Pretreatment Integrase Strand Transfer Inhibitor Resistance in Tianjin, China
Human immunodeficiency virus (HIV) infection remains a significant global public health challenge. The introduction of antiretroviral therapy (ART) in the mid-1990s transformed HIV from a life-threatening disease to a manageable chronic condition. Among the various classes of ART, integrase strand transfer inhibitors (INSTIs) have emerged as a potent option due to their high efficacy, high barrier to resistance, minimal drug interactions, and excellent tolerability. In China, the use of INSTIs has been gradually increasing, particularly since their inclusion in the National Free Antiretroviral Treatment Program (NFATP) and coverage by medical insurance. However, the rise in INSTI usage has also led to concerns about the emergence of drug resistance. This study investigates the prevalence of pretreatment INSTI resistance among ART-naïve individuals in Tianjin, China, providing critical insights into the effectiveness of INSTI-based regimens in this region.
Background and Significance of INSTIs in HIV Treatment
INSTIs are the latest class of ART drugs, approved for use in China starting with raltegravir (RAL) in 2009, followed by dolutegravir (DTG), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB) in subsequent years. Since 2018, INSTI-based regimens have been recommended as the preferred first-line ART in China. Despite their efficacy, the high cost of INSTIs initially limited their widespread use, with over 80% of people living with HIV (PLWH) in China relying on the NFATP-provided regimen of tenofovir/zidovudine + lamivudine + efavirenz. However, since 2020, the cost of INSTIs has decreased significantly, and they are now covered by medical insurance, leading to increased adoption of INSTI-based regimens. By the end of 2022, nearly half of the PLWH in Tianjin were on INSTI-containing regimens.
The growing use of INSTIs has raised concerns about the emergence of resistance mutations. While previous studies in cities like Beijing and Shenzhen reported low levels of INSTI resistance among ART-naïve individuals, the prevalence of such resistance in Tianjin remained unknown. This study aimed to fill this gap by evaluating the prevalence of INSTI-associated drug resistance among ART-naïve individuals in Tianjin.
Study Design and Methodology
The study recruited 629 ART-naïve individuals from Tianjin Second People’s Hospital between January 1, 2020, and April 1, 2023. Inclusion criteria included being an outpatient at the hospital, HIV-1 seropositivity, age 18 years or older, no prior antiviral treatment, and willingness to undergo drug resistance testing. Exclusion criteria included pregnancy, breastfeeding, incomplete data, and refusal to provide informed consent. Blood samples were collected from participants before initiating ART, and baseline clinical and demographic data, including sex, age, transmission route, CD4 count, and viral load, were obtained from the NFATP database.
The study adhered to the Declaration of Helsinki and was approved by the Ethical Committee of Tianjin Second People’s Hospital. Written informed consent was obtained from all participants. HIV-1 integrase genes were amplified and sequenced using an in-house genotyping method and standard Sanger sequencing. HIV-1 subtypes were determined using the REGA HIV-1 Subtyping Tool, and mutations were analyzed using the Stanford University HIV Drug Resistance Database. Sequences with low, intermediate, or high resistance levels were classified as resistant.
Statistical analysis was performed using SPSS software. Quantitative data with a normal distribution were expressed as mean and standard deviation, while data with an abnormal distribution were expressed as median and interquartile range (IQR). Categorical variables were compared using Fisher’s exact test, with a P-value of less than 0.05 considered statistically significant.
Results and Findings
Of the 629 participants, the HIV-1 integrase genes of 601 were successfully sequenced. The majority of participants were male (93.0%, 559/601), with a median age of 37 years (IQR: 31–49). Sexual contact was the primary transmission route, with 66.2% (398/601) reporting homosexual contact and 23.1% (139/601) reporting heterosexual contact. The median baseline viral load was 55,300 copies/mL (IQR: 19,470–163,692), and the median CD4 count was 417 cells/mL (IQR: 249–618). The most prevalent HIV-1 subtype was circulating recombinant form (CRF)01_AE (54.1%, 325/601), followed by CRF07_BC (32.1%, 193/601), B (5.0%, 30/601), CRF55_01B (3.7%, 22/601), CRF01_AE/CRF07_BC (1.3%, 8/601), and others (3.8%, 23/601).
Among the 601 cases, 14 (2.33%) harbored INSTI resistance mutations. Of these, 2 (0.33%) had major mutations, and 13 (2.16%) had accessory mutations. One sample exhibited both major and accessory mutations. The major mutations detected were G140A, Y143H, and Q148R. G140A mutations, which are non-polymorphic, typically co-occur with Q148 mutations and are associated with high resistance to EVG and RAL, as well as intermediate resistance to BIC and DTG. Y143H mutations were linked to high-level RAL resistance and potential low-level resistance to CAB and EVG but had no effect on DTG or BIC resistance.
The most common accessory mutation was L74M/LIM (57.14%, 8/14), which had minimal impact on INSTI susceptibility. Other accessory mutations included E157Q (14.29%, 2/14), S153A (14.29%, 2/14), and D232N (7.14%, 1/14). While S153A and D232N did not reduce INSTI susceptibility, E157Q was associated with potential low-level resistance to EVG and RAL.
Two cases exhibited resistance to INSTIs, with both showing RAL resistance (0.33%) and one case showing resistance to BIC (0.17%), CAB (0.17%), DTG (0.17%), and EVG (0.17%). The HIV-1 subtypes identified in the 14 INSTI-resistant cases were CRF01_AE (57.1%, 8/14), CRF07_BC (28.6%, 4/14), CRF68_01B (7.1%, 1/14), and CRF124_cpx (7.1%, 1/14). No significant differences in INSTI resistance were observed among HIV-1 subtypes.
Discussion and Implications
This study revealed a low prevalence of INSTI resistance among ART-naïve individuals in Tianjin, with only 2.33% of cases harboring resistance mutations. This rate is slightly higher than those reported in Shenzhen (1.77%), Guangdong (1.49%), and Beijing (0.53%). The major mutations identified—G140A, Y143H, and Q148R—were associated with varying levels of resistance to INSTIs. G140A and Q148R mutations significantly reduced susceptibility to EVG and RAL, while Y143H mutations were primarily linked to RAL resistance.
The accessory mutations L74M/LIM, S153A, and D232N had minimal impact on INSTI susceptibility, whereas E157Q was associated with potential low-level resistance to EVG and RAL. The low prevalence of major INSTI mutations suggests that INSTIs remain a viable and effective treatment option in Tianjin. However, the detection of high-level CAB resistance in one case highlights the need for vigilance as CAB, a recently approved long-acting INSTI, becomes more widely used in China.
The findings underscore the importance of monitoring INSTI resistance, particularly as the use of these drugs continues to rise. While the current prevalence of resistance is low, the potential for resistance to develop with increased usage necessitates ongoing surveillance. The study also highlights the need for region-specific treatment strategies based on local resistance patterns.
Conclusion
This study provides valuable insights into the prevalence of pretreatment INSTI resistance among ART-naïve individuals in Tianjin, China. The low prevalence of major resistance mutations supports the continued use of INSTIs as a first-line treatment option. However, the detection of resistance to newer INSTIs like CAB emphasizes the need for careful monitoring and proactive management of drug resistance. As the use of INSTIs expands, ongoing surveillance and research will be critical to ensuring their long-term efficacy in the fight against HIV.
doi.org/10.1097/CM9.0000000000002898
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