American Foundation for AIDS Research, December 2003
Elizabeth Paukstis

If one were to compare the HIV-related research presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) to a film, it would not be a sweeping epic. Instead it would be more like a series of short pieces, with some interesting lines of dialogue and bits of memorable scenery thrown in. As the conference is not exclusively devoted to HIV, no single groundbreaking story emerged, but a few presentations did stand out. Particularly notable studies focused on how old drugs might still be effective for treatment-experienced patients, what the latest data on new drugs showed, whether a once-daily formulation of abacavir could pass muster, and if Kaletra could stand alone in a one-drug regimen.

The Here and Now

Jean-Michel Molina of Pitié Hospital in Paris presented a study examining the use of didanosine (ddI) in a treatment-experienced population (abstract H-447). Upon entering the study, the 168 participants had a median of three thymidine analog mutations (TAMs) and four nucleoside analog mutations (NAMs). In other words, the patients were generally resistant to antiretrovirals from the nucleoside class. Most of them had also taken ddI previously. The volunteers were randomized to add either ddI or placebo to their current regimens. After four weeks, the median viral load drop in the ddI group was 0.6 log, as opposed to a viral load gain of 0.1 log in the placebo group. This difference was statistically significant. The results thus showed that ddI might be effective against resistant virus in people with treatment experience.

However, the study certainly had its limitations. “It provides short-term evidence of the activity of ddI against resistant virus, specifically with AZT mutations,” commented Daniel Kuritzkes, of Brigham and Women’s Hospital in Cambridge. “However, it provides no evidence of whether you can recycle ddI, because the follow-up was too short. It’s uncertain if a ddI mutation might have emerged beyond four weeks. I think the bottom line is that ddI is active in the background of three TAMs. But how durable this response will be remains to be seen.”

The There and Later

Jacob Lalezari of Quest Clinical Research in San Francisco presented data on T-1249, a fusion inhibitor that has been effective against HIV isolates that are resistant to T-20, or Fuzeon (abstract H-444). Like T-20, T-1249 requires injection, but unlike T-20 it may be injected once rather than twice daily. Fifty-three patients who were failing a T-20 regimen replaced it with T-1249, dosed at 192 mg daily for 10 days, while continuing their background regimen. The median drop in viral load was 1.3 log, and 73% of participants experienced at least a 1.0 log drop. Thirty-four trial participants reported injection site reactions, the painful side effect that also plagues T-20 users. The investigators claimed that these reactions were mostly mild.

While this was promising news for individuals who have developed resistance to T-20, it did not erase the fact that injection is a less than ideal way to take a drug. An entry inhibitor in pill form would be easier to take and render injection site reactions obsolete. Many ICAAC attendees eagerly anticipated new data on Pfizer’s investigational CCR5 inhibitor UK-427,857, a drug administered orally. UK-427,857 interferes with HIV after the virus binds to the cells’ CD4 receptor, but before it binds to the CCR5 receptor. The drug is therefore effective only against HIV that uses the CCR5 receptor, and not HIV that uses the CXCR4 receptor. CXCR4-tropic HIV is generally viewed as a more aggressive form of the virus and is associated with advanced disease progression.

Gerd Fätkenheurer of Köln University in Germany presented results from a trial testing UK-427,857 as short-term monotherapy (abstract H-443). Fätkenheurer began his presentation by stating that preclinical data has shown UK-427,857 to be active against HIV that is resistant to different drug classes. In his study, 24 patients who were prescreened for having CCR5-tropic virus took placebo or UK-427,857 at 25 mg once daily or 100 mg twice daily. Upon entering the trial, participants had CD4 counts greater than 250 cells/mm3 and viral loads greater than 5,000 copies/mL. By the eleventh day of treatment, people who were taking the 25-mg dose had a mean viral load drop of 0.4 log, while those who were taking the 100-mg dose saw a mean decrease of 1.4 log. The adverse events were described as neither serious nor severe. Pfizer is studying different doses for a phase II trial.

Abacavir as a Once-Daily Drug

Two studies examined regimens that contained a once-daily form of abacavir. The drug’s manufacturer, GlaxoSmithKline, is aggressively pursuing this new formulation as a way to enter the popular once-daily market.

Brian Gazzard of Chelsea and Westminster Hospital in London offered detailed results of the ZODIAC study, which compared once-daily administration of abacavir with twice-daily administration of the drug in 770 therapy-naive volunteers (latebreaker abstract H-1722b). The participants had a mean viral load of nearly 80,000 copies/mL; 44% of them had viral loads greater than 100,000 copies/mL. Both groups also took a background regimen containing efavirenz and lamivudine (3TC). After 48 weeks, 66% of people taking once-daily abacavir versus 68% of those taking twice-daily abacavir had viral loads less than 50 copies/mL. Rates of virologic failure were also similar: 10% for the once-daily group and 8% for the twice-daily group. The most common mutations observed in people experiencing virologic failure were M184V (48%), K103N (45%), and L74V (26%). Median gains in CD4 counts were 188 cells/mm3 for the once-daily arm and 200 cells/mm3 for the twice-daily arm. Hypersensitivity reaction, a potentially life-threatening side effect of abacavir, occurred in 9% of the once-daily group and 7% of the twice-daily group.

The investigators concluded that once-daily dosing of abacavir was just as effective as taking the drug twice daily. However, questions arose as to whether the potency of efavirenz, which was used in both trial arms, might have masked any differences between the once-daily and twice-daily formulations of abacavir. It will be important to see how the once-daily form of abacavir fares when used in combination with other drugs.

Another study presented at ICAAC did just that, and produced highly disappointing results. Joel Gallant of Johns Hopkins University in Baltimore presented data on Glaxo-sponsored ESS30009, a trial that compared two once-daily regimens in 345 treatment-naive people (latebreaker abstract H-1722a). Abacavir dosed with 3TC and tenofovir was tested against abacavir dosed with 3TC and efavirenz, and an unplanned interim analysis was performed on the first 194 participants to reach at least eight weeks in the study after numerous investigators reported poor outcomes. Researchers discovered that 49% of the patients in the tenofovir group had viral loads less than 400 copies/mL, as opposed to 90% in the efavirenz group. Forty-nine percent of patients taking tenofovir were classified as virologic non-responders, in comparison with 5% of those taking efavirenz. In addition, the M184V and K65R mutations (indicating resistance to all of the drugs in the regimen) had emerged in most of the tenofovir non-responders.

Based on these dismal results, investigators halted the tenofovir arm and urged that the abacavir, 3TC, and tenofovir combination not be used. Gallant offered several potential reasons for the results, two of which he all but dismissed. The first possibility is that abacavir is not adequate as a once-daily drug, but Gazzard’s study would seem to contradict that. The second is that a drug interaction exists between abacavir and tenofovir. However, Gallant pointed to a poster (abstract A-1615), authored by Brian Kearney and sponsored by tenofovir’s manufacturer Gilead Sciences, which revealed that tenofovir and abacavir do not alter each other’s pharmacokinetics, according to blood level measurements of each drug.

According to Gallant, two other explanations were more plausible. One is that although the drugs do not interact in plasma, they may do so on an intracellular level. This possibility is under investigation. “We can’t yet study intracellular levels of tenofovir, but we should be able to soon,” Gallant stated. “An assay is being developed by Gilead, but it is not yet available.”

Another hypothesis is that there may have been a low genetic barrier to resistance in this triple-nucleoside regimen. David Margolis, of the University of Texas Southwestern Medical Center at Dallas, explained: “A combination of two mutations affects the activity of all three drugs in the regimen. The K65R mutation confers resistance to tenofovir and is also selected by abacavir. M184V confers resistance to 3TC, is selected by abacavir, and also impacts tenofovir.” So once the virus became resistant to one of the drugs, it also became resistant to the other two. This translated into a weak antiviral regimen.

Whatever the reason, Gallant promised that the issue would be investigated. What was unmistakable was that many HIV-infected people who had never received treatment had both failed their first regimen and developed resistance to key drugs that will hamper their future therapy options. As a result, some conclude that a smaller pilot study of this combination should have preceded the large trial. As Gallant stressed, “I think it shows that people should prescribe drugs based on clinical trial data, and not because certain drugs seem like they would work well together.”

Monotherapy: Making a Comeback?

Results of another study involving treatment-naive people appeared on a poster from Joe Gathe of Therapeutic Concepts in Houston (abstract 2608). With the acknowledgment that HAART is both highly toxic and costly, Gathe started 30 patients on therapy with Kaletra at his inner city clinic. Kaletra is a fixed-dose combination of lopinavir and ritonavir. Since it is a single pill and ritonavir merely acts as a boosting agent, it could be considered a single drug. Gathe chose Kaletra because of its potency and because resistance is slow to develop in treatment-naive patients who take the drug.

The mean viral load of 30 volunteers at the start of the study was 262,020 copies/mL. After 24 weeks, 21 people remained, and 70% of them had viral loads less than 400 copies/mL.

Though initially impressive that a single drug could produce such a result, the concept was not universally applauded. “I think a lot of people were terrified by it, too,” remarked Margolis. “And if you look at the whole picture, there were a lot of drop-outs.” Indeed, nine patients—almost a third—abandoned the trial, for the following reported reasons: lost to follow-up (2), gastrointestinal intolerance (2), deportation (1), non-adherence (1), virologic failure (1), hepatitis B infection requiring the addition of tenofovir and 3TC (1), and virologic non-response requiring the addition of saquinavir (1).

The trial was also limited in that it did not enroll a comparative arm; a triple-drug arm might have yielded results that would have cast the Kaletra-only arm in a more unflattering light. Margolis also pointed out that a time span of 24 weeks was too short to draw any definitive conclusions. The investigators plan to extend the trial to 48 weeks.

So while this conference did not feature any stunning surprises or breakthroughs, it certainly provided attendees with plenty of food for thought until the next big HIV conference.

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