Special Report - Coverage of the 41st ICAAC: Drug resistance test shows encouraging results
Drug resistance test shows encouraging results
Kaletra shows no drug resistance in 96 weeks
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The latest research suggests that HIV drug resistance is a bigger problem than investigators and clinicians previously believed. A national study of the prevalence of drug resistance found a high rate of drug resistance among HIV patients with measurable levels of virus in their blood. The study was presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held Dec. 16-19 in Chicago. Using ViroLogic’s PhenoSense HIV phenotypic drug resistance test, the resistance study found that 78% of HIV patients with more than 500 copies of HIV RNA were infected with a strain that is resistant to at least one antiretroviral drug.1 The resistance study measured drug resistance among participants in the HIV Cost and Service Utilization Study, which included 209,000 HIV-infected adults in the United States who were receiving medical care in 1996 and were followed for at least two years after that.
Resistance rates higher than expected
"The rates of resistance are higher than people are anticipating," says Nick Hellmann, MD, vice president of clinical research for ViroLogic Inc. of South San Francisco, CA. The resistance study was the first one that studied the magnitude of drug resistance, using a broad cross-section of HIV-infected people, Hellmann says. "Most of the other studies have focused on specific geographic areas or practice settings or a clinic here or there."
Phenotypic resistance testing cannot be done on patients who have viral loads of fewer than 500 copies, so about one-third of the HIV-infected people whose samples were collected were excluded from resistance testing, Hellmann says. But even if it were assumed that those with better viral suppression had no evidence of drug resistance, HIV drug resistance would be found in half of those infected with HIV, Hellmann says. He adds that it’s likely that some portion of those with suppressed virus also have drug resistance.
Specifically, the study found HIV drug resistance to nucleoside reverse transcriptase inhibitors in 70% of tested patients, resistance to non-nucleoside reverse transcriptase inhibitors in 31% of patients, and resistance to protease inhibitors in 42% of patients. Among those who were receiving antiretroviral therapy, drug-resistant virus was evident in 87% of the subjects. Drug resistance also was found in 41% of patients who were not receiving therapy but who previously may have received treatment, and in about 20% of those who were treatment-naive, Hellmann says.
Kaletra study shows hope
An unrelated study brought more positive news: Research continues to show that the combination of lopinavir/ritonavir (Kaletra) provides prolonged potency while avoiding drug resistance. "We have three studies now in treatment-naive patients in whom we have not detected any resistance to Kaletra or any protease inhibitor," says Eugene Sun, MD, vice president of anti-infective and antiviral drugs for Abbott Laboratories of Abbott Park, IL.
One Phase III study includes about two years of observation of 300 patients on Kaletra and 300 on nelfinavir. The Kaletra arm shows no drug resistance, and the nelfinavir arm shows resistance in the range of 35% to 40%, Sun says.2 Of 40 volunteers on the Kaletra regimen, none showed resistance as measured by genotype; of 84 volunteers in the nelfinavir arm, 28 showed resistance.
With this and other evidence of high rates of drug resistance among the HIV-infected population, the Kaletra study offers hope that at least some antiretroviral drugs will remain potent for longer periods of time. The Kaletra study, while involving a limited population, is encouraging, Hellmann says. "Abbott is on the right track as far as developing drugs that are very potent and hopefully will have very favorable resistance properties so that it is more difficult for the virus to become resistant to the drug," Hellmann says. "Unfortunately, the virus can develop resistance pretty readily to lessen all the drugs at various times of patients’ life cycles."
The key is for clinicians to develop a regimen that provides the best overall viral suppression and is well-tolerated, Sun says. "There are some 15 drugs on the market for HIV now, and physicians get all kinds of mixed messages about what kinds of combinations to use them in and which to use," he says.
The sixth protease inhibitor to be approved, Kaletra is showing no drug resistance so far probably because of its high drug concentration, Sun says. "We think the whole problem with resistance in HIV and other anti-infective areas is related to inadequate drug levels, which gives the virus a chance to mutate and figure out how to get around the drug," Sun says. "The whole idea behind Kaletra was to avoid as much as possible any chances of low drug concentration."
A potent punch
With the addition of ritonavir to boost the levels of lopinavir, the combination capsule, taken twice a day, provides a very potent antiretroviral punch, Sun explains. Viral suppression rates in the two arms at week 60 were 74% in Kaletra and 62% in nelfinavir, Sun says. Phase III study participants taking Kaletra reported some side effects, including lipodystrophy (5%-7%), and about 5%-8% have discontinued the therapy because of side effects, Sun says. Drug resistance will be the key to future HIV therapies, he says. "I think one of the key features of HIV drugs is how long they last," Sun says. "HIV lasts your entire life, and you want a drug that will last several years, so the goal of successful treatment is to have drugs that last as long as possible."
With that in mind, Abbott Laboratories will continue to follow patients taking Kaletra to study the drug’s potency over three or more years, he says.
References
1. Richman D, Bozzette S, Morton S, et al. The prevalence of antiretroviral drug resistance in the US. Presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago: Dec. 16-19, 2001. Latebreaking Abstract.
2. Bernstein B, Kempf D, King J, et al. Comparison of emergence of resistance in a blinded Phase III study with Kaletra (lopinavir/ritonavir) or nelfinavir plus d4T/3TC from week 24 through 96. Presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago: Dec. 16-19, 2001. Abstract I-1768.
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