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HIV Drug Resistance Laboratory, National AIDS Research Institute (ICMR), Pune, IndiaDepartment of Microbiology, Armed Forces Medical College, Pune, India
Department of Epidemiology and Biostatistics, National AIDS Research Institute, Pune, IndiaDepartment of Community Medicine, Armed Forces Medical College, Pune, India
The free antiretroviral therapy programme in India is globally the largest and has completed a decade.
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A systematic review of acquired HIV drug resistance in the Indian setting was performed.
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Mutation K65R showed a rising trend in the temporal trend analysis.
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Resistance studies in India were limited to larger cities in urban populations.
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There is the need to develop an HIV-1 subtype C-specific database for India.
Abstract
Objective
The objective of this review was to assess the burden of HIV drug resistance mutations (DRM) in Indian adults exposed to first-line antiretroviral therapy (ART) as per national guidelines.
Methods
An advanced search of the published literature on HIV drug resistance in India was performed in the PubMed and Scopus databases. Data pertaining to age, sex, CD4 count, viral load, and prevalence of nucleoside reverse transcriptase inhibitor (NRTI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) DRM were extracted from each publication. Year-wise Indian HIV-1 reverse transcriptase (RT) sequences were retrieved from the Los Alamos HIV database and mutation analyses were performed. A time trend analysis of the proportion of sequences showing NRTI resistance mutations among individuals exposed to first-line ART was conducted.
Results
Overall, 23 studies (1046 unique RT sequences) were identified indicating a prevalence of drug resistance to NRTI and NNRTI. The proportion of RT sequences with any DRM, any NRTI DRM, and any NNRTI DRM was 78.39%, 68.83%, and 73.13%, respectively. The temporal trend analysis of individual DRM from sequences retrieved during 2004–2014 indicated a rising trend in K65R mutations (p = 0.013).
Conclusions
Although the overall burden of resistance against first-line ART agents remained steady over the study decade, periodic monitoring is essential. There is the need to develop an HIV-1 subtype C-specific resistance database in India.
Two decades back, it was feared that sparse healthcare resources coupled with the concurrent tuberculosis (TB) epidemic would lead to reckless HIV transmission in India, affecting over five million people (
). With the rollout of a free antiretroviral therapy (ART) programme in April 2004, this nightmare scenario was successfully averted. Over the past decade, this programme, the second largest globally, has not only achieved a 54% reduction in AIDS-related mortality, but has also prevented the resurgence of TB among people living with HIV and AIDS (PLWHA) (
National AIDS Control Organization, Department of AIDS Control, Ministry of Health and Family Welfare. Government of India. Annual report 2014–2015. Available at http://naco.gov.in/documents/annual-reports.
). However, the estimated prevalence of 0.26% (0.22–0.32%) in India translates into a burden of 2.11 million (1.71–2.64 million) PLWHA individuals in 2015 (
). With rapid scale-up of first-line ART coverage, the country needs to prepare to provide second-line therapy as well, due to the foreseeable emergence of resistance. Thus, much ground needs to be covered to achieve the ambitious UNAIDS 90:90:90 treatment target by 2020 (
The first-line ART regimen in India is implemented in a public health approach and comprises two nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) (
National AIDS Control Organization (NACO), Department of AIDS Control. Ministry of health and family welfare. Anti retroviral therapy guidelines for HIV infected adults and adolescents, May 2013. Available at: http://naco.gov.in/care-support-treatment.
). At its inception in 2004, ART was initiated at a CD4 cell count of ≤200 cells/μl with a stavudine (d4T)-based regimen. The national guidelines for ART initiation have undergone periodic modification based on World Health Organization (WHO) guidelines. In 2011, ART was initiated at a CD4 cell count of <350 cells/μl, which was then changed to <500 cells/μl in 2014. Recently, in May 2017, the country took the major step of adopting the WHO recommendations of initiating ART “regardless of WHO clinical stage and at any CD4 cell count” (
World Health Organization, Geneva. Consolidated guidelines on the use of antiretroviral drugs for treating HIV infection. Recommendations for public health approach. 2nd ed.; 2016. 422 p. Available at http://www.who.int/hiv/pub/arv/arv-2016/en/.
). Following the phasing out of stavudine in 2012, the NRTI option included zidovudine (AZT), abacavir (ABC), lamivudine (3TC), and tenofovir (TDF). In late 2014, the programme adopted a tenofovir, lamivudine, and efavirenz-based fixed drug combination as the preferred regimen to initiate ART. Efavirenz (EFV) and nevirapine (NVP) have been the only NNRTI options available in the programme since its inception (
National AIDS Control Organization (NACO), Department of AIDS Control. Ministry of health and family welfare. Anti retroviral therapy guidelines for HIV infected adults and adolescents, May 2013. Available at: http://naco.gov.in/care-support-treatment.
). Both of these NNRTI analogues has a low genetic barrier, and individuals failing an NVP- or EFV-based regimen often exhibit cross-resistance to the second-generation NNRTIs etravirine (ETR) and rilpivirine (RPV) (
Susceptibility to etravirine of HIV type 1 subtype C isolates from nevirapine/efavirenz-experienced patients: comparative interpretation of ANRS and STANFORD algorithms.
Increasing rate of TAMs and etravirine resistance in HIV-1-infected adults between 12 and 24 months of treatment: the VOLTART cohort study in Côte d’Ivoire, West Africa.
Hosseinipour et al. have suggested a predictable mutation pattern at 12 months of ART in resource-limited settings, when individuals are followed up by virological monitoring (
). To date, the national programme in India has relied on clinico-immunological monitoring for the diagnosis of treatment failure, wherein individuals are called for CD4 cell count estimation every 6 months. As immunological failure succeeds virological failure, the diagnosis of failure is delayed in immunological failure, and the accumulation of mutations at the time of detection of failure is common (
Rate of accumulation of thymidine analogue mutations in patients continuing to receive virologically failing regimens containing zidovudine or stavudine: implications for antiretroviral therapy programs in resource-limited settings.
). The extent of drug resistance mutation (DRM) also depends on individual adherence, the type of regimen, number of substitutions in the regimen, and the duration of therapy.
In the absence of a routine HIV drug resistance genotyping facility and a centralized database for reporting resistance patterns, it is difficult to estimate the burden of HIV drug resistance in India. A prior review recorded the regional distribution of HIV-1 drug resistance patterns among antiretroviral (ARV)-naive and experienced populations, including adults and children (
). With changes to the national guidelines, there is the need for an updated systematic review to estimate the burden of DRM against NRTI and NNRTI analogues among adults exposed to first-line ART. In addition, programme managers may be guided by temporal trends in DRM ascertained through the assessment of individual sequences submitted over the past decade. As the HIV DRM list is updated periodically, analysis using the updated list (
) will minimize errors due to polymorphism considered previously as being mutations.
Methods
Systematic review of the literature
An advanced search of the published literature on the status of HIV drug resistance in India was performed in the PubMed and Scopus databases using the following search terms: ‘HIV’ AND (‘drug’ OR antiretroviral OR antiviral OR treatment OR ARV OR ART) AND (mutation OR resistance OR resistant) AND (India OR Indian). Additional input from peers and experts in this field was also sought. Publications from 1986 (i.e., the year of the first report of HIV in India) to October 1, 2016 were taken into consideration.
The following inclusion criteria were applied: quantitative studies involving genotyping of the reverse transcriptase (RT) with or without the protease (PR) region of the pol gene, with a minimum sample size of ARV-exposed subjects of 30. The actual genotyped patients could vary depending on the rate of virological failure and genotyping efficiency. Studies with subjects primarily receiving first-line ART as per the national guidelines were considered (
National AIDS Control Organization (NACO), Department of AIDS Control. Ministry of health and family welfare. Anti retroviral therapy guidelines for HIV infected adults and adolescents, May 2013. Available at: http://naco.gov.in/care-support-treatment.
National AIDS Control Organization (NACO), Department of AIDS Control. Ministry of health and family welfare. Anti retroviral therapy guidelines for HIV infected adults and adolescents, May 2013. Available at: http://naco.gov.in/care-support-treatment.
). HIV drug resistance studies conducted among infants, children, and pregnant females receiving single-dose nevirapine were also excluded. The title, abstract, and full text of eligible publications were scrutinized independently by two authors.
Two investigators independently extracted the following data from each publication: age, sex, CD4 count, viral load, and the prevalence of NRTI/NNRTI DRM. Data were entered into a Microsoft Excel spreadsheet. Differences were resolved in consultation with the rest of the authors.
Composite analysis and temporal trend in resistance mutations from 2004 to 2014
Studies with identifiable RT or PR sequences as per GenBank accession numbers were considered for cumulative analysis. Individual study-specific sequences from India were retrieved from the Los Alamos sequence database website (http://www.hiv.lanl.gov/) based on the GenBank accession number, year of sample collection, and prior exposure to ARV. To perform a robust analysis, sequences were retrieved irrespective of the sample size of the parent study. Inclusion criteria for sequences were a minimum amino acid coverage of 40–210 for the RT region and 10–80 for the PR region. To avoid duplication, sequences with unique GenBank accession numbers were considered. Mutation analyses of year-wise and pooled sequences were performed by the Stanford University HIV Drug Resistance program (available at http://hivdb.stanford.edu/hiv). A time trend analysis was conducted using R software to look for any significant change in the proportion of sequences showing NRTI resistance mutations among first-line failure individuals over time (2004–2014) (
National AIDS Control Organization (NACO), Department of AIDS Control. Ministry of health and family welfare. Anti retroviral therapy guidelines for HIV infected adults and adolescents, May 2013. Available at: http://naco.gov.in/care-support-treatment.
) were identified (Figure 1). The data suggested a total sample size of approximately 3353 individuals, with genotyping information available for 1661 RT and 913 PR sequences (Table 1). All studies were conducted in urban settings with plasma as the preferred sample. Two studies used peripheral blood mononuclear cells (PBMCs) (
Human immunodeficiency virus type 1 drug resistance mutations in peripheral blood mononuclear cell proviral DNA among antiretroviral treatment-naive and treatment-experienced patients from Pune, India.
Susceptibility to etravirine of HIV type 1 subtype C isolates from nevirapine/efavirenz-experienced patients: comparative interpretation of ANRS and STANFORD algorithms.
Analysis of RT sequences of subtype C HIV-type 1 isolates from indian patients at failure of a first-line treatment according to clinical and/or immunological WHO guidelines.
) as the starting sample for HIV drug resistance genotyping. The number of successfully sequenced samples varied from 16 to 200 per study. An in-house method was the most common means of genotyping, except in the study by Sinha et al., which used the commercially available ViroSeq HIV-1 genotyping system (Celera Diagnostics, Alameda, CA, USA) for HIV-1 (
Human immunodeficiency virus type 1 drug resistance mutations in peripheral blood mononuclear cell proviral DNA among antiretroviral treatment-naive and treatment-experienced patients from Pune, India.
HIV–TB co-infected cohort divided into two groups based on the NNRTI analogue received in first-line ART: nevirapine (NVP) group and efavirenz (EFV) group.
followed for 6 months
PL
82.24
Mean 35.9 (SD ± 7.20)
NVP Gp: mean 228 (SD ±205) EFV Gp: mean 213 (SD ±147)
Analysis of RT sequences of subtype C HIV-type 1 isolates from indian patients at failure of a first-line treatment according to clinical and/or immunological WHO guidelines.
Suboptimal adherence associated with virological failure and resistance mutations to first-line highly active antiretroviral therapy (HAART) in Bangalore, India.
Susceptibility to etravirine of HIV type 1 subtype C isolates from nevirapine/efavirenz-experienced patients: comparative interpretation of ANRS and STANFORD algorithms.
Initial virologic response and HIV drug resistance among HIV-infected individuals initiating first-line antiretroviral therapy at 2 clinics in Chennai and Mumbai, India.
Emergence of drug resistance in human immunodeficiency virus type 1 infected patients from pune, India, at the end of 12 months of first line antiretroviral therapy initiation.
High frequency of clinically significant mutations after first-line generic highly active antiretroviral therapy failure: implications for second-line options in resource-limited settings.
Comparative analysis of drug resistance mutations in the human immunodeficiency virus reverse transcriptase gene in patients who are non-responsive, responsive and naive to antiretroviral therapy.
Cross-sectional study of virological failure and multinucleoside reverse transcriptase inhibitor resistance at 12 months of antiretroviral therapy in Western India.
Accumulation of HIV-1 drug resistance mutations after first-line immunological failure to evaluate the options of recycling NRTI drugs in second-line treatment: a study from South India.
b HIV–TB co-infected cohort divided into two groups based on the NNRTI analogue received in first-line ART: nevirapine (NVP) group and efavirenz (EFV) group.
c Group A patients (n = 126) were ART-naive and group B patients (n = 102) had exposure to mono/dual therapy prior to the initiation of first-line ART.
Most of the studies conducted genotyping following clinical or immunological failure in specimens with a plasma viral load of >1000 copies/ml. The duration of infection prior to genotyping was variable, although a minimum exposure to ARV of 6 months was considered. Two studies performed genotyping of all subjects with virological failure at 12 months of ART exposure (
Cross-sectional study of virological failure and multinucleoside reverse transcriptase inhibitor resistance at 12 months of antiretroviral therapy in Western India.
Emergence of drug resistance in human immunodeficiency virus type 1 infected patients from pune, India, at the end of 12 months of first line antiretroviral therapy initiation.
). This variation could be due to different criteria of enrolment and starting sample. The prevalence of NRTI and NNRTI mutations in patients with clinical failure varied from 6.9% to 94.45%, and in patients with immunological failure varied from 10.3% to 100%.
Composite analysis and temporal trend of reverse transcriptase mutations
Overall, 1046 RT/PR sequences from ARV-experienced Indian adult patients were retrieved from the Los Alamos database based on the year of sample collection, from 2004 to 2014. The proportion of RT sequences with any DRM, any NRTI DRM, and any NNRTI DRM was 78.39%, 68.83%, and 73.13%, respectively (Figure 2). The rising trend in yearly prevalence of NNRTI resistance mutations from 2013 onwards has also been reported previously (
Limited evolution but increasing trends of primary non-nucleoside reverse transcriptase inhibitor resistance mutations in therapy-naive HIV-1-infected individuals in India.
). As expected, M184I/V continued to be the dominant DRM over the study decade in individuals failing first-line therapy, owing to the indispensible lamivudine backbone. The overall proportions of sequences with mutations of the TAM-1 and TAM-2 pathways were 30.11% and 32.79%, respectively. M41L and D67N were the dominant mutations arising from the TAM-1 and TAM-2 pathways, respectively. K103N, Y181C, and 190A were the most common NNRTI mutations. Multi-drug resistance mutations conferring resistance to most NRTI analogues, such as 69 insertion complex and 151 complex, were reported infrequently (
Unusual insertion and deletion at codon 67 and 69 of HIV type 1 subtype C reverse transcriptase among first-line highly active antiretroviral treatment-failing South Indian patients: association with other resistance mutations.
Figure 2Composite analysis of sequences for NRTI and NNRTI drug resistance mutations, retrieved from individuals failing first-line ART over the 10-year period 2004–2014.
The temporal trend analysis of individual NRTI mutations from sequences retrieved between 2004 and 2014 indicated a significant increase in prevalence of the K65R mutation (p = 0.013) (Figure 3). Among NNRTI mutations, the rise in K103N was borderline significant (p = 0.06) (Figure 4).
Figure 3(a) Temporal trends in the most common NRTI drug resistance mutations from 2004 to 2014. (b) Proportion of ART failure patients showing the K65R mutation. Trend analysis of the K65R mutation from 2004 to 2014 showed a significant increasing trend (p < 0.01) in ART-exposed individuals.
). With rapid scale-up, the emergence and spread of drug resistance is a major threat to the ultimate goal of the National AIDS Control Programme to halt and reverse the epidemic. In this systematic review, the prevalence of resistance mutations against first-line ART, as reported by studies conducted on Indian PLWHA up until October 1, 2016, was assessed. Further, an unbiased analysis of individual RT sequences submitted to GenBank to date was performed to ascertain the burden of resistance and temporal trends in individual resistance mutations.
The development of resistance among the ARV-exposed group is inevitable, although it can be delayed by optimal adherence and monitoring. The overall burden of resistance against agents in the first-line regimen remained steady over the 10-year period. K65R and 103N were the only NRTI and NNRTI mutations, respectively, showing rising trends during 2004–2014. The dip in resistance observed in 2011 (Figure 3a) may be due to the lower number of RT sequences (only 46) available for analysis in that year. Moreover 25 of 27 sequences from ART-exposed patients from a single study did not show any DRM, causing a skewed result (
Comparative analysis of drug resistance mutations in the human immunodeficiency virus reverse transcriptase gene in patients who are non-responsive, responsive and naive to antiretroviral therapy.
). However, despite the reduction in mutation frequency in the 2011 studies, K65R still showed an overall increasing trend from 2004 to 2014 (p< 0.013).
The K65R mutation is selected mainly by tenofovir (TDF) and stavudine (d4T) (
Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903.
). In India, stavudine was phased out of the national programme in 2012 and a TDF-based fixed dose combination was introduced as the preferred regimen in 2014, based on WHO recommendations (
World Health Organization, Geneva. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, recommendations for a public health approach; June 2013. Available at http://www.who.int/hiv/pub/guidelines/arv2013/download/en/.
). Discrepant results have been reported in the literature depending on the technique used for genotyping. Toni et al. reported higher detection of K65R by allele-specific PCR in individuals who were otherwise negative for K65R by Sanger sequencing (
Development of an allele-specific PCR for detection of the K65R resistance mutation in patients infected with subtype C human immunodeficiency virus type 1.
). Although HIV drug resistance genotyping in India relies mostly on conventional Sanger sequencing, it is worthwhile to note that there may be an overestimation of K65R by UDPS due to PCR-induced errors (
HIV-1 subtype is an independent predictor of reverse transcriptase mutation K65R in HIV-1 patients treated with combination antiretroviral therapy including tenofovir.
). In the absence of virological monitoring, the emergence and spread of K65R following the nationwide introduction of TDF warrants surveillance studies.
K103N is selected by nevirapine and efavirenz and reduces susceptibility to these drugs by 50- and 20-fold, respectively (
). Nevirapine and efavirenz have been the only NNRTI options available in the programme since its inception. Although single-dose nevirapine at the time of delivery has been an important step towards the prevention of mother-to-child transmission, widespread exposure to nevirapine could be an important factor in the increasing trend of K103N (
). In January 2014, the National AIDS Control Programme introduced ‘option B plus’, wherein life-long ART is offered to pregnant and breast-feeding mothers irrespective of their CD4 count.
In India and other resource-limited countries, offering HIV drug resistance genotyping to all individuals with suspected treatment failure is not yet a feasible option. In such a setting, the limited detection of a few of the most common DRM may be a cost-effective alternative to sequencing of RT. The predominant NNRTI mutations in Indian PLWHA were K103N, Y181C, and G190A. Therefore, screening for the presence of these three mutations by allele-specific PCR is suggested as an economical option, especially in females with a prior history of exposure to NNRTI during pregnancy. M41L and D67N were most common thymidine analogue mutations (type 1 and 2, respectively), and K65R is an important mutation responsible for tenofovir resistance. Therefore the detection of these three common NRTI resistance mutations (K65R, M41L, and D67N) would be another cost-effective alternative in Indian HIV-1 subtype C-infected individuals.
The Indian HIV epidemic has been driven by subtype C. Although subtype differences do not guide the choice of ART regimen, subtype C has a higher propensity to develop certain DRM under drug pressure. For example, there is accelerated selection of the K65R mutation in subtype C-infected patients due to the unique KKK (Lys–Lys–Lys) nucleotide motif (nucleotide AAA AAG AAG) between codons 64 and 66 of RT. The poly adenine stretches cause pausing events, resulting in AAG to AGG transition and the occurrence of the K65R mutation in subtype C (
Template usage is responsible for the preferential acquisition of the K65R reverse transcriptase mutation in subtype C variants of human immunodeficiency virus type 1.
). Furthermore, studies have reported a higher prevalence of NNRTI mutations in subtype C-infected individuals following the use of single-dose nevirapine for the prevention of mother-to-child transmission (
The findings of the temporal trend and composite analyses should be considered in the light of a few limitations. As these studies were cross-sectional, a number of individuals were lost to follow-up or died, or were admitted for inter-current illnesses and were not amenable to drug resistance testing. Also sequences were not available in the public domain for a few studies. Due to the variable duration of exposure to ARV, the overall burden of resistance mutations among failing individuals may not be representative. There were limited HIV drug resistance studies in specific high-risk groups such as men who have sex with men and transgender people. As drug resistance testing is not routinely offered in the programme, these studies were restricted to a few metropolitan cities and therefore may not be representative of the rest of India. Nevertheless the pooled analysis of these studies reduced the random error caused by a small sample size. Multicentre HIV drug resistance surveillance at nationally representative ART centres would provide meaningful prevalence data. The socio-cultural background, educational status, and access to healthcare is different in rural India, thus there remains a need to explore resistance patterns in the rural healthcare setting. Improvements in logistics for sample transfer from peripheral ART centres and the use of dried blood spots could further increase the scope of resistance testing (
). A few studies did not provide patient-level data for the meaningful interpretation of resistance.
When reporting HIV genotypic resistance results, information on age, sex, high-risk group category, CD4 at ART initiation, CD4 count at failure or at genotyping, type of ART regimen, substitution or switches in the regimen, percentage adherence, and presence of any opportunistic infections should be included as a minimum. HIV-1 subtype C is the most common subtype in India and South Africa and accounts for almost 50% of global HIV infections. Systematic sequencing should be performed in order to develop a subtype C-specific HIV drug resistance database. Considering the similar first-line regimens used and the limited-resource setting, the HIV-1 resistance situation in South Africa could be comparable to that in India.
Funding
This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
There are no ethical issues involved in this review.
Conflict of interest
None of the authors have any conflicts of interest to declare.
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Vaniawala S.
Shah P.
Misra R.N.
Wani M.
Mukhopadhyaya P.N.
Development, validation and clinical evaluation of a low cost in-house HIV-1 drug resistance genotyping assay for Indian patients.
Susceptibility to etravirine of HIV type 1 subtype C isolates from nevirapine/efavirenz-experienced patients: comparative interpretation of ANRS and STANFORD algorithms.
Template usage is responsible for the preferential acquisition of the K65R reverse transcriptase mutation in subtype C variants of human immunodeficiency virus type 1.
Rate of accumulation of thymidine analogue mutations in patients continuing to receive virologically failing regimens containing zidovudine or stavudine: implications for antiretroviral therapy programs in resource-limited settings.
Analysis of RT sequences of subtype C HIV-type 1 isolates from indian patients at failure of a first-line treatment according to clinical and/or immunological WHO guidelines.
Suboptimal adherence associated with virological failure and resistance mutations to first-line highly active antiretroviral therapy (HAART) in Bangalore, India.
Initial virologic response and HIV drug resistance among HIV-infected individuals initiating first-line antiretroviral therapy at 2 clinics in Chennai and Mumbai, India.
Cross-sectional study of virological failure and multinucleoside reverse transcriptase inhibitor resistance at 12 months of antiretroviral therapy in Western India.
High frequency of clinically significant mutations after first-line generic highly active antiretroviral therapy failure: implications for second-line options in resource-limited settings.
Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903.
Increasing rate of TAMs and etravirine resistance in HIV-1-infected adults between 12 and 24 months of treatment: the VOLTART cohort study in Côte d’Ivoire, West Africa.
Comparative analysis of drug resistance mutations in the human immunodeficiency virus reverse transcriptase gene in patients who are non-responsive, responsive and naive to antiretroviral therapy.
National AIDS Control Organization (NACO), Department of AIDS Control. Ministry of health and family welfare. Anti retroviral therapy guidelines for HIV infected adults and adolescents, May 2013. Available at: http://naco.gov.in/care-support-treatment.
National AIDS Control Organization, Department of AIDS Control, Ministry of Health and Family Welfare. Government of India. Annual report 2014–2015. Available at http://naco.gov.in/documents/annual-reports.
Limited evolution but increasing trends of primary non-nucleoside reverse transcriptase inhibitor resistance mutations in therapy-naive HIV-1-infected individuals in India.
Emergence of drug resistance in human immunodeficiency virus type 1 infected patients from pune, India, at the end of 12 months of first line antiretroviral therapy initiation.
Unusual insertion and deletion at codon 67 and 69 of HIV type 1 subtype C reverse transcriptase among first-line highly active antiretroviral treatment-failing South Indian patients: association with other resistance mutations.
Human immunodeficiency virus type 1 drug resistance mutations in peripheral blood mononuclear cell proviral DNA among antiretroviral treatment-naive and treatment-experienced patients from Pune, India.
Accumulation of HIV-1 drug resistance mutations after first-line immunological failure to evaluate the options of recycling NRTI drugs in second-line treatment: a study from South India.
HIV-1 subtype is an independent predictor of reverse transcriptase mutation K65R in HIV-1 patients treated with combination antiretroviral therapy including tenofovir.
Development of an allele-specific PCR for detection of the K65R resistance mutation in patients infected with subtype C human immunodeficiency virus type 1.
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