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      Drug Resistance and Virological Failure among HIV-Infected Patients after a Decade of Antiretroviral Treatment Expansion in Eight Provinces of China

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          Abstract

          Background

          China’s National Free Antiretroviral Treatment Program (NFATP) has substantially increased the survival rate since 2002. However, the emergence of HIV drug resistance (HIVDR) limits the durability and effectiveness of antiretroviral treatment (ART) in at risk patients.

          Method

          A cross-sectional survey was conducted among patients having received a median of 13.9 months of ART in eight provinces in China. Demographic and clinical information was collected, and venous blood was sampled for CD4 cell counts, measurement of the HIV viral load (VL), and HIV drug resistance (HIVDR) genotyping. Possible risk factors for HIVDR were analyzed by the logistic regression model.

          Results

          The study included 765 patients. Among them, 65 patients (8.5%) had virological failure (VLF) defined as ≥1,000 copies/ml. Among the individuals with VLF, 64 were successful genotyped, and of these, 33 had one or more HIVDR mutations. The prevalence of HIVDR mutations among patients receiving first-line ART was 4.3% (33/765). All of the patients with HIVDR mutations were resistant to non-nucleoside transcriptase inhibitors, 81.8% were resistant to nucleoside reverse transcriptase inhibitors, and only 3% had mutations that caused resistance to protease inhibitors. Having lower ratios of drug intake in the past month and dwelling in two southwestern provinces were factors independently associated with the emergence of HIVDR.

          Conclusion

          Most patients receiving first-line ART treatment achieved sound virological and immunological outcomes. However, poor adherence is still a key problem, which has led to the high rate of HIVDR. It was notable that the proportion of drug resistance widely varied among the provinces. More studies are needed to focus on adherence.

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          Most cited references30

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          Effect of earlier initiation of antiretroviral treatment and increased treatment coverage on HIV-related mortality in China: a national observational cohort study.

          Overall HIV mortality rates in China have not been reported. In this analysis we assess overall mortality in treatment-eligible adults with HIV and attempt to identify risk factors for HIV-related mortality. We used data from the national HIV epidemiology and treatment databases to identify individuals aged 15 years or older with HIV who were eligible for highly active antiretroviral therapy between 1985 and 2009. Mortality rates were calculated in terms of person-years, with risk factors determined by Cox proportional hazard regression. Treatment coverage was calculated as the proportion of time that patients who were eligible for treatment received treatment, with risk factors for not receiving treatment identified by use of logistic regression. Of 323,252 people reported as having HIV in China by the end of 2009, 145,484 (45%) were identified as treatment-eligible and included in this analysis. Median CD4 count was 201 cells per μL (IQR 71-315) at HIV diagnosis and 194 cells per μL (73-293) when first declared eligible for treatment. Overall mortality decreased from 39·3 per 100 person-years in 2002 to 14·2 per 100 person-years in 2009, with treatment coverage concomitantly increasing from almost zero to 63·4%. By 2009, mortality was higher and treatment coverage lower in injecting drug users (15·9 deaths per 100 person-years; 42·7% coverage) and those infected sexually (17·5 deaths per 100 person-years; 61·7% coverage), compared with those infected through plasma donation or blood transfusion (6·7 deaths per 100 person-years; 80·2% coverage). The two strongest risk factors for HIV-related mortality were not receiving highly active antiretroviral therapy (adjusted hazard ratio 4·35, 95% CI 4·10-4·62) and having a CD4 count of less than 50 cells per μL when first declared eligible for treatment (7·92, 7·33-8.57). An urgent need exists for earlier HIV diagnosis and better access to treatment for injecting drug users and patients infected with HIV sexually, especially before they become severely immunosuppressed. The National Centre for AIDS/STD Control and Prevention of the Chinese Centre for Disease Control and Prevention. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Five-year outcomes of the China National Free Antiretroviral Treatment Program.

            China's National Free Antiretroviral Treatment Program began in 2002 and, by August 2008, included more than 52 000 patients. To report 5-year outcomes on adult mortality and immunologic treatment failure rates and risk factors. Open cohort analysis of a prospectively collected, observational database. China. All patients in the national treatment database from June 2002 to August 2008. Patients were excluded if they had not started triple therapy or had missing treatment regimen information. Antiretroviral therapy according to Chinese national treatment guidelines. Mortality rate and immunologic treatment failure rate, according to World Health Organization criteria. Of 52 191 patients, 48 785 were included. Median age was 38 years, 58% were men, 53% were infected through plasma or blood, and the median baseline CD4 cell count was 0.118x10(9) cells/L. Mortality was greatest during the first 3 months of treatment (22.6 deaths per 100 person-years) but decreased to a steady rate of 4 to 5 deaths per 100 person-years after 6 months and maintained this rate over the subsequent 4.5 years. The strongest mortality risk factors were a baseline CD4 cell count less than 0.050x10(9) cells/L (adjusted hazard ratio [HR] compared with a count>or=0.200x10(9) cells/L, 3.3 [95% CI, 2.9 to 3.8]) and having 4 to 5 baseline symptom categories (adjusted HR compared with no baseline symptom categories, 3.4 [CI, 2.9 to 4.0]). Treatment failure was determined among 31 070 patients with 1 or more follow-up CD4 cell counts. Overall, treatment failed for 25% of patients (12.0 treatment failures per 100 person-years), with the cumulative treatment failure rate increasing to 50% at 5 years. Immunologic treatment failure does not necessarily correlate well with virologic treatment failure. The National Free Antiretroviral Treatment Program reduced mortality among adult patients in China with AIDS to rates similar to those of other low- or middle-income countries. A cumulative immunologic treatment failure rate of 50% after 5 years, due to the limited availability of second-line regimens, is of great concern.
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              Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America.

              To describe temporal trends in baseline clinical characteristics, initial treatment regimens and monitoring of patients starting antiretroviral therapy (ART) in resource-limited settings. We analysed data from 17 ART programmes in 12 countries in sub-Saharan Africa, South America and Asia. Patients aged 16 years or older with documented date of start of highly active ART (HAART) were included. Data were analysed by calculating medians, interquartile ranges (IQR) and percentages by regions and time periods. Not all centres provided data for 2006 and 2005 and 2006 were therefore combined. A total of 36,715 patients who started ART 1996-2006 were included in the analysis. Patient numbers increased substantially in sub-Saharan Africa and Asia, and the number of initial regimens declined, to four and five, respectively, in 2005-2006. In South America 20 regimes were used in 2005-2006. A combination of 3TC/D4T/NVP was used for 56% of African patients and 42% of Asian patients; AZT/3TC/EFV was used in 33% of patients in South America. The median baseline CD4 count increased in recent years, to 122 cells/microl (IQR 53-194) in 2005-2006 in Africa, 134 cells/microl (IQR 72-191) in Asia, and 197 cells/microl (IQR 61-277) in South America, but 77%, 78% and 51%, respectively, started with <200 cells/microl in 2005-2006. In all regions baseline CD4 cell counts were higher in women than men: differences were 22cells/microl in Africa, 65 cells/microl in Asia and 10 cells/microl in South America. In 2005-2006 a viral load at 6 months was available in 21% of patients Africa, 8% of Asian patients and 73% of patients in South America. Corresponding figures for 6-month CD4 cell counts were 74%, 77% and 81%. The public health approach to providing ART proposed by the World Health Organization has been implemented in sub-Saharan Africa and Asia. Although CD4 cell counts at the start of ART have increased in recent years, most patients continue to start with counts well below the recommended threshold. Particular attention should be paid to more timely initiation of ART in HIV-infected men.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 December 2016
                2016
                : 11
                : 12
                : e0166661
                Affiliations
                [1 ]State Key Laboratory of 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
                [2 ]Sichuan Center for Disease Control and Prevention, Chengdu, China
                [3 ]Guizhou Center for Disease Control and Prevention, Guiyang, China
                [4 ]Vanderbilt Institute for Global Health, Nashville, Tennessee, United States of America
                National and Kapodistrian University of Athens, GREECE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: LL YS YR HX.

                • Data curation: ZZ WK XL.

                • Investigation: SL XS JY.

                • Methodology: LL YS YR HX.

                • Writing – original draft: ZZ SB.

                • Writing – review & editing: ZZ.

                ‡ These authors also contributed equally to this work.

                Article
                PONE-D-16-31160
                10.1371/journal.pone.0166661
                5172524
                27997554
                3f50590c-8f03-4640-ad94-ecc1a2391d80
                © 2016 Zuo et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 August 2016
                : 1 November 2016
                Page count
                Figures: 0, Tables: 3, Pages: 13
                Funding
                This study was supported by grants from the Ministry of Science and Technology of China (2012ZX10001-002), the Chinese State Key Laboratory of Infectious Disease Develop Grant, and the International Development Research Center of Canada (grant #104519-010). The fund providers had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Scottie Bussell contributed to this work during his fellowship, which was supported by National Institutes of Health (NIH) Research Training Grant R25 TW009337, funded by Fogarty International Center, the NIH Office of the Director, and the National institute of Mental Health.
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