Abstract
The purpose of this study was to assess the prevalence and characteristics of HIV drug resistance mutations among antiretroviral therapy (ART)-naive and ART-experienced patients in South Korea. A total of 50 ART-naive and 34 ART-experienced Korean HIV-1-infected patients who visited an urban hospital from February 2007 to March 2011 were included. Most patients (86.9%) were infected with clade B HIV-1. Six (12%) ART-naive and 22 (64.7%) ART-experienced patients had HIV strains with resistance mutations. Among ART-naive patients, V179D was the most common mutation, being found in five ART-naive patients. Among ART-experienced patients, M184V was the most common mutation. Eight of 34 ART-experienced patients had thymidine analogue mutations (TAMs). The prevalence of drug-resistant HIV-1 in ART-naive patients was higher than in previous reports, and 50% of patients with virologic failure harbored strains with multiple resistance mutations. HIV drug resistance testing should be recommended to guide therapy of ART-naive patients in South Korea.
Although South Korea has a relatively low HIV prevalence of less than 0.03%, HIV/AIDS poses a threat to the public health. The introduction of highly active antiretroviral therapy (HAART) for the treatment of HIV-1 has markedly changed the course of the disease. However, many HIV-1 drug-resistant mutations have been reported, and the efficacy of HAART can be limited.1 Monitoring the prevalence of resistance mutations in populations is important to provide guidelines for antiretroviral therapy (ART) resistance testing. The aim of this study was to determine the prevalence and characteristics of HIV-1 drug resistance mutations in ART-naive and ART-experienced patients in South Korea.
A total of 84 HIV-1-infected individuals who visited a tertiary care hospital in Seoul and underwent genotypic testing for HIV resistance mutations between February 2007 and March 2011 were enrolled. HIV RNA polymerase sequences were obtained using the ViroSeg HIV genotyping system 2.0. The protease (PR) and reverse transcriptase (RT) components of the pol sequences were assembled, aligned to the HXB2 consensus, and manually edited using Bioedit v.7.1.3. HIV subtypes were identified using the REGA subtyping tool v.2.0 (http://dbpartners.stanford.edu/RegaSubtyping/, accessed October 1, 2012). Antiretroviral resistance mutations were analyzed using the Stanford HIV Drug Resistance Database version 4.2.4 (http://sierra2.stanford.edu/sierra/servlet/JSierra?action=sequenceInput/, accessed October 1, 2012). The pol gene sequences of eligible patients were submitted to GenBank as accession numbers KC 120826 through KC 120908. PhyML version 2.4.4 (http://atgc.lirmm.fr/phyml/, accessed October 1, 2012) was used to estimate the maximum likelihood phylogenies of pol sequences.
A total of 50 patients were ART-naive and 34 were ART-experienced. The majority of the patients were male (76/84, 90.4%) (Table 1). Seventy-three of 84 (86.9%) patients harbored subtype B viruses. Among the remaining subjects, four (4.7%) carried subtype AE virus, four (4.7%) were subtype AG, and one (1.2%) was subtype C. Phylogenetic analysis of the pol genes revealed distinct clustering according to the subtypes.
Table 1.
Baseline Characteristics of Participants
| Variables | Naive [n=50(%)] | Experienced [n=34(%)] |
|---|---|---|
| Sex | ||
| Male | 47 (94.00) | 29 (85.29) |
| Female | 3 (6.00) | 5 (14.70) |
| Age | 43.94±12.51 | 42.32±10.12 |
| CD4 counts at enrollment (counts/μl) | ||
| <200 | 13 (26.00) | 19 (46.30) |
| 200–350 | 21 (42.00) | 11 (26.80) |
| >350 | 16 (32.00) | 10 (24.40) |
| HIV RNA at enrollment (copies/ml) | 3.71×106 | 1.09×105 |
| Subtype | ||
| B | 45 (90.00) | 28 (82.35) |
| AE | 2 (4.00) | 2 (5.88) |
| AG | 2 (4.00) | 2 (5.88) |
| C | 1 (2.00) | 0 (0.00) |
Data are frequencies and percentages in parentheses, unless otherwise indicated.
Six of 50 (12%) ART-naive participants had resistance mutations for any one class of antiretroviral drugs. The patterns of drug resistance mutations among ART-naive patients differed from those described in previous studies conducted in South Korea. In previous studies of ART-naive patients, protease inhibitor (PI)-related mutations had not been found.2 In our study, one patient (2%) harbored two PI-related mutations, encoding L10I and V71T. In addition, V179D was the most common amino acid change, which was detected in five (10%) ART-naive patients. In previous reports, V179D was more common in Korean patients than Chinese patients (13.6% vs. 0%).3 No nucleoside reverse transcriptase inhibitor (NRTI) mutations were found in ART-naive patients.
The results from ART-experienced patients were also informative. Of 34 ART-experienced patients, 22 (64.7%) harbored at least one resistance mutation. This rate is similar to previous results of 42–71%.4 In South Korea, PI-based regimens were used more commonly as initial antiretroviral therapy than nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.4 In this study, most patients (30/34, 88.2%) were treated with PI-based regimens, and only two (5.8%) were treated with NNRTI-based regimens (Table 2). Details of drug resistance profiles among patients with virologic failure may help clinicians choose secondary drugs for salvage therapy. V82A was the most frequent major PI mutation, being detected in three (8.8%) ART-experienced patients, and was associated with lopinavir resistance. Thirteen (38.2%) patients had mutations that conferred high-level resistance to NRTIs.5 The most commonly detected NRTI resistance mutation was M184V, which conferred resistance to lamivudine (3TC) or emtricitabine (FTC), but could delay or prevent the emergence of thymidine analogue mutations (TAMs).6 Eleven (32.4%) patients had M184V. K103N was the most frequently found resistance mutation associated with NNRTIs (consistent with a previous study7). K103N was found in nine (26.5%) patients, which was closely related to efavirenz resistance and could lead to resistance to all first-generation NNRTIs (Table 3).
Table 2.
Current and Past Antiretroviral Treatment Regimens and Antiretroviral Resistance-Associated Mutations in Each Patient
| |
|
|
HAART regimen |
|
||
|---|---|---|---|---|---|---|
| Patient number | Age (years) | Sex | PI | NRTI | NNRTI | Antiretroviral resistance-associated mutations |
| 1 | 42 | M | NFV | AZT, 3TC | (–) | L10I, V179D |
| 2 | 48 | M | LPV | 3TC, d4T | (–) | None |
| 3 | 33 | M | ATV | 3TC, ddI | (–) | None |
| 4 | 44 | M | IDV | AST, 3TC | (–) | V82A, L10I, M41L, M184V |
| 5 | 46 | M | ATV | ddI, 3TC | (–) | A71AV |
| 6 | 61 | M | LPV | AZT, 3TC | (–) | M46I, L90M, L10I, A71V, T74P, M41L, V75IMV, L210LW, T215FY, K103Q |
| 7 | 22 | F | LPV | AZT, 3TC | (–) | L10I |
| 8 | 72 | F | NFV, ATV, RTV/r | 3TC, ddI, d4T | EFV | M184V, A98G, K103N, P225H, M230L |
| 9 | 38 | M | LPV | AZT, 3TC | EFV | L10I, M184MV |
| 10 | 35 | M | LPV | 3TC, ddI, AZT | (–) | L33F, M184V |
| 11 | 63 | M | LPV | 3TC, ddI | EFV | L74V, M184V |
| 12 | 41 | M | LPV | 3TC, AZT | (–) | None |
| 13 | 32 | M | Medication unidentifiable | None | ||
| 14 | 40 | M | LPV | 3TC, ddI | (–) | K101Q, K103N |
| 15 | 36 | M | LPV | AZT, 3TC | (–) | V106IV, Y188L, P225HP |
| 16 | 56 | M | ATV, LPV | ABV, d4T | (–) | M46IL, G48V, I50V, I54A, V82S, L10I, A71V, M41L, L74V, M184V, L210W, T215Y, K101P, K103S |
| 17 | 35 | M | IDV | AZT, 3TC, ddI, d4T | EFV | L10I, M41L, T215D, K103N, V179D |
| 18 | 31 | F | Medication unidentifiable | M46IM, I54IV, L76LV, V82AV, L10FL, A71AV, G73GS, L89MV, L74LV, M184V, T215AT | ||
| 19 | 50 | M | IDV | 3TC, ddI | EFV | None |
| 20 | 41 | M | LPV | 3TC, AZT, d4T | (–) | L10I, T69S |
| 21 | 48 | M | ATV, IDV | AZT, 3TC | (–) | None |
| 22 | 40 | F | IDV, ATV | 3TC, AZT | EFV | None |
| 23 | 36 | M | ATV, RTV/r | AZT, 3TC | EFV | K103KN, V108IV |
| 24 | 53 | M | IDV, ATV | 3TC, ddI | (–) | L10I |
| 25 | 37 | M | (–) | 3TC, ddI | EFV | A71V, K103KN |
| 26 | 41 | M | ATV, RTV/r | 3TC, d4T, ddI | EFV | M46IM, L10FIL, M184MV, V179D |
| 27 | 37 | M | LPV | AZT, 3TC | (–) | None |
| 28 | 37 | M | LPV | 3TC, ddI | EFV | L10IL, A71AT, M184V, T215Y, K219N, L100I, K103N |
| 29 | 45 | M | LPV | 3TC, ddI | EFV | None |
| 30 | 35 | M | (–) | AZT, 3TC | EFV | A62AGV |
| 31 | 49 | M | LPV | AZT, 3TC | EFV | A71V |
| 32 | 46 | M | LPV | AZT, 3TC | EFV | D67N, K70R, M184V, K103N, P225H |
| 33 | 35 | F | NFV, ATV, RTV/r | 3TC, AZT, d4T, ddI | (–) | V82A, M41LM, L74LV, M184V, V179D |
| 34 | 34 | M | LPV | 3TC, ddI | (–) | K103N |
PI, protease inhibitor; NRTI, nucloside reverse transcriptase inhibitor; NNRTI, nonnucloside reverse transcriptase inhibitor; NFV, nelfinavir; LPV, lopinavir; ATV, atazanavir; IDV, indinavir; RTV/r, ritonavir; 3TC, lamivudine; d4T, stavudine; ddI, didanosine; AZT, zidovudine; EFV, efavirenz; ABV, abacavir.
Table 3.
Prevalence of Antiretroviral Drug Resistance Mutations
|
Mutation |
Experienced (n=50) |
Naive (n=34) |
Mutation |
Experienced (n=50) |
Naive (n=34) |
Mutation |
Experienced (n=50) |
Naive (n=34) |
|---|---|---|---|---|---|---|---|---|
| PI N(%) | NRTI N(%) | NNRTI N(%) | ||||||
| Minor | M41L | 0 | 5 (14.7) | A98G | 0 | 1 (2.9) | ||
| L10I | 1 (2) | 5 (14.7) | M184V | 0 | 11 (32.4) | K103N | 0 | 9 (26.5) |
| A71V | 0 | 3 (8.8) | V75IMV | 0 | 1 (2.9) | P225H | 0 | 3 (8.8) |
| T74P | 0 | 1 (2.9) | T215FY | 0 | 1 (2.9) | M230L | 0 | 1 (2.9) |
| L33F | 0 | 1 (2.9) | L74V | 0 | 2 (5.8) | K101Q | 0 | 1 (2.9) |
| L10FL | 0 | 1 (2.9) | L210W | 0 | 2 (5.8) | V106IV | 0 | 1 (2.9) |
| G73GS | 0 | 1 (2.9) | T215Y | 0 | 2 (5.8) | Y188L | 0 | 1 (2.9) |
| L89MV | 0 | 1 (2.9) | T215D | 0 | 1 (2.9) | K101P | 0 | 1 (2.9) |
| A71T | 1 (2) | 1 (2.9) | L74LV | 0 | 2 (5.8) | K103S | 0 | 1 (2.9) |
| T215AT | 0 | 1 (2.9) | V179D | 5 (10) | 2 (5.8) | |||
| Major | K219N | 0 | 1 (2.9) | L100I | 0 | 1 (2.9) | ||
| V82A | 0 | 3 (8.8) | D67N | 0 | 1 (2.9) | Y188L | 0 | 1 (2.9) |
| M46I | 0 | 2 (5.8) | K70R | 0 | 1 (2.9) | |||
| L90M | 0 | 1 (2.9) | ||||||
| G48V | 0 | 1 (2.9) | ||||||
| I50V | 0 | 1 (2.9) | ||||||
| I54A | 0 | 1 (2.9) | ||||||
| V82S | 0 | 1 (2.9) | ||||||
| M46IM | 0 | 1 (2.9) | ||||||
| I54IV | 0 | 1 (2.9) | ||||||
| L76LV | 0 | 1 (2.9) | ||||||
Data are frequencies and percentages in parentheses, unless otherwise indicated.
Overall, we report here the recent resistance rate and patterns of both ART-naive and ART-experienced patients in South Korea. The prevalence of drug-resistant HIV-1 in ART-naive patients was higher than identified previously, and many Korean HIV-1-infected patients with virologic failure harbored strains with multiple resistance mutations. HIV drug resistance testing should be recommended to guide therapy of ART-naive patients in South Korea.
Acknowledgments
This work was supported by a National Research Foundation of Korea grant (NRF-2011-220-E00015) and a grant by the Chronic Infectious Disease Cohort (4800-4859-304-260) from the Korea Centers for Disease Control and Prevention.
Author Disclosure Statement
No competing financial interests exist.
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