Scientific Papers

HIV-1 drug resistance and genetic transmission network among newly diagnosed people living with HIV/AIDS in Ningbo, China between 2018 and 2021 | Virology Journal


Participant characteristics

A total of 1097 newly diagnosed PLWH were enrolled in this study, and we successfully sequenced and analyzed the samples collected from 1006 (91.7%) individuals. Among them, the median age was 40 years (interquartile range 28–54 years), ranging from 18 to 84 years. There were 86.3% (868/1006) and 13.7% (138/1006) males and females, respectively. Regarding marital status, 37.5% (377/1006) were single, 42.8% (431/1006) were married, and 19.7% (198/1006) were divorce or death. Most participants were middle school or less education level (61.8%), of Han ethnicity (95.8%), living non local (56.5%), heterosexual transmission (52.7%), having < 6 sexual partners (79.6%). The proportions of CD4 + T lymphocytes counts < 200 cells/uL, 200 ~ 499 cells/uL and ≥ 500 cells/uL were 37.7% (379/1006), 52.2% (525/1006) and 10.1% (102/1006), respectively (Table 1).

Table 1 Characteristics of study participants between three groups with different HIV-1 genotypes

Drug resistance analysis

The prevalence of TDR among newly diagnosed PLWH was 6.1% (61/1006). TDR-associated mutations to NNRTI, NRTI and PI were detected in 7.9% (79/1006), 2.7% (27/1006) and 0.7% (7/1006). No INSTI-related mutations were identified. As for the NNRTI resistance, NVP (2.9%) was the highest proportion of high-level resistance, followed by EFV (2.7%). Most exhibited a low-level resistance to RPV (2.8%) and ETR (1.3%). The most frequent mutations were K103N (2.3%), E138A/G/Q (1.7%) and V179D/E (1.2%). As for the NRTI resistance, FTC and 3TC presented the highest levels (0.7%), which was related to the mutation of M184MV/V (0.7%). As for the PI resistance, the HIV-1 strains only exhibited resistance to NFV (0.7%), and mutations were M46L/I(0.7%). The above results presented in Fig. 1.

Fig. 1
figure 1

(A) Proportion of HIV-1 transmitted drug resistance (TDR) mutations to PIs, NRTIs, and NNRTIs. (B) Levels of HIV-1 TDR associated mutations to different ART drug among 1006 newly diagnosed HIV/AIDS patients. PI, Protease inhibitor;NRTI, Nucleoside reverse transcriptase inhibitor; NNRTI, Non-nucleoside reverse transcriptase inhibitor; NFV: Nelfinavir;ABC: Abacavir; AZT: Zidovudine; D4T: Stavudine; DDI: Didanosine; FTC: Emtricitabine;3TC, Lamivudine;TDF, Tenofovir; DOR,Doravirine; EFV,Efavirenz; ETR: Etravirine; RPV: Rilpivirine

Genotype analysis

Among all participants, the most common genotype was CRF07_BC (40.7%, 409/1006), followed by CRF01_AE (33.7%, 339/1006). The other genotypes were CRF08_BC (6.9%, 69/1006), subtype C (5.4%, 54/1006), CRF55_01B (5.0%, 50/1006), subtype B (2.6%, 26/1006), unique recombinant forms (URFs) (2.6%, 26/1006), CRF85_BC (1.5%, 15/1006), CRF01_BC (0.6%, 6/1006), CRF59_01B (0.4%, 4/1006), CRF67_01B (0.4%, 4/1006) and CRF68_01B (0.4%, 4/1006). The URFs included 19 CRF01AE/C, four CRF01AE/B/C, two subtype B/C, one CRF01AE/B. As shown in Table 1, the distribution of genotype revealed significant differences according to gender (χ2 = 25.799, P < 0.001), age (χ2 = 51.906, P < 0.001), education level (χ2 = 22.299, P < 0.001), route of infection (χ2 = 42.681, P < 0.001), CD4 + T lymphocytes counts (χ2 = 19.400, P = 0.038), and TDR (χ2 = 25.686, P < 0.001).

Genetic transmission network analysis

Overall, 444 (44.1%) pol sequences formed 856 links within 120 transmission clusters in the network. Comparing the sequences included to those not included in the transmission networks, we observed significant differences in age (χ2 = 4.778, P = 0.029), number of sexual partners in a life time (χ2 = 5.253, P = 0.022), HIV-1 genotypes (χ2 = 27.539, P < 0.001) and CD4 + T lymphocytes counts (χ2 = 6.581, P = 0.037). After adjustment for confounders, older age (OR = 2.038, 95%CI = 1.072 ~ 3.872, P = 0.030; ≥60 vs. <25 years) was associated with higher adjusted odds of clustering. Additionally, compared with CRF01_AE, CRF07_BC (OR = 2.147, 95%CI = 1.582 ~ 2.914, P = 0.011) and CRF55_01B (OR = 2.217, 95%CI = 1.201 ~ 4.091, P < 0.001) were significantly related to clustering (Table 2).

Table 2 Factors associated with study participants within genetic transmission networks in Ningbo, China

As seen in the set of Fig. 2, the clustering rates were 35.4% (67/189), 43.8% (49/112), 43.5% (137/315), 49.0% (191/390) between 2018 and 2021, respectively. The proportions of links with GD < 0.005 were 19.0% (36/189), 14.3% (16/112), 14.0% (44/315), 13.8% (54/390), respectively. We observed an increasing trend in clustering rate between 2018 and 2021 (χ2 = 9.546, P = 0.023). The proportion of links with GD < 0.005 did not vary significantly during the four years (χ2 = 3.153, P = 0.369).

Fig. 2
figure 2

Enrolment and clustering rate in Ningbo, China between 2018 and 2021.Dispersion measures indicate 95% confidence intervals

Of the 444 sequences evaluated, 154 (34.7%) had one link, and 290 (65.3%) had more than two links. There were 105 (87.5%) clusters with size < 5, 10 (8.3%) clusters with 5 ≤ size < 10, and five (4.2%) clusters with size ≥ 10. The five large clusters had 83, 21, 14, 10 and 10 individuals, respectively. The median degrees were 4, 20, 11, 7.5 and 9 respectively. The proportions of links with GDs < 0.005 were 19.0% (84/213), 42.9% (85/198) and 22.5% (16/71), 2.8% (1/36), 39.5% (17/43) respectively.

As shown in Fig. 3, among 444 participants who were included in these networks, 375 (84.5%) were male and 69 (15.5%) were female. We analyzed these 120 clusters, 46 (38.3%) clusters were CRF07_BC, 42 (35.0%) were CRF01_AE, 8 (6.6%) were subtype C, 7 (5.8%) were CRF55_01B, 5 (4.2%) were CRF85_BC and CRF08_BC, 3 (2.5%) were URFs, 2 (1.6%) were subtype B, 1 (0.8%) were CRF01_BC and CRF59_01B. Of 211 CRF07_BC sequences, 137 (64.9%) were connected to at least one other sequence with genetics distance < 0.005. Compared with CRF01_AE, CRF07_BC were prone to form larger clusters. The largest cluster with CRF07_BC was increased from 15 cases in 2018 to 83 cases in 2021. Considering clusters with three or more nodes, the most frequent links included persons with 25–39 years (35.2%), followed 40–59 years (31.7%). The proportion of links with GD < 0.005 varied across age: 41.0%, 31.7%, 35.7% and 42.9% in persons < 25, 25–39, 40–59 and ≥ 60 years, respectively, and was significantly higher in persons ≥ 60 years compared to all other age teams (χ2 = 14.456, P = 0.002).Considering clusters included all the four years, there were two clusters with 83 and 21 nodes, respectively. The annual growth rate of participants who were included in these two clusters were 36.3% and 76.5%. We also observed that 34.4% (21/61) of TDR cases were included in the transmission. All these TDR cases were found in 11 clusters with size < 6. The possibility of TDR clustering was higher in gender being male (80.6%), infection route being heterosexual transmission (58.1%) and genotype being CRF01_AE (51.6%). Of 856 links in the genetic transmission networks, 13 (1.5%) links were TDR connected to TDR, 9 (1.1%) were TDR linked to No-TDR, and 834 (97.4%) were No-TDR connected to No-TDR.

Fig. 3
figure 3

Genetic transmission network among newly diagnosed people living with HIV/AIDS in Ningbo, China between 2018 and 2021.Clusters are shown ordered by size in each panel. Links are coloured by genetic distance.Shapes of the nodes represent different gender.Colour of the nodes represent different participant characteristics,including genotype,age,enrolment year and transmitted drug resistance



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