NUKE WAR

Two new nuke combo tablets have just become available. How do they measure up to Combivir, the most widely prescribed HIV drug in the UK? Anna Poppa reports

It is often said that there is no one ‘best’ HIV treatment combination. But in recent years the use of efavirenz with the combined formulation of AZT and 3TC, Combivir, has become widely referred to as the ‘standard of care’ in HIV therapy, the treatment of choice for people starting HIV drugs for the first time.
In recent months, two new HIV treatments have been licensed which could challenge Combivir’s dominance. Both contain - like Combivir - two drugs from the NRTI (nucleoside reverse transcriptase inhibitor) family, each of which has previously been licensed as a single drug. Given as a so-called ‘fixed-dose combination’, these treatments produce the same effect as when given as two separate drugs. But by co-formulating them into a single pill, the number of pills which need to be taken each day is reduced, something which many people taking treatment say they prefer.
NRTIs were the first family of HIV drugs available, AZT, having been licensed in the mid-1980s. Their role in HIV therapy today is to act as the ‘backbone’ of an HIV treatment combination, because the usual way to start HIV treatment is with two drugs from the NRTI class, together with a third drug; either a protease inhibitor or a drug from the NNRTI class such as nevirapine or efavirenz.
The eight licensed NRTIs are AZT (Retrovir), 3TC (Epivir), ddI (Videx), ddC (Hivid), d4T (Zerit), tenofovir (Viread), and FTC (Emtriva). Of these, three are available combined together in fixed-dose combinations, and these are the focus of this article. They are:

•Combivir (AZT plus 3TC)
• Kivexa (abacavir plus 3TC)
•Truvada (tenofovir plus FTC)

How could HIV treatment be improved?
The findings of a recent research study involving the EuroSIDA cohort of European people living with HIV provide a picture of the state-of-play in HIV therapy. The study found that 70 out of 100 people who start HIV treatment with a three-drug HIV treatment combination will still be taking that combination one year later. Of the 30 people who will have needed to switch their combination, the majority will have done so because they were unable to tolerate the drugs’ side effects, or to manage taking the pills as directed.
This study tells us is that although most people do well on an initial HIV treatment combination, the likelihood of a good response would be improved further still if the drugs were easier to tolerate. The tolerability of new HIV treatments such as Kivexa and Truvada is therefore a major criterion by which doctors and patients will judge their value.
Tolerability can be considered to comprise two elements; the likelihood that a drug will cause harmful or intrusive side effects, and the extent to which taking the drug may get in the way of normal activities. As Table 1 illustrates, in relation to ease-of-use, Kivexa and Truvada may be preferred by some people because they are once-daily treatments, whereas Combivir is taken twice-daily. For others, this distinction may be less important - all three combinations are taken as just one pill per dose, Kivexa and Combivir have no food or fluid restrictions, Truvada should be taken with a meal.

Comparing dual NRTIs head-to-head
To get a more objective view of how dual-NRTI combinations fare against each other, we need to look to trials which have been designed to compare these drugs head-to-head. This type of information is fairly limited, and in particular, there is currently a lack of research comparing the two new combinations, Kivexa and Truvada, in people starting HIV treatment for the first time.

Combivir v Kivexa
In study CNA30024, GlaxoSmithKline compared abacavir and 3TC against AZT and 3TC. The study recruited 650 people who were beginning HIV treatment for the first time, and all took the NNRTI efavirenz as the third drug in their treatment regimen alongside either dual-NRTI combination. After a year on treatment, there was little difference between AZT/3TC and abacavir/3TC regarding the study’s primary marker, the effect on viral load. After one year, approximately 70 per cent of people in both treatment arms had an undetectable viral load (below 50 copies). This result is broadly in line with our expectations of triple-drug HIV treatment combinations in people new to treatment, based on previous studies.
There were a couple of important differences between the two combinations. CD4 counts went up higher in people allocated the abacavir/3TC combination than those given AZT/3TC, a difference overall of around 50 cells after one year of treatment. Though there was no difference in the proportion of people who needed to stop treatment because of side effects, about 14 per cent of each group, the pattern of side effects differed. The AZT group were more likely to experience problems like nausea, fatigue, vomiting and anaemia, while hypersensitivity and coughing were more common in the abacavir group.
Strictly speaking, this trial is not a head-to-head comparison of Kivexa and Combivir because all drugs were given as single agents rather than in fixed-dose combinations, and because both abacavir and 3TC were given twice daily. Despite these differences, the results are still a useful guide to how these two combinations perform against each other. What’s more, we know from the results of a second study, called CNA30021 that the performance of abacavir/3TC plus efavirenz is similar in people new to HIV treatment regardless of whether abacavir is taken once or twice daily.

Combivir v Truvada
To compare these two combinations, we need to turn to the preliminary results of a Gilead-sponsored trial, study GS934, which was designed to look at the effects of Combivir versus tenofovir/FTC (Truvada’s components given as single drugs) in around 500 people starting HIV treatments for the first time. Like the two previous studies reviewed here, these dual NRTI combinations were given with efavirenz.
Gilead presented the initial results of GS934 in a recent press release, but it won’t be until later in the year that we will get to see the results presented, and debated, more fully. After a year of treatment, overall there were more people who were undetectable in the tenofovir/FTC group than Combivir (77 per cent versus 69 per cent below 50 copies).
This difference in response was driven by differences in the numbers of people who had to stop treatment because of short-term side effects. Nine per cent of Combivir users stopped for this reason, compared to 4 per cent of people taking tenofovir/FTC. However, if people could tolerate the drugs and stayed on their treatment, they were just as likely to go undetectable with Combivir as with tenofovir.
Increases in CD4 count were also slightly higher in the tenofovir/FTC arm, by about 30 cells overall.
Summary:

Choosing a dual-NRTI combination

• Three dual NRTI fixed dose combinations are available for use within HIV treatment combinations. These are Combivir (AZT plus 3TC), Kivexa (abacavir plus    3TC), and Truvada (tenofovir plus FTC).
• Fixed-dose combinations contain fewer pills per dose than single drug therapies. Kivexa and Truvada are dosed once daily, and Combivir twice daily.
• Combivir, Kivexa, and Truvada have all been shown to be effective components of first-line HIV treatment.
• Combivir’s continued popularity among doctors and patients alike is largely based on extensive testing in clinical trials and the security that comes from years of   use in clinical practice.l Anna Poppa is a freelance medical writer.

• annapoppa@tiscali.co.uk

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