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To reduce the mortality rate of HIV-infected patients and improve their quality of life, China has launched the “Four Frees and One Care” policy (Free treatment, free voluntary counseling and testing, free prevention of mother to child transmission, free schooling for AIDS orphans, and one “Care”: provision of social assistance for HIV/AIDS patients) to provide lifelong free antiretroviral therapy (ART) for HIV-infected patients who meet the national treatment criteria since 2003 (1). In response to the Joint United Nations Programme on HIV/AIDS’s (UNAIDS) “Treatment 2.0” strategy, China has implemented a number of targeted strategies to expand the ART coverage in HIV-infected patients since 2010 (2). By the end of 2018, a total of 83.4% (748,499/861,042) of HIV-infected patients have received ART (3). However, HIV drug resistance (HIVDR) inevitably emerged along with the scale-up of ART, and the drug resistance pattern varied a lot in different regions of China (4). This study analyzed data in the national HIV/AIDS Comprehensive Response Information Management System (CRIMS) to investigate the relationship between HIVDR and death in HIV-infected patients receiving ART in seven provincial-level administrative divisions (PLADs) of China. The main finding is that the risk of death was higher in patients with HIV drug resistance or untested resistance compared with drug-sensitive patients. This helps provide a valuable reference for optimizing ART regimens and patient follow-up management in practice.
This study selected seven PLADs that reported and followed-up a large number of HIV/AIDS patients and considered geographical location (eastern and western China) and economic status. Data was collected for patients who received ART, died from all-causes during 2010–2019, and had adequate blood samples that were collected in twelve months prior to death and after ART initiation date. These samples could satisfy the volume requirements for performing viral load and drug resistance tests and were thus selected as death cases. One or two controls were selected for each case from surviving patients who received treatment at the same ART clinic as the case and was registered right before or after the case. The control should have blood samples collected in six months prior to or after the death cases’ blood samples. The eligible cases or controls must be people aged 18 years or over when ART initiated, began their ART treatment in 2010 or later, and received ART for more than 6 months.
The data was derived from the CRIMS whose information was collected by local CDCs or HIV hospitals with questionnaires or medical records. Main variables were survival status, gender, age, ethnicity, marital status, education level, occupation, residence, HIV transmission route, ART initiation date, clinic stage according to World Health Organization (WHO) definition, CD4 cell count at the beginning of ART, primary ART regimen, latest ART regimen, ART adherence, latest viral load test result, and latest drug resistance test result.
“HIVDR result” was defined as the main independent variable to analyze the relationship between HIVDR and death (by combining “Latest Viral Load test result” and “Latest drug resistance test result,” as shown in Table 1). Due to differences of HIVDR prevalence, quality of medical care services, and sample sizes in regions, multivariate logistic regression analysis was performed for each region, and the adjusted odds ratio (AOR) was obtained. Then, the AORs in different regions were merged by meta-analysis to represent the overall relationship between HIVDR and death in those HIV-infected patients receiving ART. Logistic regression analysis was performed by SAS (version 9.4, SAS Institute, Cary, NC, USA). Meta-analysis was conducted in RevMan (version 5.4, Cochrane Collaboration, Oxford) and NCSS 2004 (Kaysville, UT, USA).
Primary results of viral load and drug resistance test Redefined HIVDR categories Latest viral load test result (copies/mL) Latest drug resistance test result <1,000 Sensitivity or not be tested Drug sensitive ≥1,000 Sensitivity Drug sensitive Not be tested Sensitivity Drug sensitive <1,000 Resistance Drug resistant ≥1,000 Resistance Drug resistant Not be tested Resistance Drug resistant ≥1,000 Not be tested Viral load ≥1,000 copies/mL but drug resistance untested Not be tested Not be tested Neither viral load nor drug resistance being tested Abbreviation: HIVDR=HIV drug resistance. Table 1. Operational definition and category of HIVDR result.
A total of 19,235 HIV-infected patients were enrolled from 7 PLADs (Table 2), with 5,719 in the case group (deaths) and 13,516 in the control group (survived). The proportions of latest viral load untested were 40.0% in the case group and 17.2% in the control group, while 65.6% of case group and 60.8% of control group were latest drug resistance untested. For the HIVDR result, 25.5% of case group and 44.2% of control group were deemed as drug sensitive, and 5.0% of case group and 2.4% of control group were drug resistant. The proportions of patients with viral load ≥1,000 copies/mL but drug resistance untested were 8.6% in the case group and 2.7% in the control group. The proportions of patients who were neither viral load nor drug resistance tested were 28.7% in the case group and 2.9% in the control group, respectively.
Item Anhui Chongqing Sichuan Jiangsu Guangxi Guangdong Hunan Total Case group Control group Case group Control group Case group Control group Case group Control group Case group Control group Case group Control group Case group Control group Case group Control group n n n n n n n n n n n n n n n % n % Total 1,449 2,898 1,299 5,513 1,179 2,176 897 1,628 545 951 200 200 150 150 5,719 100.0 13,516 100.0 Age groups (years) 18–29 149 843 45 560 35 189 116 448 38 202 6 12 9 7 398 7.0 2,261 16.7 30–49 578 1,410 272 1,748 941 1,788 348 790 180 455 82 121 62 57 2,463 43.1 6,369 47.1 ≥50 722 645 982 3,205 203 199 433 390 327 294 112 67 79 86 2,858 50.0 4,886 36.1 Gender Male 1,194 2,249 1,047 3,679 907 1,411 747 1,368 432 656 161 134 122 100 4,610 80.6 9,597 71.0 Female 255 649 252 1,834 272 765 150 260 113 295 39 66 28 50 1,109 19.4 3,919 29.0 Ethnicity Han 1,434 2,856 1,172 5,476 4 11 881 1,558 232 438 199 200 − − 3,922 68.6 10,539 78.0 Other 13 41 3 16 1,175 2,165 16 19 313 513 1 0 − − 1,521 26.6 2,754 20.4 Not recorded 2 1 124 21 0 0 0 51 0 0 0 0 − − 126 2.2 73 0.5 Marital status Single 320 859 104 575 39 102 159 462 99 249 30 47 30 26 781 13.7 2,320 17.2 Married or living with partner 731 1,512 799 3,899 1,091 1,966 532 915 320 563 146 142 72 86 3,691 64.5 9,083 67.2 Other 398 527 396 1,039 49 108 206 251 126 139 24 11 48 38 1,247 21.8 2,113 15.6 Education* Primary school or less 735 920 827 2,990 1,130 2,083 293 262 231 283 48 24 − − 3,264 57.1 6,562 48.5 Junior middle school 485 1,137 282 1,727 41 78 379 612 214 423 109 115 − − 1,510 26.4 4,092 30.3 senior middle school or more 227 840 66 775 8 15 225 703 77 232 43 61 − − 646 11.3 2,626 19.4 Not recorded 0 0 124 21 0 0 0 51 0 0 0 0 − − 124 2.2 72 0.5 Occupation* Famer 876 1,391 787 3,429 985 1,981 375 413 281 421 36 36 − − 3,340 58.4 7,671 56.8 Other 573 1,507 388 2,063 194 195 522 1,164 264 530 164 164 − − 2,105 36.8 5,623 41.6 Not recorded 0 0 124 21 0 0 0 51 0 0 0 0 − − 124 2.2 72 0.5 Residence† Rural 992 1,993 797 3,328 − − − − 96 375 36 37 − − 1,921 33.6 5,733 42.4 Urban 457 905 378 2,164 − − − − 449 576 164 163 − − 1,448 25.3 3,808 28.2 Not recorded 0 0 124 21 − − − − 0 0 0 0 − − 124 2.2 21 0.2 HIV transmission route Heterosexual 1,038 1,694 1,228 5,160 289 797 534 773 444 808 115 132 120 125 3,768 65.9 9,489 70.2 MSM 282 1,019 18 233 847 1,284 0 0 9 60 11 35 5 8 1,172 20.5 2,639 19.5 Intravenous drug use 10 7 42 81 43 95 22 30 65 66 59 19 18 9 259 4.5 307 2.3 Other 119 178 11 39 0 0 341 825 27 17 15 14 7 8 520 9.1 1,081 8.0 WHO clinic stage at the beginning of ART I/II 837 2,212 684 3,981 939 1,844 555 1,172 215 475 0 4 105 120 3,335 58.3 9,808 72.6 III/IV 612 686 615 1,532 240 332 341 455 120 141 200 196 45 30 2,173 38.0 3,372 24.9 CD4 cell count at the beginning of ART, cells/mm3 <200 714 902 687 2,021 432 431 550 665 355 524 157 129 97 68 2,992 52.3 4,740 35.1 200–349 256 925 281 1,835 453 877 203 570 137 277 33 54 33 61 1,396 24.4 4,599 34.0 ≥350 154 608 94 961 261 856 56 253 47 136 10 17 10 17 632 11.1 2,848 21.1 Not recorded 325 463 237 696 33 12 88 140 0 0 0 0 10 4 693 12.1 1,315 9.7 ART initiation date Before 2015 541 1,510 529 1,329 974 1,619 548 963 312 527 194 192 125 126 3,223 56.4 6,266 46.4 2015 or later 908 1,388 770 4,184 205 557 349 665 233 424 6 8 25 24 2,496 43.6 7,250 53.6 Initial ART regimen D4T-based 69 242 83 108 46 39 89 137 100 161 106 88 25 28 518 9.1 803 5.9 AZT-based 455 1,063 218 719 432 556 467 956 188 352 57 65 62 73 1,879 32.9 3,784 28.0 TDF-based 828 1,407 988 4,643 682 1,483 339 533 218 390 35 45 52 44 3,142 54.9 8,545 63.2 LPV/r-based 95 166 1 27 18 96 1 2 0 0 12 13 11 5 138 2.4 309 2.3 Other 12 20 9 16 1 2 1 0 39 48 0 3 0 0 62 1.1 89 0.7 Latest ART regimen D4T-based 0 0 0 0 32 2 46 20 56 3 16 0 10 0 160 2.8 25 0.2 AZT-based 535 1,110 3 393 369 307 325 751 134 355 34 54 33 49 1,433 25.1 3,019 22.3 TDF-based 505 980 77 4,867 679 1,353 500 815 226 522 105 123 59 73 2,151 37.6 8,733 64.6 LPV/r-based 303 650 1 109 96 514 16 28 0 0 71 49 48 28 535 9.4 1,378 10.2 Other 106 158 1 55 3 0 10 14 129 71 23 8 0 0 272 4.8 306 2.3 Not recorded 0 0 1,217 89 0 0 0 0 0 0 0 0 0 0 1,217 21.3 89 0.7 Stop ART or lost to follow-up No 1,242 2,461 261 708 664 1,202 198 260 348 155 88 54 0 0 2,801 49.0 4,840 35.8 Yes 207 437 1,038 4,805 515 974 699 1,368 197 796 112 146 150 150 2,918 51.0 8,676 64.2 Latest viral load test result, copies/mL§ <1,000 − − 569 4,425 96 701 352 1,424 258 893 169 197 8 146 1,452 25.4 7,786 57.6 ≥1,000 − − 88 78 58 324 194 78 22 17 27 0 142 4 531 9.3 501 3.7 Not be tested − − 642 1,010 1,025 1,151 351 126 265 41 4 3 0 0 2,287 40.0 2,331 17.2 Latest drug resistance test result§ Sensitivity − − 0 0 96 1,841 71 83 2 6 24 1 73 147 266 4.7 2,078 15.4 Resistance − − 0 0 58 66 99 86 4 5 13 11 77 3 251 4.4 171 1.3 Not be tested − − 1,299 5,513 1,025 111 727 1,459 539 940 163 188 0 0 3,753 65.6 8,211 60.8 HIVDR result ¶ Sensitivity 448 2,411 − − 374 1,841 390 1,388 − − 175 187 73 147 1,460 25.5 5,974 44.2 Resistance 59 152 − − 36 66 99 86 − − 13 11 77 3 284 5.0 318 2.4 Viral load ≥1,000 copies/mL but resistance not being tested 107 221 − − 291 111 86 30 − − 8 0 0 0 492 8.6 362 2.7 Neither viral load nor drug resistance being tested 835 114 − − 478 158 322 124 − − 4 2 0 0 1,639 28.7 398 2.9 Abbreviations: PLADs=provincial-level administrative divisions; ART=Antiretroviral therapy; HIVDR=HIV drug resistance; MSM=men who have sex with men; D4T=2′,3′-Didehydro-3′-deoxythymidine; AZT=azidothymidine; TDF=Tenofovir; LPV/r=Lopinavir/Ritonavir.
* Lack of Hunan region data, the sum of proportion is not 100%.
† Lack of Sichuan, Jiangsu and Hunan region data, the sum of proportion is not 100%.
§ Lack of Anhui region data, the sum of proportion is not 100%.
¶ Lack of Chongqing and Guangxi region data, the sum of proportion is not 100%.Table 2. Characteristics of participants in 7 PLADs of China between 2010 and 2019, stratified by case group (dead) and control group (survived).
The multivariate logistic regression analysis indicated that the correlation between the HIVDR result and death was statistically significant (P<0.05) in Anhui, Sichuan, Jiangsu, and Hunan but not in Guangdong (P>0.05). No data was shown on the latest compound variable of viral load and drug resistance in Chongqing and Guangxi. After merging AORs of the HIVDR result with deaths in Anhui, Sichuan, Jiangsu, Guangdong, and Hunan, the result suggested that compared with drug-sensitive patients, the risk of death among patients with drug resistance [AOR=4.25, 95% confidence interval (CI): 2.10–8.62], with viral load ≥1,000 copies/mL but drug resistance untested (AOR=4.65, 95% CI: 1.74–12.39), and with neither viral load nor drug resistance being tested (AOR=17.52, 95% CI: 8.73–35.19) were statistically significantly higher (Table 3).
HIVDR result AOR (95% CI)* Sensitivity 1 Resistance 4.25 (2.10, 8.62) Viral load ≥1,000 copies/mL but resistance not being tested 4.65 (1.74, 12.39) Neither viral load nor drug resistance being tested 17.52 (8.73, 35.19) Abbreviations: ART=Antiretroviral therapy; HIVDR=HIV drug resistance; AOR=multivariate adjusted odds ratio; CI=confidence interval.
* AOR was conducted by meta-analysis to merge the results of PLADs.Table 3. Relationship between HIVDR and death in HIV-infected patients receiving ART.
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A cross-control survey in seven PLADs in China was conducted to investigate the relationship between HIVDR and death in HIV-infected patients receiving ART. A total of 19,235 participants were included in the analysis. Compared with drug-sensitive patients, the risk of death is higher in patients with HIV drug resistance or untested resistance.
In this large sample study, case-control analysis of patients in seven PLADs showed that HIVDR is significantly associated with death in HIV-infected patients receiving ART. Compared with drug-sensitive HIV-infected patients, the risk of death is 3.25 times higher than that of the drug-resistant HIV-infected patients. Drug-resistant patients are prone to have poor adherence to ART treatment (5) and higher incidence of virological failure (6), which could accelerate deaths of HIV-infected patients. A previous study showed that the risk of mortality in drug-resistant patients was 3.26 times higher than that of the drug-sensitive population (95% CI: 1.77–6.01), which was similar to the results of this study (7). This paper indicated that it is highly important to strengthen the drug resistance monitoring and prevention in HIV-infected patients receiving ART.
In accordance to the requirements of “Manual of the National Free Antiretroviral Treatment” (8), all treated HIV-infected patients with viral load ≥1,000 copies/mL should get drug resistance tested. However, the proportions of treated HIV patients with viral load ≥1,000 copies/mL but with drug resistance untested in some regions remained high in this study. Compared with drug-sensitive HIV-infected patients receiving ART, the risk of death was 3.65 times higher in patients with latest viral load ≥1,000 copies/mL but drug resistance untested. This result suggested that for those with viral load ≥1,000 copies/mL, drug resistance tests should be routinely conducted to know patients’ most updated drug resistance status. Therefore, ART regimens could be adjusted accordingly to improve treatment effectiveness.
Constant adherence is vital to effective ART for reducing viral load and HIV/AIDS-related opportunistic infections and mortality which used to be assessed by self-reported data of “missed doses in the past month” in previous studies (9–10). In this study, required viral load testing was used as a proxy for treatment compliance as it could promptly detect virological failure and drug resistance. The proportion of patients with latest viral load untested in the case group was higher than that in control group (40.0% vs. 17.2%). Compared with drug-sensitive HIV-infected patients receiving ART, the risk of death was 17.52 times higher than that of HIV-infected patients with neither viral load nor drug resistance being tested (95% CI: 8.73–35.19). This result indicates that during the ART follow-up management period, more attention should be paid on improving the adherence of patients, strengthening the follow-up quality of HIV clinics, and performing viral load and drug resistance testing promptly as required.
This study was subject to some limitations. First, the case-control design limited the ability to make causal inference about the proposed association. Second, some information of participants was not collected in some regions. Lack of these data may partly affect the analysis for the corresponding regions.
In summary, associations between drug resistance and death in HIV-infected patients receiving ART are highly related. It is important to strengthen the drug resistance monitoring and prevention in those patients. When conducting follow-up management of HIV-infected patients, adherence to antiviral treatment should be improved and viral load testing should be carried out as required. All treated HIV-infected patients with viral load ≥1,000 copies/mL should get drug resistance tested in a timely manner.
Acknowledgement: Anhui CDC, Chongqing CDC, Sichuan CDC, Jiangsu CDC, Guangxi CDC, Guangzhou Eighth People’s Hospital, and Hunan CDC.
Conflicts of interest: The authors who have taken part in this study declared that they did not have any other potential conflicts of interest.
Funding: The Ministry of Science and Technology of China (2017ZX10201101, 2018ZX10721102-006) and National Natural Science Foundation of China (11971479).
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