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 recently at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow).

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, and led by Jean Claude Alvarez, AP-HP and Universit de Versailles Saint-Quentin en Yvelines, Garches, France,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 re-suppressed.

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 sub-study 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.

Abstract 1
Introduction: In the absence of virologic eradication despite combination of antiretroviral therapy, patients infected by HIV have to take the treatment throughout their life. Intermittent regimen could be an alternative for those as evocated in previous studies (FOTO, BREATHER).
Material and methods: An open-label, multicentre, single-arm prospective study had been conducted to evaluate the capacity of a weekly strategy of 4 consecutive days treatment (“period on”) followed by 3 days without treatment (“period off”), in HIV-1 patients with undetectable viral load for at least 12 months. Patients had no treatment modification in the past 6 months, and were on two nucleosides analogues and either boosted protease inhibitor (PI/r) or a NNRTI. Plasma antiretroviral residual concentrations on “period on” collected at day 0, week 16, week 40 and on “period off” collected at week 4, week 8, week 12, week 32 and week 48 were measured using a validated turbulent flow chromatography method coupled to triple quadrupole mass spectrometry detection with electrospray ionization interface. The laps between the last medication intake and the sample collecting time over 48 hours were considered as off period samples.
Results: Among the 100 patients included, 12 drug combinations were used: TDF+FTC (n=89), ABC+3TC (10), ABC+TDF (1) combined with a PI/r for 29 (DRV/r: 15; ATV/r: 13; LPV/r: 1) or a NNRTI for 71 (EFV: 40; RPV: 26; ETV: 5). After 48 weeks, 96% (95% CI 90-98, Kaplan-Meier estimate) were still under intermittent 4/7 days regimen without failure. In total, 877 samples were analyzed (292 “on” and 585 “off”). A total of 94.4% of plasma samples are consistent with the timing. Significant differences had been observed between “on” concentrations and “off” concentrations for DRV (2587±1393 ng/mL vs. 17±18 ng/mL, p<0.0001), ATV (1087±644 ng/mL vs. 52±146 ng/mL, p=0.0005), LPV (39±22 ng/mL vs. <20 ng/mL), EFV (2218±1046 ng/mL vs. 692±391 ng/mL, p<0.0001) and RPV (106±51 ng/mL vs. 3920 ng/mL, p<0.0001). Many PI were undetectable on “off” period. For ETV (447±360 ng/mL vs. 269±266 ng/mL, p=0.0625) only a tendency was observed, probably because of low number of patients in this group. All “on” concentrations were in accordance with French guidelines.
Conclusion: A total of 96% of patients maintained viral load undetectable despite low or undetectable plasma concentrations after 3 days of treatment interruption on a 4-days-a-week regimen. PI plasma samples were almost always undetectable since NNRTI ones were decreased but above the limit of quantification according to their longer half-lives.

Jean Claude Alvarez; Pierre De Truchis; Emuri Abe; Lambert Assoumou; Roland Landman; Dominique Mathez; Karine Amat; Christine Katlama; Pierre Marie Girard; Damien Le Du; Martin Duracinsky; Dominique Costagliola; Jonathan Bellet; Christian Perronne

Abstract 2
Background: Previous studies (FOTO, BREATHER) have given encouraging results with a 5/7days efavirenz-based maintenance regimen. Based on pilot experience (Leibowitch, FASEBJ 2015), we conducted a 48-week multicenter, open-label, single-arm prospective study evaluating efficacy and safety of a 4/7days maintenance therapy in HIV infected patients with controlled VL.
Methods: The main inclusion criteria were age>18 years; current regimen with 2 nucleoside analogs and either a boosted protease inhibitor PI/r or a NNRTI; no treatment modification in the last 6 months; VL<50 c/ml for at least one year; no resistance mutation to the drugs in the current regimen. Maintenance therapy used the same regimen, taken 4 consecutive days of each week. Virological failure (VF) was defined as VL>50 c/ml confirmed within 4 weeks between D0-W48. Patients were evaluated at D0, W4, W8, W12, W16, W24, W32, W40, and W48. The study was designed to show that the efficacy of the strategy is superior to 80%, assuming a success rate equal to or above 90%, with a power of 87% and a 5% type-one error. Values are presented as median [range]. Adherence to therapy was assessed by questionnaires, pill count, and MEMS caps for a subgroup of patients.
Results: One hundred patients were included in the study, 82 men and 18 women, median age 47[25-75], CD4 nadir 282[7-1044] cells/µl, and receiving ARV therapy since 5.1[1.3-25.2] years with VL<50 since 4.1[0.5-15.5] years. Current regimen included tenofovir-DF+FTC (89 patients) or abacavir+3TC (11 patients), combined with a PI/r for 29 individuals (lopinavir/r:1, atazanavir/r:13, darunavir/r:15) or a NNRTI for 71 (EFV:41, RPV:25, ETV:5). After 48 weeks, 96% [95% CI 90-98, Kaplan-Meier estimate] were still under maintenance 4/7days regimen without failure; 1 patient returned to 7/7 regimen and left the study at W4, VF was confirmed in 3/100 patients at W4, W8, W40, with VL 785, 124, and 969 c/ml respectively. These 3 patients returned to 7/7 regimen and VL was subsequently suppressed in all 3.  
Conclusion: Over 48 weeks, maintenance ARV therapy with a 4 days a week regimen was effective in these patients with suppressed VL under 2 nucleosides and either a PI/r or a NNRTI, resulting in a success rate of 96%.

P de Truchis, L Assoumou, R Landman, D Mathez, J Bellet, K Amat, C Katlama, PM Girard, D Le Du, J Izopet, B Autran, M Duracinski, JC Alvarez, D Costagliola, C Perronne

Aidsmap material
HIV Glasgow abstract P081
AIDS 2016 abstract

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