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Studies of intermittent ART

When potent HIV treatment (antiretroviral therapy, ART) was first introduced in 1996, it saved people’s lives and prevented AIDS. This was the first time combination therapy had been shown to do that on a sustained basis. However, excitement about early regimens was tempered by their complexity. Most regimens in those days required twice or even three-times daily dosing. In some cases, there were strict food and water requirements that accompanied ART. People sometimes had to take a fistful of pills several times daily. Early regimens could also cause distressing side effects, including changes in appearance and body shape. All of these issues made adherence challenging.

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In France

For at least the past decade, doctors in France have been conducting studies of intermittent ART—usually taken for four or five consecutive days with two or three days off. In 2022 they published results after one year of intermittent vs. continuous therapy. In the study, called Quatuor, participants whose viral loads were suppressed, thanks to several years of daily ART, were randomly assigned to one of the following regimens:

  • continued daily ART
  • intermittent ART – four days on ART followed by three days off, then four days on ART and so on

An analysis of 636 participants (318 people per group) found that after one year the following proportions of participants had a suppressed viral load:

  • continued daily ART – 97%
  • intermittent ART – 96%

This difference was not significant. Furthermore, it indicated that, statistically, intermittent ART was no worse and no better (in its effectiveness) than daily ART. The technical term for this result is non-inferior.

Surveys found that people on intermittent ART had improved quality of life.

Reassuringly, there was no increase in inflammation and no excess risk of blood clot formation (seen in some earlier trials of intermittent ART). In those earlier trials, the period off ART was also longer, weeks or months. 

There were 10 cases of virological failure in the study, distributed as follows:

  • continued daily ART – 4 people (1%)
  • intermittent ART – 6 people (2%)

Researchers found that more people in the intermittent ART group who developed virological failure were more likely to have HIV that was resistant to treatment (three out of six people vs. one of four people on continuous ART).

Reservoirs

Although good adherence helps keep ART suppressed, a small proportion of cells of the immune system still contain HIV. Scientists refer to this pool of infected cells as the “reservoir.” Infected cells can be found deep within the lymph nodes and tissues, the spleen, the brain and the testicles (to name a few places). 

The French researchers analysed blood and semen samples for the level of infected cells. Overall, they found no significant differences between people on the two interventions; that is, the pool of infected cells was not different between the two groups. This finding is reassuring and suggests that the size of the HIV reservoir did not increase in people on either study regimen.

Note well

At publication time, intermittent therapy as used in the Quatuor study is not recommended by leading U.S. guidelines or guidelines produced by the European AIDS Clinical Society. Such guidelines influence the prescribing practices of doctors in Canada and other countries. 

However, some doctors in France (and their patients) are enthusiastic about intermittent ART.

It is important to note that when they entered the study, participants had, on average, the following characteristics:

  • highly adherent on their previous regimens
  • their CD4+ count had never fallen significantly below the 300 cell/mm3 mark
  • their CD4/CD8 ratio was at least 1.0, which indicates a normalization of their immune system
  • their current CD4+ count was nearly 700 cells/mm3
  • HIV in blood samples was susceptible to all the drugs in their ART regimen
  • they did not have chronic or active hepatitis B virus (HBV) and/or hepatitis C virus (HCV)
  • most participants (85%) were male

Thus, overall, participants in Quatuor may not be representative of the average person with HIV, and intermittent ART may not be suitable for many people.

Beyond Quatuor

People enrolled in Quatuor in 2017 and 2018 and used classes of HIV drugs that are not as commonly used today, such as protease inhibitors and non-nukes (non-nucleoside reverse transcriptase inhibitors). They also used integrase inhibitors that may not be as widely used today, such as raltegravir (Isentress) and elvitegravir (in Genvoya and Stribild).  

Today, the following combinations of drugs are widely used or recommended for HIV treatment by U.S. HIV guidelines:

  • bictegravir (in Biktarvy, a combination of bictegravir + TAF + FTC)
  • dolutegravir (in Dovato, a combination of dolutegravir + 3TC)
  • cabotegravir (in Cabenuva, cabotegravir + rilpivirine given by injection ultimately once every two months)
  • doravirine (Delstrigo, Pifeltro)

These drugs are generally well tolerated and highly effective.

For doctors who have concerns about their patients taking multiple HIV drugs, perhaps some two-drug regimens (mentioned earlier) may be an option. For doctors who have patients with adherence difficulties, perhaps regimens such as Cabenuva, which ultimately require injections every two months, may be an option. Longer periods between dosing of Cabenuva are under investigation. 

Pharmaceutical companies are developing other complete regimens with just two drugs, and they are also developing other long-acting regimens that require infrequent dosing. Thus, the landscape of daily oral dosing, which was the only option when intermittent ART  was initially developed, has changed. Furthermore, additional options will become available in the future. 

French researchers should be praised for exploring and testing patient-friendly regimens. Expect to see more results from clinical trials of intermittent ART in the future. Hopefully, there will be long-term studies of intermittent ART in hundreds of participants so that doctors can understand the potential of such regimens over the long-term.

Intermittent Biktarvy

The French studies have inspired doctors in Taiwan. A one-year pilot study there with intermittent vs. daily Biktarvy has been completed with 60 participants. Preliminary analysis of this trial—five days on ART, two days off (FOTO)—has found that both schedules had similar effectiveness. The doctors in Taiwan stated that their results provide a foundation for designing a much larger (and hopefully longer) study. 

—Sean R. Hosein

REFERENCES:

  1. Landman R, de Truchis P, Assoumou L, et al. A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial. Lancet HIV. 2022 Feb;9(2):e79-e90.
  2. Lambert-Niclot S, Abdi B, Bellet J, et al. Four days/week antiretroviral maintenance strategy (ANRS 170 QUATUOR): substudies of reservoirs and ultrasensitive drug resistance. Journal of Antimicrobial Chemotherapy. 2023 Jun 1;78(6):1510-1521. 
  3. Abe E, Landman R, Assoumou L, et al. Plasma concentrations of antiretroviral drugs in a successful 4-days-a-week maintenance treatment strategy in HIV-1 patients (ANRS 170-Quatuor trial). Journal of Antimicrobial Chemotherapy. 2024 Jun 3;79(6):1380-1384. 
  4. Sun HY, Lin YT, Liu WC, et al. Five-day-on-two-day-off (FOTO) vs daily BIC/FTC/TAF: a proof-of-concept randomized clinical trial. 25th International Conference on AIDS, Munich, Germany, 22-26 July 2024. Abstract WEPEB107.