J Antimicrob Chemother 2015; 70: 2097 – 2103 doi:10.1093/jac/dkv078 Advance Access publication 7 April 2015
Reductions in virological failure and drug resistance in Chinese antiretroviral-treated patients due to lamivudine-based regimens, 2003–12 Hui Xing†, Yuhua Ruan†, Jenny H. Hsi†, Wei Kan, Lingjie Liao, Xuebing Leng, Jing Wang, Cui He and Yiming Shao* on behalf of the National HIVDR Working Group
*Corresponding author. State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 155 Changbai Road, Changping District, Beijing, 102206, P. R. China. Tel: +86 10 58900981; Fax: +86 10 58900981; E-mail: [email protected] †These authors contributed equally to this work.
Received 14 November 2014; returned 25 January 2015; revised 25 February 2015; accepted 5 March 2015 Background: China’s National Free Antiretroviral Treatment Program (NFATP) has significantly scaled up and standardized treatment since 2008. Meanwhile, no study worldwide has examined on a large scale the effects of rapid ART programme scale-up on treatment outcomes in resource-limited settings. Methods: We used China’s national HIV drug resistance (HIVDR) surveillance database to determine virological failure, acquired drug resistance and poor adherence rates after 12–15 months of first-line ART. A total of 2252 patients were examined, with 1431 patients having initiated ART before 2008 and 821 since 2008. Findings: Since 2008, virological failure at 12 – 15 months of treatment improved from 26.6% to 12.1%, and HIVDR rates also significantly decreased from 15.4% to 5.4%. However, these successes are strongly associated with the standardized use of lamivudine-based regimens in place of didanosine-based regimens. Patients who initiated lamivudine-based regimens before 2008 showed significant improvement in adherence [missed doses adjusted OR (AOR), 0.65; 95% CI, 0.45 –0.96], virological failure (AOR, 0.29; 95% CI, 0.22–0.39) and HIVDR outcomes (AOR, 0.29; 95% CI, 0.20 – 0.42) compared with those who initiated didanosine-based regimens. Meanwhile, among only patients on lamivudine-based regimens, no significant changes were observed between those who initiated before 2008 and those who initiated since 2008. Conclusions: China’s NFATP has been largely successful throughout the scale-up, with an overall reduction in virological failure and HIVDR. However, excluding the effect of lamivudine-based regimens, it remains crucial for the programme to improve patient adherence and quality of care, particularly in key vulnerable populations such as those infected through injecting drug or blood routes. Keywords: HIV, treatment outcomes, highly active antiretroviral therapy
Introduction Since the development of HAART in 1996, successful ART has significantly reduced mortality and morbidity due to HIV infection and improved the quality of life of infected persons.1 – 8 In most resource-limited countries, HAART became widely available in 2003 when the WHO launched the ‘3 by 5’ initiative. 9 At the end of 2012, more than 1.6 million people were receiving ART in low- and middle-income countries.10 Expanding access to ART is changing the global HIV epidemic in momentous ways. In particular, China has experienced rapid expansion of ART since 2008. China’s National Free Antiretroviral
Treatment Program (NFATP) began in 2002 after an early pilot study.11 – 16 NFATP is a community-based public health programme, and has evolved from an emergency response model focused on former plasma donors in central China to a nationally standardized care and treatment programme.14,17 In its first two phases (initiation, prior to 2005, and first scale-up, 2005 – 07), a total of 42161 HIV patients began ART, while in the third phase (further scale-up and standardization, since 2008) more than 235 000 patients began treatment.18 Important policy changes in this last phase included increased testing among at-risk populations, as well as an update to the National Free ART Guideline to include patients with a CD4 cell count of 2002350 cells/mm3 or
# The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
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State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China
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Methods Study design and study population The Chinese HIVDR database was established by the National HIVDR Working Group in 2003. The database includes annual surveys of HIVDR in nationally representative ART clinics in China from 2004 to 2012. 23 – 27 As of 31 December 2012, the HIVDR database contained 8556 cases, which represented 4.1% of the 208 216 patients treated by the NFATP (NFATP Database, National Center for AIDS/STD Control and Prevention, China CDC). Survey sites included all 32 provinces and autonomous regions of mainland China. The survey protocol used was the WHO-recommended cross-sectional survey on acquired HIVDR in adult patients receiving ART for ≥12 months.22 For this study, eligibility criteria were: 18 years or older; having received first-line ART for 12– 15 months; attending a participating clinic for routine NFATP visits; and giving consent to participate. The NFATP criteria for treatment were: (i) CD4 cell count ,200/mm3 before 2008 and ,350/mm3 since 2008; (ii) total lymphocyte count ,1200 cells/mm3 before 2008; and/or (iii) WHO stage III or IV disease.19,20 First-line HAART regimens before 2008 consisted of (zidovudine or stavudine) +(didanosine or lamivudine) +(nevirapine or efavirenz). Zidovudine, stavudine, didanosine and nevirapine are generically produced in China and were standard prescriptions from the start of the programme in 2003, whereas lamivudine and efavirenz are branded drugs that became available in 2005 and gradually became more commonly prescribed following preferential use in those with strong adverse reactions to the former standard regimens. The first-line ART regimen in the second edition of the National Free ART Guideline in 2008 was revised to consist of (tenofovir or zidovudine)+lamivudine+(efavirenz or nevirapine).20 In
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particular, lamivudine was dosed either once daily in a single dose of 300 mg, or twice daily in two doses of 150 mg.
Data collection Questionnaire data from the Chinese HIVDR database on age, ethnicity, sex, education, marital status, occupation, route of HIV transmission, initial ART regimen and missed doses in the past month were collected by well-trained interviewers. Each study participant was assigned a confidential identification number used to label questionnaires and blood specimens. All subjects provided written informed consent to participate in this study. The institutional review board of the National Center for AIDS/STD Control and Prevention, China CDC approved this study.
Laboratory tests CD4 cell count was measured by flow cytometry within 24 h of specimen collection in local centres. Plasma HIV-1 RNA was quantified by real-time nucleic acid sequence-based amplification (NucliSense Easy Q, bioMerieux, France) or the Amplicor HIV-1 monitor test (COBASw, Roche Applied Science, Germany) according to the manufacturers’ recommendations. In accordance with WHO survey guidelines, successful viral suppression was defined as HIV RNA level ,1000 copies/mL using a quality-assured viral load assay. In samples with viral load ≥1000 copies/mL, HIVDR genotyping was performed by in-house PCR as previously described.28,29 Drug resistance mutation analysis and viral subtype determination were performed on a 1.3 kb section of the HIV pol gene using the Stanford University HIV Drug Resistance Database online sequence analysis tool (http://hivdb.stanford.edu/pages/algs/sierra_sequence.html). We included mutation results that conferred low-, intermediate- and high-level resistance.28,30
Statistical analysis Questionnaires and laboratory data were double entered and compared with EpiData software (EpiData 3.0 for Windows; The EpiData Association, Odense, Denmark). Data were then converted and analysed using Statistical Analysis System version 9.1 (SAS Institute Inc., USA). Univariate proportions and means were calculated for categorical and continuous variables, respectively. x2 tests and logistic regression were used for categorical variables.
Results General characteristics of study participants Of 8556 adult patients from the national HIVDR database, a total of 2282 patients met our eligibility criteria of having received first-line ART for 12 –15 months (Figure 1). Of these, 1431 patients initiated ART before 2008 and 851 initiated ART since 2008. Patients were further stratified according to their first-line regimen: 845 patients initiated didanosine-based ART before 2008, 586 patients initiated lamivudine-based ART before 2008 and 821 initiated lamivudine-based ART since 2008. The 30 patients who initiated didanosine-based ART since 2008 were excluded from the analysis due to the small sample size of this subgroup. Table 1 shows the basic demographic and treatment characteristics of the resulting 2252 patients, as well as crude P values to assess the significance of differences. In total: 52.4% were aged ,40 years; 93.3% belonged to the Han ethnic group; 59.1% were male; 42.8% had primary school education (1 – 6 years of education) or less; 73.9% were married; 43.0% were
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WHO stage I/II disease and to replace didanosine with lamivudine in the standard first-line ART regimen.19,20 Although evidence has shown that community-based ART in developing countries is capable of achieving good treatment outcomes, rapid expansion of a treatment programme raises concerns for long-term sustainability and emerging HIV drug resistance (HIVDR).21 – 28 In particular, expanded treatment without improved measures in ART adherence education and capacity building in human and organizational infrastructure is likely to result in inappropriate regimens and poor adherence, which may lead to poor treatment outcomes and drug resistance. In response to this, the Chinese Center for Disease Control and Prevention (China CDC) has established a National HIVDR Working Group to conduct surveillance on HIVDR since 2003.23 Based on the WHO HIVDR surveys, the Chinese surveillance protocol is designed particularly for resource-limited settings where decisions on ART regimens are made on a community basis rather than at the individual patient level. The aim of this study was to use China’s national HIVDR surveillance database to examine the effects of the 2008 NFATP scale-up and policy changes on treatment outcomes. Specifically, we investigated: (i) whether virological failure and drug resistance were reduced in Chinese antiretroviral-treated patients due to the adoption of lamivudine-based regimens; and (ii) whether virological outcome and adherence were improved due to standardization of care since 2008. To our knowledge, this is the first large-scale study evaluating the effects of a rapid scale-up of a community-based ART programme on HIV virological failure and drug resistance. Our findings have significant implications for improving China’s NFATP and similar programmes in other resource-limited countries.
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The national HIVDR database (2003–12) 8556
Received ART for 12–15 months 2282
Received didanosine-based regimens 845
Received lamivudine-based regimens 586
Received ART since 2008 851
Received didanosine-based regimens 30
Received lamivudine-based regimens 821
Figure 1. Study profile: 2282 patients were eligible based on duration of ART; the subgroup of 30 was excluded due to small sample size, and finally 2252 patients were included for analysis.
farmers; and 41.3%, 42.1% and 14.3% were infected through blood/plasma transmission, sexual intercourse and intravenous drug use, respectively. The proportions of patients with baseline (pre-ART) CD4 counts of ≥350, 200–349 and 50–199 cells/mm3 were 3.4%, 12.7% and 35.5%, respectively. Changes in the proportions of demographic characteristics reflect changes in HIV testing and treatment policy through the initial and latter phases of NFATP. Since 2008, significantly more patients were included who: were male; were unmarried; had received higher education; were not farmers; were infected through sexual transmission routes; and had higher (≥200 cells/mm3) CD4 cell counts (Table 1). Of note, most patients in the NFATP’s early implementation initiated treatment based on clinical presentation (WHO stage III or IV disease) without baseline pre-treatment CD4 measurement.
Comparing treatment outcomes between patients initiating ART before and since 2008 We first compared the rates of virological failure, drug resistance and poor adherence between all patients who initiated first-line ART before 2008 (both didanosine- and lamivudine-based regimens) and those who initiated lamivudine-based regimens since 2008. Without adjusting for demographic characteristics, treatment outcomes were significantly better in the latter group, with lower rates of virological failure (HIV RNA ≥ 1000 copies/mL, 12.1% versus 26.6%, P,0.01) and HIVDR (5.4% versus 15.4%, P, 0.01). However, adherence levels appeared to be similar, with no significant difference between the rates of missing doses in the past month (10.0% versus 10.3%, P .0.05). In order to identify the correlates of ART success, we next performed multivariate logistic regression on the treatment groups, controlling for age, ethnicity, sex, education level, marital status, occupation, route of HIV transmission and initial ART regimen. We
compared the rates of poor adherence, virological failure and drug resistance between (i) patients who initiated didanosine- and lamivudine-based ART regimens before 2008, and (ii) patients who initiated lamivudine-based regimens before and since 2008.
Comparing treatment outcomes between patients initiating didanosine- and lamivudine-based ART before 2008 Table 2 presents the unadjusted and adjusted effects of ART regimen (lamivudine-based versus didanosine-based) on the odds of poor adherence, virological failure and drug resistance among patients who initiated ART before 2008. We observe effects in all three treatment outcome measures. Those who initiated lamivudine-based ART had 35% lower odds of having missed doses in the past month [adjusted OR (AOR), 0.65; 95% CI, 0.45 – 0.96], 71% lower odds of virological failure (AOR, 0.29; 95% CI, 0.22 – 0.39) and 71% lower odds of HIVDR (AOR, 0.29; 95% CI, 0.20 – 0.42). In terms of specific drug resistance mutations, those who initiated lamivudine-based regimens had significantly lower odds of resistance to NNRTI and NRTI class drugs, as well as MDR to NNRTI and NRTI drugs; however, they had higher odds of resistance to PI class drugs.
Comparing treatment outcomes between patients initiating lamivudine-based ART before and since 2008 Table 3 presents the unadjusted and adjusted effects of treatment initiation year (since versus before 2008) on the odds of poor adherence, virological failure and drug resistance among patients who initiated with lamivudine-based ART regimens. Interestingly, we observe no significant effect in all three treatment outcome measures. Those who initiated lamivudinebased ART since 2008 did not have lower odds of having missed doses in the past month (AOR, 0.72; 95% CI, 0.48 – 1.08),
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Table 1. General characteristics of Chinese patients who initiated first-line ART before and since 2008 Number starting treatment (%) didanosine-based ART before 2008
lamivudine-based ART before 2008
lamivudine-based ART since 2008
Total, n (%)
Total
2252
845
586
821
Age (years) ,40 ≥40
1180 (52.4) 1072 (47.6)
406 (48.0) 439 (52.0)
373 (63.7) 213 (36.3)
401 (48.8) 420 (51.2)
,0.01
Ethnicity Han majority other minorities
2100 (93.3) 152 (6.7)
780 (92.3) 65 (7.7)
563 (96.1) 23 (3.9)
757 (92.2) 64 (7.8)
,0.01
Sex male female
1331 (59.1) 921 (40.9)
413 (48.9) 432 (51.1)
345 (58.9) 241 (41.1)
573 (69.8) 248 (30.2)
,0.01
Years of education ≤6 .6
963 (42.8) 1289 (57.2)
492 (58.2) 353 (41.8)
236 (40.3) 350 (59.7)
235 (28.6) 586 (71.4)
,0.01
Marital status married other
1665 (73.9) 587 (26.1)
674 (79.8) 171 (20.2)
440 (75.1) 146 (24.9)
551 (67.1) 270 (32.9)
,0.01
Occupation farmer other
968 (43.0) 1284 (57.0)
504 (59.6) 341 (40.4)
270 (46.1) 316 (53.9)
194 (23.6) 627 (76.4)
,0.01
929 (41.3)
621 (73.5)
140 (23.9)
168 (20.5)
947 (42.1) 322 (14.3) 54 (2.4)
144 (17.0) 64 (7.6) 16 (1.9)
279 (47.6) 162 (27.6) 5 (0.9)
524 (63.8) 96 (11.7) 33 (4.0)
,0.01
12 (1.4) 17 (2.0) 38 (4.5) 22 (2.6) 756 (89.5)
13 (2.2) 92 (15.7) 335 (57.2) 131 (22.4) 15 (2.6)
51 (6.2) 178 (21.7) 426 (51.9) 166 (20.2) —
,0.01
Route of HIV infection blood/plasma transmission sexual intercourse intravenous drug use other
P value
3
CD4 count before ART (cells/mm ) ≥350 76 (3.4) 200–349 287 (12.7) 50– 199 799 (35.5) 0 –49 319 (14.2) missing 771 (34.2)
virological failure (AOR, 0.96; 95% CI, 0.68 –1.34) or HIVDR (AOR, 1.22; 95% CI, 0.77 –1.94). The odds of HIVDR were also not significantly different for all drug classes (NNRTI, NRTI, PI and MDR to NNRTI and NRTI).
Discussion In this study, we assessed the effects of the 2008 scale-up and policy changes in China’s NFATP on ART adherence, virological outcomes and acquired HIVDR. We found that virological failure at 12 – 15 months of treatment improved from 26.6% in patients who initiated ART before 2008, to 12.1% in those who initiated since 2008. Similarly, HIVDR rates in patients who initiated ART since 2008 were significantly decreased. However, our analysis also showed that the reductions in virological failure and HIVDR
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since 2008 are strongly associated with the standardized use of lamivudine-based regimens in place of didanosine-based regimens. Patients who initiated lamivudine-based regimens before 2008 showed significant improvements in adherence, virological and HIVDR outcomes compared with those who initiated didanosine-based regimens; meanwhile, among only patients on lamivudine-based regimens, no significant changes were observed between those who initiated before and since 2008. Several observations can be drawn from these data. First, China’s ART programme has been largely successful throughout the scale-up. The virological outcomes before and since 2008 have met the WHO recommended ART targets for middle- and lower-income countries at the ‘fair’ grade (70% – 85% success) and ‘excellent’ grade (≥85% success), respectively,22,31 supporting previous arguments that these targets be revised upwards.32
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Factor
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Table 2. Adherence, virological outcomes and drug resistance in Chinese patients who initiated first-line ART before 2008 Number (%) Factors
didanosine-based ART lamivudine-based ART
OR, lamivudine-based/ didanosine-based (95% CI)
P value
AOR, lamivudine-based/ didanosine-based (95% CI)
P value
845
586
Missed doses in the past montha
102 (12.1)
46 (7.8)
0.62 (0.43–0.89)
0.01
0.65 (0.45– 0.96)
0.03
HIV RNA ≥1000 copies/mLb
302 (35.7)
79 (13.5)
0.28 (0.21–0.37)
,0.01
0.29 (0.22– 0.39)
,0.01
HIVDRb overall NNRTI NRTI PI MDR to NNRTI and NRTI
178 (21.1) 173 (20.5) 97 (11.5) 4 (0.5) 94 (11.1)
43 (7.3) 43 (7.3) 31 (5.3) 10 (1.7) 31 (5.3)
0.30 (0.21–0.42) 0.31 (0.22–0.44) 0.43 (0.28–0.66) 3.65 (1.14–11.69) 0.45 (0.29–0.68)
,0.01 ,0.01 ,0.01 0.03 ,0.01
0.29 (0.20– 0.42) 0.29 (0.20– 0.42) 0.46 (0.30– 0.69) 4.00 (1.36– 11.80) 0.45 (0.29– 0.69)
,0.01 ,0.01 ,0.01 0.01 ,0.01
a
Adjusted for: age, ethnicity, education, sex, marital status, occupation and route of HIV transmission. Adjusted for: age, ethnicity, education, sex, marital status, occupation, route of HIV transmission and missed doses in the past month.
b
Table 3. Adherence, virological outcomes and drug resistance in Chinese patients who initiated lamivudine-based first-line ART Number (%) initiated before 2008
Factors Total
586 a
Missed doses in the past month b
HIV RNA ≥1000 copies/mL
initiated since 2008
OR, before 2008/since 2008 (95% CI)
P value
AOR, before 2008/since 2008 (95% CI)
P value
821
46 (7.8)
82 (10.0)
0.77 (0.53–1.12)
0.17
0.72 (0.48– 1.08)
0.11
79 (13.5)
99 (12.1)
1.14 (0.83–1.56)
0.43
0.96 (0.68– 1.34)
0.80
43 (7.3) 43 (7.3) 31 (5.3) 10 (1.7) 31 (5.3)
44 (5.4) 36 (4.4) 38 (4.6) 24 (2.9) 31 (3.8)
1.4 (0.91–2.16) 1.73 (1.09–2.73) 1.15 (0.71–1.87) 0.58 (0.27–1.22) 1.42 (0.86–2.37)
0.13 0.02 0.57 0.15 0.17
1.22 (0.77– 1.94) 0.94 (0.62– 1.43) 1.10 (0.67– 1.80) 0.57 (0.27– 1.18) 1.22 (0.72– 2.10)
0.39 0.77 0.71 0.13 0.46
b
HIVDR overall NNRTI NRTI PI MDR to NNRTI and NRTI a
Adjusted for: age, ethnicity, education, sex, marital status, occupation and route of HIV transmission. Adjusted for: age, ethnicity, education, sex, marital status, occupation, route of HIV transmission and missed doses in the past month.
b
Second, the fact that improvements in treatment outcomes were largely attributable to the replacement of didanosine-based regimens with lamivudine-based regimens validates the standardization of the latter’s use in the second edition of the National Free ART Guideline.20 Evidence from a large-scale randomized controlled trial in southern Africa has also shown lamivudine-based regimens to yield better treatment outcomes than didanosinebased regimens.33 However, excluding the effect of lamivudine, treatment outcomes and adherence did not improve following scale-up and standardization. As the number of patients treated through the NFATP continues to increase, the number of persons at risk for treatment failure and acquired HIVDR also rises. It is therefore crucial for the NFATP to emphasize improved quality of care in its next phases of implementation. A more detailed examination may reveal points of interest in quality improvement. Among the 821 patients who initiated lamivudine-based ART since 2008, the rate of virological failure was 7.8% in those infected through sexual routes, 19.6% in
those infected through blood/plasma routes and 20.8% in injecting drug users (IDUs; data not shown). IDUs are known to have lower ART adherence and increased virological failure.25,27 Also, IDUs and those infected through blood/plasma routes in China are more likely to inhabit rural or lower-income areas, where the physical and human infrastructure for healthcare is scarcer.26 It is therefore important for the NFATP to invest in greater training and support for rural healthcare providers, and to better integrate ART with IDU-oriented programmes such as methadone-replacement clinics, which have been shown to improve patient follow-up and adherence as well as reducing the incidence of blood-borne and sexually transmitted infections.34 Third, the HIVDR mutations identified in our study were consistent with expected mutation patterns from first-line ART regimens based on NRTI and NNRTI class drugs. The great majority of HIVDR cases observed were likely to be acquired HIVDR as opposed to transmitted, since HIVDR prevalence among ART-naive patients was observed to be very low in a national
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Total
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Funding This study was supported by grants from the Ministry of Science and Technology of China (2012ZX10001-002 and 2009DFB30420), a Chinese State Key Laboratory for Infectious Disease development grant (2012SKLID103) and the International Development Research Center of Canada (grant #104519-010). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Transparency declarations None to declare.
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Author contributions H. X., Y. R., L. L. and Y. S. were responsible for study design and planning. H. X., Y. R., J. H. H. and Y. S. contributed to writing the report. Y. R., W. K., L. L., X. L., J. W. and C. H. contributed to data analysis. H. X., Y. R., J. H. H., L. L. and Y. S. contributed to interpretation. H. X., Y. R., W. K., L. L., X. L., J. W. and C. H. contributed to data collection and cleaning. All authors read and approved the final version of the paper.
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survey.29,35 In addition, the prevalence of drug resistance to PIs is low, which supports their continued use as second-line therapy in China. However, lamivudine-based regimens appear to be associated with greater prevalence of PI-resistance mutations (Table 2), and that prevalence has increased since 2008, although not statistically significantly (Table 3). While this may be attributable simply to the concurrent increase in PI use since 2008, further monitoring is required to see if the trend continues and to clarify its causes. Our study has several limitations. First, consecutive sampling was used to recruit eligible participants at the HIVDR sentinel sites, which may not be fully representative of all of China geographically. Second, patients who terminated treatment (due to adverse reactions, loss to follow-up or death) within the first 12 months would not have been sampled, which may have led to overestimated treatment effectiveness. Third, adherence was assessed by self-reporting of having missed doses in the past month, which may not reflect true adherence. Fourth, although multivariate modelling has controlled for demographic characteristics, differences in age, ethnicity, education, sex, marital status, occupation and route of HIV transmission between the main analysis subgroups suggest the possibility of selection bias that may have led to overestimation of treatment effects. Along similar lines, a large proportion of didanosine initiators began treatment during the earlier years of the NFATP, when baseline CD4 cell count was not required (Table 1) and standards of care and follow-up were lower. This may have contributed to the poorer treatment outcomes among didanosine initiators. Finally, although recommended by WHO guidelines, a 12 – 15 month treatment period is relatively short for the purposes of monitoring acquired HIVDR, and long-term monitoring will provide more insight on HIVDR-related outcomes and factors. However, these limitations should not affect our conclusion on the changes in adherence, virological outcomes and drug resistance in Chinese HIV patients following the 2008 NFATP scale-up and standardization. To our knowledge, this is the first large-scale study evaluating the outcomes of ART during a rapid programme scale-up. Our results provide evidence to guide policymakers in improving training for healthcare providers and enhancing patient education on ART adherence. Recently, China’s HIV control and prevention efforts have also initiated ART-as-prevention programmes in key at-risk populations. Further monitoring of treatment outcomes is needed to elucidate the determinants of long-term programme success.
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28 Zhong P, Pan Q, Ning Z et al. Genetic diversity and drug resistance of human immunodeficiency virus type 1 (HIV-1) strains circulating in Shanghai. AIDS Res Hum Retroviruses 2007; 23: 847–56.
18 Zhao DC, Wen Y, Ma Y et al. Expansion of China’s free antiretroviral treatment program. Chin Med J (Engl) 2012; 125: 3514 –21.
29 Liao L, Xing H, Shang H et al. The prevalence of transmitted antiretroviral drug resistance in treatment-naive HIV-infected individuals in China. J Acquir Immune Defic Syndr 2010; 53 Suppl 1: S10– 4.
19 Zhang F. China Free ART Manual. 1st edn. Beijing: People’s Medical Publishing House, 2005. 20 Zhang F, Wang Y, Wang J et al. China Free ART Manual. 3nd edn. Beijing: People’s Medical Publishing House, 2008.
30 Liu TF, Shafer RW. Web resources for HIV type 1 genotypic-resistance test interpretation. Clin Infect Dis 2006; 42: 1608 –18. 31 Jordan MR, Bennett DE, Bertagnolio S et al. World Health Organization surveys to monitor HIV drug resistance prevention and associated factors in sentinel antiretroviral treatment sites. Antivir Ther 2008; 13 Suppl 2: 15 – 23.
22 WHO. World Health Organization Global Strategy for the Surveillance and Monitoring of HIV Drug Resistance 2012. http://www.who.int/hiv/pub/ drugresistance/drug_resistance_strategy/en/.
32 McMahon JH, Elliott JH, Bertagnolio S et al. Viral suppression after 12 months of antiretroviral therapy in low- and middle-income countries: a systematic review. Bull WHO 2013; 91: 377–385E.
23 Xing H, Ruan Y, Li J et al. HIV drug resistance and its impact on antiretroviral therapy in Chinese HIV-infected patients. PLoS One 2013; 8: e54917.
33 Bussmann H1, Wester CW, Thomas A et al. Response to ZDV/ddI containing combination antiretroviral therapy among HIV-1 subtype C infected adults in Botswana: two-year outcomes from a randomized clinical trial. J Acquir Immune Defic Syndr 2009; 51: 37– 46.
24 Xing H, Wang X, Liao L et al. Incidence and associated factors of HIV drug resistance in Chinese HIV-infected patients receiving antiretroviral treatment. PLoS One 2013; 8: e62408. 25 Wang X, Yang L, Li H et al. Factors associated with HIV virologic failure among patients on HAART for one year at three sentinel surveillance sites in China. Curr HIV Res 2011; 9: 103– 11.
34 Ruan Y, Liang S, Zhu J et al. Evaluation of harm reduction programs on seroincidence of HIV, hepatitis B and C,and syphilis among intravenous drug users in southwest China. Sex Transm Dis 2013; 40: 323–8.
26 Ruan Y, Xing H, Wang X et al. Virologic outcomes of first-line HAART and associated factors among Chinese patients with HIV in three sentinel antiretroviral treatment sites. Trop Med Int Health 2010; 15: 1357 –63.
35 Liao L, Xing H, Dong Y et al. Surveys of transmitted HIV drug resistance in 7 geographic Regions in China, 2008 – 2009. Clin Infect Dis 2012; 54 Suppl 4: S320– 3.
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21 Chinese Center for Disease Control and Prevention. Analysis of HIV/STD Epidemic in 2013. Beijing, China: Chinese Center for Disease Control and Prevention.
Reductions in virological failure and drug resistance in Chinese antiretroviral-treated patients due to lamivudine-based regimens, 2003–12 Hui Xing†, Yuhua Ruan†, Jenny H. Hsi†, Wei Kan, Lingjie Liao, Xuebing Leng, Jing Wang, Cui He and Yiming Shao* on behalf of the National HIVDR Working Group
*Corresponding author. State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 155 Changbai Road, Changping District, Beijing, 102206, P. R. China. Tel: +86 10 58900981; Fax: +86 10 58900981; E-mail: [email protected] †These authors contributed equally to this work.
Received 14 November 2014; returned 25 January 2015; revised 25 February 2015; accepted 5 March 2015 Background: China’s National Free Antiretroviral Treatment Program (NFATP) has significantly scaled up and standardized treatment since 2008. Meanwhile, no study worldwide has examined on a large scale the effects of rapid ART programme scale-up on treatment outcomes in resource-limited settings. Methods: We used China’s national HIV drug resistance (HIVDR) surveillance database to determine virological failure, acquired drug resistance and poor adherence rates after 12–15 months of first-line ART. A total of 2252 patients were examined, with 1431 patients having initiated ART before 2008 and 821 since 2008. Findings: Since 2008, virological failure at 12 – 15 months of treatment improved from 26.6% to 12.1%, and HIVDR rates also significantly decreased from 15.4% to 5.4%. However, these successes are strongly associated with the standardized use of lamivudine-based regimens in place of didanosine-based regimens. Patients who initiated lamivudine-based regimens before 2008 showed significant improvement in adherence [missed doses adjusted OR (AOR), 0.65; 95% CI, 0.45 –0.96], virological failure (AOR, 0.29; 95% CI, 0.22–0.39) and HIVDR outcomes (AOR, 0.29; 95% CI, 0.20 – 0.42) compared with those who initiated didanosine-based regimens. Meanwhile, among only patients on lamivudine-based regimens, no significant changes were observed between those who initiated before 2008 and those who initiated since 2008. Conclusions: China’s NFATP has been largely successful throughout the scale-up, with an overall reduction in virological failure and HIVDR. However, excluding the effect of lamivudine-based regimens, it remains crucial for the programme to improve patient adherence and quality of care, particularly in key vulnerable populations such as those infected through injecting drug or blood routes. Keywords: HIV, treatment outcomes, highly active antiretroviral therapy
Introduction Since the development of HAART in 1996, successful ART has significantly reduced mortality and morbidity due to HIV infection and improved the quality of life of infected persons.1 – 8 In most resource-limited countries, HAART became widely available in 2003 when the WHO launched the ‘3 by 5’ initiative. 9 At the end of 2012, more than 1.6 million people were receiving ART in low- and middle-income countries.10 Expanding access to ART is changing the global HIV epidemic in momentous ways. In particular, China has experienced rapid expansion of ART since 2008. China’s National Free Antiretroviral
Treatment Program (NFATP) began in 2002 after an early pilot study.11 – 16 NFATP is a community-based public health programme, and has evolved from an emergency response model focused on former plasma donors in central China to a nationally standardized care and treatment programme.14,17 In its first two phases (initiation, prior to 2005, and first scale-up, 2005 – 07), a total of 42161 HIV patients began ART, while in the third phase (further scale-up and standardization, since 2008) more than 235 000 patients began treatment.18 Important policy changes in this last phase included increased testing among at-risk populations, as well as an update to the National Free ART Guideline to include patients with a CD4 cell count of 2002350 cells/mm3 or
# The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
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State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China
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Methods Study design and study population The Chinese HIVDR database was established by the National HIVDR Working Group in 2003. The database includes annual surveys of HIVDR in nationally representative ART clinics in China from 2004 to 2012. 23 – 27 As of 31 December 2012, the HIVDR database contained 8556 cases, which represented 4.1% of the 208 216 patients treated by the NFATP (NFATP Database, National Center for AIDS/STD Control and Prevention, China CDC). Survey sites included all 32 provinces and autonomous regions of mainland China. The survey protocol used was the WHO-recommended cross-sectional survey on acquired HIVDR in adult patients receiving ART for ≥12 months.22 For this study, eligibility criteria were: 18 years or older; having received first-line ART for 12– 15 months; attending a participating clinic for routine NFATP visits; and giving consent to participate. The NFATP criteria for treatment were: (i) CD4 cell count ,200/mm3 before 2008 and ,350/mm3 since 2008; (ii) total lymphocyte count ,1200 cells/mm3 before 2008; and/or (iii) WHO stage III or IV disease.19,20 First-line HAART regimens before 2008 consisted of (zidovudine or stavudine) +(didanosine or lamivudine) +(nevirapine or efavirenz). Zidovudine, stavudine, didanosine and nevirapine are generically produced in China and were standard prescriptions from the start of the programme in 2003, whereas lamivudine and efavirenz are branded drugs that became available in 2005 and gradually became more commonly prescribed following preferential use in those with strong adverse reactions to the former standard regimens. The first-line ART regimen in the second edition of the National Free ART Guideline in 2008 was revised to consist of (tenofovir or zidovudine)+lamivudine+(efavirenz or nevirapine).20 In
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particular, lamivudine was dosed either once daily in a single dose of 300 mg, or twice daily in two doses of 150 mg.
Data collection Questionnaire data from the Chinese HIVDR database on age, ethnicity, sex, education, marital status, occupation, route of HIV transmission, initial ART regimen and missed doses in the past month were collected by well-trained interviewers. Each study participant was assigned a confidential identification number used to label questionnaires and blood specimens. All subjects provided written informed consent to participate in this study. The institutional review board of the National Center for AIDS/STD Control and Prevention, China CDC approved this study.
Laboratory tests CD4 cell count was measured by flow cytometry within 24 h of specimen collection in local centres. Plasma HIV-1 RNA was quantified by real-time nucleic acid sequence-based amplification (NucliSense Easy Q, bioMerieux, France) or the Amplicor HIV-1 monitor test (COBASw, Roche Applied Science, Germany) according to the manufacturers’ recommendations. In accordance with WHO survey guidelines, successful viral suppression was defined as HIV RNA level ,1000 copies/mL using a quality-assured viral load assay. In samples with viral load ≥1000 copies/mL, HIVDR genotyping was performed by in-house PCR as previously described.28,29 Drug resistance mutation analysis and viral subtype determination were performed on a 1.3 kb section of the HIV pol gene using the Stanford University HIV Drug Resistance Database online sequence analysis tool (http://hivdb.stanford.edu/pages/algs/sierra_sequence.html). We included mutation results that conferred low-, intermediate- and high-level resistance.28,30
Statistical analysis Questionnaires and laboratory data were double entered and compared with EpiData software (EpiData 3.0 for Windows; The EpiData Association, Odense, Denmark). Data were then converted and analysed using Statistical Analysis System version 9.1 (SAS Institute Inc., USA). Univariate proportions and means were calculated for categorical and continuous variables, respectively. x2 tests and logistic regression were used for categorical variables.
Results General characteristics of study participants Of 8556 adult patients from the national HIVDR database, a total of 2282 patients met our eligibility criteria of having received first-line ART for 12 –15 months (Figure 1). Of these, 1431 patients initiated ART before 2008 and 851 initiated ART since 2008. Patients were further stratified according to their first-line regimen: 845 patients initiated didanosine-based ART before 2008, 586 patients initiated lamivudine-based ART before 2008 and 821 initiated lamivudine-based ART since 2008. The 30 patients who initiated didanosine-based ART since 2008 were excluded from the analysis due to the small sample size of this subgroup. Table 1 shows the basic demographic and treatment characteristics of the resulting 2252 patients, as well as crude P values to assess the significance of differences. In total: 52.4% were aged ,40 years; 93.3% belonged to the Han ethnic group; 59.1% were male; 42.8% had primary school education (1 – 6 years of education) or less; 73.9% were married; 43.0% were
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WHO stage I/II disease and to replace didanosine with lamivudine in the standard first-line ART regimen.19,20 Although evidence has shown that community-based ART in developing countries is capable of achieving good treatment outcomes, rapid expansion of a treatment programme raises concerns for long-term sustainability and emerging HIV drug resistance (HIVDR).21 – 28 In particular, expanded treatment without improved measures in ART adherence education and capacity building in human and organizational infrastructure is likely to result in inappropriate regimens and poor adherence, which may lead to poor treatment outcomes and drug resistance. In response to this, the Chinese Center for Disease Control and Prevention (China CDC) has established a National HIVDR Working Group to conduct surveillance on HIVDR since 2003.23 Based on the WHO HIVDR surveys, the Chinese surveillance protocol is designed particularly for resource-limited settings where decisions on ART regimens are made on a community basis rather than at the individual patient level. The aim of this study was to use China’s national HIVDR surveillance database to examine the effects of the 2008 NFATP scale-up and policy changes on treatment outcomes. Specifically, we investigated: (i) whether virological failure and drug resistance were reduced in Chinese antiretroviral-treated patients due to the adoption of lamivudine-based regimens; and (ii) whether virological outcome and adherence were improved due to standardization of care since 2008. To our knowledge, this is the first large-scale study evaluating the effects of a rapid scale-up of a community-based ART programme on HIV virological failure and drug resistance. Our findings have significant implications for improving China’s NFATP and similar programmes in other resource-limited countries.
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The national HIVDR database (2003–12) 8556
Received ART for 12–15 months 2282
Received didanosine-based regimens 845
Received lamivudine-based regimens 586
Received ART since 2008 851
Received didanosine-based regimens 30
Received lamivudine-based regimens 821
Figure 1. Study profile: 2282 patients were eligible based on duration of ART; the subgroup of 30 was excluded due to small sample size, and finally 2252 patients were included for analysis.
farmers; and 41.3%, 42.1% and 14.3% were infected through blood/plasma transmission, sexual intercourse and intravenous drug use, respectively. The proportions of patients with baseline (pre-ART) CD4 counts of ≥350, 200–349 and 50–199 cells/mm3 were 3.4%, 12.7% and 35.5%, respectively. Changes in the proportions of demographic characteristics reflect changes in HIV testing and treatment policy through the initial and latter phases of NFATP. Since 2008, significantly more patients were included who: were male; were unmarried; had received higher education; were not farmers; were infected through sexual transmission routes; and had higher (≥200 cells/mm3) CD4 cell counts (Table 1). Of note, most patients in the NFATP’s early implementation initiated treatment based on clinical presentation (WHO stage III or IV disease) without baseline pre-treatment CD4 measurement.
Comparing treatment outcomes between patients initiating ART before and since 2008 We first compared the rates of virological failure, drug resistance and poor adherence between all patients who initiated first-line ART before 2008 (both didanosine- and lamivudine-based regimens) and those who initiated lamivudine-based regimens since 2008. Without adjusting for demographic characteristics, treatment outcomes were significantly better in the latter group, with lower rates of virological failure (HIV RNA ≥ 1000 copies/mL, 12.1% versus 26.6%, P,0.01) and HIVDR (5.4% versus 15.4%, P, 0.01). However, adherence levels appeared to be similar, with no significant difference between the rates of missing doses in the past month (10.0% versus 10.3%, P .0.05). In order to identify the correlates of ART success, we next performed multivariate logistic regression on the treatment groups, controlling for age, ethnicity, sex, education level, marital status, occupation, route of HIV transmission and initial ART regimen. We
compared the rates of poor adherence, virological failure and drug resistance between (i) patients who initiated didanosine- and lamivudine-based ART regimens before 2008, and (ii) patients who initiated lamivudine-based regimens before and since 2008.
Comparing treatment outcomes between patients initiating didanosine- and lamivudine-based ART before 2008 Table 2 presents the unadjusted and adjusted effects of ART regimen (lamivudine-based versus didanosine-based) on the odds of poor adherence, virological failure and drug resistance among patients who initiated ART before 2008. We observe effects in all three treatment outcome measures. Those who initiated lamivudine-based ART had 35% lower odds of having missed doses in the past month [adjusted OR (AOR), 0.65; 95% CI, 0.45 – 0.96], 71% lower odds of virological failure (AOR, 0.29; 95% CI, 0.22 – 0.39) and 71% lower odds of HIVDR (AOR, 0.29; 95% CI, 0.20 – 0.42). In terms of specific drug resistance mutations, those who initiated lamivudine-based regimens had significantly lower odds of resistance to NNRTI and NRTI class drugs, as well as MDR to NNRTI and NRTI drugs; however, they had higher odds of resistance to PI class drugs.
Comparing treatment outcomes between patients initiating lamivudine-based ART before and since 2008 Table 3 presents the unadjusted and adjusted effects of treatment initiation year (since versus before 2008) on the odds of poor adherence, virological failure and drug resistance among patients who initiated with lamivudine-based ART regimens. Interestingly, we observe no significant effect in all three treatment outcome measures. Those who initiated lamivudinebased ART since 2008 did not have lower odds of having missed doses in the past month (AOR, 0.72; 95% CI, 0.48 – 1.08),
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Received ART before 2008 1431
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Table 1. General characteristics of Chinese patients who initiated first-line ART before and since 2008 Number starting treatment (%) didanosine-based ART before 2008
lamivudine-based ART before 2008
lamivudine-based ART since 2008
Total, n (%)
Total
2252
845
586
821
Age (years) ,40 ≥40
1180 (52.4) 1072 (47.6)
406 (48.0) 439 (52.0)
373 (63.7) 213 (36.3)
401 (48.8) 420 (51.2)
,0.01
Ethnicity Han majority other minorities
2100 (93.3) 152 (6.7)
780 (92.3) 65 (7.7)
563 (96.1) 23 (3.9)
757 (92.2) 64 (7.8)
,0.01
Sex male female
1331 (59.1) 921 (40.9)
413 (48.9) 432 (51.1)
345 (58.9) 241 (41.1)
573 (69.8) 248 (30.2)
,0.01
Years of education ≤6 .6
963 (42.8) 1289 (57.2)
492 (58.2) 353 (41.8)
236 (40.3) 350 (59.7)
235 (28.6) 586 (71.4)
,0.01
Marital status married other
1665 (73.9) 587 (26.1)
674 (79.8) 171 (20.2)
440 (75.1) 146 (24.9)
551 (67.1) 270 (32.9)
,0.01
Occupation farmer other
968 (43.0) 1284 (57.0)
504 (59.6) 341 (40.4)
270 (46.1) 316 (53.9)
194 (23.6) 627 (76.4)
,0.01
929 (41.3)
621 (73.5)
140 (23.9)
168 (20.5)
947 (42.1) 322 (14.3) 54 (2.4)
144 (17.0) 64 (7.6) 16 (1.9)
279 (47.6) 162 (27.6) 5 (0.9)
524 (63.8) 96 (11.7) 33 (4.0)
,0.01
12 (1.4) 17 (2.0) 38 (4.5) 22 (2.6) 756 (89.5)
13 (2.2) 92 (15.7) 335 (57.2) 131 (22.4) 15 (2.6)
51 (6.2) 178 (21.7) 426 (51.9) 166 (20.2) —
,0.01
Route of HIV infection blood/plasma transmission sexual intercourse intravenous drug use other
P value
3
CD4 count before ART (cells/mm ) ≥350 76 (3.4) 200–349 287 (12.7) 50– 199 799 (35.5) 0 –49 319 (14.2) missing 771 (34.2)
virological failure (AOR, 0.96; 95% CI, 0.68 –1.34) or HIVDR (AOR, 1.22; 95% CI, 0.77 –1.94). The odds of HIVDR were also not significantly different for all drug classes (NNRTI, NRTI, PI and MDR to NNRTI and NRTI).
Discussion In this study, we assessed the effects of the 2008 scale-up and policy changes in China’s NFATP on ART adherence, virological outcomes and acquired HIVDR. We found that virological failure at 12 – 15 months of treatment improved from 26.6% in patients who initiated ART before 2008, to 12.1% in those who initiated since 2008. Similarly, HIVDR rates in patients who initiated ART since 2008 were significantly decreased. However, our analysis also showed that the reductions in virological failure and HIVDR
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since 2008 are strongly associated with the standardized use of lamivudine-based regimens in place of didanosine-based regimens. Patients who initiated lamivudine-based regimens before 2008 showed significant improvements in adherence, virological and HIVDR outcomes compared with those who initiated didanosine-based regimens; meanwhile, among only patients on lamivudine-based regimens, no significant changes were observed between those who initiated before and since 2008. Several observations can be drawn from these data. First, China’s ART programme has been largely successful throughout the scale-up. The virological outcomes before and since 2008 have met the WHO recommended ART targets for middle- and lower-income countries at the ‘fair’ grade (70% – 85% success) and ‘excellent’ grade (≥85% success), respectively,22,31 supporting previous arguments that these targets be revised upwards.32
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Factor
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Table 2. Adherence, virological outcomes and drug resistance in Chinese patients who initiated first-line ART before 2008 Number (%) Factors
didanosine-based ART lamivudine-based ART
OR, lamivudine-based/ didanosine-based (95% CI)
P value
AOR, lamivudine-based/ didanosine-based (95% CI)
P value
845
586
Missed doses in the past montha
102 (12.1)
46 (7.8)
0.62 (0.43–0.89)
0.01
0.65 (0.45– 0.96)
0.03
HIV RNA ≥1000 copies/mLb
302 (35.7)
79 (13.5)
0.28 (0.21–0.37)
,0.01
0.29 (0.22– 0.39)
,0.01
HIVDRb overall NNRTI NRTI PI MDR to NNRTI and NRTI
178 (21.1) 173 (20.5) 97 (11.5) 4 (0.5) 94 (11.1)
43 (7.3) 43 (7.3) 31 (5.3) 10 (1.7) 31 (5.3)
0.30 (0.21–0.42) 0.31 (0.22–0.44) 0.43 (0.28–0.66) 3.65 (1.14–11.69) 0.45 (0.29–0.68)
,0.01 ,0.01 ,0.01 0.03 ,0.01
0.29 (0.20– 0.42) 0.29 (0.20– 0.42) 0.46 (0.30– 0.69) 4.00 (1.36– 11.80) 0.45 (0.29– 0.69)
,0.01 ,0.01 ,0.01 0.01 ,0.01
a
Adjusted for: age, ethnicity, education, sex, marital status, occupation and route of HIV transmission. Adjusted for: age, ethnicity, education, sex, marital status, occupation, route of HIV transmission and missed doses in the past month.
b
Table 3. Adherence, virological outcomes and drug resistance in Chinese patients who initiated lamivudine-based first-line ART Number (%) initiated before 2008
Factors Total
586 a
Missed doses in the past month b
HIV RNA ≥1000 copies/mL
initiated since 2008
OR, before 2008/since 2008 (95% CI)
P value
AOR, before 2008/since 2008 (95% CI)
P value
821
46 (7.8)
82 (10.0)
0.77 (0.53–1.12)
0.17
0.72 (0.48– 1.08)
0.11
79 (13.5)
99 (12.1)
1.14 (0.83–1.56)
0.43
0.96 (0.68– 1.34)
0.80
43 (7.3) 43 (7.3) 31 (5.3) 10 (1.7) 31 (5.3)
44 (5.4) 36 (4.4) 38 (4.6) 24 (2.9) 31 (3.8)
1.4 (0.91–2.16) 1.73 (1.09–2.73) 1.15 (0.71–1.87) 0.58 (0.27–1.22) 1.42 (0.86–2.37)
0.13 0.02 0.57 0.15 0.17
1.22 (0.77– 1.94) 0.94 (0.62– 1.43) 1.10 (0.67– 1.80) 0.57 (0.27– 1.18) 1.22 (0.72– 2.10)
0.39 0.77 0.71 0.13 0.46
b
HIVDR overall NNRTI NRTI PI MDR to NNRTI and NRTI a
Adjusted for: age, ethnicity, education, sex, marital status, occupation and route of HIV transmission. Adjusted for: age, ethnicity, education, sex, marital status, occupation, route of HIV transmission and missed doses in the past month.
b
Second, the fact that improvements in treatment outcomes were largely attributable to the replacement of didanosine-based regimens with lamivudine-based regimens validates the standardization of the latter’s use in the second edition of the National Free ART Guideline.20 Evidence from a large-scale randomized controlled trial in southern Africa has also shown lamivudine-based regimens to yield better treatment outcomes than didanosinebased regimens.33 However, excluding the effect of lamivudine, treatment outcomes and adherence did not improve following scale-up and standardization. As the number of patients treated through the NFATP continues to increase, the number of persons at risk for treatment failure and acquired HIVDR also rises. It is therefore crucial for the NFATP to emphasize improved quality of care in its next phases of implementation. A more detailed examination may reveal points of interest in quality improvement. Among the 821 patients who initiated lamivudine-based ART since 2008, the rate of virological failure was 7.8% in those infected through sexual routes, 19.6% in
those infected through blood/plasma routes and 20.8% in injecting drug users (IDUs; data not shown). IDUs are known to have lower ART adherence and increased virological failure.25,27 Also, IDUs and those infected through blood/plasma routes in China are more likely to inhabit rural or lower-income areas, where the physical and human infrastructure for healthcare is scarcer.26 It is therefore important for the NFATP to invest in greater training and support for rural healthcare providers, and to better integrate ART with IDU-oriented programmes such as methadone-replacement clinics, which have been shown to improve patient follow-up and adherence as well as reducing the incidence of blood-borne and sexually transmitted infections.34 Third, the HIVDR mutations identified in our study were consistent with expected mutation patterns from first-line ART regimens based on NRTI and NNRTI class drugs. The great majority of HIVDR cases observed were likely to be acquired HIVDR as opposed to transmitted, since HIVDR prevalence among ART-naive patients was observed to be very low in a national
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Funding This study was supported by grants from the Ministry of Science and Technology of China (2012ZX10001-002 and 2009DFB30420), a Chinese State Key Laboratory for Infectious Disease development grant (2012SKLID103) and the International Development Research Center of Canada (grant #104519-010). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Transparency declarations None to declare.
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Author contributions H. X., Y. R., L. L. and Y. S. were responsible for study design and planning. H. X., Y. R., J. H. H. and Y. S. contributed to writing the report. Y. R., W. K., L. L., X. L., J. W. and C. H. contributed to data analysis. H. X., Y. R., J. H. H., L. L. and Y. S. contributed to interpretation. H. X., Y. R., W. K., L. L., X. L., J. W. and C. H. contributed to data collection and cleaning. All authors read and approved the final version of the paper.
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survey.29,35 In addition, the prevalence of drug resistance to PIs is low, which supports their continued use as second-line therapy in China. However, lamivudine-based regimens appear to be associated with greater prevalence of PI-resistance mutations (Table 2), and that prevalence has increased since 2008, although not statistically significantly (Table 3). While this may be attributable simply to the concurrent increase in PI use since 2008, further monitoring is required to see if the trend continues and to clarify its causes. Our study has several limitations. First, consecutive sampling was used to recruit eligible participants at the HIVDR sentinel sites, which may not be fully representative of all of China geographically. Second, patients who terminated treatment (due to adverse reactions, loss to follow-up or death) within the first 12 months would not have been sampled, which may have led to overestimated treatment effectiveness. Third, adherence was assessed by self-reporting of having missed doses in the past month, which may not reflect true adherence. Fourth, although multivariate modelling has controlled for demographic characteristics, differences in age, ethnicity, education, sex, marital status, occupation and route of HIV transmission between the main analysis subgroups suggest the possibility of selection bias that may have led to overestimation of treatment effects. Along similar lines, a large proportion of didanosine initiators began treatment during the earlier years of the NFATP, when baseline CD4 cell count was not required (Table 1) and standards of care and follow-up were lower. This may have contributed to the poorer treatment outcomes among didanosine initiators. Finally, although recommended by WHO guidelines, a 12 – 15 month treatment period is relatively short for the purposes of monitoring acquired HIVDR, and long-term monitoring will provide more insight on HIVDR-related outcomes and factors. However, these limitations should not affect our conclusion on the changes in adherence, virological outcomes and drug resistance in Chinese HIV patients following the 2008 NFATP scale-up and standardization. To our knowledge, this is the first large-scale study evaluating the outcomes of ART during a rapid programme scale-up. Our results provide evidence to guide policymakers in improving training for healthcare providers and enhancing patient education on ART adherence. Recently, China’s HIV control and prevention efforts have also initiated ART-as-prevention programmes in key at-risk populations. Further monitoring of treatment outcomes is needed to elucidate the determinants of long-term programme success.
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