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Robert W. Coombs - One of the best experts on this subject based on the ideXlab platform.
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The impact of sex and contraceptive therapy on the plasma and intracellular pharmacokinetics of Zidovudine.
AIDS (London England), 2006Co-Authors: Francesca T. Aweeka, Arlene Bardeguez, Susan L. Rosenkranz, Yoninah Segal, Robert W. Coombs, Lourdes Thevanayagam, Patricia Lizak, Judith A. Aberg, D. Heather WattsAbstract:Objectives: Zidovudine remains part of combination antiretroviral therapy. Pharmacological studies rely on quantitation of active triphosphates in peripheral blood mononuclear cells. This study evaluated the impact of female sex and contraceptive therapy on Zidovudine plasma and intracellular pharmacokinetics and the impact of contraceptive therapy on HIV viral load. Methods: Serial plasma and intracellular Zidovudine pharmacokinetics following oral and intravenous dosing were determined in 18 men and 20 women treated with Zidovudine. Women could repeat pharmacokinetics assessment following 2 months oral or injectable contraceptive therapy. Zidovudine plasma and intracellular mono-, di- and triphosphate concentrations were determined by liquid chromatography tandem mass spectrometry. Plasma and cervical viral loads were determined preceding and following 2 months of contraceptive therapy in women. Results: Men exhibited higher area under the concentration versus time curve for intracellular Zidovudine and Zidovudine-monophosphate following oral and intravenous dosing and higher Zidovudine triphosphate following oral dosing. There was no difference between men and women in plasma Zidovudine parameters. Furthermore, contraceptive therapy had no effect on Zidovudine plasma or intracellular pharmacokinetics or on plasma or cervical HIV-1 RNA levels. Conclusions: Using an optimized pharmacokinetic design, this study indicated men exhibit significantly higher Zidovudine-monophosphate and Zidovudine-triphosphate exposure following Zidovudine oral administration, having implications for drug toxicity and overall tolerance of Zidovudine therapy. The lack of an effect of contraceptive therapy on Zidovudine pharmacokinetics is surprising in light of previous pharmacokinetic studies for drugs eliminated primarily through glucuronidation. Contraceptive therapy had no effect on plasma or cervical viral load, results consistent with previous findings.
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maternal viral genotypic Zidovudine resistance and infrequent failure of Zidovudine therapy to prevent perinatal transmission of human immunodeficiency virus type 1 in pediatric aids clinical trials group protocol 076
The Journal of Infectious Diseases, 1998Co-Authors: Scott P Eastman, George Mcsherry, Robert W. Coombs, David E Shapiro, Lisa M Frenkel, Paula Britto, Steven Herman, Rhoda S SperlingAbstract:Maternal samples were assessed from 96 women enrolled in Pediatric AIDS Clinical Trials Group protocol 076 to determine the prevalence of human immunodeficiency virus type 1 (HIV-1) genotypic Zidovudine resistance at entry, if Zidovudine resistance developed on study, and the role of Zidovudine resistance in vertical transmission of HIV-1 despite Zidovudine therapy. Low and high levels of genotypic resistance were assessed by differential hybridization, oligoligation, or direct sequencing of plasma HIV-1 RNA for codons K70R and T215Y/F. None of the women had high-level genotypic resistance to Zidovudine at study entry or delivery. For low-level Zidovudine resistance, the 95% confidence intervals were 0.3%-6.8% for baseline prevalence and 0.3%-14% for delivery incidence. Low-level Zidovudine resistance, adjusted for plasma viral RNA level at delivery, was not strongly associated with an increase in vertical transmission risk (odds ratio, 4.8; 95% confidence interval, 0.2-131; P = .35).
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Zidovudine resistance and hiv 1 disease progression during antiretroviral therapy
Annals of Internal Medicine, 1995Co-Authors: Richard T Daquila, Victoria A Johnson, Daniel R Kuritzkes, Robert W. Coombs, Seth L Welles, Anthony J Japour, Victor Degruttola, Patricia Reichelderfer, Clyde S Crumpacker, James O KahnAbstract:Objective: To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to Zidovudine and clinical progression. Design: Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued Zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous Zidovudine therapy. Setting: Participating ACTG virology laboratories. Patients: 187 patients with baseline HIV-1 isolates. Measurements: Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional hazards regression models. Results: Compared with other patients, 15% (26 of 170) with isolates showing high-level Zidovudine resistance (50% inhibitory Zidovudine concentration ≥1.0 μM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4 + T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly Zidovudine-resistant baseline HIV-1 isolates. Conclusions: High-level resistance of HIV-1 to Zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from Zidovudine to didanosine whether high-level HIV-1 resistance to Zidovudine is present or absent, and laboratory assessment of Zidovudine resistance is not necessary for deciding when to switch monotherapy from Zidovudine to didanosine
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combination therapy with Zidovudine and didanosine selects for drug resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations
The Journal of Infectious Diseases, 1994Co-Authors: Robert W Shafer, Michael J Kozal, Mark A Winters, Astrid K N Iversen, David Katzenstein, Margaret V Ragni, William A Meyer, Phalquni Gupta, Suraiya Rasheed, Robert W. CoombsAbstract:Drug resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol mutations of HIV-1 strains from patients treated for I year with Zidovudine, didanosine (ddI), or Zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only Zidovudine had HIV-1 strains with phenotypic Zidovudine resistance or a Zidovudine resistance pol mutation at codon 215 (P=.6). In contrast, a ddI resistance mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P<.001)
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combination therapy with Zidovudine and didanosine compared with Zidovudine alone in hiv 1 infection
Annals of Internal Medicine, 1993Co-Authors: Ann C Collier, Margaret A Fischl, Robert W. Coombs, Paul R Skolnik, Donald W Northfelt, Paul Boutin, Carol J Hooper, Lawrence D Kaplan, Paul A Volberding, Gray L DavisAbstract:Obiective: To assess safety, pharmacokinetics, and in-vivo virologic activity of five different combination regimens of Zidovudine and didanosine compared with Zidovudine alone in patients with human immunodeficiency virus type 1 (HIV-1) infection. Design: Open-label, partially randomized, dose-ranging study. Setting: University-affiliated, medical center clinics. Patients: A total of 69 patients with HIV-1 infection, CD4 + cell counts fewer than 400 cells/mm 3 , and fewer than 121 days of previous Zidovudine treatment. Interventions: Fifty-five patients received combination therapy with Zidovudine and didanosine, and 14 received Zidovudine therapy alone (600 mg/d)
Joep M A Lange - One of the best experts on this subject based on the ideXlab platform.
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development of drug resistance in patients receiving combinations of Zidovudine didanosine and nevirapine
AIDS, 2001Co-Authors: Brian Conway, Robert Curry, Marianne Harris, Patrick A. Robinson, Peter Reiss, David B Hall, David A Cooper, Stefano Vella, Mark A. Wainberg, Joep M A LangeAbstract:OBJECTIVE: To evaluate the development of phenotypic and genotypic resistance to Zidovudine, didanosine and nevirapine as a function of the virologic response to therapy in a group of drug-naive individuals receiving various combinations of these agents. DESIGN: All patients were enrolled in a double-blind controlled randomized trial (the INCAS study) and were selected for detailed resistance studies based on specimen availability and virologic response. METHODS: Within the three study groups (Zidovudine/nevirapine, Zidovudine/didanosine or Zidovudine/nevirapine/didanosine), 16, 19 and 24 patients, respectively, had evaluable baseline isolates and remained in the study > 24 weeks. Phenotypic resistance to all three drugs was evaluated using the VIRCO recombinant virus assay. Genotypic sequencing was done on selected specimens from patients receiving Zidovudine/nevirapine/didanosine. RESULTS: After 24 weeks, all available isolates taken from patients receiving nevirapine were resistant to this agent, while 18/21 (86%) patients receiving triple therapy carried such isolates at 30--60 weeks. At 24 weeks, Zidovudine resistance developed in 4/40 isolates but was more frequent after 30--60 weeks, especially in patients on two drugs. The degree of Zidovudine resistance (rise in concentration required for 50% inhibition) appeared lower in the triple therapy group compared with Zidovudine/didanosine (P = 0.0004). All nevirapine-resistant isolates that were sequenced carried at least one mutation associated with resistance, most often K103N and/or Y181C. CONCLUSION: The use of highly active drug therapies may be associated with a beneficial effect on the development of antiretroviral drug resistance. The characteristics of virologic suppression that must be maintained to avoid resistance are currently being studied in hypothesis-driven clinical trials
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a randomized controlled trial of indinavir Zidovudine and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy
The Journal of Infectious Diseases, 1999Co-Authors: Martin S Hirsch, Joep M A Lange, John W. Mellors, Bernard Hirschel, Roy T Steigbigel, S Staszewski, Ernesto G Scerpella, Kathleen Squires, Sandy Rawlins, Anne R MeibohmAbstract:A randomized, double-blind, multicenter study of indinavir, Zidovudine, and lamivudine was conducted in 320 adults with human immunodeficiency virus type 1 (HIV-1) infection, Zidovudine therapy. Patients received indinavir, 800 mg every 8 h; Zidovudine, 200 mg every 8 h, and lamivudine, 150 mg twice daily; or all 3 drugs for 24 weeks. In an intention-to-treat analysis, proportions of patients with HIV-1 RNA <500 and <50 copies/mL, respectively, at week 24 were 56% and 45% in the indinavir-Zidovudine-lamivudine group, 3% and 2% in the indinavir group, and 0% in the Zidovudine-lamivudine group. Observed mean CD4 cell increases were 95, 78, and 6 cells/mm3 in the three-, one-, and two-drug arms, respectively. Regimens were generally well tolerated. Patients with advanced HIV-1 infection benefit from triple therapy with indinavir, Zidovudine, and lamivudine, although the proportion with optimal response appeared to be lower in patients with low CD4 cell counts.
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virologic and immunologic benefits of initial combination therapy with Zidovudine and zalcitabine or didanosine compared with Zidovudine monotherapy
The Journal of Infectious Diseases, 1996Co-Authors: Robert T. Schooley, Carlos H Ramirezronda, Lewis Lefkowitz, Brendan A. Larder, James Lavelle, Marty St Clair, Joep M A Lange, David A Cooper, Mark Moore, Jan W MulderAbstract:A randomized controlled study was done to determine whether initial combination therapy with Zidovudine and zalcitabine or Zidovudine and didanosine would delay the emergence of Zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with <300 CD4 cells/mm 3 and <4 weeks of prior Zidovudine therapy were randomized to Zidovudine, Zidovudine plus zalcitabine, or Zidovudine plus didanosine. Combination therapy did not delay the emergence of Zidovudine-resistant virus isolates. However, combination therapy resulted in a significant increase in CD4 cells through 72 weeks compared with Zidovudine monotherapy and a greater and more sustained decline in serum HIV-I RNA. Although this trial was not designed as a clinical end-point study, patients assigned to Zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned to Zidovudine monotherapy.
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Virologic and Immunologic Benefits of Initial Combination Therapy with Zidovudine and Zalcitabine or Didanosine Compared with Zidovudine Monotherapy
The Journal of infectious diseases, 1996Co-Authors: Robert T. Schooley, Lewis Lefkowitz, Brendan A. Larder, James Lavelle, Marty St Clair, Joep M A Lange, David A Cooper, Carlos H. Ramirez-ronda, Mark D. Moore, Jan W MulderAbstract:A randomized controlled study was done to determine whether initial combination therapy with Zidovudine and zalcitabine or Zidovudine and didanosine would delay the emergence of Zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with
H. Green - One of the best experts on this subject based on the ideXlab platform.
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lamivudine abacavir maintains virological superiority over Zidovudine lamivudine and Zidovudine abacavir beyond 5 years in children
AIDS, 2007Co-Authors: H. Green, K Butler, A Compagnucci, Della Negra M, Guido Castelligattinara, A. S. Walker, Diana M. Gibb, Fatima Candeias, Deenan Pillay, De Rossi AAbstract:To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or Zidovudine in previously untreated children in the PENTA 5 trial.PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART).128 ART-naive children were randomised to Zidovudine\lamivudine (n = 36), Zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo.Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the Zidovudine\lamivudine, Zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% Zidovudine\lamivudine, 50%/25% Zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: Zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); Zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V).Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than Zidovudine\lamivudine or Zidovudine\abacavir, and should be preferred as first-line NRTI backbone.
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Lamivudine/abacavir maintains virological superiority over Zidovudine/lamivudine and Zidovudine/abacavir beyond 5 years in children
AIDS, 2007Co-Authors: H. Green, Pillay D, Butler K, Candeias F, Castelli-gattinara G, Compagnucci A, Della Negra M, A. S. Walker, Diana M. Gibb, De Rossi AAbstract:To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or Zidovudine in previously untreated children in the PENTA 5 trial.PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART).128 ART-naive children were randomised to Zidovudine\lamivudine (n = 36), Zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo.Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the Zidovudine\lamivudine, Zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% Zidovudine\lamivudine, 50%/25% Zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: Zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); Zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V).Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than Zidovudine\lamivudine or Zidovudine\abacavir, and should be preferred as first-line NRTI backbone.
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Lamivudine/abacavir maintains virological superiority over Zidovudine/lamivudine and Zidovudine/abacavir beyond 5 years in children
AIDS (London England), 2007Co-Authors: H. Green, K Butler, A Compagnucci, A. S. Walker, Diana M. Gibb, Fatima Candeias, Deenan Pillay, G Castelli-gattinara, M Della Negra, A. De RossiAbstract:OBJECTIVE: To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or Zidovudine in previously untreated children in the PENTA 5 trial. DESIGN: PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART). METHODS: 128 ART-naive children were randomised to Zidovudine\lamivudine (n = 36), Zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo. RESULTS: Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the Zidovudine\lamivudine, Zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% Zidovudine\lamivudine, 50%/25% Zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: Zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); Zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V). CONCLUSIONS: Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than Zidovudine\lamivudine or Zidovudine\abacavir, and should be preferred as first-line NRTI backbone.
Schlomo Staszewski - One of the best experts on this subject based on the ideXlab platform.
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hiv 1 reverse transcriptase rt genotype and susceptibility to rt inhibitors during abacavir monotherapy and combination therapy
AIDS, 2000Co-Authors: Veronica Miller, Amy Cutrell, Chris Stone, Mounir Aitkhaled, Philip Griffin, Despina Mesogiti, Christine Katlama, Schlomo Staszewski, Richard Harrigan, Gillian PearceAbstract:Objective: To examine changes in HIV-1 susceptibility (genotype and phenotype) during an initial abacavir monotherapy phase followed by the addition of Zidovudine and lamivudine. Design: Sixty HIV-1 infected, antiretroviral therapy-naive subjects were randomized to receive 100, 300 or 600 mg abacavir twice daily. Subjects completing 24 weeks of randomized therapy or meeting a protocol defined switch criterion could switch to open label abacavir/Zidovudine/lamivudine. Methods: Plasma HIV-1 reverse transcriptase was genotyped at baseline, week 12, and at the last time point on ABC monotherapy. Drug susceptibility was analysed at baseline and on subsequent samples with sufficient HIV-1 RNA levels using the recombinant virus assay. Virological responses (week 24) were correlated to week 24 genotypes. Results: Mutant viruses were not detected before week 12 with the exception of one subject. At the latest time point on abacavir monotherapy (range, weeks 6-48), 21 out of 43 subjects harboured virus with resistance conferring mutations including single, double and triple combinations of K65R, L74V, Y115F and M184V. The most common mutational pattern was L74V + M184V (11/21 cases). Twenty of the 21 subjects with isolates containing abacavir-associated mutations reached week 48, and upon addition of lamivudine/zidovudiine, 16 out of 20 (80%) had week 48 plasma HIV-1-RNA below 400 copies/ml. At week 48, 16 out of 46 genotypes were obtained; one of these was wild-type; 15 contained M184V either alone, in combination with K65R and/or L74V and/or Y115F or with thymidine analogue-associated mutations. Week 48 viral load levels for these 15 subjects was low (median 3.43 log 10 copies/ml or -1.99 log 10 copies reduction from baseline). Genotype correlated well with phenotypic resistance to ABC; four samples with three abacavir-associated mutations had high level abacavir resistance (> 8-fold) and six samples with two or three mutations showed intermediate (4-8-fold) resistance. All samples with single mutations retained full ABC susceptibility.
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Dual Resistance to Zidovudine and Lamivudine in Patients Treated with Zidovudine-Lamivudine Combination Therapy: Association with Therapy Failure
The Journal of infectious diseases, 1998Co-Authors: Veronica Miller, Schlomo Staszewski, Andrew N. Phillips, Carsten Rottmann, Rudi Pauwels, Kurt Hertogs, Marie-pierre De Béthune, S. D. Kemp, Stuart Bloor, P. Richard HarriganAbstract:Human immunodeficiency virus type 1 (HIV-1) strains dually resistant to Zidovudine and lamivudine (3TC) may arise during Zidovudine-3TC combination therapy. The objective of this cross-sectional study (n = 43 patients) was to test the association between therapy response (clinical and immunologic) to Zidovudine-3TC and the level of phenotypic Zidovudine resistance and Zidovudine resistance-associated genotype of 3TC-resistant isolates. Other variables included were baseline CD4 + cell count, baseline Centers for Disease Control and Prevention (CDC) classification, virus load, and time receiving Zidovudine. Phenotypic resistance was assessed using a recombinant virus assay. Genotypic analysis was based on population sequencing of plasma HIV-1. In a univariate analysis using a logistic regression model, it was found that therapy response was significantly associated with phenotypic and genotypic Zidovudine resistance, baseline CD4 + cell count, and virus load. After adjustment for all variables, phenotypic resistance to Zidovudine remained the only significantly associated factor, independent of baseline CD4 + cell count, baseline CDC classification, and virus load.
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Lamivudine-Zidovudine Treatment and Clinical End Points-Reply
JAMA: The Journal of the American Medical Association, 1996Co-Authors: Schlomo StaszewskiAbstract:In Reply. —The primary objective of the trial described in our article was to determine the benefit of combination treatment with Zidovudine and lamivudine relative to Zidovudine monotherapy on changes in CD4 cell counts and measures of HIV-1 viral load. The trial was not statistically powered to detect differences between treatment arms in progression to CDC category C (acquired immunodeficiency syndrome) events or death. However, the lower rate of clinical progression in the combination therapy arms in the trial is consistent with the results of a meta-analysis of trials of Zidovudine combined with lamivudine that showed a 66% reduction in progression to CDC category C events, 1 and in the recently reported CAESAR trial of combined Zidovudine and lamivudine, which has shown a 54% reduction in progression to CDC category C/death end points for patients adding lamivudine to Zidovudine-containing regimens. 2
Marc Rubin - One of the best experts on this subject based on the ideXlab platform.
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Emergence of dual resistance to Zidovudine and lamivudine in HIV-1-infected patients treated with Zidovudine plus lamivudine as initial therapy.
Journal of acquired immune deficiency syndromes (1999), 2000Co-Authors: Daniel R Kuritzkes, Marc Rubin, David Shugarts, Minoo Bakhtiari, David Poticha, Judy Johnson, Thomas R. Gingeras, Mitchell A. Kennedy, Joseph J. EronAbstract:Presence of mutations associated with resistance to Zidovudine or lamivudine was determined in isolates of HIV-1 obtained after long-term follow-up of 64 infected individuals who received Zidovudine, lamivudine, or both drugs as initial antiretroviral therapy. Zidovudine resistance mutations were less frequent in isolates from patients treated with combination lamivudine plus Zidovudine compared with Zidovudine alone, but these mutations accumulated over time. Phenotypic resistance to both drugs was found in isolates from 3 of 23 patients. In 3 other patients, lamivudine- resistant virus detected at week 12 was replaced by wild-type virus after longer follow-up, which correlated with a return to baseline levels of plasma HIV-1 RNA. These results show that dual resistance to Zidovudine and lamivudine develops over time despite the delayed emergence of Zidovudine- resistant mutations. These results also suggest a selective advantage in vivo for HIV-1 species that are wild-type at RT codon 184.
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lamivudine plus Zidovudine compared with zalcitabine plus Zidovudine in patients with hiv infection a randomized double blind placebo controlled trial
Annals of Internal Medicine, 1996Co-Authors: John Bartlett, Chris Tsoukas, Sharon L Benoit, Victoria A Johnson, Joseph B Quinn, Gladys E Sepulveda, Christopher W Ehmann, Mary Ann Fallon, Pamela L Self, Marc RubinAbstract:Objective : To compare the safety and activity of lamivudine plus Zidovudine with the safety and activity of zalcitabine plus Zidovudine in patients with moderately advanced human immunodeficiency virus (HIV) infection who had received Zidovudine. Design : A multicenter, randomized, double-blind, three-arm, 24-week study with a blinded extension through at least 52 weeks. Setting : 21 sites in the United States, Canada, and Puerto Rico. Patients : 254 patients who had received Zidovudine (median duration of previous therapy, 20 months) and had absolute CD4+ cell counts of 100 to 300 cells/mm 3 . Interventions : Patients were randomly assigned to receive one of three regimens : 150 mg of lamivudine twice daily plus 200 mg of Zidovudine three times daily (low-dose lamivudine group) ; 300 mg of lamivudine twice daily plus 200 mg of Zidovudine three times daily (high-dose lamivudine group) ; or 0.75 mg of zalcitabine plus 200 mg of Zidovudine three times daily (zalcitabine group). Measurements : Immunologic activity was assessed primarily by changes in absolute CD4+ cell counts ; virologic activity was assessed by changes in plasma HIV RNA levels as measured by reverse transcriptase polymerase chain reaction. Safety of the treatment regimens was assessed through the reporting of adverse events. Results : 78% of patients completed 24 weeks of study treatment, and 63% of patients completed 52 weeks of study treatment. Changes in absolute CD4 + cell counts were significantly better for the low-dose and the high-dose lamivudine groups than for the zalcitabine group (median changes at 52 weeks were +42.5 cells/mm 3 in the low-dose lamivudine group, +23.33 cells/mm 3 in the high-dose lamivudine group, and -29.58 cells/mm 3 in the zalcitabine group). Suppression of plasma HIV RNA levels was similar for all groups (median changes at 52 weeks were -0.48 log 10 copies/mL in the low-dose lamivudine group, -0.51 log 10 copies/mL in the high-dose lamivudine group, and -0.39 log 10 copies/mL in the zalcitabine group). No significant differences in safety were seen among the three regimens, although the low-dose lamivudine regimen appeared to be better tolerated than the others. Conclusions : In patients with HIV infection who had previously received Zidovudine, 150 mg of lamivudine plus Zidovudine resulted in greater immunologic evidence of benefit than did 0.75 mg of zalcitabine plus Zidovudine and was better tolerated than 300 mg of lamivudine plus Zidovudine.
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treatment with lamivudine Zidovudine or both in hiv positive patients with 200 to 500 cd4 cells per cubic millimeter
The New England Journal of Medicine, 1995Co-Authors: Joseph J. Eron, Sharon L Benoit, Joseph B Quinn, Mary Ann Fallon, Joseph Jemsek, Rodger David Macarthur, Jorge Santana, Daniel R Kuritzkes, Marc RubinAbstract:Background The reverse-transcriptase inhibitor lamivudine has in vitro synergy with Zidovudine against the human immunodeficiency virus (HIV). We studied the activity and safety of lamivudine plus Zidovudine as compared with either drug alone as treatment for patients with HIV infection, most of whom had not previously received Zidovudine. Methods Three hundred sixty-six patients with 200 to 500 CD4+ cells per cubic millimeter who had received Zidovudine for four weeks or less were randomly assigned to treatment with one of four regimens: 300 mg of lamivudine every 12 hours; 200 mg of Zidovudine every 8 hours; 150 mg of lamivudine every 12 hours plus Zidovudine; or 300 mg of lamivudine every 12 hours plus Zidovudine. The study was double-blind and lasted 24 weeks, with an extension phase for another 28 weeks. Results Over the 24-week period, the low-dose and high-dose regimens combining lamivudine and Zidovudine were associated with greater increases in the CD4+ cell count (P = 0.002 and P = 0.015, respec...
