Gilead Sciences, Inc. (Nasdaq: GILD) and Merck & Co., Inc. (NYSE: MRK) have reported that their investigational once-weekly oral combination of islatravir and lenacapavir maintained virological suppression in two Phase 3 switch trials involving adults with HIV-1. The Week 48 results showed noninferiority to once-daily Biktarvy in ISLEND-1 and to a range of established daily antiretroviral regimens in ISLEND-2.
The results move islatravir 2 mg and lenacapavir 300 mg closer to becoming the first complete once-weekly oral HIV treatment, although the combination remains investigational and has not been approved for clinical use. Gilead Sciences and Merck said the Phase 3 evidence will support regulatory submissions, with full results scheduled for late-breaking presentations at the 26th International AIDS Conference, AIDS 2026, in Rio de Janeiro.
The central clinical achievement is not that the regimen reduced viral load in untreated patients. Instead, the trials tested whether adults whose HIV was already suppressed on stable therapy could switch from reliable daily treatment to a weekly tablet without losing virological control. That distinction defines both the strength and the current limitation of the evidence.
What did the ISLEND-1 and ISLEND-2 Phase 3 trials establish at Week 48?
ISLEND-1 enrolled 607 adults who had maintained HIV-1 RNA below 50 copies per millilitre while taking Biktarvy for at least six months. The multicentre, randomised, double-blind and active-controlled trial assigned participants either to switch to weekly islatravir and lenacapavir or continue once-daily Biktarvy, with matching placebos used to maintain blinding.
At Week 48, none of the participants assigned to weekly islatravir and lenacapavir had HIV-1 RNA of at least 50 copies per millilitre under the United States Food and Drug Administration snapshot algorithm. One participant, representing 0.3 percent of the comparator group, met that definition while continuing Biktarvy.
The result established the prespecified noninferiority of the weekly combination. It did not demonstrate superiority over Biktarvy, and a difference involving zero versus one participant should not be interpreted as evidence that the investigational regimen controls HIV more effectively.
ISLEND-2 enrolled 626 adults who were virologically suppressed on various guideline-recommended regimens containing two or three antiretroviral medicines. This trial was randomised and active-controlled but open-label, meaning participants and investigators knew which treatment had been assigned.
At Week 48, 0.3 percent of participants receiving weekly islatravir and lenacapavir had HIV-1 RNA of at least 50 copies per millilitre, compared with 1.3 percent among those who continued their existing daily treatment. Once again, the appropriate conclusion is that the weekly regimen was noninferior within the trial’s statistical framework, not that it was superior to the collection of standard therapies used in the control group.
Taken together, the trials provide a broad Phase 3 replication of the earlier efficacy signal. ISLEND-1 offers the cleaner comparison because it was blinded and used one highly effective fixed regimen as the control. ISLEND-2 provides greater treatment diversity, but its open-label design and mixed comparator group make some tolerability and patient-reported findings more difficult to interpret.
Why does a once-weekly oral HIV regimen offer more than a simple dosing change?
Daily single-tablet regimens have made HIV treatment highly effective and comparatively straightforward for many people. The remaining burden is less about whether modern antiretroviral therapy can suppress the virus and more about maintaining treatment consistently over decades while accommodating different preferences, lifestyles, comorbidities and concerns about privacy or stigma.
A weekly tablet could occupy a distinctive position between daily oral treatment and long-acting injectable therapy. ViiV Healthcare’s Cabenuva, which combines cabotegravir and rilpivirine, can be administered monthly or every two months to eligible virologically suppressed patients. However, it requires scheduled clinical administration and intramuscular injections.
The islatravir and lenacapavir regimen would retain the familiarity and portability of an oral tablet while reducing dosing from 365 days a year to approximately 52. That could appeal to people who want less frequent treatment but do not want injections or recurring clinic appointments.
Convenience does not automatically translate into better adherence. Daily medicines can become anchored to established routines, while a weekly schedule may be easier for some people to forget. Regulators and clinicians will therefore need information on missed-dose management, pharmacological forgiveness, resistance risk and performance outside closely monitored clinical trials.
ISLEND-2 participants who switched to the weekly combination reported higher treatment satisfaction and a lower perceived treatment burden than those continuing daily therapy. Those exploratory findings support the convenience proposition, but they were collected in an open-label study and may partly reflect expectations associated with receiving a new regimen. They should not be treated as proof that weekly dosing will improve adherence or clinical outcomes in routine care.
Does the reported safety profile resolve earlier concerns surrounding islatravir?
Safety interpretation is especially important because the United States Food and Drug Administration placed clinical holds on several islatravir programmes in 2021 after reductions in total lymphocyte and CD4-positive T-cell counts were observed in some studies. Development subsequently resumed using lower doses, and the ISLEND programme evaluates islatravir at 2 mg once weekly.
In double-blind ISLEND-1, treatment-related adverse events occurred in 13.5 percent of participants receiving islatravir and lenacapavir and 13.2 percent of those continuing Biktarvy. Nausea and headache were the most frequently reported treatment-related events, each affecting approximately 3 percent of participants.
Serious adverse events occurred in 5.3 percent of the weekly-treatment group and 4.6 percent of the Biktarvy group, although those figures do not mean every serious event was caused by treatment. Discontinuations because of adverse events were also similar, at 2 percent with islatravir and lenacapavir and 1.7 percent with Biktarvy.
The ISLEND-1 data are reassuring at Week 48 because CD4-positive T-cell and total lymphocyte counts remained stable, no participant discontinued because of a reduction in those counts, and no clinically meaningful between-group difference in body-weight change was reported.
ISLEND-2 produced a more complicated tolerability picture. Treatment-related adverse events were reported in approximately 18 percent of participants who switched to the weekly combination, compared with less than 1 percent of those continuing their established daily therapy. Headache, nausea and diarrhoea were the most common treatment-related events in the weekly group.
That difference deserves attention, but it should be interpreted within the open-label design. Participants switching to a new investigational therapy may notice and report new symptoms more readily, while people continuing a regimen they have already tolerated for at least six months have effectively undergone a period of prior tolerability selection.
Despite the imbalance in treatment-related event reporting, discontinuations remained low, at approximately 1 percent with weekly therapy and less than 1 percent with standard care. The companies also reported stable lymphocyte measures and no discontinuations related to reduced CD4-positive T-cell or total lymphocyte counts.
Longer follow-up remains important. Both Phase 3 trials continue through Week 96, and the later dataset should provide a more mature assessment of sustained suppression, cumulative tolerability, discontinuations and resistance.
How do islatravir and lenacapavir support a complete treatment in one weekly tablet?
The regimen combines two agents that interfere with HIV replication through different mechanisms. Merck’s islatravir is a nucleoside analogue that inhibits reverse transcriptase through several actions, including interference with translocation and viral DNA chain completion.
Gilead’s lenacapavir is a first-in-class capsid inhibitor that affects several stages of the HIV lifecycle. Its potency and extended pharmacokinetic profile have already supported long-acting applications, including twice-yearly injectable formulations for prevention and use in combination treatment for certain heavily treatment-experienced adults with multidrug-resistant HIV.
Islatravir is no longer an entirely unvalidated clinical component. In April 2026, the United States Food and Drug Administration approved Merck’s once-daily doravirine and islatravir combination, Idvynso, as a switch treatment for certain virologically suppressed adults with no history of virological failure and no known resistance substitutions associated with doravirine.
That approval provides regulatory validation for a lower-dose islatravir-containing treatment, but it does not extend to the islatravir and lenacapavir combination. The once-weekly regimen has different dosing, companion therapy, pharmacokinetic considerations and resistance implications, all of which require a separate regulatory assessment.
The two-drug design may reduce the number of active ingredients compared with three-drug regimens such as Biktarvy. However, fewer drugs should not be equated automatically with lower toxicity or simpler prescribing. Drug interactions, prior resistance, hepatitis B status, missed doses and the long persistence of lenacapavir must still be incorporated into patient selection and labelling if the regimen is approved.
Which patients remain outside the evidence generated by the ISLEND programme?
The present findings apply to adults who were already virologically suppressed and had remained on stable therapy for at least six months. The trials did not establish the regimen as an initial treatment for people newly diagnosed with HIV or as an option for patients with uncontrolled viraemia.
ISLEND-1 also excluded people with previous virological failure, previous exposure to islatravir or lenacapavir, active hepatitis B infection, active hepatitis C infection and several clinically significant laboratory abnormalities. These exclusions create a well-defined efficacy population but limit assumptions about broader real-world use.
Hepatitis B management could become particularly important. Many established HIV regimens contain tenofovir and emtricitabine or lamivudine, which also provide activity against hepatitis B virus. Islatravir and lenacapavir do not provide an equivalent hepatitis B treatment backbone, so switching a person with HIV and hepatitis B coinfection would require separate clinical consideration and appropriate antiviral coverage.
Resistance will be another regulatory focus. The exceptionally low number of participants with HIV-1 RNA at or above 50 copies per millilitre is encouraging, but it leaves relatively few failure cases from which to characterise resistance pathways. Week 96 data and detailed analyses of any confirmed virological rebound will be important for defining how robustly the two-drug regimen protects against resistance when adherence is imperfect.
Why is the weekly HIV pill strategically important to Gilead Sciences and Merck?
For Gilead Sciences, the programme represents both product innovation and HIV franchise lifecycle management. The company reported first-quarter 2026 HIV product sales of approximately $5 billion, including $3.4 billion from Biktarvy, which remains the commercial centre of its treatment portfolio.
A successful weekly regimen could partly compete with Biktarvy, but it could also help Gilead retain patients within its portfolio as the market fragments by dosing preference. The strategic objective is increasingly to offer daily oral, weekly oral and longer-acting injectable options rather than depend on one treatment format.
Merck gains a differentiated development route for islatravir alongside the recently approved once-daily Idvynso and its separate weekly combination work with ulonivirine. The Gilead collaboration also pairs islatravir with a capsid inhibitor rather than another reverse-transcriptase agent, creating mechanistic differentiation within Merck’s broader HIV programme.
The stock market response suggests investors viewed the detailed results as constructive but not transformational on their own. Gilead Sciences shares closed at $130.28 on July 21, down 2.2 percent for the session, although the stock remained modestly higher over the preceding week and month and within a 52-week range of approximately $108.06 to $157.29.
Merck shares closed at $126.26, up 1.5 percent for the session, with gains over the previous week and month and a 52-week range of roughly $76.66 to $131.74. The contrasting daily moves should not be attributed solely to the ISLEND disclosure, particularly because both companies are large, diversified drugmakers with multiple simultaneous clinical, regulatory and commercial catalysts.
How does the weekly treatment data fit into Gilead’s wider AIDS 2026 programme?
Gilead’s AIDS 2026 programme extends beyond the weekly treatment collaboration. The company is also presenting longer-term open-label extension results from the Phase 3 PURPOSE 1 and PURPOSE 2 prevention trials of twice-yearly injectable lenacapavir.
Gilead reported no new HIV infections during the PURPOSE 1 open-label extension among participants receiving lenacapavir. In the PURPOSE 2 extension, one infection occurred among participants continuing lenacapavir, while none were reported among those switching from daily oral pre-exposure prophylaxis.
Adherence to scheduled injections remained high, with 96 percent of participants in PURPOSE 1 and 92 percent in PURPOSE 2 continuing through 52 weeks. These prevention findings should remain analytically separate from the ISLEND treatment results because pre-exposure prophylaxis and therapy for established HIV infection involve different populations, endpoints and resistance considerations.
The company is also advancing potential twice-yearly treatment combinations and earlier HIV cure research. Those programmes reinforce lenacapavir’s role as a platform molecule, but the cure studies remain exploratory, and there is currently no cure for HIV or AIDS.
For the weekly islatravir and lenacapavir regimen, the next decisive steps are regulatory submissions, full review of the AIDS 2026 presentations and completion of the Week 96 analyses. The Phase 3 programme has cleared the central efficacy test at Week 48. The remaining question is whether longer follow-up, resistance data, practical missed-dose guidance and a clearly defined label can turn a compelling dosing concept into a durable treatment option.
