Treatment Issues: Newsletter of Experimental AIDS Therapies - Volume 17, Number 7-8, July / August 2003
Bob Huff

Viread, Viread, Viread

Viread (tenofovir disoproxil fumarate) has come under a lot of scrutiny this summer after reports of pharmacokinetic interactions, creatinine increases, and a strange case of bad clinical chemistry with abacavir and 3TC set off a flurry of “Dear Doctor” letters.

First, Viread is turning out to have more pharmacological interactions than were understood at first. An interaction with Videx EC (ddI) has been recognized to raise ddI levels and a letter from Bristol-Myers Squib (BMS) recommends separating Viread dosing by two hours before or one hour after taking ddI. Some doctors have reduced dosing of Videx EC from 400mg to 250mg once-a-day taken simultaneously with Viread, but, so far, there is no clinical trial data to validate this approach.

Bristol also issued a Dear Doctor letter advising of a pharmacokinetic interaction between tenofovir and the new BMS protease inhibitor, atazanavir (Reyataz). This is strange because tenofovir is excreted through the kidneys and was not expected to affect drugs metabolized by the liver. A BMS-funded study found that, 24 hours after taking a dose, when blood levels are lowest (Cmin), concentrations of atazanavir (400mg) coadministered with tenofovir were 40 percent less than when given alone in uninfected persons. The wide variability of the Cmin of atazanavir was a topic of concern for the FDA antiviral advisory committee that evaluated the drug prior to approval. Some members of the panel were worried that atazanavir Cmins would be too low in too many people to prevent virologic breakthrough.

BMS advises that clinicians should use caution when administering atazanavir with tenofovir. As once-a-day drugs, the two seem like natural allies but the unboosted combination should probably be avoided until someone can definitively explain what’s going on and how to dose around the problem. The letter also reported that blood levels of tenofovir were raised by coadministration with atazanavir, although no increase in tenofovir-associated toxicity was noted at 24 weeks.

But all may not be lost. Preliminary data from BMS has shown that boosting atazanavir with ritonavir (300mg/100mg) raised Cmins to more comfortable levels. A study by a French group cited in the BMS letter found that the Cmin of boosted atazanavir was decreased by about 23 percent in people with HIV. BMS advises that if atazanavir is to be coadministered with tenofovir ”consideration should be given to administering Reyataz 300mg with ritonavir 100mg until additional data are obtained.“ The drugs should be given as a single daily dose with food.

As an aside, at the IAS Conference in Paris, data was presented that suggests that the 100mg ritonavir booster dose, while compromising atazanavir’s benign lipid profile a little bit, does not have a huge effect and that the combination may be more tolerable than Kaletra. Still, there is not enough being done to get the message out that unboosted atazanavir poses a big risk for someone who’s been on PIs in the past and may harbor resistance mutations. For an individual coming off of a treatment interruption or a PI-sparing regimen a current genotype might not show hidden PI-resistant strains waiting to bloom once atazanavir is started. Activists are concerned that with all the hoopla about once-daily convenience, these dosing concerns will be overlooked.

The Tenofovir / Abacavir Debacle

In the mad race to achieve reliable once-daily dosing with novel combinations, more victims are being left on the roadside. There was a peculiar little study presented at the IAS Conference in Paris that set off alarms about combining Viread and Ziagen (abacavir) and 3TC (Epivir, lamivudine) in a QD combo. A 19-person, non-randomized, uncontrolled pilot study was undertaken by Charles Farthing of the AIDS Healthcare Foundation. Patients were put on a once-a-day triple-NRTI combination of abacavir, tenofovir and 3TC and then observed to see what would happen. It failed spectacularly. Within 8 weeks over half of the people in the trial had virological failure and the study was stopped.

Simultaneously, GlaxoSmithKline (GSK), the maker of abacavir and 3TC was performing a much larger, randomized, but no less peculiar study comparing tenofovir to efavirenz, each with a background of abacavir and 3TC. Again the tenofovir/abacavir combination collapsed with about half failing at the 8-week mark and the 200-person study was stopped. Another French study is rumored to report similar results soon.

There are a number of aspects to the design of these studies that are disconcerting. First, abacavir was used as a once-daily drug with little data to support that. Second, this particular triple combination hadn’t been properly studied even as a twice-daily regimen. Finally, a number of the people enrolled had viral loads in excess of 100,000 copies — a population not expected to do well on a marginally potent regimen. The result is that several patients now have resistance to 3TC, abacavir and tenofovir.

In justification of these studies, it could be said that many people expected this should have been a potent and convenient combination, and it’s one that some clinicians had already been using in the absence of data. For Glaxo, an added incentive for undertaking the multi-million dollar trial was to generate some numbers that would make Viread look bad. Who seriously thought tenofovir was a match for efavirenz? But with a coformulated tenofovir and FTC tablet expected from drugmaker Gilead Sciences next year, Glaxo may have been seeking ammunition to protect its market-dominating Combivir from an upstart. As for AHF, some have speculated that the failed study was actually a ploy to discourage abacavir use or a petulant bid to avoid AZT. Last year AHF sued Glaxo, ostensibly over their AZT patents (the original case was tossed), in a move some say was a tactic to punish Glaxo for refusing to fund the Foundation’s international expansion. (AHF has launched clinics in Uganda and South Africa, which are in the process of scaling up to treat over 1000 people.)

To Glaxo’s credit, when it realized there was a problem, the company issued a Dear Doctor letter warning about the combination. According to Glaxo, their study began enrolling in January of 2003 and by the last week in June, the first few reports of virologic failure had been received. At that time, the company amended the protocol to call for more frequent monitoring and the study continued. Then, on July 3, one doctor called and said he had 9 patients who appeared to be failing the tenofovir arm. This sent Glaxo into a state of alert and the company began collecting patient data for a preliminary analysis. That same day the IAS abstract book was published and the company learned that the title of Farthing’s talk scheduled for July 14th seemed to confirm that there was a problem. On Thursday, July 10, with most of the Glaxo investigators in Paris for the IAS conference, the emergency data analysis reported that the catastrophe was real and the study’s global safety board ordered the trial stopped. Gilead was informed of the situation and they reported that they had heard rumors that a French study was having similar results. By Friday, July 11, Glaxo began notifying study investigators and briefed U.S. community representatives on Sunday the 13th. On Monday, Glaxo met with Farthing to show him the data supporting his findings and he included a reference to the larger trial during his presentation that afternoon.

Farthing would have submitted his abstract for the July conference sometime before the deadline in March. Gilead says they became aware of his results in the Spring but decided not to tell Glaxo because they thought it would be dangerous to draw conclusions based on that small amount of data. Yet had Glaxo known they might have increased their vigilance for problems and could have begun investigating the mechanism sooner.

The reason for the bad outcomes with this combination are subject to wide-ranging speculation pending further research. Gilead said they did a small pharmacokinetics study of tenofovir and abacavir but didn’t observe an interaction. Farthing offered that the problem may lie with once-daily dosing of abacavir or perhaps 3TC. Glaxo suspects a shared resistance pathway of abacavir and tenofovir may be the culprit and cites evidence from a successful study of tenofovir plus Trizivir (abacavir/ 3TC/AZT) to suggest that AZT may play a protective role in preventing resistance. It would be welcome news if a credible, fourth party stepped into this question to figure out what is really going on. Glaxo will present a case-by-case analysis of their study at the ICAAC conference in September.

Yet More on Viread

As for tenofovir on its own, new concerns have been raised about the drug’s effects on the kidneys after a large cohort study reported frequent mild elevations of creatinine levels. Julio Montaner conducted a study of 310 patients in Vancouver who received tenofovir on expanded access during 2002 and compared them to 404 patients who started abacavir during the same period. Within six months of starting therapy creatinine elevations greater than 1.5 times above baseline were seen in 8.4 percent of those starting tenofovir and in only 3.6 percent of those who stated abacavir. A lower baseline CD4 count was associated with a greater risk of a creatinine elevation. Nephrologists that examined the Canadian cohort data saw no indication of Fanconi’s syndrome or serious kidney impairment, yet physicians are now advised to pay careful attention to creatinine levels and to be vigilant for signs of kidney problems in patients on Viread.

Will Miracles Never Cease?

Gilead was reportedly slapped on the wrist by the FDA for sloppy statements made by sales reps downplaying the potential for developing lactic acidosis and hepatic steatosis while on tenofovir. All NRTIs carry an FDA warning about the rare but deadly possibility of developing these NRTI-associated conditions. In another incident, Reuters reports that Gilead sales reps were cited by the FDA for pitching Viread as a “miracle drug.” There are no clinical data to support the claim.

Emtriva Approved

In happier Gilead news, Emtriva (FTC, emtricitabine) was approved by the FDA on July 2. The drug is a nucleoside analog reverse transcriptase inhibitor (NRTI) comparable to 3TC (Epivir) in its resistance profile but with somewhat increased potency and a longer half-life allowing for comfortable once-daily dosing. The drug also exhibited less toxicity to mitochondria in laboratory tests. Despite the similarity to Epivir, more needs to be learned about Emtriva and its resistance profile. The sooner FTC is added to the commercial phenotypic assay panels and clinical cutoffs start to become clear, the sooner we may begin to appreciate the nuances of Emtriva’s particular resistance characteristics. All in all, the incremental benefits of FTC over 3TC should make Emtriva a welcome addition to the HIV medicine shelf, although caution is always warranted when a new drug is released since rare side effects may not show up until the drug has been in broader use over longer periods of time. One odd side effect that has been reported is a spotted discoloration on the palms of the hands of people taking Emtriva.

Fuzeon Forges Ahead

Four months after its FDA approval, prescriptions for Fuzeon (enfuvirtide, T-20) are being filled at a steady pace, says Roche. Interestingly, after all the concern about having enough T-20 to meet the demand, Roche has announced that production capacity has been increased and was now capable of supplying Fuzeon to nearly 20,000 people by the end of 2004.

Reports on 48-week data from the large, pivotal TORO 1 and TORO 2 trials confirmed 24-week results with about twice as many Fuzeon patients experiencing a greater than 1.0 log reduction in viral load as those receiving optimized background therapy without Fuzeon. The median time to virologic failure was 32 weeks for patients receiving Fuzeon vs. 11 weeks for patients receiving the background regimen alone. However, while 47 percent of Fuzeon recipients had achieved at least a 1.0 log reduction at 24 weeks, at 48 weeks this proportion had dropped to 34 percent which indicates the fragile durability of these salvage regimens.

Julio Montaner presented an analysis of factors that predicted success with Fuzeon in the TORO trials at the 24-week mark. Patients with CD4 counts over 100 and those with at least two active drugs in their background regimen were less likely to have virologic failure. This analysis reinforces the problem with finding a therapeutic niche for T-20: those who need it most are less likely to have an optimal outcome, and those who will be most likely to do well on Fuzeon may be unwilling to undergo the burdens of twice-daily injection. Other factors that predicted success were viral load below 100,000 and no prior exposure to Kaletra.

One oddity uncovered in the TORO trials was that the incidence of bacterial pneumonia, which had been recognized in earlier reports, was now 10 times higher in Fuzeon patients (6.6% vs. 0.6%) reaching 10 percent in those with CD4 counts under 200. Possible reasons for this are under investigation. In the meantime, Roche should be reminding doctors to watch for early symptoms of bacterial pneumonia in people who are starting Fuzeon.

Tipranavir Access Improves Slightly

According to Boehringer Ingelheim, enrollment in the RESIST Phase III trials for tipranavir is on track for completion by the end of the year. An open label safety study (OLSS) is now accepting persons who could benefit from tipranavir but were unable to participate in the large studies. The capacity of the OLSS has recently been doubled, which will allow 600 patients worldwide to enroll during 2003. Still, drug supply problems make a less-restrictive expanded access unlikely until the first part of 2004 when the company expects to be able to add an additional 50 persons per month. By the middle of 2004 the expanded access program is projected to be able to add 100 patients per month until approval sometime in 2005. As Julio Montaner’s analysis suggests, access to tipranavir will be especially crucial for individuals considering starting Fuzeon if they are not susceptible to other available protease inhibitors.

Wrong Path for Guidelines?

The U.S. guidelines were released during the IAS meeting where they made nary a ripple. The biggest news is that now only efavirenz or Kaletra-based regimens are recommend for first-line, first-time therapy. And, despite mounting evidence and clinical consensus that d4T is not the best choice for treatment-naïve patients with healthy immune systems, Zerit was still listed among the preferred drugs with only an asterisk to indicate its association with lipid abnormalities. By all accounts the guidelines development process can be a political snake pit, with industry partisans lobbying for this drug or that. At a minimum the guidelines reflect a reasonable, conservative take on how to approach therapy and what not to do. For those who take time to read them, they provide an education in the complexities behind making treatment decisions. The problem is that many physicians may never read them thoroughly. Table 12a (Antiretroviral Regimens Recommended for Treatment of HIV-1 Infection in Antiretroviral Naïve Patients) is such an easy pill to swallow. That’s where you can catch the new first-line drug recommendations at a glance. This table is destined to appear on a thousand power-point slides. Already I have received an email from a PR firm repping Abbott that included a disembodied copy of Table 12a. Oddly, the stavudine asterisk was in place but it led nowhere. So there was the take-home message untroubled by messy footnotes: Kaletra plus Epivir and AZT or Zerit highly recommended, and the lipids be damned.

The new guidelines had been expected at the Retrovirus Conference in February. It’s unfortunate that they arrived just as several new products hit the market. With few of 2003’s new drugs mentioned (Fuzeon is discussed in the context of treating ARV-experienced patients), and efficacy still paramount, the new guidelines seem to lag behind the times a bit. For a set of authoritative guidelines that catches up with more contemporary thinking, consult the British HIV Association, which doesn’t mince words when it comes to Zerit: “For initial therapy, combinations including D4T are not recommended because of increasing evidence of its role in the development of lipodystrophy and abnormal lipid profiles.”

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