Drugs 1997 Jun: 53 (6): 1054-1080 ADIS DRUG EVALUATION 00 12-6667/97/0006- 1054/$27 00/0

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Zalcitabine An Update of Its Pharmacodynamic and Pharmacokinetic Properties and Clinical Efficacy in the Management of HIV Infection

Julie C. Adkins, David H. Peters and Diana Faulds Adis Internation al Limited , Auckland, New Zealand

Varioussections of the manuscript reviewed by: B.G. Gazzard, Chelsea and Westminster Hospital, Lond on, England; C. Hooper, Center for AIDS and Sexua lly Transmitted Diseases, University of Washington, Seattle, Washington, USA; D. Johns, Na tional Cancer Institute, National Institutes of Hea lth, Bethesda , Maryland, USA; M. Magnani, Istituto di Chim ica Biologica 'G Fornai ni' , University of Urbino, Urbino, Italy; G. Mo yle, Chelsea and Westminster Hospital, London, England; S. Palm er, Depa rtment of Virology, Swedish Institute for Infectiou s Disease Control, Stockholm,Sweden;A.J. Pinching, Department ofI mmunology,The Medica lCollege ofSaint Bartho lomew 's Hospital, Londo n, Eng land; P. Volberding, Department of Medicine, San Francisco General Hospital, San Francisco, Califo rnia, USA.

Contents Summary . 1055 1. Overview of Pharmac odyna mic Properties 1057 1.1 Mechanism of Action . 1057 1.2 In Vitro Antiviral Activity . 1058 1.3 Cytotoxicity ...... 1059 1,4 Resistanc e to Zalcitabine 1059 1.4.1 Viral Resistanc e . . 1059 1.4.2 Ce llular Resistanc e 1060 2. Pharmac okinetic Properties . 1061 2.1 Absorption and Distribu tion 1062 2.2 Metabolism an d Eliminati on . 1062 3. Clinical Efficacy . 1062 3.1 Zalcitabine Monotherapy .. 1063 3.2 Combination Therapy . . . . 1063 3.2.1 Double Combination Therapy . 1065 3.2.2 Triple Co mbinati on Therapy . . 1068 3.3 Paediatric Use ...... 1069 3.4 Pharma coe conom ic Considerations 1069 4. Tolerability . 1070 4.1 Zalcitabine Mon oth erapy .. 1070 4.1.1 Peripheral Neuropathy 1071 4.1.2 Oral Stomatitis . . . . . 1072 4.1.3 Other Adverse Effects 1072 4.2 Combina tion Therapy . 1072 5. Drug Interactions ...... 1073 6. Dosage an d Ad ministration . . . . 1074 7. Place of Zalcitabine in the Man agem ent of HIV Infection 1074 Zalcitabine: An Update 1055

Summary Synopsis Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosphorylated to the active metabolite 2',3'-dideoxycytidine 5' -triphosphate (ddCTP) within both uninfected and HIV-infected cells. At therapeutic concentrations, ddCTP inhibits HIV replication by inhibiting the enzyme reverse transcriptase and terminating elongation ofthe proviral DNA chain. The results of3 large pivotal trials comparing zidovudine monotherapy with combination therapy have now clearly established that zalcitabine plus zldovud­ ine combination therapy improves survival, delays disease progression and is associated with an improvement in viral load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have established the efficacy ofzalcitabine in combination with the protease inhibitor saquinavir in zidovudine-experienced patients. Other studies have demonstrated the utility ofzalcitabine in combination with ritonavir and the nucleoside analogue lamivudine.Importantly, early use ofzalcitabine in the treat­ ment sequence does not appear to limit the therapeutic efficacy ofsubsequent therapy with other nucleoside analogues such as lamivudine. Peripheral neuropathy is the most frequent dose-limiting adverse effec t asso­ ciated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatiti s and mouth ulcers may occur frequently with zalcitabine therapy but tend to resolve with continuing treatment. Haematological toxicity, which is a common adverse effect associated with zidovudine. is reported infre­ quently with zalcitabine. Overall, combination therapy with zalcitabine plus zidovudine or saquinavir has been shown to have a tolerability profile compara­ ble to that ofeither agent alone, although treatment with zidovudine plus zalcitab­ ine was associated with a significant increase in the incidence ofhaematological toxicity compared with zidovudine monotherapy in one study. Therefore, current data suggest that zalcitabine is a useful antiretroviral agent for inclusion as a component ofinitial double combination therapy with zidovud­ ine or as part oftriple combination therapy including zidovudine plus a protease inhibitor in the management (if patients with HIV infection. Pharmacodynamic Zalcitabine is phosphorylated to the active antiviral compound 2' ,3'-dideoxy­ Properties cytidine 5' -triphosphate (ddCTP) within both uninfected and HIV-infected cells . ddCTP inhibits HIV replication by inhibition of the enzyme reverse transcriptase and termination of viral DNA chain elongation. In both these roles ddCTP com­ petes with endogenous deoxycytidine triphosphate. Zalcit abine has demonstrated significant antiretroviral activity against HIV-l in vitro. In addition, synergistic antiretroviral activity has been reported for zalcitabine in combination with sev­ eral other antiretroviral agents including zidovudine, stavudine and saquinavir. Resistance to zalcitabine usually arises from a series of mutations within the HIV pol gene and develops less frequently than resistance to zidovudine. Cross­ resistance between zidovudine and zalcitabine has been described. The activation state of the target cell, whether the cell under investigation is acutely or chroni­ cally infected with HIV, and/or the levels of intracellular phosphorylating en­ zymes may also contribute to variation in the antiviral activity of zalc itabine between cell lines . In vitro investigations suggest that zalcitabine-induced inhibition of an en­ zyme responsible for the synthesis of mitochondrial DNA (DNA polymerase y)

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may be responsible for the development ofperipheral neuropathy in clinical prac­ tice . Pharmacokinetic Following oral administration, zalcitabine is rapidly absorbed, with peak plasma Properties concentrations typically achieved in I to 2 hours. The oral bioavailability of zalcitabine exceeded 80% in some studies. Zalcitabine partially crosses the blood­ brain barrier; drug concentrations in the CSF represented a mean of 14 to 20% of simultaneously measured plasma concentrations. Placental transfer ofzalcitabine has been reported in vitro and in vivo. Zalcitabine has a short plasma elimination half-life of 1.1 to 1.8 hours and is predominantly excreted unchanged in the urine . Hepatic metabolism of the drug is minimal and only about 10% of an orally administered dose is excreted in the faeces. Clinical Efficacy The results of 3 large pivotal studies, ACTG 175, CPCRA 007 and Delta, have clearly demonstrated that combination therapy with zidovudine plus zalcitabine or zidovudine plus didanosine improves survival and delays disease progression compared with zidovudine monotherapy. Although not exclusively limited to zidovudine-naive patients, the benefits of zalcitabine plus zidovudine therapy appear to be greater in this patient population than in zidovudine-experienced patients. Improvements in surrogate marker and clinical end-points have also been reported in zidovudine-experienced patient populations with advanced HIV infection (CD4+ cell count 50 to 300 cells/ul) treated with 2- or 3-drug combi­ nation regimens comprising zalcitabine plus the protease inhibitor saquinavir ± zidovudine. Zalcitabine has also demonstrated utility in combination with the protease inhibitor ritonavir as first-line treatment in a pilot study. Impressive surrogate marker data have also been reported in zidovudine-experienced patients receiving a 3-drug regimen comprising lamivudine, zalcitabine and zidovudine. Furthermore, the addition of lamivudine ± loviride to ongoing therapy with zidovudine plus zalcitabine in patients with advanced HIV infection was associ­ ated with a greater reduction in disease progression compared with the addition of lamivudine ± loviride to zidovudine alone. This therefore suggests that prior use of zalcitabine does not limit the subsequent utility of other nucleoside ana­ logues such as lamivudine. Tolerability Peripheral neuropathy is the major dose-limiting adverse effect associated with zalcitabine therapy and has been reported to occur in 12 to 46 % of patients in clinical studies; risk factors for the development ofzalcitabine-induced peripheral neuropathy include a baseline CD4+ count ~50 cells/pl. diabetes mellitus and a low serum cobalamin level. Mouth ulcers and stomatitis occurred with an inci­ dence of 3 to 4% in 3 large studies and 29% in a fourth study; these effects may resolve with continuing administration of the drug . Pancreatitis is an infrequent adverse effect associated with zalcitabine therapy, generally developing in < 1% of patients. Other adverse effects associated with zalcitabine include hepatotoxi­ city and cutaneous/hypersensitivity reactions. The tolerability profile ofcombination therapy with zalcitabine plus zidovud­ ine or saquinavir generally reflects that of the individual drugs and has not been associated with the development of any unexpected adverse effects. However, the incidence of haematological adverse effects with zidovudine plus zalcitabine therapy was significantly greater than that reported for zidovudine alone in one study.

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Although tolerability data in children are limited, rash, stomatitis and periph­ eral neuropathy have been reported after administration ofthe drug to this patient group. Drug Interactions Several important drug interactions have been reported between zalcitabine and other drugs used in the management of patients with HIV infection. Potentially nephrotoxic agents, notably the aminoglycosides, amphotericin and foscarnet, may reduce the renal clearance of zalcitabine and potentially increase the inci­ dence ofzalcitabine-associated adverse effects. Importantly, the concomitant use of zalcitabine with pentamidine should be avoided because of an increased risk of the development of severe pancreatitis. Furthermore, zalcitabine should be coadministered with caution with other drugs that may cause peripheral neurop­ athy (for example, didanosine, dapsone, metronidazole, stavudine, isoniazid and pentamidine) should be avoided where possible.A reduction in the bioavailability of zalcitabine has been reported with the concomitant administration of alumin­ ium hydroxide/magnesium hydroxide antacid mixture. To date, clinically significant pharmacokinetic interactions have not been re­ ported between zalcitabine and other antiretroviral agents including zidovudine, saquinavir and nevirapine. However, inhibition of zalcitabine phosphorylation by lamivudine has been reported in vitro. Dosage and The recommended dosage of zalcitabine for use in combination with zidovudine Administration in adults and adolescents (age>13 years) is 0.75mg administered orally every 8 hours. The same dosage is recommended for use in combination with the protease inhibitor saquinavir. The optimal dosage of zalcitabine as part of triple combina­ tion therapy has yet to be determined, although 0.75mg every 8 hours has been widely used in clinical studies. Zalcitabine dosage should be reduced in patients with renal insufficiency; 0.75mg twice daily is recommended in patients with a creatinine clearance (CLCR) of 0.6 to 2.4 L/h (10 to 40 ml/min) decreasing to 0.75mg once daily in patients with a CLCR<0.6 Llh «10 ml/min). Zalcitabine should be discontinued if peripheral neuropathy develops and reinstituted (at a dose of0.375mg every 8 hours) only if symptoms become no more than mild in nature. Caution is also recommended when the drug is administered to patients with a history of poor bone marrow reserve, elevated amylase levels, pancreatitis or alcohol abuse and in patients receiving parenteral nutrition.

Zalcitabine (2',3'-dideoxycytidine, ddC) is a 1. Overview of Pharmacodynamic dideoxynucleoside that is active against Hl V, Since Properties the publication ofthe original review ofzalcitabine in Drugs in 1992 111there has been a considerable 1.1 Mechanism of Action increase in published data on the use of this drug, particularly in combination with other antiretro­ Following cellular uptake, zalcitabine is phos­ viral agents, in the treatment of HIV infection. phorylated to the active metabolite 2',3'-dideoxy­ This review updates the original zalcitabine review cytidine 5'-triphosphate (ddCTP) by intracellular and incorporates data published during the past 5 phosphorylating enzymes in both uninfected and years. HlY-infected cells.P' Zalcitabine competes with

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natural cellular deoxycytidine for these enzymes. Table I. In vitro activity of zalcitabine in combination with other The triphosphate metabolite of zalcitabine then agents against laboratory HIV-l strains competes with endogenous deoxycytidine triphos­ Reference Drug" (class) Cell cultureb Result phate (dCTP) for the enzyme HIV reverse trans­ Double combination criptase; inhibition of this enzyme subsequently Brennan et al.[5Je MKC-442 (NNRTI) C8l66, MT4 , + JM prevents viral DNA synthesis and HIV replication. (6) Bridges et a1. FTC (NRTI) MT2 + Viral DNA synthesis is also terminated through in­ Chong et al.l7]e Delavirdine (NNRTI) PBM , H9 ++ corporation of ddCTP in place of dCTP into the Connell et al.181 Saquinavir (PI) CEM ++ growing retroviral DNA chain, preventing addition Craig et al.191 Zidovudine (NRTI) CEM , MT4 ++ of subsequent nucleosides (see review by Whit­ Saquinavir (PI) CEM, MT4 ++ tington & Brogden'!'). Craig et al.l101 Saquinavir (PI) CEM-T4 ++ Degre & Beck (11) Human leucocyte PBM ++ interferon (I) 1.2 In Vitro Antiviral Activity Deminie et al.I12J Stavudine (NRTI) CEM -SS ++ 13 Eron et al.l )c Zidovudine (NRTI) H9,PBM ++ Analysis of the in vitro activity of antiviral Johnson et al.114Jd Saquinavir (PI) PBM +/++ agents is dependent upon a large number of vari­ Mathez et al.I151d Zidovudine (NRTI) PBM ++ ables including cell type, activity of intracellular Palmer et al.I16Je Foscarnet (NNRTI) PBM ++ phosphorylating enzymes, levels of endogenous Perno et al.I17J GM-CSF (CSF) M/M-enriched - dCTP pools and stage of infection (see section PBM Perno et al.[17] M-CSF(CSF) M/M-enriched - 1.4.2).1 31 Because of potential modulation of anti­ PBM viral activity by cytokines and competition be­ Taylor et al.I18J MDL -28574 (a-GI) H9, MT4 ++ tween endogenous dCTP and ddCTP for reverse Triple combination transcriptase active sites, variations in the in vitro Craig et al.19J Saquinavir (PI) plus CEM , MT4 ++ activity of zalcitabine in different cell lines have zidovudine (NRTI) been reported. Furthermore, the use of a variety of a Drug used in combination with zalc itabine. assay conditions makes between-study compari­ b All studies used cell viability (usually dye exclusion) and/or p24 ant igen production to measure anti-HIV activity except Craig sons difficult. et al.[lO) (HIV syncytium formation). C8l66, CEM-SS, CEM, Zalcitabine 0.5 umol/L showed significant anti­ CEM-T4 , H9, JM, MT2 and MT4 are T cell lines . viral activity against HIV-I in human T cell lines c Both labo ratory strains and clin ical HIV-l isolates tested. with almost complete inhibition of cytopathic ef­ d Only clinical HIV-l isolates tested. fects and p24 antigen expre ssion.If However, cur­ Abbreviations and symbols: a-GI = a-glucosidase 1 inhibitor; CSF = colony-stimulating factor; FTC = 2,3'-dideoxy-5-f1uoro-3'­ rent single agent antiretroviral drug regimens are thiacytidine; GM-CSF = granulocyte-macrophage colony-stimulating insufficient to provide long term viral suppression factor; I = immunomodulator; M-CSF = macrophage colony-stimulat­ in patients with HIV infection because of the de­ ing factor; M/M = monocyte-macrophage; PBM = peripheral blood mononuclearcells; PI =protease inhibitor; NNRTI =non-nucleoside velopment of drug-resistant viral strains. For this reverse transcriptase inhibitor; NRTI = nucleoside reverse trans ­ reason, interest is now focused on the use of com­ criptase inhibitor;- indicates antagonistic effect; + indicates additive binations of antiretroviral agents which additively effect; ++ indicates synergy. or synergistically inhibit HIV replication (see sec­ tion 3.2) and may delay or prevent the emergence of viral resistance. Although in vitrosynergy does agents, most notably zidovudine. The results of not automatically correlate with clinical benefit, it studies evaluating 2- and 3-drug combinations are nevertheless has an important role in the selection summarised in table I. of suitable antiretroviral agents for use in combi ­ Progressively greater inhibition of viral replica­ nation in the clinical seuing.!" tion (denoted by a delay in breakthrough of HIV-I Numerous studies have evaluated the in vitro replication) was reported with an increasing num­ activity of zalcitabine in combination with other ber of drugs in a CD4+ T cell line (H9) ; 4-drug

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therapy (zidovudine, didanosine, interferon and nosine.P'" However, brief periods of exposure (4 zalcitabine) was more effective than triple therapy hours) to triple drug combinations had only a mod­ (zidovudine, didanosine and interferon), which in est myelotoxic effect. turn wa s more effective than zidovudine plus In MOLT-4, CEM, PC 12 and U937 cell s, treat­ didanosine.l191 ment with zalcitabine reduced mitochondrial As intracellular phosphorylation is necessary DNA content, impaired mitochondrial function for the antiretroviral activity of zalcitabine, inves­ and/or produced mitochondrial ultrastructural tigations have focused on whether the concomitant changes.1 28-32) Defective replication of mitochon­ administration of other drugs may modify thi s pro­ drial DNA is thought to be responsible for the de­ ces s and potentially reduce the in vitro antiviral velopment of peripheral neuropathy in patients activity of zalcitabine. Using peripheral blood treated with nucleoside analogues such as zalcitab­ mononuclear cells (PBMs), and U937 and MOLT 4 ine. [33-351 Indeed, abnormal Schwarm cell mito­ cell lines, zidovudine, didanosine and stavudine chondria, with decreased myelin mitochondrial were shown to have no significant effect on RNA and axonal neuropathy, were reported in vivo zalcitabine phosphorylation.P?' Similarly, zalcita­ in rabbits treated with zalcitabine.Pv' bine did not significantly reduce the intracellular Preliminary data suggest that zalcitabine may phosphorylation of zidovudine in PBM or the be associated with less embryonic cytotoxicity hI A2v2 Iymphoblastoid cell line.P! J In contrast, than zidovudine. Cytotoxicity in murine 2-cell em­ the nucleoside analogue lamivudine inhibited bryos was significantly lower with zalcitabine than zalcitabine phosphorylation in vitro.1221The clini­ zidovudine; inhibition of blastocyst formation was cal rele vance of this interaction is currently un­ evident at zidovudine I urnol/L but only became known; however, both lamivudine and zalcitabine detectable at zalcitabine 100 IlmollL.[371 are dependent upon deoxycytidine kinase for the In US National Toxicology Program studies, a initial steps of phosphorylation. The anthracycline poorly regenerative macrocytic anaemia, which anticancer agent doxorubicin also inhibited was reversible on cessation of treatment, was re­ zalcitabine phosphorylation in vitro.1201 Conflict­ ported in mice given zidovudine and to a lesser ing results have been reported regarding the effect extent in mice that recei ved zalcitabine.Uf Fur­ of ribavirin, a broad spectrum antiviral agent, on thermore, in contrast to didanosine, zalcitabine did the phosphorylation and antiviral activity of not alter murine immune function through modifi­ zalcitabine.120.231 cation of the antibody response. Other workers in­ vestigated the in vivo toxicity of zalcitabine using 1.3 Cytotoxicity the LP-BM5 murine retrovirus-induced immuno­ deficiency modeJ.l 391 Histological examination re­ Zalcitabine is toxic to erythroid and granulo­ vealed a marked reduction in the number of mega­ cyte-macrophage progenitors, predominantly in karyocytes in the bone marrow ofboth infected and the early stages of differentiation.Pt' In vitro, uninfected mice and hepatocellular vacuolation in zalcitabine inhibited bone marrow cell develop­ the liver of uninfected mice only. In addition, a ment at concentrations that showed minimal anti­ reduction in mitochondrial DNA content was re­ viral activity. This suggested that zalcitabine may ported in both groups. be associated with haematotoxicity similar to that of zidovudinel25.261 but this has not been unequiv­ 1.4 Resistance to Zalcitabine ocally confirmed in clinical trials (see section 4). Potentially important myelotoxicity developed in 1.4.1 Viral Resistance the HL60 myeloid leukaemia cell line following The development of viral resistance to anti ­ prolonged exposure to combination therapy with retroviral drugs is a major cause of treatment fail­ zidovudine and zalcitabine, with or without dida- ure . In vivo resistance to zalcitabine or any other

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anti-HIV agent is a consequence of the extremely 106 and BW 34,225-02), treatment of zidovudine­ high replication rate of the wild-type virus and to naive patients «4 weeks of prior zidovudine ther­ a lesser extent to the high rate of incorporation of apy) with zidovudine plus zalcitabine for 48 or 112 errors by HIV reverse transcriptase.l4o-43] This re­ weeks resulted in the selection of predominantly sults in the continuous and spontaneous generation zidovudine-resistant strains.150,59.601 In 2 of these of viral mutants, including drug-resistant mutants, studies, the use of combination therapy was not even in the absence of drug . Replication of these associated with an appreciable delay in the emer­ 60I mutants usually occurs at a low rate ; however, gence of zidovudine-resistant viral isolates,150. when the wild-type virus is suppressed by drug In a subgroup analysis of zidovudine-naive pa­ therapy, one or more drug resistant mutants, which tients recruited to the Delta study, the development are already present at low levels, can replicate of zidovudine resistance caused by a mutation at freely and predominate. The development of viral codon 70 was significantly (p < 0.000 I) delayed resistance to nucleoside analogues has been re­ during combination therapy (zidovudine plus zal­ viewed by several authors.141-451 citabine or didanosine) compared with zidovudine Several mutation sites in the HIV pol gene have monotherapy; however, there was no significant been associated with resistance to zalcitabine,146] difference between the treatment groups in time to although data from clinical studies suggest that the development of other resistant mutations asso­ HIV develops reduced susceptibility to zalcitabine ciated with zidovudine.P'" Notably, the pattern of less frequently than to zidovudine.147-501 Current resistance to zalcitabine both as monotherapy and as combination therapy has led to suggestions that data suggest that the level of resistance to zalcitab­ the use of this drug early in the treatment sequence ine is generally equivalent to a <100-fold increase does not limit future therapy options,l41,43 1 in IC50 (concentration of drug required to inhibit Mutations conferring cross-resistance to zalci­ viral replication by 50%) . Mutations at codons 65 tabine have been reported.A mutation at codon 75 or 69 are typically associated with only modest re­ conferring cross-resistance to stavudine, zalcitab­ sistance to zalcitabine (<1 O-fold reduction in ine and didanosine has been described in vitro .1611 IC .141] The mutation at codon 69 is the most fre­ 50) Workers have also reported a novel mutation pat­ quently observed change in viral isolates from tern (at codons 62, 75, 77, 116 and 151) in patients patients developing resistance to zalcitabinel48,511 receiving zidovudine plus zalcitabine or didano­ but importantly does not appear to lead to cross­ sine which confers cross-resistance to stavud­ resistance to didanosine or zidovudine.141,431 ine.l621A virus with mutations at positions 75, 77, Mutation at codon 65 has been associated with re­ 103, 116, 151 and 184 which is resistant to all nu­ sistance to zalcitabine, didanosine and lamivud­ cleoside analogues and most non-nucleoside re­ ine152,53] and it may cause a reduction in viral DNA verse transcriptase inhibitors tested has also been chain termination in the presence ofddCTpl54] and described recently in a heavily pretreated pa­ selective changes in the ability of reverse trans­ tient. 1631Notably, resistance to zalcitabine, stavud­ 551 criptase to recognise ddCTP.1 A low level of in ine and nevirapine has been reported in clinical iso­ vitro resistance to zalcitabine and didanosine (4- to lates obtained from patients who had been 8-fold increase in IC50)and a marked increase in in previously treated with zidovudine only.IMI vitro resistance to lamivudine (500- to 1000-fold) have been associated with a mutation at codon 1.4.2 Cellular Resistance 184.156,571 In addition to the selection of drug -resistant Therapy with zidovudine and zalcitabine during variants of HIV, the selection of drug-resistant cell alternate months has been associated with the se­ populations may play an important role in reducing lection of clinical isolates resistant to both the antiretroviral activity of nucleoside ana­ drugs. 147,58 1 However, in 3 studies (Delta, ACTG logues,l65,66] Currently available data suggest that

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individual nucleoside analogues differ in their ac­ cyte-macrophages but lacks antiviral activity at tivity against various target cell lines and have con centrations 1000 times greater in chronically shown zalcitabine to be more effective in mono­ infected cellsp 51 cyte-macrophage than in T cell lines.l 671A reduc­ Selection of a zalcitabine-resistant U937 mono­ tion in intracellular levels of dCTP, which com­ blastoid cell line characterised by an increased petes with ddCTP for reverse transcriptase, is number of mitochondria, greater mitochondrial thought to contribute towards the greater activity DNA content and a reduction in the affinity of of zalcitabine in monocyte-macrophage cell cytoplasmic deoxycytidine kinase for zalcitabine lines.[68,69] Differences in the level of intracellular has been reported following long term exposure to phosphorylating enzymes may also contribute to the drug.l31.76.771 variations in the anti-HIV activity of zalcitabine among cell lines.I?'" Notably, levels of deoxycyti­ 2. Pharmacokinetic Properties dine kinase are exceedingly low in brain tissue, suggesting that zalcitabine is not extensively me­ The pharmacokinetic properties of zalcitabine tabolised in the brain.!? II have been investigated after oral and intravenous Other factors associated with cellular drug re­ administration to adults and children with HIV in­ sistance include the activation state of the target fection (table II) and have been reviewed pre­ cell and whether the cell under investigation is viously by several authors.l I,82-851 Pharmacoki­ acutely or chronically infected with HIV. In con­ netic data on the administration of zalcitabine to trast to zidovudine, which preferentially protects pregnant or elderly patients or to patients with activated cells from HIV infection, the antiviral ef­ hepatic impairment are currently unavailable. fect of zalcitabine was reported to be greater in Pharmacokinetic data from children are limited, resting cells.f72-741In common with zidovudine and but suggest lower bioavailability and/or faster didanosine, zalcitabine has antiviral activity at clearance of zalcitabine in children compared with subtoxic concentrations in de novo infected mono- adults (table 11) .[80,81 1

Table II. Mean pharmacokinetic data for zalcitabine . Results after single dose administration of zalcitabine in adults and children with HIV infection

Reference Zalcitab ine dose (mg) Cmax AUC F v; ",;,~ CL [no. of pts] (~g/L) (mg/L· h) (%) (Llkg) (h)

Adults with AIDS or ARC Gustavson et al.[781 0.5 PO [2] 7.6 0.018 86 1.5 0.5 POa [1] 8.5 0.019 1.1 5 PO [4] 79.0 0.208 100 1.8 0.5 IV [4] 10.5 0.022 0.64 1.3 0.336 Uh/kg Klecker et al.[791 0.09-0.5/kg PO [7] 95-316b 88 0.03-0.25/kg IV [10] 84-158c 0.54 1.2 13.62 Uh /m2

Children with symptomatic HIV infection Gould Chadwick et al.[80I 0.02lkg POa [23] 9.3 0.025 1.4 0.876 Uh/kg Pizzo et al.[811 0.03-0.04/kg PO [5] 40 0.061 54 9.3 Um 2 0.91 0.03-0.04/kg IV [5] 76 0.135 0.78 8.94 Uh /m2 a Oral solution. b Range of values for 4 patients who received zalcitabine 0.25 mg/kg PO. c Range of values for 4 patients who received zalcitabine 0.09 mglkg IV.

Abbreviations:ARC = AIDS·related complex ; AUC = area under the plasma concentration-time curve; CL = total body clearance ; Cmax = peak plasma concentration ; F = oral bioavailability ; IV = intravenous; PO = oral; pts = patients ; t1l2~ = terminal plasma elimination half-life; Vss = volume of distribution at steady-state.

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Extensive evaluation of the disposition of need for dosage adjustment in patients with poor zalcitabine was initially hampered by the limita­ renal function (see section 6) .1 911 tions of analytical methods available to measure Zalcitabine does not appear to undergo signifi­ the low plasma concentrations achieved after the cant hepatic metabolism; dideoxyuridine (ddU) is administration of clinically relevant doses.!"! the primary metabolite of zalcitabine found in the However, the recent development ofradioimmuno­ urine. Approximately 10% of an orally adminis­ assay methods for the measurement of plasma tered dose of zalcitabine is excreted in the faeces , zalcitabine concentrations has overcome this prob­ primarily as unchanged drug or ddU.l92J lem.lS6-SSI 3. Clinical Efficacy 2.1 Absorption and Distribution Because of the slowly progressive course of Zalcitabine has a linear pharmacokinetic profile HIV infection, the use of primary clinical end­ which is not significantly affected by the route points (survival, disease progression and develop­ of administration (oral or intravenousj .Fv' After ment of an AIDS-defining event) to asse ss the ef­ oral administration of zalcitabine 0.25 mg/kg to ficacy of antiretroviral therapy in clinical trials adults, the drug was rapidly absorbed, with peak may not be feasible, particularly in patients who are plasma concentrations of 95 to 316 ug/L typically asymptomatic at recruitment. The scale of the HIV achieved in I to 2 hours.l""! After oral administra­ epidemic warrants rapid evaluation of drug effi­ tion of tablets or solution to adults, the bioavaila­ cacy and tolerability and has led to the introduction bility of zalcitabine has been reported to exceed of surrogate markers of disease as an indirect as­ 80%pS,79J Concomitant administration of zalcita­ sessment of drug efficacy. bine with food reduced zalcitabine bioavailability Pla sma viral load and rate of CD4+ cell deple­ by 14% and decreased the mean plasma concentra­ tion are currently considered to be the best predic­ tion by 39%; however, these changes were not con­ tors of disease progression/death.N'l CD4+ cell sidered to be of clinical importance.P?' count, however, has been shown to be a poor on­ The concentration of zalcitabine in the CSF af­ therapy marker of response in efficacy studies of ter oral or intravenous administration was 14 to antiretroviral drugs.194,951 Instead, plasma viral 20% ofthat simultaneously measured in the plasma load is now emerging as a more accurate predictor of patients with AIDS or AIDS-related complex of disease progression and clinical outcome for pa­ (ARC) .179,901 tients receiving antiretroviral therapy;196,971the re­ sults of study ACTG 175 showed a significant as­ 2.2 Metabolism and Elimination sociation between plasma HIV RNA levels and risk Zalcitabine is rapidly eliminated, with a plasma of disease progression and death in patients treated elimination half-life (t Y2~) of 1,1 to 1,8 hours and a with zidovudine, zalcitabine and/or didanosine.l'excretion of unchanged drug is the principal neopterin levels.1931 While the use of surrogate route of elimination of zalcitabine, accounting for markers is widely accepted, their value remains a 62% and 75% of single oral and intravenous doses, controversial issue.l 99,IOOI respectively.l"?' Following a single oral dose of The majority ofstudies evaluating zalcitabine in zalcitabine (0.75mg), clearance of the drug was re­ the treatment of HIV infection have used both clin­ ported to be significantly (p < 0.05) reduced in pa­ ical and surrogate markers. Such studies have re­ tients with a creatinine clearance (CLCR) ~3 Llh cruited both asymptomatic and symptomatic (~50 ml/min) [n = 15] compared with those with a zidovudine-experienced and zidovudine-naive pa­ CLCR >3 Llh (>50 ml/min) [n = 8], suggesting the tients. Since the previous review of zalcitabine in

© Adi s International Umited . All right s reserved. Drugs 1997 Jun; 53 (6) Zalcitabine: An Update 1063

Drugs,[11 the clinical profile of this agent has been were significantly less likel y to require invasive more extensively delineated, most notably in large procedures or hospitalisation and also experienced randomised double-bl ind studies comp aring oral significantly fewer symptoms that interfered with zalcitabine (2.25 mg/day) as a component of com­ daily activity and fewer day s of disabi lity during bination therapy with zidovudine monotherapy in the first 48 weeks of follow-up.' III ] HIV-infected adults; onl y a small numb er of stud­ More favourable results have been report ed ies have been conducted in children (section 3.3) with zalcitabine monotherapy in smaller studies. and no further studies in this patient population are Sub stitution with zalcitabine was associated with planned. The value of combination antiretroviral a significant survival benefit at 12 month s (p = therapy over monotherapy in the treatment of pa­ 0.05) compared with substitution with didanosine, tients with HIV infection has now been unequivo­ remaining on zidovudine or no nucleoside therapy cally demonstrated in several large phase III stud­ in a retro spective analy sis of 154 patients (CD4+ ies. In clinical practice thi s has resulted in the count <200 cells/ul) who were intolerant of or un­ widespread substitution of antiretroviral combina­ responsive to zidovudine monotherapy.' 11 21 In tion therapy for monotherapy as standard treatment study CPCRA 002, a multicentre, nonbl ind, ran­ in patients with HIV infection. For this reason , domi sed trial , zalcitabine was at least as effective studies evaluating the use of zalcitabine in combi­ as didanosine in delaying disease progression and nation with other antiretroviral agents are the focus death in 467 patients with advanced HIV disease of the clinical section of this review and only brief (CD4+ count ~300 cells/ul) who had failed to re­ reference is given to monotherapy studies. spond to or were intolerant of zidovudine mono­ Whether zalcitabine is an effective antiretro­ therapy.1113] The results of ACTG 11 9, a nonblind, viral agent for the prevention of HIV transmission rand omised trial which recruited III patients with dur ing the perinatal period,IIO I-103]following occu­ extensi ve zidov udine expos ure (~48 wee ks), pational HIV exposurel104,105] or in the manage­ showed that substitution with zalcitabin e produced ment of patients with AIDS dementia complex[I06- I09I a small nonsign ificant surviva l advantage (esti­ has yet to be determined. mated 12-month survival rates 81 vs 75%) and a significantly (p < 0.05) slower reduction in CD4+ 3.1 Zalcitabine Monotherapy cell count at week 28 compared with continued zidovudine therapy.' 114 1 In view of the recent wide spread adoption of combination antiretroviral therapy as standard care for patients with HIV infection, the use of zalcitab­ 3.2 Combination Therapy ine monotherapy in clinical practice is no longer appropriate. Prior to this change in practice, sev­ Initial studies evaluating combinati on anti­ eral comparative studies were conducted compar­ retroviral therapy compared regimens comprising ing zalcitabine with zidovudine or didanosine 2 nucleoside analogues (including zalcitabine) monotherapy. The largest of these (ACTG 114) with anti retro viral monotherapy (table III). These was a multicentre randomised double-blind study included the 3 larg e clinical end-point studies, involving 635 patients with AIDS or ARC and <3 ACTG 175,1 1161, CPCRA 007 11 201 and Delta.lllll month s of prior zidovudine exposure . The result s Sub sequent to this, additi onal studies have eva lu­ of this study (published as an abstract) showed 1­ ated 2- and 3-drug regimens comprising a nucleo­ yea r surv ival to be significantly lower in the side analogue plus a protease inhibitor or 2 nucle­ za lcitabine (2.25 mg/day) compared with the oside anal ogues plus a protease inh ibitor or a zidovudine (600 or 1200 mg/day) treatment group non-nucleoside reverse transcriptase inhibitor. (68.4 vs 76.8%; P = 0.02).[1101 Furthermore, in a Zalcitabine has been included as a component of subgroup analysis, zidovudine-treated patients regimens eva luated in some of these later studies

© Adis Internationa l Umited . All rights reserved. Drug s 1997 Jun; 53 (6) @ » Table III. Summary of multicentre randomised do uble-blind trials evaluating oral za lcitabine (ZA L) as co mbination therapy in adults with HIV infection Q. ~ ". Reference Characteristics of pts No. of pts Treatment regimen Change in Change in No. of pts with No. of I 5" (duration of follow-up ) (disease stage) (mgJday) HIV RNA levels CD4+ count disease death s CD 3 from baseline from baseline progression" (%) 0 g (log10 copies) (cells/ul) (%) :J 1115 Q. ACTG 155 ) ZDV for ~ mo;AIDS or SYM and 285 (49 ASY) ZAL2 .25 .).32% 123 (43) 51 (18) CD4+ count ,;;300 cells/ul, or ASY 283 (54 ASY) ZDV600 .).32% 118 (42) 43 (15) ~ and CD4+ count ,;;200 cells!lI l

1117J ACTG229 ZDV for ~4mo;CD4+ count 100 (10 AIDS ; 49 SYM ; 41 ASY) ZAL 2.25 + ZDV 600 .1,0.1' .1,25%' 6 (6) 50-300 cells!lIl (';;56wk) 98 (13 AIDS ; 52 SYM; 33 ASY) ZAL 2.25 + ZDV 600 + ! O.35c;I 0%'** 3 (3) SOV 1800

99 (10 AIDS ; 52 SYM; 37 ASY) ZDV 600 + SOV 1800 10.3' .1,30%' 8 (8)

BW 34, 225-0211181 ZDV for <4wk; CD4+ count 61 (20 AIDS; 26 ARC; 15 ASY) ZAL 2.25 + ZDV 600 .I,LOdl1 135tt 26 (43)· 31 (51)· <300 cells!lIl (48-72wk) 59 (10 AIDS ; 24 ARC; 25 ASY) DID 200 + ZDV 600 ! O.6dtt 160tt 20 (34)" 22 (37)· 60 (19 AIDS; 24 ARC ; 17 ASY) ZDV6 00 ! O.3d .1,25 26 (43)· 32 (53)· CAESAR I11")' ZDV-experienced ; CD4+ cell count 475 LAM 300 + LOV 3009 38( 8)*** 13 (3)*** 25-250 cells!lIl (med 52wk) 935 LAM 3009 80 (9)*** 22( 2)*** 482 PI9 81 (17) 22 (5)

CPCRA 007(120) 77% pts ZDV-experienced 367 (127 AIDS) ZAL 2.25 + ZDV 600 112.9htt 230 (63) 182 (50) [med 7mo]; AIDS or CD4+ count 363 (110 AIDS) DID 400 + ZDV 600 119.2htt 226 (62) 176 (48) <200 celis/lil (med 35mo ) 372 (112 AIDS) ZDV600 .1,49 244 (66) 191 (51)

Deltal1211 ZDV-naive (med 30mo) 706 (91 AIDS; 212 SYM; 403 ASY) ZAL 2.25 + ZDV 600 167b 231 (33)' 107 (15)' 718 (91 AIDS; 215 SYM ; 412 ASY) DID 400 + ZDV 600 180b 188 (26)' 93 (13)1 700 (80 AIDS ; 204 SYM; 416 ASY) ZDV 600 130b 270 (39) 149 (21) b 0 ZDV for ~ 3mo(med 30mo) 366 (66 AIDS; 119 SYM; 181 ASY) ZAL 2.25 + ZDV 600 13 175 (48) 121 (33) 't! 362 (56 AIDS ; 136 SYM; 170 ASY) DID 400 + ZDV 600 120b 165 (46) 103 (28) " 355 (58 AIDS ; 110 SYM; 187 ASY) ZDV 600 ! 12b 178 (50) 126 (35) S'-J ::.- c; M500031122j' 241 pts ZDV-naive; CD4+ count 129 ZAL 2.25 + ZDV 600 1110 "'- c; ~ :J 300-500 cells/ul (105 pts 24mo) ;:: .. 127 ZDV 600 136 'J> '-"cc ~ § :e. Zalcitabine: An Update 1065

(table III), the results of which are discussed in sections 3.2.1 and 3.2.2.

000 3.2. 1 Double Combination Therapy

Zalcitabine in Combination with Other Nucleoside Analogues The results of initial comparative studies eval­ uating zalcitabine plus zidovudine combination therapy (ACTO 1061125] and BW 34,225-021118]) reported a greater and more sustained increase in CD4+ cell count and more sustained decrease in p24 antigen levels with zalcitabine plus zidovudine than with zidovudine alone. Although not the pri­ mary end-point, long term clinical follow-up of 154 patients in study BW 34,225-02 revealed a greater delay in the development of an AIDS­ so defining event or death (p = 0.022) with combina­ > tion therapy than with zidovudine monotherapy. Sl The significantly greater prolongation of survival lO 8 ;:; C\I co C\I time (p = 0.04) and time to clinical disease progres­ N C\i --' > --' sion and death (p = 0.004) reported with zidovud­ s s s ine plus didanosine compared with zidovudine plus zalcitabine in this study may have been attrib­ utable in part to the better baseline clinical and virological status of patients in the didanosine compared with the zalcitabine treatment group.IIISI ACTO 155 was the first major trial to compare zidovudine plus zalcitabine combination therapy with zidovudine or zalcitabine monotherapy using clinical efficacy as the primary end-point.I'P' In this study, which involved 991 zidovudine­ s pretreated patients with advanced disease, no sig­ 6 '"o nificant difference in time to disease progression or death was reported between those receiving zidovudine plus zalcitabine combination therapy and those treated with zidovudine mono therapy.A planned subgroup analysis revealed the combina­ tion regimen to be significantly (p = 0.029) more effective in terms of disease progression and death in patients with a CD4+ count of ~ 150 cells/pi but no significant difference was reported in patients with more advanced disease « 150 cells/ul). Re­

to sults from ACTO 193A provide further data to sug­ It) ....C\I gest that combination therapy with zidovudine plus ;; z zalcitabine is not the preferred treatment option for

© Adis International limited. All rights reserved . Drugs 1997 Jun: 53 (6) 1066 Adkins et al,

o lOY-naive pat ients with late stage disease (CD4+ count ::;50 o lOY-pretreated ce lis /~I). 11 2 6J lOY-pretreated 512mo Th e 3 cli nical end-point studies, ACTG 175, lOY-pretreated >12mo CPCRA 007 and Delta recru ited large numbers of 30 CPCRA 007 study zidov udine-naive and zidovudine-experienced pa­ 25 tients with relatively late-stage disease. All 3 trial s were randomised multice ntre doubl e-bl ind studies, 20 included a follow -up period of >2 years and en­ 15 rolled more than 1000 patients. 10 Study ACTG 175 recruite d the greatest number of zidov udine-ex perie nced patient s (n = 1400) and 5 z co mpared 4 different regimen s, zidov udine or J:: iO o did anosine monotherapy, zidovudine plus zalcitab­ "C '" 50 Delta study ine and zidovudine plus did ano sine (table I1I ).I1161 o .-- r-r-r- C .-- For the antiretrovira l-naive patients (n = 1067), ~ 40 r-r-: progression to the primary end-point (~50% de­ Cl I c: .-- cline in CD4+ cell count, occ urre nce of an AIDS :5 30 Qi "C ,.!...!. definin g eve nt or dea th) was significantly more fre­ cil o 20 quent with zidov udine mon otherapy (23%) than ~ c: with treatment with zidov udine plus zalcitabi nc ~ 10 c: ( 10%; P < 0.00 I), zidovudine plus didanosine 'uc: .S! o (14 %; p = 0.003 ) or didanosi ne alone (17 %; p = Q; a. 0.023 ). When the clinical end-points of AIDS or ~ 18 ACTG 175 study r- Vl death were con sidered in aggregate, only zidovud­ C 16 - S! ine plus zalcitabine therapy was assoc iated with a ~ 14 - - significant red uctio n in the number of patients ex­ 12 - perien cing disease progression compared with 10 zidovudine mo notherapy (6 vs 12%; P = 0.016) - 8 r-e- (fig . I); the corresponding resu lts for zidov udine

6 r- plus didanosine and didanosine monotherapy were 4 8% (p = 0.082) and 9% of patients (p = 0. 11), re­

2 spec tively. o For previously treated patient s, progression to '\,Q~ '\,Q~ the primary end-point in thi s study was sig nifi­ Q-!i> " can tly lower with the com bination of zidov udinc Treatment group plus zalcitabine (27%) or didanosine (22%), or didanosi ne alone (26 %) com pared with zidovudine Fig. 1. Percentage of patients who experienced an AIDS-defin­ mon ot herapy (38 %; p < 0.00 I). However, on ly ing event or death in 3 large, randomised multicentre studies [ACTG 175 (n =2467),11161Delta (n =3207)[121)and CPCRA 007 zidov udine plus didanosine had a significant cli n­ (n = 1102)l1 20I). Patients with advanced HIV infection were ical benefit ove r zidovudine monotherapy when randomised to receive zidovudine (ZDV) 600 mg/day plus the cli nica l end -poi nts of AIDS or death were con ­ zalcitabine (ZAL) 2.25 mglday or didanosine (DID) 400 mg/day, or lDV or DID monotherapy. Symbols: ' p < 0.05 vs ZDV mono­ sidered in aggregate in this patient group ( 13 vs therapy, thazard ratio 0.80(95% CI 0.67-0.96) vs ZDV mono­ 18%; p = 0.025). the rapy, tthazard ratio 0.63( 95% CI 0.53-0.76 ) vs ZDV monotherapy and hazard ratio 0.79(95% CI 0.65-0.96) vs ZDV In CPCRA 007, which enrolled 1102 mainly + ZAL. . zidovudine -ex perienced patients, treatment with

© Ad is Internalional Umiled . All righls reserved . Drugs 1997Jun: 53(6) Zalcitabine: An Upda te 1067

zidov udine plus zalcitabine or did anosine did not didanosine (p =0.05) and 9% for zidov udine plus significantly delay disease progression or prol ong zalci tabine (p = 0.47). Figure I shows the percent­ survival compared with zidovud ine alone (table age of patients experiencing a new AIDS event or III).I120J After a median foll ow-up time of 35 death in each of the 3 treatm ent groups. Although months, the relative risk of disease progression or not the primary comparison, Delta also provided death compared with zidov udine therapy was 0.92 some information on the comparative efficacy of [95% confidence inter val (CI) 0.76 to 1.10] and the 2 combina tion regimens. Notably, treatment 0. 86 (95% CI 0.71 to 1.03) for treatm ent with with zidov udine plus didano sine produced a signif­ zidovudine plus zalcitabine and zidov udine plus icant delay in the development of a new AIDS didanosine, respecti vely. However, in a subgroup event or death for the study population ove rall and analysis, co mbination therapy with zidov udine a significant delay in progression to AIDS or death plus zalcitabine significantly redu ced the rate of compared with zidovudine plu s zalcitabine in disea se progression or death compared with zidovudine-naive patients without AIDS at study zidovudine alone in patients who had been pre­ entry. However, there was no significant difference viously treated with zidovudine for :s; 12 months (p betw een the 2 treatment groups in term s of mortal­ < 0.05; relative risk 0.72; 95% CI 0.54 to 0.96) [fig. ity rate. I]. No significant difference was reported between In anoth er double-blind multicentre study, zidovudine plus didanosine and zidov udine alone M50003, treatment with zidovudine plus zalcita­ in this patient group. However, the zidov udine plus bine was significantly (p < 0.00 I) better than zido­ didanosine regimen did produ ce a significant re­ vudi ne monoth erapy at maintaining CD4+ ce ll duction in disease progression or death compared count above baselin e at 24 months in patients with with zidov udine monotherapy in zidov udine-naive little or no prior antiretrovi ral therapy (90 vs 52.4 % patients (p < 0.05; relative risk 0.57; 95% CI 0.36 ofpatients; p < 0.00 I).1 122J However, this study was to 0.90) . A significant difference was not reported discontinued prematurely following the results of for zalc itabine plus zidov udine combination ther­ ACTG 175 and Delta, which showed a significant apy in this respect. improvement in survival and disease progression The results of the European/Australian Delta with co mbination therapy in antiretrov iral-naive trial, the largest (n = 3207), most powerful study patients. available, provided evidence of the superior effi­ Data from large observational11271 and longitu­ cacy of zidov udine plus zalcitabine or didan osine dinal cohortl12 HI studies also dem onstrated a sig nif­ compared with zidovudine monotherapy in terms icant survival benefit with combination therapy of survival and progression to AIDS in antiretrovi­ with zidovud ine plu s zalcitabine or didanosin e ral-n aive patients (table III).11 21 1 Comp ared with compared with zidovudine monotherapy. zidovudine alone, a relative reduction in mortality Zidovudine plu s zalcitabine therapy has also (based on hazard ratios) of 32% (p = 0.003) for been compared with combination regimens co m­ zidovudine plus zalcitabine and 42 % (p < 0.0001) pri sin g zidovudine plu s the nucl eoside reverse for zidov udine plu s didanosin e therapy was re­ transcriptase inh ibitor lamivudine (300 or 600 123 ported. However, in zidovudine-experienced pa­ mg/day). In study NUCA 3002,1 1 which re­ tients there was no evidence of a direct benefit of cruited 254 zidov udine-ex perienced patients, a adding zalcitabine to therapy compared with con­ significa ntly (p < 0.05) grea ter increase in mean tinu ing with zidov udine alon e; onl y zidov udine CD4+ cell co unt was reported for the low dose plus didanosine combination therapy produ ced a (+38 .5 cells/ul) and high dose (+22.6 ce lls/ul) survival benefit compared with zidov udine mono­ lamivudine gro ups compared with the zalci tabi ne therapy in this patient gro up. The relative reduc­ group (-4.4 cells/u l) after 52 weeks of follow- up. tion in mortality was 23 % for zidov udine plus However, suppress ion of plasma HIV RNA levels

© Adi s Interna tiona l Umlted. All right s reserved . Drug s 1997 Jun; 53 (6) 1068 Adkins et al.

was similar for all groups (table III). Triple combi­ than with either agent alone. Notably, no signifi­ nation therapy with zalcitabine, zidovudine and cant difference in clinical end-points was reported lamivudine has also been evaluated in a recent between saquinavir or zalcitabine monotherapy. study (section 3.2.2). A preliminary evaluation of zalcitabine and 3.2.2 Triple Combination Therapy zidovudine combination therapy in the treatment of Multidrug combination therapy is potentially 4 patients with HIV-associated dementia demon­ the most viable therapeutic option for the success­ strated a reversal of neurocognitive dysfunction ful treatment of HIV infection, since it is poten­ and a marked reduction in serum and CSF HIV tially associated with an increase in antiviral activ­ RNA titres.I I09) ity and a greater delay in the emergence of drug resi stance compared with mono therapy. The re­ Zalcitabine in Combination with a sults of in vitro studies, demonstrating greater ac­ Protease Inhibitor tivity with triple combination therapy than with 2­ The reported in vitro synergy between zalcitab­ drug regimens,f l29J are now supported by data from ine and the protease inhibitor saquinavir and the surrogate marker and early clinical end-point stud­ non-overlapping toxicity and resistance profiles of ies. Zalcitabine has been evaluated as a component these 2 drugs has led to evaluation of their efficacy of triple combination regimens including the in combination. To date , one study (NV 14256) has protease inhibitors saquinavir or ritonavir plu s evaluated the efficacy of a 2-drug regimen com­ zido vudine or the nucleoside analogue lami vudine prising zalcitabine plus saquinavir (table III) while plus zidovudine in predominantly zidovudine­ other studies have evaluated 3-drug regimens in­ experienced patients with advanced disease. cluding zalcitabine plus saquinavir or the protease Study ACTG 229 was designed to assess the ef­ inhibitor ritonavir (section 3.2.2). fect of triple combination therapy with zidovudine, Study NV 14256, a multicentre double-blind zalcitabine and saquinavir on surrogate marker ac­ study, randomised 940 HIV-infected zidovudine­ tivity in 297 heavily zidovudine-experienced pa­ experienced patients to receive zalcitabine plus tients. Notably, changes in absolute CD4+ cell saquinavir or either agent alone (table III). The count and quantitative HIV titre to week 48 oftreat­ final results from this study have not yet been pub­ ment were reported to be significantly superior lished; however, data on disease progression and with the 3-drug combination compared with either mortality are available.U P'JAn intent-to-treat anal­ double therapy (zidovudine plus saquinavir or zal­ ys is of patients with a median follow-up of 73 citabine) [table III].III ?I Although clinical disease weeks showed the time to the first AIDS-defining progression and survival were not primary end­ event or death to be significantly longer for patients points, 17 patients developed an AIDS-defining ill­ treated with the combination regimen than for ness or died during the study, 3 in the 3-drug group, those treated with saquinavir monotherapy (p = 8 in the saquinavir plus zidovudine group and 6 in 0.0043; log rank analysis). A 74 % reduction in the zalcitabine plus zidovudine group. An analysis mortality with saquinavir plu s zalcitabine com­ of ranked quality-of-life scores obtained at base­ pared with saquinavir monotherapy (9 vs 34 line and week 20 also revealed a trend in favour of deaths) provided further evidence of the benefit the triple combination regimen for an improvement of this combination regimen in zidovudine­ in functional and psychological health and work/ experienced patients. Thi s benefit was statistically social functioning.I 130 1 significant according to an intent-to-treat log-rank Although inhibition of zalcitabine phosphoryla­ analy sis of the time to death (p = 0.000 I). A signif­ tion by lamivudine has been reported in vitro (sec­ icantly greater (p =0.000 I) and more sustained in­ tion 1.2), 2 studies have demonstrated a beneficial crease in CD4+ cell count and decrease in viral load effect from adding lamivudine to combination ther­ was also reported with saquinavir plus zalcitabine apy comprising zidovudine plus zalcitabine. In a

© Adis Inte rnati onol Umlted . All righ ts reserved. Drug s 1997Jun; 53 (6) Zalcitabine: An Update 1069

nonblind, randomised trial with a 6-m onth follo w­ cells per 107 peripheral blood mononuclear cells, up ,1 131 146 patients pretreated with zidov udine plus respectively. This was accompanied by a corre­ zalc itabi ne for ~6 months were randomised to re­ sponding increase in mean CD4+ cell count (+ 140 ceive either zidov udine, zalcitabine and lamivud­ cells/ul), ine (n = 15), zidov udine and lamiv udine (n = 15) Studies eva luating zalcitabine in combination or to co ntinue with exist ing zidov udine plus with zidov udine and thymostimulin,ll33 ] zidov ud­ zalci tabine therapy (n = 16) [control gro up]. Com­ ine and interferon-al1 341 and zidov udine and dela­ pared with baseline, mean CD4+ cell co unt in­ virdinel135J have also been conducted. Preliminary creased significantly in the triple therapy (+49 .5 evaluation ofa 4-drug regimen comprising zalcita­ cells/ul; p =0.00 12) and zidov udine plus lamivud­ bine, zidov udine, didanosine and interferon-a pro­ ine (+33 .1 cells/ul; p =0.0 21) treatment arms but duced promi sing results in term s of a reductio n in decreased in the contro l group (-21.3 cells/ul) over HIV plasma RNA and an increase in CD4+ cell count.[1361 24 week s. A corresponding decrease in mean plasma HIV-I RNA level s from baseline was re­ 3.3 Paediatric Use ported for both zidovudine plus lami vudine (-0.15 log copi es/ml ) and zidov udine plu s zalcitabine Study ACTG 138 evaluated the efficacy of plus lami vudin e (-0.45 log copies/ml; p = 0.003), zalc itabine 0.0 15 and 0.03 mg/kg/day in 170 HIV­ while an increase was report ed for the co ntrol infected children with symptomatic disease who gro up (+0.36 log copies/ml; p = 0.024) . were refractory to or intolerant of zidov udine.I'V l The CAESAR study evaluated the benefit of p24 antige n levels were reduced at 36 weeks for adding lamivud ine ± loviride to ongoing anti­ 38% of the child ren evaluated. Com bination ther­ retroviral therapy (zidovu dine plus zalcitabine or apy co mprising zalci tabine plu s zidov udine has didanosine or zidovudine monoth erapy) for 52 also been eval uated in children.P!' 13 patients re­ weeks in 1892 patients with advanced HIV infec­ ceived a regimen of zalcitabine 0.12 mg/kg/day for tion.!1191The recently reported res ults ofan interim 7 day s alternating with zidovudine 720 mg/m-zday analysis of this study showed that in com parison for 2 1 days. Of these patients, II experienced with place bo, addition of lamivudine ± loviride to weight gain and 7 an increase in CD4+ cell co unt ex isting antiretroviral therapy sig nificantly re­ and a >I0% increase in the CD4 to CD8 ratio . In a duced disease progression (8 and 9 vs 17%; p < small study, zalcitabi ne salvage therapy improved 0.000 I) and mortality rates (2.4 and 2.7 vs 4.6%; metabolic rates and nutritional parameters in chil­ p = 0.0 12). Further analysis revealed a 55% re­ dren with adva nced HIV disease.11 38JHowever, al­ duction in disease progression in the lamivudine­ ternating co mbination ther apy with zidov udine containing arms in patients who entered the trial on and zalcitabine was unable to prevent the deve lop­ zido vudine monotherapy and a 49% reduction in ment of zidovudine resistance in HIV-I isolates patients who entered the trial on zidovudine plu s from children'!1391 zalcitabine or didanosine. 3.4 Pharmacoec onom ic Considerations Impressive immunological benefits were dem­ onstrated in a pilot study evaluating a regimen In view of the potential increase in drug costs co mprising zalc itabine plus zidov udine in co mbi­ associated with the use ofco mbinatio n antiretrovi­ nation with the protease inhibitor ritonavir (1200 ral regimens, a mode l was developed to assess the mg/day) as first line therapy in 29 HIV-infected comparative cost-effective ness of addi ng zalcitab­ ad ults (C D4+ co unt <250 cel ls/u l).'1321 After 9 ine to antiretroviral therapy.' 1401The model was months of treatment the mean titre of HIV RNA based on data derived from cli nical studies (ACTG and the mean number of infec tious blood cells had 106,1141] ACTG _114[1411 and BW 34,225-02[60[ ) decreased by 2.0 log copies/ml plasma and 2.44 log demonstrating a susta ined improvement in CD4+

© Ad is Interna tional Umited . All righ ts reserved . Drugs 1997 Jun; 53 (6) 1070 Adkins et al.

Hypertriglyceridaemia

Pancreatitis

Thrombocytopenia

Hyperlipidaemia

Abdormnat pain

Abnormal liver function

Anaemia •••

Diarrhoea ••••

Raised serum amylase levels

Leucopenia ••••

Granulocytopenia •••••

Ulcerative stomatitis ••••

Peripheral neuropathY !~~!~~~!~~~~~~!!~~!~~~!__---,

o 2 4 6 8 10 12 14 Patients reporting at least one occurrence 01 each adverse event ("!o)

Fig. 2. Incidence of adverse events (all grades) at least possibly related to zalcitabine therapy and reported in <':0.8% of patients (142 (n =517) participating in the zalcitabine Expanded Access Programme . ) cell co unt in patients treated with zalci tabine plu s abil ity of this age nt, including the results of a Euro ­ zidovudine. The model predicted that the use of pean Ex pa nde d Access Programme (EAP).11421 this antiretroviral regimen for I year was a cost­ This programme pro vided data on 517 pati ents effec tive treatm ent option for patients with a CD4+ with AIDS or ARC who recei ved zalcitabine 2.25 co unt <300 ce lls/p l. Compared with zido vudine mg/day; approximately 50% of pati ents received monotherapy, co mbination therapy improv ed sur­ the dru g for>12 weeks. All patients recru ited to the vival by 0.09 to 0.11 life-years per patient and thi s study were eithe r no longer able to tolerate was associated with a modest cost increase of 1181 zidovudine, had not responded to zidov udine or to 1764 Eu ropean Currency Units per patient de­ were ineligible to receive the dru g. The adverse pending upon the country studie d. The results of even ts (all grades) ex perience d by ~0 .8 % of pa­ this study, however, are limited by the ass umption tients and at least possibl y related to za lcitab ine that C D4+ cell co unt is a good on-therapy mark er therapy are summarised in figure 2. of disease progression and surv iva l. Peripheral neu ropath y, the most frequ ent ad­ ve rse event, devel op ed in 63 patien ts ( 12.2 %) ; 4. Tolerability other adverse events occurred with a freq uency of <3.0% and incl ude d ulcerative stomatitis, granulo­ 4.1 Zalc itabine Monotherapy cy topenia and leucopenia; pancreatiti s developed Since the previous zalcitabine review in D rugs,1 11 in fewer than I% of patients. The overall incidence additio na l data have been publ ished on the toler- of severe adverse events was 2. 1% and included

© Ad is Interna ffan al Umited . All rights reserved . Drugs 1997 Jun: 53 (6) Zalcitabine: An Update 1071

pancreatitis (0.8% of patients), peripheral neurop­ 4. 1.1 Peripheral Neuropathy athy (0.4 %), hyperamylasaemia (0.2%), thrombo­ Peripheral neuropathy is the major dose­ cytopenia (0.2%), neutropenia (0.2%), abnormal limiting adverse event associated with zalci ­ liver function (0.2%) and ulcerative stomatitis tabine treatment,' 144] occurring in 12 to 46% of (0.2%). patient s receiving zalcitabine 1.125 to 2.25 mg/day.l11 2-11 5.142.145-147! Initial symptoms are pre- The se results are generally in accordance with dominantly sensory with distal dysaesthesia, pain those of 2 recently publi shed large comparative and numbness. Abnormal sural nerve conduction studies (ACTO 155 and CPCRA 002) which in­ is frequently evident with an impaired sensation of cluded an assessment of the tolerability profile of vibration, pain and temperature.U '

Table IV. Summary of adverse events [no. of patients (%)] in 2 large comparative studies of zalcitabine (ZAL) in zidovudine (ZDV)-experienced patients with advanced HIV disease Adverse event CPCRA 002[1131- ACTG 155[1151b ZAL DID ZAL ZDV ZAL +ZDV (n =237) (n =230) (n =285) (n =283) (n =423) Peripheral neuropathy 69 (29.1) 33(14.3) 18 (6) 12(4) 25 (6) Abnormal liver function 24 (10.0) 20 (8.6) 16 (6) 24(8) 25 (6) Neutropenia 18 (7.6) 21 (9.1) 26 (9) 49 (17) 82 (19) Anaemia or haemoglobinaem ia 15 (6.3) 14(6.1) 13(5) 14 (5) 35 (8) Cutaneous/allergic reaction 17 (7.1) 13(5.6) 6 (2) 4(1) 6 (1) Abdominal pain 7(2.9) 16 (6.9) Diarrhoea 9 (3.8) 48 (20.8) Nausea or vomiting 21 (8.9) 35 (15.2) 4(1) 7 (2) 4 (1) Fever 8 (3.4) 13 (5.6) 12(4) 23 (8) 17 (4) Headache 10 (4.2) 9 (3.9) 5(2) 5(2) 10(2) Fatigue 9 (3.8) 6 (2.6) 5 (2) 7 (2) 19 (4) Muscle weakness 9 (3.8) 8 (3.5) Oral lesions or stomat itis 8 (3.4) 0(0) 11 (4) 2(1) 4 (1) Hyperamylasaemia 9(3.8) 13 (5.6) Pancreatitis 0(0) 4 (1.7) 9(3) 4 (1) 8 (2) a Incidence of grade III or IV adverse events reported . b Incidence of common severe or worse adverse events reported . Abbreviation: DID =didanosine.

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peripheral nerve dysfunction and peripheral neu­ drug-induced disease,l l621 However, the patho­ ropathy has also been reported)l45,146J Notably, in physiological mechanisms involved in the devel ­ the European EAP study, zalcitabine-associated opment of drug-induced pancreatitis are in­ peripheral neuropathy was more likely in patients completely understood. Pancreatitis appears to be with a baseline diagnosis of AIDS and a CD4+ a rare but serious complication of zalcitabine ther­ count ~50 cells/1J.1.11421 apyl1631 which has mostly been reported to occur Two case reports have also highlighted the de­ with an incidence of

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tistically significant difference in the overall inci­ the incidence of peripheral neuropathy in the dence ofsevere adverse events between the 3 treat­ zalcitabine and saquinavir plu s zalcitabine groups ment groups.I 11 51However, severe neutropenia was was comparable, 21 and 20%, respectively.' 124 ) more common in the zidovudine monotherapy and combination therapy arm s ( 17 to 19% vs 9% with 5. Drug Interactions zalcitabine monotherapy; p = 0.0005) whereas moderate or severe peripheral neuropathy was Patients with HIY infection frequently recei ve more common in the zalcitabine monotherapy and multiple drug therapy comprising both antiretro­ combination therapy arm s (22 to 23% vs 13% with viral agents and drugs for the prophylaxi s and/or zidovudine monotherapy; p = 0.005). In addition, treatment of opportunistic infections; the potential the incidence of peripheral neuropathy was 34% for drug-drug interactions in this patient group is with zalcitabine monotherapy compared with only therefore high. The drug interaction potential of antiretroviral agents has been previously reviewed 4% for patients treated with zidovudine alone (p < by several authors.1167-1691 0.03) ; however, there was no significant difference Because renal excretion of unchanged zalcitab­ in thi s vari able between patients receiving zal­ ine is the primary route of zalcitabine elimination citabine monotherapy and zalcitabine plus zidovu­ in humans (section 2.2), the concomitant use of dine combination therapy.I1451 potentially nephrotoxic agents may have important In both ACTG 175 and CPCRA 007 , the inci­ clinical implications. For example, the aminogl y­ dence of haematological abnormalities (anaemia co sides, amphotericin and foscarnet may poten­ and neutropenia) was higher for patients treated tiall y augment plasma zalcitabine concentratio ns with zidovudine plus zalcitabine than for the com­ and increase the incidence of zalcitabine-associated parative treatment groups. In ACTG 175 the se adverse effects, most notably peripheral neuropa­ events occurred in 10% of patients treated with thy.11 67-1 691Conc omitant administrati on of cimeti­ zidovudine plus zalcitabine, which was signifi­ dine, probenecid or trimethoprim has also been re­ cantl y higher (p < 0.00 I) than in the other 3 treat­ ported to reduc e the renal clearance of zalcitabine ment groups (zidov udine plu s didanosine, or with inhibition of renal tubular secretion postu­ zidov udine or didanosine monotherapy ).111 6] In lated as the most probable mechanism.l170-1721 CPCRA 007 the incidence of haematological ad­ Caution should be exercised if zalcitabine is verse events for zidovudine plus zalcitabine was coadministered with other drugs that can cause 13.3 versus 11.5% for patients treated with zido­ peripheral neuropathy; these include dap sone, di­ vudine plus didanosine or zidovudine monother­ sulfiram, isoniazid, pentamidine, metronidazole , 1 apy .11 20 Severe peripheral neuropathy was also re­ stavudine and didanosine. Patients should be care­ ported to occur more frequently during treatment fully monitored for signs of peripheral neuropathy with zalcitabine plus zidovudine than during treat­ and treatment should be promptly discontinued if ment with zidovudine monotherapy or zidovudine the condition develops. One patient who had been plus didanosine in both Delta (5 vs I to 2%) and withdrawn from treatment with zalcitabine plus CPCRA 007 (15 vs 7%) .11 20.1 211 In contrast, gastro­ zidovudine experienced wor sening of neuropathic intestinal symptoms were reported less frequently symptoms upon subsequent administrati on of with zidovudine plus zalcitabine than with zido vu­ didanosine .U '"! Severe left ventricular hypokin esis dine plus didanosine.! 120.1211 has also been reported during zalcitabine therapy Tole rability data from studies NY 14256 and following didanosine treatment.I1741 Becau se of the ACTG 229 suggest that the combined use of zal­ increa sed risk of severe pancreatitis associated citabine with saquinavir doe s not alter the inci­ with the concomitant use of pentamidine and dence or severity ofadverse effects associated with zalcitabine, the co mbined use of the se 2 age nts the use of either drug alone.111 7.1 241 In NY14256, should be avoided.I167.1 691

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In view ofthe differing elimination pathways of zalcitabine therapy who have a history of elevated zalcitabine, saquinavir and zidovudine, pharmaco­ amylase levels, pancreatitis or alcohol abuse or kinetic drug interactions between these 3 agents are who are receiving parenteral nutrition.P'" considered unlikely,' 168] In addition, significant Close haematological monitoring for signs of pharmacokinetic interactions have not been re­ severe anaemia or granulocytopenia is necessary in ported during combination therapy with zalcitab­ zalcitabine recipients with poor bone marrow re­ ine and nevirapine.U'Pl serve, particularly in patients with advanced HIV The coadministration of aluminium hydroxide/ disease. In the event of significant haematological magnesium hydroxide antacid mixture resulted in toxicities (haemoglobin <7.5 mg/dl or >25 % re­ a 25% reduction in the bioavailability of zalcitab­ duction from baseline; and/or granulocyte count ine and for this reason zalcitabine should not be <750 cells/ul or >50% reduction from baseline) in­ administered concurrently with this antacid.' 1701 terruption of treatment may be necessary until ev­ Zalcitabine has been reported to significantly de­ idence of bone marrow recovery is seen. I921 crease the clearance:bioavailability ratio of dap­ sone and increase this ratio for isoniazid.' 176, I77J 7. Place of Zalcitabine in the Management of HIV Infection 6. Dosage and Administration Until recently, zidovudine monotherapy was Zalcitabine is administered orally as tablets considered to be the standard first-line treatment which are available as 0.375 and 0,75mg formula­ for patients with HIY infection. However, the de­ tions. The recommended dosage regimen for velopment of drug-resistant viral strains and in­ zalcitabine and zidovudine combination therapy complete suppression of viral replication have is zalcitabine 0.75mg and zidovudine 200mg ad­ largely limited the extent and duration of response ministered every 8 hours. Similarly, zalcitabine to monotherapy with this agent.11291 Over the past 0.75mg 3 times daily is recommended for use in 18 months important advances have been made in combination with saquinavir or other approved the treatment of HIY infection, partly attributable protease inhibitors.' 177] There are currently no rec­ to the development of several new and effective ommended dosage schedules for the use of zalcita­ drugs and also to the publication of the results of a bine as a component of triple combination therapy, number of important clinical end-point studies although zalcitabine 2.25mg/day has been used in demonstrating the clear benefits of combination clinical trials . antiretroviral therapy over monotherapy. For these Zalcitabine dosage reduction to 0.75mg twice reasons, monotherapy with any nucleoside ana­ daily and 0.75mg once daily is recommended in logue, including zalcitabine, is no longer consid­ adults and adolescents (age>13 years) with a CLCR ered to be an acceptable standard for the treatment of 0.6 to 2.4 Llh (10 to 40 ml/min) and <0.6 Llh of HIY infection; combination antiretroviral ther­ « I0 ml/min), respectively.P'" apy is now established as the optimal approach. Patients receiving zalcitabine therapy should be The 3 large clinical end-point studies, CPCRA closely monitored for signs and symptoms of pe­ 007 , ACTO 175 and Delta, have now firmly estab­ ripheral neuropathy; if these develop, zalcitabine lished that combination therapy with zidovudine therapy should be stopped until the associated plus zalcitabine or didanosine improves survival, signs and symptoms become at least mild in nature delays disease progression and is associated with and only then reintroduced at a dose of 0.375mg an improvement in viral load and CD4+ cell count every 8 hours. Permanent cessation of therapy may compared with zidovudine monotherapy.I 116,120,1211 be necessary if severe symptoms develop or if the Despite some evidence of a greater benefit with condition progressively worsens. Serum amylase zidovudine plus didanosine, the results of these levels should be monitored in individuals receiving studies do not definitively demonstrate that combi-

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nati on therap y with zidovudine plu s did anosine is duce a significant change in toler ab ility profil e. significantly bett er than zidov udi ne plus zalcitab­ Addi tional studies have also demon strated the util­ ine. Data fro m these studies also suggest a grea ter ity of zalcitabine in combinatio n wit h the protease c linical ben efit with co mbi na tio n ther ap y in in hib itor rito navir or the nucl eoside ana logue z idovudi ne- naive pat ien ts than in zidovud ine­ lam ivudi ne as co mpo nents of 3- and 4-drug re­ pretreat ed patien ts. However, the lack of a sig nifi­ gime ns. cant difference in survival bet ween these 2 pat ient No tably, ava ilable resista nce data for zalcitab­ groups in the largest, most powerful study, Delt a, ine are favo urable, with res istance devel oping less precludes an y firm co nc lus io ns in this respect. frequently than du ring zidovudi ne therap y. Fur­ Ne verth el ess, zalc ita bine in comb ina tio n with thermore, the ea rly use of za lcitabine in the treat ­ zidov udine does appea r to be more effective in pa­ ment cycle does not appear to limit the utili ty of tient s with limited prior zidov udine ex pos ure. Fur­ subsequent therapeutic option s. thermore , because of their d iffering to lerabi lity In vie w of current trends in clinical practice and profiles, za lcitabine and zidovudine are conside red availabl e c linical trial data, the main pla ce for to be suitable age nts for use in co mbination. Co m­ za lci ta bine in the treatment of HIV infecti on is bin ation therapy with these agents has ge nerally likely to be as a co mpone nt of tripl e co mbi nation been associated with a tolerability profile co mpa­ regimen s incl udi ng zidov ud ine and a protease in­ rabl e to that ofeither dru g alone, altho ugh a sig nif­ hibit or or as the second agent in initi al dou ble ther­ icant increase in the incid ence of haem atological apy in vol ving zidov udi ne. In these ro les, zalci tab­ ine wi ll need to compe te wi th ot he r nucleoside toxicity with zidovud ine plu s zalci ta bine com­ ana log ues such as didanosine and lumi vudi ne.f' P" pared with zidov udi ne monoth erap y was rep ort ed Th e cho ice of which nucleoside analog ue to use in one st udy.!' Ih l shou ld be based not only on efficacy but also on Th e pu blica tio n of addi tio nal da ta in recent several ot her factors inclu ding tolerabil ity, dr ug re­ months has furt her advance d the therapeu tic man­ sistance patterns and potential for limi ting future ageme nt of patient s with HI V infec tion and led to therapeutic options. In addition, ease of admi nis­ the ge neral co nse nsus that the co mbined use of 2 tration , drug cos t and indiv idual cli nician and pa­ nuc leoside analog ues such as zidovudine plu s tient preference will also pla y an importa nt ro le in za lcitabine or didanosin e does not represent op ti­ drug se lection. mal therap y for the treatment of HIV infect ion . For In co nclusion, avai lable data support the inclu­ these reason s, curre nt standard care is now moving sion of zalcitabine as a co mpo nent of init ial do uble tow ards the combined use of I or 2 nucleosid e ana­ co mbination regimen s with zidov udi ne or as part logues with a protease inhibitor. This trend is high­ of triple co mbinat ion therapy with zidov ud ine plus lighted in the recent guidelines from the Interna­ a protease inhibitor. It is anticipated that ongo ing tional AIDS Soc iety, whi ch reco mme nd the and future trials will provide definiti ve data to aid combined use of zalcitabine, didanosine or lami­ se lec tion of the optimal treatment regimen for pa­ vud ine with zido vudi ne (± a protease inhibitor) as tients with HIV infection. initi al therapy and the use of at least 2 new dru gs such as I or 2 nucleoside analogu es and a prot ease References inhibitor for previou sly treated pat ient s.' 17XI No ta­ I. Whittington R. Brogden RN . Zalcuubiue: a review of its phar­ bly, recent surrogate marker and cli nical data have macology i.IIH..I cli nical potential in acquired immunodefi ­ ciency syndrome (A IDS ). Drugs )99 2 Del ; -l-l: h5h-X .\ established the clinical efficacy of za lcitabine plu s 2. Cooney DA. Da lal M , Mit su ya H. eI al. Initial s"'dics o n rhe the prot ease inhibitor sa quinav ir in zidovudi ne­ ce llular pharmacology of 2' •.1' -dideoxycytidine. an inhibi­ lor of HT LV-1I1 infectivit y, Hiochem Phanuuco l II)Xh; .15; ex perienced patients. Furt hermore, co mpared with 2005-X zulcitabine or saquinavir rnon oth erapy, the co m­ .1. De Jong MD, Bo ucher CAB. Galasso CU,er al. Conscnsu » sym­ posi um on co mbined untivirul therap y. Anti viral Res 19 1)h bined use of these agents does not appear to pro - Ja n; 29 : 5-29

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4. Mit suya H. Broder S. Inhibit ion of the ill vitro infectivity and 18. Taylor DL. Brenn an TM , Bridges CG. et al. Synergist ic inh ibi­ cytopat hic effect of human T-Iymp hotropic virus type tion of hum an immunodeficiency virus type I ill vitro by 6-0­ III/l ym phadenop ath y-associated virus (HTLV-III/LAV) by butanoyicastanospermine (M DL 28 574 ) in co mb ination with 2·.3 ·-dideoxyn ucleosides. Proc Nat l Acad Sci USA 1986 inhibitors of the virus-encoded reverse transcriptase and pro­ Mar; 83: 1911-5 teinase. Antivi ral Chem Chemother 1995 May; 6: 143-52 5. Brenn an T M. Taylor DL. Bridges CG. T he inhibition of human 19. Mazzull i T. Ruscon i S. Merrill DP, et al. Alternati ng versus im munodeficiency virus type I in vitro by a non-nucleoside continuous drug regime ns in combination chem otherap y of reve rse tran script ase inhibitor MKC-44 2. alone and in co m­ human imm unodeficiency virus type I infection in vitro . Anti­ bination with other anti-HIV co mpou nds . Antiviral Res 1995 microb Age nts Chemo ther 1994 Apr; 38: 656-6 1 Mar ; 26 : 173-87 20. Veal GJ. Barry MG. Back DJ. Za icitabine (ddC) phosphoryla­ 6. Bridges EG. Dutschm an GE. Gullen EA. et al. Favo rab le inter­ tion and drug interact ions. Antiviral Chem Chem othe r 1995 actio n of ~ -L ( - ) nucleosid e ana log ues wit h clinicall y ap­ Nov; 6: 379-84 proved ant i-HIV nucleos ide analog ues for the treatm ent of 2 1. Veal GJ, Wild MJ. Barry MG. et al. Effects o f dide oxyinosine hum an immunode fic iency virus . Biochem Pharmacol 1996 and did eoxycytidine on the intracellular phosphorylati on of Mar 22; 5 1: 731-6 zidov udine in hum an mo nonuclear ce lls. Br J C lin Pharmacol 7. Cho ng K-T, Pagano PJ, Hinshaw RR . Bisheteroarylp iperazine 1994 Oc t; 38: 323-8 reverse transcriptase inh ibitor in co mbination with 3' -az ido­ 22. Veal GJ, Hoggard PG. Barr y MG . et al. Interaction between 3'-deoxythymidine or 2',3'-dideoxycytidi ne syn ergistically lami vud ine (3TC) and other nucl eoside ana log ues for intra­ inh ibit s hum an immunode ficie ncy virus type I repli cati on in ce llu lar phosph orylation . AIDS 1996 May ; 10: 546 -8 vitro. Antimicrob Agents Chemoth er 1994 Feb ; 38: 288-9 3 23. Baba M, Pauw els R. Balzarini J. et al. Ribavirin antagonizes 8. Co nnell EV. Hsu M-C , Richman DD. Co mbinative interactions inhib itory effects of pyri midin e 2 '.3' -did eoxynucleosides on of a hum an immunodeficiency virus (HIV) Tat antago­ repl ication of hum an immu nodeficiency viru s in vitro. Anti­ nist with HIV reverse transcriptase inhibitors and an HIV pro­ microb Agen ts Chemo ther 1987 Oct; 3 1 (10 ): 16 13-7 tease inhibitor. Antimicrob Agent s Chemother 1994 Feb; 38 : 24 . Faraj A. Fowl er DA . Bridge s EG . et al. Effec ts o f 2',3'­ 348 -52 dideoxynucleosides on proliferati on and differenti atio n of hu­ 9. Craig JC. Whitta ker L. Dun can lB . III vitro anti-HIV and man pluripotent proge nitors in liquid culture and their effects cy totoxico logical e valu ati on of the triple co mbi nation : on mitochondrial DNA synthes is. Antirnicrob Age nts Chem­ AZT and ddC with HIV prot ein ase inhibitor saquinavir (Ro other 1994 May; 38: 924-3 0 3 1-8959) . Antiviral Chem Chemo ther 1994 Nov; 5: 380-6 25 . John son M. Caiazzo T. Molin a J-M , et al. Inhi bition of bone 10. Cra ig JC , Duncan lB . Wh ittaker L. et al. Antiv iral synergy be­ marr ow myelopoiesis and erythro poie sis ill vitro by anti­ twee n inhib itors of HIV proteinase and reverse transcr iptase. ret roviral nucleoside derivatives. Br J Haem atol 1988 Oc t; 70: Antiviral Chem Chemo ther 1993; 4 (3 ): 161-6 137-41 II . Degre M, Beck S. Anti-HIV activity of dideoxynu cleosides, 26 . Steinberg HN. Ze kd is JB . Th e effect of the an tivir al di­ fosca rne t and fusidic ac id is potentiated by hum an leuk oc yte deoxyeytidine (DDC ) on the growth of human bone marrow interferon in bloo d-derived macrophages. Che mot herapy proge nitor ce lls in vitro . Proc Am Soc C lin Oneol 1988 Mar; 1994 May-Ju n; 40: 20 1-8 7: abstr. 14 12. Dem ine CA , Becht old CM. Stock D. et al. Eva luat ion of reverse 27. Nusbau m NJ. Abra ham T. Combination antiretroviral chemo­ trans cr iptase and protease inhibitors in two-drug co mbina­ thera py : a potential stra tegy in AIDS-rela ted ma lignancy . tion s aga inst hum an immunodeficien cy virus repl icat ion. Anticancer Drugs 1996 Jan; 7: 109-1 3 Ant imicro b Age nts Chemo ther 1996 Ju n; 40: 1346-51 28 . Zh ang H. Cooney DA. Sreenat h A. et al. Quantita tion o f mito­ 13. Eron Jr JJ. John son VA. Merr ill DP. et al. Sy nergistic inh ibit ion chondria l DNA in human Iymphobl asts by a competitive poly­ of repli cation of hum an immunodeficiency virus type I. in­ mera se c ha in reac tion method : applicatio n to the study of cluding that of a zidov udine- resis tant iso late. by zido vudine inh ibitors o f mitoch ondrial DN A conte nt. Mol Phannacol and 2',3' -dideoxycytidine in vitro. Antimicrob Agent s Chem­ 1994 Dec; 46: 1063 -9 other 1992 Jul ; 36: 1559-62 29 . Lewis LD. Hamezeh FM. Lietman PS. Ultras tructural changes 14. John son VA, Merr ill DP, Cho u T-C. et al. Hum an immunodefi­ associated with redu ced mitoc ho ndrial DNA and impa ired ciency virus type I (HIV- I) inhibitory interactions betw een mitoch ondri al function in the prescen ce of2 ' 3' -dideoxycytid­ prote ase inhi bitor Ro 3 1-8959 and zido vudine, 2'.3 ' -dideoxy­ ine. Antimicrob Agents Ch emother 1992 Sep; 36 : 206 1-5 cytid ine, or reco mbinant interferon-a -A agai nst zidovudine­ 30. Medina DJ. Tsai C-H, Hsiung GD, et al. Co mpa rison of mito­ sens itive or -resistant HIV-I in vitro . J Infect Dis 1992 Nov ; chondrial morph ology. mitoch ondrial DNA co ntent. and cell 166: 1143-6 viability in c ultured ce lls treated with three ant i-hu man 15. Mathez D. Sch inazi RF. Liotta DC. et al. Infecti ous amplifica­ immunodeficie ncy vir us dideox ynucleosid es. Antimi crob tion of wild-type hum an immunodeficiency viru s from pa­ Agent s Chemother 1994 Aug; 38: 1824 -8 tient s' lymphocytes and modul ation by reve rse transcriptase 31. Magnani M, Casablanca A, Rossi L, et al. Inhibition of HIV-I inhib itors in vitro . Antimicrob Agents Che mother 1993 Oct ; and LP-BM5 replication in macrophages by dideo xyc ytidine 37: 220 6-11 and d ideo xycytidine 5' -triphos phate . Antivira l Chern Che rno­ 16. Palmer S. Harmen berg J. Cox S. Synergistic inhibition of human ther 1995 Sep ; 6: 3 12-9 im munode fic iency virus isolates (i ncluding 3' -azido-3' ­ 32. Keilb augh SA. Hobb s GA . Simpson MY.An ti-human immu no­ deoxyth ymidine-resistant isolates) by fosca rne t in co mbina­ deficien cy virus type I therapy and per ipheral neuropathy: tion with 2·.3 '- d ideoxyinosi ne or 2· .3· -d ideoxycytidine. preventi on of 2' .3' -d ideoxycytid ine toxi city in PC 12 cells. a Antimicro b Age nts Chemo ther 1996 May; 40: 1285-8 neu ron al model. by uridin e and pyru vate. Mol Pharmacol 17. Pern o C-F. Cooney DA. Gao W-Y. et al. Effec ts of bone marrow 1993 Oct ; 44 : 702 -6 stimulatory cytokines on human imm unodeficiency virus rep­ 33. Lewis W. Dalakas Me. Mi toch ondr ial toxicity of a ntivi ra l lication and the antiviral activity of dideoxynucleosides in dru gs. Nat Med 1995 May; I: 4 17-22 c ultures of monocyte/macrophages . Blood 1992 Aug 15; 80 : 34. So mmadossi J-P. Nucleosi de analogs: similarities and di ffer­ 995- 1003 ences . Clin Infect Dis 1993 Feb ; 16 Suppl. I: S7- 15

e Adis International Umited . All rights reserved . Drugs 1997 Jun; 53 (6) Zalcitabine: An Update 1077

35. Chen C-H, Cheng Y-c. Delayed cytotoxicity and selec tive loss huma n immunodeficiency virus type I reverse transcript ase. of mitochondrial DNA in cells treated with the anti-human Antimicrob Agents Chemother 1994 Feb; 38: 282-7 immun odeficiency virus compound 2' ,3'-dideoxycytidine.J 53. Gu Z, Gao Q, Fang H, et al. Identification of a mutation at codon Bioi Chern 1989 Jul 15; 264 : 11 934-7 65 in the IKKK motif of reverse transcriptase that encodes 36. Anderson TD, Davidovich A, Feldm an D, et al. Mitochondrial human immunodeficiency virus resistance to 2' ,3' -dideoxy­ schwannopathy and peripheral myelin opath y in a rabbit cy tidine and 2' ,3' -did eoxy-3'-thiacy tidine. Antimicrob model of did eoxycytidine neurotoxicity. Lab Invest 1994 Agents Chemother 1994 Feb; 38: 275-81 May; 70: 724-39 54. Gu Z, Arts EJ, Parniak MA, et al. Mutated K65R recombinant 37. Toltzis P, Mourton T, Magnuson T. Comparative embryo nic reverse transcriptase of human immun odeficiency virus type cytotoxicity of antiretro viral nucleoside s. J Infect Dis 1994 I shows dimini shed chai n termination in the presenc e of May; 169: 1100-2 2' ,3'-dideoxycytidine 5' -triphosphate and other drugs. Proc 38. Luster MI, Rosenth al GJ, Cao W, et al. Experimental studies of Natl Acad Sci USA 1995 Mar 28; 92: 2760-4 the hematologic and immune system toxicity of nucleoside 55. Gu Z, Salomon H, Cherrington JM, et al. K65R mutation of derivatives used against HIV infection . Int J Immun o­ human imm unodefici ency virus type I reverse transcript ­ pharma col 1991; 13 Supp l I: 99- 107 ase encodes cross-resistance to 9- (2-ph osphon ylmethoxy­ 39. Brandi G, Casabianca A, Schiavano GF, et al. Efficacy and ethyl) adenine. Antimicrob Agent s Chemoth er 1995 Aug; 39: toxic ity of long-term admin istration of 2' ,3' -dideoxycytidine 1888-91 in the LP-BM5 murine-induced immunodeficiency model. 56. Gu ZX, Gao Q, Li XG, et al. Novel mutation in the human Antiviral Chem Chemother 1995 May; 6: 153-61 . imm unodefici ency virus type -I reverse trans criptase gene 40. Coffin JM. HIV popul ation dynamic s in vivo: implications for that enc odes cross-resistance to 2' ,3' -dide oxy inosine and genetic variation, pathogenesi s, and therap y. Science 1995; 2', 3'-dideoxycytidine. J Virol 1992 Dec; 66: 7 128-35 267 : 483-9 57. Gao Q, Gu Z, Parniak MA, et al. The same mutation that en­ 41. Moyle GJ. Use of viral resistance patterns to antiretroviral drugs codes low-level huma n immunodefic iency virus type I resis­ in optimising selection of drug combinations and sequences. tance to 2' ,3 '-dideoxyinosine and 2' ,3'-dideoxycytidine Drug s 1996 Aug; 52: 168-85 confers high-le vel resistance to the (- ) enantiomer of 2',3'­ 42. Arts EJ, Wainbc rg MA. Mechanisms of nucleoside analog anti­ dideoxy-3' -thiacytidine. Antimi crob AgentsChemother 1993 viral activity and resistance duri ng human immunodeficiency Jun; 37: 1390-2 virus reverse transcript ion. Antimicrob Agents Chemother 58. Fitzgibbon JE, Farnham AE, Sperb er SJ, et al. Human immu­ 1996; 40: 527-40 nodeficiency virus type-I pol gene mutations in an AIDS pa­ 43. Craig C, Moyle G. The development of resistance of HIV-I to tient treated with multipl e antiretroviral drugs. J Virol 1993 zalcitabine. AIDS 1997; II : 271-9 Dec; 67: 7271-5 44 . Smith M, Salomon W, Wainberg MA. Development and signif­ 59. Loveday C. HIV-I genotypic and phenotyp ic resistance in Delta icance of nucleoside drug resistance in infection caused by patients [abstract no. Th.B4354] . 11th International Confer­ the human immunod eficiency virus type I. Clin Invest Med ence on AIDS , Vancouver July 1996 1994 Jun; 17: 226-43 60. Larder BA, Kohl i A, Bloor S, et al. Human immunodeficiency 45. Larder BA. Viral resistance and the selection of antiretrov iral viru s type I dru g susceptibility durin g zidovudine (AZT) combinations. J Acquir Immune Defic Syndrom Hum Retro­ monotherapy compared with AZT plus 2' ,3'-dideoxyinosine virol 1995; 10 Suppl. I: 28-33 or AZT plus 2', 3' -dideoxycytidine combinat ion therapy. J 46. Tantill o C, Ding JP, Jacob o-Molina A, et al. Locations of anti­ Virol 1996; 70: 592 2-9 AIDS drug bindin g sites and resistance mutations in the three­ 61. Lacey SF, Larde r BA. Novel mutati on (V75T ) in hum an dimensional structure of HIV-I reverse transcr iptase: immunodeficiency virus type I reverse transcript ase confers implications for mechanisms of drug inhibiti on and resis­ resistance to 2' ,3' -didehydro-2' ,3' -dideoxythymid ine in tance. J Mol Bioi 1994 Oct 28; 243: 369-87 cell culture. Antimicrob Agents Chemother 1994 Jun; 38: 47. Shir asaka T, Yarchoan R, O'Brien MC, et al. Changes in drug 1428-32 sensitivity of human immunodeficiency virus type I during 62. Shir asaka T, Kavlick MF, Ueno T, et al. Emergence of human therapy with azidoth ymidine, dideoxycytidine , and dideox y­ immu nodeficiency virus type I variants with resistance to inosine: an in vitro comparative study. Proc Natl Acad Sci multiple did eoxynucl eosides in patients receiving therapy USA 1993 Jan 15; 90: 562-6 with dideoxynucleosides. Proc Natl Acad Sci USA 1995 Mar 48. Sylvester S, Caliendo A, Sepk owitz K, et al. HIV-I resistance 14; 92: 2398-402 mutations and plasma RNA levels during ZDV + ddC co m­ 63. Schmit JC, Cogniaux J, Hermans P, et al. Multiple drug resis­ bination therap y [abstract]. 3rd Conference on Retroviru ses tance to nucle otid e ana log ues and nonnucleoside reve rse and Opportuni stic Infections 1996 Jan 28: 107 transcriptase inhibitors in an efficiently replicating human 49. Harrigan PR, Kemp SD, Kinghorn I, et al. A placebo controlled immuno deficiency virus type 1 patient strai n. J Infect Dis trial of AZT alone or in combi nation with DOl or DDC: viral 1996; 174: 962-8 load and drug resistance IabstractI. AIDS 1994 Nov; 8 Suppl. 64. Najera I, Richman DD, Olivares I, et al. Natural occ urrence of 4: S20 drug resistance mutatio ns in the reverse transcript ase of hu­ 50. Richm an DD, Meng T-C, Spector SA, et al. Resistance to AZT man immuno deficien cy virus type I isolates. AIDS Res Hum and ddC during long-term co mbination therapy in patients Retroviruses 1994 Nov; 10: 1479-88 with advanced infection with human immunod efici ency vi­ 65. Cinatl Jr J, Cinatl J, Weber B, et al. Decreased anti-human im­ rus. J Acquir Immune Defic Syndr 1994 Feb; 7: 135-8 mun odeficienc y virus type- I activities of 2' ,3 '-dideoxy ­ 51. Fitzgibbon JE, Howell RM, Haber zettl CA, et al. Human im­ nucle oside analogs in MOLT-4 cell subl ines resista nt to munodeficiency virus type I pol gene mutations which cause 2' ,3'-dideoxynucle oside analogs. Acta Virol 1993 Oct; 37: decreased susce ptibility to 2' ,3' -dideoxycytidine. Anti­ 360-8 microb Agents Chemother 1992 Jan; 36: 153-7 66. Cinatl Jr J, Cinatl J, Rabenau H, et al. Failure of antiretroviral 52. Zhang D, Caliendo AM, Eron JJ, et al. Resistance to 2' ,3' ­ therapy: role of viral and cellular factors. Intervirology 1994 dideoxycytidine conferred by a mutat ion in codon 65 of the Nov-Dec; 37: 307- 14

© Adis International Limited . All right s reserved, Drugs 1997 Jun; 53 (6) 1078 Adkin« <, I til.

6 7. Perno C F, Yarchoun R, Ba lzar ini J, et al. Di fferent puuern o f (ddC) in human plasma, uri ne, and cerebrospina l fluid . An ti­ activity of inhibito rs o fthe human imm unod e fici enc y virus in micrub Agents Chemother 1994 Dec; 3X: 27 63 -7 lymphocytes and mo no c yte/ macrop hages. Antivira l Res 199 2 XX. Roberts WL, BuckleyTJ, Rainey PM, et al. So lid -p hase cx trac­ A pr; 17: 2X9-304 lion co mbined with radioimmunoassay for measurement of 6X. Perno C I ~ Yarchoan R, Cooney DA, et al. Inhibition of human za lc itubine (2' ,3' -d ideo xycytid ine ) in plasma and serum . Cli n im munodefic ie ncy virus (H IV- I/ HTLV-lI lBa-L) rep lication Chern 1994 Fe h; 40: 2 11-5 in fresh and cultured hu man pe ripher al blood monoc ytes/ X9. Naz aren o LA, Ho luzo AA , l. imj uco R, et al. T he e ffect of food macro phages by azido thymidi ne and related 2' ,3' -dideoxy­ on ph armacokinetics of za lci tab ine in Hl V-pos iti vc patients. nucleosides. J Ex p Med 19XXSe p I; 16 X: 1111-25 Pharrn Res 1995 Oct; 12: 146 2-5 69 . Perno C"~ Cooney D, Yarchonu R, et al. Inhibition o f hum an 90. Yarc hoa n R, Perno CF, T ho mas RV, et a l. Phase I st udiex o f immunodefic iency virus (H IV) infectio ns o f fresh perip hera l 2 ' ,3 ' -dideoxycytidin e in severe hu man immu nodefi ciency vi­ blood monocyte/macrophuges (M/M) by dideoxynucleosides rus infection asa single agent and alternating with zidovud ine a nd phosphonoformate. A ntivira l Res 19 XX; 9: 157 (AZT) . Lancet 19XXJan 16 ; I : 76 -XI 70 . Hen gst sch lager M, Denk C , Wawra E. Cd l cy cle regulurio u o f 9 1. Buzun ga M , Tran HT, Kertl and H, et ul. T he e ffects of re na l dcox yc ytid ine kinase. Evidence for post -uunscri pt ional co n­ impa irment o n the phar macokine tics o f Z alc ituhi ne (ddf.') trol. FEBS Lell 199 3; 32 1: 23 7-40 [ab st ract]. J C lin Ph armac ol 1996 Se p; 36 : X5 1 7 1. Arn er ESJ, Er iksso n S. Mammal ian dcuxyribo nuc leoside ki­ 92 . Roch e . HI VI D tablets; prod uc t de scripion. June 1996 nases, Pharm acol Th er 199 5 ; 67 : 155-X6 ()J. Aiuti p. Boucher C. Dianzani F. el al. Conse nsus co nference Oil 72. Gao W-Y, Agharia R, Driscoll JS, et al. Divergent an ti-human laboratory markers in HIV infection. .I Bioi Rcgul Homeosl immun odeficiency vir us activity and anabolic phosphoryla ­ Ag ents 1995 J ul-Sep; 9: 119-20 tion of 1'.3'-d ideo xy uuc leosidc analogs in resting and acti ­ 94 . Go ld man AI , C arl in BI', C ra ne LR, et al. Respon se o f C D4 vated human ce lls. J Bioi Chern 1994 Apr 29 ; 269: 12633-X lymphocytes and clinical co nseq uences of treatment using 73. Ga o W- Y, Shirasaku T, Johns DG , et al. Di fferential ph osph or ­ ddl o r dd C in patie nts with ad va nced HI V infection. .I y lation ofazido thy m id ine , did eo xycyridinc, and di deoxyino s­ Acquir Im mune Defi c Synd ro m Hu m Retrovirol 1996 l-eh I; inc in resting and acti vated peripheral 01 00<.1 mononu,...lcar II : 161 -9 ce lls . J C lin Inve st 199 3 Ma y; 9 1: 2326-33 95 . C ho i S, l.agakos S W, Schoo ley RT, et a l. CD4+ lym phocytes are 74. Watson AJ, Wilburn LM . Inhibition o f HI V in fect ion of resting all incom plete surrogare marker flu- clinical prog ress ion in peripher al blood lymphocytes by nuclcosidcs. A IDS Res Hum person s wit h asym ptomat ic HI V infection tak ing zido vudi ne . Retro viru ses 1992 Jul; X: 1221 -7 A nn Intern Med 1993; I IX: 674-XO 75 . Pern o C F, Aq uaro S, Rosenwi rth B, et al. In vitro activit y o f in­ 96 . Willia ms 1(; , De Cock KM . T he Xl ln tcm utiou ul Conference o n hihit o rs o f lat e slag es of the re pli cat io n of fl lV in chro nically A IDS Van couver 7- 12 Ju ly 1996. A re vie w o fCliniea l Scie nce infe cted macrup hages. J l.eu koc Bio i 1994 Se p; 56 : 3X I-6 Tr ack B. Genitourin Med 1996 ; 72 : 36 5- 9 76 . Mag nani M, Ga zzane lli G , Brand i G , et al. 2 ' ,3 ' -D ideoxycylid­ 97. Harrigan R.Measuring vira l load in the cli nical sell ing. J Acquir ine ind uce d dru g res ista nce in human ce lls. Life Sci 1995 Jul Immune Defi c Syndrom Hu m Retrovirol 1995; 10 Supp l. I: 2 1; 57: XX I-7 S34 -40 77 . Magn an i M , Brand i G , Cas ahiuncu A, et al. 2 ' ,3' -D idco xycytid ­ 9X. Katzen stein DA, Ham mer S M , Hug hes MD, ct ul. T he rel atio n inc metabolism in a new dru g-resistant ce ll line. Biochem J of virologic and immunologic markers 10 clini cal OU h..'OIJH':S 1995 No v 15; 3 12 ( Pt I ): 115-23 a fter nucleos ide therap y in Hl v- iutected ad ulls with 2lXl to 7X. Gustavson LE, Fuk uda 10 K, Rubio FA, et a l. A pilot study of the 5(X)C D4 ce lls per cubic m illimeter, N Engl J Med 1996 Oct bioavailah ility and pharmacokinetics of 2',3'-dideuxycytid­ 10; 3.15: 109 1-8 inc in patients with A IDS or AIDS-rdate d co mplex. J Ac q uir l)t) . Deyton L. Importance of surrogate markers in evaluation of Immune Ik lic Synd r 1990 ; 3: 2X-3 1 antivirul the rupy in HI V infection. J AM A 1996; 276: 159 -60 79. Klecker Jr RW, Co llins J M, Yarchoa n RC, ct al. Phunnucok iuc t­ 1lXl. Le vy JA. S urrogat e mark ers in A IDS research . Is there tru th in ics 0 1'2' ,3' -dideoxycyridine in patients with AIDS and related numbers? J AM A 1996 ; 276: 161 -2 di sorde rs. J C lin Phurmacol 19XX Sep ; 2X: X37-4 2 101. Forsyth BWC. Pri mary care of ch ildr en w ith HI V infe ction. XO. Gould C hadw ick 10 , Nazarene LA, Nie uwcnhuis T J, et a l. Phase C UlTO pin Pediatr 1995 O ct; 7: 502 -1 2 I evaluation ofzalci tab ine administered 10 human im munod e­ 102. Piz zo I'A, Wil fert C. Antiretrov iral therup y for infe ctio n due to fici ency virus-i nfected chi ld re n. J Infect Dis 1995 Dec ; 172 : human immunod e fici en cy virus in ch ild re n. C lin In fect Dis 147 5-9 1994 Jul ; 19: 177 -9 6 XI. I'i a o I'A, Bull er K, Bali s I <~ el al. Dideo xycytidine a lone and in 103. Mofen son L, Balsley J, Simo nds RJ , et

© Adi sIn terna tional Limited . All righ ts reserved . Druys 1997 Jun: 53 (6) Zalcitabine: An Upd ate 107<)

109. Mcintyre K, To rre s R, Luck D, el al . Pilot study of zidov ud ine va nced human immunod eficiency virus i nfection . A nn Med (AZT) and zalcitabine (dd C) combi nation in Hlv-associuted 1992 ; 116 ( I): 13-20 dementia [abst ract], 10th Inte rnational Confere nce on AIDS 126. Henry K, Tierney C, Kahn J, et ul. A rando mized, doubl e-blind , 1994; I: 20 1 placebo-cont rolled study comparing combination nucleoside 110. Fo llansbee S, Dre w L, Ol son R, el ul. Th e efficac y o f za lci tub ine and triple therapy for the treatment of advanced HIV di sease (dd C , HI VID) versus zidov udine (ZDV) us monotherapy in (CD4 < = 50/mm3 ) [ubsrract]. 41h Confe rence on Ret ro viru ses Z D V nai ve pa tien ts wi th ad vanced HIV di seu se : u ra ndo m­ and Opport un istic lnfections: 1997 Ja n 22-26; Washington , DC ized , double-blind, comparative triul (A CT G 114: N3 3(0) 127. T hompson M,Creagh '1', Harmon M, et al. Impact on surv iva l [abstract]. 9th Int Co nf A ids 1993; I: 487 ofco mbinat ion or seq ue ntia l anrire trovi ra l rherupy co mpared III . Bozzeue S A, Kanouse DE, Berry S, eI al. Heal th status and wi th AZT monorherapy [abstract ]. 3rd Co nfe re nce o n Ret ro ­ function with zidovudi ne o r zulc ita bine us initial the rapy for viruses and Opport un istic infection s 1996 Jan 28: 106 AIDS: a ra ndom ize d controll ed trial. JAMA 1995 Jan 25; 128. Graha m N M H, Hoover DR , Park LP, et al. S urv iva l in H IV-in ­ 273: 295-301 fecred pa tients wh o ha ve rece ive d zidov udi ne: co mparison of 112. To rres RA, Burr MR , Mcintyre KI , et a l, A compariso n o f combi nati on therapy w ith se q ue ntia l monorherapy and con­ zidovudine, didanosine, zalcitabine and no antiretrovirul ther­ tinu ed zido vud ine monorherapy. A nn Intern Med 1996 Jun upy in patients wi th adva nced HIV di seuse. Int J STDA IDS 15; 124 : 10.110-10.18 1995 Jan-Feb; 6: 19-26 129 . Lan ge JMA. Triple combinati on s: prese nt and futu re . J Acquit IU. Abrams DI , Goldman A I, Laune r C, et al. A co mp arati ve trial Immune Defi c Sy nd ro m Hum Retrovirol 1995 ; 10 Suppl. I: of didanosin e o r zalc itabine aft er treauuent with zido vud ine 77 -82 in pati ents w ith hu man immunodeficiency virus in fectio n. N 130. Testa MA, l.end er kin g WR , Fisc he r L, el al. Eflc cts o f co mbi­ Engl J Med 1994 Mar 10; 330: 65 7-62 nation therapy w ith saq uinav ir, zidovud ine and zalcita h ine o n 114. Fisch l MA , Olson RM , Foll an sbee S E, et al. Za lc itab ine com­ quality o f life labstract ]. 11th Intern ati onal Conference on pa red w ith zidovud ine in pati ent s with ad vanced H IV- I infec­ AIDS 1996JuI7; I: 23 9 tion w ho rece ived previ o us zido vudi ne therapy. Ann Intern 1.11. Ruiz L, Romeu J, Martinez-Picad o J, et a l. Efficacy o f trip le Med 199 3 May 15; 118: 76 2-9 combinati o n the rapy wi th zidov ud ine (Z DV) plus zalc ita bine 115. Fischl MA, S ta nley K, Co llier Ac . Combination an d monoiher­ (ddC ) plu s lam ivud ine (3TC) vers us double (ZDV + 3TC) a py wi th zidovud ine and za lci tubine in patients wit h ad van ced co mbination therap y in patients pre viou sl y treated w ith Z DV HIV di sease . A nn Intern Med 1995 Jan I; 122: 24-32 + dd e. A IDS 1996 ; 10: 1'61- 6 116 . Hummer SM , Kat zen stei n DA , Hugh es MD, el al. A trial com­ 132. Mathez D, Bagn arelli P, Dc T ruc h is P, e l al. A tripl e co mb inauon paring nucleoside monorherap y w ith combinat ion therapy in of ritonavir+ AZ T +DDC as a first line treatm ent of patie nts Hlv-infecred adults with C D4 cell counts fro m 200 to 51X)pe r wit h A IDS: upd at e [ab st ract]. ll th Internation al Co nference cubic millimeter. N Eng l J Med 1996 Oct 10; 33 5: 1081 -90 o n A IDS 1996 Jul 7; I: 19 133 . Co nde -Me rcado JM , Feregrino G M, Eid L idt C;, c t al. A ntiviral 117. Co llier AC , Coombs RW, Sc hoenfeld DA, e l al. Treatment o f co mb ined an d thy mos tim ulin in pat ien ts w ith H IV slag es III hu man im munode fic ie ncy vir us infectio n w ith sa q ui na vir, and IV. Effects on the C D4 ce lls counts [uhstract] . 10th Inter ­ zidov ud ine, and zalcitubine. N Engl J Med 1996 Apr 18; 33 4 : 1011 -7 national Co nference on A IDS 1994 ; I: 211 1.14. La vell e J, Haas D, HIV /Wellferon"" Clinical Trial Teum . Lo uu ­ 118. Schooley RT, Ramirez-Ronda C, Lange JMA, et al. Virol ogic te rm safety and e fficacy of init ial tripl e co mbi nat ion th era l~Y and immunologic ben efi ts of initi al combination therapy wi th wi th Z D V, dd C and interferon alpha- u l vs Z D V and ddC in zid ovudiue and zal c ita binc or didano sinc compa red w ith pat ient s wi th C D4+ ce ll counts 300 -500 cells/nun.'. 3rd Con ­ zidov ud ine mo nothera py. J Infect Dis 1996 Jun; 173: 1.154-66 terence o n Re tro viruses and O pportunist ic Inf ect ions 1996 119. Kutlama C. Cl inic al and sur vival benefit o f .1TCTMin comhina­ Jan 28: 107 tion wi th zid ov ud ine -co mai ning regimen s in HI V-I infection: 135. Freimuth W, Wan g Y, Docsa S, et a l. Surrogate mark er re­ interim results of the CAESA R study [ubstract no. SS2 .11. spo nses fro m an op en -label , ex te nde d lise dc lav ird inc me sy l­ AIDS 1996; 10 S uppl. 2: S9 ate ID LV ) treatment in triple combinat ion (Z DV+DL V + DDI 120. Saravol.uz LD , Wins low DL , Collins G, et al. Z ido vud ine alone or ZDV+DLV+DDC) for HI V-I+ pati ent s [uhstract ]. 11th In­ or in combination wit h d idanosin c or zulc itah ine in HIV -in­ te rna tional Conferen ce on A IDS 1996 Jul 7; I : 78 fccted pati ents w ith the acquired immunodeficienc y syn­ 136 . Sc hei oel S F, Sager 13 , Eloe ik '1', et al. Ex tre me suppress io n o f drome o r fe wer tha n 2(x) C D4 cell s per cu bic millimeter. N HIV-I pl as ma RNA using a co mh inario n o f zidovudi uc, Eng l J Med 1996 Oct 10; 33 5: 1099 -106 d iJ anosinc, za lc itahine, e piv ir. saqll inf.lvir, and inh:rrcroll -(t 121 . Delt u Coordinati ng Co mm ittee. Delt a: u rundomised douole­ in pati ents w ith HIV-I inlCction lab str act! . 11th Intem atio nal o lind controlled trial co mparing comoinations o f zidovud ine Conferen ce o n AIDS 1996 Jul 7; 2: 78 plu s didanosin e or za k itao ine wi th zidovudi ne alone in HI V­ Ln. Sp ector SA , Blanchard S, Connor EM , et al. Results o fa clinical inlccted ind ividuals. Lancet 1996 Au g .1; 348: 283-91 trial comparing two doses o f 2' 3' -d ideo xycytid ine (ddC) in 122. Moyle GJ, Wulk er M, Harri s R, et al. Early versus delayed the Ircatmenl o f ch ild ren w ith sympto matic human imlllullo­ zakituo ine (d dC )lz idovud ine (Z DV) comoi natio n in IIIV­ de fici enc y virus (HIV ) inlec tion who were intolerant o r had positive person s wi th C D4 cell co unts .1(X)-5(X)/mm ': a dou­ fa iled zi dov ud ine (Z D V ) therapy (ACH, 138) la bs tract /. hle-olind placeoo co ntro lled Iri al (Roc he study M500(3) Pedi atr Res 1994 Apr; 35 (l't 2 ): 197A luostract no . P491 . AIDS 1996; 10 S upp l. 2: S31 1.18. Dankner WM , Ric e M, Nyhan WL , et a l. Effect of salvage 123. Bart lett JA, Ben o it SL , Johnson VA. Lamivudine plu s zidovud ­ d ide ox yc ytidinc 011 g row th. nutritional para metcr s and met a­ inc compared w ith za kita hi nc plu s zidov ud inc in patienls ool ic rates o f ch ildren wi th ad van ced IlI V di sease lao stractl . wi th HIV infectio n: a ra ndo m ize d, douole-ol ind , placeoo­ 2 nd Nalional Co nferc nce O il Human Retro viruses I()()5 Jan controlled tria l. Ann Intern Med 1996 Au g I; 125: 161-72 29: 104 124 . HolTman-Lu Roche . HIVID® : co moi nat io n therapy in IIIV di s­ 139. Hus son R, S h iras aka '1', Butler K, et al. Ili gh lev el res istance to easc. Clinical expert report AZT, ou t no t to ddC or ddl in HI V from child ren recei ving 125 . Men g ' I ~C, Fischl MA , Boota AM , et al. C o mo inutio n therap y long -term antiretrovir al therap y lao stract no. 57 11. 32 nd Int w ith zido vud ine and dideoxyc ytidine in pati ent s w ith ad - Co nI' A ntim icr o Ag C he mo the r 199 2: 206

I!:I Ads Intern ati onal Limited. All righ ts re served . Drugs 1997 Jun : 53 (6) 1080 Adki ns et al.

140. Simpson K, Hatzi andreu EJ, Andersson F, et al. Co st effect ive­ 160. Ta ncrede -Bohli n E, Gr ang e F, Bournerias I. Hypersensiti vity ness of antiviral treatment with zalcitabine plus zidov udine sy ndrome associated with zalcitabi ne therapy. Lancet 1996 for A IDS patients with CD4+ co unts less than 33 /~ 1 in 5 Eu­ Apr 6; 347 : 97 1 ropea n co untries. PharmacoEconomi cs 1994 Dec; 6: 55 3-62 161. Hen ry K, Acosta EP. Hepatotoxicity and rash associated with 141. Meri gan T'C, Treatm ent of AIDS with co mbinations of anti­ zid o vudine and za lcitabine chemop rophylaxis. Ann Intern retro vir al age nts . Am J Med 1991; 90 Suppl. 4A : 8S- 17S Med 1996 May I; 124: 855 142. Moyle G , Goll A, Snape S, et al. Safet y and tolerability of 162. Bri vet FG, Naveau SH , Lemaigre GF, et al. Pancreatic lesions za lcitabine (ddC) in patients with AIDS or adv anced AIDS­ in HIV-infected patients.Baillieres Clin Endocrino l Metab re lated co mple x in the European Expand ed Acce ss Pro­ 1994 Oct; 8: 859-77 gramme. Int J Ant imicrob Agents 1996 ; 7 ( I): 4 1-8 163. Aponte-Cipriani SL, Tepl itz C. Yanc ovitz S. Pancreat itis possi­ 143. Moore RD , Fortgang I, Keruly J, et a l. Adv er se e vents from drug bly related to 2'- 3'-dideoxycytidine. Ann Intern Med 1993 ther apy fo r human immunodeficiency virus disea se. Am J Sep 15; 119: 539 -40 Med 1996Jul; 101: 34-40 164 . Moyle GJ. Oc c urrence of lymphom as during dd C or dd C/ 144. Simpson DM, Tagliat i M . Nucleoside anal ogue-a ssocia ted pe­ zidov udine co mbination therapy in per sons infected with HIV riph eral ne uropathy in human immunodeficiency virus infec­ type I [letter]. J Acquir Immun e Defi c Syndrom Hum Retro­ tio n. J Acq uir Immune Defic Syndro m Hum Retro virol 1995 viro l 1996; 13 (5): 464-5 Jun I; 9 : 153-61 165. Moyle GJ, Walke r M, Harris R, et al. Safety and activity of 145. Blum AS , Dal PGJ , Fe inberg J, et al. Low -dose zalcitabine-re­ zalcitabine and zidovudine combina tion in HI V-positive peo­ lated tox ic neu ropath y: frequency, natural history, and risk ple with CD4 ce ll counts ::::300 ce lls/rnm ' . Antivira l Th er 1996 factors. Neurology 1996 Apr; 46: 999- 1003 Aug; I (3) : 180-8 146. Fichtenbaum CJ, Cliffo rd DB, Powderly WG. Ris k factors for 166. Acosta EP, Fletcher CY. An tiretroviral drug interaction s. Int J d ideoxynucleoside-induced toxic neuropathy in patients wit h Antimicrob Age nts 1995 Apr ; 5: 73-83 the human imm unodeficiency virus infection. J Acq uir Im­ 167. Taburet A-M, Singlas E. Drug interactions wit h antiviral dru gs. mun e Defi c Syndrom Hum Retrovirol 1995 Oct I; 10: 169-74 C lin Pharmacokinet 1996 May; 30 : 385-40 I 147. Berger AR , Arezzo JC , Schaumburg HH, et al. 2' ,3' -d ideo xy­ 168. Hey len R, Mill er R. Interactions wit h antiretrov iral dru gs. cy tidine (ddC) tox ic ne uropathy: a study of 52 patients. Neu­ Pharm J 1993 Feb 13; 250: 2 14-6 ro logy 1993 Feb ; 43: 358-62 169. Massarella JW, Holazo AA , Koss-Twardy S, et al. Th e effec ts 148. Dubinsky RM , Yarchoan R, Da laka s M, et al. Reversible axon a l o f c ime tidi ne and MaaloxlRm 1on the pharmacok inet ics of neuropath y from the treatment of A IDS and related disorders za lcitabine in HIV-positive patient s [abstr act) . Pharm Res with 2' ,3' -did eoxycytidine (ddC) . Muscl e Ner ve 1989; 12: 1994 Oct ; II Suppl. : S-4 15 856 -60 170. Massare lla JW, Nazare no LA , Passe S, et a l. Th e effect of pro­ 149. Lip sky JJ . Zalcitabine and didanosi ne. Lancet 1993 Jan 2; 34 1: benecid on the pharm acokinetics of zalcitabine in HIV-posi­ 30- 2 tive patients. Pharm Res 1996 Mar; 13: 44 9-52 150. Powderl y WG , Klebert MK , C lifford DB . O totoxicity associ ­ 171. Lee BL, Taub er MG , Ch ambers HF, et al. T he effec t o f trime tho­ ated with did eoxy cytidine [letter). Lan cet 1990 May 5 ; 335 : prim on the pharm acokinetics of zalcitabine in HIV-infected 1106 patients (abstr act) . 35th Int Conf Antimicro Ag C hemo ther 151. Martinez OP, French MAH. Acou stic neu rop ath y associated 1995 Sep 17: 6 with za lcitabine-i nduced peripheral ne urop ath y. AIDS 1993 172. LeL acheur SF, Sim on GL. Exacerbat ion of did eoxycytidine­ Jun ; 7: 90 1-2 induced neu ropathy with dideo xyin osin e. J Acquir Immune 152. Faller JP, Zie gler F, Balblanc JC, et al. Acute para lysis of the Defic Syndr 1991 ; 4: 538-9 se rratus muscl e in an HIV positive pat ient treated by DDC 173. Herskowi tz A, Willoughby S B, Ba ughman KL, et al. Ca rd iomy­ [ab stract). 10th International Confere nce on A IDS 1994; I: opathy associated w ith antiretro vira l therapy in patien ts w ith 191 HIV infecti on : a report of six ca ses. Ann Intern Med 1992 Feb 153. Jay e. Ropka M, Dalakas Me. The dr ugs 2' ,3' -d ideoxyinosine 15; 116: 311- 3 (dd l) and 2',3 ' -dideoxycy tidi ne (ddC) are sa fe alternatives in 174 . MacGregor TR , Lam son MJ , Cort S, et al. Ste ad y state pharm a­ peop le wi th A IDS with zidovudine-indu ced my opa thy. J cokinetics of nev irap ine, didan osine , zalc itabine, and Acquir Immune Defic Syndr 1994 Ju n; 7: 630- 1 zidovudine combination the rapy in HIV-I positive patients 154. Greenspa n D, Hilton JF, Ca ncho la AJ, et al. Association be­ (abstract]. Pha rm Res 1995 Se p; 12 Suppl.: S IOI tween ora l ulcers and zalcitab ine [abstract ]. 10th Intern ation al 175 . Lee BL, Tauber MG , C ha mbers HF, et al. Zalci tabine and dap­ Co nfe rence on AIDS 1994 ; I: 62 so ne phar macokinetic inte raction in HI V-infected patients 155. Ra mire z-Ron da C H, San tana J, Rivera- Vazqu ez C, et al. Ora l [abstract) . C lin Pha rmacol Th er 1995 Feb ; 57 : 186 ulcers in HI V infec ted pe rson s taking zalcitabine plu s 176. Lee BL, Tauber MG, Chambers HF, et al. T he effect of za lcitab­ zid ovud ine: initial res ults [abstract ). 2nd National Co nfe rence ine on the pharmacokinetics of iso niaz id in Hf V-inte cted on Human Retroviruses 1995 Jan 29: 153 patients [abstract no. A4] . 34th Int Conf Antimi cro Ag C he rn­ 156. Indorf AS , Pegra m PS . Esophageal ulceration re lated to othe r 1994: 3 za lcit ab ine (ddC). Ann Intern Med 1992 Jul 15; 117: 133-4 177. Hoffman La Roche.Zalcitabine pres cribing information . Basel. 157. Meri gan TC , Skowron G, Bozzette SA , et al. Ci rculating p24 Swi tzerland , 1997 antige n levels and responses to d ideoxycytidi ne in hum an im­ 178. Carpenter CC J, Fisc hl MA , Hammer SM , e t al. An tiretrovira l munod eficiency virus (HIV ) infec tion s. A pha se I and II st udy. thera py for HIV infection in 1996 : recommendation s of an Ann Intern Med 1989 Feb I; 110: 189-94 international panel. JAM A 1996 Ju liO; 276: 146-54 158. McNeel y Me. Yarch oan R, Brod er S, et al. Dermatologi c com­ pli cati ons associated with administration of 2' ,3' -d ideoxy­ cy tid ine in patients wi th human immunodeficiency virus Correspondence: [ulie C. Adkins, Ad is International Lim­ infec tio n. J Am Acad Dermatol 1989 Dec; 2 1: 1213-7 159. Ward ropper AG, On g ELe. Erythema multi forme secondary to ited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, did eox ycytidine (DDC) . Int J STD AIDS 1995 Nov-De c; 6 : Auckland 10, New Zealand. 450 E-mail : [email protected]

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