Dolutegravir used alone without other antiretrovirals was unable to keep viral load suppressed in some people who switched from a standard three-drug combination regimen, according to research presented at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) last month in Seattle. But evidence continues to show that dolutegravir plus a single other drug can work well as maintenance therapy.
In an effort to make antiretroviral therapy (ART) more convenient, better tolerated and less expensive, researchers have tried to simplify HIV treatment by reducing the number of drugs in maintenance regimens for people who have achieved undetectable viral load on multi-drug combinations.
Dolutegravir (Tivicay) is a potent and well tolerated integrase inhibitor with a high genetic barrier to resistance, making it a good candidate for simplified therapy.
Dolutegravir dual therapy
Results from the phase 3 SWORD trials, also presented at CROI, showed that people who switched from standard ART to a two-drug regimen of dolutegravir plus the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (Edurant) were able to maintain viral suppression for 48 weeks.
Another study at the conference showed that switching from a three-drug regimen to a dual combination of dolutegravir plus lamivudine (3TC or Epivir) maintained viral suppression for 40 weeks. Lamivudine is a well tolerated nucleoside reverse transcriptase inhibitor (NRTI) that is available in low-cost generic versions worldwide.
The French ANRS 167 Lamidol trial enrolled 110 participants with undetectable viral load (< 50 copies/ml) for at least two years on their initial ART regimen. They first substituted 50mg once-daily dolutegravir for their current NNRTI, protease inhibitor or integrase inhibitor. After eight weeks, those whose viral load was still suppressed – 104 people – replaced their current two NRTIs with 300mg once-daily lamivudine.
After 40 weeks on dolutegravir plus lamivudine, 97% of participants maintained viral suppression and are continuing in the study. One person experienced virological failure after four weeks on dual therapy, one was lost to follow-up and in one case the investigator decided to modify the regimen. Another two people experienced transient viral 'blips' but stayed on dual therapy.
"Switching to [dolutegravir + 3TC] combination maintained virologic suppression at week 40 [and] was safe and well-tolerated in this population of selected patients without previous virological failure," the researchers concluded.
As reported at the International AIDS Conference last July, the PADDLE pilot study showed that dolutegravir plus lamivudine led to sustained undetectable viral load in most people starting ART for the first time; the phase 3 GEMINI trials are evaluating this approach in a larger population.
But another study at the conference added to the evidence that a single antiretroviral drug is not enough to reliably maintain viral suppression when used alone.
Ingeborg Wijting of Erasmus University Medical Centre in Rotterdam and colleagues conducted a randomised trial to test whether dolutegravir monotherapy is non-inferior to standard combination ART.
The DOLUMONO study included 104 people at multiple centres in the Netherlands. Just over 90% were men and the median age was 46 years. At baseline they were on combination ART with HIV RNA < 50 copies/ml for more than six months, never more than 100,000 copies/ml, a CD4 count never less than 200 cells/mm3, no drug resistance and no history of virological failure.
Participants were randomly assigned to switch to 50mg once-daily dolutegravir monotherapy immediately, or to continue on their current combination regimen for 24 weeks then switch to dolutegravir monotherapy.
At week 24, the dolutegravir regimen appeared as effective as continued combination therapy: 98% and 100% in the respective arms maintained undetectable viral load, defined in this analysis as > 200 copies/ml.
But with longer follow-up, results began to diverge. Looking at the entire study population who switched to dolutegravir monotherapy either immediately or after 24 weeks, the viral suppression rate fell to 92% at week 48. This was significantly lower than the 98% suppression rate seen in a similar group of people who were not in the randomised study and stayed on continuous combination therapy through week 48 (p = 0.03).
By the time 77 people in the dolutegravir monotherapy arm had reached 48 weeks, eight of them had experienced virological failure. Of these, six underwent successful genotypic testing and three were found to have integrase resistance-associated viral mutations (N155H, R263K and S230R). They all restarted combination ART and were resuppressed to < 50 copies/ml within 12 weeks.
There were no clear risk factors for viral rebound. Among those who experienced virological failure, time on ART ranged from 2 to 14 years, highest-ever viral load ranged from 7420 to 99,270 copies/ml, and they switched from regimens containing dolutegravir, rilpivirine, efavirenz (Sustiva) or nevirapine (Viramune) plus two NRTIs. All of them reported excellent adherence.
"Whereas dolutegravir monotherapy was non-inferior to combination ART at week 24, virological failure continued to occur after week 24 and led to integrase resistance associated mutations in three patients," the researchers concluded.
"The genetic barrier against resistance of dolutegravir is insufficient to allow for maintenance monotherapy," they continued. "Future studies about maintenance therapy with dolutegravir should evaluate dolutegravir + 3TC rather than dolutegravir monotherapy."
In a recent editorial in the journal Antiviral Therapy, Joel Gallant and Jeremy Sugarman of Johns Hopkins discussed the ethics of using dolutegravir monotherapy in clinical practice in light of the mounting evidence that it can lead to treatment failure and drug resistance.
"Since lamivudine is a generic drug with virtually no toxicity, it seems more appropriate to study the two-drug combination before prematurely jumping to monotherapy," they wrote. "If monotherapy is to be studied at all – and the scientific rationale is debatable at best – it should be in the context of carefully controlled clinical prospective trials that maximize patient safety and include a robust informed consent process."
Joly V et al. Promising results of dolutegravir + lamivudine maintenance in ANRS 167 Lamidol trial. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 458, 2017.
Wijting I et al. Dolutegravir as maintenance monotherapy for HIV-1: a randomized clinical trial. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 451LB, 2017.
Gallant J and Sugarman J. Dolutegravir monotherapy: when should clinical practice be clinical research? Antiviral Therapy. 15 December 2016 (online ahead of print).