Four days on, three days off is NOT as effective as daily ART: French study results need to be interpreted with caution
Early results from a late-breaker study at IAS 2019 reported that reduced-dose ART had similar outcomes as a switch strategy compared to people who continued taking ART every day. However, this led to multidrug resistance in people with treatment failure and is therefore difficult to recommend, certainly not for people on rilpivirine or raltegravir. 
As background, studies that support less than daily dosing – FOTO in adults and BREATHER in children and young adults – used efavirenz/emtricitabine/TDF as these drugs all have long half-lives. Both these studies reported that this specific combination does allow dosing five days a week, with weekends off. [2, 3] A Spanish group also used this combination to drop down to only three doses a week but only included 30 people. 
In contrast, several French groups, have used reduced dosing irrespective of individual drugs. These have generally been small observational studies that are not powered to show either safety or efficacy. [5, 6]
The new results at IAS 2019 are controversial because a randomised study is seen as providing a high level of evidence. However, the detailed results showed there was a real risk of viral load rebound. And depending on the individual drugs in the combination, the rebound led to multidrug resistance.
Results were presented by Roland Landsman from Université Paris Diderot as a late-breaker oral abstract.
This study randomised 647 participants on stable ART (viral load < 50 copies/mL for >12 months) – and with no history of drug resistance – to either switch to 4 consecutive days per week (4/7) or to remain on daily 7-day ART (7/7). However, only 636 participants who started the study were included in the modified intent-to-treat analysis (318 in each arm) and only 623 were included in the per protocol analysis (n=313 vs 310).
Baseline characteristics were balanced between arms and included median age 49 years (IQR: 41 to 55); 85% were male; 78% were European, 14% African. Viral load was <50 copies/mL for a median of 5.8 years (IQR: 3.3 to 9.6) and median CD4 count was 689 cells/mm3 (IQR: 533 to 884). CD4 nadir was 298 cells/mm3 (IQR: 195 to 419).
Just under half the group were using either NNRTI- or integrase-based ART, with 6% using a boosted PI. The breakdown by dual NRTIs included TDF/FTC (56%), TAF/FTC (16%) and abacavir/3TC (27%).
The study enrolled very quickly, within four months – from September 2017 to January 2018 – and the last person reached week-48 follow-up by April 2019. The primary endpoint was viral suppression at week-48 with follow-up extending for another year (during which participants in the 7/7 arm switched to 4/4 dosing. Substudies will look at pharmacokinetic (PK) drug levels, markers of inflammation and immune activation, total DNA and viral load in semen and a quality of life survey.
At week 48, viral load remained undetectable in 95.6% in the 4/7 group vs 97.2% in the 7/7 group (adj. diff. –1.6%; 95% CI: –4.5% to 1.3%). This met the definition for non-inferiority using the predefined margin of 5% cut-off. It also met non-inferiority for treatment failure (1.9% vs 1.3%) using the FDA upper margin of 4%.
Viral failure was reported by 6 (1.9%) vs 4 (1.3%) participants in the 4/7 and 7/7 groups respectively.
In subgroup analyses, there were no differences by CD4 nadir, CD4:CD8 ratio, duration <50 copies/mL or previous viral failure. However, although not reported as statistically significant, numerically there were more viral failures in the 4/7 group in participants on INSTI-based ART (n=3 vs n=1), similar failure on NNRTIs (n=3 in each arm) and no viral failures in people using PI-based ART.
The two deaths in the 4/7 arm were due to cardiac arrest and lung cancer.
Summary details for the 10 cases of viral failure included that drug resistance was reported in 3/6 vs 1/4, respectively. All three of the participants in the 4/7 arm with drug resistance failed with two-class resistance (2 x rilpivirine + 3TC/FTC and 1 with raltegravir + 3TC/FTC). The single case of drug resistance in the 7/7 arm was to rilpivirine only.
Most of these cases of viral failure were detected very early, when viral load was confirmed at low levels in 3/4: at 105, 129, 230 and 75,000 copies/mL. Switching to three-drug ART brought viral load to <50 copies/mL.
Viral blips did not occur more frequently in the reduced dosing arm.
There were no differences in adverse events between the two arms, including for liver enzymes and lipid results, except for eGFR which significantly improved in the 4/7 arm: +5.5 mL/min (95% CI: –1.2 to +13.6 vs +1.3 mL/min (95% CI: –6.1 to +7.5), p<0.001.
Although the study concluded that this strategy could save money in high income settings, the presenter also wrongly suggested that this would enable more people to access ART in low income settings.
Firstly, results from a high income country with easy access to sensitive viral load and resistance testing cannot be transferred to countries where there are higher rates of background drug resistance, significantly fewer treatment options less access to sensitive monitoring (viral load tests commonly have a cut-off at 1000 copies/mL and are only available once a year).
Secondly, drug costs only make up a much smaller percentage of overall management costs in low- compared to high-income countries. Any short-term cost savings on drug could easily be lost on additional complications relating to management of HIV drug resistance.
The multidrug drug resistance results in participants on NNRTI or INSTI based ART whose viral load rebounded is more important than the non-inferiority findings.
In an earlier study these researchers reported that reduced dosing leads to suboptimal drug levels for some participants. The development of drug resistance in the context of sub-optimal drug levels is only a factor of luck and time and with longer follow up more people are likely to see their treatment fail.
The PK properties of rilpivirine make it especially unsuitable for anything other than daily dosing and this is probably also the case with integrase inhibitors.
Similarly, the low failure rate that allowed non-inferiority is likely to be explained by use of NRTIs with a long intracellular half-life, providing dual therapy cover for most of the three days off-ART. Drug resistance on dual therapy is just a matter of time and luck.
Also, France is a high-income country that has easy access to sensitive viral load tests and resistance tests for people in who this strategy fails.
Monitoring is likely to be more frequent in a clinical study than in routine care, with treatment failure detected very early. Less frequent monitoring (often 6-12 monthly) might lead to extensive drug resistance in a real world setting. This risks both the development of more complex drug resistance and HIV transmission.
This study does however provide good evidence that modern ART is easily able to cover odd missed doses, even if this is once or twice and for most weeks.
- Landman R et al. ANRS 170 QUATUOR 4/7 days maintenance strategy in antiretroviral treated adults with HIV-1 infection: an open randomised parallel non-inferiority phase III trial. 10th IAS Conference on HIV Science (IAS 2019), 21-24 July 2019, Mexico City. Late-breaker oral abstract WEAB0406LB.
- Cohen C et al. The FOTO study: The 48 week extension to assess durability of the strategy of taking efavirenz, tenofovir and emtricitabine Five days On, Two days Off (FOTO) each week in virologically suppressed patients. IAS 2009, Cape Town. Abstract MOPEB063.
- PENTA Study Group. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial. The Lancet HIV , Volume 3 , Issue 9 , e421 – e430. DOI: http://dx.doi.org/10.1016/S2352-3018(16)30054-6.
- Rojas J et al. Three-day per week Atripla maintains viral suppression and decreases sub-clinical toxicity: a pilot study. 18th International Workshop on Comorbidities and Adverse Drug Reactions in HIV, 12-13 September 2016, New York. Oral abstract O22.
- de Truchis P et al. Efficacy of a maintenance four-days-a-week regimen, the ANRS162-4D trial. AIDS 2016. Poster THPEB063.
http://programme.aids2016.org/PAGMaterial/eposters/0_5947.pdf (PDF poster)
- Collins S. Four day a week ART: sub-optimal drug levels but few virological failures. HTB 1 October 2016.