FDA Approval of DOR/ISL Expands HIV Treatment Options Beyond INSTIs: Amy Colson, MD, MPH

Following the recent FDA approval of the novel 2-drug HIV regimen combining doravirine and islatravir (DOR/ISL; Idvysno; Merck), providers are gaining a new option for patients who are virologically suppressed but may struggle with tolerability on standard therapies. As the first regimen of its kind to exclude both integrase strand transfer inhibitors (INSTIs) and tenofovir, the approval marks a notable shift in the evolving HIV treatment landscape, emphasizing simplification without compromising efficacy. In an interview with The American Journal of Managed Care^® (AJMC^®), Amy Colson, MD, MPH, an experienced HIV clinician, medical director of Cambridge Hospital's Zinberg Clinic, and research director of clinical trials at the Community Resource Initiative, discussed the unmet needs this regimen aims to address, the clinical trial data supporting its use, and its potential role in improving long-term management, particularly for aging patients navigating comorbidities and complex medication regimens.

This transcript has been lightly edited for clarity.

AJMC: This regimen is the first nonintegrase inhibitor 2-drug combination approved for HIV. What unmet need were you and your colleagues aiming to address with the DOR/ISL treatment, and why did you utilize this approach?

Colson: The availability of a simple 2-drug regimen, which doesn't include an integrase inhibitor or tenofovir, provides another treatment option for patients who are virologically suppressed but who may have difficulty tolerating an INSTI-based regimen due to INSTI side effects like sleep disturbance, mood change, diarrhea, nausea, or other symptoms potentially related to INSTI treatment.

AJMC: The studies demonstrated noninferior viral suppression at 48 weeks compared with established regimens. Were there any subgroup findings or secondary end points that you found particularly noteworthy?

Colson: In the safety realm, many of the findings were particularly noteworthy. At an islatrovir dose of 0.25 mg daily, DOR/ISL did not adversely affect lymphocyte or CD4 counts in either of the 051 or 052 trials, and there was no difference in mean change in CD4 count or lymphocyte count between the 2 treatment groups. These findings provide reassurance regarding the impact of islatravir on immune function. Tolerance was also high in the DOR/ISL group; switching to [DOR/ISL] had a similar safety profile to continuing baseline regimens in both trials. Few participants on [DOR/ISL] discontinued due to adverse events. The discontinuation rates due to adverse events were similar in the [DOR/ISL] arm and comparative regimens.

AJMC: Doravirine and islatravir have complementary mechanisms of action. How did this dual mechanism influence your expectations for efficacy and resistance compared with existing regimens?

Colson: They do have complementary mechanisms of action. Doravirine is an already approved, safe, and effective non-nucleoside reverse transcriptase inhibitor. And islatravir is a next-generation nucleoside reverse transcriptase inhibitor that inhibits reverse transcription through multiple mechanisms, including inhibiting the translocation of the reverse transcriptase enzyme and also through delayed chain termination. We expected, and we ultimately discovered, that the combination would present a potent and effective 2-drug combination.

AJMC: Islatravir previously raised concerns about lymphocyte reductions at higher doses. How were those concerns addressed in the final dosing strategy evaluated in these trials?

Colson: Based on modeling studies and simulation analyses, it was predicted that the islatravir dose of 0.25 mg, which was used in this study, would not impact lymphocyte count or CD4 count. And indeed, that's what both of the trials found, as we discussed, there was no impact on the CD4 count or lymphocyte count in either one of the trials.

AJMC: The approval is currently for patients who are already virologically suppressed. How do you envision clinicians identifying appropriate candidates for switching to this regimen?

Colson: That's an important question. [DOR/ISL] should only be used in people who are virologically suppressed with no history of treatment failure and no known doravirine-resistant mutations. Pro-viral DNA testing is not necessary for people who meet these criteria to determine eligibility for the combination. Idvysno should not be used in people who are taking medications that are considered strong or moderate CYP3A4 inducers. I would also just generally avoid [DOR/ISL] in people whose complete HIV treatment history is not known, as these individuals may have a prior history of treatment resistance or doravirine mutations.

AJMC: Given the persistent disparities in HIV care, how can innovations like DOR/ISL help improve access, adherence, or outcomes in these underserved populations?

Colson: It's important to recognize that [DOR/ISL] was tested in a really diverse patient population, including [that] in the blinded trial, 31% of participants were Black or African American and 23% identified as Latino. And in the open-label trial, 45% were Black and 15% identified as Latino. So, the diversity of the clinical trial populations enhances generalizability to the patients we may be seeing in our own clinic and indeed to the global HIV population. Access is a little difficult to comment on. In my practice, patients are facing challenges obtaining multiple medications, and these challenges could be the same for [DOR/ISL], and chief among these in my own practice is access to reasonable and continuous health insurance coverage.

AJMC: Is there anything else you’d like to highlight?

Colson: I would like to comment on the value of this medication for our patients who age. I have had my own clinical practice for about 27 years, and I am watching my patients face additional multimorbidity and polypharmacy, and I'm pleased to have an option to offer them, which is a simplified, 2-drug regimen.