HIV Cure: Three Strategies, Zero Approvals, 5 Years Out

Gilead Sciences closed at $130.21 with a $161.7 billion market cap. Its HIV franchise generated $20.75 billion in 2025 revenue, with Biktarvy alone at $14.33 billion. GSK, through ViiV Healthcare, reported HIV sales of £7.69 billion (about $9.8 billion) in 2025 and trades at $51.69 with a $103.6 billion market cap. Together, those two franchises print roughly $30 billion a year suppressing HIV with daily or monthly antiretroviral therapy.

Now consider the economics of a functional cure. A one-time or twice-yearly treatment that eliminates the need for daily ART would cannibalize the revenue base that pays Gilead’s and ViiV’s dividends. The two companies with the balance sheets to fund a cure are the two companies with the most to lose from one. That tension between cure economics and franchise revenue is the structural fact that defines the HIV cure pipeline, and it explains why cure research with real urgency comes from a $60 million private startup and academic consortia rather than from the incumbents. If you want deeper context on how Gilead’s HIV franchise already faces internal cannibalization from its own pipeline, see the analysis of BIC/LEN competing with Biktarvy. For ViiV’s competitive positioning, the Dovato vs Biktarvy head-to-head breakdown covers the same dynamic from the GSK side.

The three cure strategies

The field has converged on three approaches, each targeting a different part of the HIV lifecycle. None has produced a Phase 3 trial. The earliest any approach reaches Phase 3 is 2028 at the absolute soonest, and that assumes the current early data holds up.

Strategy 1: CRISPR excision of proviral DNA. Excision Biotherapeutics, a private company backed by $60 million in investor financing and based on work from Temple University, dosed five participants with EBT-101, an AAV-delivered CRISPR/Cas9 therapy that uses dual guide RNAs to cut HIV proviral DNA out of infected cells (NCT05144386). The Phase 1/2 trial met its safety and biodistribution endpoints. But when three participants underwent analytical treatment interruption, all three experienced viral rebound and had to restart antiretrovirals. The single-dose editing was insufficient to clear the latent reservoir. Excision is now testing a higher dose in a second cohort and exploring non-AAV delivery, but the first-in-human result confirmed what gene-editing skeptics predicted: the reservoir is too large and too distributed for a one-time cut to eliminate. For the broader context on how in vivo CRISPR works, see the guide to in vivo gene editing and the survey of CRISPR companies.

Strategy 2: Broadly neutralizing antibodies with long-acting capsid inhibition. Gilead’s teropavimab (GS-5423) and zinlirvimab (GS-2872) are two bNAbs delivered twice yearly alongside lenacapavir, the capsid inhibitor that Science named its 2024 Breakthrough of the Year. The FDA granted the LTZ combination Breakthrough Therapy designation in January 2025. The Phase 1b data is the cleanest clinical signal in the cure pipeline: 96% of participants (51 of 53) on LTZ maintained virologic suppression through Week 26, matching the 96% rate (26 of 27) in the standard-based regimen comparator arm. During analytical treatment interruption starting at Day 35, 70% of participants (14 of 20) met restart criteria and went back on ART. But 30% (6 participants) remained off ART through Week 48, and 4 of those remained off through Week 60. That is not a sterilizing cure. It is a functional cure signal in a subset, and the open question is whether a larger Phase 2 trial can identify the biomarkers that predict who responds. Gilead’s pipeline page lists the program as active, and the company presented updated data at AIDS 2026. The therapeutic implication is real, but the investment implication for a $161.7 billion company is not: even a successful twice-yearly functional cure regimen would largely replace existing Biktarvy revenue rather than add to it. For more on how lenacapavir is already reshaping HIV prevention, see the coverage of the PrEP approval.

Strategy 3: Induce and reduce. ViiV Healthcare, through its HIV Cure Center partnership with UNC-Chapel Hill and Qura Therapeutics, is pursuing a latency-reversal approach. The strategy: use latency-reversing agents to flush dormant HIV out of reservoir cells (induce), then eliminate the newly visible virus with immune effectors (reduce), all while patients stay on ART to protect uninfected cells. The lead compound class is IAP inhibitors, which activate a non-canonical NF-kB signaling pathway to reactivate latent HIV. The research was named one of Nature’s top ten discoveries of 2020. But the program has no clinical-stage asset disclosed as of mid-2026. ViiV’s cure strategy page describes the approach in preclinical terms, and the five-year UNC partnership renewal signals continued investment. The gap between a Nature-recognized preclinical concept and a human trial is the gap that has killed every latency-reversal approach for 15 years: the agents that reactivate HIV tend to reactivate other things too, including inflammatory cascades and, in some cases, oncogenes. For a look at how ViiV’s commercial HIV business is performing while the cure program stays in the lab, the Cabenuva adolescent superiority analysis covers the long-acting injectable franchise that funds the research.

The structural problem: reservoir size and distribution

Every cure strategy shares the same enemy. HIV integrates into the genome of long-lived memory CD4 T cells, creating a latent reservoir that persists for decades. Estimates put the reservoir at roughly 1 million infected cells in a treated individual, distributed across lymphoid tissue, the gut, the central nervous system, and bone marrow. No single-mechanism approach reaches all of them. CRISPR delivered via AAV has tissue tropism limits. bNAbs neutralize free virus but do not kill latently infected cells unless they are also engineered for Fc-mediated effector function. Latency reversal exposes the virus but depends on the immune system clearing the reactivated cells before they produce new virions. The Berlin patient and the London patient were cured because they received allogeneic stem cell transplants from CCR5-delta32 donors, replacing their entire immune system. That works for the handful of patients who need a transplant for leukemia and find a matched delta32 donor, but it does not scale. The reservoir problem is why every “cure” headline you read for the next five years will include the word “functional” or the phrase “analytical treatment interruption.”

The economic tension

Gilead’s 2025 HIV revenue was $20.75 billion. GSK/ViiV’s was roughly $9.8 billion. A functional cure that replaces daily ART with a twice-yearly infusion would need to be priced high enough to replace the foregone daily revenue, which is roughly $25,000 to $40,000 per patient per year in the US. If the cure regimen costs $50,000 twice a year, the payer math works for the system but not for the manufacturer, who collects $100,000 per year for a cure instead of $30,000 per year for a lifetime of ART. The revenue per patient drops if the dosing interval stretches and the patient stops paying after a functional cure is achieved. This is why Gilead’s LTZ program is structured as a twice-yearly maintenance regimen rather than a one-time cure: it preserves the recurring revenue model while delivering something close to a functional cure for the subset who respond. The honest framing is that Gilead is not trying to cure HIV. It is trying to extend the dosing interval far enough that the product feels like a cure to the patient while still being a recurring revenue product for the company. The same logic applies to ViiV’s long-acting Cabenuva, which is a monthly or bimonthly injectable, not a cure. If you want the sector-level context for how these catalysts rank, the infectious disease biotech catalysts ranking places HIV cure research behind commercial HIV catalysts for exactly this reason.

The investment implication

Moderna at $21.75 billion market cap has an HIV mRNA vaccine program (mRNA-1644 and mRNA-1574) in Phase 1, including a trial in Rwanda and South Africa with IAVI. The program is a vaccine, not a cure, and it has not produced efficacy data that would justify the market cap. Moderna’s platform investment thesis is driven by flu and cancer vaccines, not HIV. If you want to see how Moderna’s platform economics work, the cancer vaccine analysis covers the intismeran program that actually moves the stock. The HIV vaccine is option value, not thesis value.

Excision Biotherapeutics is private and not investable through public markets. Its $60 million in financing is roughly 0.04% of Gilead’s market cap. The company’s EBT-101 result, while disappointing, is the only clinical-stage CRISPR data in HIV and will inform the next generation of excision therapies. If Excision goes public or is acquired, it would be because the higher-dose cohort shows meaningfully better reservoir reduction. Until then, it is a watch item, not a trade.

The closest analog to a functional cure in a related virus is the hepatitis B space, where Ionis’s bepirovirsen showed HBsAg loss in a subset of patients and now faces an October 2026 PDUFA. The bepirovirsen PDUFA analysis covers that program, and the parallel is instructive: a functional cure in a chronic viral infection is possible, it serves a subset of patients, and the regulatory and commercial path is messy. HIV is harder than HBV because the reservoir is integrated into the genome rather than existing as a cccDNA template, but the investment framework is the same.

The framework for evaluating cure claims

When you read the next HIV cure headline, ask four questions. First, is the data from an analytical treatment interruption, or just from viral suppression on therapy? Suppression is treatment, not cure. Second, what fraction of participants maintained undetectable viremia off ART, and for how long? Gilead’s 30% at Week 48 is the benchmark to beat. Any number below that is not an advance. Third, is the approach a one-time intervention or a recurring regimen? If it is recurring, it is a long-acting treatment, not a cure, and the commercial model is the same as ART with a longer dosing interval. Fourth, who funded it? If the answer is an incumbent with $20 billion in annual HIV revenue, the incentive is to extend the dosing interval, not to eliminate the revenue stream. If the answer is a startup or an academic center, the incentive is to cure, but the resources are a fraction of what the incumbents spend on marketing.

The verdict

A functional HIV cure reaches Phase 3 no earlier than 2028, and that assumes Gilead’s LTZ Phase 2 identifies a responsive subgroup worth advancing. A sterilizing cure via stem cell transplant remains real for the handful of patients who need it for leukemia but is not a commercial product. The investable conclusion: hold GILD and GSK for the HIV franchise cash flow, not for the cure pipeline, because neither has the economic incentive to accelerate it. Watch Excision Biotherapeutics for an IPO or acquisition if its higher-dose CRISPR cohort shows reservoir reduction that the first cohort did not. The HIV cure trade, right now, is not a trade. It is a waiting game with a 5 to 10 year time horizon, and the two companies who could accelerate it have no economic reason to hurry.