Merck & Co., Inc. (NYSE: MRK) has reached a pivotal milestone in the HIV treatment landscape, announcing successful Phase 3 results for its once-daily oral regimen combining doravirine and islatravir (DOR/ISL). The data, presented at the 33rd Conference on Retroviruses and Opportunistic Infections (CROI 2026), confirms that the two-drug combination is non-inferior to the current gold standard, Biktarvy, marketed by Gilead Sciences (NASDAQ: GILD). With these results, Merck has solidified its path toward a potential regulatory approval, aiming to offer a potent non-integrase inhibitor (non-INSTI) alternative for millions of patients living with HIV-1.

The clinical success marks a significant redemption for islatravir, a compound that faced severe setbacks in 2021 due to safety concerns regarding immune cell counts. By recalibrating the dosage to a lower 0.25 mg concentration, Merck appears to have solved the safety riddle while maintaining high efficacy. The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for the regimen, with a high-stakes target action date (PDUFA) set for April 28, 2026.

Clinical Triumph: Redefining the HIV Treatment Paradigm

The Phase 3 program for DOR/ISL centered on three major trials: MK-8591A-052, MK-8591A-051, and MK-8591A-053. In the MK-8591A-052 "Switch Study," which focused on virologically suppressed adults, only 1.5% of participants who switched from Biktarvy to Merck’s DOR/ISL regimen had HIV-1 RNA levels ≥50 copies/mL at Week 48. This was statistically non-inferior to the 0.6% observed in those who remained on Biktarvy. Furthermore, 96-week follow-up data showed durable viral suppression at 88.9%, proving that the lower dose of islatravir did not sacrifice long-term control of the virus.

The safety data was perhaps the most scrutinized aspect of the presentation, given islatravir's history. In 2021, the FDA placed a full clinical hold on several islatravir programs after higher doses were linked to drops in total lifestyle and CD4+ T-cell counts. However, the current Phase 3 data for the 0.25 mg dose showed that changes in lymphocyte and CD4+ counts were comparable to those seen in the Biktarvy arm. No participants in the trial were forced to discontinue treatment due to immune cell depletion, effectively clearing the primary hurdle that had previously clouded the drug's future.

Market reactions have been cautiously optimistic, as Merck looks to diversify its revenue streams ahead of the late-decade patent cliff for its blockbuster cancer drug, Keytruda. Industry analysts noted that the "weight-neutral" profile of DOR/ISL—showing almost no weight change compared to the slight weight gain associated with Biktarvy—could be a decisive factor for clinicians and patients. This differentiator, combined with the non-INSTI mechanism, positions Merck to capture a significant niche of the market that has grown weary of the metabolic side effects common in modern integrase inhibitor-based therapies.

Competitive Fallout: A New Threat to Established Leaders

The primary "loser" in this development is Gilead Sciences (NASDAQ: GILD), whose flagship product Biktarvy (BIC/FTC/TAF) currently dominates the HIV market with over $12 billion in annual sales. While Biktarvy remains a highly effective and widely trusted treatment, Merck’s DOR/ISL is the first two-drug regimen to demonstrate such robust non-inferiority against it in a head-to-head switch trial. If approved, DOR/ISL could peel away patients who are experiencing weight gain or metabolic issues on Biktarvy, which currently affects approximately 20% of the patient population annually.

GSK plc (NYSE: GSK), through its specialist HIV company ViiV Healthcare, also faces a renewed challenge. GSK has pioneered the two-drug regimen space with Dovato (dolutegravir/lamivudine). However, Merck’s combination offers an alternative mechanism of action (non-INSTI), which is a critical option for patients who develop resistance or intolerance to the integrase inhibitors that form the backbone of both Biktarvy and Dovato. While GSK has its own long-acting injectables, Merck’s oral daily pill provides a simpler alternative for those not yet ready to transition to monthly or bi-monthly injections.

For Merck & Co., Inc. (NYSE: MRK), the success of the DOR/ISL program is a much-needed victory for its infectious disease pipeline. After the 2021 setbacks, many investors had written off islatravir as a viable candidate. The pivot to a lower dose and the subsequent successful Phase 3 readout suggests that Merck can still innovate in a crowded HIV field. Success here could lead to peak annual sales of $1.7 billion by the early 2030s, providing a steady, high-margin revenue stream that offsets some of the upcoming competitive pressures in oncology.

Industry Trends: The Shift Toward Two-Drug Regimens and Fewer Side Effects

The success of DOR/ISL reflects a broader industry trend toward "drug sparing" regimens. For decades, the standard of care was a three-drug "cocktail." However, as patients live longer with HIV, the cumulative toxicity and side effects of lifelong medication have become a primary concern. Reducing the number of active pharmaceutical ingredients from three to two—without losing efficacy—decreases the long-term burden on the liver and kidneys, a move that the medical community has increasingly embraced.

Furthermore, the focus is shifting from mere viral suppression to "quality of life" metrics. In the CROI 2026 data, the weight-neutrality of Merck’s regimen was a standout feature. As integrase inhibitors like those in Biktarvy and Dovato have been linked to significant weight gain and metabolic syndrome in some populations, the availability of a potent non-INSTI regimen like DOR/ISL provides a tailored solution for at-risk patients. This move toward personalized HIV care is a hallmark of the current era of infectious disease management.

Historically, the HIV market has been characterized by intense rivalry and rapid innovation cycles. Merck's resurgence with islatravir mirrors past scenarios where companies "fixed" a promising molecule by adjusting dosages or delivery methods. The regulatory precedent for such a pivot is strong, and provided the safety profile remains stable through the FDA's final review, the 0.25 mg dose is expected to set a new safety benchmark for the islatravir molecule, which was once feared to be dead on arrival.

Looking Ahead: The Road to April 28 and Beyond

The short-term focus for investors and the medical community is the April 28, 2026, PDUFA date. Between now and then, the FDA will conduct a final review of the MK-8591A-052 data. Given the "non-inferiority" status and the clean safety profile regarding CD4+ counts at the 0.25 mg dose, approval is widely anticipated by market observers. Should the FDA grant approval, a commercial launch would likely follow in late Q2 2026, supported by an aggressive marketing campaign highlighting the regimen's weight-neutrality and non-INSTI status.

In the longer term, Merck may look to leverage islatravir's potency in other areas. Although the once-monthly oral PrEP (pre-exposure prophylaxis) program was previously halted, the success of the 0.25 mg daily dose in treatment trials could lead to a re-evaluation of islatravir for prevention in a different dosing schedule or formulation. Additionally, the potential for long-acting formulations—perhaps in combination with other novel Merck molecules—remains a strategic pivot that could keep the company competitive against GSK's and Gilead’s long-acting injectable dominance.

The market opportunity for Merck is substantial but requires precise execution. The HIV market is notoriously sticky, with physicians often hesitant to switch stable patients to new therapies unless there is a compelling reason. Merck’s challenge will be to convince providers that the long-term metabolic benefits and the safety of the lower-dose islatravir outweigh the comfort of staying with established integrase inhibitor brands.

Final Assessment and Market Watch

Merck's Phase 3 results for the DOR/ISL regimen represent a significant technological and clinical comeback. By demonstrating non-inferiority to the market-leading Biktarvy at 48 and 96 weeks, and by effectively mitigating previous safety concerns, Merck has positioned itself as a serious contender in the multibillion-dollar HIV treatment space once again. The 0.25 mg dose has proven to be the "Goldilocks" solution—strong enough to suppress the virus but low enough to protect the patient's immune system.

As the market moves toward the April 2026 regulatory decision, the HIV landscape is poised for a shake-up. Investors should watch for any early signals from the FDA or potential updates to the label regarding weight gain and lymphocyte monitoring. While Gilead's Biktarvy is unlikely to be dethroned overnight, Merck’s entry provides a necessary alternative that could capture a meaningful percentage of switch-patients and new starts.

For Merck, the success of DOR/ISL is a testament to the value of persistence in drug development. For the public and the patient community, it offers the promise of a potent, simpler, and potentially "cleaner" treatment option. Investors should keep a close eye on the PDUFA date of April 28, 2026, as a positive outcome would likely trigger a re-rating of Merck’s infectious disease pipeline and its long-term growth prospects.

This content is intended for informational purposes only and is not financial advice