JAC Advance Access originally published online on January 28, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):689-693; doi:10.1093/jac/dkn002
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Original research |
Trends of antiretroviral drug resistance in treatment-naive patients with human immunodeficiency virus type 1 infection in Taiwan
1 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan 2 Department of Laboratory Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 3 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
* Correspondence address. Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel: +886-2-23123456 ext. 7552; Fax: +886-2-23707772; E-mail: hcc0401{at}ntu.edu.tw
Received 1 October 2007; returned 21 December 2007; revised 2 November 2007; accepted 1 January 2008
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Abstract |
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Objectives: To determine the prevalence and trends of antiretroviral drug resistance among HIV-1-infected Taiwanese patients who have been provided with free-of-charge antiretroviral therapy (ART) since 1990.
Methods: Blood samples collected from 786 HIV-1-infected patients from 1999 to 2006 were subjected to genotypic resistance assay. Antiretroviral resistance mutations were identified in accordance with the antiretroviral resistance mutation list of the International AIDS Society-USA Consensus Guidelines. Trends of resistance were studied in patients enrolled in two periods: before (period 1, January 1999 to December 2003) and after (period 2, January 2004 to December 2006) the CRF07_BC outbreak among injection drug users (IDUs).
Results: The frequency of HIV-1 isolates harbouring one or more primary mutations associated with antiretroviral resistance to reverse transcriptase inhibitors or protease inhibitors increased significantly from 6.6% in period 1 to 12.7% in period 2 (P = 0.003). A significant increase in prevalence of antiretroviral drug resistance was observed among men who have sex with men and patients infected with HIV subtype B. In multivariate analysis, hepatitis C virus (HCV) exposure, which exhibited collinearity with injection drug use and infection with CRF07_BC, represented a lower risk for infection with resistant viruses.
Conclusions: Our findings suggest that the prevalence of antiretroviral resistance has increased in Taiwan over the past 8 years after the introduction of combination ART. IDUs who were HCV-seropositive and infected with CRF07_BC were at lower risk for infection with antiretroviral-resistant viruses.
Keywords: HIV-1 , antiretroviral therapy , highly active antiretroviral therapy , protease inhibitors , nucleoside reverse transcriptase inhibitors , non-nucleoside reverse transcriptase inhibitors
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Introduction |
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With the widespread use of combination antiretroviral therapy (CART), emergence and transmission of antiretroviral-resistant viruses have been observed in several developed countries.1–4 The prevalence of antiretroviral resistance may vary with study populations, stages of HIV infection and subtypes of HIV-1. Among persons with acute or recent HIV infection in North America, the prevalence of resistance ranged from 8.3% in a cohort study of 10 US cities (1997–2001) to 12.2% in Canada (2000–01), which increased to 24.1% in the US between 2003 and 2004.1–3 In Europe, the prevalence was 10.4% according to the CATCH study of 19 European cities (1996–2002), which remained relatively constant over time.4 Among persons with established HIV infection, the prevalence of resistance was lower than that in patients with primary infection.2,4 To improve the effectiveness of CART, baseline antiretroviral resistance testing is recommended for patients in areas with prevalence of antiretroviral resistance higher than 5%.5 Indeed, baseline antiretroviral resistance testing has been shown to significantly reduce the risk of treatment failure in persons who were infected with resistant viruses.3,6,7
Most of the antiretroviral susceptibility and genotypic resistance profiles are reported in areas where subtype B was the predominant subtype and antiretroviral therapy (ART) was introduced earlier. Information on antiretroviral resistance has been relatively limited for other HIV subtypes circulating in areas with limited access to CART and HIV care, such as subtype C in India, CRF01_AE in Thailand and CRF07_BC/CRF08_BC in China. In Taiwan, subtypes B and CRF01_AE have been the predominant subtypes in homosexual and heterosexual populations, respectively, until the outbreak of CRF07_BC among injection drug users (IDUs), which has accounted for the largest proportion of HIV infection in Taiwan after 2004.8 Although ART containing one or two nucleoside reverse transcriptase inhibitors (NRTIs) and CART containing two NRTIs with protease inhibitor(s) (PIs) or non-NRTI (NNRTI) have been provided without charge to all HIV-1-infected individuals at designated hospitals around Taiwan in 1990 and 1997, respectively, the prevalence of primary antiretroviral resistance remains unknown. Therefore, we aimed to determine the prevalence and trends of antiretroviral resistance from 1999 to 2006 and to identify factors associated with antiretroviral resistance in Taiwan.
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Materials and methods |
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Study population
From 1999 to 2006, blood samples were collected from consecutive HIV-1-infected patients who were antiretroviral-naive and received HIV care at the National Taiwan University Hospital, a major referral hospital for HIV care. A standardized case collection form was used to record data regarding demographics, clinical characteristics and laboratory results, such as plasma HIV RNA load (PVL) and CD4 cell counts. PVL and the CD4 counts were determined as described previously.8 Hepatitis B surface antigen (HBsAg) and hepatitis C antibody were determined using the HBsAg ELISA kit (Abbott Laboratories, Abbott Park, IL, USA) and anti-hepatitis C virus (HCV) ELISA kit (Ax SYM HCV III, Abbott Laboratories, North Chicago, IL, USA), respectively. This study was approved by the Institutional Review Board of the hospital.
Genotypic resistance assay was performed using extracted viral RNA, as described previously.8 Antiretroviral resistance mutations were identified using the HIVdb program of the Stanford University HIV Drug Resistance Database (http://hivdb.stanford.edu; 21 December 2007, date last accessed), in accordance with the drug resistance mutation list of the International AIDS Society-USA Consensus Guidelines.9 Multidrug resistance (MDR) was defined as having genotypic resistance to more than one class of antiretroviral agent.
All statistical analyses were performed using SAS statistical software (Version 8.1, SAS Institute Inc., Cary, NC, USA). Patients enrolled were categorized into two groups according to the time of enrolment: period 1, January 1999 to December 2003 and period 2, January 2004 to December 2006, when an outbreak of HIV-1 infection due to CRF07_BC occurred among IDUs in Taiwan. Temporal changes in antiretroviral resistance were analysed by Fisher's exact test for trends. Categorical variables were compared by 
2 or Fisher's exact test. Non-categorical variables were compared by Student's t-test. To determine the factors associated with infection of resistant viruses, all clinical and laboratory parameters were first tested using univariate analysis. The parameters with a P value less than 0.2 were put into the model of multivariate analysis. A stepwise model comparison and selection were used to determine the final model of multiple variables analysis. All tests were two-tailed and a P value less than 0.05 was considered significant.
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Results |
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Baseline characteristics
Baseline characteristics of the 786 patients enrolled in this study are shown in Table 1. They were predominantly males (93.1%) with a median CD4 count of 248 cells/mm3 (IQR, 56–432) and a PVL of 5.05 log10 copies/mm3 (IQR, 4.54–5.55). Patients enrolled in period 2 were significantly older (P < 0.001) and more likely to be IDUs, females and seropositive for HCV (P < 0.001) than those in period 1. Although subtype B remained the predominant subtype throughout the study periods, its prevalence decreased significantly from period 1 to period 2 (P < 0.001), due to the increase in CRF07_BC isolates among IDUs (P < 0.001).
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Trends of antiretroviral resistance
Of the 786 blood specimens analysed, 74 (9.4%) had one or more primary mutations associated with antiretroviral resistance (Table 1). The overall prevalence of antiretroviral resistance increased from period 1 (6.6%) to period 2 (12.7%) (P = 0.003) (Table 1). The prevalence of antiretroviral resistance to an individual drug class or MDR increased from period 1 to period 2, although only the increase in resistance to PIs was significant (P = 0.005). Between the two study periods, a statistically significant increase in resistance to nelfinavir (4.7-fold increase from 0.94% to 4.42%, P = 0.002) and atazanavir (4.7-fold increase from 0.71% to 3.31%, P = 0.008) was noted.
Clinical characteristics associated with antiretroviral drug resistance
In univariate analysis, we found that CD4 <200 cells/mm3 and HCV seronegativity were statistically significantly associated with infection with resistant viruses (Table 2). When univariate analysis was performed, respectively, in periods 1 and 2, we found that no statistically significant factor was identified in patients enrolled in period 1. In period 2, patients with CD4 <200 cells/mm3 and MSM were at a higher risk of being infected with antiretroviral-resistant viruses; IDUs, patients infected with CRF07_BC or those with HCV seropositivity were at a lower risk of being infected with antiretroviral-resistant viruses (Table 2). In multivariate analysis, because HCV seropositivity, injection drug use and infection with CRF07_BC exhibited collinearity, these parameters were not put in the final model simultaneously. Patients with HCV seropositivity were at a statistically significantly lower risk of being infected with drug-resistant viruses with an adjusted odds ratio of 0.118 (95% CI, 0.016–0.875).
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Discussion |
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This is the first report describing the prevalence of primary drug resistance of CRF07_BC among IDUs. In this study, we found that patients with HCV seropositivity were at significantly lower risk for infection with resistant viruses than those with HCV seronegativity. In Taiwan, HCV seropositivity was highly associated with HIV-1-infected IDUs; the estimated seroprevalence of HCV among HIV-1-infected IDUs was 96.8% (1003/1036), compared with 6.8% (103/1525) of patients infected with HIV by sexual transmission (C.-C. Hung, unpublished results). Therefore, the association of lower antiretroviral resistance with HCV seropositivity may reflect the association of lower antiretroviral resistance with infection with CRF07_BC and IDUs, who were recently infected with HIV and had limited access to HIV care and CART. Continuing surveillance of antiretroviral drug resistance among those IDUs infected with CRF07_BC is indicated when more patients initiate CART with time.
Unlike other reports that have demonstrated a relatively stable prevalence of antiretroviral resistance among subtype B-infected individuals and an increasing prevalence of antiretroviral resistance among non-subtype B-infected individuals,4 the prevalence of antiretroviral resistance in subtype B-infected patients in Taiwan increased significantly from period 1 to period 2 (P = 0.001) and only a modest increase in resistance was observed in non-B subtypes. Also, in our univariate analysis, we identified that MSM had a higher risk of being infected with resistant viruses. These data, along with our observation that some resistant sequences isolated from MSM infected at different time points clustered together (data not shown), suggest that resistant viruses are currently circulating among the MSM population. More effective measures, which can efficiently prevent the spread of resistant viruses among MSM, are urgently required in Taiwan.
There are several limitations of our study and interpretations of the results should be made cautiously. First, our study population may not be representative of the entire HIV-infected population in Taiwan, given the fact that most of the HIV-infected IDUs, which account for 39% of the accumulated cases of HIV infection in Taiwan, were incarcerated or were lost to medical follow-up. Secondly, the date when HIV transmission occurred was not available for most of the patients and we did not perform the detuned assay to determine whether these patients had recent infection or not. Given the observation that most mutant viruses were out-competed by wild-type viruses after removal of ART,10 the prevalence of drug resistance we observed may be underestimated.
In summary, although prevalence of antiretroviral drug resistance in Taiwan is increasing with subtype B as the major subtype harbouring resistant mutations, the prevalence of resistance among the IDUs infected with CRF07_BC remains low since the outbreak of HIV infection in 2004.
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Funding |
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This work was supported by grants (DOH-92-DC-1024 and DOH-93-DC-1019) from the Centers for Disease Control, Department of Health, Taiwan.
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None to declare.
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References |
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