HIV treatment, prevention, and cure research are all moving faster than at any point in the epidemic’s history. Monthly and twice-yearly injections are replacing daily pills for both treatment and prevention. A new class of drug called a capsid inhibitor has achieved near-perfect protection in large prevention trials. And multiple cure strategies, from gene editing to engineered immune cells, are producing early but real results in clinical studies. The picture is not uniformly bright, though, and the gap between laboratory breakthroughs and the people who need them remains one of the field’s defining tensions.
Where the Global Epidemic Stands
The international framework for measuring progress against HIV is built around three targets: 95% of people living with HIV knowing their status, 95% of those diagnosed on treatment, and 95% of those on treatment achieving viral suppression. By the end of 2020, global figures stood at roughly 84% diagnosed, 87% of those on treatment, and 90% of those treated virally suppressed.1PLOS ONE. Achieving the 95 95 95 targets for all: A pathway to ending AIDS Those numbers have continued climbing, and projections suggest the three targets could be met globally by the mid-2030s.
That global average, however, masks enormous regional disparities. Much of the progress is driven by Eastern and Southern Africa, where large-scale treatment programs have dramatically expanded coverage. A 2025 analysis warned that extrapolating Africa’s success to the rest of the world creates “a statistical illusion of a global HIV endgame,” with persistent transmission and limited treatment access in parts of Latin America, Asia, and elsewhere revealing how uneven the response remains.2PubMed Central. The statistical illusion of a global HIV endgame: disparities in regional progress toward 95-95-95 targets Relying on a single framework risks masking crises that need tailored strategies rather than a one-size-fits-all approach.
Long-Acting Injectable Treatment
For decades, HIV treatment meant taking pills every day. The approval of long-acting injectable cabotegravir plus rilpivirine changed that. Given as an intramuscular injection once a month (or every two months), this combination was the first complete parenteral antiretroviral regimen, eliminating the need for daily oral dosing entirely.3PubMed. Therapeutic review of cabotegravir/rilpivirine long-acting antiretroviral injectable and implementation considerations at an HIV specialty clinic In the pivotal trial, about 93% of participants on the injectable regimen maintained viral suppression at 48 weeks, meeting the statistical bar for being as effective as daily pills.4PubMed. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression
Real-world data have largely confirmed the trial findings. A nationwide observational study in the Netherlands found that switching to injectable cabotegravir and rilpivirine did not increase the risk of losing viral control among people without a history of prior treatment failure.5The Lancet HIV. Effectiveness of long-acting injectable cabotegravir and rilpivirine in individuals with HIV-1 in the Netherlands: a nationwide observational cohort study People who had experienced virological failure before, however, faced a higher risk of losing suppression on the injectable regimen, underscoring the importance of patient selection. Beyond the clinical numbers, patient-reported outcomes have been consistently positive. People on the injections report better convenience and reduced stigma compared to carrying and taking daily pills.
Lenacapavir and the Capsid Inhibitor Class
Perhaps the most exciting new drug in HIV is lenacapavir, a first-in-class capsid inhibitor that works by a completely different mechanism than older antiretrovirals. Rather than targeting the enzymes the virus uses to replicate, lenacapavir interferes with the protein shell (capsid) that surrounds the viral genetic material, disrupting multiple stages of the virus’s life cycle at once.6Clinical Infectious Diseases. Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multidrug-Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial It is given as a subcutaneous injection just twice a year.
Lenacapavir was initially approved for people with multidrug-resistant HIV who had run out of other options. In the trial that led to approval, a meaningful viral-load drop was seen in 88% of patients receiving the drug by day 15, and by week 26, about 81-83% had achieved full viral suppression.7PubMed. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection Those are striking numbers in a population where previous treatments had failed. What has generated even more excitement, though, is its role in prevention.
Prevention Advances and Twice-Yearly PrEP
Pre-exposure prophylaxis, or PrEP, has been available as a daily pill for years. But adherence to a daily medication is hard for many people, and real-world effectiveness has lagged behind the near-perfect protection seen in trials. Long-acting alternatives could close that gap. In two large phase 3 trials, twice-yearly lenacapavir injections achieved a 100% prevention rate in cisgender women and a 96% rate in a trial that enrolled cisgender men who have sex with men, transgender men, transgender women, and gender non-binary individuals.8Current Treatment Options in Infectious Diseases. Lenacapavir for HIV PrEP: Narrative Review of Clinical Trials and Implications for Patient Access A systematic review of the trial data confirmed that HIV incidence in the lenacapavir arms was essentially zero, compared to rates of roughly 1 to 2.4 per 100 person-years in the control groups.9PubMed. Efficacy and safety of long-acting lenacapavir for HIV treatment and prevention: A systematic review of randomized trials
A separate line of development involves multipurpose prevention technologies, or MPTs, which combine HIV prevention with protection against other sexually transmitted infections and unintended pregnancy in a single product. Over two dozen MPT candidates are in active development, ranging from intravaginal rings and gels to implants and oral tablets.10PubMed Central. Multipurpose Prevention Technologies: Opportunities and Challenges to Ensure Advancement of the Most Promising MPTs The logic is practical: many people at risk for HIV also need contraception, and combining those functions into one product could improve uptake of both.
The Vaccine Problem
Unlike COVID-19 or influenza, HIV has resisted every traditional vaccine strategy tried over four decades. The virus mutates rapidly, integrates into the host’s DNA, and attacks the very immune cells meant to fight it. The most ambitious current approach, called germline targeting, tries to train the immune system from scratch to eventually produce broadly neutralizing antibodies, the rare type of antibody that can block a wide range of HIV strains.
Early results in mouse models have been encouraging. Researchers have shown that mRNA lipid nanoparticle vaccines, the same basic platform used in COVID-19 vaccines, can deliver HIV immunogens that successfully prime the precursor B cells needed to start the journey toward broadly neutralizing antibodies.11PubMed Central. Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for Self-Assembly into Nanoparticles Subsequent work has demonstrated that mRNA boosters can drive those primed B cells further along the maturation pathway, generating the mutations and affinity improvements needed for the antibodies to eventually become broadly neutralizing.12PubMed Central. mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies
A key challenge has been whether the immune system can be trained to produce precursors targeting multiple vulnerable spots on the virus at the same time, or whether the different immunogens would compete with each other. A recent study found that simultaneous delivery of a cocktail of four mRNA-based immunogens activated four distinct classes of antibody precursors in a balanced way, suggesting that multiepitope priming could work in humans.13PubMed Central. Simultaneous priming of HIV broadly neutralizing antibody precursors to multiple epitopes by germline-targeting mRNA-LNP immunogens in mouse models These are still preclinical results in engineered mice, so a deployable vaccine remains years away. But for the first time, the path from lab to clinic looks plausible rather than purely theoretical.
Broadly Neutralizing Antibodies as Treatment
While vaccines aim to make the body produce broadly neutralizing antibodies on its own, another approach gives them directly as treatment, essentially infusing the finished product. These antibodies, called bNAbs, can suppress HIV when matched to sensitive virus strains, but a single antibody used alone is not enough. Monotherapy leads to viral escape and rebound within a few weeks.14PubMed Central. The Use of Broadly Neutralizing Antibodies (bNAbs) in HIV-1 Treatment and Prevention Combination bNAb therapy, using two or more antibodies that target different parts of the virus, does better: in clinical trials, combinations achieved deeper viral-load drops and delayed rebound to roughly 15 to 33 weeks compared with 4 to 8 weeks for single antibodies.15PubMed Central. Broadly neutralizing antibodies for HIV therapy in clinical trials: a systematic review
The most striking recent result came from the RIO trial, a phase 2 study that combined standard antiretroviral therapy with two long-acting bNAbs before stopping the antiretrovirals. By week 20, 75% of participants who received the antibodies had not experienced viral rebound, compared with just 11% in the control group. The antibody-treated group was 91% less likely to rebound.16The Lancet HIV. Safety, duration, and efficacy of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (RIO): a double-blind, randomised, placebo-controlled, phase 2 trial That is not a cure, but it is the strongest evidence yet that bNAbs could allow extended treatment-free periods for some people.
Cure Research and the Reservoir Problem
The central obstacle to curing HIV is the viral reservoir: a population of long-lived cells, mostly resting CD4+ T cells, that harbor dormant copies of the virus integrated into their DNA. These cells are invisible to the immune system and unaffected by antiretroviral drugs because the virus is not actively replicating in them. The reservoir forms within days of infection and persists for decades on treatment.
The reservoir is not confined to one tissue. Lymph nodes, spleen, and gut-associated lymphoid tissue harbor the largest concentrations of infected cells, but non-T-cell reservoirs including tissue-resident macrophages have also been implicated.17PubMed Central. The multifaceted nature of HIV tissue reservoirs Lymph nodes are a particularly stubborn site because antiretroviral drugs may not penetrate them as effectively as they do the bloodstream.18PubMed Central. The Lymph Node Reservoir: Physiology, HIV Infection, and Antiretroviral Therapy And recent work has documented intact, potentially replication-competent HIV proviruses in brain tissue, including the basal ganglia and white matter, during suppressive therapy.19eLife. Persistence of intact HIV-1 proviruses in the brain during antiretroviral therapy Although frequencies in the brain were low compared with lymphoid tissue, the finding complicates any cure strategy that depends on reaching every infected cell.
Starting antiretroviral treatment as early as possible after infection shrinks the reservoir considerably. People who begin treatment within 30 days of acquiring HIV show a steeper and more sustained decline in reservoir markers compared with those who start later, and the decay continues into a second phase that is not seen in people who begin treatment during chronic infection.20PubMed Central. Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study Very early treatment may also shift the composition of the reservoir toward a profile resembling that of people who naturally control HIV without medication.21PubMed Central. How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs? Early treatment does not eliminate the reservoir entirely, but it appears to give other cure strategies a better starting point.
Strategies to Attack the Reservoir
Two competing strategies dominate cure research. The first, known as “shock and kill,” aims to wake up dormant virus in reservoir cells using latency-reversing agents, then rely on the immune system or the virus itself to destroy those cells once they are active. Various compounds can successfully reactivate HIV in lab settings, but translating this to meaningful reservoir reduction in people has proven difficult. A promising direction combines latency-reversing agents with immune boosters to improve the killing step.22PubMed Central. Latency Reversing Agents and the Road to an HIV Cure The fundamental challenge is that waking the virus up without efficiently clearing the newly active cells risks doing more harm than good.23PubMed Central. Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV
The opposite approach, “block and lock,” gives up on eliminating the reservoir and instead tries to permanently silence it, locking the dormant virus in a state where it can never reactivate, even if treatment is stopped.24PubMed Central. Block-And-Lock Strategies to Cure HIV Infection Several agents have shown the ability to suppress viral reactivation in lab and animal models.25PubMed Central. Block-and-Lock Approaches for HIV Cure: Mechanistic Insights, Challenges, and Emerging Role of CPSF6 The worry is durability: recently uncovered mechanisms show that the epigenetic changes used to silence HIV can be reversed rapidly upon viral reactivation, raising the question of whether any silencing strategy can truly be permanent.26PubMed Central. The sounds of silencing: dynamic epigenetic control of HIV latency
Stem Cell Transplants, Gene Editing, and CAR-T Cells
The only confirmed cures of HIV have come through stem cell transplants. The first, known as the Berlin patient, received a transplant from a donor who carried two copies of a rare genetic mutation, CCR5-delta32, that makes cells resistant to HIV. After the transplant, the patient remained free of detectable virus for more than 20 months off all antiretroviral therapy.27PubMed. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation A second patient was subsequently cured by the same approach.28PubMed Central. Curating evidence for a cure of HIV-1 infection by hematopoietic stem cell transplantation These cases proved that a cure is biologically possible, but stem cell transplants carry serious risks and require a matched donor with the rare CCR5 mutation, making the procedure impractical as a general strategy.
Gene editing, particularly CRISPR-based approaches, aims to replicate the principle of the transplant cures without the transplant. One line of research targets the CCR5 gene in a patient’s own cells, trying to recreate the protective mutation.29PubMed Central. A CRISPR-Cas Cure for HIV/AIDS Another directly targets the HIV provirus integrated into the host genome, attempting to cut it out or disable it in place.30PubMed Central. Targeting and Understanding HIV Latency: The CRISPR System against the Provirus Both approaches face the same delivery problem: how do you get the editing machinery into enough of the right cells, in enough tissues, to meaningfully reduce the reservoir?
CAR-T cell therapy, borrowed from cancer treatment, represents another cell-based strategy. These are immune cells engineered to recognize and kill HIV-infected cells. Preclinical work has shown that CAR-T cells can reach viral reservoirs and persist over the long term.31PubMed Central. CAR-T Cell Therapy for HIV Cure: Current Challenges, Advances and Future Directions An early-phase human trial of a novel CAR-T product called M10 cells, engineered to both kill infected cells and neutralize free virus while homing to the lymphoid tissue where reservoirs concentrate, treated 18 people with HIV. About 74% of the infusions led to significant suppression of viral rebound, with viral loads dropping by an average of roughly 67%, and 10 patients showed persistently reduced levels of cell-associated HIV RNA over 150 days.32Cell Discovery. Efficacy and safety of novel multifunctional M10 CAR-T cells in HIV-1-infected patients: a phase I, multicenter, single-arm, open-label study This is very early data, but it suggests the approach has real potential.
What We Can Learn From Natural Controllers
A small fraction of people living with HIV maintain undetectable viral loads without any treatment at all. These “elite controllers” have long fascinated researchers as living proof that the human immune system can, in rare circumstances, suppress HIV indefinitely. A second group, called post-treatment controllers, achieve viral suppression after stopping antiretroviral therapy. Both groups offer clues about what a functional cure might look like, but their immune profiles differ in important ways.33PubMed Central. HIV controllers: hope for a functional cure
Studies of post-treatment controllers have found that they tend to have lower levels of immune activation and exhaustion, stronger HIV-specific CD4+ T cell responses, and more functional natural killer cells compared with people whose virus rebounds after stopping treatment.34PubMed Central. HIV post-treatment controllers have distinct immunological and virological features Understanding the immune signatures that distinguish controllers from non-controllers is guiding the design of therapeutic interventions, including bNAb combinations and therapeutic vaccines, that aim to reproduce these conditions in a wider population.35PubMed Central. Learning From the Exceptions: HIV Remission in Post-treatment Controllers
Living Longer With HIV and the Metabolic Trade-Offs of Modern Treatment
Effective antiretroviral therapy has transformed HIV from a fatal illness into a manageable chronic condition. As of 2015, nearly half of people with HIV in the United States were over 50, and about 16% were over 65.36PubMed Central. Aging and HIV infection: focus on cardiovascular disease risk This aging population faces a new challenge: even with fully suppressed virus, markers of inflammation remain elevated compared to HIV-negative people, contributing to a higher risk of cardiovascular disease and other age-related conditions that tend to appear earlier than expected.37PubMed Central. Inflammation, immune activation, and cardiovascular disease in HIV
The drugs themselves are not neutral in this picture. Modern regimens built around integrase inhibitors, particularly when combined with the newer tenofovir formulation known as TAF, are associated with more weight gain than older regimens. Dolutegravir and bictegravir appear to drive the most weight gain among integrase inhibitors.38PubMed. Impact of Integrase inhibitors and tenofovir alafenamide on weight gain in people with HIV In a large cohort study, switching from the older tenofovir formulation (TDF) to TAF was associated with about 1.7 kg of weight gain over 18 months versus 0.7 kg for those who stayed on TDF, along with modest increases in total cholesterol and triglycerides.39PubMed. Weight and Metabolic Changes After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in People Living With HIV Among people who started with a normal weight, about 14% who switched to TAF became overweight or obese within 18 months, compared with about 8% of those who stayed on TDF.
A European cohort analysis found that people on an integrase inhibitor combined with TAF also had higher rates of hypertension and abnormal cholesterol levels. Adjusting for weight gain explained some but not all of the increased risk.40The Lancet HIV. Weight gain and metabolic outcomes after switching to or current use of integrase strand-transfer inhibitors and tenofovir alafenamide in people with HIV in the RESPOND cohort consortium These metabolic shifts matter because they compound the cardiovascular risk already elevated by chronic HIV-related inflammation. Clinicians are increasingly weighing these trade-offs, sometimes opting to keep patients on older tenofovir formulations when kidney function allows it, or monitoring metabolic health more aggressively with newer regimens.
Drug Resistance With Current Regimens
One of the reassuring features of current first-line drugs is how rarely resistance develops. A systematic review of the three main integrase inhibitors, dolutegravir, bictegravir, and cabotegravir, found that virological failure in treatment-naïve patients occurred in a low single-digit percentage of cases across all three drugs. Actual resistance mutations were even rarer. Bictegravir stood out as having no detected resistance mutations across the 11 studies reviewed. Cabotegravir had the highest resistance mutation rate among the three, ranging from about 0.1% to 5.4% in treatment-naïve patients, while dolutegravir showed mutations in only one study at 0.3%.41PubMed. HIV-1 resistance and virological failure to treatment with the integrase inhibitors bictegravir, cabotegravir, and dolutegravir: a systematic literature review These low rates are encouraging but not grounds for complacency. The long-acting injectable form of cabotegravir has a uniquely long pharmacokinetic tail, meaning that if someone misses injection appointments, drug levels can linger at sub-therapeutic concentrations for weeks, creating a window where resistance could emerge.
Getting Breakthroughs to the People Who Need Them
The most sophisticated treatments in the world are meaningless if the people who need them cannot access them. Long-acting injectables, in particular, face steep implementation barriers in the regions hardest hit by HIV. A scoping review of sub-Saharan Africa identified a string of obstacles: lack of regulatory approval in many countries, high drug costs, limited supply chains, insufficient numbers of trained health workers to administer injections, and a shortage of cold-storage facilities required for the drugs.42PubMed Central. Bridging the gap: identifying barriers and strategies for widespread implementation of long-acting injectable antiretroviral therapy in Sub-Saharan Africa: a scoping review Lenacapavir, with its twice-yearly dosing, could reduce some of these logistical burdens, but its cost remains a major concern. Generic manufacturing agreements are under negotiation, but the timeline for affordable access in low-income countries is unclear. The history of antiretroviral therapy is a cautionary tale: it took a decade after the first effective treatments became available in wealthy nations before large-scale access programs reached the countries that needed them most. Whether that delay repeats with the next generation of drugs depends largely on pricing decisions being made right now.