Background

In the past year, several studies have examined the efficacy of triple nucleoside regimens, with universally disappointing results. The combination of abacavir + lamivudine + zidovudine was shown to provide suboptimal virologic suppression when compared with an efavirenz-based regimen, with a virologic failure (VF) rate of 21% at 32 weeks.(1) The combination of abacavir + lamivudine + tenofovir failed at rates of up to 52% in two studies,(2,3) and the combination of abacavir + didanosine + stavudine showed failure rates of 57% at 48 weeks.(4)

In these studies, VF was associated with the rapid emergence of resistance mutations. The K65R mutation, selected by abacavir, didanosine, and tenofovir and causing significant resistance to these and other nucleoside analogues, appears to be central to the failure of several triple-nucleoside regimens, particularly those that do not contain a thymidine analogue.

At CROI, three small noncomparative studies evaluated the efficacy of nucleoside-only regimens, including one four-nucleoside regimen.

Poor Virologic Responses and Early Emergence of Resistance in Treatment Naive, HIV-Infected Patients Receiving a Once-Daily Triple Nucleoside Regimen of Didanosine, Lamivudine, and Tenofovir DF

Abstract: Jemsek J, Hutcherson P, Harper E. Poor Virologic Responses and Early Emergence of Resistance in Treatment Naive, HIV-infected Patients Receiving a Once Daily Triple Nucleoside Regimen of Didanosine, Lamivudine, and Tenofovir DF 11th CROI, Abstract 51.

Description: This pilot study, the subject of an "Important Drug Warning" from the FDA last year, was presented for the first time. Twenty-two antiretroviral-naive patients were given didanosine + lamivudine + tenofovir (all dosed once daily). At baseline, their mean HIV RNA level was 4.91 log₁₀ copies/mL and mean CD4 cell count was 133 cells/mm³.

Results: At week 12, the rate of VF (defined as <2 log₁₀ reduction in HIV RNA) was 91%. On this basis, the study was terminated early. Resistance testing in 20 subjects showed the K65R plus the M184V mutations in 50% of subjects and the M184V mutation alone in 50%.

Low Genetic Barrier to Resistance Is a Possible Cause of Early Virologic Failures in Once-Daily Regimen of Abacavir, Lamivudine, and Tenofovir: The Tonus Study

Abstract: Landman R, Peytavin G, Descamps D, et al. Low Genetic Barrier to Resistance Is a Possible Cause of Early Virologic Failures in Once-Daily Regimen of Abacavir, Lamivudine, and Tenofovir: The Tonus Study 11th CROI, Abstract 52.

Description: In this pilot study, 38 antiretroviral-naive patients were treated with a once-daily combination of abacavir + lamivudine + tenofovir (the same combination studied in last year's ESS30009 study (2)). At baseline, the median HIV RNA level was 4.9 log₁₀ copies/mL and the CD4 count was 222 cells/mm³. The primary endpoint was VF, defined as failure to attain HIV viral load (VL) <400 copies/mL, or failure to rebound after decrease.

Results: An unplanned interim analysis showed VF in 12/36 patients (33%); at baseline all of these had HIV viral loads >4 log₁₀ copies/mL. Viral suppression to <50 copies HIV/mL was seen in 17/26 patients (65%) at 6 months; of those with baseline VL >4 log₁₀ copies/mL, 9/18 achieved viral suppression compared with 8/8 of those with lower pretreatment viral loads (p=0.03). Resistance testing of 11 subjects with VF showed the K65R and M184V mutations in 9 subjects, and M184V alone in 2 subjects. Pharmacokinetic testing performed at 1 month demonstrated adequate serum concentrations of all three of the study drugs in 32/37 patients and low concentrations of at least one drug in 5/37.

COL40263: Resistance and Efficacy of Once-Daily Trizivir and Tenofovir DF in Antiretroviral-Naive Subjects

Abstract: Elion R, Cohen C, DeJesus E, Redfield R, Gathe J, Hsu R, Yau L, Ross L, Ha B, Lanier R, Scott T, and COL40263 study team. COL40263: Resistance and Efficacy of Once-Daily Trizivir and Tenofovir DF in Antiretroviral-Naive Abstract 53. 11th CROI, Abstract 53.

Description: This study evaluated the efficacy and safety of a once-daily, four-nucleoside combination of abacavir + lamivudine + tenofovir + zidovudine in initial therapy. The selection of this combination was based in part on the observation that zidovudine appears to inhibit the emergence of the K65R mutation (involved in the failure of several triple-nucleoside regimens containing abacavir, didanosine, or tenofovir). Interim analysis was performed on 88 subjects with at least 8 weeks of follow-up; 54 subjects had data to 6 months. At baseline, the median VL was 5.1 log₁₀ copies/mL, and the median CD4 count was 226 copies/mm³.

Results: In as-observed analysis, 67% of subjects achieved HIV VL <50 copies/mL at 6 months (of those with baseline VL >100,000 copies/mL, 60% achieved <50 copies/mL). Resistance testing was performed on 8 subjects with VL >400. This showed that 3 subjects had >= 1 thymidine-associated mutation (TAM) plus the M184V mutation, 2 had >= 1 TAMs without M184V, 1 had the K65R mutation, and 2 had wild-type virus.

Discussion

The first two studies, of triple-nucleoside combinations without thymidine analogues, show very high rates of early VF with rapid emergence, in many cases, of the K65R and the M184V mutations. COL40263, in which once-daily zidovudine was added to the combination of abacavir + lamivudine + tenofovir, demonstrated a somewhat better response at 6 months, with TAMs, rather than the K65R mutation, predominating in resistance tests of those with VF.

Although it appears that zidovudine may modulate the development of resistance, it is not clear whether the COL40263 regimen was more effective than the triple-nucleoside regimens presented here because it contained zidovudine or because it contained four nucleoside analogues. The earlier ACTG 5095 trial, which studied abacavir + lamivudine + zidovudine (the COL40263 regimen minus tenofovir) appeared to have results similar to those of the four-nucleoside combination.(1) None of the nucleoside-only regimens reported to date achieve the rates of virologic suppression seen in regimens containing efavirenz or lopinavir/ritonavir.

Reasons for high rates of VF in nucleoside-only regimens still are not clear. Most evidence points toward low genetic barrier to resistance, as the K65R and M184V mutations emerge rapidly in several of these regimens (particularly those without zidovudine) and confer significant resistance to one or more of the agents in the regimens. These nucleoside combinations also may lack potency, especially in patients with high baseline viral loads. There is no evidence to date for adverse intracellular interactions of these nucleoside analogues, but these issues require further study.

Although there may be differences among particular nucleoside-only regimens (eg, zidovudine-containing regimens may be more effective than others), it now is abundantly clear that triple-nucleoside regimens are inferior to PI- and NNRTI-containing regimens and should be avoided if possible

References

1. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Meyer WA, Klingman K, Squires KE, Snyder S, Kuritzkes, DR. ACTG 5095: A Comparative Study of Three Protease Inhibitor-Sparing Antiretroviral Regimens for the Initial Treatment of HIV Infection. The 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, July 13-16, 2003. Abstract 41.

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

3. 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. The 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, July 2003. Abstract 43.

4. Gerstoft J, Kirk O, Obel N, Pedersen C, Mathiesen L, Nielsen H, Katzenstein TL, Lundgren JD. Low efficacy and high frequency of adverse events in a randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine. AIDS. 2003 Sep 26;17(14):2045-2052.