Safety and tolerability of zalcitabine (ddC) in patients with AIDS or advanced AIDS-related complex in the European expanded access programme

Moyle, Graeme; Göll, A.; Snape, Sue; Harris, Ray; Wilkes, Carol; Warburg, Marie; Salgo, Miklos

doi:10.1016/0924-8579(96)00008-8

Cited by 11 publications

(8 citation statements)

References 20 publications

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“…Of these, three had their diagnosis con®rmed by electromyogram. This incidence is similar to, or less than, that observed in a number of monotherapy studies of these two NRTIs [21,22]. Indeed, before the introduction of antiretroviral therapy, studies report distal symmetrical polyneuropathy in between 10 and 44% of symptomatic HIV patients [23±25].…”

Section: Discussionsupporting

confidence: 77%

MIKADO: a multicentre, open‐label pilot study to evaluate the antiretroviral activity and safety of saquinavir with stavudine and zalcitabine

et al. 2001

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BackgroundSince eradication of HIV is unlikely, long-term management of the disease necessitates careful evaluation of the combinations of currently available drugs to determine the most potent and useful rational sequencing of regimens. ObjectiveTo determine the antiretroviral ef®cacy and tolerability of saquinavir soft gelatin capsule (SQV-SGC) plus zalcitabine (ddC) and stavudine (d4T), as ®rst-line treatment in HIV-infected patients. DesignMulticentre, open-label, non-comparative study. Patients and methodsThirty-®ve asymptomatic, HIV-infected adults with no prior antiretroviral treatment, a CD4 count b 250 cells/mL and baseline b 5000 HIV RNA copies/mL were included in the study. Patients received SQV-SGC 1200 mg three times a day (tid), ddC 0.75 mg tid and d4T 30 or 40 mg twice a day (bid) for 24 weeks. Plasma HIV RNA, CD4 and CD8 cell counts, HIV reverse transcriptase and protease resistance genotypes, SQV plasma concentration and tolerability were evaluated. ResultsAt baseline, median HIV RNA (interquartile range) was 4.99 (4.81±5.48) log 10 copies/mL, and median CD4 count was 370 (318±504) cells/mL (n = 35). At week 24, the median decrease in HIV RNA was 3.05 (2.19±3.68) log 10 copies/mL. A viral load below the level of quanti®cation (200 copies/mL and 20 copies/mL) was achieved in 63% and 34% of patients, respectively (intent-to-treat analysis). The only mutations detected were L90M substitutions in two patients. At week 24, the median CD4 count increased (P < 0.0001), and CD8 cell counts decreased (P < 0.0001), relative to baseline. In total, there were ®ve cases of peripheral neuropathy (14%). Mean triglyceride and cholesterol levels remained within normal ranges. ConclusionsTriple therapy with SQV-SGC plus ddC and d4T is a reasonably well tolerated regimen that markedly and rapidly reduces viral load with immunological improvement. This combination is an effective (d4T) have not been combined in therapy regimens. One explanation for this is the suggestion that they may cause neurological toxicity [2,9]. This pilot study was designed therefore to determine the ef®cacy and tolerability of SQV-SGC, plus an NRTI backbone of ddC and d4T, in antiretroviral-naive individuals. Patients and methods Study designThis multicentre, phase III, open-label, non-comparative study was conducted in nine centres in France for 24 weeks, with visits scheduled every 4 weeks. Local ethical committees approved the protocol and patients were required to provide written informed consent before enrolling. Inclusion criteriaAsymptomatic, adult HIV-infected patients with no previous antiretroviral treatment, a CD4 count b 250 cells/mL and a plasma viral load of b 5000 HIV RNA copies/mL at baseline were included in the study. The baseline characteristics of the study patients are presented in Table 1. Treatment regimensPatients received SQV-SGC (Fortovase q ; Roche Pharmaceuticals, Basel, Switzerland) 1200 mg three times a day (tid), ddC (Hivid q ; Roche Pharmaceuticals) 0.75 mg tid and d4T (Zerit q ; Bristol-Myers Squibb Europe...

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Section: Discussionsupporting

confidence: 77%

MIKADO: a multicentre, open‐label pilot study to evaluate the antiretroviral activity and safety of saquinavir with stavudine and zalcitabine

et al. 2001

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“…The design of the abacavir EAP shared many of the features of EAPs for other antiretroviral agents reported elsewhere [18][19][20][21][22][23]. Consistent with the definition of an EAP, this program included patients with a life-threatening disease (HIV infection) and a paucity of therapeutic alternatives.…”

Section: Discussionmentioning

confidence: 99%

“…Although EAPs have been initiated after enrollment in phase 3 trials has been completed [12], the abacavir EAP was initiated soon after phase 1/ 2 efficacy or safety data were available, and it was conducted in parallel with the controlled phase 3 trials. The population evaluated in the abacavir EAP was comparable in size to that evaluated in the stavudine EAP (112,000 persons) [23], larger than that in the zalcitabine European EAP (517 persons) [22], and smaller than that in the didanosine EAP (127,000 persons) [23]. Low baseline CD4 ϩ cell count was a requirement of other EAPs [21], as it was for part A of the abacavir EAP.…”

Section: Discussionmentioning

confidence: 99%

Abacavir Expanded Access Program for Adult Patients Infected with Human Immunodeficiency Virus Type 1

Kessler

Johnson

Follansbee³

et al. 2002

Clinical Infectious Diseases

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Expanded access programs (EAPs) provide medication to patients with life-threatening, treatment-refractory illnesses before regulatory approval and allow the acquisition of safety information. A 2-part, multisite EAP to evaluate abacavir, a carbocyclic nucleoside reverse-transcriptase inhibitor for use in combination antiretroviral therapy, was conducted. The EAP involved >13,000 adults infected with human immunodeficiency virus type 1 (HIV-1) who no longer responded to commercially available treatment regimens. Part A (open-label trials) examined the efficacy, safety, and tolerance of abacavir, and part B (provision of abacavir through expanded access) assessed only the occurrence of serious adverse events. By month 2 of abacavir-containing treatment, plasma HIV-1 RNA levels decreased by > or =0.5 log(10) in 31.4% of patients, and 5.6% of the patients had HIV-1 RNA levels decrease to <400 copies/mL. Drug-related serious adverse events were reported by 7.7% of patients, the most common of which were nausea, skin rash, diarrhea, malaise or fatigue, and fever. Approximately 4.6% of patients experienced a hypersensitivity reaction that was possibly drug related. Overall, the types and incidences of adverse events reported in the abacavir EAP were similar to those reported in phase 2 and 3 clinical trials evaluating abacavir.

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“…In Phase I trials, rates of PN per 100 person years were 21 at both 0.5 and 1.0 mg/kg/day and 66 at 2 mg/kg/day. Rates were lower in the Phase II study: 17 at 0.5 mg/kg/day and 41 at 2.0 mg/kg/day, with an association between the development of PN and lower baseline CD4 [41] similar to that reported with other potentially neurotoxic nucleoside analogues [57,58]. Neuropathy resolved within 1 -9 weeks in 15 of 27 patients with a median time to resolution of 3 weeks in the 2 mg/kg/day group [41].…”

Section: Clinical Safetymentioning

confidence: 54%

Stavudine:pharmacology,clinical use and future role

Moyle

1997

Expert Opinion on Investigational Drugs

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Stavudine is a nucleoside analogue reverse transcriptase inhibitor of HIV-1 and HIV-2 and demonstrates in vitro activity with an acceptable therapeutic index in a range of T-lymphocyte and haematopoietic precursor cell lines. It is additive or synergistic in vitro with a range of other antiretrovirals, including the proteinase inhibitor saquinavir, in two- and three-way combinations and is active against zidovudine (ZDV)-resistant virus. It exhibits excellent oral bioavailability, with cerebrospinal fluid (CSF)/plasma penetration. In clinical use, stavudine monotherapy exhibits similar antiretroviral activity to ZDV, and is of proven clinical benefit in ZDV-pre-treated patients. In combination with ddI and/or nelfinavir it results in more substantial and durable responses in immunological and virological markers than reported with either drug alone. Further data on stavudine in combination with other antiretrovirals are now awaited. Comparative trials in ZDV-experienced patients suggest a similar frequency of adverse events to that observed with ZDV. Peripheral neuropathy is the most common dose-limiting toxicity, with haematological and hepatic function disturbance being infrequent. Resistance to stavudine develops slowly in vitro and in vivo but may lead to co-resistance to ZDV or ddI. Stavudine will be used clinically as a combination agent both in initial therapy and in patients with prior ZDV experience.

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Safety and tolerability of zalcitabine (ddC) in patients with AIDS or advanced AIDS-related complex in the European expanded access programme

Cited by 11 publications

References 20 publications

MIKADO: a multicentre, open‐label pilot study to evaluate the antiretroviral activity and safety of saquinavir with stavudine and zalcitabine

MIKADO: a multicentre, open‐label pilot study to evaluate the antiretroviral activity and safety of saquinavir with stavudine and zalcitabine

Abacavir Expanded Access Program for Adult Patients Infected with Human Immunodeficiency Virus Type 1

Stavudine:pharmacology,clinical use and future role

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