Transmitted HIV Drug Resistance Among Individuals With Newly Diagnosed HIV Infection

A Multicenter Observational Study

Jingrong Ye; Mingqiang Hao; Hui Xing; Fujie Zhang; Hao Wu; Wei Lv; Tianjun Jiang; Yuncong Wang; Juan Wang; Yi Feng; Ruolei Xin; Ji Zeng; Shuai Zhao; Yinxiao Hao; Jing Chen; Yuhua Ruan; Xue Li; Yiming Shao; Hongyan Lu


AIDS. 2020;34(4):609-619. 

In This Article


Study Population

As of 31 October 2017, the national HIV epidemiology database had recorded 25 648 HIV-positive individuals diagnosed in Beijing, which represents about 2.7% of all individuals ever diagnosed with HIV infection in China, according to data from the China CDC. We included about 40% of the samples, resulting in a total of 10 290 individuals. We excluded 175 as they were younger than 18 years old. The final analysis included 10 115 participants, from whom we successfully genotyped 9203 (91.0%) viruses from plasma specimens (Figure 1). Specimens without genotypes occurred at random and the prevalence was within the expected range. Characteristics were broadly similar between individuals with and without genotyped virus (data not shown). The baseline characteristics of the individuals sampled within each of the four phases were similar in terms of sex, age, and ethnicity. However, from 2009 to 2017, there was a significantly higher percentage of MSM compared with 2001–2008. The majority of participants were men, and of Han ethnicity. The men were younger than the women. The predominant transmission risk groups were MSM and heterosexual contact (Table 1).

Figure 1.

Study profile.

Phylogenetic Analysis

The most common viral subtypes, in order of decreasing frequency, were CRF01_AE (44.4%), CRF07_BC (22.8%), B (17.7%), CRF08_BC (1.1%), and CRF55_01B (1.0%), whereas no other subtype represented more than 0.8% of the sample. After rigorous phylogenetic analysis, the final national reference alignment consisted of 12 452 sequences of the long stretch of 1002 nucleotides, corresponding to HBX2 nucleotides 2273--3,276 (Figure 1). Phylogenetic analysis using the merged dataset, which consisted 21 655 sequences (9203 from our study and 12 452 reference) revealed that viral sequences from both sources were intermixed, suggesting that both sampling frames were drawing from the same overall population (Figure S1, In addition, viral phylogenetic trees also showed that each sequence was from a different individual, and there was no evidence of laboratory carry-over contamination. The GenBank accession numbers of nucleotide sequences reported in this article are provided in supplementary results,

Prevalence and Patterns of Transmitted HIV Drug Resistance

The overall prevalence of TDR was 4.1% (95% CI: 3.7–4.5%), with mutations associated with protease inhibitors being the most common form of mutation (2.3%, 95% CI: 2.0–2.6), followed by mutations associated with NRTIs (1.1%, 95% CI: 0.9–1.3%) and NNRTIs (1.0%, 95% CI: 0.8–1.2%). Dual-class resistance was uncommon (0.25%, 95% CI: 0.16–0.37%), and triple-class resistance was rare (0.02%, 95% CI: 0.002–0.063%). Women tended to have lower prevalence of TDR than men (Figure S2, In the heterosexual transmission risk group, men had twice the prevalence of TDR than women (4.2%, 95% CI: 3.3–5.3% in men, vs. 2.0%, 95% CI:1.0–3.2% in women). The prevalence of TDR was similar in rural and urban regions. Notably, the prevalence of TDR in CRF07_BC viruses was significantly lower than in other viral strains (Figure S3, The prevalence of TDR varied substantially between provinces, ranging from 2.0% (95% CI: 0.2–5.5%) in Tianjin, to 5.9% (95% CI: 3.3–9.3%) in Anhui (Figure 2). The prevalence of TDR did not differ significantly between transmission risk groups (Table 2).

Figure 2.

Geographical distribution of the prevalence of transmitted HIV drug resistance. Samples were from 32 provinces of China. Five provinces in eastern China: Shanghai, Zhejiang, Fujian, Jiangxi, and Taiwan. Three provinces in southwest China: Guizhou, Yunnan, and Tibet. Data are prevalence of transmitted drug resistance (%) and number of patients with drug resistance/total number in each province or region.

The most prevalent mutation associated with PI TDR was M46L (1.5% 95% CI: 1.3–1.8%) and was present in 3.2% (95% CI: 2.6–3.7%) of the CRF01_AE HIV strains tested, whereas the most frequent mutations associated with NRTI TDR were thymidine analogue mutations (TAM), of which the most prevalent were mutations of M184V/I (0.28%, 95% CI: 0.18–0.4%), T215S/I/Y/F (0.21%, 95% CI: 0.12–0.3%), and M41L (0.1%, 95% CI: 0.05–0.2%). K103N, Y181C, K101E, and V106M were the most common mutations associated with NNRTI TDR, which were found in 0.29% (95% CI: 0.19–0.4%), 0.24% (95% CI: 0.15–0.35%), 0.16% (95% CI: 0.09–0.26%), and 0.14% (95% CI: 0.08–0.23%) of samples tested, respectively (Table S1,

Time Trends and Correlates of Transmitted HIV Drug Resistance

The annual prevalence of TDR in our study ranged from 2.9 to 7.1% of the samples tested. There was a statistically significant decline in the annual trend of TDR over the study period (Figure S4, in the univariable analysis (P = 0.048), but not in the multivariable analysis (P = 0.08). There was also a significant decline in the prevalence of TDR according to the time trend, and in both the univariable and multivariable analyses (Figure 3 and Table 2). In the comparisons of TDR by ART class, the protease inhibitors followed the same time trend as the overall prevalence (P = 0.046), but there was no time trend for NRTIs or NNRTIs (P = 0.55 for NRTIs, P = 0.15 for NNRTIs) (Figure S5,

Figure 3.

Temporal trends of prevalence of transmitted drug resistance by sampling phase. Vertical bars indicate 95% CI. The trend line is predicted prevalence transmitted drug resistance or ART coverage. NRTIs=nucleoside reverse transcriptase inhibitors. ART, antiretroviral treatment; CI, confidence interval; NNRTIs, non-NRTIs; PIs, protease inhibitors.

In univariable logistic analyses, any TDR was significantly associated with sex, province, subtype, ART coverage, and sampling phase. In the multivariable analysis, the risk of TDR differed significantly according to sex (odds ratio [OR] for women vs. men: 0.41, 95% CI: 0.22–0.69, P = 0.002); infection type (OR for CRF07_BC vs. CRF01_AE: 0.24, 95% CI: 0.16–0.36, P < 0.001); and sampling period (OR for 2009–2012 vs. 2001–2008: 0.57, 95% CI: 0.41–0.79; P = 0.01) The risk of TDR was significantly higher among individuals from Hebei province than in those from Beijing (OR: 1.43, 95% CI: 1.05–1.96; P = 0.02) (Table 2). In two sensitivity analyses, which included individuals younger than 18 years old, and excluding individual province, respectively the strength of the associations did not change significantly (data not shown).

Transmitted HIV drug Resistance in Recently Infected Individuals

We identified a group of 5898 recently infected individuals in the analysis by means of selecting sequences that contained mixtures at 0.5% or less of their nucleotide positions – a proxy for recent infection. The prevalence of TDR among these individuals was shown in Table S2,