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From 2014 to 2020, the annual number of patients who received ART was 687, 942, 1,467, 1,905, 2,408, 2,642, and 3,094, respectively. A total of 307 patients with virologic failure after ART were recruited. The annual prevalence of virologic failure in patients after ART was 2.62% (18/687), 2.87% (27/942), 1.50% (22/1,467), 0.58% (11/1,905), 1.54% (37/2,408), 1.97% (52/2,642), and 4.52% (140/3,094), respectively (Figure 1).
Figure 1. The prevalence of virologic failure and drug resistance (DR) over time from 2014 to 2020. PLWH, people living with HIV-1. ART, antiretroviral therapy.
Of the 307 patients with virologic failure after ART, 66 patients were excluded due to a lack of personal information or failure of HIV-1 sequencing. Finally, a total of 241 (78.5%, 241/307) HIV-1 available pol sequences and corresponding medical records were analyzed in this study. From 2014 to 2020, the annual proportion of sequences was 7.05% (17/241), 9.13% (22/241), 7.47% (18/241), 3.73% (9/241), 12.45% (30/241), 17.84% (43/241), and 42.32% (102/241), respectively. Moreover, from 2014 to 2020, the annual proportion of sequences among patients on ART varied from 0.47% to 3.33% (Figure 1).
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A closer inspection of the ML tree (Figure 2) revealed the HIV-1 subtype diversity in the Hainan Province. Among 241 patients, CFR01_AE accounted for 68.88% (166/241), followed by CFR07_BC (41/241, 17.01%) and CRF55_01B (10/241, 4.14%). In addition, eight CRF65_CPX strains, eight CRF08_BC strains, three subtype B strains, two CRF57_BC strains, one CRF59_01B strain, one CRF104_0107 strain, and one subtype C strain were detected.
Figure 2. Phylogenetic tree of HIV-1 pol sequences obtained from patients with ART-failure in Hainan Province. The maximum likelihood phylogenetic tree (ML tree) was constructed using 365 HIV-1 pol sequences, including 241 Hainan sequences and 124 reference sequences. A total of 166 HIV-1 CRF01_AE query sequences branched with 47 HIV-1 CRF01_AE reference sequences (dark green color), bootstrap value was 0.98. Forty-one HIV-1 CRF07_BC query sequences branched with 22 reference sequences (dark blue color), bootstrap value was 0.90. Ten HIV-1 CRF55_01B query sequences were identified (dark red color), bootstrap value was 1.0. Eight HIV-1 CRF08_BC (lilac color) and eight HIV-1 CRF65_cpx (deep purple color) query sequences were identified (bootstrap value = 0.97 and 1, respectively) with nine and three reference sequences, respectively. Meanwhile, CRF57_BC (brown color), CRF59_01B (orange color), CRF104_0107 (light blue color), subtype B (blue-green color) and subtype C (bright green color) were detected. The green diamond of tip shape corresponds to Hainan sequences, and red diamond corresponds to reference sequences.
The demographic characteristics of 241 patients are described in Table 1. Among them, the median age was 32 (IQR: 26–42) years, 83.4% were male, and 67.63% were single. Ninety-nine cases (41.08%) had a middle school edducation. The main routes of HIV-1 infection were heterosexual transmission (119, 49.38%) and homosexual transmission (86, 35.68%). The majority of infections (77%) occurred between 2017 and 2020. Nearly half of the patients (49.79%) had baseline CD4 cell counts lower than 200 cells/mm3, 67.22% used TDF+3TC+EFV/NVP, and 62.66% received ART within seven months after diagnosis. The median VL was 32,529 copies/mL (IQR: 9,071–101,453 copies/mL).
Variables Number (N) Percent (%) Total 241 100 Sex Female 40 16.60 Male 201 83.40 Age, years: median 32, IQR (26, 42) 19−29 97 40.25 30−39 73 30.29 40−49 39 16.18 ≥ 50 32 13.28 Marital Status Married and cohabiting 78 32.37 Single 163 67.63 Ethnics Han 203 84.23 Others 32 13.28 Unknown 6 2.49 Region Northern Hainan 92 38.17 Eastern Hainan 22 9.13 Southern Hainan 63 26.14 Western Hainan 39 16.18 Central Hainan 25 10.37 Education Primary school or lower 46 19.09 Secondary school 99 41.08 High school or above 90 37.34 Unknown 6 2.49 Occupation Farmer 83 34.44 Unemployment 64 26.56 Others 79 32.78 Unknown 15 6.22 Risk factors Homosexual 86 35.68 Heterosexual 119 49.38 Others 36 14.94 Sampling time, year 2014−2016 57 23.65 2017−2020 187 77.59 Basic line CD4 cell count, cells/mm3: median 195, IQR: 80–324 < 200 120 49.79 200−350 70 29.05 301−500 24 9.96 > 500 18 7.47 Unknown 9 3.73 HIV-1 subtype CRF01_AE 166 68.88 CRF07_BC 41 17 Other (B/C/CRF08_BC/CRF59_01B/CRF55_01B/CRF65_cpx /CRF57_BC/CRF104_0107) 34 14.12 Initial therapeutic regimen AZT+3TC+EFV/NVP 64 26.56 TDF+3TC+EFV/NVP 162 67.22 Others 15 6.22 Hypoimmunity or opportunistic infections Yes 76 31.54 No 165 68.46 The duration from diagnosis to ART, month: median 3, IQR: 0–20.5 < 7 151 62.66 ≥ 7 90 37.34 Time on ART, month: median 20, IQR: 10–39.5 < 13 82 34.02 13−25 58 24.07 > 25 101 41.91 Co-infection hepatitis B Yes 34 14.11 No 127 52.70 Unknown 80 33.20 Co-infection hepatitis C Yes 30 12.45 No 112 46.47 Unknown 99 41.08 Viral load, log10 copies/mL Viral load median: 32,529 copies/mL, IQR: 9,071−101,453 copies/mL 4.00−4.99 116 48.13 ≥ 5.00 62 25.73 ≤ 3.99 63 26.14 Note. IQR, interquartile range; ART, antiretroviral therapy; CRF, circulating recombinant form; AZT, zidovudine; 3TC, lamivudine; EFV, efavirenz; NVP, nevirapine; TDF, tenofovir. Table 1. Characteristics of HIV-infected patients with virologic failure from 2014 to 2020 in Hainan Province, China
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Table 2 shows the prevalence of HIVDR among the 241 patients with virologic failure. The overall prevalence of HIVDR to antiretroviral drugs was 61.41% (148/241). From 2014 to 2020, the annual prevalence of HIVDR was 47.06%, 68.18%, 66.67%, 77.78%, 63.33%, 72.09%, and 54.90%, respectively. The prevalence of HIVDR remained stable over time (χ2 = 8.824, P = 0.218, Figure 1).
Variables N Drug resistance Univariate Multivariate Number (N) Percent (%) χ2 P1 aOR (95% CI) P2 Total 241 148 61.41 Sex Male 201 113 66.17 11.571 0.001 Ref. Female 40 15 37.50 0.11 (0.03, 0.38) 0.001 Ages, years 0.077 19−29 97 67 69.07 15.587 0.001 Ref. 30−39 73 50 68.49 1.31 (0.49, 3.46) 0.590 40−49 39 14 35.90 0.27 (0.08, 0.94) 0.039 ≥ 50 32 17 53.13 0.51 (0.13, 2.05) 0.343 Marital status Single 163 109 66.87 6.336 0.012 Ref. Married and cohabiting 78 39 50.00 0.53 (0.21, 1.32) 0.172 Ethnics Han 203 123 60.59 2.450 0.118a Ref. Others 32 24 75.00 3.386 0.083 Unknown 6 1 16.67 Region 0.467 Central Hainan 25 12 48.00 4.128 0.389 Ref. Northern Hainan 92 59 64.13 1.87 (0.45, 7.75) 0.39 Eastern Hainan 22 11 50.00 0.63 (0.11, 3.75) 0.61 Southern Hainan 63 42 66.67 2.09 (0.45, 9.76) 0.347 Western Hainan 39 24 61.54 2.08 (0.39, 11.20) 0.394 Education 0.183 Primary school or lower 46 26 56.52 1.061 0.588a Ref. Secondary school 99 62 62.63 1.34 (0.45, 4.01) 0.607 High School or above 90 59 65.56 0.48 (0.12, 1.87) 0.291 Unknown 6 1 16.67 Occupation 0.034 Farmer 83 48 57.83 4.873 0.087a Ref. Unemployment 64 48 75.00 4.32 (1.38, 13.51) 0.012 Others 79 49 62.03 1.51 (0.54, 4.19) 0.433 Unknown 15 3 20.00 Risk factors 0.321 Homosexual 86 63 73.26 10.685 0.005 Ref. Heterosexual 119 61 51.26 0.54 (0.17, 1.66) 0.282 Others 36 24 66.67 0.24 (0.04, 1.68) 0.152 Sampling time, year 2014−2016 57 35 61.40 < 0.001 0.999 Ref. 2017−2020 187 116 62.03 3.26 (1.12, 9.47) 0.030 Basic line CD4 cell count, cells/mm3 0.419 < 200 120 86 71.67 15.914 0.001a Ref. 200−350 70 38 54.29 0.44 (0.14, 1.34) 0.148 301−500 24 13 54.17 0.42 (0.10, 1.82) 0.246 > 500 18 5 27.78 0.35 (0.07, 1.83) 0.214 Unknown 9 6 66.67 HIV-1 subtype 0.001 CRF01_AE 166 115 69.28 17.634 < 0.001 Ref. CRF07_BC 41 14 34.14 0.14 (0.05, 0.40) < 0.001 Others 34 19 55.88 0.26 (0.07, 0.88) 0.031 Initial therapeutic regimen 0.006 AZT+3TC+EFV/NVP 64 43 67.19 1.230 0.541 Ref. TDF+3TC+EFV/NVP 162 96 59.26 0.15 (0.04, 0.48) 0.002 Others 15 9 60.00 0.46 (0.07, 2.92) 0.410 Hypoimmunity or opportunistic infections Yes 76 60 78.95 14.405 < 0.001 Ref. No 165 88 53.33 0.32 (0.10, 0.99) 0.049 The duration from diagnosis to ART, month < 7 151 93 61.59 0.005 0.941 Ref. ≥ 7 90 55 61.11 0.87 (0.34, 2.24) 0.769 Time on ART, month 0.610 < 13 82 53 64.63 0.594 0.743 Ref. 13−25 58 34 58.62 0.89 (0.29, 2.72) 0.843 > 25 101 61 60.40 0.60 (0.21, 1.74) 0.348 Co-infection hepatitis B 0.689 Yes 34 21 61.76 0.003 0.999 Ref. No 127 78 61.42 0.59 (0.17, 2.07) 0.407 Unknown 80 49 61.25 0.61 (0.15, 2.56) 0.501 Co-infection hepatitis C 0.361 Yes 30 18 60.00 0.108 0.947 Ref. No 112 70 62.50 0.29 (0.05, 1.59) 0.155 Unknown 99 60 60.61 0.35 (0.06, 2.13) 0.256 Viral load, log10 copies/mL 0.935 4.00−4.99 116 69 59.48 2.317 0.314 Ref. ≥ 5.00 62 43 69.35 0.97 (0.36, 2.65) 0.955 ≤ 3.99 63 36 57.14 0.84 (0.33, 2.14) 0.717 Note. aOR, adjusted odd ratio; ART, antiretroviral therapy; CRF, circulating recombinant form; AZT, zidovudine; 3TC, lamivudine; EFV, efavirenz; NVP, nevirapine; TDF, tenofovir; P1, significant values of univariate analysis; P2, significant values of multivariate logistic regression analysis; a, among the corresponding independent variables, the number of the last group is too small to be included in the analysis. Table 2. Factors associated with drug resistance among HIV-1 patients with virologic failure from 2014 to 2020 in Hainan Province, China
Among the 241 patients, 59.34% were high-level DR, 1.24% were intermediate-level DR, and 0.83% were low-level DR. The prevalence of HIVDR to NRTIs, NNRTIs, and PIs was 45.64% (110/241), 59.75% (144/241), and 2.49% (6/241), respectively (Figure 3). For NRTI drugs, the prevalence of HIVDR against ABC was the highest (45.23%, 109/241), followed by FTC and 3TC (106/241, 43.98%). NVP (59.75%, 144/241), EFV (59.35%, 143/241), and doravirine (DOR) (43.57%, 105/241) were the most common HIVDR drugs to NNRTIs. For PIs, the highest prevalence of HIVDR was 1.66% (NFV, 4/241) (Figure 3). Among the 241 patients, four cases (1.66%) showed triple drug resistance to NRTIs, NNRTIs, and PIs, and 108 cases (44.81%) were resistant to both NRTIs and NNRTIs (Figure 4D).
Figure 3. Drug-resistant levels against antiretroviral drugs among ART-failure individuals in Hainan Province from 2014 to 2020. Among the 241 participants, 59.34% acquired high-level drug resistance, 1.24% was intermediate-level drug resistance, and 0.83% was belong to low-level drug resistance (DR). For antiretroviral drugs, 45.29% of patients had DR to ABC, which belongs to NRTIs. About 59% of patients was DR to NVP and EFV belonging to NNRTIs. NRTIs, nucleoside reverse transcriptase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, boosted protease inhibitors. ABC, abacavir; AZT, zidovudine; d4T, sanilvudin; DDI, dideoxynosine; FTC, emtricitabine; 3TC, lamivudine; TDF, tenofovir; DOR, doravirine; EFV, efavirenz; ETR, etravirine; NVP, nevirapine; RPV, rilpivirine; ATV/r, atazanavir with ritonavir; DRV/r, darunavir with ritonavir; FPV/r, fosamprenavir with ritonavir; IDV/r, indinavir with ritonavir; LPV/r, lopinavir with ritonavir; NFV, nelfinavir; SQV/r, saquinavir with ritonavir; TPV/r, tipranavir with ritonavir.
Figure 4. Frequency of drug resistance mutations (DRMs) and drug resistance prevalence among 241 patients with virologic failure after ART in Hainan Province, 2014–2020. (A) Frequency of DRMs to nucleoside reverse transcriptase inhibitors (NRTIs). (B) Frequency of DRMs to non-nucleoside reverse transcriptase inhibitors (NNRTIs). (C) Frequency of DRMs to boosted protease inhibitors (PIs). (D) Drug resistance prevalence by ART drugs.
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In the univariate model, male patients had a higher prevalence of HIVDR than female patients (66.17% vs. 37.50%), while those aged 40–49 had the lowest prevalence (35.90%). Single participants had a higher prevalence than others (66.87% vs. 50.00%), and patients who acquired HIV through homosexual behavior and whose baseline CD4 cell counts were lower than 200 cells/mm3 had the highest prevalence of HIVDR (73.26% and 71.67%). In addition, patients infected with HIV-1 CRF01_AE strain and hypoimmunity or opportunistic infections had higher HIVDR prevalence than other patients (Table 2).
In the multivariate model, sex, initial therapeutic regimen, age, HIV-1 subtype, patient occupation, sampling time, and hypoimmunity or opportunistic infections were independently associated with HIVDR (Table 2). Compared with male patients, the aOR for female patients was 0.11 (95% CI: 0.03−0.38). HIVDR was more common in patients on TDF-based regimens than on AZT-based regimens (aOR: 0.15, 95% CI = 0.04−0.48). HIVDR was discovered less frequently in patients with CRF07 BC than in those with CRF01 AE (aOR: 0.14, 95% CI: 0.05−0.40) and in patients aged 40–49 years than in patients aged 19–29 years (aOR: 0.27, 95% CI: 0.08−0.94). Unemployed patients were more likely to be HIVDR than farmers (aOR: 4.32, 95% CI: 1.38−13.51). Similar to the samples from 2014 to 2016, the samples from 2017 to 2020 had a higher prevalence of HIVDR (aOR: 3.26, 95% CI: 1.12−9.47). We also found that patients with hypoimmunity or opportunistic infections had a lower prevalence of HIVDR (aOR: 0.32, 95% CI: 0.101−0.996).
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Regarding DRMs against NRTIs, the most common DRM was M184V, causing high-level resistance to 3TC and FTC, found in 68 of 241 patients (28.22%); K65R, causing high-level resistance to FTC, was detected in 46 of 241 patients (19.09%) (Figure 4A). Against NNRTIs, the K103N, leading to high-level resistance against NVP, was the most common and was found in 53 of 241 patients (21.99%); Y181C and V106M were observed in 20.33% (49/241) and 12.45% (30/241) of the patients, respectively (Figure 4B). M46I and Q58E mutations, which PIs selected, occurred in 0.83% (2/241) (Figure 4C).
HIV-1 Subtype Diversity and Factors Affecting Drug Resistance among Patients with Virologic Failure in Antiretroviral Therapy in Hainan Province, China, 2014–2020
doi: 10.3967/bes2023.077
- Received Date: 2022-09-21
- Accepted Date: 2023-01-04
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Key words:
- HIV-1 subtypes /
- Antiretroviral therapy /
- Virological failure /
- Drug resistance
Abstract:
The authors declare no conflicts of interest related to this study.
&These authors contributed equally to this work.
Citation: | YU De E, XU Yu Jun, LI Mu, YANG Yuan, LIANG Hua Yue, ZHONG Shan Mei, QIN Cai, LAN Ya Nan, LI Da Wei, YU Ji Peng, PANG Yuan, QIN Xue Qiu, LIANG Hao, ZHU Kao Kao, YE Li, LIANG Bing Yu. HIV-1 Subtype Diversity and Factors Affecting Drug Resistance among Patients with Virologic Failure in Antiretroviral Therapy in Hainan Province, China, 2014–2020[J]. Biomedical and Environmental Sciences, 2023, 36(9): 800-813. doi: 10.3967/bes2023.077 |