Delavirdine - A review of its use in HIV infection

Delavirdine, a bisheteroarylpiperazine derivative, is a non-nucleoside reve rse transcriptase inhibitor (NNRTI) that allosterically binds to HIV-I reve rse transcriptase. inhibiting both the RNA- and DNA-directed DNA polymerase functions of the enzyme. Delavirdine in combination with nucleoside reverse transcriptase inhibitors (NRTIs) produced sustained reductions in plasma viral loads and improvemen ts in immunological responses in Large randomised, double-blind, placebo-co ntrolled studies of 48 to 54 weeks' duration. In patients with advanced HIV infection, triple therapy with delavirdine, zidovudine and lamivudine, did anosine or zalcitabine for 1 year significantly prolonged the lime to virol ogical failure compared with dual therapy (delavirdine plus zidovudine or 2 NRTIs; p < 0.0001). After 50 weeks' treatment, plasma HIV RNA levels were below the limit of detection (LOD; <50 copies/ml) for 40% of patients recei ving triple therapy but for only 6% of those receiving dual NRTI therapy. Preliminary results suggest that delavirdine also has beneficial effects on surrogate markers as a component of protease inhibitor-containing triple o r quad ruple regimens. At 16 to Sg weeks, the minimum mean reduction in pla sma viral load from baseline was 2.5 log(10) copies/ml and mean CD4+ counts increased by 100 to 313 cells/mul. The proportion of patients with plasma HIV RNA levels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after greater than or equal to 16 weeks. Delavirdine was also effec tive as a component of saquinavir soft gel capsule-containing salvage regim ens. Since delavirdine shares a common metabolic pathway (cytochrome P450 3A pat hway) with other NNRTIs, HIV pretense inhibitors and several drugs used to treat opportunistic infections in patients infected with HIV, the drug is a ssociated with a number of pharmacokinetic interactions. Some of these drug interactions are clinically significant, necessitating dosage adjustments or avoidance of coadministration, Delavirdine is not recommended for use wi th lovastatin, simvastatin, rifabutin, rifampicin, sildenafil, ergot deriva tives, quinidine, midazolam, carbamazepine, phenobarbital or phenytoin. Imp ortantly, the drug favourably increases the plasma concentration of several protease inhibitors. Delavirdine is generally well tolerated, Skin rash is the most frequently r eported adverse effect, occurring in Is to 50% of patients receiving delavi rdine-containing combination therapy in clinical trials. Although a high pr oportion of patients developed a rash, it was typically mild to moderate in intensity, did not result in discontinuation or adjustment of treatment in most patients and resolved quickly. The occurrence of Stevens-Johnson synd rome was rare (1 case in 1000 patients). A retrospective analysis of pooled clinical trial data indicated that there was no significant difference in the incidence of liver toxicity, liver failure or noninfectious hepatitis b etween delavirdine-containing and non-delavirdine-containing antiretroviral treatment groups. In addition, the incidence of lipodystrophy, metabolic l ipid disorders, hyperglycaemia and hypertriglyceridaemia was not significan tly different between these 2 treatment groups. Conclusions: In combination with NRTIs, delavirdine produces sustained impr ovements in surrogate markers of HN disease and prolongs the time to virolo gical failure in adult patients with HIV infection. Preliminary data of del avirdine as a component of protease inhibitor-containing triple or quadrupl e highly active antiretroviral therapy regimens indicate that patients achi eve marked improvements in virological and immunological markers. The drug is generally well tolerated, with a transient skin rash, typically of mild to moderate intensity being the most common adverse effect. Delavirdine is an effective component of recommended antiretroviral treatment strategies f or adult patients with HIV infection and, in combination with 2 NRTIs as a first-line therapy, the drug has the advantage of sparing protease inhibito rs for subsequent use. Since delavirdine favourably increases plasma concen trations of several protease inhibitors, the drug may also be beneficial as a component of salvage therapy in combination with protease inhibitors.