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Efficacy and Tolerability of Zalcitabine Twice Daily (HIVBID Study)

Antunes, F. MD*; Walker, M. PhD; Moyle, Graeme J. MD, MBBSon Behalf of the HIVBID Study Group

JAIDS Journal of Acquired Immune Deficiency Syndromes: February 1st, 2004 - Volume 35 - Issue 2 - p 205-206
Letters to the Editor

*Hospital de Santa Maria, Lisbon, Portugal

†F. Hoffman-La Roche, Basel, Switzerland

‡Chelsea and Westminster Hospital, London, UK

To the Editor:

Regimens of 3 or more antiretroviral agents, typically 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor (PI or boosted PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI), are the standard of care for HIV therapy. 1 These regimens effectively and durably suppress viral replication to levels below detection, delay the development of drug-resistant isolates, and delay disease progression. 2 Choice of therapy is individualized, taking into account such factors as antiviral efficacy, tolerability, adverse effects, coinfections, drug interactions, and convenience of administration. Because HIV-infected patients require long-term therapy, all available drug options should be investigated to provide the best possible standard of care.

Zalcitabine (2´,3´-dideoxycytidine [ddC]) is an NRTI with antiretroviral and clinical therapeutic benefits established in the dual-therapy era (Table 1). 3–6 Unlike other NRTIs, which are routinely dosed twice daily, it is still dosed three times daily. Its intracellular half-life is up to 10 hours, however, similar to other twice-daily dosed NRTIs. 7 Pharmacokinetic modeling and preliminary clinical data suggest that twice-daily dosing of ddC is feasible with no decrease of antiviral activity. A retrospective analysis of switching ddC from thrice-daily to twice-daily dosing (1.125 mg twice daily) in a cohort of 17 patients in London showed no loss of therapeutic effect or unexpected adverse events over a median 130 days of follow-up. 8 The low frequency of ddC resistance selection, either genotypic or phenotypic, and the low level of susceptibility changes when resistance is observed represent potentially useful properties of ddC-based therapy. 9 Although its use has declined substantially, ddC remains an active antiretroviral agent with acceptable tolerability and safety. It may be of particular use in “salvage therapy” settings involving patients with extensive prior treatment experience and multiple reverse transcriptase mutations. ddC is often the nucleoside analogue agent in which the smallest shift in phenotypic susceptibility is observed when multiple nucleoside analogue resistance-associated mutations are present. 10



We conducted a randomized, open-label, 24-week pilot study (with a treatment extension to 48 weeks) of 1.125 mg of ddC twice daily versus 150 mg of lamivudine (3TC) twice daily, both combined with zidovudine (ZDV) and a PI, in treatment-naive HIV–1-infected individuals. Criteria for inclusion included HIV RNA levels ≥5000 copies/mL and CD4 cell counts ≥200 cells/mm3, with no genotypic mutations conferring resistance to study medications (determined at screening). Patients with preexisting peripheral neuropathy or active opportunistic disease were excluded.

Patients were screened 3 weeks prior to initiating treatment. Study visits took place every 4 weeks until week 24 and every 12 weeks thereafter until week 48. Patients received the following medications in each treatment arm: 1.125 mg of ddC twice daily, plus 300 mg of ZDV twice daily, plus 1250 mg of nelfinavir twice daily or 1600 mg of saquinavir (soft gel) twice daily; 150 mg of 3TC twice daily, plus 300 mg of ZDV twice daily, plus 1250 mg of nelfinavir twice daily or 1600 mg of saquinavir (soft gel) twice daily (arm B). The primary efficacy outcome was the proportion of patients with plasma HIV-1 RNA levels ≤400 copies/mL at week 24 by intention-to-treat (ITT) noncompleter-failure analysis. A similar analysis was performed at week 48. Secondary variables included the proportion of patients with plasma HIV-1 RNA levels below 50 copies/mL, the time to first response (HIV RNA ≤400 copies/mL), and the absolute change in CD4 cell counts. Safety was assessed in terms of adverse events (AEs) and laboratory variables.

A total of 47 patients were included in the ITT population, distributed across 12 centers from 5 countries. The majority of patients were male (38 vs. 9). Treatment groups were similar in terms of age (mean: 36.6 years ± 10.5), baseline levels of plasma HIV-1 RNA (mean: 380,087 copies/mL ± 974,197), and CD4 cell counts (mean: 398 cells/mm3 ± 172).

At week 24, 42% (10/24) of patients in the ddC group and 52% (12/23) in the 3TC group had HIV RNA ≤400 copies/mL, with no significant difference between treatment groups. A similar pattern was observed at week 48. The proportion of patients with HIV RNA ≤50 copies/mL was numerically higher in the 3TC group at week 24. By week 48, however, a similar number of patients in both groups had HIV RNA ≤50 copies/mL. Median time to first response was more rapid in the ddC group (55 days) than in the 3TC group (71.5 days). By week 24, mean HIV RNA levels were reduced by −2.27 log10 copies/mL in the ddC group versus −2.72 log10 copies/mL in the 3TC group. Corresponding changes from baseline by 48 weeks were −2.31 (ddC) and −2.32 (3TC). Both groups showed steady increases in CD4 count from baseline. By week 24, CD4 counts had increased by 144 and 236 cells/mm3 for the ddC and 3TC groups, respectively. Corresponding changes from baseline at week 48 were 127.5 and 115.1 cells/mm3.

The proportion of patients reporting AEs, irrespective of relationship to trial medication, was similar in both groups (75% in the ddC group vs. 71% in the 3TC group). The majority of AEs were mild in severity. Diarrhea was the most common treatment-related AE, reported in 11 of 24 (46%) patients on ddC and in 5 of 21 (24%) patients on 3TC. Other AEs attributed to therapy included vomiting (4/24 patients [17% on ddC], 1/21 patients [5% on 3TC]) and abdominal pain (3/24 patients [13% on ddC]). No cases of peripheral neuropathy were reported. No serious adverse events (SAEs) were reported in the ddC group, with 1 SAE reported in the 3TC group (infection requiring hospitalization). Four patients prematurely discontinued medication due to AEs (3 in the ddC group [diarrhea, urticaria, and rash] and 1 in the 3TC group [urticaria and bronchospasm]).

Overall, the data show similar antiretroviral activity of the twicedaily ddC-based triple therapy with the 3TC-based regimen. The present results are also comparable in terms of efficacy and safety to those in the MIKADO study, in which ddC was dosed three times daily with saquinavir soft gel and stavudine (d4T), 11 although the proportion of patients with HIV RNA <400 or <50 copies/mL at weeks 24 and 48 in our study is relatively low. This may be related to the high baseline viral load or choice of cotherapies. The reported adverse events do not suggest a difference between arms, with the majority of drug-related adverse events being characteristic of ZDV or PIs.

These are the first prospective data to support the feasibility of twice-daily dosing of ddC, and this is one of the few studies conducted in the triple-therapy era to investigate this agent.

The HIVBID Study Group includes the following individuals: Dr David Hawkins, Chelsea and Westminster Hospital, London, UK; Dr Edmund Wilkins, North Manchester General Hospital, Manchester, UK; Dr Ian Williams, University College and Middlesex Hospital, London, UK; Dr Clifford Leen, The Lothian University Hospitals NHS Trust, Edinburgh, UK; Prof Francesco Mazzotta, Ospedale S. Maria Annunziata, Florence, Italy; Prof Mauro Moroni, Ospedale “L Sacco,” Milan, Italy; Prof Israel Yust, Sourasky Medical Center, Tel-Aviv, Israel; Prof Shimon Pollack, Rambam Medical Center, Haifa, Israel; Prof Meliço Silvestre, Hospitais da Universidade de Coimbra, Coimbra, Portugal; Prof Francisco Antunes, Hospital de Santa Maria, Lisbon, Portugal; Dr Rui Proença, Hospital Curry Cabral, Lisbon, Portugal; Dr Fernando Rosas Vieira, Centro Hospitalar Vila Nova de Gaia, Vila Nova de Gaia, Portugal; and Dr Allen Stein, Care Resource, Coral Gables, FL.

F. Antunes, MD

M. Walker, PhD

Graeme J. Moyle, MD, MBBS

on Behalf of the HIVBID Study Group

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© 2004 Lippincott Williams & Wilkins, Inc.