What happened? The FDA approved abacavir to be administered twice daily. Later, some pharmacokinetic studies suggested that one could potentially take this drug once-a-day. A clinical study, though preliminary, presented last year in Buenos Aires, added to the fuel. Thus a GlaxoSmithKline (GSK) sponosored study, ESS30009, was designed to look at a "fixed dose tablet" or "Easy Tablet," that is, a new formulation of 3TC (Epivir) and abacavir in one pill and to be administered once daily. The study compared Epivir + Ziagen + Viread against another regimen of Epivir + Ziagen fixed tablet + efavirenz (Sustiva) with all regimens dosed once daily. As a principle investigator in this study, I found the protocol to be of interest, especially in light of data showing both Ziagen and Viread as being quite potent. In another study, the potency of Viread was compared with the protease inhibitor, ritonavir (Norvir); preliminary work with Ziagen monotherapy also showed it to be a strong and potent agent.
In study ESS30009, investigators knowing full well what regimen their patients were randomly assigned to (being open-label) soon observed obvious differences between the regimens. Our clinic, Northstar Healthcare in Chicago, enrolled 14 patients in this study, six of whom were on the Viread regimen and eight patients on the Sustiva based regimen; nine of whom have reached between 8 and 16 weeks. In the global study 345 patients were randomized and only 125 individuals had reached 12 weeks. At this early point differences in the study arms were already being observed, which forced an early interim analysis.
Thus, in mid-July, principle investigators received urgent communications from GSK. So, as soon as the early indications emerged, GSK sought to notify the unexpected results to their investigators, however disconcerting. Their letters described that a substantial number of patients on the Epivir + Ziagen + Viread regimen were failing and recommended that our clinical judgment and practice should take steps to ensure the best possible care of our individual patients. This meant that if our judgment dictated withdrawing certain individuals from the study, then this should be done. Additionally, talking with scientists at Gilead Sciences, makers of Viread, it was obvious they were also working diligently in investigating the cause for these outcomes.
The letter to physicians from GlaxoSmithKline provided the following: Of 102 individuals ramdomized, 50 subjects or 49% who were on the fixed dose of Ziagen/Epivir in combination with Viread with at least 8 weeks of viral load data (HIV-RNA) demonstrated non-response. Non-response means those individuals failed to achieve viral load drops greater than 2 logs or were already showing increases in viral load from their previous visit values. This compared with only 5/92 patients or 5.4% randomized to the Ziagen/Epivir + Sustiva combination. Looking at the data in fewer patients but at 12 weeks, again the results were similar. 30/63 patients or 47.6% on the Ziagen/Epivir + Viread arm were non-responders vs. 3/62 or 4.8% on the Ziagen/Epivir + Sustiva arm.
Although this analysis was carried out at an early juncture of the study, the results were of much concern. Under normal circumstances with effective regimens, this phenomenon of high "non-responders" should not normally be observed.
This in concert with another study reported at the International AIDS Society meeting in Paris during July only confirmed and intensified the implications. Dr. Charles Farthing from Los Angeles studied 20 patients also naïve to antiviral treatment. The subjects were placed on a once-daily regimen of the same agents, Ziagen, Epivir and Viread. Nine of 17 patients (52%) had viral load rebound. These patients were adherent to their regimen based on pill count during their follow-up visits.
It is worthy to note that Gilead Sciences has conducted its own studies on the pharmacokinetic interactions of both drugs, finding that neither agent significantly compromised blood levels of the other.
Dr. Michael Miller, Director of Clinical Virology at Gilead Sciences, says two principle possibilities may explain the regimens poor potency. First, it is possible that an intracellular interaction between Ziagen and Viread may be occurring and lowering drug levels in cells. Second, resistance to the drugs themselves may be at fault. Whatever the reason, patients being administered these agents once-daily may only be exacerbating the manifestations of the problem. If, however, resistance was the start of the problem or primarily at fault, one would expect more complete resistance mutations in those failing patients. In Dr. Farthings cohort the Epivir-associated M184V mutation was observed in many failure patients, the K65R was seen in only half of the failures. Thus complete resistance occurred in relatively too few patients and does not explain the observation of high levels of failure; in general, I believe that the presence of K65R as the sole mutation is not as common, nor significant enough cause for individuals to completely fail their regimens clinically.
Moreover, resistance mutations can often be due to one of several causes including non-adherence, not enough antiviral penetration into body compartments, or not enough blood levels of drug. And it may be that once-daily doses of Ziagen and Epivir may not be enough throughout a 24-hour period to maintain enough suppression and pressure on HIV in some select patients. Recently in the ACTG 5095 study (see "The Buzz" May/June 2003) we saw another triple nucleoside regimen, Trizivir, also demonstrate lower potency compared to a Sustiva based regimen. Although this particular drug regimen of Trizivir was twice daily we may be receiving the same message: triple nucleoside regimens are not consistently effective as non-nuke or protease inhibitor based regimens -- clinician beware.
However, many argue that there is a place for triple nucleoside therapy, particularly for individuals without a heavily compromised immune function. Alternatively, one should remember that resistance occurs usually after having responded initially to treatment. The fact that many patients in ESS30009 did not respond from the get-go leads one to consider possible drug interactions. Researchers at Gilead Sciences note that various other studies are ongoing in which Viread and Ziagen are being used successfully in combination. These studies are not once-daily, triple nucleoside regimens, however. Additionally other studies being sponsored by GlaxoSmithKline using the once-daily abacavir-Epivir "Easy Tablet" are also showing favorable response in other regimens.
It may be premature to invoke a rule of not using these two drugs in combination in other clinical scenarios at this time. Physicians should use their clinical judgment in their individual patients. However for now, it would be prudent for clinicians not to use these two agents in a once-daily regimen, especially in naïve patients. Furthermore, physicians should not initiate patients on a once-daily regimen of Epivir, Ziagen and Viread. Both companies, GSK and Gilead are aggressively pursuing the challenge of identifying the direct cause of the problem with laboratory and intracellular research. Patient care is paramount.
Daniel S. Berger, M.D., is Medical Director of Chicagos largest private HIV treatment and research center, NorthStar Healthcare, Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDSInfosource (www.aidsinfosource.com). He also serves as medical consultant and columnist for Positively Aware. He has contributed to the recently released The First Year -- HIV, An Essential Guide for the Newly Diagnosed (2003; Marlowe & Company, New York). Dr. Berger can be reached at DSBergerMD@aol.com or (773) 296-2400.