Frequency Of Drug Resistance Mutations Research Articles

Frequency of Primary Resistance to Antiretroviral Drugs and Genetic Variability of HIV-1 Among Infected Pregnant Women Recently Diagnosed in Luanda-Angola

The determination of the prevalence of primary resistance to antiretroviral therapy in different places of the world is of extreme importance in molecular epidemiology monitoring, and it can guide the initial patient therapy in a given geographical area. The frequency of drug resistance mutations (DRM) and the genetic variability of HIV-1 isolates from newly diagnosed HIV-infected pregnant women attending the antenatal clinics of the Lucrecia Paim and Augusto N'Gangula maternities, Luanda-Angola, were determined. Thirty five out of 57 samples (61.4%) were sequenced and one mutation associated with resistance to nucleoside reverse transcriptase inhibitors was detected. Additionally, two mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors were also detected. No primary mutations associated with protease inhibitors (PI) were found. Subtypes A1, C, D, F1, G, H, CRF 13, CRF 37, and other mosaics were detected.

Impact of CRF01_AE-specific polymorphic mutations G335D and A371V in the connection subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on susceptibility to nucleoside RT inhibitors

Certain mutations in the connection subdomain and RNase H domain of reverse transcriptase (RT) of subtype B HIV-1 contribute to resistance to nucleoside reverse transcriptase inhibitors (NRTIs). However, the impact of non-B subtype polymorphisms in this region on drug resistance remains unclear. In this study, we determined the frequencies of drug resistance mutations of the entire RT in patients with treatment failure from a cohort of Circulating recombinant form (CRF) 01_AE HIV-1-infected patients in Hanoi, Viet Nam. Subsequently, we assessed the impact of CRF01_AE polymorphisms G335D and A371V with or without thymidine analogue mutations (TAMs) on susceptibility to NRTI with recombinant viruses. In 49 patients with treatment failure, resistance mutations to NRTIs in the N-terminal half of RT were observed in 89.8%. In the C-terminal half, G335D (100%), N348I (36.8%), A371V (100%), A376S (5.3%) and A400T (97.4%) were detected, although G335D, A371V and A400T were considered polymorphisms of CRF01_AE. Drug susceptibility showed G335D, A371V, or both did not confer resistance by themselves but conferred significant resistance to NRTIs with TAMs, especially in mutants containing G335D, A371V and TAM type 2. Our results suggest the important role of CRF01_AE polymorphisms in the C-terminal half of RT in drug resistance.

High Frequency of Clinically Significant Mutations after First‐Line Generic Highly Active Antiretroviral Therapy Failure: Implications for Second‐Line Options in Resource‐Limited Settings

Continuation of failed highly active antiretroviral therapy regimens can lead to the accumulation of mutations that may limit options for second-line treatment. We studied the pattern of drug resistance mutations among 138 Indian patients who experienced failure of nonnucleotide reverse-transcriptase-containing first-line highly active antiretroviral therapy. This study demonstrates a high frequency of drug resistance mutations in human immunodeficiency virus-infected Indians who experience immunologic treatment failure and suggests the need for viral load monitoring.

The frequency of drug resistance mutations in Mycobacterium leprae isolates in untreated and relapsed leprosy patients from Myanmar, Indonesia and the Philippines

The magnitude of drug resistance in Mycobacterium leprae to dapsone, rifampicin, and ofloxacin was studied in three Southeast Asian countries with a high prevalence of leprosy. M. leprae from the skin of leprosy patients was collected in North Maluku and North Sulawesi in Indonesia, Yangon in Myanmar, and Cebu in the Philippines. Mutations in the drug resistance determining regions in the folP1, rpoB, and gyrA genes, which have been proven to confer resistance, were analysed. In addition, samples from 51 newly diagnosed cases and 13 patients with leprosy relapse in Cebu were submitted for susceptibility testing in the mouse footpad. Of 252 isolates obtained from new cases, 3% were dapsone resistant and 2% were rifampicin resistant. In samples taken from patients with relapsed leprosy (n = 53), significantly more resistance mutations were detected: 15% had dapsone resistance mutations, and 8% had rifampicin resistance mutations. Two patients with relapsed leprosy had mutations for both dapsone and rifampicin resistance. No mutations conferring quinolone resistance were detected. No mutations were detected in the folP1 gene of M. leprae isolates with a low degree of resistance to dapsone. Detection of drug-resistant cases by mutation detection in the drug resistance determining region of the genome is a practical method for monitoring resistance. A comparison of the results obtained in this study with previous data obtained prior to the use of multidrug therapy (MDT), does not indicate clearly whether the magnitude of drug resistance has changed. Larger studies of resistance mutations in M. leprae isolated from patients with relapsed leprosy are needed to confirm our results. We recommend monitoring the magnitude of drug resistance globally, by testing M. leprae DNA from relapse cases and a representative sample of new cases.

High Frequency of Drug Resistance Mutations in Human Immunodeficiency Virus Type 1-Infected Korean Patients Treated with HAART

We have investigated the frequency of resistance mutations to highly active antiretroviral therapy (HAART) in 37 Korean HIV-1-infected patients, 22 of whom had experienced previous monotherapy. CD4(+) T cell counts significantly increased from 135 +/- 110/microl to 523 +/- 259/microl for 39 +/- 3 months by HAART (p < 0.0001). Over 39 +/- 3 months of HAART, 18 of 37 patients (48.6%) harbored drug resistance mutations. The most frequently observed mutation was M184V (24.3%, 9/37). Seven of 35 patients (20.0%) exposed to protease inhibitors and 2 of 11 (18.2%) exposed to nonnucleoside reverse transcriptase inhibitors developed resistance mutations to their respective drugs. When we measured HIV-1 RNA viral loads over 30 months of HAART in 31 patients, we found that 13 patients (41.9%) showed virological treatment failure, with viral load >400 copies/ml. In conclusion, we found that the frequency of resistance mutations to antiretroviral drugs over 30 months was high in HAART-treated patients. As the first report on resistance mutations to HAART in Korea, our data suggest that genotyping-guided treatment as well as education for compliance are required for better care.

Polymorphism of the Genome Region Coding for Protease and Reverse Transcriptase in HIV Type 1 Subtype A Variants Prevailing in CIS Countries

The pol nucleotide sequences coding for protease and reverse transcriptase were examined to study the frequency of drug resistance mutations in HIV-1 subtype A in Russia. The sample included 141 HIV-infected subjects who had never received antiretroviral drugs before. Primary resistance mutations occurred at a low (less than 1%) frequency, while unusually high frequencies were observed for the secondary mutations causing substitutions V77I in protease (67%) and A62V in reverse transcriptase (63%). The V77I and A62V mutations were associated in most cases. HIV-1 isolates carrying both mutations (MutV77I/A62V) had several synonymous substitutions in pol, which was indicative of their common origin. Examination of a larger sample of HIV-1 isolates (N = 319) by hybridization with biological microchips and by restriction enzyme analysis showed that the MutV77I/A62V variant dominated in Russia in terms of both frequency (56%) and geographic distribution, prevailing in regions with the highest incidence of HIV-1 infection (e.g., Irkutsk, Samara, and Moscow regions). In addition, analysis revealed the genotypes that contained none of the V77I and A62V mutations or only one of them. The evolutionary relationships of the four HIV-1 variants and the role of pol gene polymorphism in replicative activity and drug resistance of HIV-1 are discussed.

Characterization of Mutations in CRF01_AE Virus Isolates From Antiretroviral Treatment-Naive and -Experienced Patients in Singapore

To determine the frequency of drug resistance mutations among antiretroviral treatment-naive and -experienced patients infected with CRF01_AE virus. Prospective observational study. We recruited antiretroviral-experienced HIV-infected patients with suspected drug resistance and consecutive newly diagnosed drug-naive patients. Viral sequencing was performed using standard methods. Frequencies of mutations in CRF01_AE virus isolates were compared with reference data for subtype B virus. Sequences were obtained for CRF01_AE virus isolates from 69 patients with treatment exposure and 35 treatment-naive patients. Treatment-naive patients had numerous polymorphisms but no major drug resistance mutations. There were differences between CRF01_AE and subtype B viruses in several drug resistance mutations including the following: D67N, L210F, K101E, V106M, V179I/D, G190A/S/E, and G48V (which were more common in CRF01_AE virus) and M41L, T215Y, and V82A (which were less common in CRF01_AE virus). The pattern of treatment-related mutations in CRF01_AE virus differs from that in subtype B virus at a number of positions determining drug resistance. Understanding these differences is important for interpreting results of resistance tests and determining treatment choices.

Human Immunodeficiency Virus Type 1 Infection in Oman: Antiretroviral Therapy and Frequencies of Drug Resistance Mutations

Highly active antiretroviral therapy (HAART), consisting mainly of two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI), is offered to <10% of HIV-infected subjects in Oman. The aims of the present study were to determine the frequency of resistance-associated mutations in these patients, and to assess the contribution of drug resistance to treatment outcome. Among 29 patients on HAART for ≥6 months, virological, failure was observed in 27 (93%). Genotypic analysis indicated that in five of these 27 patients, there were no mutations that confer resistance to reverse transcriptase inhibitors (RTIs). The genotypes of 17 other patients carried one or two RTI mutations, mainly the lamivudine-associated resistance mutation M184V. Three or more RTI mutations were found in only five (14.7%) patients with virological failure, including three patients on the nonnucleoside RTI efavirenz. Major PI mutations were infrequent, and were detected in seven (26%) of 27 patients failing HAART, mainly as single mutation at codons 82 or 90. In contrast, accessory mutations in the protease gene were present in all patients. However, there were significant differences in the prevalence of accessory mutations at codons 36 and 77 among clade B and non-B viruses. When genotypic data of this study were used to change therapy of seven patients whose isolates had multiple resistance mutations, adequate viral suppression was observed in five. Our results indicate that the high rate of treatment failure among patients in Oman is mainly due to factors other than resistance to antiretroviral drugs. These factors, which may include nonadherence to therapy and treatment interruptions, need to be investigated.

Human Immunodeficiency Virus Type 1 Infection in Oman: Antiretroviral Therapy and Frequencies of Drug Resistance Mutations

Highly active antiretroviral therapy (HAART), consisting mainly of two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI), is offered to < 10% of HIV-infected subjects in Oman. The aims of the present study were to determine the frequency of resistance-associated mutations in these patients, and to assess the contribution of drug resistance to treatment outcome. Among 29 patients on HAART for > or =6 months, virological, failure was observed in 27 (93%). Genotypic analysis indicated that in five of these 27 patients, there were no mutations that confer resistance to reverse transcriptase inhibitors (RTIs). The genotypes of 17 other patients carried one or two RTI mutations, mainly the lamivudine-associated resistance mutation M184V. Three or more RTI mutations were found in only five (14.7%) patients with virological failure, including three patients on the nonnucleoside RTI efavirenz. Major PI mutations were infrequent, and were detected in seven (26%) of 27 patients failing HAART, mainly as single mutation at codons 82 or 90. In contrast, accessory mutations in the protease gene were present in all patients. However, there were significant differences in the prevalence of accessory mutations at codons 36 and 77 among clade B and non-B viruses. When genotypic data of this study were used to change therapy of seven patients whose isolates had multiple resistance mutations, adequate viral suppression was observed in five. Our results indicate that the high rate of treatment failure among patients in Oman is mainly due to factors other than resistance to antiretroviral drugs. These factors, which may include nonadherence to therapy and treatment interruptions, need to be investigated.