The findings confirmed that the prevalence of virological failure on ART (41.81%) among PLWH was high in this area, which was higher than that in other high HIV epidemic areas of China (11.8%-17.5%) , and even higher than that in East and West Africa (9.1%-25.4%) [23–25]. The prevalence of drug-resistance was as high as 32.10%, which is lower than that of other places of Sichuan province (35.4%-50.7%) [21, 26] and other HIV epidemic areas of China (50%-65%) [27, 28]. A high prevalence of subtype CRF07_BC (95.62%) was observed among PLWH with virological failure on ART, which was different from other areas of China. Thus, it is a great challenge to successfully suppress HIV and decrease drug resistance in PLWH in this area.
Our study found that male PLWH, illiteracy, and those in the clinical stage of AIDS were associated with a higher likelihood of incomplete viral suppression of virological failure on ART. Compared to females, males are more likely to discontinue from ART, which results in virological failure[29, 30]. Part of the reasons for this may be explained by (1) Compared to women, men generally have poorer healthcare-seeking behaviors, poorer ART uptake and a higher risk of immunotherapy failure observed in this study (2) Women have a lower body mass index and are more likely to maintain a higher concentration of drugs in their bodies than men, so they are more likely to achieve viral suppression, (3) Men have more unhealthy behaviors such as smoking and drinking than women, which can lead to poorer adherence to medication and lower overall treatment success. Illiteracy patients often lack sufficient understanding of the importance of ART and regular medication, as well as lack of communication skills with physicians[34, 35], which may increase the risk of virological failure. Also, patients in the AIDS stage generally have complications, such as tuberculosis and pneumocystis carinii pneumonia. Previous studies have shown that concurrent ART and tuberculosis treatment are associated with incomplete virus suppression, mainly due to poor treatment adherence and pharmacokinetic interactions between drugs[29, 30]. Therefore, it is necessary to develop effective measures to promote drug compliance of ART targeting males PLWH, illiteracy, and those in the stage of AIDS in Liangshan.
We also found that patients who had shared needles, been on ART ≤ 12 months, and had changed ART regimens were more likely to experience virologic failure. Sharing needles is a risk factor for virological failure, which may be due to the patients who had ever taken drugs and shared needles have less self-control, which leads to lower medication compliance[31, 32]. At present, there is a lack of research in this aspect, and the underlying reasons need to be explored. Time on ART ≤ 12 months was associated with a high risk of virological failure than time on ART ≥ 12 months. This result was similar to a finding from a study in Zimbabwe, which showed that compare to time on ART ≥ 4 years, patients whose time on ART ≤ 4 years had more risk of treatment failure. Because the latter may have taken the wrong medicine or forgotten it due to lack of experience[33, 34]. Therefore, the current results all suggest the necessity of increasing the medication guidance, strengthening the management of treatment follow-up, and urging the patients to take medicine on time and following the prescribed amount. Finally, the replacement of the ART regimen was also associated with virological failure. Patients who had replaced the ART regimen were more likely to experience treatment failure, possibly because they were not systematically tested for viral load and drug resistance before replacement. However, our study didn't obtain the information on the reasons for the replacement of the ART regimen. Therefore, the capacity of doctors should be improved, and the process of changing the ART regimen should be standardized. Viral load and drug resistance detection should be required before the replacement of the ART regimen.
Our studies found that the subtype CRF07_BC (95.62%) was most prevalent and was the predominant subtype, followed by CRF08_BC. CRF07_BC, which was one of the most prevalent CRFs in China [37–42] and was first identified in the intravenous drug use (IDU) population in Xinjiang in 1997[41, 42]. CRF07_BC was first introduced into Yunnan and then spread into Sichuan and Gansu, and finally to Xinjiang along drug transporting routes [43, 44]. Liangshan is located along the drug trafficking routes from the "Golden Triangle" to the northwest and central China, and injection drug use was the main infection risk factors of HIV infection and about 33.2%-56.9% of the new HIV-1 patients were drug users , and it can be assumed that CFR07_BC strain is prevalent in this area. Given the changing profile of the HIV epidemic with the shift of high-risk behaviors from IDU to sexual contact, the heterosexual transmission has surpassed injective drug use and became the predominant route of HIV transmission in this area [2, 3]. The dominant prevalent of CRF07_BC illustrated that infected IDUs are the main source of transmission to other populations. Thus, surveillance of the HIV epidemic in IDUs would help predict the spread of the HIV epidemic in the general population.
Due to the limited availability of drugs in China, the regimen composed of two NRTIs, TDF/AZT and 3TC, and one NNRTI, either EFV or NVP, is currently the most commonly used free first-line therapy. Besides, AZT has been used to prevent vertical transmission. Our findings TDF showed a relatively lower drug resistance than AZT. TDF has been recommended as the preferred NRTI when PLWH with other complications in China, such as HBV, HCV and Tuberculosis . A recent multicenter cohort reported a similar TDF associated drug resistance mutations among PLWH in high-income countries (20–22%), which illustrated widely use of TDF could improve the effectiveness of first-line ART regimens in China .
According to our findings, drug-resistant frequency to NNRTIs was much higher than that to NRTIs and PIs in this area among PLWH with virologic failure in ART. A similar pattern was also found in other places in China and low- and middle-income countries [48–51], but the prevalence of NNRTI resistance in this area is lower than in other places (50%-90%) . Thus, the high prevalence of virologic failure in ART and related low prevalence of drug resistance may be mainly attributed to poor treatment adherence, and strategies are needed to improve treatment adherence and reduce the treatment failure in ART.
The most common K103N/KN and V179D/E mutations may be attributed to the long use of NNRTIs as part of the first-line ART regimens in China, which are the major NNRTI-related mutations in China and other countries [53, 54]. A study in Henan province showed a similar mutation pattern related to NNRTIs with our study . NNRTIs associated with drug-resistant mutations could greatly impact viral replicative fitness, and therefore cause persistence of the virus in the absence of antiretroviral drugs and promote infection to a new host . M184 V/I was the most common NRTI-related mutation, which might be due to the frequent use of Lamivudine (3TC) in ART, and 3TC resistance mutation M184V/I was highly prevalent in PLWH [56, 57]. M184V/I may alter optimal binding of NRTIs and decrease 3TC removal and enzymatic processivity, and results in drug resistance .
There were several limitations in this study. First, this study was a cross-sectional survey, time-based sequence and cause-effect relationships among these variables cannot be established. Second, some HIV related behaviors were self-reporting, which may lead to recall bias. Third, some important factors of treatment failure in ART, such as ART adherence, should be considered as potential factors in our study, but such information did not collect during the follow-up. Fourth, the participants enrolled in the study were not newly diagnosed with HIV-1 infection, and some patients may have pretreatment drug resistance. Therefore, we could not identify the time of virologic failure and the resistance to ART before and after genotyping in the first virologic failure.