Despite the success of antiretroviral therapy, a subset of people with HIV experience low-level viraemia (LLV), a challenging condition with inconsistent definitions and management across settings. We conducted a scoping review of the literature and developed international consensus recommendations through a modified Delphi process involving a multidisciplinary panel of experts. Available evidence shows wide variability in definitions of persistent LLV, most commonly encompassing repeated viral loads between 50 and 1000 copies per mL. Outcomes associated with LLV are heterogeneous. Despite associations between LLV at 50-200 copies per mL and virological failure of more than 1000 copies per mL, resistance emergence or adverse clinical outcomes are inconsistent; stronger evidence links LLV of 200-1000 copies per mL to these endpoints. Based on these findings, we propose a pragmatic management framework that includes prompt confirmation of LLV, assessment of adherence and drug interactions, consideration of resistance testing (especially at viral loads of 200-1000 copies per mL), a broader clinical evaluation, individualised treatment optimisation (according to viral load strata, the genetic barrier to resistance of current and potential antiretroviral regimens, and the HIV resistance profile), and individual prevention strategies for viral loads of 200-1000 copies per mL. This international guidance aims to support clinicians in identifying when LLV requires action, reduce variability in clinical practice, and inform management strategies across diverse health-care settings.

Histoplasmosis is a leading opportunistic infection and cause of mortality in people with advanced HIV disease. Yet, histoplasmosis is largely neglected in the global HIV response. Previously considered endemic only in the region of the Americas, histoplasmosis is now recognised to be distributed throughout much of sub-Saharan Africa, southeast Asia, and other parts of the world. Making a diagnosis is the greatest challenge. Commercial Histoplasma antigen tests are highly sensitive and specific and provide the best tool for early diagnosis of disseminated histoplasmosis, but global access is extremely scarce, leading to misdiagnosis, inadequate knowledge on the global burden of disease, and ultimately impeding progress towards ending deaths from advanced HIV disease. The number of effective antifungal agents remains limited; current regimens rely on amphotericin B with high efficacy but substantial toxicity, and itraconazole with suboptimal absorption and potency. Latin America's progress towards coordinated surveillance, diagnostic scale-up, and standardised treatment protocols, offer a practical model for other endemic countries seeking to reduce deaths from histoplasmosis. This Review assesses current knowledge in epidemiology, diagnosis, and treatment histoplasmosis, and calls for urgent investment in research and integration of Histoplasma antigen screening into the advanced HIV disease package of care to end the systemic neglect of histoplasmosis within the global HIV response.

Analytical treatment interruption (ATI) is an important tool to evaluate interventions designed to achieve HIV eradication or long-term control without antiretroviral therapy. We convened a stakeholder workshop to update the published recommendations for the conduct of ATI studies. Important changes to the recommendations include more lenient entry criteria on CD4 count, CD4 nadir, and past medical history, and allowance for greater variation based on regional standards. As the mechanism of potential HIV remission might rely on immune control, the criteria for antiretroviral therapy resumption now allow for longer periods of viraemia at higher levels to stimulate a more robust immune response. Greater emphasis is placed on the importance of psychosocial monitoring and support, the prevention of HIV transmission to partners during ATI, and the integration of sociobehavioural research into ATI studies. Recommendations for the conduct of paediatric and adolescent ATI trials, absent from previous guidelines, are now included. These recommendations, based on current available data, expert opinion, and community consultation, aim to help steer the safe and ethical implementation of the next generation of ATI trials as we continue the search for an HIV cure.

The US Food and Drug Administration's clinical hold on Gilead Sciences' once-weekly combination of GS-1720 and GS-4182 due to unexpected CD4 T-cell and lymphocyte count declines represents a key safety signal in long-acting HIV therapy development. This event parallels the earlier islatravir trials, in which similar immunological effects led to a downsized development programme with lower doses of the drug. The current safety signal must involve different mechanisms, as the combination contains an integrase inhibitor and a capsid inhibitor rather than a nucleoside reverse transcriptase translocation inhibitor. Although GS-1720 appears well tolerated in early studies, the high doses used might have contributed to toxicity. As GS-4182 is a prodrug that converts to lenacapavir, the parent compound warrants careful evaluation, particularly given lenacapavir's anticipated widespread use for HIV prevention. Existing lenacapavir data show favourable safety profiles. However, CD4 T-cell reporting has been inconsistent across trials, and different study populations and dosing regimens might not fully capture all potential immunological effects. CD4 T-cell declines represent a key concern for people with HIV. Future trials should implement standardised monitoring protocols with individual participant trajectories, predefined decline thresholds, and clear discontinuation criteria. As long-acting antiretroviral therapy advances, maintaining rigorous immunological surveillance becomes essential to balance dosing convenience against potential immunological risks.

The expansion of the global HIV response has led to substantial reductions in mortality and new infections over the past two decades. Yet, despite these gains, rates of new HIV infections remain much higher than projected, resulting in long-term consequences for controlling the epidemic. Challenges include siloed delivery approaches shaped by the demands and priorities of external funding, lack of integrated data systems for prevention, unaddressed structural risks, and limited community and multisectoral engagement. There is substantial concern that the inability of health systems to consistently reach vulnerable groups, especially with extraordinarily effective new biomedical tools, threatens the long-term control of the HIV epidemic. In this framing paper (the first paper in a six-part Series), we argue that countries that have adopted (or are planning to adopt and invest in) a more integrated health systems approach to the HIV response will be better able to achieve sustainable prevention outcomes and withstand external funding shocks. Focusing on sub-Saharan Africa, we examine current systemic barriers, the risks of continued fragmentation of programmes and accountability, and opportunities to realign HIV programmes-that will be explored thoroughly in the other papers in this Series-through a focus on strengthened governance, a decentralised health systems approach, community engagement, and strengthened pathways for new product introduction and scale-up.

Successful uptake of existing and new HIV prevention interventions demands meaningful, systematic, and participatory engagement integrated across the conception, design, implementation, and assessment phases of programming. Despite proven impact of community engagement, it remains chronically underfunded and is often not conducted consistently or as part of harmonised national policy and practice, causing gaps that are likely to worsen in the current funding environment. Systematic models of community engagement-from peer-led outreaches to community-led monitoring and advisory boards-strengthen trust, responsiveness, and accountability. Equally crucial are mechanisms for harmonising and incorporating community insights into the design and implementation of new prevention tools, and using these insights to inform more responsive programmes and policies. Harnessing benefits of community engagement requires increased resource allocation; clear policy frameworks with measurable performance indicators; leadership opportunities for community members, especially youth and key populations; and the use of innovative technologies to expand the reach and impact of interventions. Only with concerted and inclusive community engagement backed by resources and political commitment will HIV prevention efforts elicit the trust and buy-in needed to sustainably manage the HIV pandemic over the long term.

HIV programmes globally continue to face two persistent challenges: advanced HIV disease and high HIV incidence. These issues are often viewed separately, with advanced HIV disease viewed as a late-stage clinical failure and high HIV incidence as a failure of early prevention. However, these issues are closely linked at the individual and population level; both reflect the inability of current care models to engage and sustain viral suppression among a sizeable subgroup of people living with HIV who initiate antiretroviral therapy late or cycle in and out of care. In sub-Saharan Africa, where the HIV burden is highest, most individuals with advanced HIV disease are people who have previously initiated antiretroviral therapy and subsequently disengaged, often multiple times. This type of interruption in care has substantial implications for immune decline, viral rebound, and mortality. As donor funding decreases, there is a risk that global HIV responses will revert focus to maintaining aggregate antiretroviral therapy coverage, overlooking harder-to-reach populations with persistent viraemia.