Paul Stoffels

Virological and immunological analysis of a triple combination pilot study with loviride, lamivudine and zidovudine in HIV-1-infected patients

Objective:To compare two antiretroviral regimens, loviride plus lamivudine (3TC) plus zidovudine (ZDV) (triple combination) and loviride plus ZDV (double combination) in terms of pharmacokinetic interactions, tolerability, safety, and immunological and virological efficacy. Study design:An open, case-controlled, pharmacokinetic and 24-week continuous treatment pilot study. Patients:Twenty p24 antigen-positive patients, 10 per treatment group, were matched according to p24 antigenaemia less or more than l00 pg, CD4 count less or more than 150×106/l, and gender. Eight out of 10 cases and seven out of 10 controls had received previous antiretroviral therapy. Results:No clinically relevant pharmacokinetic interactions were observed. Both treatment combinations were well tolerated. Median absolute and percentage CD4 count increases above baseline were more pronounced in the triple combination arm than in the double combination arm. Median p24-antigen and plasma viraemia level decreases below baseline were more pronounced in the triple combination arm. The M184I/V mutation was detected in all plasma samples of triple combination patients examined at week 12. Mutations conferring resistance to loviride and ZDV were found in a significant subset of patients in both treatment arms. Conclusions:Both combination regimens have an excellent safety/tolerability profile, but a higher level of in vivo efficacy is achieved by the triple combination, despite genotypic changes conferring resistance to one or all of these agents. The conclusions drawn are limited by small population size and the heterogenous pretreatment history. However, they support the validity of and strongly encourage a rationally designed multidrug combination approach to HIV therapy.

Itraconazole pulse therapy for onychomycosis and dermatomycoses: An overview

BACKGROUND Itraconazole is a broad-spectrum antifungal agent that has been used to treat dermatomycosis and onychomycosis using continuous therapy. More recently the drug has been used as pulse dosing. OBJECTIVE Our purpose was to review the studies in which itraconazole pulse therapy (PT) has been administered in the management of dermatomycoses. RESULTS For tinea pedis and manuum, the recommended dosage is itraconazole 200 mg twice daily for 1 week (n = 220). A clinical response and mycologic cure rate of 90% +/- 4% and 76% +/- 6%, respectively, has been obtained. For tinea corporis/cruris, itraconazole 200 mg/day for 1 week (n = 354) resulted in a clinical response and mycologic cure rate of 90% +/- 4% and 77% +/- 6%, respectively. When three pulses of itraconazole are used to treat toenail onychomycosis (n = 1389), the clinical cure rate, clinical response, and mycologic cure rate at follow-up 12 months after the start of therapy were 58% +/- 10%, 82% +/- 3%, and 77% +/- 5%, respectively. With two pulses for onychomycosis of the fingernails, the clinical cure rate, clinical response, and mycologic cure rate at follow-up, 9 months after the start of therapy, were 78% +/- 10%, 89% +/- 6%, and 87% +/- 8%, respectively. CONCLUSION Itraconazole PT is effective and safe in the treatment of tinea pedis/manuum, tinea corporis/cruris, and onychomycosis.

Discovery, Development and Characterization of Agents Active Against the Aids Virus

Despite major efforts by academic and pharmaceutical research teams, no definitive prevention or cure of AIDS has been achieved. Nevertheless, this research has yielded important information on how HIV replicates and causes disease. Moreover, several inhibitors, targeted at different steps in the life cycle of HIV, have been discovered, some of which have been licensed or are being studied in the clinic. One of the major obstacles towards more effective drugs or a vaccine, is the extraordinary variability in HIV strains which occur in different parts of the world over time, and in patients. The driving force behind these numerous variants is the combination of an error-prone reverse transcriptase, a viral enzyme transcribing the viral RNA genome into DNA on the one hand and the human immune system on the other hand. This puts a constant selection pressure on the HIV population leading to the emergence of escape mutants. It therefore poses an additional challenge on the discovery and development of HIV inhibitors. A research strategy should therefore encompass the following steps: (i) the identification of new lead compounds targeted at known or unknown steps in the HIV replicative cycle, (ii) the characterization and validation of their molecular targets with emphasis on the potential for lead optimization and the likelihood of resistance development, (iii) the study of combination strategies, and (iv) clinical evaluation and validation of the aforementioned concepts.