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Clinicians and patients who are disenchanted with protease inhibitors (PIs) typically have two major concerns: The drugs cause side effects that make life uncomfortable for patients, and clinicians are finding more PI resistance among their HIV patients, possibly because side effects of PIs are discouraging patient adherence to PI regimens.
"A lot of doctors, including myself, have been avoiding protease inhibitors because of the gastrointestinal side effects of nausea, bloating, gas, and diarrhea, which made patients very uncomfortable," says Charles F. Farthing, MD, medical director of AIDS Healthcare Foundation (AHF) Healthcare Center in Los Angeles. The community-based provider of HIV medical care serves 4,500 patients in nine clinics.
"So patients would stop taking the drugs and didn’t adhere well to them, and of course, if you don’t do that, you are lost," Farthing adds. He has been involved in research into a new drug that seems to answer some of these concerns: the next-generation PI lopinavir/ritonavir (Kaletra), produced by Abbott Laboratories of Abbott Park, IL.
"Kaletra came out as an approved drug last September, and it was available in expanded access for a good 18 months before that, so we have good clinical trial experience with the drug," Farthing says. "It’s a well-studied drug, and I think it’s fair to say that it’s more potent than anything else we have at the present time, and certainly within the PI class, it’s definitely the most tolerable."
A 48-week study of treatment-naive patients showed that of those who experienced viral rebound while being treated with lopinavir, none were found to have PI-resistant HIV by genotypic analysis. By comparison, 32% of the patients treated with a nelfinavir-based regimen had PI-resistant HIV, according to data presented at the 8th Conference on Retroviruses and Opportunistic Infections, held Feb. 4-8 in Chicago.
In fact, none of the patients in a two-year lopinavir clinical trial of naive patients have become resistant to the drug, Farthing notes. "But a few people who previously were resistant to other PIs and then were introduced to Kaletra became resistant to it," he adds.
In a separate study presented at the conference, investigators showed that at 48 weeks of treatment with lopinavir and other antiretrovirals, 84% of children who were treatment-naive and 75% of children who had treatment experience had undetectable levels of HIV. Only 2% of the 100 children were forced to discontinue treatment because of side effects. Unlike other PIs, lopinavir is indicated for children as young as six months.
Lopinavir research also may address some clinicians’ concerns about cross-resistance, Farthing says. A study of viral isolates from 56 patients who already were resistant to a single protease inhibitor but had not taken lopinavir prior to the study were treated with lopinavir for rescue. Four of these patients subsequently developed resistance to lopinavir, but those viruses still showed susceptibility to amprenavir and saquinavir.
"Some doctors have been concerned about using this protease inhibitor first because if a virus becomes resistant to it, they thought it would become resistant to all other PIs," Farthing explains. "This research demonstrates that that certainly is not always the case."
Lopinavir’s main drawbacks are the same ones found with other protease inhibitors. While lopinavir apparently produces fewer gastrointestinal side effects, it is associated with elevated levels of cholesterol, triglycerides, and plasma glucose, similar to the effects seen in patients taking other PIs, Farthing says.
Also, the drug may be associated with a similar amount of fat redistribution, although it’s too early to know for certain. "Like other PIs, Kaletra can cause raised fat levels, and that’s something the doctor has to watch for and either treat or take the patient off of Kaletra," Farthing says. "It’s not a big enough concern when putting a patient on the drug in the first place, but it might be a reason to switch away from the drug if it becomes a problem."
The drug is taken as three pills twice a day, and there are no food restrictions.
"The most useful thing is Kaletra can salvage some patients because it can treat some resistant viruses, and I suppose that’s what impresses me the most about the drug," Farthing adds.