July 26, 2005
In the beginning, there was zidovudine (AZT, Retrovir). As the first antiretroviral drug approved for the treatment of HIV, its benefits during the early years of the epidemic were incalculable. However, zidovudine's use also had at least one downside: It was associated with high rates of anemia.
Zidovudine remains almost as ubiquitous today as it was when it first became available. Fortunately, current use of zidovudine involves far lower concentrations, and the drug is thus associated with far lower rates of anemia. However, concern remains that zidovudine may still be associated with toxicity to a greater extent than other nucleosides.
It is important for clinicians to understand the extent to which zidovudine-associated anemia is likely to be problematic -- not only because zidovudine is used in a wide array of today's regimens, but also because clinicians have access to a growing number of regimens that do not include zidovudine, a relevant fact when zidovudine-related toxicities are still of concern.
In this study, Mark Edwards et al of GlaxoSmithKline (the maker of zidovudine) attempted to assess the modern-day risks of anemia with zidovudine. They performed a meta-analysis of 54 Glaxo-sponsored trials containing more than 12,000 patients conducted between January 1995 and January 2004, in which patients had received treatment with antiretroviral drugs for at least 24 weeks.
Anemia was identified on the basis of hemoglobin levels in a total of 5,174 trial participants who had received a zidovudine-containing regimen, as well as 7,511 participants who had received regimens that did not contain zidovudine. Of the populations evaluated, 71% of the individuals who received a zidovudine-containing regimen had been treatment naive at the time of therapy initiation, compared to only 42% of individuals who did not receive zidovudine.
The investigators found that the incidence of anemia in treatment-naive patients was very similar between those who had received zidovudine (1.5%) and those who had not (1.3%). However, somewhat higher levels of anemia were observed in patients who were not treatment naive; among these patients, anemia incidence reached 1.7% among patients who received zidovudine versus only 0.8% in individuals who did not.
Of particular interest is that the use of zidovudine as part of a fixed-dose combination tablet (zidovudine/lamivudine [AZT/3TC, Combivir] or zidovudine/lamivudine/abacavir [AZT/3TC/ABC, Trizivir]) was associated with lower overall incidence of anemia.
Incidence of anemia was 1.1% among patients taking one of these fixed-dose drugs, compared to 2.0% among patients who received zidovudine as a separate drug.
These results suggest that the toxic effects of zidovudine may not be as high as initially feared, and that these effects may further be mitigated if zidovudine is taken as part of a fixed-dose combination. This point assumes greater importance in view of the fact that the patent for zidovudine will soon expire, allowing other companies to incorporate generic zidovudine into other fixed-dose combinations.
On a related note, a subject not touched on in this study is the possibility that even lower doses of zidovudine than those currently used may still be effective. For instance, there has been considerable debate about the potential to use fixed-dose combinations of zidovudine and tenofovir (TDF, Viread), in view of the fact that the presence of thymidine-associated mutations (which are associated with resistance to zidovudine) and the K65R mutation (which is associated with resistance to tenofovir) may be mutually exclusive. It would be interesting to see these issues examined further.
Finally, this study is notable for one other, fascinating reason: It shows that, more than 18 years after its approval, the full potential for employment of zidovudine in HIV treatment regimens has yet to be explored.