Doing More With Less: Moving Toward Intermittent ART Dosing Strategies for Extended Virologic Suppression in France

Key Takeaways

• Now that people with HIV have life expectancies similar to individuals without HIV, they can have many decades of exposure to antiretroviral therapy (ART).
• Intermittent ART dosing, may provide a way to decrease the therapeutic burden of ART without compromising efficacy.

One of the major goals of HIV antiretroviral therapy (ART) is to reach and maintain full HIV-1 RNA suppression. Unfortunately, with HIV, there is no cure, and there is no remission. Any discontinuation of the ART leads to viral replication rebound within 1-2 weeks. Therapy must continue for life, which is one of the challenges for individuals. 

The median age at initiation of treatment is between 30 and 40 years. Now that people with HIV (PWH) have life expectancies similar to individuals without HIV, that can mean 40-45 years of treatment. So, now we must address how we can best manage treatment for the long term and reduce the toxicities and secondary issues caused by therapy.

2-Drug vs 3-Drug Therapy
The pill burden required for viral suppression was alleviated with the consolidation of 3 separate medications into single-tablet ART regimens. Since then, research has addressed the question of whether we actually need 3 agents to demonstrate durable viral control, or if there are different combinations that might be comparatively effective.

The efficacy of monotherapy with protease inhibitors (PIs) was evaluated but commonly led to viral rebound. Then researchers moved on to dual therapy—a boosted PI plus lamivudine (3TC). The GARDEL study presented in 2013 showed noninferior virologic outcomes for 3TC plus lopinavir/ritonavir and a standard 3-drug regimen in ART-naive PWH. This was the first time these results were seen, but because the study treatment was 3 pills twice daily, there was little uptake in the real world.

More recently, the ANDES trial showed dual therapy with another boosted PI—darunavir/ritonavir plus 3TC—to be well tolerated and noninferior to a 3-drug combination in ART-naive PWH.

The GEMINI trial showed that the integrase strand transfer inhibitor (INSTI) dolutegravir paired with 3TC was as effective as a 3-drug regimen for ART-naive PWH. Viral suppression was the same, durability was good, and there was a reduction in drug-related adverse events, as well as improvements in renal and bone biomarkers. Previously we had had good results with dual therapy as a switch strategy that combined an integrase inhibitor plus 3TC and INSTIs plus nonnucleoside reverse-transcriptase inhibitors (NNRTIs), but I think GEMINI helped sway most guidelines to include dual therapy as a recommended option for ART-naive PWH.

Intermittent Antiviral Therapy
Another approach that has been very popular in France, where I practice, is intermittent therapy. BREATHER was the pilot trial for this approach and looked at efavirenz-based short-cycle therapy (5 days on and 2 days off) as a switch strategy for virologically suppressed PWH receiving 3-drug ART regimens. Short-cycle therapy was found to be noninferior to continuous therapy, with sustainable efficacy, for a median of 3.6 years.

The National Agency for Research on AIDS and Viral Hepatitis in France sponsored the QUATUOR study, which took the intermittent approach 1 step further by seeing if an undetectable HIV-1 RNA could be maintained with 3-drug ART taken only 4 days per week. Study participants were randomly assigned to receive either the intermittent regimen or their existing continuous maintenance regimen, stratified by the third therapeutic agent, most of which were NNRTIs or an integrase inhibitor. Participants receiving intermittent therapy took medication for 4 days—Monday through Thursday. (Note: There was nothing very magical about choosing these days; most patients simply love to be off on the weekends.) The data clearly showed that there was no difference in efficacy or durability over 48 weeks, with those receiving the intermittent regimen getting 40% less drug exposure at 40% of the cost compared with those receiving continuous therapy.

The intermittent approach also is being studied as a switch strategy for virologically suppressed PWH using dual therapy with dolutegravir/rilpivirine, dolutegravir/3TC, or darunavir/ritonavir/3TC given 4 days per week vs 7 days per week for 48 weeks (NCT04867083). This trial is still recruiting, but we are hoping to see some preliminary data within the next year.

Personally, I think it is important to decrease drug exposure on an individual basis as much as possible, as long as efficacy is not compromised. Since the triple-drug strategy was adopted in the early 2000s, we have learned much about the consequences of drug exposure. We have much more potent agents now, so as long as our goals of full viral suppression over extended periods with excellent tolerability are met, we should be promoting real-life individualized strategies. For example, we see approximately 4300 patients in my unit. Approximately one half are receiving a drug-reduced strategy with either dual therapy or intermittent therapy. So, I am interested to see data for 4-day dual-agent therapy. I think the future must provide a way to decrease the therapeutic burden without compromising efficacy—improving the overall experience for the patient and doing more with less.

Your Thoughts?
Have you used intermitted ART dosing for PWH in your practice? Join the discussion by posting a comment.