Pre-existing Low-frequency Resistance Mutations Increase the Risk of Antiretroviral Treatment Failure in HIV-1 Naïve Patients
The impact of pre-existing low-frequency resistance mutations on the efficacy of antiretroviral therapy (ART) in human immunodeficiency virus type 1 (HIV-1) naïve patients has been a topic of significant interest and controversy in the field of HIV research. While high-frequency resistance mutations, typically detected by conventional resistance assays, have long been associated with ART failure, the role of low-frequency resistance mutations remains less clear. This study aimed to investigate the influence of pre-existing low-frequency resistance mutations on virological response in HIV-1 naïve patients using the MiSeq second-generation sequencing platform, which offers higher sensitivity and specificity compared to traditional methods.
The study enrolled HIV-1 ART-naïve patients attending the Second Hospital of Nanjing from January 1, 2018, to December 31, 2020. Patients with drug-sensitive results from traditional pre-existing drug resistance tests were included. All participants received ART and were followed up for 12 months, with viral load monitoring at 1, 3, 6, 9, and 12 months of treatment. The study was conducted in accordance with the Declaration of Helsinki, and all patients provided written informed consent. The Medical Ethics Committee of the Second Hospital of Nanjing approved the study.
Virological response failure was defined based on three criteria: (1) HIV-1 RNA levels exceeding 200 copies/mL at 6, 9, and 12 months of treatment without any change in the treatment regimen; (2) patients who changed drugs within 6 months of treatment due to high viral loads or slow decline in viral loads; and (3) patients with drug resistance detected after treatment. Successful virological response was defined as a viral load of HIV-1 RNA below 50 copies/mL at 6, 9, and 12 months of treatment. Exclusion criteria included patients with poor adherence, missing viral load test data, and those who changed treatment regimens due to allergies, economic reasons, or simplified treatment.
A total of 76 patients were included in the study, with 38 patients classified as the failure group and 38 as the control group based on successful virological response. The two groups were matched using a 1:1 propensity score matching method, considering baseline CD4+ T-lymphocyte counts and viral loads. The MiSeq second-generation sequencing platform was used to detect pre-existing low-frequency drug resistance mutations in all patients.
The study found that the overall pre-existing low-frequency resistance detection rate was 14.5%, with a significantly higher rate in the failure group (23.7%) compared to the control group (5.3%). This difference was statistically significant, indicating that pre-existing low-frequency resistance mutations are associated with an increased risk of virological failure. The mutations were predominantly in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, accounting for 53.8% of the detected mutations. Specific mutations included V179, Y188, and E138. The nucleoside reverse transcriptase inhibitor (NRTI) class mutations accounted for 38.5%, with K65 and D67 being the most common. Additionally, one patient had low-frequency resistance in the protease inhibitor (PI) class, and one had resistance in the integrase strand transfer inhibitor (INSTI) class.
The initial treatment regimen for the majority of patients (77.6%) was 2NRTI + NNRTI, while the remaining patients were on an INSTI-based regimen. The study compared viral load levels at 4, 12, 24, and 48 weeks post-treatment between patients with and without low-frequency resistance mutations. While there was no significant difference in viral load levels at baseline, 4 weeks, 12 weeks, and 48 weeks, a statistically significant difference was observed at 24 weeks of treatment. This finding is particularly relevant as the 24-week mark is a critical time point for determining ART failure and the need for treatment switching according to AIDS treatment guidelines.
The study’s findings suggest that pre-existing low-frequency resistance mutations, particularly in the NNRTI class, are associated with an increased risk of virological failure in HIV-1 naïve patients. This highlights the importance of considering low-frequency resistance mutations when initiating ART, especially in regions where NNRTI-based regimens are predominant. The study also underscores the potential benefits of switching to INSTI- or PI-based regimens in cases of virological failure due to low-frequency resistance mutations.
However, the study has some limitations. It was a single-center study with a relatively small sample size, which may limit the generalizability of the findings. Additionally, the impact of low-frequency resistance mutations occurring at different frequencies was not analyzed in depth, and further research is needed to explore this aspect.
In conclusion, this study provides valuable insights into the role of pre-existing low-frequency resistance mutations in ART outcomes for HIV-1 naïve patients. The findings emphasize the need for more sensitive detection methods, such as second-generation sequencing, to identify low-frequency resistance mutations and inform treatment decisions. By doing so, clinicians can better tailor ART regimens to individual patients, potentially improving virological response and reducing the risk of treatment failure.
doi.org/10.1097/CM9.0000000000002901
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