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Journal of Clinical Microbiology, April 2002, p. 1319-1325, Vol. 40, No. 4
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.4.1319-1325.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Frequency of Mutations Conferring Resistance to Nucleoside Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus Type 1-Infected Patients in Korea

Young Keol Cho,^1* Heungsup Sung,^1,2 Sun Hee Ahn,¹ In Gyu Bae,^1,3 Jun Hee Woo,³ Young Ho Won,⁴ Dae Ghon Kim,⁵ and Moon Won Kang⁶

Departments of Microbiology,¹ Clinical Pathology,² Internal Medicine, University of Ulsan College of Medicine,³ Department of Dermatology, College of Medicine, Chonnam National University,⁴ Department of Internal Medicine, College of Medicine, Chonbuk National University,⁵ Department of Internal Medicine, College of Medicine, Catholic University, Seoul, South Korea⁶

Received 19 September 2001/ Returned for modification 20 October 2001/ Accepted 12 January 2002

Top Abstract Introduction Materials and Methods Results Discussion References

 
A nested PCR and direct sequencing methods were used to define human immunodeficiency virus type 1(HIV-1) reverse transcriptase codons 41 to 219 in DNA from 127 peripheral blood mononuclear cell samples obtained from 35 patients treated with nucleoside reverse transcriptase inhibitors (NRTI). The follow-up period after the initiation of NRTI therapy was 61.8 ± 31 months (mean and standard deviation). In addition to NRTI therapy, 32 of 35 patients were simultaneously treated with Korean red ginseng. The annual decrease in the CD4⁺ T-cell count over 5 years was 13.2/µl. Twenty-eight (80%) of the 35 patients had mutations conferring resistance to NRTI. The frequencies of K70R, T215S/Y/F (i.e., mutation of T at codon 215 to S, Y, or F), D67N/E, K219Q, T69N/S/A, M41L, and L210W mutations conferring resistance to zidovudine were 57.6, 36.4, 36.4, 27.2, 24.2, 21.2, and 12.1%, respectively. Mutations conferring resistance to didanosine and lamivudine were detected in 2 (L74V and M184I; 14.2%) of 11 patients tested and in 4 (M184V; 57%) of 7 patients tested, respectively. In particular, the frequency of T69N/S/A increased sharply after more than 48 months of zidovudine monotherapy. However, Q151M was not detected. As the first report on the frequency of NRTI resistance mutations in Korea, our data suggest that genotypic antiretroviral drug testing should be considered for the design of better drug regimens to improve the management of HIV-1-infected patients.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Currently available antiretroviral therapies involve mainly the inhibition of the viral enzymes reverse transcriptase (RT) and protease (PR) of human immunodeficiency virus (HIV) type 1 (HIV-1); both are encoded by the pol gene. Highly active antiretroviral therapy (HAART) including at least two RT inhibitors (RTI) and one PR inhibitor (PI) cannot eradicate HIV-1, although effective control of its replication is possible for variable periods (22). This means that viruses can increase survival fitness under drug pressure, and several amino acid variations associated with resistance to RTI and PI occur in the genes for RT and PR (8, 15). The rate and pattern of drug-resistant mutants seen in an individual patient are highly variable and depend on the type and effectiveness of the treatment regimen (8, 19).

Since the first report of HIV-1 infection in Korea in 1985, the cumulative numbers of HIV-1 infection and deaths in Korea, according to the Korean National Institute of Health, are 1,439 and 316, respectively, as of 30 June 2001. Although the numbers are relatively low compared to those in other Asian countries, new incidences are gradually increasing in the domestic population.

In Korea, zidovudine (ZDV) monotherapy was first introduced in 1991 for HIV-1-infected patients with a CD4⁺ T-cell count of less than 500/µl (2). Although the effects of low-dose ZDV monotherapy (400 to 600 mg per day) were not maintained for up to 12 months, it was the only antiretroviral therapy until early 1997 (2). Disease progression in patients with ZDV monotherapy in Korea coincided with the emergence of drug-resistant strains having mutations at RT codon amino acid positions 41, 67, 70, 210, 215, and 219 (5, 10, 14, 15, 16). Although three-drug combination therapy with ZDV or didanosine (ddI), lamivudine (3TC), and indinavir (IDV) began in 1997, nonnucleoside RTI, first introduced in 2000, have not been widely used until now. Some patients are still being treated with nucleoside RTI (NRTI) monotherapy, such as ZDV, ddI, and 3TC, mainly because of side effects. Although the molecular nature of RT and the frequency of resistance mutations in antiretroviral therapy-naive patients (24) have already been reported, there has been no report on mutations conferring resistance to NRTI.

In this study, we investigated the frequency of NRTI resistance mutations in 35 patients treated with the combination of NRTI and Korean red ginseng (KRG) for a prolonged period. These data show that the frequency of resistance mutations is low compared to those in other reports (13-17), that there is no multinucleoside drug resistance (MDR) mutation, and that there is high frequency of T69N/S/A (i.e., mutation of T at codon 69 to N, S, or A). Our epidemiologic data suggest that T69N/S/A may be associated with resistance to ZDV. This is the first report on NRTI resistance mutations in Korea.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Patients. Thirty-five HIV-1-infected patients diagnosed from 1987 to 1998 were randomly recruited nationwide (1, 3). At baseline, 23, 7, and 5 patients were at U.S. Centers for Disease Control and Prevention (CDC) stages A, B, and C, respectively. Seven patients (2, 4, 5, 8, 20, 31, and 35) and two patients (27 and 29) had a past history of shingles and Pneumocystis carinii pneumonia, respectively. Patients 12 and 23 had acute gastroenteritis. Patients 23 and 24 had cytomegalovirus retinitis and pulmonary tuberculosis, respectively. The CD4⁺ T-cell count decreased from 253 ± 114/µl at baseline to 185 ± 198/µl at 61.8 ± 31 months (values are given as mean and standard deviation). Of the 35 patients, 17 were positive for immune complex dissociated (ICD)-p24 antigen.

Treatment. The follow-up period after the initiation of NRTI therapy was 61.8 ± 31 months; for 46.6 ± 30 months, all the patients took NRTI. Table 1 provides a detailed description about the duration of treatment of each patient with NRTI and KRG. Thirty-five patients received one or more of the therapeutic agents ZDV, ddI, and 3TC. The daily doses of ZDV, ddI, and 3TC were 400 to 600, 400, and 300 mg, respectively. The mean duration of therapy for 11 patients treated with ddI was 11.9 ± 11 months (range, 1 to 29), and that for 7 patients treated with 3TC was 9.7 ± 11 months (range, 1 to 31). Although 16 patients are being treated with HAART, this study was limited to a review of the period of NRTI treatment prior to the beginning of HAART.

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TABLE 1. Characteristics of last sampling for 35 patients treated with NRTI and KRG

In addition to NRTI therapy, 32 of 35 patients were simultaneously treated with KRG for 31.7 ± 30 months (range, 0 to 100) during the study period. Twenty-eight patients were treated with KRG for >6 months, and 4 patients (15, 24, 26, and 34) were treated for KRG for <6 months. The daily dose of KRG was 5.4 g. Patients were told to take six capsules (300 mg per capsule) orally three times daily (1, 3, 6; Y. K. Cho, H. J. Lee, W. I. Oh, and Y. K. Kim, Abstr. 97th Gen. Meet. Am. Soc. Microbiol., abstr. E-44, p. 247, 1997).

CD4⁺ T-cell counting and measurement of ICD-p24 antigen. CD4⁺ and CD8⁺ T-cell counts were measured with a FACScan (Becton Dickinson, Fullerton, Calif.) flow cytometer after staining of peripheral blood mononuclear cells (PBMC) with phycoerythrin and fluorescein isothiocyanate-conjugated antibodies for CD4 and CD8 antigens (Becton Dickinson) (1). HIV-1 p24 antigen in serum was detected by the immune complex dissociation method (DuPont Medical Products, Boston, Mass.) (3). The tests were performed according to the manufacturers' instructions.

DNA preparation. DNA for PCR amplification was prepared directly from patients' PBMC. PBMC were isolated from 10 ml of whole blood in a sodium heparin tube by using Ficoll-Hypaque (Pharmacia, Piscataway, N.J.) density gradient centrifugation and divided into two vials. One of two vials stored at -80°C was thawed and centrifuged. Cell pellets were denatured by heating for 10 min at 95°C (6).

Nested PCR and sequencing. Denatured DNA samples (10 µl) were amplified by nested PCR. The outer primer pairs were JA99 (25) or JA100 (21) and RIT 137, and the three inner primer pairs were 523 and 526 for fragment A (257 bp), RT-A and RT-D for fragment B (428 bp), and 527 and 530 for fragment C (239 bp) (5, 6). After the first denaturation at 95°C for 3 min, 30 cycles were run at 94°C for 30 s, 50 and 72°C for 1 min each, and a final extension at 72°C for 10 min. The second PCR was done with 5 µl of the first PCR product. The cycling conditions were the same, except for 58°C for 1 min with primers 523 and 526 and 64°C for 1 min with primers 527 and 530. The sequencing primers used were 523 for fragment A, RT-D for fragment B, and 527 for fragment C.

Top Abstract Introduction Materials and Methods Results Discussion References

 
NRTI resistance mutations. Sequences covering RT codons 31 to 225 were determined for 127 PBMC samples obtained at different times during NRTI therapy from 35 patients. Of these patients, 28 (80%) had one or more NRTI resistance mutations (41L, 67N/E, 69N/S/A, 70R, 74V, 118I, 184V/I, 210W, 215S/F/Y, and 219Q). The actual duration of NRTI intake was 46.6 ± 30 months (75.4% of 61.8 months). The earliest detection of resistance mutations after the initiation of monotherapy with ZDV, 3TC, or ddI was 7, 3, or 14 months, respectively. As the duration of therapy was prolonged, the frequency of mutations conferring resistance to ZDV increased. In particular, the frequencies of D67N/E, T69N/S/A, K70R, and K219Q gradually increased (Fig. 1). ZDV resistance mutations K70R, T215S/Y/F, D67N/E, K219Q, T69N/S/A, M41L, and L210W were detected in 19 (57.6%), 12 (36.4%), 12 (36.4%), 9 (27.2%), 8(24.2%), 7 (21.2%), and 4 (12.1%) of 33 patients, respectively (patients 34 and 35 had ddI monotherapy) (Fig. 1).

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FIG. 1. Frequency of ZDV resistance mutations in the RT gene for 33 HIV-1-infected patients treated with ZDV. The percentage of samples showing ZDV resistance mutations according to months of therapy and the percentage of patients with resistance mutations are shown.

ddI and 3TC resistance mutations. ddI resistance mutations (L74V in patient 34 and M184I in patient 15) were detected in 2 (18.2%) of 11 patients treated with ddI. One of these patients (34), who had ddI monotherapy, showed L74V only three times during 14 months of therapy, and the other patient (15), treated with ddI and ZDV (Table 1), showed 184I, 67N, 69S, and 70R. 3TC resistance mutation M184V was detected in four (57%) of seven patients treated with 3TC. In addition, we detected V118I in four patients (11.4%; 2, 16, 33, and 34) treated with ZDV or ddI monotherapy, although V118I is known to be a 3TC intermediate mutation (19) and there has been no report on whether V118I is associated with resistance to ZDV or ddI. Other NRTI resistance mutations were not found.

No-MDR mutations (A62V, V75I, F77L, F116Y, and Q151 M). We could not detect any of the five mutations associated with MDR in our patients. Although patient 2 had a low CD4⁺ T-cell count at baseline (131/µl), he maintained a CD4⁺ T-cell count over the baseline with ZDV-KRG therapy for 60 months. After 68 months of ZDV monotherapy, he started ddI-ZDV combination therapy for 8 months. Although a mutation to ddI was not detected, D67E instead of D67N was detected three times over 8 months of ddI therapy. Then, D67E changed to D67G four times during HAART. Despite the best compliance, the patient did not show any response to HAART and died in January 2000 (4).

T69S/D/N/A. Eight of 35 patients showed mutations (T69S/D/N/A) at codon 69 during NRTI therapy (Tables 2 and 3). Of these, 7 patients showed a decrease in the CD4⁺ T-cell count after the appearance of the mutation at codon 69. However, we could not observe any change in the ICD-p24 antigen level because it was below the detection limit (Table 2). Except for the results for patients 15 and 33, all the mutations at codon 69 were detected after >34 months. When the mutation at codon 69 developed, other resistance mutations, including K70R, were always detected. Surprisingly, the frequency of T69N/S/A increased sharply after more than 48 months of ZDV monotherapy (Fig. 1). T69S was detected after 34 months and later than T69N.

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TABLE 2. Changes in clinical data for eight patients showing resistance mutations at RT codon 69

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TABLE 3. Deduced amino acid polymorphisms in RT codons of 35 patients treated with NRTIa

Maximum numbers of NRTI resistance mutations. Seven of 35 patients (20%) did not have resistance mutations in the RT coding region (Table 4). Four patients (5, 19, 21, and 22) were treated intermittently with ZDV only, two patients (24 and 27) were treated with ZDV and ddI, and patient 35 was treated with ddI only. Except for the compliance of patients 5 and 35, the drug compliance of the other patients was poor. The numbers of patients with the maximum numbers of resistance mutations (1, 2, 3, 4, 5, and 6) during follow-up were 9 (25.7%), 4 (11.4%), 4 (11.4%), 5 (14.3%), 5 (14.3%), and 1 (2.9%), respectively (Table 4).

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TABLE 4. Distribution of maximum number of NRTI resistance mutations in patients

Top Abstract Introduction Materials and Methods Results Discussion References

 
Although the frequency of the emergence of Q151M and related mutations has been reported to be 3.5 to >19% for patients treated with multiple NRTI for >1 year (13, 18, 23), we could not detect the mutations in 127 PBMC samples from 35 patients receiving long-term NRTI therapy in Korea. Furthermore, we could not detect Q151M in another 20 patients treated with a PI regimen in Korea (unpublished data). In particular, patients 1, 2, and 3 had taken ddI as HAART (ddI, 3TC, and IDV) for 49 36, and 43 months since the initiation of ZDV monotherapy, respectively.

We presume that the reason for the lack of Q151M in this study is mainly the short duration of two-drug combination therapy with ZDV plus ddI or 3TC compared to that in other studies, and the absence of this finding may be due in part to long-term intake of KRG (6). The reason for the latter conclusion is that in patient 34, treated with ddI monotherapy for 29 months, L74V for ddI was detected as early as month 14 of therapy, whereas in patient 35, treated with the combination of ddI for 22 months and KRG for 96 months, no mutation was detected during 22 months of ddI therapy, although the patient did not take ddI and KRG for the most recent 9 months. Patient 15, treated with ZDV plus ddI, also showed M184I for ddI and 67N, 69S, and 70R for ZDV. In addition, for patients 8 and 9, treated with KRG for 95 and 93 months, respectively, the second ZDV resistance mutation was detected at 119 months in patient 8 and was not detected in patient 9.

KRG has been used singly or together with ZDV for HIV-1-infected patients since late 1991 as an alternative medicine (1, 3, 6; Cho et al., Abstr. 97th Gen. Meet. Am. Soc. Microbiol.). Many beneficial effects have been found, including delayed development of ZDV resistance mutations (6; Cho et al., Abstr. 97th Gen. Meet. Am. Soc. Microbiol.) and the maintenance of CD4⁺ T-cell counts with KRG only for 10 years (unpublished data). Of note is the significant and consistent decrease in soluble CD8 antigen levels in patients treated with KRG for a prolonged period (1; Cho et al., Abstr. 97th Gen. Meet. Am. Soc. Microbiol.). Furthermore, it is well known that the progression to AIDS is associated with a generalized activation of the immune system, manifested by elevated concentrations in serum of neopterin, soluble interleukin-2 receptor, soluble CD8 antigen, and ß₂-microglobulin, and with the activation of a large proportion of CD8⁺ T cells (11). Recently, there has also been a report that panaxagin, from Chinese ginseng, has inhibitory activity against HIV RT (20).

It is known that T69D/N/A mutations cause resistance to ddC and ddI (26). Although T69N/S/D/A mutations were not detected in 29 therapy-naive patients in Korea (24), these mutations were detected in 8 patients in the present study. Therefore, our data support the notion that T69D/N/S/A may be associated not only with ddI and ddC but also with ZDV, as reported recently by Winters and Merigan (26). Previous reports on ZDV resistance were based mainly on short-term monotherapy because the introduction of combination therapy began only in early 1990, whereas the data in this study are based on long-term ZDV monotherapy. Actually, in patients 4 and 8, T69S had begun to be detected after 91 months of ZDV monotherapy. Fitzgibbon et al. (9) reported that the T69N mutation is a likely intermediate in the pathway to T69D; the same phenomenon was observed in patients 1 and 11 in this study (Table 2), and a change from T69S to T69A was also detected in patient 20.

It is known that V118I and E44D/A in RT confer a moderate level (4- to 50-fold) of phenotypic resistance to 3TC when they occur together with a ZDV resistance background (41L and 215Y) (12). Therefore, the significance of V118I in 3TC-naive patients in this study needs to be elucidated in the future.

Although we focused on the period of treatment with NRTI in this study, the frequency of NRTI resistance mutations was not decreased except during the first 2 years after some patients (1 and 3) changed from NRTI to HAART (7). These data suggest that genotypic antiretroviral drug testing should be considered for the design of better drug regimens to improve the management of HIV-1-infected patients showing therapeutic failure in the first regimen in Korea.

 
We thank Hee-Jung Lee for excellent technical assistance and Chun-Sik Park and Inn-Soo Suh for helpful advice. We are grateful to the Korea Ginseng Corporation for supplying KRG for this study.

This work was supported by grants from the Korean Society of Ginseng (2001) and the Asan Institute for Life Sciences (2001-062).

 
* Corresponding author. Mailing address: Department of Microbiology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-ku, Seoul 138-040, Korea. Phone: 82-2-3010-4283. Fax: 82-2-3010-4283. E-mail: ykcho2{at}amc.seoul.kr.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Journal of Clinical Microbiology, April 2002, p. 1319-1325, Vol. 40, No. 4
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.4.1319-1325.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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