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Differing results on ziagen with high starting viral load.

Two recent studies produced different findings on the strength of Ziagen (abacavir) in a first-ever antiretroviral combination taken by people with a viral load above 100,000. An AIDS Clinical Trials Group (ACTG) study found that Ziagen plus Epivir (lamivudine) did not stop HIV as well as Viread (tenofovir) plus Emtriva (emtric-itabine) when given with Sustiva (efavirenz) or Reyataz (atazanavir) to people starting their first antiretrovirals with a viral load over 100,000.(1) But analysis of six already-completed trials by GlaxoSmith Kline, maker of Ziagen, found no evidence that this medication is significantly weaker in people beginning therapy with a high viral load.(2)

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* How the studies worked.

ACTG researchers signed up 1858 people with no antiretroviral treatment record; 797 of them had a viral load above 100,000. (1) Study participants started either Ziagen/Epivir (Epzicom) or Viread/Emtriva (Truvada) with either Sustiva or Reyataz/Norvir. The investigators figured rates of virologic failure in the different treatment groups, defining failure as a viral load above 1000 between study weeks 16 to 24 or above 200 after week 24. They also kept track of side effects in the different antiretroviral groups.

GlaxoSmithKline investigators used the same definitions of treatment failure and side effects to compare Ziagen combinations with non-Ziagen combinations in people whose initial viral load lay above or below 100,0009(2). - This study involved people from six trials who took Ziagen/Epivir with Sustiva, Reyataz/Norvir, Kaletra (lopinavir/Norvir), or Lexiva (fosamprenavir)/Norvir. In these studies 1027 people started treatment with a load above 100,000 and 1182 started with a lower load.

* What the studies found.

In the ACTG trial, time to virologic failure was more than twice faster with Ziagen regimens than with Viread regimens if the starting viral load was over 100,000.' Among study participants who reached an undetectable viral load, HIV rebound rates did not differ in the two treatment groups.

Time to grade 3 or 4 side effects (the most serious side effects) was almost twice as fast with Ziagen/Epivir (Epzicom) as with Viread/Emtriva (Truvada) in people who began treatment with a viral load above 100,000. Because of these differences between the two treatment groups, an independent panel advised stopping the comparison of Ziagen with Viread in people with a high viral load. The ACTG noted that "most of these side effects (or laboratory test changes) were obvious to patients or study doctors and would have been readily managed or treated.":(3)

The six-trial analysis by GlaxoSmithKline showed very little difference in time to virologic failure between people starting Ziagen-containing combinations with a viral load above 100,000 and those starting with a lower viral load.(2) These investigators also described a 96-week analysis of the HEAT trial,4 the only one of the six trials that compared Ziagen/Epivir with Viread/Emtriva. Measuring the proportion of study participants with a viral load under 50 at 96 weeks, the researchers found no difference between the two treatments. This 96-week analysis found no meaningful side effect differences between people starting Ziagen/Epivir versus Viread/Emtriva with a viral load above 100,000.

* What the findings mean J or you.

In light of the GlaxoSmithKline six-trial analysis, (2) it is hard to say whether the ACTG findings' should affect decisions about taking a first regimen containing Ziagen/Emtriva with a viral load over 100,000. If you are already taking a Ziagen-containing combination and have an undetectable viral load, this treatment can be continued with a low risk of viral rebound.

Why did the ACTG and GlaxoSmithKline reach different conclusions about Ziagen? Differences between the several studies analyzed may account for differing results. Who enters a trial, how many people enter a trial, how the trial is planned, and what other drugs are used (besides Ziagen and Viread) could all affect study results. Further analysis of the ACTG findings--looking at pretreatment resistance, treatment interruptions, and adherence, for example--may help explain the poor Ziagen results in that study.

In November 2008 the US government-sponsored antiretroviral treatment panel moved Ziagen plus Epivir off the "preferred" list of nucleoside combinations to the "alternative" list. The change, the panel said, reflects "concerns regarding an increased risk of myocardial infarction [heart attacks] in patients with high cardiac risk factors, as suggested by large observational cohort studies, and concerns regarding virolog-ic potency in patients with [pretreatment] viral loads above 100,000 copies."(5)

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References

(1.) Sax P, Tierney C, Collier A, et al. ACTG 5202: shorter time to virologic failure with ABC/3TC than TDF/FTC in treatment-naive subjects with HIV RNA > 100,000. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract THAB0303.

(2.) Pappa K, Hernandez J, Ha B, et al. ABC/3TC shows robust virologic responses in ART-naive patients for baseline viral loads of > 100.000 c/mL and < 100,000 c/mL by endpoint used in ACTG5202. XVII International AIDS Conference. August 3-8. 2008. Mexico City. Abstract THAB0304.

(3.) The A5202 Team. Letter to A5202 participants. February 22, 2008.

(4.) Smith K, Fine I), Patel I', et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavii) through 48 weeks in the HEAT study. 15th Conference on Retroviruses and Opportunistic Infections.

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February 3-6, 2008. Boston. Abstract 774.

(5.) DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-l-infected adults and adolescents. November 3, 2008 (http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf).
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Publication:HIV Treatment: ALERTS!
Date:Dec 1, 2008
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