Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex

doi:10.1016/0140-6736(90)92085-V

The Lancet

Volume 336, Issue 8714, 1 September 1990, Pages 526-529

https://doi.org/10.1016/0140-6736(90)92085-V Get rights and content

Abstract

To evaluate the long-term toxicity and activity profile of 2',3'-dideoxyinosine (ddl), a potent inhibitor of human immunodeficiency virus (HIV) replication, in vitro. 58 patients with AIDS or AIDS-related complex were studied with additional reference to the effect of previous treatment with zidovudine, and the effect of ddl on HIV-induced cognitive dysfunction. Doses above 9·6 mg/kg per day of ddl were frequently associated with toxicity (peripheral neuropathy, pancreatitis, or hepatitis). Doses of 9·6 mg/kg per day or below were well tolerated for up to 21 months. A subset of patients receiving 3·2-9·6 mg/kg per day of ddl had long-term immunological improvement and reduction of serum HIV p24 antigen. Immunological changes were especially seen in patients who had little previous zidovudine therapy. 5 patients with HIV-induced cognitive impairment improved with ddl. Thus, ddl may have anti-HIV activity at doses which are tolerated for long-term therapy, although pancreatitis could be a life-threatening complication.

References (25)

G. Ahluwalia et al.
Initial studies on the cellular pharmacology of 2',3'-dideoxyinosine, an inhibitor of HIV infectivity
Biochem Pharmacol
(1987)
A. Mallory et al.
Drug-induced pancreatitis: a critical review
Gastroenterology
(1980)
C. Grunfeld et al.
Hypertriglyceridemia in the acquired immunodeficiency syndrome
Am J Med
(1989)
Gn Fuller et al.
Association of painful peripheral neuropathy in AIDS with cytomegalovirus infection
Lancet
(1989)
H. Mitsuya et al.
Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy virus-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides
Proc Natl Acad Sci USA
(1986)
H. Mitsuya et al.
Long-term inhibition of human T-lymphotropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2',3'-dideoxynucleosides in vitro
Proc Natl Acad Sci USA
(1987)
Dl Du et al.
Myelotoxicity of new anti-HIV drugs (2',3'-dideoxynucleosides) on human hematopoietic progenitor cells in vitro
Exp Hematol
(1989)
J-M. Molina et al.
Bone marrow toxicity of dideoxyinosine
N Engl J Med
(1989)
C-F. Perno et al.
Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine
J Exp Med
(1989)
G. Ahluwalia et al.
Cellular pharmacology of the anti-HIV agent 2',3'-dideoxyadenosine
(1988)

R. Yarchoan et al.

In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine

Science

(1989)

R. Yarchoan et al.

The National Cancer Institute phase I study of ddI administration in adults with AIDS or AIDS-related complex: analysis of activity and toxicity profiles

Rev Infect Dis

(1990)

Cited by (226)

The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic
2010, Antiviral Research
In the last 25 years, HIV-1, the retrovirus responsible for the acquired immunodeficiency syndrome (AIDS), has gone from being an “inherently untreatable” infectious agent to one eminently susceptible to a range of approved therapies. During a five-year period, starting in the mid-1980s, my group at the National Cancer Institute played a role in the discovery and development of the first generation of antiretroviral agents, starting in 1985 with Retrovir^® (zidovudine, AZT) in a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). We focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from the laboratory to the clinic in response to the pandemic of AIDS, then a terrifying and lethal disease. These drugs proved, above all else, that HIV-1 infection is treatable, and such proof provided momentum for new therapies from many sources, directed at a range of viral targets, at a pace that has rarely if ever been matched in modern drug development. Antiretroviral therapy has brought about a substantial decrease in the death rate due to HIV-1 infection, changing it from a rapidly lethal disease into a chronic manageable condition, compatible with very long survival. This has special implications within the classic boundaries of public health around the world, but at the same time in certain regions may also affect a cycle of economic and civil instability in which HIV-1/AIDS is both cause and consequence. Many challenges remain, including (1) the life-long duration of therapy; (2) the ultimate role of pre-exposure prophylaxis (PrEP); (3) the cardiometabolic side-effects or other toxicities of long-term therapy; (4) the emergence of drug-resistance and viral genetic diversity (non-B subtypes); (5) the specter of new cross-species transmissions from established retroviral reservoirs in apes and Old World monkeys; and (6) the continued pace of new HIV-1 infections in many parts of the world. All of these factors make refining current therapies and developing new therapeutic paradigms essential priorities, topics covered in articles within this special issue of Antiviral Research. Fortunately, there are exciting new insights into the biology of HIV-1, its interaction with cellular resistance factors, and novel points of attack for future therapies. Moreover, it is a short journey from basic research to public health benefit around the world. The current science will lead to new therapeutic strategies with far-reaching implications in the HIV-1/AIDS pandemic. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol. 85, issue 1, 2010.
Peripheral neuropathy in HIV infection
2007, Handbook of Clinical Neurology
Citation Excerpt :
TN is associated with neurotoxic adverse effects of the dideoxynucleoside analogues of reverse transcriptase inhibitors (ddN). Early clinical trials showed that the effects of specific ddN, including didanosine (ddI), stavudine (d4T) and zalcitabine (ddC), are dose‐dependent (Simpson and Tagliati, 1995), and may trigger, aggravate or unmask painful DSP (Yarchoan et al., 1990). ddC is more potent than ddI, which is more potent than d4T in causing sensory neurotoxicity.
This chapter discusses the various forms of neuropathies associated with HIV and their pathogenetic mechanisms and treatment strategies. HIV-1 infection is associated with a variety of central and peripheral nerve diseases. The most frequent neurologic complication in the context of HIV infection is peripheral neuropathy. Other patterns of neuropathy include mononeuropathy multiplex, inflammatory demyelinating polyneuropathy, and progressive polyneuropathy. Pain is the major symptom of HIV peripheral neuropathy, with a major impact on the activities of daily living and the quality of life. The types of peripheral neuropathies and their symptoms, signs, mechanisms, diagnoses, and therapies are summarized in the chapter in a tabulated form. Distal symmetrical peripheral neuropathy (DSP) is the most commonly reported type of neuropathy in HIV infection, affecting approximately one-third of the individuals. Concomitant conditions—such as diabetes mellitus, alcohol abuse, uremia, vitamin B12 or thiamine deficiencies, weight loss, and low albumin or hemoglobin levels—may increase the risk of the development of HIV-associated neuropathy.
Novel and facil synthesis and evaluation of antitumor activities of 6,7-bisaryl-1-(β-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones
2010, Heterocycles
Didanosine
2017, Kucers the Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, Antiparasitic, and Antiviral Drugs, Seventh Edition
HIV Treatment and Associated Mitochondrial Pathology:Review of 25 Years of in Vitro, Animal, and Human Studies
2014, Toxicologic Pathology
Toolbox: Neuropsychiatric adverse effects of antimicrobial agents
2013, Mental Health Clinician

View all citing articles on Scopus

View full text

Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex

Abstract

Biochem Pharmacol

Gastroenterology

Am J Med

Lancet

Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy virus-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides

Proc Natl Acad Sci USA

Long-term inhibition of human T-lymphotropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2',3'-dideoxynucleosides in vitro

Proc Natl Acad Sci USA

Myelotoxicity of new anti-HIV drugs (2',3'-dideoxynucleosides) on human hematopoietic progenitor cells in vitro

Exp Hematol

Bone marrow toxicity of dideoxyinosine

N Engl J Med

Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine

J Exp Med

Cellular pharmacology of the anti-HIV agent 2',3'-dideoxyadenosine

In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine

Science

The National Cancer Institute phase I study of ddI administration in adults with AIDS or AIDS-related complex: analysis of activity and toxicity profiles

Rev Infect Dis