NIAID Expresses Concerns about Potency of Abacavir/3TC (Epzicom) among Patients with High Viral Loads in ACTG Trial

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The independent Data and Safety Monitoring Board (DSMB) of the ongoing government-funded trial known as ACTG 5202 is offering patients receiving abacavir/3TC (Epzicom) who initiated the trial with high viral loads the opportunity to switch to a different treatment regimen.

In an interim analysis of the study data, The DSMB of the study concluded that the regimens containing Epzicom were significantly less effective in suppressing HIV than those containing tenofovir/emtricitabine (Truvada) among patients with a high viral load (greater than 100,000 copies/mL)

GlaxoSmithKline (GSK), the manufacturer of Epzicom, disagrees with the DSMB recommendations, and has posted a statement voicing their opinion about the interim results.

Following is the text of the statement on the NIAID DSMB recommendations published by the NIAID/NIH, followed by the text of GSK's statement on these recommendations.

NIAID/NIH Press Release on ACTG 5202

An independent Data and Safety Monitoring Board (DSMB) met recently to review data from a clinical trial examining the safety, tolerability and effectiveness of four different antiretroviral treatment regimens in HIV-infected adults who had never taken anti-HIV drugs before.

The trial, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, involves a randomized comparison of the HIV drug efavirenz (EFV) [Sustiva] with atazanavir [Reyataz] boosted with ritonavir (ATV/r), and a double-blind, randomized comparison of co-formulations of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) [Truvada] with abacavir/lamivudine (ABC/3TC) [Epzicom].

The DSMB has recommended changes to the study on the basis of new findings in a subset of participants who have been receiving ABC/3TC.

This study is being conducted by the NIAID-funded AIDS Clinical Trials Group (ACTG) and is known as ACTG 5202. The trial is important for examining initial HIV treatment regimens because existing regimens may vary both in their ability to suppress the level of HIV in the blood (viral load) and in the side effects with which they may be associated.

Investigators enrolled 1,858 eligible men and women into the Phase III efficacy study between September 2005 and November 2007 at 64 sites in the United States.

Participants were divided into two groups based on HIV levels at the time of screening: those with high viral loads (100,000 or more copies of HIV RNA per milliliter of blood) and those with lower viral loads (fewer than 100,000 copies/mL). Each volunteer was assigned at random to one of the four treatment groups:

(1) EFV, FTC/TDF, and placebo for ABC/3TC.

(2) EFV, placebo for FTC/TDF, and ABC/3TC.

(3) ATV/r, FTC/TDF, and placebo for ABC/3TC.

(4) ATV/r, placebo for FTC/TDF, and ABC/3TC.

All regimens effectively reduced the amount of virus in most participants.
However, the DSMB found that among participants with high viral loads at the time of screening, treatment combinations that included ABC/3TC were not as effective in controlling the virus as those on regimens containing FTC/TDF.

This was the DSMB's primary concern. Secondarily, the DSMB found that among participants with a high viral load at screening, those receiving ABC/3TC experienced a shorter time to developing non-specific side effects, such as body aches, and laboratory test abnormalities, such as elevated cholesterol and triglyceride levels, than those receiving FTC/TDF.

In general, these side effects were obvious to participants or the study physicians and would have been readily managed or treated.

The DSMB had no safety concerns regarding EFV or ATV/r and recommended that study participants in the lower viral load group who were taking ABC/3TC should continue with their assigned treatment regimen.

Based on its findings, the DSMB recommended that all participants who had high viral loads at screening be told which treatment regimen they are receiving and stop taking their placebo pill. The DSMB also recommended that those participants receiving ABC/3TC who had high viral loads at screening be counseled on what the DSMB findings might mean for them and possibly be shifted to another regimen, if appropriate.

Finally, the DSMB recommended that the remainder of the study continue as originally designed.

NIAID concurred with the DSMB's recommendations.

ACTG has notified the site investigators and the affected study participants of the DSMB's recommendations. In consultation with the site study teams and their physicians, these participants may continue taking ABC/3TC, switch to FTC/TDF or switch to alternative antiretroviral combinations.

3/01/08

Source
NIAID/NIH. NIAID Modifies HIV Antiretroviral Treatment Study Combination Therapy that Includes ABC/3TC. Press Release. February 28, 2008.

GSK Statement Sent to HIV Community Members and Press on DSMB Recommendations for Patients in ACTG Study 5202 with High Viral Loads Receiving Epzicom

As part of our ongoing efforts to keep you informed, we are including a GSK statement regarding the results of ACTG 5202 concerning Epzicom® (abacavir sulfate and lamivudine). The NIAID posted their position today on their website.

February 28, 2008 - GlaxoSmithKline today commented that data from the AIDS Clinical Trials Group (ACTG 5202) are inconsistent with previous clinical trial and other study experience with Epzicom (abacavir sulfate and lamivudine).

The ACTG study shows that both the Epzicom and Truvada arms were effective in reducing viral load in patients with HIV, yet the rates of reduction in viral load are slightly below what we have seen in GSK clinical data on Epzicom.

Data from six GSK studies with 2,595 patients show higher viral load reduction (94% and above in patients with viral load 100,000 copies at 24 weeks) than was seen in the ACTG study.

In addition, 48-week results from the recently reported HEAT study - directly comparing Epzicom to Truvada combined with Kaletra - showed treatment with Epzicom reduced viral load to the target at 24 weeks in 94% of patients, compared to 95% in the Truvada arm - a comparable level of effectiveness.

Importantly, across the GSK studies, viral reduction between patients with high (greater than100,000 copies) and low (less than 100,000 copies) viral loads was similar.

The following confounding factors in the ACTG study may account for the unexpected results:

• The ACTG study did not routinely exclude patients at risk for a known reaction with Epzicom, which might have accounted for some adverse events recorded.

• The ACTG did not test all patients for baseline resistance to treatment. GSK clinical trials have shown that resistance reduces the ability to achieve a reduction in viral load, particularly in combination with the NNRTI, efavirenz [Sustiva].

We understand that the ACTG study did not identify any safety signals not already noted in the product labeling, and that the ACTG study is continuing. The trial remains unchanged in those patients with viral loads less than 100,000.

These patients with lower viral loads will continue the study on Epzicom if randomized to one of the treatment arms containing Epzicom.

We understand that trial investigators will be allowed the choice of changing treatments for patients with the viral loads greater than 100,000 copies who do not achieve the target viral load reduction.

GSK does not believe the interim results of this single, ongoing study warrant a change to clinical practice. Epzicom offers a potent, effective, and generally well-tolerated HIV treatment backbone for many patients with HIV.

3/01/08

Source
GlaxoSmithKline. GlaxoSmithKline Comments on Data Concerning Epzicom from ACTG Study. February 28, 2008.