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HIV-1 subtypes and mutations associated to antiretroviral drug resistance in human isolates from Central Brazil
Cerqueira, Daniela Marreco;Ramalho, Eduardo Dias;Oliveira, Claudiner Pereira;Silva, Ruiter Roberto;Franchini, Miriam;Felipe, Maria Sueli Soares;Martins, Cláudia Renata Fernandes;
Brazilian Journal of Microbiology , 2004, DOI: 10.1590/S1517-83822004000200003
Abstract: the detection of polymorphisms associated to hiv-1 drug-resistance and genetic subtypes is important for the control and treatment of hiv-1 disease. drug pressure selects resistant variants that carry mutations in the viral reverse transcriptase (rt) and protease (pr) genes. for a contribution to the public health authorities in planning the availability of therapeutic treatment, we therefore described the genetic variability, the prevalence of mutations associated to drug resistance and the antiretroviral resistance profile in hiv-1 isolates from infected individuals in central brazil. nineteen hiv-1 rna samples from a public health laboratory of the federal district were reversely transcribed and cdnas were amplified by nested pcr. one fragment of 297 bp coding the entire protease gene, and another of 647 bp, corresponding to the partial rt gene (codons 19-234), were obtained. automated sequencing and blast analysis revealed the presence of 17 b and 2 f1 hiv-1 subtypes. the amino acid sequences were analyzed for the presence of resistance-associated mutations. a total of 6 pr mutations, 2 major and 4 accessory, and 8 rt mutations related to drug resistance were found. our data suggest a high prevalence of hiv-1 b subtype in the studied population of federal district as well as the presence of genetically-resistant strains in individuals failing treatment.
HIV-1 primary drug resistance mutations in antiretroviral therapy-na ve patients in Istanbul, Turkey
M Sayan,O Aydin,B Mete,N Uzun
Journal of the International AIDS Society , 2012, DOI: 10.7448/ias.15.6.18181
Abstract: According to the official information of Turkish Ministry of Health of HIV/AIDS surveillance data, in the period 1985 to the end of 2011, there are 4826 HIV-1 infected cases in Turkey. However, there is no data available on the antiretroviral (ART) drug resistance. The objective of this study was to determine primary drug resistance in HIV-1 infections in newly diagnosed, ART-na ve Turkish patients in Istanbul, Turkey. The study was carried out between June 2009 and June 2012 and 59 HIV-1-infected patients were included (gender; 52 male/7 female, age, median years (range); 37.9 (20–57), CD4+ T-cell count, median mm3 (range); 280 (3–813), HIV-RNA load, median IU/ml (range); 4.1 + E5 (2.6 + E3–2.9 + E6)). For HIV-1 subtyping most widely known algorithm; the HIVdb-Stanford University genotypic resistance interpretation algorithm has been used. According to population-based sequencing of the reverse transcriptase and protease genes of HIV-1, the patients had pre-existing primary ART drug resistance mutations and were related to NRTIs (M41L, D67N, T215D, T215E, T215S), NNRTIs (V179D) and PIs (I54V, V82A). The prevalence of overall primary ART drug resistance were 11.8% (7/59) in Turkish patients and according to NRTIs, NNRTIs and PIs drug groups were 10% (6/59), 1.7% (1/59) and 1.7% (1/59), respectively (in one patient has been either NRTIs and PIs resistance detected). The high prevalence of HIV-1 primary drug resistance in ART-na ve patients suggested the resistance testing must be an integral part of the management of HIV infection and the choice of first-line therapy regime should be guided by genotypic resistance interpretation in Turkey.
HIV Drug Resistance-Associated Mutations in Antiretroviral Na?ve HIV-1-Infected Latin American Children  [PDF]
Luis E. Soto-Ramirez,Roberto Rodriguez-Diaz,D. Robert Harris,Rohan Hazra
Advances in Virology , 2010, DOI: 10.1155/2010/407476
Abstract: Our goal was to describe the presence of HIV drug resistance among HIV-1-infected, antiretroviral (ARV) na?ve children and adolescents in Latin America and to examine resistance in these children in relation to drug exposure in the mother. Genotyping was performed on plasma samples obtained at baseline from HIV-1-infected participants in a prospective cohort study in Brazil, Argentina, and Mexico (NISDI Pediatric Study). Of 713 HIV-infected children enrolled, 69 were ARV na?ve and eligible for the analysis. At enrollment, mean age was 7.3 years; 81.2% were infected with HIV perinatally. Drug resistance mutations (DRMs) were detected in 6 (8.7%; 95% confidence interval 3.1–18.2%) ARV-na?ve subjects; none of the mothers of these 6 received ARVs during their pregnancies and none of the children received ARV prophylaxis. Reverse transcriptase mutations K70R and K70E were detected in 3 and 2 subjects, respectively; protease mutation I50?V was detected in 1 subject. Three of the 6 children with DRMs initiated ARV therapy during followup, with a good response in 2. The overall rate of primary drug resistance in this pediatric HIV-infected population was low, and no subjects had more than 1 DRM. Mutations associated with resistance to nucleoside reverse transcriptase inhibitors were the most prevalent. 1. Introduction Primary HIV-1 drug resistance has been reported in up to 20% of HIV-infected adults in the United States and Europe [1–3] and has led to recommendations that all treatment-na?ve adults undergo resistance testing when they enter care [4]. Data on primary (or initial) resistance in HIV-infected infants and children are more limited but have led to similar recommendations [5]. Recent studies of infected infants in the United States have demonstrated rates of primary resistance to at least one antiretroviral (ARV) in the range of 19–24%, with most being mutations associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance [6, 7]. Rates reported from older children in the United Kingdom are lower (3 of 44, 6.8%) [8]. In a study from Brazil, primary resistance was seen in 7 of 26 (27%) perinatally infected children [9], and a study from Argentina demonstrated primary resistance in 5 of 22 (23%) infected infants but much lower rates (1 of 45, 2.2%) in infected children 1–14 years of age [10]. When examined in some of these studies, maternal ARV history did not generally provide a clear explanation for the results seen in the infants and children. The primary objectives of this analysis were to describe the presence of HIV drug
Emergence of HIV-1 drug resistance mutations among antiretroviral-na ve HIV-1-infected patients after rapid scaling up of antiretroviral therapy in Thailand
Sungkanuparph Somnuek,Sukasem Chonlaphat,Kiertiburanakul Sasisopin,Pasomsub Ekawat
Journal of the International AIDS Society , 2012, DOI: 10.1186/1758-2652-15-12
Abstract: Background After rapid scaling up of antiretroviral therapy in HIV-1-infected patients, the data of primary HIV-1 drug resistance in Thailand is still limited. This study aims to determine the prevalence and associated factors of primary HIV-1 drug resistance in Thailand. Methods A prospective observational study was conducted among antiretroviral-na ve HIV-1-infected Thai patients from 2007 to 2010. HIV-1 subtypes and mutations were assayed by sequencing a region of HIV-1 pol gene. Surveillance drug resistance mutations recommended by the World Health Organization for surveillance of transmitted HIV-1 drug resistance in 2009 were used in all analyses. Primary HIV-1 drug resistance was defined as the presence of one or more surveillance drug resistance mutations. Results Of 466 patients with a mean age of 38.8 years, 58.6% were males. Risks of HIV-1 infection included heterosexual (77.7%), homosexual (16.7%), and intravenous drug use (5.6%). Median (IQR) CD4 cell count and HIV-1 RNA were 176 (42-317) cells/mm3 and 68,600 (19,515-220,330) copies/mL, respectively. HIV-1 subtypes were CRF01_AE (86.9%), B (8.6) and other recombinants (4.5%). The prevalence of primary HIV-1 drug resistance was 4.9%; most of these (73.9%) had surveillance drug resistance mutations to only one class of antiretroviral drugs. The prevalence of patients with NRTI, NNRTI, and PI surveillance drug resistance mutations was 1.9%, 2.8% and 1.7%, respectively. From logistic regression analysis, there was no factor significantly associated with primary HIV-1 drug resistance. There was a trend toward higher prevalence in females [odds ratio 2.18; 95% confidence interval 0.896-5.304; p = 0.086]. Conclusions There is a significant emergence of primary HIV-1 drug resistance in Thailand after rapid scaling up of antiretroviral therapy. Although HIV-1 genotyping prior to antiretroviral therapy initiation is not routinely recommended in Thailand, our results raise concerns about the risk of early treatment failure in patients with primary HIV-1 drug resistance. Interventions to prevent the transmission of HIV-1 drug resistance and continuation of surveillance for primary HIV-1 drug resistance in Thailand are indicated.
HIV-1 drug resistance-associated mutations among antiretroviral-na ve Thai patients with chronic HIV-1 infection
W Manosuthi,S Thongyen,S Nilkamhang,S Manosuthi
Journal of the International AIDS Society , 2012, DOI: 10.7448/ias.15.6.18203
Abstract: Purpose of study: Antiretroviral therapy (ART) has been scaled up in resource-limited settings. This study aimed to determine the prevalence of HIV-1 drug resistance-associated mutations (DRAMs) among patients with chronic HIV-1 infection and to compare DRAMs between CRF01_AE and B subtypes. Methods: ART-na ve Thai patients who were indicated for ART initiation between 2010 and 2011 were prospectively enrolled. Genotypic assays of reverse transcriptase and protease genes were performed within 4 weeks prior to ART. DRAMs were assessed using International AIDS Society USA 2011 list. Summary of results: A total of 330 patients were included. HIV-1 subtypes included CRF01_AE (241, 73.0%), B (79, 23.9%), and others (10, 3.1%). Median (IQR) CD4 was 66 (23–172) cells/mm3 and median (IQR) HIV-1 RNA was 5.2 (4.6–5.8) log copies/mL. The prevalence of patients with≥1 DRAMs to any antiretroviral agents was 17.6%; 17.0% to NNRTIs, 0.6% to NRTIs, and 0.6% to protease inhibitors (PIs). V106I (23, 7.0%), V179D (14, 4.2%), V179T (6, 1.8%), E138A (5, 1.5%), V90I (4, 1.2%), K103N (3, 0.9%), Y181C (3, 0.9%), and P225H (1, 0.3%) were DRAMs to NNRTIs. M184V (1, 0.3%) and T215S (1, 0.3%) were DRAMs to NRTIs. M46L (2, 0.6%) was the only major DRAM to PI. Minor DRAMs to PIs including I13V, M36I, H69K, and L89M were more frequently observed in CRF_01 AE but A71V/T and V77I were more common in subtype B (P < 0.05). By multivariate analysis, the factors ‘HIV-1 subtype B’ and ‘low pretreated CD4 cell count’ were associated with higher rate of DRAMs. Conclusion: HIV-1 DRAMs, especially to NNRTIs, is emerging in a middle-income country after a widespread use of NNRTI-based ART. HIV genotypic assay prior to ART initiation in patients with chronic HIV-1 infection should be considered.
Minority HIV-1 Drug Resistance Mutations Are Present in Antiretroviral Treatment–Na?ve Populations and Associate with Reduced Treatment Efficacy  [PDF]
Jeffrey A Johnson ,Jin-Fen Li,Xierong Wei,Jonathan Lipscomb,David Irlbeck,Charles Craig,Amanda Smith,Diane E Bennett,Michael Monsour,Paul Sandstrom,E. Randall Lanier,Walid Heneine
PLOS Medicine , 2008, DOI: 10.1371/journal.pmed.0050158
Abstract: Background Transmitted HIV-1 drug resistance can compromise initial antiretroviral therapy (ART); therefore, its detection is important for patient management. The absence of drug-associated selection pressure in treatment-na?ve persons can cause drug-resistant viruses to decline to levels undetectable by conventional bulk sequencing (minority drug-resistant variants). We used sensitive and simple tests to investigate evidence of transmitted drug resistance in antiretroviral drug-na?ve persons and assess the clinical implications of minority drug-resistant variants. Methods and Findings We performed a cross-sectional analysis of transmitted HIV-1 drug resistance and a case-control study of the impact of minority drug resistance on treatment response. For the cross-sectional analysis, we examined viral RNA from newly diagnosed ART-na?ve persons in the US and Canada who had no detectable (wild type, n = 205) or one or more resistance-related mutations (n = 303) by conventional sequencing. Eight validated real-time PCR-based assays were used to test for minority drug resistance mutations (protease L90M and reverse transcriptase M41L, K70R, K103N, Y181C, M184V, and T215F/Y) above naturally occurring frequencies. The sensitive real-time PCR testing identified one to three minority drug resistance mutation(s) in 34/205 (17%) newly diagnosed persons who had wild-type virus by conventional genotyping; four (2%) individuals had mutations associated with resistance to two drug classes. Among 30/303 (10%) samples with bulk genotype resistance mutations we found at least one minority variant with a different drug resistance mutation. For the case-control study, we assessed the impact of three treatment-relevant drug resistance mutations at baseline from a separate group of 316 previously ART-na?ve persons with no evidence of drug resistance on bulk genotype testing who were placed on efavirenz-based regimens. We found that 7/95 (7%) persons who experienced virologic failure had minority drug resistance mutations at baseline; however, minority resistance was found in only 2/221 (0.9%) treatment successes (Fisher exact test, p = 0.0038). Conclusions These data suggest that a considerable proportion of transmitted HIV-1 drug resistance is undetected by conventional genotyping and that minority mutations can have clinical consequences. With no treatment history to help guide therapies for drug-na?ve persons, the findings suggest an important role for sensitive baseline drug resistance testing.
Characterization of the patterns of drug-resistance mutations in newly diagnosed HIV-1 infected patients na?ve to the antiretroviral drugs
Claudia Alteri, Valentina Svicher, Caterina Gori, Roberta D'Arrigo, Massimo Ciccozzi, Francesca Ceccherini-Silberstein, Marina Selleri, Stefano Bardacci, Massimo Giuliani, Paola Elia, Paola Scognamiglio, Roberta Balzano, Nicoletta Orchi, Enrico Girardi, Carlo Perno, SENDIH Study Group
BMC Infectious Diseases , 2009, DOI: 10.1186/1471-2334-9-111
Abstract: Prevalence of transmitted drug resistant strains is determined in 255 newly diagnosed HIV-1 infected patients enrolled in different counselling and testing (CT) centres in Central Italy; the Avidity Index (AI) on the first available serum sample is also used to estimate time since infection. Logistic regression models are used to determine factors associated with infection by drug resistant HIV-1 strains.The prevalence of HIV-1 strains with at least one major drug resistance mutation is 5.9% (15/255); moreover, 3.9% (10/255) of patients is infected with HIV nucleoside reverse transcriptase inhibitor (NRTI)-resistant viruses, 3.5% (9/255) with HIV non-NRTI-resistant viruses and 0.4% (1/255) with HIV protease inhibitor (PI)-resistant viruses. Most importantly, almost half (60.0%) of patients carries HIV-1 resistant strains with more than one major drug resistance mutation. In addition, patients who had acquired HIV through homosexual intercourses are more likely to harbour a virus with at least one primary resistance mutation (OR 7.7; 95% CI: 1.7–35.0, P = 0.008).The prevalence of drug resistant HIV-1 strains among newly diagnosed individuals in Central Italy is consistent with the data from other European countries. Nevertheless, the presence of drug-resistance HIV-1 mutations in complex patterns highlights an additional potential risk for public health and strongly supports the extension of wide genotyping to newly diagnosed HIV-1 infected patients.The development of resistance to the currently available antiretroviral drugs against HIV-1 infection is one of the major limitations to the maintenance of a successful treatment. Its frequent detection among HIV-infected treatment failing patients [1-3] can in turn increase the risk of new infections driven by drug-resistant viral strains [4]. This can carry important clinical implications. Indeed, once transmitted, a drug-resistant virus can persist for months to years without reversion to wild-type [5]. In addition, th
Prevalence of reverse transcriptase and protease mutations associated with antiretroviral drug resistance among drug-na?ve HIV-1 infected pregnant women in Kagera and Kilimanjaro regions, Tanzania
Balthazar M Nyombi, Carol Holm-Hansen, Knut I Kristiansen, Gunnar Bjune, Fredrik Müller
AIDS Research and Therapy , 2008, DOI: 10.1186/1742-6405-5-13
Abstract: The prevalence of mutations associated with antiretroviral drug resistance in protease (PR) and reverse transcriptase (RT) regions among antiretroviral treatment-na?ve HIV-1 infected pregnant women was investigated in Bukoba (Kagera) and Moshi (Kilimanjaro) municipalities, Tanzania, between September and December 2005. The HIV-1 pol gene was amplified using primers recognizing conserved viral sequences and sequenced employing BigDye chemistry from 100 HIV-1 seropositive treatment-na?ve pregnant women and 61 HIV-1 seropositive women who had received a single dose of Nevirapine (sdNVP). Positions 1–350 of the RT and 1–99 of the PR genes were analyzed for mutations based on the Stanford University HIV Drug Resistance Database.HIV-1 subtypes A, C, D, CRF10_CD and Unique Recombinant Forms (URF) were detected. Primary mutations associated with NRTI and NNRTI resistance were detected among 3% and 4% of treatment-na?ve strains, respectively. Primary mutations associated with NRTI and NNRTI resistance were detected in 1.6% and 11.5% of women who had received sdNVP, respectively. None of the primary mutations associated with PI resistance was found. Polymorphisms detected in RT and PR sequences were mainly mutations that are found in the consensus sequences of non-B subtypesBased on the WHO HIV Drug Resistance Research Network Threshold of less than 5%, the baseline prevalence of primary mutations among treatment-na?ve HIV-1 infected pregnant women in Kagera and Kilimanjaro regions was low. The significance of HIV-1 subtype B polymorphic positions with respect to antiretroviral resistance identified among the prevalent HIV-1 subtypes is unknown. More studies addressing the correlation between polymorphic mutations, antiretroviral resistance and clinical outcome are warranted in regions where non-B subtypes are prevalent.Tanzania is one of the countries in sub-Saharan Africa (SSA) most affected by the HIV pandemic. It was estimated that by the end of 2005 approximately 6.5% of
Prevalence and Clinical Significance of HIV Drug Resistance Mutations by Ultra-Deep Sequencing in Antiretroviral-Na?ve Subjects in the CASTLE Study  [PDF]
Max Lataillade,Jennifer Chiarella,Rong Yang,Steven Schnittman,Victoria Wirtz,Jonathan Uy,Daniel Seekins,Mark Krystal,Marco Mancini,Donnie McGrath,Birgitte Simen,Michael Egholm,Michael Kozal
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010952
Abstract: CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-na?ve subjects from 5 continents.
Prevalence of HIV type 1 drug resistance mutations in treatment-na?ve and experienced patients from resource-limited settings with universal access to antiretroviral therapy: a survey in two small Brazilian cities
Eyer-Silva, Walter A;Couto-Fernandez, José Carlos;Silva-de-Jesus, Carlos;Morgado, Mariza G;
Memórias do Instituto Oswaldo Cruz , 2008, DOI: 10.1590/S0074-02762008000200004
Abstract: concerns have been raised that universal availability of antiretroviral agents in resource-limited settings might lead to the emergence and spread of resistant strains. we present the largest survey on human immunodeficiency virus type 1 (hiv-1) resistance among treatment-na?ve and experienced patients followed in small, relatively underprivileged cities in brazil with universal availability to standard of care antiretroviral combinations. samples were collected between 2004 and 2006 from 95 patients followed in the cities of saquarema and santo antonio de pádua, state of rio de janeiro. a proviral fragment encompassing protease and reverse transcriptase (rt) regions was generated and drug susceptibility level was inferred. among 50 strains from drug-na?ve subjects, one (2%) had intermediate-level resistance to rt inhibitors. among 38 patients on therapy as of sampling, 28 (73.7%) had plasma viral load (pvl) below detection limit (26 of whom without evidence of resistance mutations) and 11 (28.9%) harbored strains with reduced susceptibility. only two strains harbored both protease and rt inhibitor mutations. among seven patients who were off-treatment as of sampling, two (28.5%) harbored strains with reduced susceptibility to rt inhibitors. the relatively high frequency of undetectable pvl among patients on treatment and the overall low prevalence of resistance-associated mutations are reassuring. continued surveillance, however, is necessary.
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