PHWR Public Health Weekly Report

Human immunodeficiency virus (HIV) is the causative agent for acquired immune deficiency syndrome (AIDS) and is primarily transmitted via sexual contact, blood exposure, and vertical transmission. HIV infection targets CD4+ T cells and progressively impairs immune function, thereby increasing the risk of opportunistic infections and tumor development. If left untreated, it follows a fatal course. Recently, with the introduction and development of antiretroviral therapy (ART), HIV infection has transitioned to a chronic disease that can be effectively managed. However, no curative treatment has yet been established, and because lifelong treatment is required for people with HIV, it remains an important public health issue.

According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), approximately 40.8 million people worldwide are estimated to be HIV-positive as of 2024, and approximately 1.3 million new HIV infections are reported annually [1]. In the Republic of Korea (ROK), approximately 1,000 new HIV infections occur annually, and in 2024, 975 newly infected individuals were reported, bringing the cumulative number of HIV-positive cases to 20,451. Moreover, although trends in annual incidence do not show a clear pattern of increase or decrease, the proportion of foreign nationals among all people with HIV more than doubled from 11.6% in 2015 to 26.8% in 2024 and continues to increase [2].

HIV is an RNA virus with a high mutation rate, recombination capacity, and genetic diversity. HIV-1 is classified into groups M (major), N (new), O (outer), and P (pending the identification of further human case). Among these, group M accounts for most HIV cases worldwide and is further divided into nine major subtypes (A–D, F–H, J, and K) and various recombinant forms [3]. To date, circulating recombinant forms (CRFs) up to CRF184 have been identified and named and reported in the Los Alamos National Laboratory database, and these genotypes show different distributions by region and population group [4]. Globally, subtype C accounts for the highest proportion of cases, whereas subtype B is mainly reported in North America, Europe, and the ROK. However, recently, with increasing international mobility and changes in transmission routes, the proportion of cases with recombinant forms has gradually increased [5].

Meanwhile, antiretroviral agents have continued to advance, and in particular, the introduction of integrase strand transfer inhibitors (INSTIs)-based regimen has contributed substantially to increasing the survival rate among people living with HIV and effectively suppressing viral transmission. Nevertheless, the emergence and transmission of drug resistance mutations, including resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), remain important public health concerns. In addition, as specific mutations associated with genotype might affect resistance to antiretroviral agents, genotype diversity is closely related to responsiveness to antiretroviral agents and the emergence of resistance. In addition, it has important implications for establishing treatment strategies and analyzing patterns of infection spread. In particular, because drug resistance mutations may be observed even in treatment-naive patients, molecular epidemiological characterization and continuous surveillance at the early stage of infection are essential.

Therefore, this study analyzed the distribution of HIV-1 genotypes and patterns of antiretroviral drug resistance among people with newly acquired HIV infection in the ROK from 2024 to 2025, with the aim of identifying changes in the HIV epidemic in the ROK.

1. Specimen Selection and Generation of Genetic Information

This study was conducted using specimens from ART-naive Korean patients with newly acquired HIV infection reported in the ROK from 2024 to 2025. The specimens included in the analysis comprised a total of 248 specimens (92 from 2024 and 156 from 2025), including specimens wherein HIV nucleic acid was detected using nucleic acid testing based on diagnostic test results or specimens randomly selected based on western blot antibody test results. After HIV nucleic acid was extracted from the selected specimens, polymerase chain reaction targeting the gag and pol genes was performed, and after purification, the samples were subjected to Sanger sequencing.

2. Genotyping Method

Genotyping was performed using HIV BLAST, an online analysis program provided by the U.S. Los Alamos National Laboratory (Los Alamos HIV Database; https://hiv.lanl.gov/content/sequence/BASIC_BLAST/basic_blast.html). The final genotype was determined by integrating the gag and pol gene analysis results based on the genotype showing the highest genetic similarity identified in the program.

3. Drug Resistance Analysis Methods

Drug resistance analysis was performed using HIVDR, the Stanford University HIV Drug Resistance Database (version 10.1; https://hivdb.stanford.edu/hivdb). Based on the pol gene analysis regions, four classes of antiretroviral agents—protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, and INSTIs—were analyzed, and all and all relevant drugs amenable to analysis were included. In addition, the program assigns drug resistance scores according to mutations and classifies resistance into four levels (potential resistance, low-level resistance, intermediated-level resistance, and high-level resistance). In this study, among these levels, drug resistance was analyzed as low-level resistance or higher; however, potential resistance was excluded.

1. Distribution of HIV-1 Genotypes

Among the 248 specimens, excluding those wherein the gag and pol genes were not amplified, genotyping was performed on 85 specimens from 2024 and 134 specimens from 2025. The overall genotype distribution showed that subtype B accounted for the highest proportion of specimens (51.6%), while recombinant forms accounted for 44.4% of specimens. Other genotypes included subtypes A6 (3.7%) and C (0.5%) (Figure 1A). Detailed analysis of recombinant forms showed that CRF01_AE accounted for most cases (23.7%), followed by CRF_BC (6.4%), CRF_01B (4.6%), CRF56_cpx (3.7%), CRF_02A6 (2.7%), and CRF_0107 (2.3%). CRF03_A6B and CRF06_cpx each accounted for 0.5% of specimens. According to the year, subtype B and recombinant forms accounted for 57.6% and 36.5% of specimens in 2024 and 47.8% and 49.3% of specimens in 2025. Examination of recombination patterns showed that genotypes derived from the recombination of subtype B, the predominant strain in the ROK, and CRF01_AE-related recombinant forms, including CRF_0107 and CRF_01B, increased from 2.4% in 2024 to 9.7% in 2025. In addition, CRF06_cpx and CRF03_A6B, which are new forms recombined with subtype A and had not been identified in previous studies [6], were detected in 2024 and 2025, respectively (Figure 1B, C).

Figure 1. Distribution of HIV-1 subtypes among newly diagnosed individuals in the Republic of Korea, 2024–2025
(A) A total of 219 samples; (B) 85 in 2024; (C) 134 in 2025 were subjected to subtype analysis using the HIV BLAST tool provided by Los Alamos National Laboratory (USA). HIV=human immunodeficiency virus; CRF=circulating recombinant form; cpx=complex.

2. Antiretroviral Drug Resistance Analysis Results by Drug Class

A total of 212 of 248 specimens were included in the drug resistance analysis (84 in 2024 and 128 in 2025). The prevalence of antiretroviral drug resistance in specimens with resistance to at least one drug among those included in the analysis decreased slightly from 10.7% in 2024 to 9.9% in 2025, and the average prevalence of drug resistance by drug class also decreased from 3.5% in 2024 to 2.8% in 2025. Analysis of annual trends in drug resistance by drug class showed that the prevalence of resistance to PIs increased substantially from 2.5% to 5.6%, whereas the prevalence of resistance to NRTIs increased slightly from 2.5% to 2.8%. Moreover, resistance to NNRTIs decreased from 6.3% to 2.8%, while resistance to INSTIs decreased from 2.5% to 0.0% in 2025 (Figure 2). The major mutations affecting drug resistance in PIs were analyzed as follows: in 2024, one case each of multiple mutations, such as L76EV, G73GC, M46I, and N88G, was identified, and in 2025, one case with I54V (or S) and four cases with M46I were identified, with M46I being the most frequently analyzed (Supplementary Figure 1; available online). NRTIs and NNRTIs showed sporadic mutations at various positions, and in the NNRTI class, particularly, V179E/D and E138A were analyzed as two cases each in 2024 and zero and one case, respectively, in 2025. In addition, resistance to dolutegravir (DTG), a World Health Organization–recommended drug in the INSTI class for which regular monitoring is recommended [7], was detected in one case in 2024 and no case in 2025 (Figure 3).

Figure 2. Proportion of drug resistance rate in transmitted drug resistance over time, 2024–2025
Drug resistance analysis by antiretroviral class was performed (PIs, NRTIs, and NNRTIs: 79 cases in 2024 and 107 cases in 2025; INSTIs: 80 cases in 2024 and 112 cases in 2025) using the online Stanford University HIV Drug Resistance Database (version 10.1). PI=protease inhibitor; NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=non-nucleoside reverse transcriptase inhibitor; INSTI=integrase strand transfer inhibitor.

Figure 3. Number of drug resistance mutations by antiretroviral drugs among treatment-naive newly diagnosed individuals in the Republic of Korea
Drug resistance analysis by individual antiretroviral drugs was performed (PIs, NRTIs, and NNRTIs; n=186, INSTIs; n=193) using the online Stanford University HIV Drug Resistance Database (version 10.1). PI=protease inhibitor; NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=non-nucleoside reverse transcriptase inhibitor; INSTI=integrase strand transfer inhibitor; ATV=atazanavir; DRV=darunavir; FPV=fosamprenavir; IDV=indinavir; LPV=lopinavir; NFV=nelfinavir; SQV=saquinavir; TPV=tipranavir; ABC=abacavir; AZT=zidovudine; D4T=stavidine; DDI=didanosine; FTC=emtricitabine; 3TC=lamivudine; TDF=tenofovir; DOR=doravirine; DPV=dapivirine; EFV=efavirenz; ETR=etravirine; NVP=nevirapine; RPV=rilpivirine; BIC=bictegravir; CAB=cabotegravir; DTG=dolutegravir; EVG=elvitegravir; RAL=raltegravir.

HIV is a chronic virus with high genetic diversity, and its recombinant forms continue to increase [5]. Consistent with previous studies, the present study revealed subtype B as the predominant genotype in the ROK, followed by CRF01_AE and CRF_BC. In addition, as recombination patterns were analyzed to be in the form that some genotypes previously circulating in the ROK are recombined and circulate, or genotypes circulating outside the ROK are recombined, and new genotypes are generated, it was confirmed that the genetic diversity in the ROK is expanding. In particular, genotypes such as CRF06_cpx and CRF03_A6B, which were novel recombinant forms identified in this study, are forms recombined with subtype A, which is prevalent in Eastern Europe and Central Asia [8]. This finding indicated that attention should be paid to changes in the current status of genotype distribution in neighboring countries. In addition, these changes suggest that the HIV epidemic pattern in the ROK might become more complex in the future. As these patterns reflect increased genotype diversity associated with increased international mobility and expanded contact between population groups, it is necessary to identify changing trends through continuous surveillance.

The overall prevalence of resistance to all drugs among treatment-naive people with HIV, including cases with resistance to at least one antiretroviral agent, and the average prevalence of resistance by drug class were analyzed separately. Since current ART consists of combination regimens, drug resistance was analyzed by classifying it into the overall prevalence of resistance to all drugs and the average prevalence by drug class. Both the prevalence of resistance to at least one antiretroviral agent and the average prevalence of resistance by drug class mildly decreased in 2025 compared with 2024, and compared with previous findings (average prevalence of resistance by drug class of 5.9% in 2022–2023) [6], the average prevalence of resistance by drug class for each year shows a decreasing trend to 3.2% (p=0.039), indicating a stabilizing trend. By drug class, the prevalence of resistance to NRTIs showed no significant change, the prevalence of resistance to PIs increased, whereas the prevalence of resistance to NNRTIs and INSTIs decreased substantially. Among mutations associated with PI resistance, the most frequent mutation was M46I, which has been detected in patients previously. Although the distribution of this mutation varies worldwide, it is a common PI-associated mutation and is known to be frequently reported among treatment-naive people with HIV regardless of genotype [9]. According to a study on drug resistance in China, the most frequently reported mutation was M46L, followed by K103N and M46I, and although most drug resistance mutations tend to reduce transmission fitness, M46I has been reported as a commonly transmitted drug resistance mutation that increases transmission fitness [10]. In addition, the mutations requiring attention as factors contributing to the decrease in resistance to NNRTIs in this study were V179E/D and E138A. V179E/D is a common and most frequently detected mutation among those associated with potential drug resistance. In addition, this mutation does not confer resistance on its own, but it is known to substantially increase drug resistance when accompanied by other mutations. A similar finding was obtained in the present study. Therefore, this mutation requires attention because of its high detection rate and because, when accompanied by other mutations, it might impair the initial viral load reduction achieved with NNRTI-based regimens and increase the prevalence of resistance [11]. The E138A mutation confers low-level drug resistance only against dapivirine (DPV) among NNRTIs. This drug was added relatively recently (January 2025) to the list of drugs analyzed in HIVDR, the Stanford University HIV drug resistance program [12], and because it is used as a preventive agent rather than a therapeutic drug, in vivo data related to resistance are limited [13]. Therefore, among the mutations mainly identified in this study, no mutation was confirmed to increase the risk of resistance; however, continuous surveillance is required. In addition, in the case of NRTIs and INSTIs, several resistance-associated mutations were identified, but they occurred sporadically at various positions, and no characteristic mutation was identified. Drugs commonly prescribed in the ROK are single formulations wherein multiple drug classes are combined, namely DTG and lamivudine (3TC), or bictegravir (BIC), emtricitabine (FTC), and tenofovir (TDF) combined in a single formulation [14]. In the resistance analysis for these drugs, no case showing resistance to all of these drugs was identified, indicating that resistance to drugs prescribed in the ROK showed an overall stable trend. In addition, considering DTG-based treatment strategies, resistance to INSTIs remained at a low level. However, some resistance was identified against NRTI class drugs (3TC, FTC, and TDF) included in combination regimens, indicating that caution is required in clinical management.

This study presents recent trends in HIV genotypes and drug resistance; however, several limitations exist. First, because this study was conducted among Korean nationals, our findings cannot be generalized to foreign nationals. In addition, the analysis was performed focusing on the gag and pol gene regions, and because whole-genome analysis was not performed, there may be limitations in the accurate classification of some recombinant forms. Finally, because the study was conducted among patients with no history of ART, there were limitations in evaluating patterns of change in clinical resistance mutations associated with drug prescriptions and causal relationships in patients receiving treatment. Nevertheless, this study was meaningful in that it analyzed genotype distribution and drug resistance patterns among people with recently acquired HIV infection in the ROK. In particular, the increasing diversity of HIV genotypes among people living with HIV in the ROK suggests the importance of identifying transmission characteristics through future analyses of epidemic patterns and epidemiological associations. In addition, drug resistance–related mutations continue to be reported, and in this study, a partial increasing trend was observed in the PI class, whereas other drug classes showed relatively stable patterns. Therefore, continuous surveillance is needed to precisely evaluate annual trends in these changes. In the future, studies are needed to conduct long-term follow-up of changes in the prevalence of drug resistance according to the type of drug and trends in mutation sites by linking with clinical data. Therefore, continuous molecular epidemiological surveillance and monitoring of drug resistance are essential for establishing effective treatment strategies and suppressing the spread of infection.

Ethics Statement: Ethical review and approval were waived for this study owing to the use of anonymized residual samples. Researchers had no access to donor identification (IRB No.: KDCA-2025-01-03-PE-01).

Funding Source: None.

Acknowledgments: None.

Conflict of Interest: The authors have no conflicts of interest to declare.

Author Contributions: Conceptualization: HC, JSW, DYL, GYK, YHC. Data curation: GYK, YHC. Formal analysis: YHC. Methodology: GYK, YHC. Project administration: HC, JSW, DYL, GYK. Supervision: HC. Visualization: YHC. Writing – original draft: YHC. Writing – review & editing: HC, JSW, DYL, GYK.

Supplementary data are available online.