive treatment 4 days a week and the other half 7 days a week, for 48 weeks. If similar results are noted in the two groups, all patients will be put on the 4 times a week regimen for a further 48 weeks. The aim is to show that the 4 times a week regimen is not inferior to the everyday regimen, ie, the efficacy is the same and the patients on treatment 4 days a week experience additional benefits (fewer side effects, better adherence…).
Professor Jean-François Delfraissy, Director of ANRS, observed that “These results encourage us to pursue our aims of improving quality of life on treatment and meeting a strong demand from some patients for a lower drug burden.” Should the 4 days a week regimen now be recommended in everyday practice? “Only a randomized trial will be able to approve this strategy,” says Professor Delfraissy. Current international recommendations stipulate that continuous treatment should be initiated as soon as possible after discovering positive HIV serostatus, regardless of CD4 cell count.
Founded in 1988, the French Research Agency ANRS brings together researchers from different fields and institutions in the developed world and resource-limited countries to work on scientific questions regarding HIV/AIDS or viral hepatitis. The ANRS funds research projects approved by international expert committees. It oversees projects from conception to completion and ensures that the results are used for the benefit of the populations concerned. Its annual budget of around 45 million euros is provided by the ministries in charge of Research and Health. Since 2012 it has been an autonomous agency of Inserm (French National Institute of Health and Medical Research).
Efficacy of a maintenance four-days-a-week regimen, the ANRS162-4D trial
P. de Truchis(1), L. Assoumou(2), R. Landman(3), D. Mathez(4), K. Amat(3), C. Katlama(5), P.M. Girard(6), D. Le Du(7), J. Izopet(8), B. Autran(9), M. Duracinski(10), J.C. Alvarez(11), D. Costagliola(2), C. Perronne(12)
1) APHP Hopital Raymond Poincare, CHU Paris Ile de France Ouest, Infectious Diseases, Garches, France, 2) Institut Pierre Louis Epidemiologie et Sante Publique, INSERM, UPMC Universite Paris 6, Paris, France, 3) IMEA, APHP CHU Bichat, Paris, France, 4) APHP CHU Paris Ile de France Ouest, Virology, Garches, France, 5) APHP Hopital Pitie-Salpetriere, Universite Paris 06, Infectious Diseases, Paris, France, 6) APHP Hopital St Antoine, Universite Paris 06, Paris, France, 7) APHP Hopital R Poincare, Garches, France, 8) CHU Toulouse, Hopital Purpan, Virology, Toulouse, France, 9) APHP Hopital Pitie-Salpetriere, Universite Paris 06, Immunology, Paris, France, 10) APHP CHU Bicetre, Paris, France, 11) APHP Hopital R Poincare, Universite Versailles St Quentin, INSERM U 1173, Pharmacology, Garches, France, 12) APHP Hopital R Poincare, Universite Versailles St Quentin, INSERM U 1173, Infectious Diseases, Garches, France