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Simon Mallal - One of the best experts on this subject based on the ideXlab platform.
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contribution of nucleoside analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level
Antiviral Therapy, 2003Co-Authors: D Nolan, E Hammond, I James, E Mckinnon, Simon MallalAbstract:Objectives: It has been proposed that the contribution of nucleoside-analogue reverse transcriptase inhibitor (NRTI) therapy to subcutaneous fat wasting involves adipose tissue-specific mitochondrial DNA toxicity. We have investigated the relationships between NRTI therapy, adipocyte mitochondrial DNA content, evidence of toxicity in adipose tissue and fat wasting in Caucasian male Western Australian HIV Cohort study participants. Methods: Longitudinal mixed effects analysis of fat wasting was undertaken in individuals receiving initial Stavudine- or zidovudine-containing highly active antiretroviral therapy (HAART) (n=49, 149 DEXA measurements). Adipocyte mitochondrial DNA (mtDNA) depletion was also assessed according to current NRTI therapy in 92 subcutaneous fat biopsies from 69 HIV-positive individuals and seven healthy controls, and results were correlated with fat wasting among a subset of patients with biopsy data receiving initial Stavudine- or zidovudine-containing HAART (n=22, 103 DEXA measurements). Confocal microscopy was performed in 22 biopsy samples obtained before and after initiating/switching NRTI therapy. Results: Stavudine therapy was associated with more severe adipocyte mitochondrial DNA depletion (P<0.001) and fat wasting over time (P=0.002) compared with zidovudine therapy in independent analyses. Among patients with concurrent biopsy and longitudinal DEXA data, fat wasting was associated with duration of NRTI therapy (P=0.001) and adipocyte mtDNA copies/cell (P=0.01). In this analysis, the significant association between choice of Stavudine versus zidovudine and fat wasting (P=0.03) was lost after adjustment for the effect of mtDNA depletion (P=0.13). Confocal analysis provided direct evidence of a relationship between severity of adipose tissue toxicity and mitochondrial DNA depletion. No significant effects of HIV protease inhibitor therapy were detected in these analyses. Conclusions: Severity of subcutaneous fat wasting is primarily determined by choice of NRTI therapy (Stavudine versus zidovudine) and by duration of exposure to the relevant NRTI. At the cellular level, evidence is provided that this effect manifests through NRTI-induced mitochondrial DNA depletion.
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mitochondrial proliferation dna depletion and adipocyte differentiation in subcutaneous adipose tissue of hiv positive haart recipients
Antiviral Therapy, 2003Co-Authors: Craig S Pace, D Nolan, E Hammond, A Martin, Cyril D S Mamotte, Simon MallalAbstract:Objectives: To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype. Design and methods: DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPARg, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype. Results: Stavudine-based HAART recipients (n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARgamma (53.9% of control, P=0.021), UCP2 (62.2% of control, P=0.024) and UCP3 (51.8% of control, P=0.047) mRNA compared with controls. Zidovudine-based HAART recipients (n=7) also displayed significant mtDNA depletion (34.45% of control, P=0.031), increased mitochondrial protein mass (5.7-fold of control, P=0.009), and markedly increased UCP1 (18-fold of control, P=0.009) mRNA. Elevated UCP1 mRNA expression was found to be associated with non-Stavudine (zidovudine or abacavir), protease inhibitor (PI)-containing HAART (95-fold of non-Stavudine, non-PI-containing HAART, P=0.006). Conclusion: Differential effects of Stavudine and zidovudine therapy on mtDNA depletion and expression of adipocyte differentiation markers PPARgamma and UCP2 were observed, consistent with increased adipose tissue toxicity associated with Stavudine therapy. Increased UCP1 mRNA, a marker of brown adipose tissue phenotype, was associated with non-Stavudine, PI-containing HAART, and may represent an adaptive response to the increased fatty acid flux associated with PI therapy, and may contribute to the increased resting energy expenditure reported in such patients.
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randomized controlled 48 week study of switching Stavudine and or protease inhibitors to combivir abacavir to prevent or reverse lipoatrophy in hiv infected patients
Journal of Acquired Immune Deficiency Syndromes, 2003Co-Authors: M John, D Nolan, I James, E Mckinnon, S Herrmann, C Moore, Alex J White, Simon MallalAbstract:Objective: HIV-1 protease inhibitors (versus no protease inhibitors) and Stavudine (versus zidovudine) are independently associated with a higher risk of lipoatrophy in HIV-infected patients. We sought to determine whether the revision of Stavudine and/or protease inhibitor-containing regimens to combivir/abacavir would result in prevention and/or reversibility of lipoatrophy in HIV-1-infected patients. Design: The investigation was a prospective, randomized, controlled, open-label study. Subjects: The subjects included 37 HIV-1-infected individuals with stable undetectable HIV-1 loads who were taking a regimen containing either Stavudine or zidovudine with lamivudine and a protease inhibitor. Intervention: Subjects were randomized to continue therapy or switch Stavudine to zidovudine and protease inhibitor to abacavir, such that the universal switch regimen was combivir (zidovudine/lamivudine) and abacavir. Main Outcome Measures: Total body, leg, and arm fat mass was measured at baseline, 24 weeks, and 48 weeks using whole-body dual-energy x-ray absorptiometry. Single-cut L4 computed tomography and assays of multiple metabolic parameters were also performed. Results: There was an average gain in fat mass of 0.009 kg/(leg.mo) in switch patients versus a loss of 0.010 kg/(leg.mo) in controls (p =.04, on-treatment analysis) over 48 weeks. Significant arm fat restoration was observed in patients who switched regimens, with an average gain of 0.014 kg/(arm.mo) (p =.004), whereas controls did not have a significant change from baseline. Analyses of percentage changes in arm and leg fat masses showed similar findings. No significant effects on intraabdominal fat, blood lipid levels, glycemic indices, and lactate levels were detected, although most baseline mean values were normal in study subjects. Combivir/abacavir maintained virological control in all but one case, and three (13.6%) of 22 individuals had adverse reactions to abacavir therapy. Conclusions: A switch to combivir/abacavir therapy was associated with objective evidence of limb fat-sparing and fat restoration compared with continued treatment with Stavudine and/or protease inhibitor.
Jeanmichel Molina - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of emtricitabine vs Stavudine in combination therapy in antiretroviral naive patients a randomized trial
JAMA, 2004Co-Authors: Michael S Saag, Jeanmichel Molina, Pedro Cahn, Francois Raffi, Marcelo Wolff, Daniel Pearce, William G Powderly, Audrey L Shaw, Elsa Mondou, John HinkleAbstract:ContextEmtricitabine is a new, once-daily nucleoside reverse transcriptase inhibitor (NRTI) with potent activity against human immunodeficiency virus (HIV).ObjectiveTo assess the efficacy and safety of emtricitabine as compared with Stavudine when used with a background regimen of didanosine and efavirenz.Design, Setting, and PatientsRandomized, double-blind, double-dummy study conducted at 101 research clinics in North America, Latin America, and Europe. The first patient was enrolled on August 21, 2000; no investigator or patient was unblinded until the last patient randomized completed the week 48 visit on October 24, 2002. Analyses were based on data collected in a double-blind setting with a median follow-up of 60 weeks. Patients were 571 antiretroviral-naive, HIV-1–infected adults aged 18 years or older with viral load levels greater than or equal to 5000 copies/mL.InterventionsReceipt of either 200 mg of emtricitabine once daily (plus Stavudine placebo twice daily) (n = 286) or Stavudine at standard doses twice daily (plus emtricitabine placebo once daily) (n = 285) plus open-label didanosine and efavirenz, once daily.Main Outcome MeasurePersistent virological response, defined as achieving and maintaining viral load at or below the limit of assay quantification (≤400 or 50 copies/mL).ResultsAt the interim analysis on June 14, 2002, when the last patient randomized completed 24 weeks of double-blind treatment (median follow-up time of 42 weeks), patients in the emtricitabine group had a higher probability of a persistent virological response ≤50 copies/mL vs the Stavudine group (85% vs 76%, P = .005). This was associated with a higher mean CD4 cell count change from baseline for the emtricitabine group (156 cells/µL vs 119 cells/µL, P = .01 [of note, there was no statistical difference at 48 weeks {P = .15}, although a sensitivity analysis, using an intent-to-treat population with the last CD4 cell count observation carried forward to week 48 showed a difference {P = .02}]). The independent data and safety monitoring board recommended offering open-label emtricitabine based on the interim analysis. The probability of persistent virological response ≤50 copies/mL through week 60 was 76% for the emtricitabine group vs 54% for the Stavudine group (P<.001). The probability of virological failure through week 60 was 4% in the emtricitabine group and 12% in the Stavudine group (P<.001). Patients in the Stavudine group had a greater probability of an adverse event that led to study drug discontinuation through week 60 than did those in the emtricitabine group (15% vs 7%, P = .005).ConclusionOnce-daily emtricitabine appeared to demonstrate greater virological efficacy, durability of response, and tolerability compared with twice-daily Stavudine when used with once-daily didanosine and efavirenz.
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comparison of genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 isolates from patients treated with Stavudine and didanosine or zidovudine and lamivudine
The Journal of Infectious Diseases, 2001Co-Authors: Veronique Picard, Francoise Ferchal, Genevieve Chene, Emmanuelle Angelini, Anne Maillard, Esther Race, Francois Clavel, Jeanmichel MolinaAbstract:Sequencing of reverse-transcriptase genes and recombinant virus assays were performed on paired isolates from antiretroviral drug-naive patients randomized to Stavudine and didanosine (group 1; n = 21) or zidovudine and lamivudine (group 2; n = 21) at baseline and after ≥12 months of follow-up. The T215Y mutation emerged in 13 (61.9%) and 2 (9.5%) isolates in groups 1 and 2, respectively (P 38 in groups 1 and 2, respectively (P<.0001, all comparisons). These results suggest that the combination of Stavudine and didanosine is associated more frequently with the emergence of zidovudine resistance and a decrease in susceptibility to Stavudine than the combination of zidovudine and lamivudine.
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the albi trial a randomized controlled trial comparing Stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with human immunodeficiency virus
The Journal of Infectious Diseases, 1999Co-Authors: Jeanmichel Molina, Francoise Ferchal, Isabelle Pellegrin, Marienoelle Sombardier, Valerie Journot, Corinne Rancinan, Laurent Cotte, Genevieve Chene, Isabelle Madelaine, T. DebordAbstract:A total of 151 previously untreated patients infected with human immunodeficiency virus type 1 (HIV-1) with CD4 cell counts ≥200/μL and plasma HIV-1 RNA levels of 10,000-100,000 copies/mL were randomly assigned to 24 weeks of open-labeled Stavudine plus didanosine (group 1), zidovudine plus lamivudine (group 2), or Stavudine plus didanosine followed by zidovudine plus lamivudine (group 3). The mean decrease in HIV-1 RNA level was greater in group 1 (2.26 log 10 copies/mL) than in groups 2 (1.26 log 10 copies/mL) or 3 (1.58 log 10 copies/ mL; P<.0001). The mean increase in CD4 cell counts was greater in groups 1 (124 cells/μL) and 3 (118 cells/μL) than in group 2 (62 cells/μL; P =.02). All regimens were generally well tolerated. The combination of Stavudine plus didanosine reduced plasma HIV-1 RNA concentrations and increased CD4 cell counts more effectively than did the combination of zidovudine plus lamivudine or the regimen alternating both combinations.
Sophie Matheron - One of the best experts on this subject based on the ideXlab platform.
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impact of Stavudine phenotype and thymidine analogues mutations on viral response to Stavudine plus lamivudine in altis 2 anrs trial
Antiviral Therapy, 2002Co-Authors: Vincent Calvez, Dominique Costagliola, Diane Descamps, Anne Yvon, Gilles Collin, Agnes Cecile, Constance Delaugerre, Florence Damond, Annegenevieve Marcelin, Sophie MatheronAbstract:Objective: Stavudine-based antiretroviral combinations are less effective in zidovudine-experienced patients than in naive subjects and recently, mutations have been described to be associated to the use of both Stavudine and zidovudine. In the ALTIS 2 trial, it was shown that a combination of Stavudine and lamivudine is less effective in zidovudine-experienced patients than in naive patients. We conducted a retrospective genotypic and phenotypic resistance study (expressed as Stavudine phenotypic index, calculated by dividing the inhibitory concentrations 50% [IC 50 ] by the mean value of the sensitive viruses) to evaluate the factors associated with decrease in plasma HIV-1 RNA. Design: Associations with continuous variables were studied using non-parametric Spearman correlation coefficients. Associations with categorical variables were studied using non-parametric Mann-Whitney tests. Multivariate stepwise regression analyses were used to determine independent prognostic factors of the virological response. Results: At baseline, most of the subjects harboured zidovudine-associated mutations in plasma and peripheral blood mononuclear cells. Zidovudine and Stavudine IC 50 and IC 90 were strongly associated with response. It appears that a cut-off of Stavudine phenotypic index of 1.8-fold of IC 50 , much lower than the usually used value, could be clinically significant for response to Stavudine. In the multivariate analysis, the stepwise model with the higher multiple correlation coefficient (R 2 =0.742) included the presence of a 215 Y/F mutation, the number of previously used nucleoside analogues and a resistant Stavudine phenotype. Conclusion: These results argue for a phenotypic and genotypic cross resistance between Stavudine and zidovudine. Modest increases of IC 50 and IC 90 for Stavudine had an important impact on the virological response during the trial and plead for a new definition of the threshold value for Stavudine phenotypic index.
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low rate emergence of thymidine analogue mutations and multi drug resistance mutations in the hiv 1 reverse transcriptase gene in therapy naive patients receiving Stavudine plus lamivudine combination therapy
Antiviral Therapy, 2001Co-Authors: Mireille Mouroux, Diane Descamps, Anne Yvon, Constance Delaugerre, Sophie Matheron, Jacques Izopet, Anne Coutellier, Marcantoine Valantin, Manuella Bonmarchand, Henri AgutAbstract:179 Objectives: Mutations usually associated with zidovudine exposure have been observed in zidovudine-naive patients treated by Stavudine in combination. These mutations were named thymidine analogue mutations (TAMs). This fact, combined with phenotypical and biochemical findings provided additional evidence for cross-resistance between zidovudine and Stavudine. A recent genotypic study in naive patients receiving Stavudine/didanosine combination showed emergence of TAMs and a multidrug-resistance mutation (MDR), Q151M, in 36 and 10% of cases, respectively. Stavudine plus lamivudine is one of the most used binucleoside associations in the antiretroviral combinations. The objective of this study was to assess the genotypic changes in the HIV-1 reverse transcriptase (RT) gene in antiretroviralnaive patients treated by Stavudine plus lamivudine. Methods: We analysed the RT gene of 44 HIV-1 patients, naive of antiretroviral therapy, who were treated for 24 or 48 weeks with Stavudine/lamivudine. Results: At the end of the follow-up, all patients acquired the lamivudine-associated mutation M184V. Only two subjects (4.5%) developed a TAM (T215Y; M41L), one subject developed a V75T/A mutation and one subject developed the particular MDR pattern F116Y, Q151M. Conclusions: Our study clearly demonstrated that naive subjects treated with Stavudine/lamivudine for 24‐48 weeks selected a low rate of TAMs and MDR Q151M. One hypothesis explaining these results could be the development of the M184V mutation.
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efficacy and tolerability of Stavudine plus lamivudine in treatment naive and treatment experienced patients with hiv 1 infection
Annals of Internal Medicine, 1998Co-Authors: C Katlama, Vincent Calvez, Diane Descamps, Sophie Matheron, Anne Coutellier, Marcantoine Valantin, Christophe Longuet, Manuela Bonmarchand, Roland Tubiana, Remi LancarAbstract:Background: A combination of two nucleoside analogues is currently the core of any antiretroviral regimen for HIV-1 infection. Stavudine plus lamivudine has shown an additive effect in vitro, as we...
D Nolan - One of the best experts on this subject based on the ideXlab platform.
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contribution of nucleoside analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level
Antiviral Therapy, 2003Co-Authors: D Nolan, E Hammond, I James, E Mckinnon, Simon MallalAbstract:Objectives: It has been proposed that the contribution of nucleoside-analogue reverse transcriptase inhibitor (NRTI) therapy to subcutaneous fat wasting involves adipose tissue-specific mitochondrial DNA toxicity. We have investigated the relationships between NRTI therapy, adipocyte mitochondrial DNA content, evidence of toxicity in adipose tissue and fat wasting in Caucasian male Western Australian HIV Cohort study participants. Methods: Longitudinal mixed effects analysis of fat wasting was undertaken in individuals receiving initial Stavudine- or zidovudine-containing highly active antiretroviral therapy (HAART) (n=49, 149 DEXA measurements). Adipocyte mitochondrial DNA (mtDNA) depletion was also assessed according to current NRTI therapy in 92 subcutaneous fat biopsies from 69 HIV-positive individuals and seven healthy controls, and results were correlated with fat wasting among a subset of patients with biopsy data receiving initial Stavudine- or zidovudine-containing HAART (n=22, 103 DEXA measurements). Confocal microscopy was performed in 22 biopsy samples obtained before and after initiating/switching NRTI therapy. Results: Stavudine therapy was associated with more severe adipocyte mitochondrial DNA depletion (P<0.001) and fat wasting over time (P=0.002) compared with zidovudine therapy in independent analyses. Among patients with concurrent biopsy and longitudinal DEXA data, fat wasting was associated with duration of NRTI therapy (P=0.001) and adipocyte mtDNA copies/cell (P=0.01). In this analysis, the significant association between choice of Stavudine versus zidovudine and fat wasting (P=0.03) was lost after adjustment for the effect of mtDNA depletion (P=0.13). Confocal analysis provided direct evidence of a relationship between severity of adipose tissue toxicity and mitochondrial DNA depletion. No significant effects of HIV protease inhibitor therapy were detected in these analyses. Conclusions: Severity of subcutaneous fat wasting is primarily determined by choice of NRTI therapy (Stavudine versus zidovudine) and by duration of exposure to the relevant NRTI. At the cellular level, evidence is provided that this effect manifests through NRTI-induced mitochondrial DNA depletion.
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mitochondrial proliferation dna depletion and adipocyte differentiation in subcutaneous adipose tissue of hiv positive haart recipients
Antiviral Therapy, 2003Co-Authors: Craig S Pace, D Nolan, E Hammond, A Martin, Cyril D S Mamotte, Simon MallalAbstract:Objectives: To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype. Design and methods: DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPARg, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype. Results: Stavudine-based HAART recipients (n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARgamma (53.9% of control, P=0.021), UCP2 (62.2% of control, P=0.024) and UCP3 (51.8% of control, P=0.047) mRNA compared with controls. Zidovudine-based HAART recipients (n=7) also displayed significant mtDNA depletion (34.45% of control, P=0.031), increased mitochondrial protein mass (5.7-fold of control, P=0.009), and markedly increased UCP1 (18-fold of control, P=0.009) mRNA. Elevated UCP1 mRNA expression was found to be associated with non-Stavudine (zidovudine or abacavir), protease inhibitor (PI)-containing HAART (95-fold of non-Stavudine, non-PI-containing HAART, P=0.006). Conclusion: Differential effects of Stavudine and zidovudine therapy on mtDNA depletion and expression of adipocyte differentiation markers PPARgamma and UCP2 were observed, consistent with increased adipose tissue toxicity associated with Stavudine therapy. Increased UCP1 mRNA, a marker of brown adipose tissue phenotype, was associated with non-Stavudine, PI-containing HAART, and may represent an adaptive response to the increased fatty acid flux associated with PI therapy, and may contribute to the increased resting energy expenditure reported in such patients.
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randomized controlled 48 week study of switching Stavudine and or protease inhibitors to combivir abacavir to prevent or reverse lipoatrophy in hiv infected patients
Journal of Acquired Immune Deficiency Syndromes, 2003Co-Authors: M John, D Nolan, I James, E Mckinnon, S Herrmann, C Moore, Alex J White, Simon MallalAbstract:Objective: HIV-1 protease inhibitors (versus no protease inhibitors) and Stavudine (versus zidovudine) are independently associated with a higher risk of lipoatrophy in HIV-infected patients. We sought to determine whether the revision of Stavudine and/or protease inhibitor-containing regimens to combivir/abacavir would result in prevention and/or reversibility of lipoatrophy in HIV-1-infected patients. Design: The investigation was a prospective, randomized, controlled, open-label study. Subjects: The subjects included 37 HIV-1-infected individuals with stable undetectable HIV-1 loads who were taking a regimen containing either Stavudine or zidovudine with lamivudine and a protease inhibitor. Intervention: Subjects were randomized to continue therapy or switch Stavudine to zidovudine and protease inhibitor to abacavir, such that the universal switch regimen was combivir (zidovudine/lamivudine) and abacavir. Main Outcome Measures: Total body, leg, and arm fat mass was measured at baseline, 24 weeks, and 48 weeks using whole-body dual-energy x-ray absorptiometry. Single-cut L4 computed tomography and assays of multiple metabolic parameters were also performed. Results: There was an average gain in fat mass of 0.009 kg/(leg.mo) in switch patients versus a loss of 0.010 kg/(leg.mo) in controls (p =.04, on-treatment analysis) over 48 weeks. Significant arm fat restoration was observed in patients who switched regimens, with an average gain of 0.014 kg/(arm.mo) (p =.004), whereas controls did not have a significant change from baseline. Analyses of percentage changes in arm and leg fat masses showed similar findings. No significant effects on intraabdominal fat, blood lipid levels, glycemic indices, and lactate levels were detected, although most baseline mean values were normal in study subjects. Combivir/abacavir maintained virological control in all but one case, and three (13.6%) of 22 individuals had adverse reactions to abacavir therapy. Conclusions: A switch to combivir/abacavir therapy was associated with objective evidence of limb fat-sparing and fat restoration compared with continued treatment with Stavudine and/or protease inhibitor.
Catherine L Cherry - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in camkk2 associate with susceptibility to sensory neuropathy in hiv patients treated without Stavudine
Journal of NeuroVirology, 2019Co-Authors: Jessica Gaff, Catherine L Cherry, P B Price, Fitri Octaviana, Ibnu Ariyanto, Simon M LawsAbstract:HIV-associated sensory neuropathy (HIV-SN) is a debilitating neurological complication of HIV infection potentiated by the antiretroviral drug Stavudine. While Stavudine is no longer used, HIV-SN now affects around 15% of HIV+ Indonesians. Here, we investigate whether polymorphisms within the P2X-block (P2X4R, P2X7R, CAMKK2) and/or ANAPC5 mark susceptibility to HIV-SN in this setting. As polymorphisms in these genes associated with HIV-SN in African HIV patients receiving Stavudine, the comparison can identify mechanisms independent of Stavudine. HIV patients who had never used Stavudine (n = 202) attending clinics in Jakarta were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Open-array technology was used to type 48 polymorphisms spanning the four genes. Haplotypes were derived for each gene using fastPHASE. Haplogroups were constructed with median-joining methods. Multivariable models optimally predicting HIV-SN were based on factors achieving p < 0.2 in bivariate analyses. Minor alleles of three co-inherited polymorphisms in CAMKK2 (rs7975295*C, rs1560568*A, rs1132780*T) associated with a reduced prevalence of HIV-SN individually and after adjusting for lower CD4 T cell count and viremia (p = 0.0002, pseudo R2 = 0.11). The optimal model for haplotypes linked HIV-SN with viremia and lower current CD4 T cell count, plus CAMKK2 haplotypes 6 and 11 and P2X7R haplotypes 2 and 12 (p = 0.0002; pseudo R2 = 0.11). CAMKK2 haplogroup A (includes 16 haplotypes and all instances of rs7975295*C, rs1560568*A, rs1132780*T) associated with reduced rates of HIV-SN (p = 0.02, OR = 0.43 CI = 0.21–0.88). These findings support a protective role for these three alleles, suggesting a role in the pathogenesis of HIV-SN that is independent of Stavudine.
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hiv neuropathy risk factors and symptom characterization in Stavudine exposed south africans
Journal of Pain and Symptom Management, 2011Co-Authors: Antonia L Wadley, Catherine L Cherry, P B Price, Peter R KamermanAbstract:Abstract Context HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of both HIV and neurotoxic antiretroviral medications such as Stavudine. Objectives To determine the prevalence, risk factors, and clinical characteristics of symptomatic HIV-SN in a Black South African cohort of patients exposed to Stavudine. Methods HIV-positive Black South Africans ( n =395) who had received Stavudine for at least six months were recruited at the Virology Clinic of the Charlotte Maxeke Academic Johannesburg Hospital, South Africa, and screened for neuropathy using the AIDS Clinical Trials Group neuropathy screening tool. HIV-SN was defined as present if the patient had both symptoms and signs of peripheral neuropathy. If present, the distribution and intensity of symptoms were recorded. In addition, anthropomorphic, demographic, and clinical information were recorded and analyzed as risk factors. Results The prevalence of symptomatic HIV-SN was 57% (226 of 395). Increasing age and height were independently associated with the development of SN among patients who had used Stavudine. Pain was the primary symptom reported by participants with HIV-SN (76%, 172 of 226), followed by numbness (48%, 108 of 226), and pins and needles (46%, 105 of 226). About three-quarters of participants rated their symptoms as being of moderate to severe intensity. Symptoms were always present in the feet and only 23% experienced symptoms proximal to the feet. Conclusion HIV-SN was common in this population and frequently associated with moderate to severe pain in the feet. HIV-SN was significantly associated with increasing age and height, factors that could be measured at no added cost prior to Stavudine prescription, allowing higher risk patients to be offered priority access to nonneurotoxic drugs.
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age and height predict neuropathy risk in patients with hiv prescribed Stavudine
Neurology, 2009Co-Authors: Catherine L Cherry, Jacquita S Affandi, Darma Imran, Evy Yunihastuti, K Smyth, Sasheela Vanar, Adeeba Kamarulzaman, P B PriceAbstract:Objective: Sensory neuropathy is a common problem in HIV-infected patients and is the dose-limiting toxicity of Stavudine. Affordable methods of predicting neuropathy risk are needed to guide prescribing in countries where some use of Stavudine remains an economic necessity. We therefore aimed to identify factors predictive of neuropathy risk before antiretroviral use. Methods: A total of 294 patients attending clinics in Melbourne, Kuala Lumpur, and Jakarta were enrolled in a cross-sectional neuropathy screening program in 2006. Neuropathy was defined by the presence of symptoms and signs on the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Demographic, laboratory, and treatment details were considered as possible risk factors for neuropathy. The role of patient demographics in predicting Stavudine neuropathy were then assessed in 181 patients who reported that they were free of neuropathy symptoms when first prescribed this drug. Results: The prevalence of neuropathy was 42% in Melbourne (n = 100), 19% in Kuala Lumpur (n = 98), and 34% in Jakarta (n = 96). In addition to treatment exposures, increasing age ( p = 0.002) and height ( p = 0.001) were independently associated with neuropathy. Age and height cutoffs of ≥170 cm or ≥40 years predicted neuropathy. Among 181 patients who were asymptomatic before Stavudine exposure, the risk of neuropathy following Stavudine was 20% in younger, shorter patients, compared with 66% in older, taller individuals. Conclusions: Stavudine neuropathy risk increases with patient age and height. Prioritizing older and taller patients for alternative agents would be an inexpensive strategy to reduce neuropathy rates in countries where the burden of HIV disease limits treatment options.
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can we predict neuropathy risk before Stavudine prescription in a resource limited setting
AIDS Research and Human Retroviruses, 2008Co-Authors: Jacquita S Affandi, Darma Imran, Evy Yunihastuti, P B Price, Samsuridjal Djauzi, Catherine L CherryAbstract:Abstract A toxic sensory neuropathy associated with exposure to inexpensive nucleoside analogue reverse transcriptase inhibitors (NRTIs) [particularly Stavudine (d4T)] causes dilemmas in the manage...
