For HIV-positive people whose anti-retroviral therapy is lifelong, simplification of treatment use can lower the rates of side effects, treatment costs, improve acceptability and adherence.
ANRS (National Agency for AIDS Research) 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 anti-retrovirals 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 antiretroviral therapy for four times a week was not inferior to the everyday regimen. It had the same efficacy and patients experienced fewer side effects and better adherence.’
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, non-randomized trial (ANRS 162-4D) run by Professor Christian Perronne (Hôpital Raymond Poincaré, Garches, France) in which patients received the same anti-retroviral 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 anti-retroviral therapy for an average of 5 years and their viral load had been undetectable for 4 years. Their combination therapy comprised 2 nucleoside analogs 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 the 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.