The Future of HIV Associated Neurocognitive Disorders Treatment: A Growing Crisis with Limited Solutions

HIV-associated neurocognitive disorders, commonly referred to as HAND, represent one of the most persistent neurological complications affecting people living with HIV. Despite remarkable advances in antiretroviral therapy that have transformed HIV from a fatal disease into a manageable chronic condition, neurocognitive impairment continues to affect a significant proportion of those infected—between 25 to 60 percent of HIV-positive individuals worldwide face cognitive challenges or remain at risk of developing them.

The Evolution of HIV Neurological Complications

The landscape of HIV-associated neurological disorders has undergone a dramatic transformation since the introduction of combination antiretroviral therapy in 1996. Before the advent of modern treatment, severe dementia, formerly known as AIDS Dementia Complex, represented the most common and devastating neurological manifestation of advanced HIV, typically proving fatal within six months. The implementation of highly active antiretroviral therapy marked a turning point, substantially reducing the prevalence and severity of HIV-associated dementia while paradoxically shifting the clinical picture toward milder, more persistent forms of cognitive impairment.​​

Today, while severe dementia cases have decreased tenfold, milder neurocognitive disorders remain highly prevalent even among patients with well-controlled systemic viral loads. This persistence highlights a critical challenge: HIV enters the central nervous system within days of initial infection and establishes persistent reservoirs that continue to cause damage throughout the disease course, regardless of peripheral viral suppression.

Current HAND Treatment Landscape: The Central Role of Antiretroviral Therapy

The cornerstone of HAND management remains effective antiretroviral therapy aimed at suppressing HIV replication throughout the body, including the central nervous system. Early initiation and continuous viral suppression with combination therapy are associated with improved neuropsychological test performance and can prevent progression of mild impairment to more severe forms. Following treatment initiation or regimen optimization, cognitive improvements may be observed within 12 weeks and may persist for up to 18 months.​​

However, a critical limitation constrains therapeutic effectiveness: many antiretroviral agents exhibit poor blood-brain barrier penetration, failing to achieve therapeutically adequate concentrations in the central nervous system. This inadequate penetration allows continued viral replication and inflammation within brain tissues despite peripheral viral suppression, potentially contributing to the persistence of HAND in up to 50 percent of treated patients.​

The concept of Central Nervous System Penetration Effectiveness has emerged as an important consideration in regimen selection. Antiretroviral drugs are ranked by their ability to cross the blood-brain barrier, with agents like zidovudine demonstrating superior CNS penetration, while many protease inhibitors show limited CNS penetration. Research suggests that regimens optimized for CNS penetration may be associated with better neurocognitive outcomes, particularly for patients with established HAND. However, controversy persists regarding the clinical significance of this approach.​​

Current HAND treatment regimens utilize several drug classes, including nucleoside/nucleotide reverse transcriptase inhibitors (such as abacavir and zidovudine), non-nucleoside reverse transcriptase inhibitors (including efavirenz and nevirapine, though efavirenz may cause neuropsychiatric side effects), integrase strand transfer inhibitors (like dolutegravir and raltegravir), and protease inhibitors (such as lopinavir and indinavir). These agents form the backbone of combination therapy, typically using three or more drugs to maximize viral suppression while minimizing the development of resistance.

HAND Market Size and Epidemiological Burden

The global burden of HAND remains substantial, with approximately 40 million people living with HIV worldwide, of whom millions experience or face risk of neurocognitive disorders. In the leading markets (the United States, Germany, France, Italy, Spain, the United Kingdom, and Japan), the total HAND market size reached approximately USD 14.1 billion in 2024 and is projected to grow at a CAGR of 1.5% during the forecast period 2025-2034.​

Among these markets, the United States accounts for the highest burden, with approximately 610,000 diagnosed prevalent cases of HAND in 2024 out of roughly 1.3 million people living with HIV. Type-specific distribution reveals that asymptomatic neurocognitive impairment constitutes the majority at approximately 70%, followed by mild neurocognitive disorder and HIV-associated dementia, accounting for smaller proportions.​

The market is dominated by several therapeutic classes based on 2024 data: NNRTI-based regimens command the largest market share at USD 6.7 billion, followed by protease inhibitor-based regimens, boosted protease inhibitor dual therapy, integrase inhibitor-based regimens, boosted protease inhibitor monotherapy, and other approaches, including antioxidants, psychostimulants, anti-inflammatory drugs, and interferons.​

The Empty Pipeline: Limited Therapeutic Innovation

Despite the significant unmet need, the therapeutic pipeline for HAND remains remarkably sparse, with minimal pharmaceutical industry engagement. Currently, there are no FDA-approved medications specifically indicated for the treatment of HAND, with antiretroviral therapy serving as the sole disease-modifying intervention.​​

Pirenzepine, developed by WinSanTor as a muscarinic M1 receptor antagonist, represents the most advanced investigational therapy, having completed Phase II clinical evaluation for HIV-associated distal sensory polyneuropathy, a common comorbid condition affecting approximately 40% of HAND patients in Europe. Market forecasts anticipate potential market entry around 2029-2030, with projected uptake reaching USD 1.27 billion by 2034, though regulatory approval timelines remain uncertain.​

Baricitinib, a JAK1/JAK2 inhibitor already approved for rheumatoid arthritis and other inflammatory conditions, is currently being evaluated by Emory University in collaboration with the National Institute of Mental Health in a Phase II trial examining its potential to reduce HIV levels in the central nervous system. The study, led by Dr. William Tyor, is actively recruiting participants with a primary completion date anticipated in January 2028. However, Eli Lilly’s absence as the pharmaceutical sponsor raises questions about commercial development prospects and regulatory pathways.​

Additional non-industry-sponsored trials include the investigation of a neuroactive steroid for treating major depressive disorder in people with HIV, and a comparative study of pramipexole versus escitalopram for the treatment of major depressive disorder and comorbid MDD with mild neurocognitive disorder in people living with HIV, initiated by NIAID in collaboration with Cipla. These trials focus primarily on psychiatric comorbidities rather than direct cognitive enhancement, reflecting the multidimensional nature of HAND management.

HAND Treatment: Unmet Needs and Future Directions

Several critical unmet needs characterize the HAND therapeutic landscape. The absence of curative therapy remains paramount, as existing treatments address only viral replication and do not directly target neuroinflammation, neuronal repair, or cognitive restoration. Enhanced drug delivery to the central nervous system represents a major technical challenge, as the blood-brain barrier continues to impede adequate penetration of most antiretroviral agents and potential adjuvant therapies.​​

The development of validated biomarkers for early detection, disease staging, and treatment monitoring would transform clinical management and facilitate drug development. Such biomarkers include neuroimaging signatures, cerebrospinal fluid markers, blood-based indicators of neuroinflammation, or novel cognitive assessment tools suitable for routine clinical application.​​

Therapeutic approaches may need to address multiple pathogenic mechanisms simultaneously, combining enhanced CNS-penetrant antiretrovirals with adjuvant agents targeting neuroinflammation, oxidative stress, excitotoxicity, or neurotrophic support. The potential for repurposing existing CNS drugs, such as anti-inflammatory or neuroprotective agents, offers opportunities to accelerate development timelines. Novel delivery strategies, including nanoformulations, focused ultrasound for temporary blood-brain barrier disruption, or direct CNS administration routes, represent emerging technological frontiers.​​

Increased awareness among healthcare providers of the prevalence and impact of HAND, coupled with routine screening, could improve early detection and intervention. Comprehensive supportive care incorporating physical therapy, occupational therapy, speech therapy, cognitive rehabilitation, and mental health support for depression and anxiety remains an essential component of holistic management, helping patients maintain function and quality of life even without disease-modifying treatments.

In summary, the near-complete absence of pharmaceutical pipeline activity, coupled with substantial unmet medical needs, presents both a significant healthcare challenge and a potential opportunity for therapeutic innovation. Addressing HAND will require increased research investment, the development of validated biomarkers, improved CNS drug-delivery technologies, and comprehensive care models integrating pharmacological and supportive interventions. As the population of people living with HIV continues to age and grow, the burden of HAND is projected to increase, making the development of effective neuroprotective and cognitive-enhancing therapies an urgent priority for the field.