The Triple Nucleoside Combination of Abacavir, Zidovudine, and Lamivudine Proves "Virologically Inferior" to a Non Nucleoside Efavirenz- based Regimen in HIV Treatment-naïve Patients

By Ronald Baker, PhD

In a group of previously untreated HIV patients, the triple nucleoside analogue (NRTI) combination of abacavir (Ziagen), zidovudine (Retrovir), and lamivudine (Epivir) proved to be "virologically inferior" to a regimen containing the non nucleoside inhibitor efavirenz plus two or three nucleoside analogues.

Preliminary results of this large trial were released last year, when a planned review of the data resulted in the stopping of the triple nucleoside arm of the trial.

The preliminary findings generated a lively debate among researchers, clinicians and patients about the value (and future) of triple nucleoside regimens for the treatment of HIV positive individuals. Heated discussions about which patients might or not benefit from this particular triple nucleoside regimen continue today. The three-drug combination of abacavir-zidovudine-lamivudine is now commercially available in a single pill, called Trizivir, which is widely used by persons with HIV infection.

Final results of the randomized, double blind trial appear in the current (April 29, 2004) issue of The New England Journal of Medicine. Dr. Roy Gulick of the Cornell Clinical Trials Unit in New York City was the lead author of this important study, which is summarized below.

This randomized, double blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1:

(1) zidovudine–lamivudine–abacavir;

(2) zidovudine–lamivudine plus efavirenz; and

(3) zidovudine–lamivudine–abacavir plus efavirenz.

Results

A multicenter team of researchers enrolled a total of 1,147 subjects with a mean baseline HIV-1 RNA level of 4.85 log₁₀ (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter.

A scheduled review last year by the data and safety monitoring board with the use of pre-specified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups.

After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001).

This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P0.001 for both comparisons).

Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups.

In conclusion, the authors write, “In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides”

"Our findings suggest that an efavirenz-containing regimen is more potent than the triple-nucleoside regimen and support current guidelines that recommend efavirenz-based regimens among the preferred options for the initial treatment of HIV-1 infection," they write.

"Clinicians," the investigators note, "should factor in the results of appropriately designed, comparative studies such as ours in selecting the optimal initial antiretroviral regimen with an individual patient."

Following is a statement released by GlaxoSmithKline about the use of Trizivir in HIV infection.

Use of Trizivir in the Management of HIV

Preliminary results of ACTG 5095 are published in the April 29 issue of the New England Journal of Medicine, following presentation of these data at the International AIDS Society meeting in July 2003.  GlaxoSmithKline provides the following information as background for journalists and others on the development of its antiretroviral drug TRIZIVIR^â (abacavir sulfate, lamivudine and zidovudine), which was one of the medications evaluated in this study.

The components of TRIZIVIR have been researched and refined for nearly a decade, involving more than 1,700 patients in 14 clinical trials testing the combined three nucleoside components. TRIZIVIR, or a combination of its three individual components, has been prescribed alone or with other antiretrovirals for many thousands of patients since 1999.  TRIZIVIR is indicated alone or in combination with other antiretroviral agents for the treatment of HIV‑1 infection. The indication for TRIZIVIR is based on two controlled trials with abacavir of 16 and 48 weeks in duration that evaluated suppression of HIV RNA and changes in CD4 cell count.  At present, there are no results from controlled trials evaluating the effect of abacavir on clinical progression of HIV.  There are limited data on the use of this triple‑combination regimen in patients with higher viral load levels (>100,000 copies/mL) at baseline.

The dose of one tablet taken twice daily alone or in combination with other antiretrovirals, with no food and water restrictions, offers patients the benefit of dosing simplicity.  Based on sound clinical research, GlaxoSmithKline continues to support the use of TRIZIVIR.

“We believe TRIZIVIR has a valuable role in the continuum of HIV care,” said Doug Manion, M.D., GSK vice president of clinical development and medical affairs.  “We also believe it is important to put the interim preliminary results from ACTG 5095 into context with data reported in other controlled, clinical evaluations of TRIZIVIR.”

ACTG 5095, a placebo-controlled, double-blinded study conducted by the Adult AIDS Clinical Trials Group (ACTG), compared a treatment arm involving TRIZIVIR alone to two other regimens: Combivirâ (lamivudine/zidovudine) + efavirenz, and TRIZIVIR + efavirenz. The National Institute of Allergy and Infectious Diseases (NIAID) Data and Safety Monitoring

Board (DSMB), which oversees ACTG 5095, announced in a Notice to Physicians March 10, 2003, that the treatment arm containing only TRIZIVIR met predefined criteria related to virologic failure when TRIZIVIR was compared to each of the efavirenz containing arms. This required the discontinuation of the arm. The two arms containing efavirenz continued; patients taking only TRIZIVIR whose viral loads were suppressed, could elect to continue with the regimen and are being provided the drug off study.

The preliminary data that prompted the DSMB action was related to one of the study’s primary endpoints – time to virologic failure (HIV-1 RNA <200 copies/mL); and a secondary endpoint – a comparison of the proportion of patients who achieved HIV-1 RNA <200 copies/mL at 48 weeks. After a median time period of 32 weeks into the 96-week study, a greater proportion of the 167 antiretroviral-naïve patients who experienced virologic failure were in the treatment group taking TRIZIVIR alone (21 percent) than in the other two treatment groups combined (10 percent). At the same time, among 33 percent of patients who reached 48 weeks, 74 percent of patients in the group taking TRIZIVIR alone had a viral load of <200 copies/mL, compared to 89 percent in the other groups combined.

GSK provides the following information for context:

Viral Suppression

§          43 percent  of the patients in the arm taking TRIZIVIR alone entered with a viral load >100,000 copies/mL.  There are limited data on the use of this triple-combination regimen in patients with higher viral load levels >100,000 copies/mL at baseline.

§          74 percent of the naïve patients treated with TRIZIVIR alone achieved viral suppression of <200 copies/mL, which is clinically acceptable and consistent with other published data on TRIZIVIR. 

§          While lower than in the other two treatment arms, the 74 percent success rate is actually high when considered against the strict criterion for virologic failure.  In ACTG 5095 virologic failure was defined as a confirmed HIV RNA ≥200 copies/mL at least 16 weeks after starting the study treatment.  

CD4 Cell Count

§          48 percent of the patients in the arm taking TRIZIVIR alone entered with a CD4 count of 200 or below.

§          There were no significant differences between treatment arms with respect to CD4 cell count change from baseline.  At week 48, the mean change was 174 cells/mm³ in the arm taking TRIZIVIR alone and 173 cells/mm³ in the pooled efavirenz arms.

§          Although data on CD4+ T cell counts were not available at the time of the interim analysis, the DSMB (National Institute of Allergy and Infections Diseases’ Data and Safety Monitoring Board) felt that they would not reverse the outcome

Dosing Convenience

TRIZIVIR is approved to be dosed as one tablet taken twice a day alone or in combination with other antiretrovirals with no food or water restrictions. Dosing simplicity offered by TRIZIVIR is an important factor when considering antiretroviral therapy.

As stated in the letter from the NIAID Division of AIDS to health care providers:  “It is important to consider this interim study finding in the context of published results, particularly those from prior studies that investigated either triple nucleoside regimens or efavirenz-based regimens.  The risk of virologic failure is clearly an important factor in selecting an initial antiretroviral regimen.  Other factors such as safety, toxicity, adherence, preservation of future treatment options, access, cost and other issues also remain important in selecting the optimal first regimen for an individual patient.”

GlaxoSmithKline has informed health care professionals who treat HIV/AIDS patients of these details to clarify the study parameter, and also has posted this and other information on clinical trials involving TRIZIVIR on the web site www.treathiv.com.

Product Information

HIV medicines do not cure HIV infection/AIDS or prevent passing HIV to others.

There are limited data on the use of this triple‑combination regimen in patients with higher viral load levels (>100,000 copies/mL) at baseline.

For full prescribing information please go to www.treathiv.com.

04/30/04

References
R M Gulick and others (for the AIDS Clinical Trials Group Study A5095 Team). Triple-Nucleoside Regimens versus Efavirenz-Containing Regimens for the Initial Treatment of HIV-1 Infection. The New England Journal of Medicine 350(18): 1850-1861. April 29, 2004.

GlaxoSmithKline. USE OF TRIZIVIR IN THE MANAGEMENT OF HIV. Press Release. April 28, 2004.