Original article
Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial

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Abstract

The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4+ cell counts between 50 and 350 cells/μl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (>10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.

Introduction

Delavirdine, a bisheteroarylpiperazine (BHAP), is a non-nucleoside reverse transcriptase inhibitor (NNRTI) [1], [2]. Several non-nucleoside inhibitors have been described including the pyridinone derivatives, TIBO-compounds, a-APA derivatives, nevirapine and BHAPs [3], [4], [5], [6], [7]. NNRTIs are antiretroviral compounds that are structurally unrelated but have a common mechanism for inhibition of HIV-1 reverse transcriptase (RT). All NNRTIs bind to a hydrophobic pocket in the RT at a site distinct from the nucleotide-binding site but close to the residues of the polymerase catalytic site [8], [9], [10], [11], leading to a significant slowing of the rate of polymerization catalyzed by the enzyme. Inhibition of RT interferes with the conversion of viral RNA to proviral DNA and its integration into host-cell DNA [12]. Antiretroviral therapy that interferes with the function of this enzyme has been shown to improve the prognosis of the HIV infection and delay the progression of clinical disease [13]. NNRTIs will probably have low toxicity because of their extraordinary specificity for HIV-1 RT [6]. NNRTIs are generally well tolerated, but mild skin rash is a frequently observed side effect [14], [15], [16].

Nowadays, there is consensus that the optimal first-line treatment of HIV infection consists of combination therapy with at least three antiretroviral agents [17]. At the time this study was performed, the exact place of NNRTIs in such combination regimens was not yet defined. Several studies have shown a beneficial effect of NNRTIs in combination with nucleoside RT inhibitors (NRTIs) because the development of NNRTI resistance is delayed [18] and the antiviral efficacy is higher due to synergism [3], [19], [20], [21], [22]. Monotherapy with any antiretroviral agent is considered obsolete nowadays, and this is also true for NNRTIs. In fact, studies have shown that there is a rapid development or selection of resistant virus variants during NNRTI monotherapy [23], [24], [25].

While resistance to NNRTIs caused by substitutions at amino acids 103 and 181, confers cross-resistance to all NNRTIs, delavirdine remains active against these mutant strains with a 50% inhibitory concentration (IC50) of 8 mM [26]. Further, delavirdine increases the susceptibility to other antiretroviral agents, both NNRTIs and NRTIs. For example, a proline-to-leucine substitution at amino acid number 236 causes an approximately 70-fold increase in the IC50 of delavirdine, but increases the susceptibility to nevirapine, TIBO, and L-697,661 by 7–10-fold [26], [27]. A tyrosine-to-cysteine substitution in Y181C increases the IC50 of all NNRTIs, but suppresses the development of resistance to zidovudine (approximately 35-fold reduction in IC50) [28]. Mutant virus isolates harbouring a K103N, P236L, or Y181C substitution are reported to develop following delavirdine monotherapy [29].

Taking these findings into consideration, we hypothesized that the combination of delavirdine and zidovudine would increase the efficacy of zidovudine in individuals already receiving zidovudine. We designed a prospective study to compare the antiviral effect, safety, and effect on the development of drug resistance of delavirdine–zidovudine combination therapy with the effect of continued zidovudine monotherapy in symptomatic HIV-1 infected individuals.

Section snippets

Study design

The study was designed as a multi-centre, double-blind, placebo-controlled trial. The patients were enrolled at 15 centres (three Australian and 12 European). Between October 1993 and July 1994, 89 patients were randomized to one of the four treatment arms (three arms with delavirdine, one arm with placebo). As the optimal daily dose of delavirdine was not yet defined when we started the study, we used two dose regimens, i.e. 200 and 400 mg tds delavirdine. Further, in order to investigate its

Study population

Eighty-nine patients participated in the study: 23 were randomized to delavirdine 600 mg/day; 23 to delavirdine 1200 mg/day; 19 to the delavirdine escalating dosage regimen, and; 24 to placebo. After 12 weeks, the 24 patients in the placebo group were offered delavirdine at a dose of 900 mg/day: 20 patients started delavirdine, two patients had been withdrawn because of medical events, and two patients withdrew from the study in week 12 for personal reasons. Table 1 shows the entry

Discussion

The results of this trial demonstrate that addition of delavirdine to treatment with zidovudine resulted in a significant reduction of viral burden. This beneficial effect was most pronounced during the first 4–8 weeks of the study. With the highest dose of delavirdine, i.e. 1200 mg daily, the effect was prolonged but was no longer significant at the end of the study. The transient antiviral effect of the drug is consistent with the emergence of a delavirdine-resistant virus population within

Acknowledgements

We thank all study-participants for their cooperation during the course of this trial. Further, we greatly acknowledge the help of the study-nurses in the different centres and Dr Michael Rawlinson from NCHECR, Australia.

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