Nonnucleoside reverse transcriptase inhibitor
| Clinical Use|
Data supporting the effectiveness of combination therapies including delavirdine are limited. Because resistance mutations emerge rapidly when delavirdine is used as monotherapy, fully suppressive combinations should be used.
| Use in Initial vs Subsequent Therapy|
Treatment guidelines of the U.S. Department of Health and Human Services state that delavirdine is "not recommended" as a component of antiretroviral regimens for initial treatment of HIV infection, because of inferior efficacy.
Data supporting the effectiveness of delavirdine in combination regimens are limited, both for initial therapy and subsequent therapy. In current clinical practice, agents of demonstrated potency are preferred, and delavirdine is rarely used.
In initial therapy, delavirdine in combination with didanosine + zidovudine did not appear to be more effective than the two nucleoside analogues alone.(1) In NNRTI-naive subjects with virologic failure on dual-nucleoside analogue regimens containing lamivudine, switching to delavirdine + indinavir + a new nucleoside analogue provided superior viral load suppression compared with indinavir + a new nucleoside analogue + lamivudine.(2) A study of indinavir-experienced, NNRTI-naive subjects found a short-term benefit (in terms of viral suppression) associated with the addition of delavirdine to a new regimen containing 2 protease inhibitors and adefovir.(3) In a subset of patients followed for 48 weeks, this benefit was not found to persist.
| Potential Adverse Effects|
The most common symptomatic side effect of delavirdine is rash, usually occurring within 1 to 3 weeks of initiation of treatment. Rash is seldom serious, and usually resolves without interruption of delavirdine.
| Interactions with Other Drugs|
Delavirdine inhibits metabolism by cytochrome P450 3A (CYP3A) and possibly other hepatic enzyme systems, affecting the levels of many coadministered drugs, including antiretrovirals. Because of this effect, coadministration with delavirdine may allow indinavir or saquinavir to be dosed twice daily (instead of the usual 3 times a day; see Special Uses). Drugs that induce CYP3A, such as rifampin and rifabutin, significantly decrease levels of delavirdine. Information on drug interactions should be consulted, as dosage adjustments are frequently required.
Because virus resistant to all available NNRTIs is rapidly selected during failure of an NNRTI-containing regimen, it is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with delavirdine is initiated.
Resistance to delavirdine is associated with the selection of 1 or more of several resistance mutations.
| Implications of delavirdine resistance for treatment with other antiretrovirals|
Resistance mutations selected by delavirdine are usually associated with resistance to nevirapine and efavirenz, and may confer resistance to rilpivirine and etravirine.
Delavirdine may select a mutation (P236L) associated with increased sensitivity to nevirapine. The clinical consequences of this phenomenon are unknown.
| Implications of resistance to other antiretrovirals for delavirdine treatment|
Resistance to efavirenz or to nevirapine is frequently associated with resistance to delavirdine; resistance to rilpivirine and etravirine may decrease efficacy of delavirdine.
| Special Uses|
As noted above, delavirdine may be used in combination with indinavir (4,5) or saquinavir (6) to prolong the elimination half-life of these protease inhibitors. This combination may allow twice-daily (instead of 3-times-daily) dosing of the protease inhibitor. When studied for this purpose, delavirdine was also given twice a day instead of the usual 3 times a day. It is not clear whether this dosing of delavirdine results in the selection of NNRTI resistance, particularly in the setting of incomplete virologic suppression, but this possibility should be considered, especially in patients without preexisting NNRTI resistance for whom the option of strong NNRTI-containing regimens should be preserved. The use of delavirdine as a pharmacokinetic enhancer of protease inhibitors is not recommended.
|| || Friedland GH, Pollard R, Griffith B, et al. Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team. J Acquir Immune Defic Syndr 1999;21:281-92.|
|| || Kuritzkes DR, Bassett RL, Johnson VA, et al. Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370. AIDS. 2000 Jul 28;14(11):1553-61.|
|| || Gulick RM, Hu XJ, Fiscus SA, et al. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. J Infect Dis 2000;182:1375-84.|
|| ||Tran JQ, Petersen C, Garrett MK, et al. The pharmacokinetics (PK) and tolerability of indinavir (IDV) and delavirdine (DLV) administered twice-daily (BID) in the absence and presence of food in healthy volunteers. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 1634.|
|| ||Blanco JL, Mallolas J, Sarasa M, et al. A pilot study of a twice-daily (BID) combination of indinavir/delavirdine plus two nucleoside analogues for salvage therapy in HIV-1 infected patients. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 1543.|
|| ||Cox S, Bonway B, Freimuth W, et al. Pilot Study of BID and TID combinations of saquinavir-SGC, delavirdine, zidovudine, and lamivudine as initial therapy: pharmacokinetic interaction between S-SGC and D. In: Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco. Abstract 82.|