Advances and Challenges in Antiretroviral Therapy for Acquired Immunodeficiency Syndrome
Since the isolation of human immunodeficiency virus (HIV) in 1983, the global HIV/AIDS epidemic has claimed nearly 50 million lives, with an estimated 37.9 million people living with HIV (PLWH) worldwide as of 2018. Combination antiretroviral therapy (ART) has transformed HIV infection from a fatal diagnosis to a manageable chronic condition by suppressing viral replication, reducing transmission, and restoring immune function. The World Health Organization’s 2015 recommendation to initiate ART for all PLWH regardless of CD4 count marked a pivotal shift in treatment guidelines. Global initiatives, including the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets (90% of PLWH diagnosed, 90% on treatment, and 90% virally suppressed by 2020), have driven progress. By 2019, 79% of PLWH knew their status, 78% of diagnosed individuals received ART, and 86% of those on treatment achieved viral suppression. Despite these advances, challenges persist, including 1.7 million new infections and 770,000 AIDS-related deaths in 2018. This article examines recent developments in ART, emerging strategies, and ongoing barriers to ending the HIV epidemic.
Rapid-Start and Test-and-Treat Strategies
A cornerstone of modern HIV management is the rapid initiation of ART, often on the same day as diagnosis. This approach aims to reduce transmission risks, improve individual health outcomes, and align with the UNAIDS targets. The “Undetectable = Untransmittable” (U=U) campaign, launched in 2016, underscores that sustained viral suppression (viral load <200 copies/mL) eliminates sexual transmission of HIV. Clinical trials and observational studies support rapid ART’s efficacy in curbing the epidemic and reducing morbidity. For example, the Strategic Timing of Antiretroviral Treatment (START) trial demonstrated that early ART initiation reduces AIDS-related events by 72% and non-AIDS complications by 39%.
However, universal implementation of same-day ART faces challenges. Structural barriers, such as limited healthcare access in low-resource settings, and individual factors, including mental health or socioeconomic instability, may hinder adherence. Furthermore, U=U messaging requires nuance: while it applies to sexual transmission, it does not address risks from breastfeeding, needle sharing, or other sexually transmitted infections (STIs). Tailored counseling and support systems are critical to ensuring the success of rapid-start programs.
Novel Antiretroviral Agents and Regimens
The development of new antiretroviral (ARV) agents has expanded treatment options, improved tolerability, and addressed drug resistance. Over 30 ARV drugs and 10 fixed-dose combinations are approved, with integrase strand transfer inhibitors (INSTIs) like dolutegravir (DTG) and bictegravir now preferred for first-line therapy due to their high efficacy, resistance barriers, and minimal side effects. Despite these advances, challenges such as adherence to daily regimens, long-term toxicity, and emerging resistance necessitate ongoing innovation.
Capsid Assembly Inhibitors
GS-6207, a first-in-class capsid assembly (CA) inhibitor, disrupts HIV replication by blocking capsid disassembly and nuclear transport. Administered via subcutaneous injection, it maintains drug concentrations above the 95% effective threshold for ≥12 weeks post-dose. Preclinical data show activity against HIV-1 variants resistant to other ARV classes, including those with Gag polymorphisms conferring resistance to maturation inhibitors (MIs). Notably, GS-6207 also inhibits HIV-2, broadening its therapeutic potential.
Maturation Inhibitors (MIs)
MIs like GSK3532795 (BMS-955176) target the Gag polyprotein, preventing proteolytic cleavage and halting virion maturation. Phase II trials demonstrate robust antiviral activity at daily doses of 50–200 mg, with sustained efficacy against multidrug-resistant strains.
Nucleoside Reverse Transcriptase Translocation Inhibitors (NRTTIs)
Islatravir (MK-8591), an NRTTI, combines dual mechanisms: inhibiting reverse transcriptase translocation and inducing chain termination. Its inhibitory quotient exceeds those of tenofovir, zidovudine, and lamivudine (3TC), even against NRTI-resistant HIV. Islatravir’s long half-life and tolerability make it a candidate for pre-exposure prophylaxis (PrEP), particularly in implant formulations.
Broadly Neutralizing Antibodies (bnAbs) and Fusion Inhibitors
PGT121, a bnAb targeting the HIV Env V3 loop, neutralizes 60–70% of global HIV-1 isolates. Albuvirtide (ABT), a long-acting fusion inhibitor with a 12-day half-life, was approved in China in 2018. Current trials explore ABT combined with bnAb 3BNC117 as a maintenance regimen for virologically suppressed individuals.
Attachment and Entry Inhibitors
Fostemsavir, an attachment inhibitor targeting gp120, is approved for multidrug-resistant HIV. Elsulfavirine, a next-generation NNRTI, shows high selectivity and was approved in Russia in 2017.
Long-Acting (LA) Antiretroviral Therapies
LA-ART formulations aim to improve adherence and quality of life by reducing dosing frequency. Injectable cabotegravir (INSTI) and rilpivirine (NNRTI), administered monthly, demonstrate non-inferiority to daily oral regimens in maintenance therapy. Patient preference studies highlight greater satisfaction with injectables due to reduced pill burden. Emerging LA technologies include implants, patches, and nanotechnology-based delivery systems (e.g., lipid nanoparticles, hydrogels), which enhance lymphatic tissue penetration and prolong drug release.
Two-Drug Regimens (2DR)
2DRs challenge traditional three-drug paradigms by minimizing toxicity and cost while maintaining efficacy. Recommended regimens include:
- DTG + 3TC: For initial therapy in patients without hepatitis B coinfection.
- Darunavir/ritonavir (DRV/r) + raltegravir (RAL): For patients with viral loads 200 cells/µL.
- Monthly LA cabotegravir + rilpivirine: For maintenance in virologically suppressed individuals.
However, 2DRs are contraindicated in hepatitis B coinfection, tuberculosis, pregnancy, or renal impairment due to insufficient data.
Challenges in Antiretroviral Therapy
Drug Resistance and Adherence
Transmitted and acquired resistance remains a barrier, particularly in regions with limited ART access. Non-adherence, driven by stigma, mental health issues, or regimen complexity, exacerbates resistance risks. INSTIs like DTG mitigate this through high genetic barriers, but emerging resistance mutations (e.g., R263K) underscore the need for vigilance.
Metabolic and Long-Term Complications
INSTIs, though safer than older ARVs, are linked to weight gain and metabolic dysregulation. DTG use in pregnancy raises concerns about neural tube defects, necessitating careful risk-benefit analysis. Aging PLWH face increased cardiovascular, renal, and neurocognitive comorbidities, requiring integrated care models.
Access and Equity
Despite global progress, disparities persist. In 2018, only 62% of PLWH in low- and middle-income countries received ART, compared to 87% in high-income countries. Patent barriers, supply chain inefficiencies, and underfunded health systems hinder equitable access to newer agents like DTG or LA-ART.
The Quest for a Functional Cure
A functional cure—defined as sustained viral remission without ART—remains elusive due to HIV’s latent reservoir in CD4+ T cells. Strategies under investigation include:
- “Kick and Kill”: Latency-reversing agents (e.g., histone deacetylase inhibitors) activate dormant virus, enabling immune clearance.
- Gene Editing: CRISPR/Cas9 targets proviral DNA, excising integrated HIV genomes.
- Broadly Neutralizing Antibodies: bnAbs like 3BNC117 enhance immune control by targeting conserved Env epitopes.
- CAR-T Cell Therapy: Chimeric antigen receptor T cells engineered to recognize HIV-infected cells show promise in preclinical models.
While these approaches are experimental, combined bnAbs and LA-ART may bridge the gap toward remission.
Conclusion
Four decades of ART advancements have transformed HIV/AIDS into a chronic condition, yet the epidemic persists. Scaling up rapid-start programs, expanding access to novel agents, and addressing systemic inequities are critical to achieving global targets. Concurrently, research must prioritize long-term safety, adherence tools, and curative strategies. The integration of biomedical, behavioral, and structural interventions will determine whether the vision of ending HIV/AIDS by 2030 becomes reality.
doi: 10.1097/CM9.0000000000001226
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