The city of Dehong is located in the China-Myanmar border area near the “Golden Triangle” and is a hotspot of HIV transmission and recombination, having a strong impact on the HIV-1 epidemic in China.[25, 26] We determined and statistically analyzed the age distribution of newly reported HIV infections in Dehong city (Table 1). TDR can better guide future ART regimens, prevent mother-to-child transmission and aid pre-/post-exposure prophylactic therapy. Untreated youths (<25 y) are more likely to have recent and incident infections.[2, 16, 17] Therefore, we analyzed the TDR of untreated youths (16~25 y) newly diagnosed with HIV-1 over a relatively long period (from 2009 to 2017) in Dehong.
The distribution of HIV-1 genotypes in China is mainly CRF01AE, CRF07BC, CRF08BC, and B, while C, URF, and other circulating recombinant forms (CRFs) account for only a small proportion of cases. However, the distribution of genotypes differs in Dehong, which has a high prevalence of URF and C subtypes.[28, 29] Similar to previous studies, the distribution of HIV genotypes in this study was diverse and complex. Interestingly, the prevalence of B and C has decreased annually, while that of CRF01AE, CRF07BC and URFs continues to increase. We also found that the proportion of URFs in Burmese and PWID populations was significantly higher than that in other populations. The result may indicate that due to the influence of drug injection in the "Golden Triangle", the presence of HIV-1 recombination networks occurred early among PWID in Dehong.[30-32] This has had a long-term impact on the HIV-1 epidemic in this area, making Dehong a hotspot for HIV recombination.
Frequent recombination is more effective than mutation in spreading drug resistance mutations.[33, 34] Frequent communication around the China-Myanmar border has increased the frequency of recombination[28, 35] and the probability of TDRM transmission. Overall, the average prevalence of TDR was 5.4%, a value that exceeds the 5% moderate prevalence level. It is worth noting that during 2016~2017, the prevalence of TDR was 9.48%, significantly higher than the average TDR prevalence in China and Myanmar. The prevalence of TDR in this study does not represent the average resistance level in China and Myanmar but indicates the increase in TDR among youths in hotspots of HIV transmission and recombination. In this study, no significant difference was found in TDR prevalence between Burmese and Chinese subjects. Furthermore, whereas the prevalence of TDR in Chinese subjects increased from 2009 to 2017 (from 3.92% to 5.93%), the prevalence of TDR in Burmese migrants increased significantly from 2010 to 2017 (from 4.00% to 13.16%). Burmese migrants are a key population for HIV prevention in this region.
Resistance to NNRTIs (2.92%) was the most frequently observed TDRM. Among these mutations, K103N (n=9) and Y181C/I (n=7) were the most common DRMs. These mutations caused a high level of drug resistance to first-line treatment drugs (EFV and NVP). Among NRTI-related TDRMs (2.34%), most (75%, 12/16) exhibited only potential resistance. Azidothymidine (AZT), lamivudine (3TC), and tenofovir (TDF), as first-line NRTI drugs in China, have meager rates of transmission resistance (0.3%, 0.15%, and 0%, respectively). However, unlike the findings reported in other studies,[4, 5, 36-40] NRTI resistance showed the most significant increase (from 0% to 5.17%) from 2009 to 2017 in this study. Although the prevalence of TDR to PIs (0.44%) was significantly lower than the prevalence of TDR to NNRTIs/NRTIs, the I54M mutation caused universal resistance to PI drugs. These results suggest that, in the future, resistance testing before initiating ART is essential.
Previous studies suggested that DRMs impair viral fitness, resulting in increased CD4 count.[6, 7] However, some DRMs have a low impact on viral fitness and even improve it, which may lead to a more rapid decline in CD4 count.[9, 41] In the latest research, no association was found between DRMs and decreased CD4 count. In this study, HIV-1-infected youths with TDRMs had low CD4 counts; this provides some evidence for a relationship between TDRMs and decreased CD4 count.
We analyzed TDR transmission based on the molecular transmission network. The rate of entry into the network (46.1%) of youths in our study was significantly higher than that reported in other studies.[42, 43] Moreover, youths with TDR (63.89%) were more likely to enter the network. These results indicate that youths in Dehong are in an active period of HIV transmission. Youths who had TDRMs were more likely to be linked to others in the HIV-1 transmission network. Moreover, the Y181C, D67E, and V106M mutations have recent transmissions (gene distance <0.5%) and were shared TDRMs among 8 youths during 2016~2017. The result indicates that the rapid increase in TDR during 2016~2017 is related to the recent spread of TDRMs such as Y181C, D67E, and V106M. The result also indicates the need for monitoring and intervention in the spread of HIV through molecular transmission network analysis of youths.
Our research has some limitations. Since the first years of ART scale-up, TDR strains of HIV are likely to be limited, and all youths were ART-naïve; in addition, the total number of TDRMs is small (n=36), possibly resulting in statistical bias. In 2016-2017, we increased the sample capacity and observed a significant increase in TDR. This suggests that TDR may be increasing rapidly among young people in this border region. In addition, we did not investigate TDR to integrase inhibitor (INSTI); because these sequences were previously amplified and stored by our laboratory, the primers did not include the INSTI region. We will continue to increase the sample capacity and to monitor TDR (including INSTI) in the China-Myanmar border region.