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Zalcitabine (Hivid)
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Class
Background
U.S. Manufacturer
Discontinuation
Approval
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of zalcitabine resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for treatment with zalcitabine
References
Related Resources
DHHS Guidelines
Characteristics of NRTIs
Drug Interactions with NRTIs
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
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Drug Labeling (Package Insert)
Zalcitabine (Hivid)
Class

Deoxycytidine nucleoside analogue

Background
U.S. Manufacturer

Roche

Discontinuation

Roche Pharmaceuticals has discontinued the sale and distribution of zalcitabine tablets. The announcement was made in a "Dear Health Care Professional" letter dated June 2006.

Approval

FDA approval of zalcitabine for use in combination with zidovudine in adults was granted in 1992. Initial approval was based on trial data showing that increases in CD4 T-lymphocyte counts were somewhat greater and more sustained in patients treated with the combination of zalcitabine and zidovudine than in those who received zidovudine alone as initial therapy. A clinical study (1) found zalcitabine to be inferior to zidovudine as monotherapy for advanced HIV disease (CD4 count ≤200 cells/µL) in previously untreated patients, with significantly increased mortality observed in the group receiving zalcitabine. Two studies of initial therapy (2,3) found the combination of zalcitabine + zidovudine to be superior to zidovudine in delaying disease progression or death, but the differences were small, especially when compared with the effects of potent triple-drug combinations discovered shortly thereafter.

Formulation and Dosing

Dosing of Zalcitabine
Adult0.75 mg TID
Pediatric*InfantUnknown
Pediatric0.01 mg/kg Q 8 hours

Key to abbreviations: Q, every; TID, 3 times daily.

* Zalcitabine is not FDA approved for use in children. However, it has been studied in younger children; usual doses are indicated.

There are no food restrictions.
Dosage adjustment is recommended in renal insufficiency.
Please consult product labeling for detailed dosing information.
Clinical Use
Combinations

There is little evidence from large-scale trials for the effectiveness of triple-antiretroviral combinations including zalcitabine.

Zalcitabine and didanosine should not be used in combination because of their overlapping potential side effects of peripheral neuropathy and pancreatitis, their similar resistance profiles, and the lack of demonstrated efficacy of this combination. Zalcitabine and stavudine should not be used together because of the overlapping side effect of peripheral neuropathy. Patients receiving zalcitabine together with other potentially neurotoxic drugs (such as isoniazid or vincristine) should be monitored closely for the development of neuropathic symptoms.

Use in Initial vs Subsequent Therapy

Treatment guidelines of the U.S. Department of Health and Human Services do not consider zalcitabine to be a "preferred," "alternative," or "acceptable" component for initial treatment of HIV infection. The guidelines recommend against using the combination of zalcitabine and either didanosine or stavudine because of additive toxicity. They also recommend against using zalcitabine + lamivudine because of adverse drug interactions, or zalcitabine + zidovudine, because of limited antiviral activity.

Few data are available regarding the effectiveness of zalcitabine outside initial combination therapies. Two large studies (2,3) found no advantage in survival or disease progression when patients previously treated with zidovudine monotherapy added zalcitabine.

Factors Affecting Adherence

Symptomatic side effects of zalcitabine include peripheral neuropathy, which is common and may be disabling. Zalcitabine should be avoided in individuals with previously existing peripheral neuropathy. Other side effects that may affect adherence include mucosal ulcerations and rash.

There is evidence that nucleoside analogues may be associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis and disorders of lipid metabolism. Compared with other nucleoside analogues, zalcitabine appears to be a relatively potent inhibitor of mitochondrial DNA polymerase in vitro.(4) The clinical implications of this observation are unclear.

Resistance

Resistance to zalcitabine is associated with the selection of 1 or more of several resistance mutations.

Implications of zalcitabine resistance for treatment with other antiretrovirals
Resistance mutations selected by zalcitabine in some cases are expected to confer resistance to didanosine and/or lamivudine as well.
The codon 151 mutation, associated with resistance to multiple nucleoside analogues, has been reported in a small number of patients taking zalcitabine + zidovudine for 1 year.
Implications of resistance to other antiretrovirals for treatment with zalcitabine
The codon 69 mutation, which may be selected by regimens containing lamivudine, confers resistance to zalcitabine.
The codon 151 mutation, associated with resistance to multiple nucleoside analogues including zalcitabine, occurs infrequently but is most frequently observed in patients treated with zidovudine + didanosine or stavudine + didanosine.
References
1.  Follansbee S, Drew L, Olson R, et al. The efficacy of zalcitabine (ddC, Hivid) versus zidovudine (ZDV) as monotherapy in ZDV-naive patients with advanced HIV disease; a randomized, double-blind, comparative trial (ACTG 114; N3300). Abstract PO-B26-2113. IXth International Conference on AIDS, June 7-11, 1993; Berlin.
2.   Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Delta Coordinating Committee. Lancet 1996;348:283-91.
3.   Katzenstein DA, Hammer SM, Hughes MD, Gundacker H, Jackson JB, Fiscus S, Rasheed S, Elbeik T, Reichman R, Japour A, Merigan TC, Hirsch MS. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med 1996;335:1091-8.
4.   Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000;22:685-708.