Antiretrovirals in Clinical Development

Date of Report: 11/06/2002
Author:  Laurence Peiperl, MD, Medical Director, AETC NRC
Source: National Resource Center
Description: Coverage of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

Atazanavir

Atazanavir (ATV) QD and Efavirenz (EFV) QD with Fixed-Dose ZDV+3TC: Comparison of Antiviral Efficacy and Safety (AI424-034)

Results of follow-up through week 48 were presented from protocol BMS-034, a randomized, double-blind, Phase III study of the azapeptide protease inhibitor atazanavir (ATV, BMS-232632). Treatment-naive subjects (n = 910) with CD4 count >100 cells/mm³ and HIV viral load >2,000 RNA copies/mL were randomized to receive ATV (400 mg once per day) or the nonnucleoside reverse transcriptase inhibitor efavirenz (EFV), (600 mg once per day), each with zidovudine-lamivudine fixed-dose combination (Combivir), (1 tablet two times per day).

Thirty-six percent of subjects were women, and 67% of subjects were non-white. Mean baseline CD4 count was approximately 320 cells/mm³ and mean viral load 4.8 log copies/mL in both arms.

The following table summarizes viral load suppression results of the intent-to-treat analysis:

The relatively low rate of viral load suppression (compared with other trials of combination antiretroviral therapy) may reflect the fact that in the intent-to-treat analysis, discontinuation, substitution, or dose-reduction of any drug in the regimen for any reason was counted as treatment failure. However, the on-treatment analysis also showed lower rates than seen in previous studies of EFV + zidovudine/lamivudine, suggesting possible adherence issues in the study:

Viral load suppression (on-treatment analysis):

There was no statistically significant difference in viral load suppression between arms in either analysis. Mean CD4 count increase was 171 cells/mm³ in the ATV arm and 161 cells/mm³ in the EFV arm, a statistically significant but probably not clinically relevant difference.

Rebound of viral load to >400 copies/mL at week 24 or thereafter occurred in 17% of participants in each arm. The protease I50L mutation associated with ATV resistance was uncommon, but the reverse transcriptase mutation M184V was seen in approximately half of patients with viral rebound in each arm, and K103N was present in the majority (13/25) of rebounds in the EFV arm, again suggesting suboptimal adherence.

Both arms were well tolerated, with rash and CNS symptoms more common with EFV and jaundice more common with ATV. Moderate to high elevations in bilirubin occurred in 33% of patients on ATV (versus <1% on EFV) , but rarely required dose-reduction or drug discontinuation. In contrast to other protease inhibitors, ATV was not associated with increases in total cholesterol, LDL, or fasting triglycerides compared with baseline values, and also showed no difference or else slight improvements in these values compared with EFV, which was in turn associated with slight increases in HDL compared with ATV.

ATV shows potential as an effective, convenient (2 capsules once daily), and well tolerated protease inhibitor and appears less likely than several licensed protease inhibitors to cause lipid abnormalities.

A related poster presentation by Colonno, et al found that in vitro resistance to atazanavir was usually associated with mutations at 5 or more of 7 key amino acids of the protease (positions 10, 20, 46, 54, 73, 82, and 90), suggesting a relatively high barrier to the development of resistance.

Squires KE, Thiry A, and Giordano M. Atazanavir (ATV) QD and Efavirenz (EFV) QD with Fixed-Dose ZDV+3TC: Comparison of Antiviral Efficacy and Safety Through Wk 24 (AI424-034). 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27 - 30, 2002, San Diego, California, Abstract H-1076.

Colonno RJ, Thiry A, and Parkin NT. Amino Acid Substitutions that Correlate with Decreased Susceptibility to Atazanavir and Other HIV-1 Protease Inhibitors. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27 - 30, 2002, San Diego, California, Abstract H-2049.

Emtricitabine (FTC)

A Randomized, Double-blind, Multicenter Comparison of Emtricitabine QD to Stavudine BID

This randomized, double-blind, placebo-controlled study in 571 antiretroviral-naive patients compared the nucleoside analogue emtricitabine (FTC) (200 mg once per day) to stavudine (d4T), (standard two times per day dosing), each in combination with didanosine and efavirenz. Median log viral load was 4.9 at baseline, corresponding to almost 100,000 RNA copies/mL. The study, planned to follow participants through 48 weeks of treatment, was stopped by the data safety monitoring board because of a significant difference in virologic outcome after the last patient had reached 24 weeks, at which time 87% of subjects randomized to FTC, compared to 79% on d4T, had HIV viral load <400 RNA copies/mL plasma. Viral load <50 RNA copies/mL was reported in 81% of subjects randomized to FTC, compared to 70% in the d4T group. At week 52, the mean increase in CD4-cell count was also greater in the FTC group (152 cells/mm³ versus 117 cells/mm³; p = .004). However, the discontinuation rate for adverse events was significantly higher in the d4T arm than in the FTC arm (13.9% vs 6.7%; p = .03), suggesting that differences in outcome may reflect the additive side effects of d4T and didanosine taken in combination, rather than an increased potency of FTC. Overall, safety outcomes did not differ significantly between the two groups, although more gastrointestinal symptoms were seen with d4T and more cough with FTC. Hyperlactatemia occurred in 2% of the d4T group and in none of the FTC group.

A new drug application for FTC (brand name Coviracil) has been filed with the FDA. While it is not clear that FTC will offer any advantage over lamivudine (3TC), which has similar tolerability and resistance profile, the rate of viral load suppression observed in this trial for the combination of FTC + didanosine + efavirenz compares favorably with rates observed in other trials of initial therapy.

Saag M, Cahn P, Raffi F, Wolff M, Pearce D, Molina JM, Hinkle J, Shaw A, Quinn JB, and Rousseau F. A Randomized, Double-blind, Multicenter Comparison of Emtricitabine QD to Stavudine BID. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27 - 30, 2002, San Diego, California, Abstract LB-1.

Entry Inhibitors

Enfuvirtide (T-20) in combination with an optimized background (OB) regimen vs. OB alone: Week 24 response among categories of treatment experience and baseline (BL) HIV antiretroviral (ARV) resistance

Initially reported at the XIV International AIDS Conference in July 2002, the Toro-1 study of the entry inhibitor enfuvirtide (T-20, a synthetic peptide administered by subcutaneous injection) found that adding T-20 (90 mg SC two times per day) to an optimized background regimen in 326 treatment-experienced patients resulted in a decrease in viral load of 1.7 log after 24 weeks, compared to a decrease of only 0.76 log in 165 patients randomized to switch to optimized background treatment alone (p < .0001). New data reported at ICAAC from 74 patients showed that this advantage of adding enfuvirtide was most dramatic (resulting in approximately 1 log decrease in viral load) when the number of drugs to which the virus showed genotypic susceptibility was low (ie, when enfuvirtide was the only drug in the background regimen, or one of only a few drugs, to which resistance was not detected by genotype testing.) However, the effect of enfuvirtide in lowering the viral load persisted even in regimens containing 3 or 4 drugs to which no viral resistance was predicted by genotype testing. In a multivariate analysis, factors showing a statistically significant association with improved viral load response included addition of enfuvirtide, high baseline CD4 count, high genotypic (or phenotypic) susceptibility score, presence of lopinavir/ritonavir in the background combination, and better adherence. Experience with lopinavir/ritonavir prior to the current background regimen was associated with poorer viral load response.

Enfuvirtide is likely to prove useful as a component of salvage therapy in highly treatment-experienced patients.

Lalezari JP, Henry K, O'Hearn M, Lefebvre E, Monaner J, Piliero P, Walmsley S, Chung J, Fang L, Delehanty J, Salgo M, and the TORO 1 Study Group. Enfuvirtide (T-20) in Combination with an Optimized Background (OB) Regimen vs. OB alone: Week 24 Response Among Categories of Treatment Experience and Baseline (BL) HIV Antiretroviral (ARV) Resistance. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27 - 30, 2002, San Diego, California, Abstract H-1074.

Henry K, Lalezari J, O'Hearn M, Trottier B, Montaner J, Piliero P, Walmsley S, Chung J, and Fang L. Enfuvirtide (T-20) in combination with an optimized background (OB) regimen vs. OB alone in patients with prior experience or resistance to each of the three classes of approved antiretrovirals (ARVs) in North America and Brazil. 14th International AIDS Conference, Barcelona, Spain, July 7-12, 2002, Abstract LbOr19B.

Complete Analysis of T1249-101: Safety, Pharmacokinetics, and Antiviral Activity of T-1249, a Peptide Inhibitor of HIV Membrane Fusion

T-1249 is a 39-amino-acid peptide entry inhibitor that binds to a different segment of the gp41 envelope subunit than does enfuvirtide (T-20). In vitro, T-1249 retains activity against T-20-resistant HIV isolates. This dose-escalation study enrolled 10 dosing cohorts of 12 highly treatment-experienced participants each. Entry requirements included viral load between 5,000 and 500,000 RNA copies/mL, no prior treatment with an entry inhibitor, and no antiretroviral therapy within 2 weeks of screening. Participants received open-label T-1249 monotherapy (ranging from 6.5 mg to 200 mg per day) by subcutaneous injection for 14 days. Median CD4 count of participants was 57 cells/mm³.

Local injection site reactions, including subcutaneous nodules, occurred in 57% of participants, but no patients discontinued treatment for injection site reactions, which were more frequent at doses above 50 mg. Headache, fevers, and gastrointestinal side effects were also reported, but only two patients discontinued treatment early (one for a hypersensitivity/allergic reaction, and one for missed study visits). One case of neutropenia and one local reaction with fever also occurred. Over the 14-day study period, dose-dependent reductions in viral load were observed at T-1249 doses of 12.5 mg two times per day and higher, and ranged from 0.5 log to 2 log decreases, depending on dose. Over the 14-day study period, CD4 increases were observed at T-1249 doses above 25 mg once per day. Pharmacokinetic data supported once-daily dosing. Compared with viral load reductions of approximately 1.6 log seen with T-20 doses of 90 mg two times per day, the effect of T-1249 appears potent and merits further study for use in antiretroviral-experienced patients.

Gulick R, Eron J, Bartlett JA, Merigan T, Yangco B, Kilby J, Rusnak P, Hui J, Demasi R, Diers A, Spence B, Duff F, and Miralles G. Complete Analysis of T1249-101: Safety, Pharmacokinetics, and Antiviral Activity of T-1249, a Peptide Inhibitor of HIV Membrane Fusion. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27 - 30, 2002, San Diego, California, Abstract H-1075.