Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

Pfizer

Delavirdine was approved by the FDA in 1997 for use in combination with other antiretrovirals in adults with HIV infection. Approval was based on studies showing that the combination of delavirdine with a single nucleoside analogue (zidovudine or didanosine) resulted in slightly greater decreases in plasma HIV viral load than did monotherapy with the nucleoside analogue alone. A trial comparing the 2-drug combination of zidovudine + didanosine with the 3-drug combination of zidovudine + didanosine + delavirdine showed no consistent, statistically significant difference in CD4 T-lymphocyte counts or viral load between the 2-drug and 3-drug treatment arms.(1) These studies did not demonstrate any clinical benefit of delavirdine.

Delavirdine is available in tablet formulation.

Dosing of Delavirdine Adult 400 mg TID Pediatric Birth-16 years Not FDA approved Adolescent, age >=16 years Adult dose

Key to abbreviations: TID, 3 times daily.

		There are no food restrictions.

		Delavirdine interacts with the antiretroviral medications indinavir and saquinavir; see Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for the delavirdine/indinavir interaction and delavirdine/saquinavir interaction.

		No dosage adjustment is necessary in renal insufficiency.

		Please consult product labeling for detailed dosing information.

		FDA Pregnancy Category C.

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.

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 dose adjustments are frequently required.

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 on the effectiveness of delavirdine in subsequent regimens are limited. Subsequent regimens using NNRTIs appear most effective in individuals who have not previously experienced virologic failure while using drugs of this class. In this situation, however, NNRTI-containing regimens of demonstrated potency would be preferred.

A study of NNRTI-naive subjects with virologic failure on dual-nucleoside analogue regimens containing lamivudine found that, when switching the other nucleoside analogue and adding indinavir, substituting delavirdine for lamivudine provided superior viral load suppression than continuing 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.

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.

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. The commonly selected delavirdine resistance mutations frequently confer resistance to nevirapine and efavirenz as well.

Implications of delavirdine resistance for treatment with other antiretrovirals

Resistance mutations selected by delavirdine are usually associated with resistance to nevirapine and efavirenz. 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.

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, 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.