ABSTRACT In China, Henan Province is a region with a high HIV burden. Furthermore, drug resistance (DR) among people living with HIV/AIDS (PLWHA) on antiretroviral therapy (ART) is becoming

a critical barrier to achieving viral suppression. Monitoring DR in PLWHA with detectable viremia after ART is crucial, especially given the widespread use of NNRTI and NRTI, which have

historically been the backbone of China’s national ART program due to affordability and availability. In this study, plasma samples from PLWHA with viral load (VL) ≥ 40 copies/mL after ≥ 6 

months of ART from January 2023 to December 2023 were collected for genotypic DR testing. Of 804 individuals with detectable viremia, a total of 14 HIV-1 subtypes were detected. The top five

integrase strand transfer inhibitors (INSTIs) were 62.94% (506/804), 53.23% (428/804), 7.34% (59/804), and 3.98% (32/804), respectively. The prevalence of DR among PLWHA below and ≥ 200

copies/mL were 40.63% (13/32) and 68.91% (532/772), respectively. Multivariate regression analysis showed that age < 29 years and 40–49 years, baseline CD4 count < 500 cells/µL,

current VL of 103–105 copies/mL, and initial ART regimen of NRTIs + NNRTIs were closely associated with the occurrence of DR. These findings highlight the urgent need for expanded access to

drug resistance testing and the adoption of WHO-recommended regimens, such as dolutegravir (DTG), to mitigate the growing threat of DR. Our results suggest that drug resistance testing

should be applied to all PLWHA with detectable viremia, and treatment strategies should be optimized to align with global guidelines. SIMILAR CONTENT BEING VIEWED BY OTHERS CHARACTERISTICS

OF DRUG RESISTANCE MUTATIONS IN ART-EXPERIENCED HIV-1 PATIENTS WITH LOW-LEVEL VIREMIA IN ZHENGZHOU CITY, CHINA Article Open access 09 May 2024 HIV-1 SUPPRESSION AND RARE DOLUTEGRAVIR

RESISTANCE IN ANTIRETROVIRAL-EXPERIENCED PEOPLE WITH HIV IN LIBERIA Article Open access 09 May 2025 HIV-1 DIVERSITY AND PRE-TREATMENT DRUG RESISTANCE IN THE ERA OF INTEGRASE INHIBITOR AMONG

NEWLY DIAGNOSED ART-NAÏVE ADULT PATIENTS IN LUANDA, ANGOLA Article Open access 10 July 2024 Since China launched antiretroviral therapy (ART) in 2003, the viral load (VL) of most human

immunodeficiency virus type 1 (HIV-1) infected individuals can be effectively controlled, greatly prolonging the life expectancy of people living with HIV/AIDS (PLWHA)1. However, widespread

ART inevitably leads to the emergence of drug resistance (DR) due to multiple factors, such as low genetic barrier of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside

reverse transcriptase inhibitors (NRTIs) and poor adherence2. The National Free Antiretroviral Treatment Program initially adopted NNRTIs and NRTIs as the main drugs in the standardized

regimens due to their affordability and availability, which subsequently brings new challenges to the effectiveness of current mainstream ART in China3. In Henan Province, a region with a

historical HIV burden linked to blood-selling practices in the 1990s, the epidemic has shifted to sexual transmission (92.78% in newly diagnosed HIV-1 infection)4. It is reported that about

10–30% of patients cannot effectively control their viral load (VL) after receiving standard ART5. Socioeconomic challenges, such as stigma and financial barriers to follow-up care, further

exacerbate suboptimal treatment outcomes6,7. Understanding the prevalence and drug resistance characteristics of this group and timely adjusting effective ART regimens have positive

significance for achieving the "95–95-95" goal and ending the AIDS epidemic by 20303. The overall incidence of acquired drug resistance mutations (DRMs) in PLWHA in China from 2001

to 2017 is about 44.7%8. According to the previous data of Henan Province, the incidence of DRMs in PLWHA with failed ART from 2018 to 2022 exceeded 80%9,10. This alarming rate underscores

the urgency of aligning treatment protocols with the WHO’s 2021 Consolidated Guidelines, which emphasize routine resistance testing and rapid transition to integrase strand transfer

inhibitors (INSTIs) like dolutegravir (DTG)11. While China has adopted DTG, its rollout in Henan is limited. Currently, research on DR mainly focuses on treatment-naive patients or PLWHA

with complete ART failure. However, more detailed research reveals that DR in other patient groups, like those with low-level viremia (LLV), cannot be overlooked. LLV refers to a relatively

low HIV-1 VL in the blood during ART (usually with a VL between 50 and 999 copies/mL)12. Apart from the facts that PLWHA with a VL < 1,000 copies/mL exhibit a reduced risk of transmitting

the infection as opposed to those with a VL of ≥ 1,000 copies/mL, further researches indicated that, relative to those with a VL of ≤ 50 copies/mL, individuals with LLV carry an increased

risk of ART failure13,14 and DR6,15. Given the significance of understanding the DR profiles in PLWHA with different levels of VL and its potential impact on ART effectiveness, in this

study, we specifically focused on PLWHA with detectable viremia (VL ≥ 40 copies/mL) after ART in Henan Province in 2023. By analyzing the distribution and drug resistance characteristics of

HIV-1 subtypes among them, we aim to provide valuable data to support for the clinical treatment and management of HIV-1, which is crucial for optimizing ART regimens and achieving better

treatment outcomes. RESULTS PATIENT CHARACTERISTICS A total of 987 PLWHA with detectable viremia after ART were included in this study. Samples from 804 patients were successfully genotyped,

giving a detection rate of 81.46%. Among the 804 successfully genotyped individuals, the median age was 49 years (IQR, 34–58), 73.51% (591/804) were male, 56.97% (458/804) were married, and

99.13% (797/804) were of Han ethnicity. The main route of transmission was sexual transmission (61.57%, 495/804), within which MSM accounted for 40.92% (329/804). Farmers accounted for

40.17% (323/804). According to the analysis, those with educational levels below junior college accounted for 68.28% (549/804). Detailed demographic characteristics of the patients are

presented in Table 1. GENOTYPE DISTRIBUTION The obtained _pol_ gene sequences were submitted to the REGA online HIV-1 subtype analysis tool for subtype analysis. Furthermore, a phylogenetic

tree was constructed based on the _pol_ gene sequences. All determined subtypes clustered with reference strains, indicating accurate subtype classification (Supplementary Fig. 1). A total

of 14 subtypes were detected. The subtype with the highest frequency was subtype B (55.97%, 450/804), followed by CRF01_AE (22.14%, 178/804), CRF07_BC (15.42%, 124/804), CRF55_01B (3.36%,

27/804), CRF08_BC (1.00%, 8/804), C (0.62%, 5/804), and other subtypes (1.49%, 12/804), including CRF67_01B (0.50%, 4/804), CRF62_BC (0.25%, 2/804), CRF02_AG (0.12%, 1/804), CRF03_A6B

(0.12%, 1/804), CRF52_01B (0.12%, 1/804), CRF59_01B (0.12%, 1/804), CRF68_01B (0.12%, 1/804), and G (0.12%, 1/804) (Table 2). CHARACTERISTICS OF DR Among 804 PLWHA with detectable viremia

after ART, 545 samples showed low-level or greater resistance to at least one ART drug, resulting in a total DR incidence of 67.79% (545/804). The prevalence of DR among PLWHA with the VL of

below and ≥ 200 copies/mL were 40.63% (13/32) and 68.91% (532/772), respectively (data not shown). Chi-squared analysis results indicated significant differences in DR incidence rates among

different subtypes (Table 2). Further analysis of DRMs revealed that NNRTIs-related mutations had the highest frequency (62.94%, 506/804), with mutation sites dominated by K103 (33.58%),

G190 (18.16%), V106 (17.91%), V179 (14.30%), and Y181 (14.05%). NRTIs-related mutations had a frequency of 53.23% (428/804), dominated by M184 (45.90%), K65 (19.28%), K70 (17.41%), S68

(16.04%), and D67 (11.94%). PIs-related mutations had a relatively low frequency of 7.34% (59/804), dominated by M46 (3.73%), V82 (3.23%), and I54 (2.86%). INSTIs-related mutations had the

lowest rate (3.98%, 32/804), dominated by E157 (1.37%), G163 (1.00%), and E138 (0.75%) (Fig. 1). Further analysis showed DRMs incidences: 20.90% (168/804) for single-class drugs, 45.77%

(368/804) for dual-class drugs, 6.47% (52/804) for triple-class drugs, and 0.37% (3/804) for quadruple-class drugs. Since over 90% of PLWHA in China were prescribed with free ART drugs,

namely abacavir (ABC), zidovudine (AZT), and lamivudine (3TC) of the NRTIs, tenofovir (TDF), efavirenz (EFV), and nevirapine (NVP) of the NNRTIs, and lopinavir/ritonavir (LPV/r) of the PIs,

we thus analyzed the DRMs against these seven drugs separately. The results showed that the prevalence of DRMs against the seven drugs is 65.30% (525/804), with ABC at 51.74% (416/804), AZT

at 14.43% (116/804), 3TC at 51.12% (411/804), TDF at 37.31% (300/804), EFV at 60.95% (490/804), NVP at 61.32% (493/804), and LPV/r at 4.85% (39/804). For individual drugs, NVP (60.32%,

485/804), EFV (55.22%, 444/804), and 3TC/emtricitabine (FTC) (45.77%, 368/804) showed the highest incidence of high-level resistance. Doravirine (DOR; 21.64%, 174/804), etravirine (ETR;

17.16%, 138/804), and TDF (17.04%, 137/804) have the highest incidence of medium-level resistance. Rilpivirine (RPV; 13.31%, 107/804), ABC (12.69%, 102/804), and TDF (9.95%, 80/804) have the

highest incidence of low-level resistance (Fig. 2). Detailed information on the drug resistance of ART drugs related to DRMs are presented in Fig. 2. ANALYSIS OF FACTORS INFLUENCING DRMS

Univariate logistic regression analysis found that patients aged 40–49 years old, baseline CD4 < 200 cells/µL, current VL of 103–105 copies/mL, current CD4 < 100 cells/µL, years of

infection ≥ 10 years, and those initially using the NRTI plus NNRTI ART regimen had a higher possibility of developing DR. Further multivariate logistic regression analysis showed that age 

< 29 years old and 40–49 years old, baseline CD4 < 500 cells/µL, current VL of 103–105 copies/mL, and the initial ART regimen consisting of NRTI plus NNRTI only were closely related to

the occurrence of DR (Table 3). DISCUSSION Clarifying the occurrence of drug resistance at different VL levels is crucial for formulating personalized treatment plans and enhancing ART

effectiveness. In this study, we analyzed the genotype distribution and drug resistance characteristics of PLWHA with detectable viremia (VL ≥ 40 copies/mL) after six months of ART in Henan

Province in 2023, and our results provided critical insights for local HIV management. The high prevalence of DR (67.79%) highlights urgent challenges in Henan, where historical

blood-selling practices and current socioeconomic disparities (40.17% farmers, 68.28% education below junior college) drive suboptimal treatment outcomes. These factors lead to delayed

diagnosis, poor treatment adherence, and limited access to VL monitoring, all of which significantly exacerbate the DR risk7,16. Moreover, residual viremia, even at low levels (50–999

copies/mL), acts as a reservoir for continuous viral replication under the selective pressure of ART, and over time, this facilitates the accumulation of DRMs17,18. Notably, DR prevalence

among PLWHA with VL < 200 copies/mL was 40.63%, comparable to our previous data from Zhengzhou City (42.31% in 2022–2023) among low-level viremia (LLV) cases19, comfirming that LLV is not

negligible and requires proactive resistance testing beyond high VL cases. Compared with the prevalence of DR (about 80%) of PLWHA with ART failure in Henan Province from 2018 to 20229,10,

our findings (67.79%) reflect a moderate decrease but slightly higher than the survey data of Hainan Province from 2014 to 2020 (61.41%)20, Jilin Province from 2019 to 2021 (58.8%)21, and

Shanghai from 2017 to 2021 (48%)22. Our findings, when combined with those from other regions such as India (NNRTI and NRTI resistance rates of 73.13% and 68.83%, respectively)23 and

Tanzania24, highlight the global severity of the DR issue in HIV management. The data from these regions suggest that prolonged use of NNRTIs and NRTIs significantly raises the DR risk,

further emphasizing the need for treatment regimen optimization. Additionally, studies from Eastern Europe, Central Asia25 and Russia26 emphasize the importance of high genetic barrier

regimens like dolutegravir (DTG), in reducing DR. Our data, with a low INSTI resistance (3.98%), support WHO’s recommendation to shift to DTG-based regimens, especially in regions like Henan

where NNRTI resistance is high. Regional disparities in DR prevalence, for instance, Botswana (83.3%)27, Indonesia (22.1%)28, Suriname in South America (45.8%)29, underscore the need for

context-specific interventions tailored to local ART access and regimen choices. In this study, a total of 14 subtypes were detected. The predominance of subtype B (55.97%), followed by

CRF01_AE, CRF07_BC, mirrors historical Henan profiles9,10, but slightly differs from the subtype distribution characteristics reported in other regions of China21,22, and also different from

the subtype distribution characteristics of newly diagnosed PLWHA in Henan Province (mainly CRF07_BC subtype, followed by CRF01_AE, B, CRF55_01B and CRF08_BC)4,30, indicating different

subtype distribution characteristics in different regions and among different populations. This diversity implies that treatment policies cannot be generalized. When formulating treatment

strategies, local subtype distribution should be considered because different subtypes may respond differently to drugs, which can affect treatment outcomes. In 2023, among PLWHA with

detectable viremia, DRMs were predominantly in NNRTIs (62.94%, 506/804) and NRTIs (53.23%, 428/804). DRMs for PIs (7.34%, 59/804) and INSTIs (3.98%, 32/804) were relatively low, in line with

China’s ART regimens choices and the low DR barrier of NNRTIs drugs. The most common DRMs were NRTIs-related M184, K65, K70 and NNRTIs-related K103, G190, V106. M184 confers high-level

resistance to 3TC and FTC; K65 causes medium-level resistance to TDF, ABC, and 3TC/FTC, and is common in TDF/3TC regimen. K65R may increase sensitivity to AZT, but for INIST-naive patients

with K65R, TDF/3TC/DTG are more effective than AZT/3TC/DTG31,32. K70 leads to low-level resistance to ABC and TDF. Mutations at K103, G190, and V106 cause high-level resistance to NVP and

EFV33. Notably, DRMs related to PIs and INSTIs showed an upward trend compared to 2018–2022 (PIs: 7.34% vs. 5.2%; INSTIs: 3.98% vs. 3.1%)9. The most common PI mutation M46I/L reduces

susceptibility to ATV/r and LPV/r34. Among INSTIs mutations, minor mutations E157 and G163 predominated. A R263K mutation (0.50%) was identified, resulting an approximately two-fold

reduction in susceptibility to DTG, BIC, and CAB35. DRM profiles are crucial for accurate drugs selection, which can improve treatment success. Multivariate analysis indicated that age < 

29 years and 40—49 years, baseline CD4 < 500 cells/µL, current VL of 103–105 copies/mL, and initial ART regimen of NRTI + NNRTI were closely associated with DR in PLWHA with detectable

viremia (Table 3). These populations require intensified monitoring and early initiation of WHO-recommended INSTI-based regimens to mitigate resistance accumulation. Expanding free

resistance testing to all detectable viremia cases, including LLV, and integrating DTG into first-line treatment are critical steps to align with global guidelines and address Henan’s unique

epidemic context. MATERIALS AND METHODS ETHICAL STATEMENT This study was approved by the Institutional Ethics Committee of The Sixth People’s Hospital of Zhengzhou, China

(IEC-KY-2022–005-2) and performed in compliance with all relevant ethical regulations such as the Declaration of Helsinki (2008). Signed informed consent was obtained from everyone before

the collection of blood samples. STUDY POPULATION From January to December 2023, PLWHA who visited the Sixth People’s Hospital of Zhengzhou, had received ART for more than 6 months, and had

a VL ≥ 40 copies/mL were included in this study. Demographic data and medical records of the patients, including HIV VL, CD4 + T-cell count, and transmission route, were collected. Informed

consent for participating in the study was obtained from the patients prior to sample collection. GENOTYPIC DRUG RESISTANCE TESTING The in-house genotypic drug resistance testing was carried

out as described in our previous studies35,36. Briefly, for patients with a viral load ≥ 400 copies/mL, whole blood was collected and centrifuged at low speed to obtain plasma. RNA was then

extracted using an RNA extraction kit (Liferiver, Shanghai, China) by following the manufacturer’s instructions. For those with a viral load < 400 copies/mL, 1–5 mL plasma was

ultracentrifuged at 28,000 g for 30 min at 4 °C to enrich HIV. The pellet was resuspended in phosphate buffered saline (0.01 M, pH 7.2) and used for RNA extraction. After that, the HIV-1

partial _pol_ and full-length integrase (INT) gene sequences were reverse-transcribed and amplified. Finally, the determined sequences were submitted to the regularly updated Stanford HIV-1

drug resistance database (http://hivdb.stanford.edu/) for analyses of drug resistance mutations (DRMs) and antiretroviral susceptibility. The estimated level of resistance to a drug is

determined by adding up the penalty scores associated with each of the DRMs present in a sequence. Once the total score is calculated the estimated level of resistance can be calculated as

follows: susceptible (total score 0 to 9); potential low-level resistance (total score 10 to 14); low-level resistance (total score 15 to 29); intermediate resistance (total score 30 to 59);

and high-level resistance (total score ≥ 60). Polymorphic mutations and polymorphic accessory mutations, when combined with other DRMs, may lead to reduced susceptibility to certain

antiretroviral drugs, so they are included in our analysis. The determined sequences have been deposited into the NCBI database, and the assigned accession numbers range from PV347152 to

PV347955. SUBTYPING AND PHYLOGENETIC ANALYSIS Subtyping and phylogenetic analyses were carried out as described previously. Briefly, the subtypes of HIV-1 isolates based on the partial _pol_

region was determined using the REGA HIV-1 Subtyping Tool (http://dbpartners.stanford.edu:8080/RegaSubtyping/stanford-hiv/typingtool/) and further confirmed by phylogenetic analysis.

Phylogenetic analysis was conducted using Molecular Evolutionary Genetic Analysis software (version XI), based on the maximum likelihood method and General Time Reversible model. Bootstrap

analysis with 1000 replicates was performed to test the tree topology. Reference sequences included in the ML tree (GenBank No. U51189, AF286226, AF286229, AF069670, AY945737, DQ207940,

U21135, AF067155, JX574661, AF077336, AF061642, AF190127, AF082395, AJ249235, AF286236) were downloaded from the Los Alamos HIV Sequence Database (https ://www.hiv.lanl.gov/). STATISTICAL

ANALYSIS Statistical analysis was carried out using SPSS 20.0 software. For continuous variables with a normal distribution, the mean ± standard deviation is employed. In the case of skewed

distributions, the median along with its interquartile range (from the first to the third quartile) is utilized. Categorical variables are presented as frequency or constituent ratio (%).

The t-test or chi-square test is used to analyze differences between groups. A two-sided test is conducted with a significant level of _α_ = 0.05. A _p_-value < 0.05 is considered

statistically significant. DATA AVAILABILITY The data used and analyzed in this study are available upon reasonable request. Please contact the corresponding author Yuqi Huo at

1246105,[email protected] to inquire about accessing the relevant datasets. We will review each request to ensure compliance with ethical and legal obligations and make every effort to provide the

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(2017–2019). _Arch. Virol._ 165(6), 1453–1461 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS We would like to thank all the doctors,

nurses, and patients who participated in this study. FUNDING This study was supported by the Science and Technology Project of Henan Province (232102310203). AUTHOR INFORMATION Author notes

* Jinjin Liu, Chaohong Fu and Xuan Yang contributed equally to this work. AUTHORS AND AFFILIATIONS * Affiliated Infectious Diseases Hospital of Zhengzhou University (Henan Infectious

Diseases Hospital, The SixthPeople’s Hospital of Zhengzhou), Erqi District, No.29, Jingguang South Road, Zhengzhou, 450000, China Jinjin Liu, Chaohong Fu, Xuan Yang, Xiaohua Zhang, Shuguang

Wei, Jie Ma, Qingxia Zhao & Yuqi Huo Authors * Jinjin Liu View author publications You can also search for this author inPubMed Google Scholar * Chaohong Fu View author publications You

can also search for this author inPubMed Google Scholar * Xuan Yang View author publications You can also search for this author inPubMed Google Scholar * Xiaohua Zhang View author

publications You can also search for this author inPubMed Google Scholar * Shuguang Wei View author publications You can also search for this author inPubMed Google Scholar * Jie Ma View

author publications You can also search for this author inPubMed Google Scholar * Qingxia Zhao View author publications You can also search for this author inPubMed Google Scholar * Yuqi Huo

View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Yuqi Huo and Qingxia Zhao: Conceptualization, Methodology, Software, Validation, Data

curation, Visualization, Investigation. Jinjin Liu, Chaohong Fu, Xuan Yang, Xiaohua Zhang, Shuguang Wei and Jie Ma: Data curation, Investigation, Software, Validation. Jinjin Liu:

Visualization, Writing-original draft, review & editing. Yuqi Huo: Writing-review & editing. CORRESPONDING AUTHORS Correspondence to Qingxia Zhao or Yuqi Huo. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps

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http://creativecommons.org/licenses/by-nc-nd/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Liu, J., Fu, C., Yang, X. _et al._ HIV-1 subtype distribution and drug

resistance profiles among PLWHA with detectable viremia in Henan Province, China, 2023. _Sci Rep_ 15, 17825 (2025). https://doi.org/10.1038/s41598-025-02949-1 Download citation * Received:

27 December 2024 * Accepted: 16 May 2025 * Published: 22 May 2025 * DOI: https://doi.org/10.1038/s41598-025-02949-1 SHARE THIS ARTICLE Anyone you share the following link with will be able

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initiative KEYWORDS * Human immunodeficiency virus (HIV) * Antiretroviral therapy (ART) * Detectable viremia * Drug resistance (DR) * Subtype