American Foundation for AIDS Research, October 2003
Elizabeth Paukstis

As much of the fanfare at this year's 2nd IAS Conference on HIV Pathogenesis and Treatment in Paris centered on appearances by Nelson Mandela and Jacques Chirac, a grim certitude was present throughout each plenary, forum and wine-tasting reception: people with HIV still need new drugs.

Indeed, one of the largest stories to break was the CATCH study, which tested 1,633 recently infected people in 17 European countries (abstract LB1). The study found that 10% of patients were already resistant to at least one of three types of antiretrovirals. New drugs that work against drug-resistant strains are particularly in demand.

Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, underscored these points in his keynote lecture, titled "20 Years of HIV Science." After referring to the 22 formulations and 19 drugs that have been approved for HIV, Fauci described the limitations and difficulties associated with them, concluding, "the challenges of new and better drugs are an important part of our scientific agenda for the coming years."

Out with Old, in with Not Much New

One latebreaker session included presentations on two new drugs currently in human trials. Pedro Cahn of the Hospital Fernandez in Buenos Aires presented data on Shire's SPD754, a cytidine analog active against nucleoside-resistant isolates (abstract LB15). In a 10-day monotherapy trial, 62 treatment-naïve people took placebo or SPD754 at doses of 400, 800, 1,200 or 1,600 mg. Baseline viral loads ranged from 5,000 to 100,000 copies/mL. The biggest drop in viral load, 1.65 log, occurred in the 1,200-mg group. This difference was clinically significant compared with placebo. There were no significant changes in CD4 count, and researchers described the adverse events as mild to moderate and unrelated to the dose. The lack of CD4 response to SPD754 will warrant careful observation during longer-term studies.

The results of a study involving Tibotec's investigational protease inhibitor, TMC114, were also presented (abstract LB16). Fifty patients who had failed two to four PI-based regimens received TMC114 boosted with ritonavir at 300/100 mg twice daily, 600/100 mg twice daily or 900/100 mg once daily. A control arm continued on its failing regimen. After 14 days, viral loads declined by 1.13 log in the 900-mg arm, 1.24 log in 300-mg arm and 1.50 log in the 600-mg arm. Adverse events, described by the investigators as mostly mild and not associated with dose, were primarily gastrointestinal or CNS-related. The company is planning a phase IIb trial.

Though these studies may be promising, they both represent drugs from classes that already contain several approved agents. So another question arose: where were data on the newer drug classes, such as integrase inhibitors and entry inhibitors?

Emilio Emini, Merck's Senior Vice President for Vaccine Research, discussed his company's development program for integrase inhibitors and vaccines at a pharma-sponsored meeting before the conference. Although he reported some encouraging results from a monkey study with L-870810, an integrase inhibitor, progress appears slow. "Preclinical observations [of L-870810] require investigation before proceeding with continued human testing," said Emini, adding that Merck had several more integrase inhibitors in the preclinical stage.

Indeed, Robert Murphy of Northwestern University in Chicago asserted that for many new drugs, it was just too early. "There's a lot of new stuff in preclinical," Murphy said, "and it's just not ready to be presented yet." Still, data from CCR5 antagonists that are being tested in humans, such as Pfizer's UK-427,857 and Schering-Plough's SCH-D, were not presented. Chris Hitchcock of Pfizer said that early phase II data on UK-427,857 would be disclosed at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September. "We presented a lot of data last February at the Retrovirus conference. We wanted to give people a much bigger overall picture-which is what we'll do at ICAAC-and that's why we didn't present anything at the IAS meeting."

Daniel Kuritzkes from Harvard Medical School in Boston also attributed the lack of new drug data at IAS to the conference's timing. "I think this is a symptom of too frequent meetings," Kuritzkes remarked. "There were a great deal of new drug data presented at the Retrovirus conference in February, and it's been only five months since then. I don't think this reflects a loss of momentum. Various companies are moving forward with their products, and I wouldn't have expected too much from these companies at this time."

New Info on the Newly Approved

While investigational drugs were not the conference's focus, presentations on two recently approved drugs offered a few insights. Atazanavir, approved in June 2003, was the subject of two back-to-back oral abstracts. Cal Cohen of the Community Research Initiative of New England in Boston presented data on BMS AI424-043, in which 290 people who were failing a PI regimen were randomized to unboosted atazanavir 400 mg once daily or Kaletra, plus two nucleosides (abstract 117). The 24-week results showed viral load decreases of 2.0 log for the Kaletra group and 1.7 log for the atazanavir group, a difference that was clinically significant. Atazanavir was not as effective as Kaletra, though average cholesterol levels were lower in the atazanavir arm.

But 24-week results from BMS AI424-045, presented by Bonaventura Clotet from Hospital Universitari Germans Trias I Pujol in Badalona, Spain suggest that boosting atazanavir with ritonavir improves its effectiveness without necessarily boosting cholesterol (abstract 118). In this study, 347 people took tenofovir and one nucleoside, plus either Kaletra or atazanavir boosted with ritonavir or saquinavir. Drops in viral load were 1.5 log for atazanavir/saquinavir, 1.9 log for atazanavir/

ritonavir and 1.9 log for Kaletra. Both atazanavir arms had better lipid profiles than Kaletra. But it will be important to see how these results play out beyond just 24 weeks.

In a latebreaker (abstract LB2) from David Cooper of the University of New South Wales, Australia, another newly approved drug took center stage. Cooper's presentation showed that T-20, approved in March 2003, continued its durability after 48 weeks of treatment. Past research indicated that 33% of people taking T-20 and 15% of those on an optimized background regimen had undetectable viral loads after 24 weeks. After 48 weeks, those numbers were 30% and 12%-a statistically significant difference.

The atazanavir and T-20 studies serve as reminders of how 2003 has already seen the approval of three new drugs (FTC debuted in July). The lack of phase II/III drug data at the Paris IAS conference suggests that the rate of new drug approval in 2004 may struggle to maintain the pace set in 2003.

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