HIV drug resistance (HIVDR) remains a pivotal obstacle in the worldwide battle against HIV/AIDS, profoundly affecting antiretroviral therapy (ART) effectiveness, resulting in treatment failures, heightened transmission of resistant variants, escalated healthcare expenditures, and hurdles in attaining viral suppression. This in-depth review amalgamates data from premier indexed sources, including WHO reports, peer-reviewed journals, and clinical guidelines spanning 2023 to 2025, to explore molecular resistance mechanisms, prevalence patterns across regions, genetic mutations by drug class, surveillance techniques, and progressive management approaches. Contemporary statistics reveal acquired drug resistance (ADR) to integrase strand transfer inhibitors (INSTIs) like dolutegravir (DTG) varying from 3.9% to 8.6% in broad populations on DTG regimens, intensifying to 19.6% in extensively treated individuals with persistent viremia. Recent 2025 updates from IAS-USA highlight new mutations such as S147G for DTG and A105T for lenacapavir, underscoring the evolving landscape. Resistance mechanisms chiefly encompass point mutations, insertions, or deletions in viral genes for enzymes like reverse transcriptase (RT), protease, and integrase, aggravated by issues such as inconsistent adherence, elevated initial viral loads, pharmacological interactions, and partial suppression. Worldwide monitoring shows stabilizing or diminishing non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance in affluent nations owing to superior diagnostics and regimen adjustments, juxtaposed with ascending trends in low- and middle-income countries (LMICs), where pretreatment drug resistance (PDR) to NNRTIs frequently surpasses 10-15%, notably in sub-Saharan Africa. Among youth and adolescents, PDR figures are strikingly elevated, peaking at 42% in untreated cohorts in high-prevalence zones. This amplified examination, broadened eightfold in scope from earlier versions to provide exhaustive depth, integrates recent breakthroughs like lenacapavir (endorsed in 2025 for treatment and prevention), providing semiannual dosing and a multifaceted action mechanism devoid of cross-resistance to prior classes. Additionally, we probe innovative tactics such as CRISPR gene editing for cures, mRNA therapeutics targeting latent reservoirs, and pharmacogenomic personalization to avert resistance. Surveillance modalities, encompassing genotypic and phenotypic assays, proviral DNA sequencing, and bedside diagnostics, are rigorously appraised for shaping public health tactics. The review accentuates the necessity for bolstered international oversight, adherence enhancements, fair access to cutting-edge treatments, and cohesive management of comorbidities like tuberculosis and hepatitis to uphold strides toward UNAIDS 95-95-95 objectives and eradicate HIV as a public health menace by 2030. Forecasts indicate that absent intensified measures, DTG resistance might ascend to 10-15% universally by 2030, potentially undoing years of HIV control advancements. This amalgamation promotes interdisciplinary methodologies, incorporating community-driven adherence aids, digital monitoring instruments, and transnational partnerships to tackle the dynamic HIVDR panorama. Furthermore, we delve into socioeconomic ramifications, noting that treating resistant forms escalates costs by 50-70% over baseline, encompassing hospitalizations (30-50% rise), pricier alternatives (40-60% costlier), and productivity dips (yearly global losses $10-20 billion). Economic evaluations demonstrate that intervention investments recoup 2-5 times via diminished complications, transmission, and mortality. The COVID-19 pandemic induced a 10-25% global adherence drop due to lockdowns, supply shortfalls (deficits in 15-20% regions), economic hardships (15-30% unemployment-linked drops), and stress, boosting 10-15% failure and 10% resistance hikes. Migration worsens barriers (10-30% care gaps), while climate changes (African/Asian floods/droughts forecasting 5-15% 2030 adherence falls from infrastructure loss) compound challenges. Expanding further, this review incorporates 2025 data showing declining NRTI and NNRTI resistance trends amid modern ART shifts, with global, regional, and national meta-analyses revealing PDR at 0.41% for first-generation INSTIs and 0.04% for second-generation. Noncanonical mutations outside traditional targets are emerging, necessitating updated surveillance. In children and treatment-experienced populations, resistance burdens remain high, with sub-Saharan Africa accounting for 80% of pediatric cases. Projections from modeling studies warn of amplified resistance if funding declines, as highlighted in recent Global Fund reports. This comprehensive synthesis also addresses equity issues, with calls for integrated action plans like the WHO's i-GAP for 2025-2030 to combat resistance across HIV, hepatitis, and STIs.

HIV; drug resistance; antiretroviral therapy; mutations; dolutegravir; lenacapavir; prevalence; integrase inhibitors; reverse transcriptase inhibitors; protease inhibitors; global surveillance; treatment guidelines; low- and middle-income countries; children and adolescents; long-acting injectables; gene editing; pharmacogenomics; viral reservoirs; UNAIDS targets; public health interventions; economic burden; COVID-19 impact; migration; climate change; noncanonical mutations; regional disparities; future projections; equity in access; integrated action plans

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