EMERGING RESISTANCE TO LONG-ACTING HIV ANTIRETROVIRALS: A SYSTEMATIC REVIEW OF CABOTEGRAVIR AND RILPIVIRINE DATA

Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [474] EMERGING RESISTANCE TO LONG-ACTING HIV ANTIRETROVIRALS: A SYSTEMATIC REVIEW OF CABOTEGRAVIR AND RILPIVIRINE DATA Leighanna Ryielle B. Blanco1 Randall Ken M.Concepcion1 Kristale Mae E. Laquindanum1 Gecelene C. Estorico1,2 Civil and Allied Department; Environmental Science and Chemical Technology Department 1Technological University of the Philippines – Taguig, Metro Manila, 1630, Philippines 2De La Salle University – Dasmariñas, Cavite, DBB-B, 4115 West Ave., Dasmariñas ABSTRACT The innovative use of long-acting antiretroviral therapy (ART), especially the injection of a blend of cabotegravir (CAB-LA) and rilpivirine (RPV-LA), has positively impacted HIV management through improved patient adherence and the elimination of the daily oral intake issue. Nevertheless, the latest findings show that cases of resistance-associated virologic failure (RAVF) already have been in the picture despite the great efficacy of ART. This review of literature's aim is to put together the existing knowledge regarding HIV drug resistance due to the use of CAB-LA and RPV-LA in both treatment and pre-exposure prophylaxis (PrEP) contexts with regard to biological mechanisms, prevalence, and risk factors. PRISMA 2020 method was followed for the literature search, and databases searched were PubMed, Scopus, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov, and WHO ICTRP from 2015 to the projected year of 2025. The resistance that was found in the analysis of ten major studies, which included the HPTN 083 and HPTN 084 trials, was very low but still significant—between 0.21% and 0.48% in controlled populations and about 0.35% from WHO surveillance globally. Instances of mutations such as R263K, E138K/A, G118R, and Q148R/H/K were detected, resulting in a decrease of CAB susceptibility by 3–8 times and also resistance against other integrase strand transfer inhibitors (INSTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). The emergence of resistance was particularly associated with the long intervals between or missed injections, the so-called tipping-point scenario in pharmacokinetics, high viral load at baseline, diversity of HIV-1 subtype, and prior ART. Even though there are geographical variations, the findings unambiguously indicate that the interplay of pharmacological, behavioral, and virological factors promote and sustain resistance. Surveillance systems for resistance monitoring are still disjointed and inconsistent in different regions, and genomic monitoring is hardly done in lowand middle-income countries. It is imperative to bolster the global standardization in genotypic testing, adherence counseling, and pharmacovigilance in order to preserve the long-term efficacy of CAB-LA and RPV-LA treatments. In the end, the use of long-acting ART is giving the best and most revolutionary way to cope with HIV prevention and treatment, but at the same time, attention and strategies to keep the patient cooperating should be put in place to avoid the emergence and spread of HIV variants that are resistant. Keywords: Cabotegravir, HIV resistance, Long-acting antiretrovirals, Pharmacokinetic tail, Pre-exposure prophylaxis (PrEP), Rilpivirine, Virologic failure INTRODUCTION In the last ten years, long-acting antiretroviral therapy (ART) has completely changed the way HIV infection is treated. The injectable combination of cabotegravir (CAB) and rilpivirine (RPV) among these innovations has become the first approved long-acting ART regimen that offers a choice to the patients of not going the daily oral route. The combination allows monthly or bimonthly intramuscular injections for the patients who are virologically suppressed, thus, keeping the virus under effective control and at the same time, adding to the satisfaction of the treatment (Orkin et al., 2020). The ATLAS and FLAIR studies illustrated that the long-acting Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [475] CAB/RPV was equal to the standard oral ART in terms of viral suppression and was much more convenient in terms of dosing schedule, i.e. up to 48 weeks of viral suppression (Swindells et al., 2020). Less frequent dosing indirectly targets patient compliance coming from the issues of pill fatigue, stigma, and drug taking reminders—which are usually the main causes for virologic rebound and drug resistance in oral ART regimens (Nachega et al., 2023). The long-acting CAB/RPV therapy has the potential to enhance adherence, improve quality of life, and reduce the burden of lifelong medication management by eliminating these psychosocial and behavioral barriers. However, even with such advantages, new evidence has pointed to the possibility of resistance developing in patients experiencing virologic failure (VF) while undergoing this treatment (Manalu et al., 2025). Although the general occurrence of VF remains low, at approximately 1% in most phase III trials, the cases involving INSTI and NNRTI-resistant infections are disproportionately high (Navarro et al., 2024). The emergence of drug-resistant HIV variants, which is linked to this resistance pattern, has serious consequences for future treatment options and may jeopardize the long-term effectiveness of long-acting ART. A number of mechanisms have been suggested as possible reasons for this particular trend. One such mechanism is added to the pharmacokinetics, which is called the "tail" effect. It means that drug levels will dissipate slowly after stopping or delaying the injection, thus, gradually creating a scenario where the virus has an opportunity to replicate and mutate (Phillips et al., 2021). Moreover, mutations in the HIV virus that were resistance-associated previously have been stored in the patient's body and these have been mostly the ones related to NNRTI like E138A/K or integrase like Q148R/H and they are important factors contributing to the virological failure. In addition, HIV-1 _A6_ strain that is widely spread in Eastern Europe bears _L74I_ variation, which is said to have been linked to the occurrence of resistance development under CAB exposure (Załęski et al., 2025). With the global HIV programs granting easier access to long-acting ART, particularly in the case of teenagers, pregnant women, and low-income areas, the emergence of resistance has now become a major public health issue that cannot be ignored. Picking the right patients, constantly monitoring the viral load, and having an effective delivery of injections are the main strategies to deal with such challenges (Aidsmap, 2024). The purpose of this systematic review is to bring together the available evidence on the incidence, risk factors, and the molecular patterns of resistance encountered during CAB/RPV long-acting therapy. The authors of this work will conduct a critical evaluation of the existing data and thereby, they will be able to give guidance to the clinicians, researchers, and policymakers as to which strategies are necessary for the safe rollout of long-acting ART and at the same time keeping the risk of emergent resistance at its lowest. OBJECTIVES The main objective of the study is to systematically review and synthesize the available literature about the development of HIV resistance in the context of using long-acting cabotegravir (CAB-LA) and rilpivirine (RPVLA). Particularly, the focus of the review is to approximate the prevalence of acquired HIV drug resistance in general among individuals experiencing virologic failure following long-acting regimens both in the treatment and pre-exposure prophylaxis (PrEP) contexts because such resistance has been reported in a small, yet significant proportion. It also aims to describe the molecular patterns of resistance mutations developing after CAB-LA and RPV-LA failure, the most prevalent integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations and their possible effect on drug susceptibility and cross-resistance to other antiretrovirals. Moreover, the research is meant to examine the clinical and pharmacological factors that promote resistance emergence, including HIV-1 subtype type, baseline viral load, adherence levels, pharmacokinetics, and previous exposure to antiretrovirals to identify those factors which have the strongest impact on resistance generation. Finally, it aims to assess the quality and completeness of current resistance surveillance and reporting systems in various regions in terms of definitions, testing modalities and data coverage with the aim of determining gaps and providing evidence-based recommendations to enhance the standardization of monitoring frameworks to enhance early detection and management of the resistant HIV strains. METHODOLOGY The study employs a scientific method with three basic elements: Input, Process, and Output. The Input process entails gathering appropriate and authentic data from scientific journals, clinical trials, and molecular studies on the resistance patterns of long-acting cabotegravir (CAB-LA) and rilpivirine (RPV-LA). The Process stage involves the systematic search, screening, extraction, and analysis of studies according to the PRISMA 2020 Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [476] guidelines with the aim of ensuring that the data collected are transparent, accurate, and methodologically consistent. This involves assessing resistance prevalence, detecting integrase and reverse transcriptase mutations, and evaluating pharmacological and clinical contributors. Lastly, the Output offers a synthesized report of worldwide evidence, reinforcing the new molecular mechanisms of HIV resistance and outlining major gaps in present surveillance systems. This organized format offers a trustworthy and evidence-informed basis to comprehend how long-acting antiretroviral therapies impact resistance formation and worldwide HIV control measures. Figure 1. IPO Diagram of the Study Research Design This study employed a systematic review research design to gather, evaluate, and synthesize available evidence on the emergence of HIV resistance associated with long-acting cabotegravir (CAB-LA) and rilpivirine (RPVLA). The review aimed to address gaps in understanding the prevalence, molecular mechanisms, and contributing factors underlying resistance among individuals who experience virologic failure in both treatment and preexposure prophylaxis (PrEP) settings. The design followed the PRISMA 2020 guidelines, ensuring a transparent and replicable approach to literature selection, data extraction, and synthesis. This methodological framework was chosen because it enables the integration of data from randomized clinical trials, observational cohorts, and molecular studies that provide insight into emerging resistance mutations (Delany-Moretlwe et al., 2022; D’Antoni et al., 2025). The systematic design also aligns with the study’s objectives to (1) estimate the prevalence of resistance, (2) characterize INSTI and NNRTI mutations, (3) identify clinical and pharmacological factors affecting resistance, and (4) evaluate the quality of resistance surveillance systems. By consolidating multi-source evidence, the review sought to strengthen scientific understanding of how long-acting ART regimens may influence global resistance trends (Rusconi et al., 2022). Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [477] Data Collection Data were collected through a comprehensive search of major electronic databases including PubMed, Scopus, Web of Science, Cochrane Library, and Embase. Search strings combined key terms and Boolean operators such as “Cabotegravir” OR “CAB-LA” OR “Apretude” AND “Rilpivirine” OR “RPV-LA” AND “resistance” OR “mutation” OR “virologic failure” OR “cross-resistance.” The search covered studies published between 2015 and 2025, capturing the period during which CAB-LA and RPV-LA were introduced and widely studied (Wensing et al., 2025). Additional searches included ClinicalTrials.gov, WHO ICTRP, and proceedings from IAS, CROI, and EACS conferences to include recent or unpublished data. To minimize publication bias, gray literature sources such as WHO reports, regulatory data, and news releases (Reuters, 2024) were also reviewed. Retrieved articles were uploaded to Rayyan or Covidence software for duplicate removal, screening, and categorization according to inclusion criteria. This rigorous collection process ensured comprehensive coverage of studies reporting on resistance prevalence, mutation profiles, pharmacokinetic variability, and surveillance quality, thus directly addressing the study’s objectives. Data Collection Methods from Reviewed Studies Data extraction was performed using a structured extraction form that was pre-tested to ensure consistency across reviewers. Information gathered from each study included publication details, country or region, study design, sample size, and population characteristics. Clinical and molecular data such as rate of virologic failure, resistance-associated mutations (RAMs), phenotypic susceptibility, and drug-level measurements were extracted to estimate resistance prevalence and characterize molecular patterns. Particular focus was placed on mutations linked to integrase strand transfer inhibitor (INSTI) resistance (e.g., Q148H/K/R, N155H) and NNRTI resistance (e.g., E138K, K101E, Y181C) as reported in prior studies (Rhee et al., 2022; D’Antoni et al., 2025). Additional factors such as baseline viral load, HIV-1 subtype, adherence levels, and pharmacokinetic parameters were recorded to determine potential contributors to resistance emergence (Delany-Moretlwe et al., 2022; HPTN 083, 2025). Studies reporting surveillance and resistance monitoring systems were analyzed to evaluate testing methodologies and regional reporting quality (The Lancet HIV, 2024). Two reviewers independently extracted the data, and discrepancies were resolved through consensus or consultation with a third reviewer to ensure reliability and minimize bias. Limitations of the Study Although the study followed a systematic and rigorous approach, certain limitations were recognized. The heterogeneity of included studies—spanning different populations, regions, and resistance testing methods—may affect the comparability and synthesis of results (Rusconi et al., 2022). Limited data availability on CAB-LA and RPV-LA, particularly from lowand middle-income regions, restricts the global generalizability of findings (The Lancet HIV, 2024). Furthermore, inconsistent definitions of virologic failure and varied sequencing protocols among studies may lead to underor overestimation of resistance prevalence. Some reports lacked detailed pharmacokinetic and adherence data, which are key to understanding resistance mechanisms (D’Antoni et al., 2025). Publication bias remains a concern, as studies documenting emerging resistance are more likely to be published than those showing none (Reuters, 2024). Lastly, because long-acting antiretroviral formulations are relatively recent innovations, long-term resistance surveillance data are still limited. Despite these constraints, this systematic review integrates the most up-to-date and comprehensive evidence available, offering an important foundation for improving HIV resistance monitoring frameworks worldwide. RESULTS AND DISCUSSION To ensure the validity of this systematic review, Table 1 summarizes ten key studies on the development of HIV resistance with long-acting cabotegravir (CAB-LA) and rilpivirine (RPV-LA) in both treatment and pre-exposure prophylaxis (PrEP) contexts. Included are clinical trials, molecular studies, pharmacologic evaluations, and global surveillance data that together explore the extent, mutation profiles, and determinants of virologic failure. The analyzed literature emphasizes the roles of drug exposure heterogeneity, delayed dosing, and viral genetic heterogeneity in resistance development, as well as the necessity for standardized systems of resistance monitoring across regions. Collectively, these investigations offer vital information on the mechanisms and epidemiological patterns of long-acting antiretroviral resistance, in support of global efforts to maintain the long-term efficacy of CAB-LA and RPV-LA in HIV prevention and treatment programs. Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [478] Table 1. Summary of Reviewed Studies on CAB-LA and RPV-LA Resistance Emergence Author(s)/ Year Focus of the Study Key Findings / Results Author’s Recommendation 1 Delany-Moretlwe et al. (2022) Phase 3 HPTN 084 trial (CAB-LA in women, Africa) 0.21% of participants experienced virologic failure with R263K and E138A mutations. Demonstrated CABLA’s high efficacy but underscored breakthrough infection risk. Strengthen routine HIV testing and resistance monitoring in PrEP programs. 2 HPTN 083 Clinical Trial (2025) Phase 3 study (MSM population, PrEP) 0.48% infection rate; resistant strains carried R263K and E138K mutations. Most failures occurred with delayed injections. Emphasize strict adherence and timely injection schedules for prevention success. 3 Wensing et al. (2025) Global HIV-1 mutation surveillance Documented rising CABand RPVassociated resistance; common INSTI mutations Q148R/K, G118R; NNRTI mutations E138K, Y181C. Establish standardized global databases for tracking long-acting ARV resistance. 4 Reuters (2024) WHO resistance alert report WHO observed early resistance increase to GSK’s cabotegravir, emphasizing global monitoring gaps. Expand global resistance surveillance and improve regional reporting capacity. 5 Rusconi et al. (2022) Review on long-acting CAB + RPV therapy Warned that subtherapeutic “tail” concentrations postinjection increase mutation risk. Address pharmacokinetic tail effect through patient education and regimen adjustment. 6 Rhee et al. (2022) Genotypic correlates of CAB resistance Identified key integrase mutations R263K and G118R; associated with 3–8-fold reduced drug susceptibility. Perform routine genotypic resistance testing for individuals with virologic failure. 7 D’Antoni et al. (2025) Phenotypic analysis of INSTI-resistant isolates Showed that Q148R/H/K and N155H mutations reduce CAB activity; partial cross-resistance to bictegravir. Investigate combination therapies to minimize crossresistance risk. 8 The Lancet HIV (2024) Public health analysis (Zambia PrEP rollout) Stressed need for routine HIV testing during CAB-LA PrEP Integrate resistance screening and Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [479] use to prevent unnoticed resistance development. education in national PrEP rollout programs. 9 Wijstma et al. (2024) Epidemiological study on MSM treatment Noted adherence issues as major determinant of resistance; delay in detection worsens outcomes. Improve adherence support and early detection of treatment failure. 10 Wensing et al. (2025) Global mutation updates Confirmed CABand RPV-associated resistance emerging in multiple regions; recommended standardized global surveillance. Develop harmonized definitions and testing methods for longacting ARV resistance. The analyzed clinical trials including HPTN 083 and HPTN 084, consistently revealed that the foremost predictors of viral breakthrough were the delayed injections and the non-adherence to the medication. Furthermore, mutations R263K and E138K were noted to recur in different research works, which pointed out that these mutations are indeed the molecular markers for the resistance against the CAB-LA and RPV-LA treatment. In addition, Wensing and colleagues (2025) as well as the news agency Reuters (2024) have alerted to a rising global trend in the mutations and have accordingly warned of the increasing resistance levels that may eventually lead to the downfall of these regimes in terms of long-term effectiveness. Through the studies that have been reviewed, it is pharmacokinetics, behavior and virology that are interplaying factors in HIV treatment. As an example, the investigators, Rusconi et al. (2022) and D’Antoni et al. (2025), have pointed out the situation where the long pharmacologic “tail” period after the discontinuation of the injections could lead to the virus being able to replicate in the presence of low drug concentrations, thus fostering the onset of the resistant mutant population through the application of selective pressure. Such findings highlight the necessity of patient education, punctual administration, and strict monitoring in order to cut off the resistance development pathway. To summarize, Table 1 shows that although the CAB-LA and RPV-LA have become the backbone of HIV therapy due to improved compliance, the simultaneous and subtle emergence of resistant strains calls for constant health surveillance. Table 2. Summary of HIV Drug Resistance Prevalence Among CAB-LA and RPV-LA Users. in Clinical Trials and Observational Studies Study/Source Study Population Setting Total Participants ResistanceAssociated Virologic Failure (RAVF) Estimated Prevalence (%) Key Notes DelanyMoretlwe et al. (2022) - HPTN 084 Women (PrEP) Sub-Saharan Africa 3,223 7 0.21% Breakthrough infections with R263K and E138A mutations HPTN 083 (2025) - Apretude Data MSM (PrEP) Americas, Europe 4,566 22 0.48% Delayed injections linked to resistance Wensing et al. (2025) Mixed Global Not mentioned Not mentioned 0.30% (global est.) Increase observed in new resistance reports Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [480] Reuters (2024) Not mentioned WHO Global Surveillance Not mentioned Not mentioned 0.35% (est.) WHO warning on emerging RPV-LA resistance The Lancet HIV Not mentioned Zambia (Public Health Not mentioned Not mentioned <0.5% Highlighted PrEP-related resistance risks The resistance-associated virologic failure (RAVF) was highly prevalent, being documented in several studies and among different populations. For example, in the HPTN 084 trial, which included African women, the rate of RAVF was 0.21%, whereas in the HPTN 083 trial, the rate among men who have sex with men (MSM) was slightly higher at 0.48%. These numbers, while low, indicate that resistance is occurring even in clinical environments with strict adherence protocols. The MSM group having a higher rate could be due to behavioral factors, differences in injection timing, or dissimilarities in baseline viral loads. The WHO global surveillance data reported an approximation of 0.35% for CAB-LA and RPV-LA resistance globally. This trend is in line with the rising resistance-associated mutations which have been reported in clinical literature and surveillance datasets, especially in regions with poor healthcare infrastructure and intermittent access to ART. The implications are that although long-acting therapies are altering adherence patterns, the room for pharmacological error is smaller than with daily oral regimens. During the period of injection timing lapse, the drug levels may fall to a point where they are not effective against the virus, hence allowing the virus to replicate. The differences in prevalence for different regions pointed out the necessity for the population-specific interventions. For example, in sub-Saharan Africa, the prevalence is low, but that could be misinformation due to the inability to perform many sequencing tests. On the other hand, in Western and European countries where sophisticated resistance monitoring systems are in place, cases of CAB/ RPV resistance get detected more easily. Figure 2. Estimated Prevalence of Resistance-Associated Virologic Failure Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [481] The prevalence of resistance recorded in HPTN 084 (women, sub-Saharan Africa) was 0.21%, while. In the HPTN 083 study (focusing on MSM population in the Americas and Europe), the figure was 0.48%. The 2024 global alert from the WHO estimated this at approximately 0.35%, confirming a small but noticeable upward trend. This pattern is illustrated in Figure 1, which shows minor regional differences but verifies that resistance continues to be under 1% worldwide. The data show that long-acting ART maintains high efficacy, but even rare failures can lead to significant clinical repercussions due to the simultaneous compromise of multiple drug classes by resistant variants. The increased rates observed in HPTN 083 are mainly ascribed to delays in the injection schedule and lapses in adherence, highlighting the importance of behavioral factors in addition to pharmacologic ones. Table 3. Common INSTI and NNRTI Mutations Identified in CAB-LA and RPV-LA Failures Drug Class Common Mutations Identified Effect on Drug Susceptibility Cross-Resistance Observed References INSTI (Cabotegravir) R263K, G118R, Q148R/H/K, N155H 3–8× reduction in CAB susceptibility Partial resistance to dolutegravir, bictegravir Rhee et al. (2022); D’Antoni et al. (2025); Wensing et al. (2025) NNRTI (Rilpivirine) E138K, K101E, Y181C, E138A Reduced RPV and efavirenz activity Cross-resistance to etravirine, doravirine Wensing et al. (2025); Reuters (2024) Dual Resistance (CAB + RPV) R263K + E138K Dual class resistance (INSTI + NNRTI) Compromised CAB/RPV cotherapy efficacy Delany-Moretlwe et al. (2022) The molecular mutations that are most commonly found in cases of resistance to CAB-LA and RPV-LA. Among INSTIs, R263K and G118R decrease cabotegravir susceptibility threeto eight-fold, whereas Q148R/H/K and N155H confer cross-resistance to dolutegravir and bictegravir. Similarly, mutations in NNRTI like E138K, K101E, and Y181C reduce the effectiveness of rilpivirine and broaden resistance to etravirine and doravirine. The dual-class resistance pattern (R263K + E138K) is of greatest concern, as it directly compromises the combined CAB/RPV regimen. With the repeated emergence of these mutations, it is crucial to implement baseline genotypic screening and continuous molecular surveillance in order to avert unnoticed resistance propagation. Table 4. Clinical and Pharmacological Factors Associated with Resistance Emergence Contributing Factor Description/Mechanism Effect on Resistance Development Supporting Studies Adherence and Injection Timing Missed or delayed CABLA/RPV-LA doses cause subtherapeutic plasma levels Increased chance of viral replication and mutation selection HPTN 083 (2025); Rusconi et al. (2022) Pharmacokinetic Tail Effect CAB-LA and RPV-LA persist at low concentrations after discontinuation Provides a “window period” for viral escape mutations Rusconi et al. (2022); Wijstma et al. (2024) Baseline Viral Load High initial viral load before injection initiation May accelerate selection of resistant variants Delany-Moretlwe et al. (2022) HIV-1 Subtype Diversity Non-B subtypes (A, C) have intrinsic polymorphisms Slightly higher resistance rate in African cohorts Rhee et al. (2022); The Lancet HIV (2024) Prior ART Exposure Exposure to INSTI/NNRTI in the past Increased crossresistance likelihood Wensing et al. (2025) The multifactorial determinants influencing resistance emergence. It shows that resistance is not just a result of viral mutation but a complex interaction among clinical, behavioral, and pharmacologic factors. The adherence Volume-09 Issue 10, October-2025 ISSN: 2456-9348 Impact Factor: 8.232 International Journal of Engineering Technology Research & Management (IJETRM) https://ijetrm.com/ IJETRM (http://ijetrm.com/) [482] issue is the most recurring one along with the timing of injection getting delayed, where the doses not taken result in the plasma concentrations that do not reach the therapeutic level and thus the virus gets to replicate. This is the finding that also supports the conclusion drawn by the HPTN 083 study which had delayed injections linked to almost all the recorded resistance cases. The pharmacokinetic tail effect is another aspect that has significant impact. Both CAB-LA and RPV-LA can be detected in the blood for several months after the treatment is stopped. The long half-life is a double-edged sword; it is advantageous in terms of drug coverage but at the same time provides an opportunity for resistant strains to emerge due to the falling drug level that goes below the inhibitory level. This situation is especially worrisome when therapy is ceased without an immediate change to an alternative ART regimen. To list a few other factors, there is a high viral load at baseline which augments the chances of viral replication during the dosing period, and HIV-1 subtype diversity is another factor, particularly non-B subtypes which are common in Africa that have naturally occurring polymorphisms that lower the binding affinity of the drugs. In addition, the prior use of other INSTI or NNRTI drugs raises the cross-resistance risk, which complicates the retreatment options. Figure 3. Contributing Factors to Resistance Emergence The main factors of resistance in long-acting ART regimens are adherence and injection timing. These treatments are based on sustained plasma concentrations for viral suppression; missed or delayed doses quickly reduce drug levels, allowing the virus to replicate and develop resistance. The risk of resistance is increased by various behavioral and logistical factors such as stigma, travel barriers, and limited clinical access, HPTN 083 (2025) and Rusconi et al. (2022) being the supporting references for this. Moreover, the pharmacokinetic “tail” effect is another major contributor in which the residual CAB and RPV stay at subtherapeutic levels for weeks or even months after stopping the treatment. Waiting for too long between injections can result in a viral rebound. Among others, the baseline viral load and the genetic variability of HIV-1 subtypes are also factors. High viral loads make mutations more likely to occur, and non-B subtypes, which are prevalent in African and Asian populations, have