HIVID is the Hoffmann-La Roche brand of zalcitabine [formerly called 2',3'-dideoxycytidine (ddC)], a synthetic pyrimidine nucleoside analogue active against the human immunodeficiency virus (HIV). HIVID is available as film-coated tablets for oral administration in strengths of 0.375 mg and 0.750 mg. Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, and polysorbate 80 along with the following colorant system: 0.375 mg tablet — synthetic brown, black, red and yellow iron oxides, and titanium dioxide; 0.750 mg tablet — synthetic black iron oxide and titanium dioxide. The chemical name for zalcitabine is 4-amino-1-beta-D-2', 3'-dideoxyribofuranosyl-2-(1H)-pyrimidone or 2',3'-dideoxycytidine with the molecular formula C₉H₁₃N₃O₃ and a molecular weight of 211.22. Zalcitabine has the following structural formula:

Zalcitabine is a white to off-white crystalline powder with an aqueous solubility of 76.4 mg/mL at 25°C

Mechanism of Action: Zalcitabine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxycytidine, in which the 3'-hydroxyl group is replaced by hydrogen. Within cells, zalcitabine is converted to the active metabolite, dideoxycytidine 5'-triphosphate (ddCTP), by the sequential action of cellular enzymes. Dideoxycytidine 5'-triphosphate inhibits the activity of the HIV-reverse transcriptase both by competing for utilization of the natural substrate, deoxycytidine 5'-triphosphate (dCTP), and by its incorporation into viral DNA. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The active metabolite, ddCTP, is also an inhibitor of cellular DNA polymerase-beta and mitochondrial DNA polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture.

In Vitro HIV Susceptibility : The in vitro anti-HIV activity of zalcitabine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and clinical isolates of HIV. The IC₅₀ and IC₉₅ values (50% and 95% inhibitory concentration) were in the range of 30 to 500 nM and 100 to 1000 nM, respectively (1 nM = 0.21 ng/mL). Zalcitabine showed antiviral activity in all acute infections; however, activity was substantially less in chronically infected cells. In drug combination studies with zidovudine (ZDV) or saquinavir, zalcitabine showed additive to synergistic activity in cell culture. The relationship between the in vitro susceptibility of HIV to reverse-transcriptase inhibitors and the inhibition of HIV replication in humans has not been established.

Drug Resistance : HIV isolates with a reduction in sensitivity to zalcitabine (ddC) have been isolated from a small number of patients treated with HIVID by 1 year of therapy. Genetic analysis of these isolates showed point mutations (Lys 65 Arg or Asn, Thr 69 Asp, Leu 74 Val, Val 75 Thr or Ala, Met 184 Val or Tyr 215 Cys) in the pol gene that encodes for the reverse transcriptase. Combination therapy with HIVID and ZDV does not appear to prevent the emergence of zidovudine-resistant isolates.

Cross-resistance : The potential for cross-resistance between HIV-reverse transcriptase inhibitors and HIV-protease inhibitors is low because of the different enzyme targets involved. The point mutation at position 69 appears to be specific to ddC in its selection and effect. Additionally, the point mutations at positions 65, 74, 75, and 184 are associated with resistance to didanosine (ddI), that at position 75 with resistance to stavudine (d4T), and those at positions 65 (Lys to Arg), and 184 (Met to Val) with resistance to lamivudine (3TC). HIV isolates with multidrug resistance to ZDV, ddI, ddC, d4T, and 3TC were recovered from a small number of patients treated for 1 year with the combination of ZDV, ddI or ddC. The pattern of resistance mutations in the combination therapy was different (Ala 62 Val, Val 75 Ile, Phe 77 Leu, Phe 116 Tyr and Gln 151 Met) from monotherapy with mutation 151 being most significant for multidrug resistance.

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