“The big issue in my neck of the woods is access in terms of cost of therapy,” said Joseph Gathe, who runs an inner city clinic in Houston. “ADAP [the AIDS drug assistance program] is going broke. People with low-paying jobs and no insurance are ineligible for ADAP. Even if you have insurance, there are outrageous copays. People have to switch medicines based not on science, but on cost. We have to make treatment decisions based on insurance copayments and formularies. This is not the way people should be treated.”

After watching many of his patients forgo therapy because they could not afford it, Gathe postulated that one antiviral, if potent enough, could suppress HIV and shave two thirds off the cost of therapy. He chose Kaletra because HIV is comparatively slow to develop resistance to it.

At the XV International AIDS Conference in Bangkok last July, Gathe presented the results of his trial (abstract MoOrB1057). He enrolled 30 people who had never taken antiretrovirals and prescribed only Kaletra for 48 weeks. Ten participants dropped out, for reasons ranging from virologic failure (2), to adverse events (2), adherence problems (2), “lost to follow-up” (2), hepatitis B (1), and deportation (1). The remaining 20 individuals suppressed their viral loads to below 400 copies/mL; 10 of them suppressed viremia to less than 50 copies/mL. According to Gathe, none of the remaining participants have developed any “discernible resistance” to date.

Although Gathe cautioned that one-drug therapy should not become routine clinical practice, it could be a strategy for patients who cannot afford three drugs.

“It’s a bad idea,” stated Howard Grossman of the Polari Medical Group, one of the largest HIV clinics in New York. Grossman pointed out that in an intent-to-treat analysis of the trial, which counts patients who discontinue the therapy as failures, the success rate was only 67%. “Joe Gathe is an outstanding physician, and he works with a difficult population,” Grossman acknowledged. “But a third of his patients failed. That’s not an acceptable number.”

Gathe plans to move forward with a larger study financed by Kaletra’s manufacturer, Abbott Laboratories. Abbott has also enrolled 150 patients in additional trials in the US and Europe to also examine this controversial approach.

Although Gathe’s study will not have a control group, Abbott’s comparative trial will match Kaletra against a three-drug regimen of efavirenz and Combivir (AZT/3TC). Monotherapy participants will begin taking Kaletra and the two nucleosides, then either continue this regimen or drop the nucleosides and take only Kaletra. The control group will take efavirenz and Combivir throughout the trial.

“It’s too early to draw conclusions about how this strategy will work, if it works,” commented Scott Brun, Abbott’s divisional vice president for infectious disease development. “Potent, single-agent therapy is interesting because eliminating agents has advantages. With fewer drugs, one might expect less toxicity. And a simpler regimen may improve adherence.”

Brun commended Kaletra as the ideal candidate for monotherapy, “because an accumulation of data supports this.” He cited the Abbott 720 study data that demonstrated that over 5 years 65% of people had viral loads below 50 copies/mL, “with no evidence of lopinavir [Kaletra’s main ingredient] or protease inhibitor resistance.”
Grossman disputed this argument. “Abbott is always saying that people who fail don’t have Kaletra resistance,” he said. “But there are always new mutations. It’s like when Bristol-Myers Squibb said that d4T resistance didn’t exist because they couldn’t find it. There’s resistance with every drug.”

Grossman also criticized the claim that Kaletra monotherapy reduces the side effects of combination therapy. “Most side effects in a triple-drug regimen are from Kaletra. It causes lots of gastrointestinal problems and high lipids.”

Rob Camp, antiviral project director at Treatment Action Group in New York, echoed this concern. “I don’t have many qualms with Kaletra, but the drug has lots of side effects. It’s no day at the beach.”

Posters displaying short-term results from the Abbott-funded trials were available at the Bangkok conference. One study recruited 19 volunteers whose triglyceride levels shot up 90% after 24 weeks of monotherapy (abstract TuPeB4577). Another trial enrolled 18 people, three of whom stopped the drug because of diarrhea (abstract TuPeB4595). Gathe emphasized that his next trial will investigate the drug’s side effects or lack of them. “We want to determine whether the side effects really go away with monotherapy. If we could identify the toxicities for each drug, we could dispel controversies over which drugs cause which toxicities.”

But Grossman warned, “People won’t want suboptimal therapy with one drug when they can have more potent therapy with three.” He does not believe monotherapy will catch on, especially in the US. Grossman also speculates that Abbott is putting money into testing Kaletra monotherapy for the developing world, where people are desperate for treatment.

Abbott’s critics refer to the monotherapy trial as evidence that the company is more interested in marketing its existing products than developing new ones. This claim has been substantiated by data from Pharmaprojects, a pharmaceutical tracking company. Abbott has not reported any anti-HIV compounds in development this year.

“Basically Abbott has closed down their HIV department,” said Camp. “They haven’t presented a new molecule for at least 2 years. They’re trying to make as big a buck as possible with what they already have.”

Brun dismissed this allegation. “We’re certainly doing both,” he said, referring to reformulating old drugs and testing new ones. “You want to make sure that you use the tools you already have. Right now we’re focusing on protease inhibitor development, because that’s our expertise. We’re evaluating preclinical candidates that address Kaletra’s shortcomings but can maintain its potency. We’re also working extensively on hepatitis C, which is immensely important for people with HIV.”

Abbott made enemies in the activist community last December, when it increased the price of its protease inhibitor ritonavir (Norvir) by 400% (see the April 2004 Treatment Insider, “Abbott Finds Profit in Old Drug”). Now, some regard Abbott with suspicion.

“Abbott knows the game plan,” Camp remarked. “If they get monotherapy approved, they’ll probably raise the price of Kaletra to be the same as triple-drug therapy. These people really do stay up all night thinking of ways to take home all the bacon.”

Grossman disagreed, arguing that the chances of the FDA approving Kaletra as monotherapy were slim. Yet he insisted that this is a secondary issue. “You don’t have to get it approved to get people to write the prescriptions,” he contended. “By testing the approach, Abbott got people talking about it. After Gathe’s presentation in Bangkok, I heard people saying, ‘I should try that.’ Doctors will start writing it off label. It happens all the time, but it’s not the way to do science.”

Gathe admitted that Abbott’s past behavior was questionable, but argued that his first priority is addressing his own patients’ lack of resources. For now, Kaletra monotherapy is the best option. “Regarding ritonavir’s price increase, I share everyone’s concerns about that predatory action. I’ve made these concerns known to the Abbott corporate executives,” he said. “But at the end of the day, I have to treat my patients with what I have.”