43rd ICAAC: Abacavir in Initial Therapy

Date of Report: 10/08/2003
Author:  Susa Coffey, MD
Source: AETC National Resource Center

The choice of two nucleoside or nucleotide analogues for use in combination antiretroviral regimens is based on several factors, including potency, tolerability, dosing convenience, and barrier to resistance.

Several studies presented at ICAAC may elucidate the role of abacavir in the nucleoside backbone of initial combination antiretroviral therapy and in once-daily treatment regimens.

Abacavir versus Zidovudine

Background

There is interest in defining the efficacy of abacavir as a component of initial therapy, and in establishing the potency of dual-nucleoside backbones that do not contain thymidine analogues (zidovudine or stavudine). This study compared the combination of abacavir + lamivudine + efavirenz to the well-established regimen zidovudine + lamivudine + efavirenz in treatment-naive individuals.

Efficacy and Safety of Abacavir (ABC) versus Zidovudine (ZDV) in Antiretroviral Therapy Naive Adults with HIV-1 Infection (Study CNA30024). Dejesus E, Herrera G, Teofilo E, Castillo S, Bonny T, Thorpe D, Hernandez J, Scott T. 43rd ICAAC, Chicago, September 2003. Abstract H-446.

Description

In this double-blind, placebo-controlled study, 654 patients with no prior antiretroviral experience were randomized to treatment with abacavir + lamivudine + efavirenz or zidovudine + lamivudine + efavirenz. The two groups were well matched for baseline demographic characteristics and stage of disease, with a median HIV viral load of approximately 4.8 log₁₀ copies/mL and median CD4 count of 258-267 cells/mm³. The primary endpoint was virologic response at 48 weeks, while secondary endpoints were immunologic, safety, and tolerability outcomes. The study was powered to demonstrate non-inferiority of the abacavir-containing regimen.

Results

At 48 weeks, by intent-to-treat (ITT) analysis, viral suppression to <50 copies/mL was seen at similar rates in the two treatment groups: 70% in the abacavir arm versus 69% in the zidovudine arm (95% confidence interval (CI) for the difference = -6.3%, 7.9%). On-treatment analysis also showed nearly identical rates of viral supression in the two groups. Response rates were statistically similar between treatment groups for patients with baseline HIV viral loads greater than 100,000 copies/mL and for those with baseline viral loads less than 100,000 copies/mL. CD4 increase was significantly greater in the abacavir arm than in the zidovudine arm (209 cells/mm³ versus 155 cells/mm³, p = .0039). Adverse effects of nausea, vomiting, fatigue, and treatment-limiting anemia were seen at significantly higher rates in the zidovudine treatment group, while cough was seen more frequently in the abacavir group. Hypersensitivity reactions were seen in 8% of abacavir recipients, a higher rate than reported in earlier studies. Overall, rates of discontinuation for adverse events or other reasons were similar in the two treatment groups.

Conclusion

This study suggests that the nucleoside backbone of abacavir + lamivudine is potent when used in combination with efavirenz, and that, over 48 weeks of treatment, abacavir + lamivudine + efavirenz is not inferior to the standard-of-care regimen zidovudine + lamivudine + efavirenz as initial therapy.

Once-Daily Abacavir

Background

The relative convenience of once-daily antiviral regimens is likely to facilitate adherence. Several studies examined once-daily antiretroviral regimens.

Abacavir (ABC) Once Daily (OAD) Plus Lamivudine (3TC) OAD in Combination with Efavirenz (EFV) OAD is Well-Tolerated and Effective in the Treatment of Antiretroviral Therapy (ART) Naive Adults with HIV-1 Infection (ZODIAC Study: CNA30021). Gazzard B, DeJesus E, Cahn P, Castillo S, Zhao H, Gordon D, Spreen W, Scott T. 43rd ICAAC, Chicago, September 2003. Abstract H-1722b.

Description

This randomized, double-blind, placebo-controlled study in treatment-naive patients compared once daily (QD) abacavir to standard twice-daily (BID) abacavir, each in combination with once-daily lamivudine + efavirenz. The treatment groups (approximately 385 patients each) had similar baseline characteristics, and median HIV viral load of 4.9 log ₁₀ copies/mL (43% with viral load > 100,000 copies/mL) and mean CD4 count approximately 260 cells/mm³. The trial was a non-inferiority study with the primary endpoint of virologic response at 48 weeks.

Results

In the ITT analysis, statistically similar rates of virologic response were seen at 48 weeks: 66% and 68% of patients in the abacavir once daily and twice daily arms, respectively, achieved HIV viral loads of <50 copies/mL (95% CI for the difference = -8%, 5%). Virologic response was similar between treatment groups in subjects with baseline HIV viral loads >100,000 copies/mL and those with lower viral loads. In the as-treated analysis, 87% of the QD abacavir group and 86% of the BID abacavir group had viral loads <50 copies/mL at 48 weeks. Causes of treatment failure (virologic failure, discontinuation due to adverse events or other causes) were similar between groups. CD4 increase also was similar in the treatment arms (188 cells/mm³ in the QD abacavir group, 200 cells/mm³ in the BID group). The rates of adverse effects were similar between treatment groups, and 7-9% of subjects were reported to have hypersensitivity reactions. In patients with virologic failure, resistance profiles were similar between the groups, with M184V/I, K103N, and L74V seen as the most common resistance mutations.

Conclusion

This study suggests that the once-daily combination of abacavir + lamivudine + efavirenz offers effective and durable viral control. It also provides clinical data demonstrating the efficacy of once-daily administration of abacavir. This dosing possibility is supported by a poster presentation on the pharmacokinetics of abacavir and its active metabolite.(¹)

Early Non-Response to Tenofovir DF (TDF) + Abacavir (ABC) and Lamivudine (3TC) in a Randomized Trial Compared to Efavirenz (EFV) + ABC and 3TC: ESS30009. Gallant JE, Rodriguez AE, Weinberg W, Young B, Berger D, Lim ML, Liao Q, Ross L, Johnson J, Shaefer MS. 43rd ICAAC, Chicago, September 2003. Abstract 1722a.

Description

This randomized controlled study compared two once-daily antiretroviral regimens in treatment-naive patients: abacavir (ABC) + lamivudine (3TC) + tenofovir (TDF) versus abacavir + lamivudine + efavirenz (EFV). Abacavir + lamivudine was given as a fixed-dose combination tablet. Subjects in each arm had comparable baseline median viral loads (approximately 4.6 log ₁₀ copies/mL) and median CD4 levels (approximately 260 cells/mm³). The primary endpoint was intended to be the proportion of patients with viral load less than 50 copies/mL at 48 weeks.

Results

An unplanned interim analysis of patients with at least 8 weeks on treatment (194 of 345 randomized patients) revealed a high rate of early virologic non-response in the ABC/3TC/TDF treatment group. Virologic non-response was defined as <2 log₁₀ decline in HIV RNA by week 8, or >= 1 log₁₀ rebound in viral load from nadir, or HIV viral load rebound to >400 copies/mL after suppression. By these criteria, 49% of the ABC/3TC/TDF recipients experienced virologic non-response, versus 5.4% of the ABC/3TC/EFV recipients. Consequently, the ABC/3TC/TDF study arm was terminated. Genotypes performed on 36 non-responders showed resistance mutations K65R + M184V in 23 patients and M184V without K65R in 13 patients.

Conclusion

This study reinforces findings of a pilot study presented at IAS in July, which also showed virologic non-response to abacavir + lamivudine + tenofovir.(²) The reason for the failure of this regimen is not yet understood and is the subject of ongoing investigation.

Discussion

The ZODIAC study suggests that the once-daily regimen of abacavir + lamivudine + efavirenz is effective, and that once-daily abacavir in this combination is not inferior to twice daily abacavir. The ESS30009 study, however, shows a high rate of early virologic failure on a once-daily regimen of abacavir + lamivudine + tenofovir and suggests that these antiretroviral agents cannot be combined successfully in a once-daily regimen. Any possible pharmacologic interaction between tenofovir and abacavir remains to be elucidated. The surprising result of ESS30009 points to the importance of clinical trials to guide our selection of antiretroviral combinations.

References

1.		Piliero P, Shachoy-Clark AD, Para M, Preston S, Lou Y, Drusano G, Stein DS, Yuen GJ. A study examining the pharmacokinetics of abacavir and the intracellular carbovir triphosphate (GSK protocol CNA10905) 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 2003. Abstract A-1797.
2.		Farthing C, Khanlou H, Yeh V. Early virologic failure in a pilot study evaluating the efficacy of abacavir, lamivudine and tenofovir in the treatment naive HIV-infected patients. 2nd IAS Conference on HIV Pathogenesis and Treatment, Paris, July 2003. Abstract 43.