A new “four days on, three days off“ antiviral regimen controls viral load, French pilot study says

An experimental `four days on, three days off` antiretroviral regimen kept viral load fully suppressed in 96% of people for 48 weeks in a French study presented at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) last week.

The study recruited people whose viral load had been fully suppressed on treatment for a median of four years, not people who had started treatment recently.

Although people living with HIV are recommended to take antiretroviral drugs every day as prescribed, there is evidence from therapeutic drug monitoring that sufficient blood levels of many antiretroviral drugs persist for several days after dosing, keeping HIV under control even when a single dose is missed.

Several clinical trials have investigated whether it is possible to miss two consecutive doses and take a weekend off treatment. The FOTO study found that taking two days off treatment each week maintained viral suppression in people taking efavirenz-based treatment, and a larger study conducted in Uganda found it was just as effective as continuous treatment. The BREATHER study in adolescents and young people found that taking two days off efavirenz-based treatment each week was just as likely to keep viral load suppressed as daily treatment, and was highly acceptable to this group of people.

Sponsored by the French national HIV research agency ANRS, the ANRS-162-4D trial was designed to test whether four days on treatment and three days off treatment each week maintained viral suppression in people with undetectable viral load. A four-day regimen may suit those with a standard working week who do not wish to think about taking medication over the weekend. In the study participants were offered two patterns of pill-taking: take medication each day from Monday to Thursday, or take medication each day from Tuesday to Friday. The regimen also reduces the cost of treatment.

The study recruited 100 people taking a three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a boosted protease inhibitor (29%) or an NNRTI (71%). At the time of study entry participants had undetectable viral load for a median of four years.

Participants were predominantly male (82%) and white (81%). Approximately two-thirds were men who have sex with men.

Treatment failure in this study was defined as two consecutive viral loads above 50 copies/ml two to four weeks apart, or discontinuing the study strategy for more than one month. After 48 weeks of follow-up 96 of 100 participants had maintained viral suppression below 50 copies/ml. Three participants experienced virologic rebound and another discontinued the treatment strategy after four weeks.

Whereas short interruptions have been thought to maintain viral suppression because drug levels persist, this study found that even where drug levels declined to barely-detectable levels by the end of the off-treatment period, viral suppression was maintained.

Etravirine, taken by five participants, was the only agent that maintained effective concentrations by the end of the off-treatment period, but this observation may have been a consequence of the small number of people treated with the drug. Average levels of efavirenz (40 persons), rilpivirine (26), darunavir (15), atazanavir (15) and lopinavir (1) were sub-therapeutic by the end of the off-treatment period.

The researchers reported on drug levels of the protease inhibitor or NNRTI in the regimen but did not evaluate the levels of the nucleoside reverse transcriptase inhibitor (NRTI). Ninety of the 100 participants were taking tenofovir as part of their regimen. Tenofovir concentrations take 50 hours to decline by half from peak levels in cells, resulting in prolonged antiviral activity, suggesting that tenofovir may have contributed to viral suppression in the absence of other drugs.

Intracellular DNA levels, indicating the size of the HIV reservoir in cells, were relatively low, at 2.4 log, both at baseline and after 48 weeks of the treatment strategy. There is some evidence that a lower level of HIV DNA is associated with slower viral rebound after treatment interruption.

Virologic rebound occurred in three people, two taking abacavir-based treatment in combination with a boosted protease inhibitor. Rebound was detected 4, 12 and 40 weeks respectively after starting the new regimen. In one case the pattern of rebound suggested a viral blip – viral load was 124 copies/ml at the week 12 visit and had fallen to 55 copies/ml when tested again nine days later. In the two other cases, viral load rose above 200 copies/ml but was subsequently resuppressed.

All participants who experienced rebound reported 100% adherence to the study strategy.

An adherence sub-study, previously presented at the 21st International AIDS Conference (AIDS 2016) in Durban in July 2016, examined adherence by electronic pill bottle caps and self-report in 26 participants. The substudy found that MEMS caps were opened on exactly four days a week in a median of 44 weeks during the study, but were opened less frequently than four days a week in a median of four weeks during the study. Self-report of adherence during the previous week showed that 21% reported taking fewer than 80% of their medication on at least one visit and only 6% reported 100% adherence at one visit.

Liver enzyme levels (AST, ALT and GGT) declined significantly during the follow-up period. A modest but statistically significant increase in glycaemia was observed. Cholesterol and triglycerides did not change significantly. Seven serious adverse events occurred during the study but were not considered to be treatment-related.

ANRS is planning a larger follow-up study, QUATUOR, which will randomise 640 people to continuous or four-day-a-week treatment. The trial will include people taking integrase inhibitors in order to reflect newer treatment recommendations, and will follow patients for up to two years to check virological outcomes and impact on side-effects and quality of life.

De Truchis P et al. Efficacy of a maintenance four-days-a-week regimen: the ANRS162-4D trial. 21st International AIDS Conference (AIDS 2016), Durban, South Africa, abstract THPEB 063, 2016. (Poster available at AIDS 2016 website).

Alvarez JC et al. Efficacy of antiretroviral drugs during intermittent maintenance treatment with a 4-days-a-week regimen despite low plasma concentrations (ANRS 162-4D trial). International Congress on Drug Therapy in HIV Infection (HIV Glasgow), abstract P081, 2016.