Efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) versus double (ZDV+3TC) combination therapy in patients previously treated with ZDV+ddC

Ruiz, Lı́dia; Romeu, Joan; Martínez-Picado, Javier; Jc, Schmit; Vandamme, Anne‐Mieke; Balagué, Montserrat; Cabrera, Cecilia; Puig, Teresa; Tural, Cristina; Segura, Abraham; Sirera, Guillem; Clercq, Erik De; Clotet, B

doi:10.1097/00002030-199612000-00003

Cited by 21 publications

(12 citation statements)

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“…Only one study with lamivudine and zalcitabine, which evaluated the efficacy, has been conducted and could show that triple therapy of lamivudine, zalcitabine, and zidovudine was slightly more effective than lamivudine and zidovudine, and both regimens exceeded the combined therapy of zalcitabine and zidovudine (Ruiz et al, 1996). However, a potential contribution of other transporters [e.g., the organic anion transporter (OAT) 1] should also be considered as Jin and Han (2006) described uptake of zalcitabine in Chinese hamster ovary cells transfected with OAT1 and Wada et al (2000) detected uptake of zalcitabine and lamivudine in Xenopus laevis oocytes injected with rat OAT1.…”

Section: Discussionmentioning

confidence: 99%

Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection

Jung

Lehmann²,

Rubbert³

et al. 2008

Drug Metab Dispos

131

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ABSTRACT:Carrier-mediated transport across cell membranes is an important determinant of activity, resistance, and toxicity of chemotherapeutic agents including antiretroviral (ARV) drugs (ARDs). The organic cation transporters (OCTs) 1 and 2 have been implicated in the translocation of different cationic drugs but so far were insufficiently tested for interactions with ARDs. Here, we assessed among cationic drugs commonly used in human immunodeficiency virus (HIV) therapy inhibitors and substrates of OCTs, and analyzed the tissue distribution of OCTs and their expression in lymph nodes (LNs), the primary intracellular target of HIV and ARDs. Inhibitors were identified by measuring the attenuated uptake of the radiolabeled model substrate 1-methyl-4-phenylpyridinium into OCTtransfected human embryonic kidney-293 cells in the presence of ARDs. Substrates were identified by measuring OCT-specific intracellular accumulation using liquid chromatography/tandem mass spectrometry. Inhibitory drugs were (in order of increasing potency): nelfinavir < ritonavir < saquinavir < indinavir < trimethoprim < pentamidine, with consistently lower IC 50 values determined for OCT1. Substrates with highest transport efficacy (V max /K m ) were lamivudine (OCT1, 8 l/mg protein/min; OCT2, 4.4 l/mg protein/min) and zalcitabine (OCT1, 4.1 l/mg protein/min; OCT2, 2.6 l/mg protein/min). Using quantitative real-time polymerase chain reaction, a marked expression level of OCT1 was detected in human samples of liver, ovary, prostate, and testis, and of OCT2 in kidney, colon, heart, skeletal muscle, and testis. Expression of OCTs in LNs was low in HIV-negative control individuals but dramatically increased in HIV-infected persons. These data suggest that drug interactions about the OCTs may be relevant for the ARV therapy, in particular by influencing drug accession to infected tissues and hepatic or renal elimination.

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Section: Discussionmentioning

confidence: 99%

Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection

Jung

Lehmann²,

Rubbert³

et al. 2008

Drug Metab Dispos

131

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“…In another study that is inconsistent with current patterns of care, 46 patients previously treated with ZDV/ddC were randomised to receive ZDV/3TC or ZDV/ddC/3TC [64]. Modest (but indistinguishable) virologic benefit was noted in both groups.…”

Section: Three Nucleoside Analoguesmentioning

confidence: 99%

Combination therapy for HIV: towards long term control of disease progression

Conway

Routy²,

Sékaly³

1998

Expert Opinion on Investigational Drugs

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The difficulty of curing HIV patients with currently available agents has now been demonstrated and the model of care has returned to the long-term use of antiretroviral therapy. As such, the current minimum standard of care is triple drug therapy, with two nucleoside analogues,along with either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRT). Such regimens induce long-term virologic suppression in only 50 - 67% cases, so new approaches are needed. The most promising of these includes the use of two protease inhibitors,particularly in drug-naive patients, with the addition of one or two nucleoside analogues. Newer agents that merit further study include hydroxyurea,abacavir, adefovir, amprenavir and efavirenz. Their role in clinical practice remains to be defined. More complex regimens (including six drugs) are also under consideration. Although they may be more effective, long-term adherence to therapy may be problematic, and such approaches may be more appropriate for short-term use to 'induce' a virologic remission that could then be 'maintained' using a much simpler regimen. Preliminary data generated using such an approach have been disappointing, but this may relate to the specific selection of patients and regimens rather than a basic conceptual flaw with the approach itself. Although much progress has been made in the field of antiretroviral therapy, there is still a long way to go. The insightful study of new combinations of older and newer agents will help us to get closer to our goal of long-term control of HIV infection in all patients.

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“…Let p I denote the probability that an observation and subsequent ones are missing at week k(k" 4,8,12,16,20,24), conditional on having observed data prior to that time. p I is computed using a logistic function, on the basis of the speci"cation of the drop-out process of Diggle and Kenward in a modelling framework developed for continuous longitudinal data with missing data:…”

Section: Missing-data Patternsmentioning

confidence: 99%

Visit-driven endpoints in randomized HIV/AIDS clinical trials: impact of missing data on treatment difference measured on summary statistics

1999

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In randomized HIV/AIDS clinical trials, CD4 lymphocyte counts and plasma HIV-1 RNA measurements are often used as endpoints. The comparison between treatment groups is mainly based on a summary measure of outcome, so-called summary statistic. Such analyses are often complicated by missing data occurring as drop-outs. For the most currently used summary statistics in these trials, we examined the impact of missing data occurring as drop-outs on test size, in order to help choosing between these statistics. A simulation of missing-data patterns was performed, using HIV-1 plasma RNA measurements as the main endpoint, to compare the effect of three plausible informative patterns, depending on treatment group, and on baseline or current plasma viral load, on eight different summary statistics. Missing data resulted in test sizes over the nominal value for the area under the curve minus baseline, the least-squares slope, the slope estimated with use of a mixed effects linear model, assuming a linear trend over the entire study, the difference between baseline and nadir, and the difference between baseline and week 24. The difference between baseline and week 8 was an acceptable summary with respect to the test size, but did not reflect accurately the durability of the effect of treatment. Two criteria appeared as the best summary statistics: the slope estimated by a mixed effects model, with a change of slope after two weeks of treatment, and to a lesser degree, the area under the curve after carrying forward the last observation.

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Efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) versus double (ZDV+3TC) combination therapy in patients previously treated with ZDV+ddC

Cited by 21 publications

References 0 publications

Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection

Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection

Combination therapy for HIV: towards long term control of disease progression

Visit-driven endpoints in randomized HIV/AIDS clinical trials: impact of missing data on treatment difference measured on summary statistics

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