The Experts below are selected from a list of 40020 Experts worldwide ranked by ideXlab platform

Jose R Arribas - One of the best experts on this subject based on the ideXlab platform.

Mike Sharland - One of the best experts on this subject based on the ideXlab platform.

  • Triple Nucleoside Reverse Transcriptase Inhibitor Therapy in Children
    Pediatric Drugs, 2004
    Co-Authors: Jennifer Handforth, Mike Sharland
    Abstract:

    Much of the success attributed to HIV therapy in the last few years has resulted from improved ways of using existing drugs in combination therapy regimens. The availablity of new, more potent drugs such as protease Inhibitors and more accurate viral load tests to aid decisions to start or change treatment has also contributed to the success. Published recommendations for pediatric HIV therapy, generated by a panel of experts and specialists, are readily available and regularly updated. Preferred regimens of ‘potent’ therapy (referred to as highly active antiretroviral therapy, or HAART) currently consist of two nucleoside reverse transcriptase Inhibitors (NRTIs) combined with either a non-nucleoside reverse transcriptase Inhibitor (NNRTI) or a protease Inhibitor. More intense four-drug regimens using an NNRTI or a second protease Inhibitor as a fourth drug are being evaluated. Problems with HAART include: unpalatable drug formulations and adverse effects, coupled with lack of data on the pharmacokinetics, efficacy, and safety of various drug combinations. Adherence is a major factor influencing the efficacy and outcome of antiretroviral therapy. Many children cannot adhere to complex multidrug regimens, which cause virologic failure, despite excellent CD4+ cell count responses. This means a rapid progression through the limited number of treatment regimens available. Simpler regimens such as those containing three NRTIs have been proposed as a method of treatment that will allow suppression of the virus, yet circumvent many of the problems previously mentioned. An additional benefit would be the preservation of antiretroviral drugs from other classes for future treatment options if required. The major advantages of triple NRTI regimens are the simplicity of the regimen, good tolerability, few drug-drug interactions, and infrequent adverse effects coupled with a low pill burden. However, abacavir hypersensitivity remains a major problem. Up to 3% of patients may develop an early idiosyncratic hypersensitivity reaction — fever, malaise, and mucositis with or without rash, which can progress to more advanced stages of shock and death. A major concern is the apparently inferior virologic control of triple NRTI therapy as demonstrated in the AIDS Clinical Trials Group A5095 study with zidovudine/lamivudine/abacavir (Trizivir®) combination in adults. Such a combination should only be considered in special situations. Examples cited include informed patient choice based on anticipated poor adherence on other treatment regimens, or if concomitant drugs such as tuberculosis medication are prescribed. The low pill burden of triple NRTI regimens (especially if combined in a single pill such as Trizivir®), offers hope that regimen simplification may still be possible in the future.

  • Triple nucleoside reverse transcriptase Inhibitor therapy in children.
    Paediatric drugs, 2004
    Co-Authors: Jennifer Handforth, Mike Sharland
    Abstract:

    Much of the success attributed to HIV therapy in the last few years has resulted from improved ways of using existing drugs in combination therapy regimens. The availablity of new, more potent drugs such as protease Inhibitors and more accurate viral load tests to aid decisions to start or change treatment has also contributed to the success. Published recommendations for pediatric HIV therapy, generated by a panel of experts and specialists, are readily available and regularly updated. Preferred regimens of ‘potent’ therapy (referred to as highly active antiretroviral therapy, or HAART) currently consist of two nucleoside reverse transcriptase Inhibitors (NRTIs) combined with either a non-nucleoside reverse transcriptase Inhibitor (NNRTI) or a protease Inhibitor. More intense four-drug regimens using an NNRTI or a second protease Inhibitor as a fourth drug are being evaluated. Problems with HAART include: unpalatable drug formulations and adverse effects, coupled with lack of data on the pharmacokinetics, efficacy, and safety of various drug combinations.

Jade Ghosn - One of the best experts on this subject based on the ideXlab platform.

  • Nucleoside reverse transcriptase Inhibitor-sparing regimen (nonnucleoside reverse transcriptase Inhibitor + protease Inhibitor) was more likely associated with resistance comparing to nonnucleoside reverse transcriptase Inhibitor or protease inhibito
    AIDS, 2009
    Co-Authors: Cathia Soulié, Dominique Costagliola, Lambert Assoumou, Jade Ghosn, Claudine Duvivier, Gilles Peytavin, Zaina Ait-arkoub, Jean-michel Molina, Christine Katlama, Vincent Calvez
    Abstract:

    The use of nonnucleoside reverse transcriptase Inhibitor (NNRTI) + protease Inhibitor regimen for the treatment of antiretroviral-naive patients was less successful than classical nucleoside reverse transcriptase Inhibitor (NRTI) based regimen and associated with more resistance for protease Inhibitors and NNRTIs. The selection for NNRTI resistance was particularly observed in patients with high viral load (>100 000 copies/ml) and low efavirenz trough levels (

  • greater decrease in bone mineral density with protease Inhibitor regimens compared with nonnucleoside reverse transcriptase Inhibitor regimens in hiv 1 infected naive patients
    AIDS, 2009
    Co-Authors: Claudine Duvivier, Lambert Assoumou, Jade Ghosn, S Kolta, Sylvie Rozenberg, Robert L Murphy, C Katlama
    Abstract:

    OBJECTIVE: To evaluate the change in bone mineral density (BMD) at specific sites in patients initiating antiretroviral therapy in a substudy of the ANRS 121 trial. METHODS: Antiretroviral-naive patients were randomized (2: 1: 1) into three treatment strategy arms: a nonnucleoside reverse transcriptase Inhibitor (NNRTI) and a boosted protease Inhibitor (PI/r), a PI/r and two nucleoside reverse transcriptase Inhibitors (NRTIs) or an NNRTI and NRTIs. Hip and lumbar spine standardized BMD were evaluated at baseline and week 48 by dual X-ray absorptiometry by a central reading laboratory. RESULTS: Seventy-one patients were enrolled: 36 in the PI/r and NNRTI, 19 in the PI/r and NRTIs and 16 in the NNRTI and NRTIs arms. Baseline characteristics were [median (interquartile range)]: male (77%), age 40 years (33-49), 69% white, 58% smokers, BMI 23 kg/m2 (21-24), CD4 cell count 219 cells/microl (144-285). In the arms with NRTIs, 86% of patients received zidovudine/lamivudine. At baseline, 31% had osteopenia and 3% had osteoporosis. At week 48, there was a mean change in BMD of -4.1 +/- 3.9% at lumbar spine and -2.8 +/- 4.7% at hip (both P< or = 0.001). The decrease of BMD at lumbar spine was significantly worse in the PI/r and NNRTI arm (-4.4 +/- 3.4%) and in the PI/r and NRTIs arm (-5.8 +/- 4.5%) compared with the NNRTI and NRTIs arm (-1.5 +/- 2.9%), P = 0.007 and P = 0.001, respectively. CONCLUSION: BMD was impaired in 34% of patients, before starting any antiretrovirals. After 1 year, the decrease in lumbar spine BMD was more pronounced in patients receiving either PI/r-containing regimen compared with NNRTI and NRTIs. BMD at specific sites should be monitored during lifelong antiretroviral therapy.

  • HIV-1 resistance to first- and second-generation non-nucleoside reverse transcriptase Inhibitors.
    AIDS reviews, 2009
    Co-Authors: Jade Ghosn, Marie-laure Chaix, Constance Delaugerre
    Abstract:

    Resistance to the first-generation non-nucleoside reverse transcriptase Inhibitors nevirapine and efavirenz is characterized by rapid selection of viruses carrying one or several mutations in the reverse transcriptase gene, which immediately confer high-level resistance as well as cross-resistance to the two drugs. Such mutations have been detected close to the non-nucleoside reverse transcriptase Inhibitor binding site and also in the connection domain of HIV reverse transcriptase. They lead to a loss of drug affinity without affecting viral fitness. As a single mutation is enough to confer high-level resistance, transmission of non-nucleoside reverse transcriptase Inhibitor-resistant viruses (currently 2-7% of cases) is strongly associated with virologic failure of non-nucleoside reverse transcriptase Inhibitor-based first-line regimens. The development of second-generation non-nucleoside reverse transcriptase Inhibitors is a major challenge. The most promising compounds, etravirine and rilpivirine, are active on mutant viruses and possess a relatively high genetic barrier for resistance. Data on etravirine resistance in patients already exposed to first-generation non-nucleoside reverse transcriptase Inhibitors show that, among 17 mutations in the reverse transcriptase gene, at least three must be present simultaneously in order to diminish etravirine activity. Recent studies of the prevalence of resistance in large databases of patients already exposed to nevirapine and efavirenz show that more than three-quarters of strains will still be sensitive to etravirine in both the southern and northern hemispheres. The first data on rilpivirine resistance are encouraging, but still too preliminary.

Grace A Mccomsey - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and tolerability of 3 nonnucleoside reverse transcriptase Inhibitor sparing antiretroviral regimens for treatment naive volunteers infected with hiv 1 a randomized controlled equivalence trial
    Annals of Internal Medicine, 2014
    Co-Authors: Jeffrey L Lennox, Heather J Ribaudo, Raphael J Landovitz, Ighovwerha Ofotokun, Catherine Godfrey, Daniel R Kuritzkes, Manish Sagar, Todd T Brown, Susan E Cohn, Grace A Mccomsey
    Abstract:

    Author(s): Lennox, Jeffrey L; Landovitz, Raphael J; Ribaudo, Heather J; Ofotokun, Ighovwerha; Na, Lumine H; Godfrey, Catherine; Kuritzkes, Daniel R; Sagar, Manish; Brown, Todd T; Cohn, Susan E; McComsey, Grace A; Aweeka, Francesca; Fichtenbaum, Carl J; Presti, Rachel M; Koletar, Susan L; Haas, David W; Patterson, Kristine B; Benson, Constance A; Baugh, Bryan P; Leavitt, Randi Y; Rooney, James F; Seekins, Daniel; Currier, Judith S; ACTG A5257 Team | Abstract: Nonnucleoside reverse transcriptase Inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.To evaluate 3 nonnucleoside reverse transcriptase Inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954).57 sites in the United States and Puerto Rico.Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase Inhibitors or protease Inhibitors.Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability.Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease Inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.The trial was open-label, and ritonavir was not provided.Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen.National Institute of Allergy and Infectious Diseases.

  • changes in proteinuria and albuminuria with initiation of antiretroviral therapy data from a randomized trial comparing tenofovir disoproxil fumarate emtricitabine versus abacavir lamivudine
    Journal of Acquired Immune Deficiency Syndromes, 2014
    Co-Authors: Christina M Wyatt, Douglas Kitch, Samir K Gupta, Camlin Tierney, Eric S Daar, Belinda Ha, Kathleen Melbourne, Grace A Mccomsey
    Abstract:

    Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase Inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. Methods We examined changes in urine protein:creatinine (UPCR) and albumin:creatinine (UACR) ratios in 245 ART-naive participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n=124 or TDF/emtricitabine, TDF/FTC, n=121) with open-label protease Inhibitor (PI) atazanavir/ritonavir (ATV/r) or non-nucleoside reverse transcriptase Inhibitor (NNRTI) efavirenz (EFV).

  • a randomized trial of raltegravir replacement for protease Inhibitor or non nucleoside reverse transcriptase Inhibitor in hiv infected women with lipohypertrophy
    Aids Patient Care and Stds, 2012
    Co-Authors: Jordan E Lake, Grace A Mccomsey, Todd Hulgan, Christine Wanke, Alexandra Mangili, Sharon Walmsley, Sean M Boger, Ralph R Turner, Heather Mccreath, Judith S Currier
    Abstract:

    Lipohypertrophy in HIV-infected patients is associated with metabolic abnormalities. Raltegravir (RAL) is not known to induce fat changes or severe metabolic perturbations. HIV-infected women with central adiposity and HIV-1 RNA less than 50 copies per milliliter on non-nucleoside reverse transcriptase Inhibitor (NNRTI)- or protease Inhibitor (PI)-based antiretroviral therapy (ART) continued their nucleoside reverse transcriptase Inhibitor (NRTI) backbone and were randomized to switch to open label RAL immediately or after 24 weeks. The primary end point was 24-week between-group change in computed tomography (CT)-quantified visceral adipose tissue (AT) volume. Fasting lipids, glucose, C-reactive protein (CRP), anthropometric measurements, and patient-reported quality of life assessments were also measured. Thirty-six subjects provided 80% power to detect a 10% between-group difference in visceral AT over 24 weeks. Thirty-seven of 39 enrolled subjects completed week 24. At entry, subjects were 75% black or Hispanic, and on 62% PI-based and 38% NNRTI-based regimens. The median age was 43 years, CD4 count 558 cells per microliter, and body mass index (BMI) 32 kg/m2. After 24 weeks, no statistically significant changes in visceral or subcutaneous AT, anthropometrics, BMI, glucose, or CRP were observed. In subjects receiving RAL, significant improvements in total and LDL cholesterol (p=0.04), self-reported belly size (p=0.02) and composite body size (p=0.02) were observed. Body size changes correlated well with percent visceral AT change. No RAL-related adverse events occurred. Compared to continued PI or NNRTI, switch to RAL was associated with statistically significant 24-week improvements in total and LDL cholesterol but not AT volumes. Additional insights into AT and metabolic changes in women on RAL will be provided by 48-week follow-up of the immediate-switch arm.

Heather J Ribaudo - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and tolerability of 3 nonnucleoside reverse transcriptase Inhibitor sparing antiretroviral regimens for treatment naive volunteers infected with hiv 1 a randomized controlled equivalence trial
    Annals of Internal Medicine, 2014
    Co-Authors: Jeffrey L Lennox, Heather J Ribaudo, Raphael J Landovitz, Ighovwerha Ofotokun, Catherine Godfrey, Daniel R Kuritzkes, Manish Sagar, Todd T Brown, Susan E Cohn, Grace A Mccomsey
    Abstract:

    Author(s): Lennox, Jeffrey L; Landovitz, Raphael J; Ribaudo, Heather J; Ofotokun, Ighovwerha; Na, Lumine H; Godfrey, Catherine; Kuritzkes, Daniel R; Sagar, Manish; Brown, Todd T; Cohn, Susan E; McComsey, Grace A; Aweeka, Francesca; Fichtenbaum, Carl J; Presti, Rachel M; Koletar, Susan L; Haas, David W; Patterson, Kristine B; Benson, Constance A; Baugh, Bryan P; Leavitt, Randi Y; Rooney, James F; Seekins, Daniel; Currier, Judith S; ACTG A5257 Team | Abstract: Nonnucleoside reverse transcriptase Inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.To evaluate 3 nonnucleoside reverse transcriptase Inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954).57 sites in the United States and Puerto Rico.Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase Inhibitors or protease Inhibitors.Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability.Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease Inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.The trial was open-label, and ritonavir was not provided.Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen.National Institute of Allergy and Infectious Diseases.

  • impact of minority nonnucleoside reverse transcriptase Inhibitor resistance mutations on resistance genotype after virologic failure
    The Journal of Infectious Diseases, 2013
    Co-Authors: Jonathan Z Li, Roger Paredes, Heather J Ribaudo, Michael J Kozal, Evguenia S Svarovskaia, Jeffrey A Johnson, Anna Maria Geretti, Karin J Metzner, Martin R Jakobsen, Katherine Huppler Hullsiek
    Abstract:

    Drug-resistant human immunodeficiency virus type 1 (HIV-1) minority variants increase the risk of virologic failure for first-line nonnucleoside reverse transcriptase Inhibitor (NNRTI)-based regimens. We performed a pooled analysis to evaluate the relationship between NNRTI-resistant minority variants and the likelihood and types of resistance mutations detected at virologic failure. In multivariable logistic regression analysis, higher NNRTI minority variant copy numbers, non-white race, and nevirapine use were associated with a higher risk of NNRTI resistance at virologic failure. Among participants on efavirenz, K103N was the most frequently observed resistance mutation at virologic failure regardless of the baseline minority variant. However, the presence of baseline Y181C minority variant was associated with a higher probability of Y181C detection after virologic failure. NNRTI regimen choice and preexisting NNRTI-resistant minority variants were both associated with the probability and type of resistance mutations detected after virologic failure.

  • initial viral decay to assess the relative antiretroviral potency of protease Inhibitor sparing nonnucleoside reverse transcriptase Inhibitor sparing and nucleoside reverse transcriptase Inhibitor sparing regimens for first line therapy of hiv infect
    AIDS, 2011
    Co-Authors: Richard Haubrich, Heather J Ribaudo, Sharon A Riddler, Gregory Direnzo, Karin L Klingman, Kevin W Garren, David L Butcher, James F Rooney, Diane V Havlir, John W. Mellors
    Abstract:

    OBJECTIVES: To evaluate the effects of sex and initial antiretroviral regimen on decay of HIV-RNA and virologic outcome. METHODS: We conducted a viral dynamics substudy of A5142, a trial comparing lopinavir (LPV)/ritonavir with efavirenz (LPV/EFV) versus LPV and two nucleoside reverse transcriptase Inhibitor (NRTI) (LPV) versus EFV and two NRTI (EFV) in antiretroviral (ARV)-naive individuals. HIV-RNA was measured at days 2, 10, and 14 in the substudy and at weeks 1, 4, and 8 in A5142 participants. Two-phase viral decay was estimated in the substudy with biexponential mixed-effects modeling and compared using Wilcoxon tests. Week 1 HIV-RNA change was assessed as a predictor of virologic failure (HIV-RNA above 50 or 200  copies/ml) at weeks 24-96 using logistic regression. RESULTS: Sixty-eight individuals were enrolled in the substudy (median HIV-RNA 4.9 log(10)  copies/ml). Median rates of phase 1 viral decay by treatment were 0.61(EFV/LPV), 0.53(LPV), and 0.63(EFV) per day. Phase 1 decay was significantly faster for EFV than LPV (P = 0.023); other comparisons were not significant (P > 0.11). Viral decay did not differ by sex (P = 0.10). Week 1 HIV-RNA change, calculated in 571 participants of A5142, was greater for the EFV (median -1.47 log(10)  copies/ml) than either the LPV/EFV or LPV groups (-1.21 and -1.16 log(10 ) copies/ml, respectively; P < 0.001). Week 1 HIV-RNA change was associated with virologic failure above 50  copies/ ml at weeks 24 and 48 (P < 0.018), but not above 200  copies/ml at these time points or for any value at week 96. CONCLUSION: Phase 1 decay was faster for EFV than LPV or LPV/EFV. Week 1 HIV-RNA change predicted virologic outcome up to week 48, but not at week 96.