Conference Highlights on Non-Nucleoside Reverse Transcriptase Inhibitors

Sharon Anderson

This article presents selected reports from the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held in Toronto, Ontario, September 28 - October 1, 1997.

Delavirdine

Delavirdine Blood Levels Highly Variable, Monitoring Recommended

• Study was ACTG 260
• Researchers measured blood levels of delavirdine (Rescriptor) and its primary metabolite (N-DLV)
• Based on blood level results, patientŐs delavirdine dose was adjusted to a specific target concentration
• Results were used to model delavirdine pharmacokinetics
• Delavirdine blood levels were highly variable
• Researchers looked at the influence of gender, age, race, weight, and liver enzymes on pharmacokinetic parameters
• No patient characteristics predicted of any of the [pharmacokinetic] parameters studied
• Researchers recommended that delavirdine doses be individualized based upon patientŐs blood levels.

Delavirdine Pharmacokinetics Unaffected by Ritonavir

• Study done in 10 HIV positive subjects receiving background ritonavir therapy
• Levels of delavirdine and its primary metabolite were unaltered by ritonavir therapy
• Blood levels were compared with historical controls
• Delavirdine alone was not studied due to ethical concerns.

Triple Therapy with Delavirdine/AZT/3TC Superior to AZT/3TC or AZT/Delavirdine

• Protocol 0021 Part II
• Participants had not take antiretroviral drugs (85%) or had less than six months of AZT monotherapy (15%)
• Interim analysis was conducted following 32 weeks of therapy
• The study of 412 volunteers included a significant percentage of women (13%) and persons of color (about 40%)
• Mean baseline viral load was 4.406 logs, which decreased by 2.0 logs in triple therapy group, 1.3 logs in the AZT/3TC group and 0.5 logs in the AZT/delavirdine group
• Undetectable viral load (detection limit 40 copies per mL) in 50.0% in triple therapy group, by 10.2% in AZT/3TC group and none in AZT/delavirdine group
• Undetectable viral load (detection limit 400 copies per mL) in 62.5% in triple therapy group, by 30.6 percent in AZT/3TC group and 4.5% in AZT/delavirdine group
• Based on viral load, the triple therapy group was statistically superior to both dual therapy groups for weeks 8 through 32
• Mean baseline CD4 cell count was 360 cells/mm³, increasing by 95.9 cells/mm³ in triple therapy group, by 73.0 cells/mm³ in AZT/3TC group and by 19.3 cells/mm³ in AZT/delavirdine group
• CD4 cell count differences were not statistically significant.

Nevirapine

Use of Nevirapine with Nucleoside Analogs Shows Benefit in Persons with Advanced HIV-Infection

• ISS 047
• 71 naive participants had never taken antiretroviral drugs (61 male, 10 female)
• 30 participants had clinical AIDS at study entry
• Participants received either dual (AZT/ddI) or triple therapy (AZT/ddI/nevirapine)
• Patients in the triple therapy group, had a baseline viral load of 5.7 logs, which decreased by 2 logs after 48 weeks of therapy
• Participants in the dual therapy group had a baseline viral load of 5.5 logs, which decreased by 0.8 logs at 48 weeks
• At 48 weeks, 42% of participants on triple therapy had an undetectable (detection limit 400 copies/mL) viral load, compared with 21% of participants on dual therapy
• Patients on triple therapy had a mean baseline CD4 cell count of 65 cells/mm³ as compared with 88 in the dual therapy group
• After 48 weeks, CD4 cell counts increased by 130 cells/mm³ among the triple therapy group and by 40 cells/mm³ among those on dual therapy
• Rash was seen in 5 participants receiving triple therapy and 1 patient receiving AZT plus ddI.

Early Use of Nevirapine with Nucleoside Analogs Can Result in Prolonged Viral Suppression

• 5 Canadian participants enrolled in the INCAS study
• None had ever taken antiretroviral drugs
• Participants had a median baseline viral load of 7, 257 copies per mL and a median CD4 cell count of 415 cells/mm³
• All participants were below test detection limit (20 copies per mL) for 22-29 months
• Following one year in study, 4 participants replaced their ddI with 3TC.

Magnitude of Nadir Predicts Duration of Suppression with Nevirapine-Containing Regimens

• Study to determine ratio between viral load nadir (lowest point) and length of suppression
• Researchers looked at 150 participants given AZT/nevirapine, AZT/ddI or AZT/nevirapine/ddI
• Magnitude of nadir predicted duration of suppression and difference between AZT/nevirapine and AZT/ddI/nevirapine regimens
• No difference in length of suppression seen between AZT/ddI and AZT/ddI/nevirapine regimens
• Baseline CD4 cell count and change in CD4 cell count unrelated to length of viral load suppression.

Efavirenz

No Interaction between Fluconazole and Efavirenz

• Study enrolled 20 healthy males
• 10 participants were given fluconazole (Diflucan) 400 mg per day for one day, then fluconazole 200 mg for six days, then fluconazole 200 mg per day in combination with efavirenz (Sustiva) 400 mg per day for 7 days
• A 15% increase in efavirenz plasma concentrations (AUC) was observed. This is not believed to be clinically significant
• 10 participants were given efavirenz 400 mg per day for 7 days, then efavirenz 400 mg with fluconazole 400 mg for one day then efavirenz 400 mg and fluconazole 200 mg for 6 days
• No effect on fluconazole levels was observed.

Efavirenz Has Poor CNS Penetration

• Researchers analyzed CSF levels in 3 HIV positive participants receiving efavirenz (200 mg per day) in combination with indinavir
• Efavirenz plasma/CSF ratio was 0.96%
• Efavirnez concentrations in the CSF exceed the IC90 (an amount of drug that inhibits the growth of 90% of virus) for most wild-type and some NNRTI-resistant strains of HIV
• Efavirenz concentrations in the CSF were approximately equal to the IC90 for the most resistant strain, K103N.

Efavirenz Resistance

• Efavirenz is highly bound to plasma proteins
• Patients receiving efavirenz 200 mg daily will have free drug concentrations greater than that needed to inhibit wild-type and many resistant strains
• Some participants receiving efavirenz 600 mg daily will have free drug concentrations adequate to inhibit L100I and K103N strains
• Viral strains with multiple resistance mutations are unlikely to respond to efavirenz
• 6 of 17 participants who received prolonged indinavir monotherapy had a significant rebound in viral load
• The K103 N mutation was seen in 96% of participants who failed efavirenz
• Use of efavirenz as monotherapy will lead to the rapid development of resistance and is not recommended.

Efavirenz Increases Nelfinavir Blood Levels

• Study included 18 healthy male volunteers
• Eight participants received nelfinavir for seven days, followed by nelfinavir/efavirenz for 7 days
• No change in efavirenz pharmacokinetics was observed
• Ten subjects received efavirenz for 7 days, followed by nelfinavir/efavirenz for 7 days
• These results are unexpected as efavirenz is an inducer of CYP3A (an enzyme that metabolizes many drugs in the liver) and suggest that efavirenz may inhibit an enzyme needed for nelfinavir metabolism.

Other NNRTI

Loviride plus 3TC

• Addition of loviride to 3TC does not increase quality of life or decrease healthcare costs compared with the use of 3TC alone
• All participants were receiving AZT, AZT/ddI or AZT/ddC
• Patients were randomly assigned to receive placebo, 3TC or 3TC/loviride in addition to background therapy
• Quality-of-life measures were higher among participants receiving 3TC or 3TC/loviride than those receiving placebo
• Compared to placebo, participants receiving 3TC or 3TC/loviride had a significantly decreased incidence of hospitalization (p=0.002), unscheduled outpatient visits (p=0.013) or prescribed medications for HIV-related events (p<0.001)
• There were 47% hospitalizations and hospital stays were 51% shorter in the 3TC containing groups than the placebo groups
• There were no differences between participants receiving 3TC/loviride and those receiving 3TC alone.