Editor's Note: With the widespread adoption of antiretroviral therapy (ART), AIDS has gradually become a manageable chronic condition. However, approximately 600,000 people worldwide still die from advanced HIV disease annually, making this "neglected disease group" an emerging challenge in prevention and treatment. During the recently held 2025 Asia-Pacific AIDS & Co-Infections Conference (APACC 2025), Infectious Disease Frontier conducted an exclusive interview with Professor Joe Jarvis of the National Institute for Health and Care Research (NIHR). In this interview, he analyzed existing gaps in advanced HIV disease management from three key perspectives—clinical practice, research data, and policy formulation—shared insights on the application of risk-stratified management tools for cryptococcal meningitis, and provided recommendations for future prevention and treatment priorities.IDF: You described individuals with advanced HIV infection as a ‘neglected disease group’ in your report. What evidence supports this characterization? Which critical findings in World Health Organisation (WHO) reports reflect this neglected status?
Prof. Jarvis: I believe there was an anticipation that widespread rollout of antiretroviral therapy would eliminate advanced HIV disease. The prevailing view was that this was primarily a problem of late presentation to care – people either not getting tested until very late in their illness or not starting treatment until an advanced stage. The expectation was that expanding testing and early treatment would resolve the issue.
However, what we’ve observed contradicts this. Global AIDS-related deaths have remained relatively steady over the past four or five years, at approximately 600,000 people annually. These deaths are caused by AIDS or advanced HIV disease, yet they are not adequately measured. Current metrics in HIV treatment programs focus on the number of people tested, initiated on treatment, and achieving virological suppression. We are no longer systematically tracking how many people are becoming seriously ill or dying.
Data now reveal two key issues: first, a significant proportion of people globally – about 30% – still present for care very late, with a CD4 count of 200 cells/μL or less at their first presentation. Second, we increasingly see individuals who initiated care and achieved virological suppression interrupting their treatment. Following interruption, viral load rapidly rebounds, CD4 counts decline, and advanced HIV disease develops.
It is increasingly this group who present with opportunistic infections and account for the fatalities. Therefore, refocusing on this currently neglected group – overlooked by our monitoring and evaluation systems, research efforts, and programs – is critically important. To address this, the World Health Organization is expected to release updated guidance on managing advanced HIV disease later this year.
IDF: Cryptococcal meningitis, a major opportunistic infection threatening the survival and quality of life of people living with HIV, requires risk-stratified management. The AMBITION-cm trial you participated in developed a novel tool for predicting mortality risk. How does this tool guide clinicians in developing personalised treatment regimens?
Prof. Jarvis: As part of the AMBITION trial, we did assess mortality-associated risks and developed a risk score, recently published in The Lancet Global Health[1]. This score is freely available online for clinicians to utilize in developing risk models for their patients.
At this stage, however, I don’t believe we’re ready to implement management stratification based on antifungal therapy. We recommend that all patients with cryptococcal meningitis receive one of the WHO-recommended regimens: either the AMBITION-cm regimen (based on a single high dose of liposomal amphotericin B) or other recommended regimens using amphotericin B deoxycholate combined with flucytosine.
Looking ahead, we hope to stratify treatment based on risk. Some patients with low-risk scores might be discharged very early after their initial bolus dose of liposomal amphotericin B and managed as outpatients. Conversely, others will require much more intensive management; identifying these patients early for intensive care could reduce mortality. We are not yet at that stage, though. For now, uniform treatment is appropriate.
As new treatments emerge – such as more potent adjunctive immune therapies to reduce mortality in the sickest patients, or novel oral therapies suitable for less severe cases – future stratification may become feasible. Currently, however, we recommend all patients receive one of the standard WHO-approved treatments.
IDF: Although the widespread availability of antiretroviral therapy (ART) has transformed AIDS into a manageable chronic condition, preventable deaths persist. To further reduce such mortality, in which key areas should future HIV control efforts be strengthened?
Prof. Jarvis: As I mentioned earlier, we’re essentially observing two distinct patient populations developing advanced HIV disease and facing mortality risks.
The first group consists of individuals who initially present late for care. To address this, it is crucial to expand testing services and ensure timely initiation of treatment so that these patients can receive treatment quickly before the disease progression.
However, in many settings, a significantly larger group comprises those who have already entered care but subsequently interrupt their treatment. Understanding the underlying reasons for treatment discontinuation, implementing measures to improve care retention, and preventing therapy interruptions are therefore critical to curbing advanced HIV disease development.
Regarding mortality reduction, it’s imperative that treating clinicians recognize the high probability of advanced HIV disease – whether in first-time presenters or treatment interrupters. In many clinical scenarios, there’s approximately a one-in-three chance that the patient before them has advanced HIV disease. This underscores the importance of performing CD4 counts during patient care to identify advanced cases.
For confirmed advanced HIV disease cases, consistent implementation of the WHO-recommended screening, prophylactic, and treatment protocols is essential for mortality prevention.
References:
[1] Samuels THA, Molloy SF, Lawrence DS, et al. Personalised risk-prediction tools for cryptococcal meningitis mortality to guide treatment stratification in sub-Saharan Africa: a prognostic modelling study based on pooled analysis of two randomised controlled trials. Lancet Glob Health. 2025;13(5):e920-e930. doi:10.1016/S2214-109X(25)00010-5
National Institute for Health and Care Research (NIHR)
Professor Joe Jarvis is an NIHR Global Health Research Professor, currently dividing his time between the London School of Hygiene & Tropical Medicine (LSHTM) and Gaborone, Botswana, where he serves at the Botswana Harvard AIDS Institute Partnership. His primary research focuses on advanced HIV disease, opportunistic infections, cryptococcal meningitis and other CNS infections, as well as strategies for rapid and safe antiretroviral therapy (ART) initiation in individuals with low CD4 counts.
Professor Jarvis served as the Chief Investigator for the AMBITION-cm trial, which evaluated new treatments for HIV-associated cryptococcal meningitis across Botswana, Zimbabwe, South Africa, Malawi, and Uganda. He recently held the position of Research Director for the CDC Implementation Protocol of the Botswana Combination Prevention Project (BCPP).
Holding an NIHR Global Health Research Professorship, he leads an NIHR Global Health Group dedicated to HIV-associated fungal infections. Professor Jarvis contributes his expertise as a member of the external review group for the WHO Guidelines on Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy. He also serves on the guidelines development group for WHO’s recommendations on preventing, diagnosing, and managing cryptococcal disease in HIV-infected adults, adolescents, and children.
Beyond his research activities, Professor Jarvis maintains clinical practice as an infectious diseases consultant in Botswana and at the Hospital for Tropical Diseases in London.
