2',3'-Didehydro-3'-deoxythymidine (d4T) in Patients with AIDS or AIDS-Related Complex: A Phase I Trial

Abstract

2',3'-didehydro-3'-deoxythymidine (d4T) is a pyrimidine analogue and inhibitor of reverse transcriptase with potent in vitro activity against human immunodeficiency virus (HIV). A phase I trial of d4T was conducted in 41 HIV-infected patients, 12 with AIDS and 29 with AIDS-related complex (ARC). Thirty-six patients were evaluatable. The maximum tolerated dose was 2 mg/kg/day. The dose-limiting toxicity was sensory peripheral neuropathy, which occurred in 20 patients (55%). Four patients (11%) developed hepatotoxicity. Five (14%) developed anemia requiring a transfusion but not discontinuation of drug. The mean +/- SE plasma elimination half-life at all dose levels was 1.2 +/- 0.09 h. Increased or stable absolute CD4 counts were seen in most patients. The majority of patients with detectable serum p24 antigen levels had a persistent decrease by 6 months. d4T is a promising drug for patients with AIDS or ARC. This clinical trial is continuing to determine the minimal effective dose.

The frequency of peripheral neuropathy in a group of HIV positive patients in Brazil

“…Decreased distal superficial sensibility was the common sign occurring in 73.5% of the patients, one (3%) had only absent ankle jerks and 8 (23.5%) had sensibility and tendon reflexes altered.Two patients had only symptoms and two had sub-clinical peripheral neuropathy with neither symptoms nor signs -the peripheral neuropathy was diagnosed by the neurophysiologic study. Thirty two (94.1%) patients were taking drugs supposed to be neurotoxic (d4T,ddI, ddC, isoniazid) [22][23][24][25] .Thirty nine patients had electroneuromyography performed. Thirteen (33.3%) of those had features of peripheral neuropathy.…”

“…The types of peripheral neuropathy are shown in Table 2. Seventy five per- [22][23][24][25] . Laboratory analysis did not show any significant abnormalities (42 patients were tested), except in four who had VDRL positive.…”

“…It can be caused by the direct or indirect action of HIV and antibody production, or secondary to infections (CMV,MAC ), toxic effects of certain drugs (isoniazid, vincristine, d4T, ddi, ddC), or nutritional deficiencies (vitamin B12) 4,7,[22][23][24][25][26][34][35][36] . In our study, almost all the patients that had diagnosis of peripheral neuropathy were taking drugs probably neurotoxic (ddi, d4t,ddC isoniazid).…”

A Review of the Toxicity of HIV Medications

“…Failure of the sympathetic nervous system can present as orthostatic hypotension, syncope, diarrhea, and anhidrosis while parasympathetic dysfunction is associated with resting tachycardia, urinary dysfunction, and sexual dysfunction [49]. While peripheral neuropathy is known to complicate untreated HIV infection, most cases result from exposure to NRTI, particularly the dideoxynucleosides didanosine, zalcitabine, and stavudine [52,53].…”

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

“…10 PN can develop in HIV-infected persons during exposure to NRTIs, especially didanosine (ddI) and stavudine (d4T). 11,12 This debilitating complication is characterized by symmetric distal anesthesia and/or painful dysesthesia. 13 PN is also a common finding in inherited mitochondrial disease.…”