Study on prevalance of drug resistance and genetic mutation for drug resistance hiv on hiv/aids patients with first - line antiretroviral treatment failure at dongda hospital Ha Noi

Nội dung text: Study on prevalance of drug resistance and genetic mutation for drug resistance hiv on hiv/aids patients with first - line antiretroviral treatment failure at dongda hospital Ha Noi

1. Journal of military pharmaco-medicine n 08-2017 STUDY ON PREVALANCE OF DRUG RESISTANCE AND GENETIC MUTATION FOR DRUG RESISTANCE HIV ON HIV/AIDS PATIENTS WITH FIRST-LINE ANTIRETROVIRAL TREATMENT FAILURE AT DONGDA HOSPITAL HA NOI Pham Ba Hien*; Do Tuan Anh**; Tran Viet Tien** SUMMARY Objectives: To study prevalence of drug resistance and genotype testing for drug resistance HIV on HIV/AIDS patients with first-line antiretroviral treatment failure at Dongda Hospital, Hanoi. Subjects and methods: Cross-sectional, descriptive, prospective study on 47 HIV/AIDS patients with first-line antiretroviral treatment failure at Dongda Hospital, Hanoi during period from 6 - 2011 to 12 - 2016. Results: The prevalence of drug resistance HIV was 90.7%; 97.7% resisted NNRTIs, following NRTIs: 95.3% and PIs group 11.6%. Among genetic mutations resistance to NNRTIs: G190A mutation was the highest (51.2%); K103N mutation was 39.5% and Y181C mutation was 34.9%. Genetic mutations in NRTIs: M184V mutation was 88.4%; in TAM mutations, K70R mutation was the most common (37.2%); followed D67N, T215F, T69N mutation was 27.9%; 27.9% and 25.6%, respectively. Genetic mutations in PIs: M36I and K20R mutation made up 9.3%. In NNRTIs, the prevalence of NVP resistance was 95.3% and ETR resitance was 4.7%. In NRTIs, lamivudine resistance was 93.0% and AZT resistance was 9.3%. No LVP/r resistance was recorded. Conclusions: Patients with first-line antiretroviral treatment failure had high prevalence of NNRTIs and NRTIs resistance but still susceptible to PIs. * Keywords: HIV; Drug resistance; First-line antiretroviral treatment failure; Genetic mutation for drug resistance. INTRODUCTION and improving the quality of life of AIDS patients. However, the emergence and Thanks to antiretroviral (ARV) drugs widesrpead of drug resistance HIV are that inhibit the growth of HIV, patients inevitable trend due to prolonged treatment. treated with ARV can live long and have Moreover, side effects of ARV are reasonably heathy lives. ARV therapy is sustainable factors leading to non- recommended due to the capacity assist adherence to treatment, which contribute the immune function and reduces HIV- to drug resistance HIV and uncontrolled related adverse outcomes. ARV therapy disease in community. The development widely used in patients with indication, of drug-resistant virus strains predisposes contributes to a new pathway in the prevention treatment failure and patients who had and treatment of HIV/AIDS by reducing treatment failure should be changed to the risk of HIV transmission in the population use higher-line ARV therapy (higher-level). * Dongda Hospital ** 103 Military Hospital Corresponding author: Pham Ba Hien (phambahien@yahoo.com) Date received: 20/08/2017 Date accepted: 21/09/2017 207
2. Journal of military pharmaco-medicine n 08-2017 In Vietnam, drug-resistance HIV testings Conducted at Molecular Biology are extravagant and are not performed regularly. Laboratory, National Institute of Hygiene Therefore, to help clinicians optimize and Epidemiology. The study focused on the effectiveness of ARV treatment, we identifying antiretroviral resistance mutations, performed this study with aims: To determine Pol gene sequences (~ 1,800 bp) including the proportion of drug resistance and the entire Prot (protease) gene and at least genetic mutation for drug resistance in 250 codons of the reverse transcriptase patients with first-line ARV treatment failure. (RT) gene; used Trugene® HIV-1 SUBJECTS AND METHODS Genotyping Kit and OpenGene® DNA sequencing system. Mutations are recorded 1. Subjects. when nucleotide mutations occur 47 HIV patients with fist-line ARV treatment simultaneously on both downstream and failure in HIV/AIDS outpatient clinic in inverted pathways and lead to changes Dongda Hospital from June, 2011 to December, 2016 were enrolled. in amino acids. Gene sequences were collated with the Stanford University * Selected criteria: Genomic Database (USA) using the - Age ≥ 18. HIVdb (Stanford HIV Drug Resistance - Patients were diagnosed HIV positive Database) software. Show each amino 3 times, using 3 different commercial kits acid corresponding to each of Prot and with different principles and antigens [2]. RT sites to detect resistance mutations and - Patients were treated by first-line ARV estimate resistance levels (potent, low, (zidovudine + lamivudine + nevirapine or medium or high) for each drug in the three stavudine + lamivudine + nevirapine) and diagnosed treatment failure according to groups NRTIs, NNRTIs, PIs. This drug guidelines for diagnosis and treatment resistance compiler is based on the HIV/AIDS issue in 2009 [2]. International AIDS Society (USA Panel - Agree to participate in this study. Guidelines) 2010 [6]. * Exclusion criteria: SPSS 20.0 for Windows program was - Do not come to the examination, test, used for statistical analysis. take medicine by appointment. RESULTS AND DISCUSSION - No cooperation (compliance) in the research process. 1. The propotion of patients having HIV with genetic mutation for drug resistance. 2. Methods. Among the 47 patients enrolled, Cross-sectional, descriptive, prospective 43 patients had genetic mutation for drug study. resistance (accounted for 90.7%). Tran Thi * Nucleotid sequencing testing to indentify Phuong Thuy’s research demonstrated the drug resistance mutations: that 5% of patients with HIV-1 treatment 208
3. Journal of military pharmaco-medicine n 08-2017 failure had not resistance mutation [1]. drugs such as metabolism for example, The proprotion of these patients was absortion, drug interactions; low baseline 2.8% in Nguyen Huu Chi’s study [3]. TCD4 cell count and high pre-treatment Thus, it can be seen that HIV in patients viral loads.... When drug resistance testing with treatment failure do not mean that are not used, doctor probably determines they resist ARV drugs. There are many to unnecessary conversion to second-line factors that affect the viral replication, regimens. Meanwhile, delaying the transition which lead to treatment failure with HAART to second-line regimens upon failure of including poor adherence to ARV therapy, first-line regimen increases the occurrence factors related to the pharmacokinetics of of new drug-resistant mutations. Table 1: Variation in expression of ARV resistance mutation in patients with treatment failure. Drug resistance mutations Quantity (n = 43) Percentage % NNRTI resistance mutations 42 97.7 NRTI resistance mutations 41 95.3 PI resistance mutations 5 11.6 NNRTI + NRTI resistance mutations. PI non-resistance mutations 35 81.4 NNRTI + NRTI + PI resistance mutations 5 11.6 NNRTI resistance mutations. NRTI and PI non-resistance mutations 2 4.7 NRTI resistance mutations. NNRTI and PI non-resistance mutations 1 2.3 Nguyen Huu Chi investigated drugs resistance mutation in 71 treatment failure patients who had drug resistance mutation testing. Among them, the highest percentage resistance was seen in NRTI, accounted for 97.2%, followed by NNRTI resistance with 87.3% and PI resistance with 5.6% [3]. According to Vietnamese researchers, the rates of PIs resistance were low in our country due to the PI drugs are rarely used and transmitted drug resistance HIV is also rare in Vietnam [3]. Adversely, NRTI resistance was the most common as it is the first-choice drug. 2. Drug resistance mutations. Table 2: The location of NNRTIs resistance mutations. The percentage in patiens The percentage in Location of Number Quantity with drug resistance patients with treatment mutant gene mutation (n = 43) failure (n = 47) 1. A98G 3 7.0 6.4 2. M230L 1 2.3 2.1 3. K101H 6 14.0 12.8 4. K101E 10 23.3 21.3 5. K101PQ 1 2.3 2.1 209
4. Journal of military pharmaco-medicine n 08-2017 6. K101EQ 1 2.3 2.1 7. K101HQ 1 2.3 2.1 8. K103N 17 39.5 36.2 9. G190S 1 2.3 2.1 10. G190A 22 51.2 46.8 11. Y181I 1 2.3 2.1 12. Y181C 15 34.9 31.9 13. Y181V 1 2.3 2.1 14. Y188L 3 7.0 6.4 15. V106I 3 7.0 6.4 16. V108I 1 2.3 2.1 17. V179T 3 7.0 6.4 18. Y179D 1 2.3 2.1 19. V179E 1 2.3 2.1 20. P225H 2 4.7 4.3 G190A is a mutation selected by NVP and EFV. G190A is highly resistant to NVP and has a moderate resistance to EFV as well as causing resistance in the NNRTI group. This mutation has accumulated over long periods of treatment with all NNRTIs. Most of the main resistance, Y181C, G190A, K103N, K101E, K101H were found. This is a group with low genetic barriers. All mutations were associated with cross-resistance in the NNRTI group. The occurrence of these mutations resulted in failure of the NNRTI treatment regimen. Therefore, patients with NNRTI resistance mutations should avoid using these agents in the alternative regimen. Table 3: The location of NRTIs resistance mutation. The percentage in patiens The percentage in Location of Number Quantity with drug resistance patients with treatment mutant gene mutation (n = 43) failure (n = 47) 1. D67N* 12 27.9 25.5 2. 3. D67N* 12 27.9 25.5 4. V75M 16 37.2 34.0 5. V75IM 1 2.3 2.1 6. V106I 2 4.7 4.3 7. V108I 5 11.6 10.6 8. V118I 4 9.3 8.5 9. K65R 5 11.6 10.6 10. K70R* 16 37.2 34.0 210
5. Journal of military pharmaco-medicine n 08-2017 11. K101Q 2 4.7 4.3 12. K101H 2 4.7 4.3 13. K210R 1 2.3 2.1 14. K219E* 4 9.3 8.5 15. K219E/Q* 2 4.7 4.3 16. K219Q* 7 16.3 14.9 17. T69D 2 4.7 4.3 18. T69N* 11 25.6 23.4 19. T215Y 2 4.7 4.3 20. T215F* 12 27.9 25.5 21. T215FS 1 2.3 2.1 22. T215F/Y 1 2.3 2.1 23. M41L* 6 14.0 12.8 24. M184I/V 2 4.7 4.3 25. M184V 38 88.4 80.9 26. A62V 2 4.7 4.3 27. A98G 1 2.3 2.1 28. L74V 3 7.0 6.4 29. L210W* 5 11.6 10.6 30. F77L 2 4.7 4.3 31. F116Y 2 4.7 4.3 32. Q151M 3 7.0 6.4 33. E44D 2 4.7 4.3 34. H208Y 1 2.3 2.1 * TAM mutation: The rate of M184V mutation was high, accounted for 88.4%. This may explain that lamivudine which was a selected drug for this mutation is present in all first-line regimens. Lamivudine is a widely used drug in Vietnam for the treatment of chronic hepatitis B, which is a highly prevalent disease in the population. This drug is considered to have poor resistance barrier and has a very high rate of drug resistance after initial treatment in chronic hepatitis B [7]. In many studies and reports in Vietnam, the incidence of TAM mutations has also been mentioned extensively: in Doan Thu Tra’s study, TAM mutations including the K70R and K219E accounted for 20.25% and 13.95%, respectively [5]. According to Huynh Hoang Khanh Thu’s research, the mutation at the D67N site accounted for 37% and was higher than other mutations [4]. Tran Thi Phuong Thuy had found that TAM mutation usually occurred at K65R site T215F, K219 E/Q, K70R and 67.4% of patients had both M184V/I and TAM mutations [1]. 211
6. Journal of military pharmaco-medicine n 08-2017 Table 4: The location of PIs resistance mutation. The percentage in drug Location of The percentage in treatment Number Quantity resistance mutation mutant gene failure patients (n = 47) patients (n = 43) 1. L33F 1 2.3 2.1 2. M36I 4 9.3 8.5 3. K20R 4 9.3 8.5 4. L10I 1 2.3 2.1 5. A71V 1 2.3 2.1 In Vietnam, there was few reports on PIs resistance mutation. Studies had shown that PIs resistance mutation has low rate. In Doan Thu Tra’s study on patients with L89M, I13V mutation accounted for 6.3% and 5.1%, respectively; Huynh Hoang Khanh Thu indicated that the two main mutants recorded were M46I (0.9%) and V82V (0.9%) [4, 5]. Low rates of PIs resistance were a favorable factor in treatment. Figure 1: Degree of NNRTIs resistance. NVP is a low genetic barrier drug, one mutation in the center of RT (Reverse Transctiptase) activity will occur drug resistance. The occurrence of major mutations at high frequency has resulted in the ineffectiveness of NVP (95.3% drug resistance). EFV is substituted for NVP when the patient is allergic to NVP. Therefore, the rate of EFV resistance was low with 55.8% due to less common. The level of resistance to ETR was lower than that of other drugs in the group because ETR resistance mutations occurred when at least 3 new mutations were accumulated. 212
7. Journal of military pharmaco-medicine n 08-2017 Figure 2: Degree of NRTIs resistance. The percentage of patients with 3TC resistance was high (93%). Although, there was no case reported with a history using, the similar result was seen in FTC resistance because FTC has similar mechanism to 3TC. In patients with combination regimens of d4T or AZT, TAM mutations and secondary mutations occurred, which resulted in multiple drug resistance (41.9% D4T resistance; 9.3% AZT resistance). The rate of patients with TDF resistance was 25.6%. Table 5: The degree of PIs resistance (n = 43). Degree of resistance Resistance Ability Non-resistance Drug n % n % n % ATV/r 0 0 0 0 43 100 DRV/r 0 0 0 0 43 100 FPV/r 0 0 0 0 43 100 IDV/r 0 0 0 0 43 100 LPV/r 0 0 0 0 43 100 NFV 0 0 0 0 43 100 SQV/r 0 0 2 4.7 41 95.3 TPV/r 0 0 0 0 43 100 Among 5 patients with resistant mutation genes to the PI group, however, only two cases were ability to be resistant to SQV/r. There were no cases of resistance to other PIs, especially no resistant to LPV/r and ATV/r which were being introduced in second line ARV regimen in Vietnam. 213
8. Journal of military pharmaco-medicine n 08-2017 CONCLUSION REFERENCES 1. Tran Thi Phuong Thuy . Study on antiretroviral In 47 patients with first-line ARV therapy resistance in HIV/AIDS patients treated at the failure, 90.7% had HIV with drug resistance Central Hospital for Tropical Diseases. Doctor genes. Among them, the highest resistance of Medicine Thesis. Institute for Clinical Pharmaco- medical Science Research 108. 2012. rate was seen in NNRTI group with 97.7%, 2. Viet Nam Ministry of Health. Guidelines followed by NRTIs (95.3%) and PIs (11.6%). for Diagnosis and Treatment of HIV/AIDS. In location of NNRTIs resistance mutation, Hanoi Medical Publishing House. 2009. 3. Nguyen Huu Chi, Nguyen Tran Chinh, G190A had the highest rate with 51.2%, Vo Minh Quang. ARV resistance characteristics followed by K103N, Y181C with 39.5% in AIDS patients failing treatment with HAART and 34.9%, respectively. In the NRTI- at the Tropical Hospital. City Medicine Hochiminh. 2008, Vol 12. resistant mutant genotypes, the highest 4. Huynh Hoang Khanh Thu. Understanding percentage was seen in M184V accounted the antiretroviral resistance (ARV) of HIV in for 88.4%; in TAM mutations, K70R mutation HIV-infected patients. Master Thesis in Genetics. University of Natural Sciences, Vietnam was the most common 37.2%, followed by National University Hochiminh City. 2010. D67N, T215F, T69N with 27.9%; 27.9% 5. Doan Thu Tra . Determination of drug and 25.6%, respectively. In the location of resistance of HIV in patients with first-line PIs resistance mutation, M36I and K20R therapy failure and evaluation of the efficacy of second-line antiretroviral therapy in HIV- accounted for 9.3%. In the NNRTI group, infected patients. Doctor of Medicine Thesis. NVP had the highest resistance rate of Institute for Clinical Pharmaco-medical Science Research 108. 2016. 95.3%. The lowest was the 4.7% ETR. 6. Johnson V.A, Brun-Vezinet F, Clotet B In NRTIs, lamivudine had the highest et al. Update of the drug resistance mutations resistance rate (93.0%) and the lowest in HIV-1: December 2010. Top HIV Med. rate was seen in AZT with 9.3%. In PIs, 2010, 18 (5), pp.156-63. 7. Lok A.S, McMahon B.J. Chronic hepatitis no LVP/r resistance was recorded but B: update 2009. Hepatology. 2009, 50 (3), might be resistant to SQV/r. pp.661- 662. 214