Journal of Clinical Virology 60 (2014) 154–160
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
The prevalence of antiretroviral multidrug resistance in highly active antiretroviral therapy-treated patients with HIV/AIDS between 2004 and 2009 in South Korea Ju-yeon Choi, Oh-Kyung Kwon, Byeong-Sun Choi, Mee-Kyung Kee, Mina Park, Sung Soon Kim ∗ Division of AIDS, Department of Immunology and Pathology, National Institute of Health South Korea, The Korea Centers for Disease Control and Prevention, Republic of Korea
a r t i c l e
i n f o
Article history: Received 22 November 2013 Received in revised form 20 January 2014 Accepted 12 February 2014 Keywords: Genotypic drug resistance assay Multidrug resistance HAART-experienced South Korea
a b s t r a c t Background: Highly active antiretroviral therapy (HAART) including protease inhibitors (PIs) has been used in South Korea since 1997. Currently, more than 20 types of antiretroviral drugs are used in the treatment of human immunodeficiency virus-infected/acquired immune deficiency syndrome patients in South Korea. Despite the rapid development of various antiretroviral drugs, many drug-resistant variants have been reported after initiating HAART, and the efficiency of HAART is limited by these variants. Objectives: To investigate and estimate the annual antiretroviral drug resistance and prevalence of antiretroviral multi-class drug resistance in Korean patients with experience of treatment. Study design: The amplified HIV-1 pol gene in 535 patients requested for genotypic drug resistance testing from 2004 to 2009 by the Korea Centers for Disease Control and Prevention was sequenced and analyzed annually and totally. The prevalence of antiretroviral drug resistance was estimated based on “SIR” interpretation of the Stanford sequence database. Results: Of viruses derived from 787 specimens, 380 samples (48.3%) showed at least one drug classrelated resistance. Predicted NRTI drug resistance was highest at 41.9%. NNRTI showed 27.2% resistance with 23.3% for PI. The percent of annual drug resistance showed similar pattern and slightly declined except 2004 and 2005. The prevalence of multi-class drug resistance against each drug class was: NRTI/NNRTI/PI, 9.8%; NRTI/PI, 21.9%; NNRTI/PI, 10.4%; and NRTI/NNRTI, 21.5%. Conclusions: About 50% and less than 10% of patients infected with HIV-1 have multidrug and multiclass resistance linked to 16 antiretroviral drugs, respectively. The significance of this study lies in its larger-scale examination of the prevalence of drug-resistant variants and multidrug resistance in HAART-experienced patients in South Korea. © 2014 Elsevier B.V. All rights reserved.
1. Background Although the mortality and morbidity of patients with human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) have been dramatically decreased because of highly active antiretroviral therapy (HAART), problems related to antiretroviral drug resistance still arise [1,2]. Moreover, the appearance of many drug-resistant HIV-1 variants involving major and
∗ Corresponding author at: Division of AIDS, Department of Immunology and Pathology, National Institute of Health South Korea, The Korea Centers for Disease Control and Prevention, 187 Osongsaengmyeong2-ro, Osong-eup, Cheongwon-gun, Chungbuk, 363-951, Republic of Korea. Tel.: +82 43 719 8410; fax: +82 43 719 8459. E-mail addresses: [email protected], [email protected] (S.S. Kim). http://dx.doi.org/10.1016/j.jcv.2014.02.004 1386-6532/© 2014 Elsevier B.V. All rights reserved.
minor mutation of target genes has resurfaced as the main obstacle to effective HAART. More than 30 commercial US FDA-approved antiretroviral drugs are used worldwide in the treatment of HIV-infected patients [3]. In South Korea, HAART was commenced with the introduction of zidovudine, alone or in a combination of two nucleoside analog NRTIs, in the late 1990s [4–6]. In particular, HAART containing protease inhibitors (PIs) has been used in South Korea since 1997 [7]. In South Korea, the formal cumulative number of HIV-infected patients was reported as 6881 from 1985 to 2009 (Korea Centers for Disease Control and Prevention). It has been reported that the transmission route for the majority of patients is heterosexual or homosexual contact. Public health centers have operated an HIV/AIDS patient management and care program since HIV was first known to be introduced in Korea in the mid-1980s.
J.-y. Choi et al. / Journal of Clinical Virology 60 (2014) 154–160
Approximately 16 antiretroviral drugs have been used including 6 PIs (indinavir, ritonavir, nelfinavir, saquinavir, Kaletra and atazanavir), 7 nucleoside reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, and tenofovir disoproxil fumarate) and 3 non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine, and efavirenz) [8]. And, about 60 hospitals treat patients to monitor disease progression in South Korea [8]. To predict drug resistance, an HIV-target sequence-based genotyping assay is widely recommended as a standard to predict drug-resistant strains in clinical practice [9]. In South Korea, genotypic drug resistance assaying as requested by several hospitals was commenced without charge from July 2004, beginning by monitoring the national prevalence of HIV-1 drug-resistant variants in drug-naïve patients since 1999. Eight hospitals first began genotypic drug resistance assays in 2004; 58 hospitals subsequently requested the assay in 2009. Since 2006, the antiretroviral drug resistance assay is conducted before and after HAART on the decision of each patient’s physician, while only patients with assumed treatment failure were tested by the Korea National Institute of Health from 2004 to early 2005. Few studies on the prevalence of drug resistance using largescale populations have been found in the literature compared with drug resistance-related studies focusing on patients with treatment experience using small-scale populations in South Korea. Currently, multiclass resistance is a matter of great concern in HIV/AIDS treatment worldwide [10,11].
155
antiretroviral drug resistance-related mutations, focusing on the HIV-1 pol gene, were investigated in 535 patients with treatment experience, whose physicians had requested antiretroviral drug resistance testing by the KNIH, KCDC from 2004 through 2009. 3. Study design 3.1. Study population and HIV-1 RNA extraction Specimens from 535 HAART-experienced patients, who had a genotypic antiretroviral drug resistance test from 2004 to 2009 in the KNIH, KCDC were included in this analysis. During the 6 years, 787 specimens were collected from the HAART-experienced patients and tested; 16 tests in 2004, 55 tests in 2005, 146 tests in 2006, 151 tests in 2007, 206 tests in 2008, and 213 tests in 2009. HIV-1 RNA was extracted using an Abbott m2000sp automated sample preparation system (m2000sp; Abbott Molecular, Des Plaines, IL, USA). Subsequently, the extracted HIV-1 RNA was used for a genotypic assay. The data were anonymized before analysis and all indications were converted into designated labels at the KCDC. 3.2. Data analysis by categorized groups To assess the interrelationship between drug resistance and the approximate treatment period after the year of diagnosis, the 787 specimens from the 535 patients with experience of HAART were classified into three groups according to the year of HIV infection diagnosis as follows: group I (1990–1996, n = 55, 92 cases), group II (1997–2003, n = 207, 344 cases), and group III (2004–2009, n = 273, 351 cases). The criteria for ranges were determined by the use of HAART since 1997 and commencement of antiretroviral drug resistance testing in 2004 in South Korea.
2. Objectives The purpose of this study was to estimate the annual prevalence of predicted drug resistance and multi-class drug resistance in HAART-experienced patients in South Korea. Moreover,
Table 1 Demographic characteristics of patients with experience of HAART requested for antiretroviral drug resistance testing by the KNIH from 2004 to 2009 (n = 787). Characteristics
Person (no. of cases) b
Sex, total n (%) Male Female Unknown
Subtype, person (cases) B Non-B
Treatment-experienced patients (n = 535, 787 cases) Categorya Group I (1990–1996)
Group II (1997–2003)
Group III (2004–2009)
Total (1990–2009)
55 (92)
207 (344)
273 (351)
535 (787)
55 53 2 0
207 198 9 0
273 246 23 4
535 497 34 4
52 (86) 3 (6)
194 (312) 15 (32)
252 (325) 21 (26)
498 (723) 39 (64)
Age (years) Median Range
41 22–56
Transmission risk category Heterosexual contact Homosexual contact Blood transfusion Unidentified
24 20 4 7
116 85 0 6
129 113 0 31
269 218 4 44
Plasma HIV RNA level Mean log copies/mL No. of tested Range
5.2 92 1.8–6.3
5.3 344 3.0–6.5
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
The prevalence of antiretroviral multidrug resistance in highly active antiretroviral therapy-treated patients with HIV/AIDS between 2004 and 2009 in South Korea Ju-yeon Choi, Oh-Kyung Kwon, Byeong-Sun Choi, Mee-Kyung Kee, Mina Park, Sung Soon Kim ∗ Division of AIDS, Department of Immunology and Pathology, National Institute of Health South Korea, The Korea Centers for Disease Control and Prevention, Republic of Korea
a r t i c l e
i n f o
Article history: Received 22 November 2013 Received in revised form 20 January 2014 Accepted 12 February 2014 Keywords: Genotypic drug resistance assay Multidrug resistance HAART-experienced South Korea
a b s t r a c t Background: Highly active antiretroviral therapy (HAART) including protease inhibitors (PIs) has been used in South Korea since 1997. Currently, more than 20 types of antiretroviral drugs are used in the treatment of human immunodeficiency virus-infected/acquired immune deficiency syndrome patients in South Korea. Despite the rapid development of various antiretroviral drugs, many drug-resistant variants have been reported after initiating HAART, and the efficiency of HAART is limited by these variants. Objectives: To investigate and estimate the annual antiretroviral drug resistance and prevalence of antiretroviral multi-class drug resistance in Korean patients with experience of treatment. Study design: The amplified HIV-1 pol gene in 535 patients requested for genotypic drug resistance testing from 2004 to 2009 by the Korea Centers for Disease Control and Prevention was sequenced and analyzed annually and totally. The prevalence of antiretroviral drug resistance was estimated based on “SIR” interpretation of the Stanford sequence database. Results: Of viruses derived from 787 specimens, 380 samples (48.3%) showed at least one drug classrelated resistance. Predicted NRTI drug resistance was highest at 41.9%. NNRTI showed 27.2% resistance with 23.3% for PI. The percent of annual drug resistance showed similar pattern and slightly declined except 2004 and 2005. The prevalence of multi-class drug resistance against each drug class was: NRTI/NNRTI/PI, 9.8%; NRTI/PI, 21.9%; NNRTI/PI, 10.4%; and NRTI/NNRTI, 21.5%. Conclusions: About 50% and less than 10% of patients infected with HIV-1 have multidrug and multiclass resistance linked to 16 antiretroviral drugs, respectively. The significance of this study lies in its larger-scale examination of the prevalence of drug-resistant variants and multidrug resistance in HAART-experienced patients in South Korea. © 2014 Elsevier B.V. All rights reserved.
1. Background Although the mortality and morbidity of patients with human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) have been dramatically decreased because of highly active antiretroviral therapy (HAART), problems related to antiretroviral drug resistance still arise [1,2]. Moreover, the appearance of many drug-resistant HIV-1 variants involving major and
∗ Corresponding author at: Division of AIDS, Department of Immunology and Pathology, National Institute of Health South Korea, The Korea Centers for Disease Control and Prevention, 187 Osongsaengmyeong2-ro, Osong-eup, Cheongwon-gun, Chungbuk, 363-951, Republic of Korea. Tel.: +82 43 719 8410; fax: +82 43 719 8459. E-mail addresses: [email protected], [email protected] (S.S. Kim). http://dx.doi.org/10.1016/j.jcv.2014.02.004 1386-6532/© 2014 Elsevier B.V. All rights reserved.
minor mutation of target genes has resurfaced as the main obstacle to effective HAART. More than 30 commercial US FDA-approved antiretroviral drugs are used worldwide in the treatment of HIV-infected patients [3]. In South Korea, HAART was commenced with the introduction of zidovudine, alone or in a combination of two nucleoside analog NRTIs, in the late 1990s [4–6]. In particular, HAART containing protease inhibitors (PIs) has been used in South Korea since 1997 [7]. In South Korea, the formal cumulative number of HIV-infected patients was reported as 6881 from 1985 to 2009 (Korea Centers for Disease Control and Prevention). It has been reported that the transmission route for the majority of patients is heterosexual or homosexual contact. Public health centers have operated an HIV/AIDS patient management and care program since HIV was first known to be introduced in Korea in the mid-1980s.
J.-y. Choi et al. / Journal of Clinical Virology 60 (2014) 154–160
Approximately 16 antiretroviral drugs have been used including 6 PIs (indinavir, ritonavir, nelfinavir, saquinavir, Kaletra and atazanavir), 7 nucleoside reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, and tenofovir disoproxil fumarate) and 3 non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine, and efavirenz) [8]. And, about 60 hospitals treat patients to monitor disease progression in South Korea [8]. To predict drug resistance, an HIV-target sequence-based genotyping assay is widely recommended as a standard to predict drug-resistant strains in clinical practice [9]. In South Korea, genotypic drug resistance assaying as requested by several hospitals was commenced without charge from July 2004, beginning by monitoring the national prevalence of HIV-1 drug-resistant variants in drug-naïve patients since 1999. Eight hospitals first began genotypic drug resistance assays in 2004; 58 hospitals subsequently requested the assay in 2009. Since 2006, the antiretroviral drug resistance assay is conducted before and after HAART on the decision of each patient’s physician, while only patients with assumed treatment failure were tested by the Korea National Institute of Health from 2004 to early 2005. Few studies on the prevalence of drug resistance using largescale populations have been found in the literature compared with drug resistance-related studies focusing on patients with treatment experience using small-scale populations in South Korea. Currently, multiclass resistance is a matter of great concern in HIV/AIDS treatment worldwide [10,11].
155
antiretroviral drug resistance-related mutations, focusing on the HIV-1 pol gene, were investigated in 535 patients with treatment experience, whose physicians had requested antiretroviral drug resistance testing by the KNIH, KCDC from 2004 through 2009. 3. Study design 3.1. Study population and HIV-1 RNA extraction Specimens from 535 HAART-experienced patients, who had a genotypic antiretroviral drug resistance test from 2004 to 2009 in the KNIH, KCDC were included in this analysis. During the 6 years, 787 specimens were collected from the HAART-experienced patients and tested; 16 tests in 2004, 55 tests in 2005, 146 tests in 2006, 151 tests in 2007, 206 tests in 2008, and 213 tests in 2009. HIV-1 RNA was extracted using an Abbott m2000sp automated sample preparation system (m2000sp; Abbott Molecular, Des Plaines, IL, USA). Subsequently, the extracted HIV-1 RNA was used for a genotypic assay. The data were anonymized before analysis and all indications were converted into designated labels at the KCDC. 3.2. Data analysis by categorized groups To assess the interrelationship between drug resistance and the approximate treatment period after the year of diagnosis, the 787 specimens from the 535 patients with experience of HAART were classified into three groups according to the year of HIV infection diagnosis as follows: group I (1990–1996, n = 55, 92 cases), group II (1997–2003, n = 207, 344 cases), and group III (2004–2009, n = 273, 351 cases). The criteria for ranges were determined by the use of HAART since 1997 and commencement of antiretroviral drug resistance testing in 2004 in South Korea.
2. Objectives The purpose of this study was to estimate the annual prevalence of predicted drug resistance and multi-class drug resistance in HAART-experienced patients in South Korea. Moreover,
Table 1 Demographic characteristics of patients with experience of HAART requested for antiretroviral drug resistance testing by the KNIH from 2004 to 2009 (n = 787). Characteristics
Person (no. of cases) b
Sex, total n (%) Male Female Unknown
Subtype, person (cases) B Non-B
Treatment-experienced patients (n = 535, 787 cases) Categorya Group I (1990–1996)
Group II (1997–2003)
Group III (2004–2009)
Total (1990–2009)
55 (92)
207 (344)
273 (351)
535 (787)
55 53 2 0
207 198 9 0
273 246 23 4
535 497 34 4
52 (86) 3 (6)
194 (312) 15 (32)
252 (325) 21 (26)
498 (723) 39 (64)
Age (years) Median Range
41 22–56
Transmission risk category Heterosexual contact Homosexual contact Blood transfusion Unidentified
24 20 4 7
116 85 0 6
129 113 0 31
269 218 4 44
Plasma HIV RNA level Mean log copies/mL No. of tested Range
5.2 92 1.8–6.3
5.3 344 3.0–6.5
