Background
A total of 37.9 million people living with HIV (PLWH) worldwide, and 24.5 million people were receiving antiretroviral therapy (ART) at the end of 2018 [
1]. However, the problem of drug resistance (DR) has been a focus with the increasing use of ART. DR, including transmitted drug resistance (TDR) and acquired drug resistance (ADR), develops because of viral replication in the presence of ART drugs. TDR is found in ART-naïve populations infected with the virus carrying DR mutations. TDR surveys effectively guide future first- and second-line ART regimens [
2].
The monitoring of population levels of DR is also critical to achieving the WHO/UNAIDS 90–90–90 targets. The WHO HIV drug resistance 2019 report noted that 12 of the 18 countries that reported survey findings of TDR had reached levels above 10%. The 2019 report also reported that the average TDR of the three countries bordering China exceeded the 5% moderate level: Myanmar 5.40% (3.10% ~ 9.20%), Vietnam 5.80% (3.40% ~ 9.50%), and Nepal 12.90% (8.80% ~ 18.50%). Overall, the average TDR among newly reported HIV individuals is relatively low (4.10%) in most recently research in China [
3]. Another national survey in 2015 reported that [
4], the average TDR of Chinese youth was 3.6% (32/894), including 3.00% of MSM and 5.80% of heterosexual transmission. However, estimates of the rates of TDR in the HIV epidemic vary throughout China. Several surveys reported that the TDR of some cities in Yunnan Province of China exceeded the WHO 5% moderate prevalence level [
5,
6].
Yunnan Province is in the southwestern part of China, bordering Myanmar, Vietnam, and Laos. By the end of 2016, the number of PLWH in Yunnan (91,986) was the second-highest of all provinces in China; of these, 70,577 (76.7%) were receiving ART. Dehong city is a major city for trading in the Yunnan-Myanmar border area. Dehong shares an international border with Kachin and the Shan state, Myanmar, which are two of the major states of the “Golden Triangle”. The “Golden Triangle” is one of the world’s largest drug production centers [
7], and there is a severe HIV transmission problem around this area. The first HIV spread in Chinese people who inject drugs (PWID) was found in Dehong [
8].
The prevalent HIV-1 stains (92.3%) in most regions of China are CRF01_AE, CRF07_BC, subtype B′/B, CRF08_BC. Subtype C, URFs or other CRFs were less than 3% [
9]. However, Dehong City is a hotspot of HIV recombination and transmission, [
10] from which most of the HIV-1 strains currently circulating in China first appeared [
11‐
14]. In a previous survey of HIV-1-infected youths in Yunnan found that the URF were as high as 64% [
15]. Whether frequent recombination increases the spread of drug resistance in treatment-naïve population is not clear. It is essential to monitor TDR in this recombination and transmitted hotspots.
According to the WHO HIV drug resistance (HIVDR) threshold survey method [
16], untreated youths (< 25 y) are more likely to have recent infection and are representative of TDR [
17,
18]. To better understand TDR and its effect on CD4 count, we investigated TDRMs and HIV genotypes in youths over a 9-year period and examined the effect of TDRMs on CD4 counts in the China-Myanmar border near the “Golden Triangle”.
Discussion
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, with a strong impact on the HIV-1 epidemic in China [
12,
24]. From 2009 to 2017, 10,832 people were newly reported with HIV-1 infection at the Dehong border of China, 2210 (20.40%) of whom were youths (< 25 y). As youths are more likely to have recent infections and are highly representative of TDR, [
16‐
18] we analyzed the TDR and genotype of untreated youths (16 ~ 25 y) newly diagnosed with HIV-1 infections over a 9-year period in Dehong.
The distribution of HIV-1 genotypes in China primarily includeCRF01AE, CRF07BC, CRF08BC, and B, while C, URF, and CRFs account for only a small proportion [
9]. However, the distribution of genotypes differs in Dehong, which has a high prevalence of URFs [
15,
25]. Similar to previous studies, the distribution of HIV genotypes in this study was diverse and complex. Notably, the prevalence of genotypes B and C decreased annually, and CRF01AE, CRF07BC, and URFs continues to increase. We also found that the proportion of URFs in Burmese and PWID populations was significantly higher than other populations. This prevalence 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 [
26‐
28]. This has had a long-term impact on the HIV-1 epidemic in this area and made Dehong a hotspot for HIV recombination.
Previous studies indicated that frequent recombination was more effective than mutation in spreading drug resistance mutations [
29,
30]. Frequent communication around the China-Myanmar border has increased the frequency of recombination [
15,
31]. However, this previous study was based on patients after treatment. Recombination allows the genome to combine beneficial mutations that existed before, which is conducive to the survival of viruses in the ARV. Our subjects were treatment-naïve, and there was no choice pressure of ARV drugs. This factor may be why the connection between TDR and reorganization was not significant (
p = 0.793), despite the increasing reorganization. Overall, the average prevalence of TDR was 6.28%, which exceeds the 5% moderate prevalence level. Since the early years of ART scale-up, TDR strains of HIV are likely to be limited, and all youths were ART-naïve. The total number of TDRMs was small (
n = 36), which may result in a statistical bias. We increased the sample capacity in 2016–2017 and observed a significant increase in TDR. Notably, the TDR was 9.48% in 2016–2017, which is significantly higher than the average TDR prevalence in China [
3] and Myanmar [
2]. The TDR in this study does not represent the average resistance level in China and Myanmar but it indicates the TDR increase among youths in hotspots of HIV transmission and recombination. In this study, found no significant difference in TDR prevalence between Burmese and Chinese subjects. 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 frequent TDRM. Among these mutations, K103N (
n = 9) and Y181C/I (
n = 7) were the most common TDRMs. These two 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 (0.30, 0.15, and 0%, respectively). However, unlike the findings reported in other areas, [
3,
32‐
37] 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 the need for considering resistance testing before initiating ART. We did not investigate integrase inhibitor (INSTI) TDR; these sequences were previously amplified and stored by our laboratory, and the primers did not include the INSTI region because INSTI drugs are not widely used in China and Myanmar. We will continue to increase the sample capacity and to monitor TDR (including INSTI) in the China-Myanmar border region.
Previous studies [
38,
39] associated TDRMs with high CD4 counts, but our research found that HIV-1-infected youths with TDRMs had low CD4 counts. This discrepancy was also found in at least two other studies [
40,
41]. A 2019 study [
42] suggested that the detection of primary resistance was not associated with the speed of CD4 decline. We divided these six studies into two groups based on whether CD4 decreased. There were not many similarities in the resistance sites within the group. Notably, all of the studies had limitation. Infected persons at any stage of infection can enter the queue. The decline of CD4 was likely related to different stages of the disease course. In our study, the distribution of transmission routes and genotypes were similar to the overall HIV-1 situation in this region. Demographic information has no correlation with TRDMs, which minimized the error caused by sampling. Moreover, our survey objects were newly reported ART-naïve youths, which reduces the error of infection time as possible and excludes individuals with long-standing infections or prior ART. Therefore, this relationship between CD4 count and TDRMs may be generalized to individuals infected with HIV-1 at the China-Myanmar border. We compared the CD4 count between NNRTI/NRTI/PI mutation and non-TDRM youths. Although all groups with TDRMs showed a lower mean CD4 count than the group without TDRMs, the difference was not statistically significant. Due to the small number of other TDRMs, we could not determine the correlation between other single TDRMs and CD4 counts. In summary, large sample size and more epidemiological data are required to evaluate the potential role of three classes of TDR (NNRTI/NRTI/PI) or K103N, Y181C in affecting the decline of CD4 count.
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