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HIV Glasgow: 4-Days-On-3-Days-Off HIV Treatment Controls Viral Load in Pilot Study


An experimental "4 days on, 3 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 standard treatment for a median of 4 years, not people who had started therapy recently.

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Although people living with HIV are recommended to take antiretroviral drugs every day as prescribed, there is evidence from therapeutic drug monitoring analyses that adequate 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 2 consecutive doses and take a weekend off treatment. The FOTO study found that taking 2 days off treatment each week maintained viral suppression in people taking efavirenz-based antiretroviral therapy (ART), and a larger study conducted in Uganda found it was just as effective as continuous treatment. Similarly, the BREATHER study of adolescents and young adults found that taking 2 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, the ANRS-162-4D trial was designed to test whether 4 days on treatment and 3 days off treatment each week maintained viral suppression in people with undetectable viral load. A 4-day regimen may suit those with a standard working week who do not wish to think about taking medication over the weekend. In this study participants were offered 2 patterns of pill-taking: take medication each day from Monday to Thursday, or take medication each day from Tuesday to Friday. This schedule also reduces the cost of treatment.

The study recruited 100 people taking a standard 3-drug ART regimen of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and either a boosted protease inhibitor (29%) or a NNRTI (71%). At the time of study entry participants had undetectable viral load for a median of 4 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 2 consecutive viral loads above 50 copies/mL, taken 2 to 4 weeks apart, or discontinuing the study strategy for more than a month. After 48 weeks of follow-up, 96 of 100 participants had maintained viral suppression below 50 copies/mL. There were 3 participants who experienced virological rebound and another who discontinued the treatment strategy after 4 weeks.

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

The NNRTI etravirine (Intelence), taken by 5 participants, was the only agent that maintained effective drug 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 (Sustiva, 40 people), rilpivirine (Edurant, 26 people), darunavir (Prezista, 15 people), atazanavir (Reyataz, 15 people), and lopinavir (Kaletra, 1 person) 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 NRTIs. 90 of the 100 participants were taking tenofovir (Viread, also in Truvada and single-tablet regimens) 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 on the treatment strategy. There is some evidence that a lower level of HIV DNA is associated with slower viral rebound after treatment interruption.

Virological rebound occurred in 3 people, 2 of whom were taking abacavir (Ziagen, also in Epzicom) in combination with a boosted protease inhibitor. Rebound was detected 4, 12, and 40 weeks after starting the new schedule. 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 9 days later. In the 2 other cases, viral load rose above 200 copies/mL but was subsequently re-suppressed. All participants who experienced rebound reported 100% adherence to the study strategy.

An adherence sub-study, previously presented at the International AIDS Conference in July 2016, examined adherence as assessed by electronic pill bottle caps and self-report in 26 participants. The sub-study found that MEMS caps were opened on exactly 4 days a week over a median of 44 weeks during the study, but were opened less frequently than 4 days a week over a median of 4 weeks. Self-reports of adherence during the previous week showed that 21% reported taking less 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 glycemia was observed. Cholesterol and triglycerides did not change significantly. There were 7 serious adverse events reported during the study, but these were not considered to be treatment-related.

ANRS is planning a larger follow-up study, QUATUOR, which will randomize 640 people to continuous or 4-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 2 years to check virological outcomes and the impact on side effects and quality of life.



JC Alvarez, P de Truchis, E Abe, 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). HIV Drug Therapy 2016. Glasgow, October 23-26, 2016. Abstract P081.

P de Truchis, L Assoumou, R Landman, et al. Efficacy of a maintenance four-days-a-week regimen: the ANRS162-4D trial. 21st International AIDS Conference (AIDS 2016). Durban, July 18-22. Abstract THPEB 063