High Prevalence of Human Immunodeficiency Virus Type 1 Drug Resistance Mutations in Antiretroviral Treatment-Experienced Patients from Pune, India

Sen, Sourav; Tripathy, Srikanth; Patil, Ajit; Chimanpure, Vaishali M.; Paranjape, Ramesh

doi:10.1089/aid.2007.0090

Cited by 40 publications

(45 citation statements)

References 18 publications

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“…A study done in India found that 50% of HIV-1 subtype C strains containing nonnucleoside RT inhibitor drug resistance mutations included the 41L mutation (19). In addition, there was only one instance of the mixed pathway as seen in the African study, but it came from an isolate that included viral clones with all of the accessory TAMs, including the 219Q mutation.…”

Section: Discussionmentioning

confidence: 95%

Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1

Armstrong¹,

Lee²,

Essex³

2009

J Virol

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In order to understand the impact of zidovudine resistance and thymidine analog mutations (TAMs) on subtype C human immunodeficiency virus type 1, we created mutants in subtype C reverse transcriptase (RT). The subtype B RT was placed in a subtype C backbone to act as a control. Mutants and wild-type (WT) virus were competed in a head-to-head competition assay to determine how different clones grew in the same culture. Different viruses were distinguished by sequence tags in nef and a quantitative-PCR assay. The 67N and 70R accessory mutations gave an advantage over the WT in subtype C, but these mutations in subtype B had replication capacities similar to that of the WT. Of the triple mutants examined, the TAM-1 types, 41L210W215Y, were the most fit in both subtypes, but only in subtype C was the replication capacity the same as that of the WT. The TAM-2 mutants, 67N70R215F, had the slowest replication in both clones. The mixed TAM pathway mutant, 67N70R215Y, in subtype C had a significant advantage over the TAM-2 mutant, but this was not seen in subtype B. When the WT viruses were competed with each other, the subtype B RT had enhanced replication relative to subtype C. The increased capacities of the 67N and 70R mutations may indicate that there will be greater transmitted resistance and persistence in a subtype C setting than what is known for subtype B.Human immunodeficiency virus type 1 (HIV-1) remains a leading cause of morbidity and mortality worldwide. With the advent of highly active antiretroviral therapy (HAART), the life expectancy for those on treatment has increased dramatically. Given HIV-1's ability to replicate and mutate quickly, drug resistance has been a significant problem since treatment began. While drug resistance has been studied extensively in the developed world, HIV-1 subtypes that affect developing countries are rarely targeted for drug resistance research (9).Sub-Saharan Africa continues to bear the bulk of the burden of the HIV-1 epidemic, with 22.5 million infections out of the 33.2 million global infections (22). However, the developed world has begun to take notice by contributing unprecedented amounts of money and expertise to combat the epidemic. Much of the support for developing countries has gone toward drug treatment programs for those in need, making research into drug resistance of paramount importance. As more and more people get the treatment they require, drug resistance will increasingly play a major role in the epidemic in these hard-hit areas, where expertise and laboratory tests for clinical monitoring are often not available.Some in vivo data point to different patterns of resistance between subtypes. Brenner et al. (3) have shown for subtype C that the 65R mutation occurs faster in cell culture in response to tenofovir pressure than it does in subtype B. A study from Brazil looked at 160 sequences from treatment-experienced HIV-1-infected individuals (21). It was found that subtype C viruses accumulated drug resistance mutations at a lower rate than subtype B i...

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Section: Discussionmentioning

confidence: 95%

Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1

Armstrong¹,

Lee²,

Essex³

2009

J Virol

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“…Reports of the 106A mutation have been rare in subtype C, but they do occur (11,12,27,29,31,38); however, the functionality of these subtype C 106A mutant RTs is unknown. The 106M mutation appears in the same studies at least three times as often as the 106A mutation in the same cohorts.…”

Section: Discussionmentioning

confidence: 99%

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

Armstrong

Lee

Essex

2011

Antimicrob Agents Chemother

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Single-dose nevirapine (NVP) is quite effective in preventing transmission of the human immunodeficiency virus (HIV) from mother to child; however, many women develop resistance to NVP in this setting. Comparing outcomes of clinical studies reveals an increased amount of resistance in subtype C relative to that in other subtypes. This study investigates how nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations of subtype C affect replication capacity. The 103N, 106A, 106M, 181C, 188C, 188L, and 190A drug resistance mutations were placed in a reverse transcriptase (RT) that matches the consensus subtype C sequence as well as the HXB2 RT, as a subtype B reference. The replicative fitness of each mutant was compared with that of the wild type in a head-to-head competition assay. The 106A mutant of subtype C would not grow in the competition assay, making it the weakest virus tested. The effect of the 106M mutation was weaker than those of the 181C and 188C mutations in the consensus C RT, but in subtype B, this difference was not seen. To see if the 106A mutation in a different subtype C background would have a different replicative profile, the same NNRTI resistance mutations were added to the MJ4 RT, a reference subtype C molecular clone. In the context of MJ4 RT, the 106A mutant was not the only mutant that showed poor replicative fitness; the 106M, 188C, and 190A mutants also failed to replicate. These results suggest that NNRTIs may be a cost-effective alternative for salvage therapy if deleterious mutations are present in a subtype C setting.The emergence of drug-resistant mutants is common among HIV-infected patients undergoing antiviral therapy. Clinically, the standard practice is to drop the antiviral to which the resistance has developed from the treatment regimen in such drug failure cases. However, a notable exception to this is the continuing use of lamivudine (3TC) as a salvage regimen because the 184V mutation linked to 3TC treatment has decreased replication ability relative to that of the wild type (WT) in subtype B (7). Mechanistically, Back et al. (2) found that the 184V mutant is less processive than wild-type RT under conditions of limiting deoxynucleoside triphosphates (dNTPs), and in primary lymphoid cells, the mutant is less fit than wildtype virus. These studies were extended further in vivo by Paredes et al. (35), who looked at multidrug-resistant virus from patients who were ending 3TC treatment. They used an allele-specific PCR assay to track the reversion of the M184V sequence and found that there was a fitness cost of 4 to 8% for the 184V mutation compared to that of the viral sequence that grew without 3TC drug pressure. Taken together, these studies illustrate how clinical management of HIV-infected patients can benefit from the study of the fitness cost of HIV drugresistant mutants.The use of antiretroviral drugs is increasing in the developing world. In particular, the use of single-dose nevirapine (NVP) has been shown to be an effective means of mitigat...

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“…Sen et al 6 demonstrated that there were no reverse transcriptase inhibitor-associated or major PR resistance mutations seen in ARV-naive patients from Pune, while treatment-experienced participants with evidence of virologic failure revealed 81.81% with one or more HIVDR mutations in individuals. Subsequently, Lall et al 7 reported HIVDR mutations in 10% of treatment-naive HIV-1-infected individuals.…”

Section: Figmentioning

confidence: 99%

“…While there are Indian studies describing the prevalence of (HIVDR) mutations in adults, [3][4][5][6][7] the prevalence of HIV drug resistance in the pediatric HIV-1-infected Indian population is largely unknown. This study describes the prevalence of mutations associated with HIVDR by the genotypic method in treatment-naive, HIV-1-infected children in Pune, India.…”

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confidence: 99%

Prevalence of Drug Resistance in Human Immunodeficiency Virus Type 1-Infected Treatment-Naive Children in Pune, India

Kumar

Sen²,

Gupta³

et al. 2014

AIDS Research and Human Retroviruses

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We report the presence of drug resistance mutations in 7.4% (2/27) of the treatment-naive, HIV-1-infected children in Pune, India, who had HIV-1 RNA levels > 1,000 copies/ml. Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, namely A98G and K103N, were observed in two separate sequences. In addition, three study sequences displayed three separate HIV-1 protease minor resistance mutations-L10I, A71T, and T74S. These preliminary data from Pune, India, reporting the presence of HIVDR in treatment-naive, HIV-1-infected children, reinforces the need to conduct large-scale studies to assess the prevalence of primary HIVDR in the pediatric population, which in turn will aid in planning protocols and policies related to antiretroviral treatment for the pediatric population.

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High Prevalence of Human Immunodeficiency Virus Type 1 Drug Resistance Mutations in Antiretroviral Treatment-Experienced Patients from Pune, India

Cited by 40 publications

References 18 publications

Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1

Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

Prevalence of Drug Resistance in Human Immunodeficiency Virus Type 1-Infected Treatment-Naive Children in Pune, India

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