Concerns in US study over abacavir/3TC's potency in patients with a high viral load

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Patients taking abacavir/3TC who started antiretroviral therapy with a high viral load in a US clinical trial are being offered the chance to switch to an alternative treatment after it was shown that these patients were significantly less likely to achieve drops in their viral load to certain levels than patients taking tenofovir/FTC.

Interim analysis of the trial also showed that the abacavir/3TC-treated patients were more likely to experience increases in their blood fats and sugars and complain of body aches.

But the makers of abacavir/3TC, GlaxoSmithKline, points out that a number of other studies have shown that abacavir/3TC has good virological efficacy in patients who start anti-HIV treatment with high viral loads.

Study details

The US AIDS Clinical Trials Group (ACTG) Study A5202 is a randomised, double-blind study designed to assess the safety and effectiveness of four different antiretroviral regimens in patients starting treatment for the first time.

Glossary

data safety monitoring board (DSMB)

An independent committee of clinical research experts that reviews data not available to the study team while a clinical trial is in progress to ensure that participants are not exposed to undue risks. A DSMB can recommend that the study be stopped if the intervention is not effective, is causing harm to participants or the study is not likely to serve its scientific purpose. Also known as an Independent Data Monitoring Committee (IDMC).

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

blinding

When a clinical trial is blinded, the participants are unaware as to whether they are receiving the experimental drug or a placebo (or another drug). Double blinding refers to the participant, their doctor and researchers running the trial not knowing which treatment is received by each group until all data have been recorded. Blinding is done to reduce bias in clinical trials.

cholesterol

A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).

clinical trial

A research study involving participants, usually to find out how well a new drug or treatment works in people and how safe it is.

A total of 1600 patients have been recruited to the study who were randomised to receive either abacavir/3TC (Kivexa in Europe and the EU, Epzicom in the US) plus efavirenz (Sustiva), or abacavir/3TC plus atazanavir (Reyataz) boosted by ritonavir (Norvir), or tenofovir/FTC (Truvada) plus efavirenz, or tenofovir/FTC plus atazanavir/ritonavir. Recruitment to the study started in 2005 and it will last 96 weeks. In each of the four arms of the study patients were stratified into one of two groups according to their pre-treatment viral load – those with a viral load above 100,000 copies/ml, considered high, and those with a viral load below this level.

Interim analysis

Interim analysis showed that abacavir/3TC and tenofovir/FTC had similar virologic efficacy for most individuals.

However, patients taking abacavir/3TC who had a high baseline viral load were significantly less likely to achieve a viral load below 1000 copies/ml after 16 weeks of treatment, and a viral load below 200 copies/ml after 24 weeks of treatment, than those taking tenofovir/FTC.

Based on this interim analysis the study’s independent data and safety monitoring board (DSMB) is recommending that patients who started treatment with a viral load above 100,000 copies/ml should be told whether they are taking abacavir/3TC or tenofovir/FTC and be given the option of switching to tenofovir/FTC, or an alternative nucleoside combination, if they wish.

Rates of side-effects in the study have been low, but the DSMB also noted that patients receiving abacavir/3TC were more likely to have had increases in their cholesterol and triglycerides than those taking tenofovir/FTC and also to have experienced an aching body.

“As a result of the efficacy findings, the DSMB recommend that blinded follow-up of [abacavir/3TC] in the subjects with the high viral load strata be stopped. The DSMB stressed that their decision was based on virological efficacy findings in this strata and that safety differences were not the primary consideration for their recommendations”, said the DSMB in a memo to trial investigators and patients.

Patients who entered the study with a viral load below 100,000 copies/ml are unaffected by this development and will not be told which combination of drugs they are receiving.

Abacavir/3TC vs. tenofovir/FTC in context

Both abacavir/3TC and tenofovir/FTC are recommended for first-line antiretroviral therapy in current UK treatment guidelines.

Results of the HEAT study presented to the recent Conference on Retroviruses and Opportunistic Infections found that patients treated with abacavir/3TC or tenofovir/FTC in combination with lopinavir/ritonavir (Kaletra) were equally likely to have an undetectable viral load (below 50 copies/ml) after a year of treatment.

This study also looked at the virological efficacy of the two combinations in patients with viral loads above 100,000 copies/ml and showed them to be equal.

Makers of abacavir/3TC, GSK, has issued a statement noting the results of this study, and also drawing attention to the outcome of six of its studies involving over 2,500 patients. These GSK studies showed “viral load reduction of 94% and above in patients with a viral load [of or above] 100,000 copies/ml at week 24 in the abacavir/lamivudine study groups.”

The statement adds that GSK is taking the results of the latest study very seriously and is working with the ACTG to understand the findings. However it continues “these [data] are inconsistent with those that we have seen in GSK clinical data. GSK does not believe the interim results of this single, ongoing study warrant a change in clinical practice. Abacavir/lamivudine offers a potent, effective, and generally well-tolerated HIV treatment backbone and clinicians must consider the sum of available data, as well as the patient’s individual profile, when making treatment decisions.”

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