Zidovudine Compared With Didanosine in Patients With Advanced HIV Type I Infection and Little or No Previous Experience With Zidovudine

Dolin, Raphael; Amato, David A.; Fischl, Margaret A.; Pettinelli, Carla; Beltangady, Mohan; Liou, Song-Heng; Brown, Michael J.; Cross, Anne; Hirsch, Martin S.; Hardy, William; Mildvan, Donna; Blair, Donald C.; Powderly, William G.; Para, Michael F.; Fife, Kenneth H.; Steigbigel, Roy T.; Smaldone, Laurie; Crumpacker, Clyde S.; Cooley, Tim; Mitsuyaso, Ronald T.; John, Ric; Sanders, Carsandra; Reitman, Dinah; Hewitt, Ross G.; Reichman, Richard C.; Gelb, Lawrence D.; McGuire, M; Jones, M. E.; Neidig, Judith L.; Zwickl, Beth; Hartman, Paula B.; Roarke, Mary Elizabeth; Burk, Ruth Ann; Fuhrer, Jack; Somogyi, Karen A.; Sepkowitz, Kent A.; Telzak, Edward E.; McAuliffe, Vincent J.; Valentine, Fred T.; Vásquez, Margarita; Merigan, Thomas C.; Katzenstein, David; Fessell, Jeffrey; Havlir, Diane V.; Richman, Douglas D.; Spector, Stephen A.; Kahn, James O.; Johnson, Linda; Coleman, Ryan G.; Ho, Monto; McMahon, Deborah; Pazin, George J.; Antoniskis, Diana; McNamara, B. J.; Diamond, DeAnn M.; Collier, Ann C.; Paradise, Mary; Wald, Anna; DePaolis-Jones, Ann; Henry, Keith; Waskin, Hetty; Hyslop, Newton E.; Mushatt, David; Zachary, James A.; Soeiro, R.; Harris, Carol; Zingman, Barry S.; Giordano, M; Sledz, Sandra; Murray, Henry W.; Carey, John T.; Davis, Traci L.; Bagby, Brenda; Kessler, Harold A.; Murphy, Robert; Hirschtick, Robert E.; Cheeseman, Sarah H.; Lai, Kwan Kew; Fairchild, Patrick G.; Ehmann, W. Christopher; Zurlo, John; Millard, R.; Troiani, Luigi; Heggen, Aline A.; Horst, Charles M. van der; McKinley, George; Grieco, Michael H.; Kolatch, Brenda R.; Goldsmith, Jonathan C.; Gomperts, Edward D.; Woods, Lin; Grue, Louis; Mayjo, K.; Becker, Rebecca L.; Jayaweera, D.; Rolfe, Lisa; Cole, J. E.; Jermano, John

doi:10.1001/archinte.1995.00430090111012

Cited by 38 publications

(6 citation statements)

References 27 publications

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“…Hepatotoxicity as measured biochemically by modest elevations in hepatic transaminases appears to occur at a rate of 5 to 15% in HIV patients treated with NRTIs (Dolin et al, 1995). The pathophysiology is likely to be multifactorial; however, hepatosteatosis appears to account for at least some of the liver dysfunction seen in HAART-treated patients (Duong Van Huyen et al 2003).…”

Section: Hepatic Pathologymentioning

confidence: 99%

HIV Treatment and Associated Mitochondrial Pathology

et al. 2013

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Antiretroviral therapy has dramatically reduced mortality in human immunodeficiency virus (HIV) infection. In 1988, the suggestion that the first antiretroviral drug, zidovudine, was the potential cause of muscle pathology in HIV-infected persons resulted in structural and biochemical patient studies demonstrating acquired mitochondrial dysfunction. Assessment of subsequent nucleoside analog reverse transcriptase inhibitor (NRTI) antiretroviral drugs has indicated that mitochondria are a common target of NRTI toxicity in multiple tissues, leading to a wide variety of pathology ranging from lipodystrophy to neuropathy. Overwhelmingly, these complications have emerged during post-licensing human studies. Subsequent animal and in vitro studies have then elucidated the potential pathological mechanisms, suggesting that NRTI-associated mitochondrial toxicity arises principally from inhibition of the sole mitochondrial DNA (mtDNA) polymerase gamma, leading to a reduction in mtDNA content (depletion). Millions of patients have been treated with mitochondrially toxic NRTIs and these drugs remain the backbone of antiretroviral rollout in much of sub-Saharan Africa. Here we describe the 25-year history of antiretroviral associated mitochondrial pathology and critically review the strength of evidence linking clinical, histopathological, and molecular data. We discuss recently described novel mechanisms of NRTI-associated mitochondrial damage and whether or not recently licensed NRTIs may be considered free from mitochondrial toxicity.

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Section: Hepatic Pathologymentioning

confidence: 99%

HIV Treatment and Associated Mitochondrial Pathology

et al. 2013

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“…Indeed, one trial reported a clinical benefit associated with a change from zidovudine to didanosine after as little as 8-16 weeks of zidovudine therapy [11]. We compared the antiretroviral efficacy and safety of 3 different dual-nucleoside treatments in patients with HIV infection who had received no prior antiretroviral therapy: stavudine plus didanosine, zidovudine plus lamivudine, and an alternating regimen of stavudine plus didanosine followed by zidovudine plus lamivudine.…”

mentioning

confidence: 99%

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

et al. 1999

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A total of 151 previously untreated patients infected with human immunodeficiency virus type 1 (HIV-1) with CD4 cell counts >/=200/microL 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 log10 copies/mL) than in groups 2 (1.26 log10 copies/mL) or 3 (1.58 log10 copies/mL; P<.0001). The mean increase in CD4 cell counts was greater in groups 1 (124 cells/microL) and 3 (118 cells/microL) than in group 2 (62 cells/microL; 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.

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“…42 Didanosine is currently approved for treatment at doses of 400 mg daily or less, but was previously investigated at dose levels as high as 750 mg daily. [43][44][45] The toxicity of didanosine is dose related and the risk for pancreatitis increases further at doses above currently recommended levels, and lower doses have not been associated with a reduction in efficacy. Therefore, the history of HIV drug development presents several examples of drugs that were initially used at excessively high (toxic) doses; however, the same drugs in reduced doses eventually became invaluable tools against HIV.…”

Section: Discussionmentioning

confidence: 99%

Lowering the Dose of Hydroxyurea Minimizes Toxicity and Maximizes Anti-HIV Potency

Friedman

Pollard

Whitman

et al. 2005

AIDS Research and Human Retroviruses

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The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.

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Zidovudine Compared With Didanosine in Patients With Advanced HIV Type I Infection and Little or No Previous Experience With Zidovudine

Abstract: In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine.

Cited by 38 publications

References 27 publications

HIV Treatment and Associated Mitochondrial Pathology

HIV Treatment and Associated Mitochondrial Pathology

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

Lowering the Dose of Hydroxyurea Minimizes Toxicity and Maximizes Anti-HIV Potency

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