Ju-yeon Choi

National survey for drug-resistant variants in newly diagnosed antiretroviral drug-naive patients with HIV/AIDS in South Korea: 1999-2005.

We investigated the prevalence of drug-resistant variants and assessed their severity against antiretroviral drugs among patients in South Korea. Three hundred antiretroviral drug-naive patients were collected and drug-resistant variants were analyzed using the Stanford database with sequences and mutation data of the HIV-1 genes for protease (codons 1-99) and reverse transcriptase (codons 1-250). Of this group, 199 isolates (66.3%) showed at least 1 or more sites related to drug resistance. However, the average prevalence of drug resistance for patients newly diagnosed with HIV-1 but still treatment-naive between 1999 and 2005 was very low (4.3%, by “SIR” interpretation) compared with other countries. Most of the newly infected patients carried HIV subtype B (96%, n = 288) based on phylogenetic analysis of the conserved pol region. In summary, there has been no significant increase in the prevalence of drug resistance among antiretroviral drug-naive patients infected with HIV-1 for the last 7 years in South Korea. This study is quite significant regarding its larger scale of prevalence study for drug-resistant variants comparing to other drug-resistant studies using small scale of populations in South Korea. It is also important to provide suitable guidelines of genotyping assays for Korean drug-naive patients.

Evaluation of the NucliSens EasyQ HIV-1 v1.1 and RealTime HIV-1 kits for quantitation of HIV-1 RNA in plasma

Human immunodeficiency virus type-1 (HIV-1) RNA viral load is an important biomarker to evaluate the therapeutic efficacy of antiretroviral drugs and to monitor disease progression in HIV-infected individuals. We compared HIV-1 RNA quantitation between two different kits, the NucliSens EasyQ HIV-1 v1.1 (EasyQ, bioMérieux) and RealTime HIV-1 (RealTime, Abbott), using HIV-1 RNA quality control (QC) materials, cell-cultivated viruses, and the plasma samples of 104 patients with HIV. Correlation between the two kits for HIV RNA-1 quantitation with clinical samples was high (R=0.91). Based on results obtained with quality control standards, the reproducibility of the RealTime kit was higher than the EasyQ kit: the viral load value and coefficient of variation of each kit was 4.11+/-0.136 and 3.3% for EasyQ and 3.55+/-0.042 and 1.2% for RealTime, respectively (P<0.002). This is the first comparative analysis of the detection limit and reproducibility of two different quantitation kits using clinical plasma samples from Korean HIV-1-infected patients. It will serve a useful reference to determine correction values for each HIV-1 RNA quantitation kits and to choose an appropriate assay kit for each laboratory.

Trend of CD4+ Cell Counts at Diagnosis and Initiation of Highly Active Antiretroviral Therapy (HAART): Korea HIV/AIDS Cohort Study, 1992-2015

Background CD4+ cell counts reflect immunologic status of human immunodeficiency virus (HIV) patients. Recommended CD4+ cell counts for the initiation of highly active antiretroviral therapy (HAART) has increased over the past several years in various HIV treatment guidelines. We investigated the trend of CD4+ cell counts at diagnosis and treatment start using data from the Korea HIV/acquired immune deficiency syndrome (AIDS) Cohort Study. Materials and Methods The Korea HIV/AIDS Cohort Study started in 2006 and enrolled HIV patients from 21 tertiary and secondary hospitals in South Korea. The data for CD4+ cell counts at diagnosis and HAART initiation from these HIV patients were analyzed by three-year time intervals and presented by number of CD4+ cells (≤100, 101-200, 201-350, 351-500 and >500 cells/mm3). The HIV-RNA titer at diagnosis and HAART initiation were presented by 3-year intervals by groups ≤50,000, 50,001-100,000, 100,001-200,000, 200,001-1,000,000, and >1,000,000 copies/mL. Results Median values of CD4+ cell count and HIV-RNA titer at initial HIV diagnosis were 247 cells/mm3 and 394,955 copies/mL, respectively. At time of initiating HAART, median values of CD4+ cell count and HIV-RNA were 181 cells/mm3 and 83,500 copies/mL, respectively. Patients with low CD4+ cell count (CD4+ cell count ≤200 cells/mm3) at diagnosis (31-51%) and initiation of HAART accounted for the largest proportion (30-65%) over the three-year time intervals. This proportion increased until 2010-2012. Conclusion CD4+ cell count at initiation of HAART was found to be very low, and the increase in late initiation of HAART in recent years is of concern. We think that this increase is primarily due to an increasing proportion of late presenters. We recommend early detection of HIV patients and earlier start of HAART in order to treat and prevent spread of HIV infection.

The prevalence of antiretroviral multidrug resistance in highly active antiretroviral therapy-treated patients with HIV/AIDS between 2004 and 2009 in South Korea

BACKGROUNDnHighly 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.nnnOBJECTIVESnTo investigate and estimate the annual antiretroviral drug resistance and prevalence of antiretroviral multi-class drug resistance in Korean patients with experience of treatment.nnnSTUDY DESIGNnThe 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.nnnRESULTSnOf viruses derived from 787 specimens, 380 samples (48.3%) showed at least one drug class-related 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%.nnnCONCLUSIONSnAbout 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.

Infectivity of Homologous Recombinant HIV-1 Pseudo-virus with Reverse Transcriptase Inhibitor-related Mutations from Highly Active Antiretroviral Therapy Experienced Patients.

Objectives In this study, the viral fitness of pseudo-viruses with a drug-resistant site in the reverse transcriptase (RT) region of the genome was investigated. The pseudo-viruses were derived from highly active antiretroviral therapy (HAART)-experienced HIV/AIDS patients. Methods HIV-1 RNA was extracted from the plasma of HAART-experienced (KRB9149, KRB7021, KRC1097) and HAART-naïve (KRC5180, KRC5123) HIV-1 patients. The RT gene from the extracted viral RNA was amplified and the polymerase chain reaction product was cloned from the pHXB2Δ2-261 RT vector. C8166 and TZM-bl cell lines were used as the HIV-1 replication capacity measurement system. To quantify the infectivity of homologous recombinant HIV-1, the infectivity derived from each pseudo-virus was compared with the infectivity of the reference strain HXB2. Results Patient-derived HIV-1 was cotransfected into C8166 cells and the expression level of the p24 antigen was measured. The expression was high in the HIV-1 isolates from patients KRC5180 and KRB9149 and low in patients KRB7021, KRC5123, and KRC1097, when compared with the reference strain. The infectivity of the pseudo-virus measured in TZM-bl cells decreased in the order, reference strain HXB2 > KRC5180 > KRC5123 > KRB9149 > KRB7021 > KRC1097. Conclusion In this study, HIV-1 infectivity of the drug-resistant strain isolated from HAART-experienced patients with HIV/AIDS was found to be lower than the infectivity of the reference strain HXB2. This study provides useful data for the phenotypic susceptibility assay in HAART-experienced patients infected with HIV-1.

Metabolic Complications among Korean Patients with HIV Infection: The Korea HIV/AIDS Cohort Study

Currently, metabolic complications are the most common problem among human immunodeficiency virus (HIV)-infected patients, with a high incidence. However, there have been very few studies regarding metabolic abnormalities published in Asia, especially in Korea. This cross-sectional study was performed to investigate the prevalence of and risk factors for metabolic abnormalities in 1,096 HIV-infected patients of the Korea HIV/AIDS cohort study enrolled from 19 hospitals between 2006 and 2013. Data at entry to cohort were analyzed. As a result, the median age of the 1,096 enrolled subjects was 46 years, and most patients were men (92.8%). The metabolic profiles of the patients were as follows: median weight was 63.8 kg, median body mass index (BMI) was 22.2 kg/m2, and 16.4% of the patients had a BMI over 25 kg/m2. A total of 5.5% of the patients had abdominal obesity (waist/hip ratio ≥ 1 in men, ≥ 0.85 in women). Increased levels of fasting glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were present in 10.4%, 6.0%, 5.5%, and 32.1% of the patients. Decreased high-density lipoprotein (HDL) cholesterol levels were observed in 44.2% of the patients. High systolic blood pressure was present in 14.3% of the patients. In multivariate analysis, high BMI and the use of protease inhibitors (PIs) were risk factors for dyslipidemia in HIV-infected patients. In conclusion, proper diagnosis and management should be offered for the prevalent metabolic complications of Korean HIV-infected patients. Further studies on risk factors for metabolic complications are needed.

Causes of HIV Drug Non-Adherence in Korea: Korea HIV/AIDS Cohort Study, 2006-2015

We aimed to determine the initial adherence of HIV cohort patients to ART (antiretroviral therapy), and reasons for non-adherence. Patients who received ART at the time of enrollment in the Korea HIV/AIDS Cohort were included in this study. Treatment adherence was determined at the baseline interview by self-reported questionnaire. Eight-hundred thirty two HIV-infected patients received ART. Of these, 253 (30.4%) patients skipped ART more than once a month. The most common reason of skipping medication was “simply forgot” (60.4%).

The Prevalence and Risk Factors of Renal Insufficiency among Korean HIV-Infected Patients: The Korea HIV/AIDS Cohort Study

Background Renal disease is one of the leading causes of morbidity and mortality among people infected with human immunodeficiency virus (HIV). However, there are very few published studies about renal insufficiency in HIV-infected persons in Asia, especially in South Korea. Materials and Methods A cross-sectional study was performed to investigate the prevalence and risk factors of renal insufficiency, defined as <60 mL/min/1.73 m2, in subjects in the Korea HIV/AIDS Cohort Study enrolled from 19 institutions between December 2006 and July 2013. Data at entry into the cohort were analyzed. Results Of 454 enrolled subjects, 24 (5.3%) showed renal insufficiency at entry into the cohort. The mean age of patients in the renal insufficiency group was 5.28 years and the majority were male subjects (91.7%). All the patients were receiving antiretroviral agents, mostly protease inhibitor-based regimens (76.4%), for an average of 19 months. In univariate analysis, older age (P = 0.002), diabetes mellitus (DM) (P = 0.0002), unknown route of transmission (P = 0.007), and taking indinavir (P = 0.0022) were associated with renal insufficiency. In multivariable analysis, older age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.03–1.12, P = 0.002], DM [OR 3.03, 95% CI 1.17–7.82, P = 0.022], unknown route of transmission [OR 6.15, 95% CI 1.77–21.33, P = 0.004], and taking indinavir [OR 3.07, 95% CI 1.17–8.05, P = 0.023] were independent risk factors of renal insufficiency. Conclusion The prevalence of renal insufficiency in HIV-infected subjects in this study was relatively low, similar to that in other countries. Aging, DM, and taking indinavir were significantly associated with decreased glomerular filtration rate. Furthermore, unknown route of transmission was an independent risk factor, which was interpreted as a reflection of patient compliance. Further studies on the incidence and risk factors of renal insufficiency during HIV infection using follow-up cohort data are necessary.

The trend of transmitted drug resistance in newly diagnosed antiretroviral-naive HIV/AIDS patients during 1999–2012 in South Korea

BACKGROUNDnThe use of antiretroviral drugs has reduced the mortality and morbidity of patients with HIV/AIDS. More than 20 antiretroviral drugs have been used in patients with HIV/AIDS since zidovudine was first introduced in 1991 in South Korea.nnnOBJECTIVESnTo investigate and estimate the annual prevalence of transmitted drug resistance and drug-resistant variants of HIV-1 in newly diagnosed antiretroviral-naive patients in South Korea during 1999-2012.nnnSTUDY DESIGNnPlasma specimens were collected from 928 antiretroviral-naive patients during 1999-2012. Mutations in the protease and reverse transcriptase sections of the HIV-1 pol gene were identified using the Stanford HIV Drug Resistance Database (Stanford DB).nnnRESULTSnAmong 928 HIV-1 isolates from antiretroviral-naive patients, 45 (4.8%) showed intermediate or resistant drug resistance. The predicted prevalence of drug resistance among isolates was 2.2%, 2.7%, and 0.3% for resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively.nnnCONCLUSIONSnThere was no significant increase in the prevalence of drug resistance among antiretroviral-naive patients infected with HIV-1 during 1999-2012 in South Korea, although there was a slight increase during 2009-2012. The emergence of drug-resistant variants will continue to be monitored by national surveys.

Development of candidate reference reagent for HIV-1 RNA and comparison analysis for different HIV-1 RNA quantitative assay

Abstract Background: Human immunodeficiency virus type-1 (HIV-1) RNA viral load is a surrogate marker that is routinely used to determine indications for, and monitor the effectiveness of HIV-1 treatment. We developed three reagents for potential use in routine quality control of HIV-1 RNA quantitative assays. In this report, we compare the stability of these re-agents in storage and compare their performance in three different HIV-1 RNA quantitative assays. Methods: The candidate reagents were derived from readily available pre-existing reagents and examined for stability at different storage temperatures. They were compared in three commercially available HIV-1 RNA quantitative assays: the Cobas TaqMan HIV-1 Test (Cobas TaqMan), the RealTime HIV-1 Assay (Abbott RealTime), and the NucliSens EasyQ HIV-1 Assay v1.1 (NucliSens EasyQ). Results: The candidate reagent derived from an HIV culture supernatant (candidate CS) was the most stable of the three candidates and showed good reproducibility. Candidate CS yielded the highest HIV-1 titer of the three candidates in the Cobas TaqMan assay and the lowest HIV-1 titer and stability of the three candidates in the NucliSens EasyQ system. Conclusions: The candidate CS is the most appropriate of the three candidate reagents for quantitative testing of HIV-1 RNA. This working reagent should be useful for use in routine calibration for quality control in centers with limited financial resources. The Cobas TaqMan assay tended to yield higher viral load results than the other assays when used with our three candidate reagents.