Islatravir plus doravirine maintains viral suppression for a year

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Islatravir, the first nucleoside reverse transcriptase translocation inhibitor, plus the non-nucleoside reverse transcriptase inhibitor doravirine (Pifeltro) kept viral load suppressed for 48 weeks with only a small number of study participants experiencing virological failure, researchers reported at the 23rd International AIDS Conference (AIDS 2020: Virtual). Thus, this well-tolerated two-drug regimen may offer a new simplified maintenance therapy option.

Islatravir (formerly known as MK-8591 or EFdA) works in two ways, both halting construction of new viral DNA by acting as a defective building block and acting at a later step in the viral replication process. Previous studies showed that it has more than tenfold greater potency than other approved antiretrovirals, is active against HIV with drug-resistance mutations and has a long half-life in the body. Islatravir is being studied for long-acting pre-exposure prophylaxis (PrEP) as well as for HIV treatment.

Professor Chloe Orkin of Queen Mary University of London presented the latest findings from a phase 2b study evaluating the safety and efficacy of islatravir plus doravirine versus a three-drug regimen of doravirine, tenofovir disoproxil fumarate (TDF) and lamivudine, the drugs in the Delstrigo single-tablet regimen.

Glossary

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

viral rebound

When a person on antiretroviral therapy (ART) has persistent, detectable levels of HIV in the blood after a period of undetectable levels. Causes of viral rebound can include drug resistance, poor adherence to an HIV treatment regimen or interrupting treatment.

detectable viral load

When viral load is detectable, this indicates that HIV is replicating in the body. If the person is taking HIV treatment but their viral load is detectable, the treatment is not working properly. There may still be a risk of HIV transmission to sexual partners.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

This randomised, double-blind trial enrolled 121 previously untreated people with no known antiretroviral resistance. More than 90% were men, three-quarters were white and the median age was 28 years. About a quarter had a viral load above 100,000 copies/ml at baseline.

In part 1 of the study, participants were randomly assigned to receive islatravir at one of three doses (0.25mg, 0.75mg or 2.25mg) plus doravirine (100mg) and lamivudine (300mg), or to receive Delstrigo, for 24 weeks. In part 2, those in the islatravir arm who achieved an undetectable viral load (below 50 copies/ml) dropped lamivudine and stayed on the two-drug regimen through week 48.

The efficacy results from the study were presented at the International AIDS Society Conference on HIV Science last summer in Mexico City. Those results showed that the dual combination at the optimal dose (0.75mg) suppressed viral load at least as well as the three-drug regimen, with 90% versus 84% having undetectable viral load at 48 weeks.

Orkin focused on study participants who stopped the islatravir regimen with protocol-defined virological failure (PDVF). Regardless of regimen, a small proportion of people who start antiretroviral therapy continue to have low-level virus, especially if they start with a high level, she noted as background.

PDVF was defined conservatively to include both non-response and viral rebound, according to Orkin. Participants with PDVF were required to stop the study and return to a standard regimen.

Non-response was defined as having either a viral load of 200 copies/ml or higher at any time between weeks 24 and 48 or a confirmed (repeated on a second test within two weeks) viral load of 50 copies/ml or higher at week 48. Viral rebound was defined as either a viral load of 50 copies/ml or higher after achieving viral suppression or a greater than 1 log10 increase in HIV RNA after seeing a 1 log10 decrease from the baseline level.

Six participants experienced PDVF. Viral rebound was experienced by two people (7%) in the 0.25mg islatravir group, two (7%) in the 0.75mg islatravir group, and one (3%) in the Delstrigo group. There was one non-responder (3%) in the 2.25mg islatravir group.

In all these cases, viral load remained at a low level – below 100 copies/ml – and no one had a confirmed viral load of 80 copies/ml or more. A viral level of 200 copies/ml or more is considered 'clinically significant', Orkin noted. None of these participants met the criteria for drug resistance testing (400 copies/ml).

Even after they switched from islatravir plus doravirine to another regimen, three of the six participants continued to have low-level detectable viral load during 42 weeks of follow-up.

Rates of PDVF were low and all participants who discontinued the regimen due to PDVF had HIV levels below the clinically significant level of 200 copies/ml, the researchers concluded. This low-level viraemia was comparable to levels seen in past studies of previously untreated people.

Islatravir plus doravirine side effects

In a related presentation, Dr Edwin DeJesus of the Orlando Immunology Center in Florida described 48-week safety results from the same clinical trial.

Treatment was generally safe and well tolerated. Overall, side effects occurred with similar frequency in all islatravir dose groups and the Delstrigo group. In all treatment arms, adverse events were reported more often during the first 24 weeks of treatment compared with the second 24-week period, DeJesus noted.

"Phase 3 trials for previously untreated people and for those who wish to switch from another regimen after achieving viral suppression are currently underway."

During the first period, five people in the combined islatravir groups (6%) and six people in the Delstrigo group (19%) reported any drug-related adverse event. In the second period, three people in the islatravir groups (4%) and one in the Delstrigo group (4%) reported such events. Two islatravir recipients (2%) and one Delstrigo recipient (4%) stopped treatment due to adverse events.

Headache was reported more frequently in the combined islatravir groups compared with the Delstrigo group (11% vs 7%), while diarrhoea was more common in the Delstrigo arm (7% vs 16%, respectively). About 9% in both groups experienced nausea.

Islatravir plus doravirine had minimal effect on liver or kidney function biomarkers, or on metabolic parameters including blood glucose and total cholesterol levels.

Looking at body weight – a growing concern for people starting antiretroviral – 38% of participants in the combined islatravir groups and 23% in the Delstrigo group had a weight increase of at least 5%. This primarily occurred during the first 24 weeks and may reflect a 'return to health' effect, DeJesus suggested.

The researchers concluded that islatravir plus doravirine was well tolerated regardless of dose through 48 weeks. Adverse events were usually mild and transient and did not lead participants to drop out of the study.

The 0.75mg dose of islatravir has been selected for further development, Orkin noted. Phase 3 trials for previously untreated people and for those who wish to switch from another regimen after achieving viral suppression are currently underway.

References

Orkin C et al. Analysis of protocol defined virologic failure through week 48 from a phase 2 trial (P011) of islatravir and doravirine in treatment-naïve adults with HIV-1 infection. 23rd International AIDS Conference, abstract OAB0302, 2020.

DeJesus E et al. Islatravir safety analysis through week 48 from a phase 2 trial in treatment naive adults with HIV-1 infection. 23rd International AIDS Conference, abstract OABO305, 2020.