Drug Combinations Reduce HIV Levels in Untreated Patients
Barcelona – Combinations of drugs can significantly reduce the concentration of HIV in patients' bodies, even in those with advanced HIV disease, according to interim results of a study presented today (July 9, 2002) at the XIV International AIDS Conference in Barcelona, Spain.
Researchers led by John A. Bartlett, M.D., professor of medicine at Duke University Medical Center (Durham, NC), found that at least 75 percent of never-treated HIV-positive patients had "viral loads" decrease to the target level of less than 400 copies/mL when treated for 48 weeks using any of three drug combinations.
The term "viral load" -- measured in copies of the HIV-1 genetic material RNA per milliliter of blood -- describes the activity of the HIV in a person's body. The viral load is one indicator physicians use to determine how advanced a patient's HIV disease is. Drugs classified as "antiretroviral" reduce a person's viral load by preventing HIV from replicating within the body.
A viral load greater than 55,000 copies/mL is considered high enough to need treatment; physicians strive to reduce patients' viral loads to below the limits of detection.
"Our preliminary results suggest that even patients with advanced HIV infection can benefit substantially from currently available therapies," said Bartlett. "The challenge to researchers and physicians is to find the combinations that will achieve the best long-term results with the fewest side effects."
These findings represent interim results of the Clinically Significant Long-term Antiretroviral Sequential Sequencing Study (CLASS) sponsored by GlaxoSmithKline. The study was conducted at 43 sites in the United States and Central America.
The CLASS study enrolled 291 HIV-positive patients with initial viral loads greater than 5,000 copies/mL. Forty-two percent of the patients had viral loads of more than 100,000 copies/mL at the beginning of the study.
Patients who had previously used antiretroviral treatments for more than two weeks were excluded from the study.
Each patient in the study was prescribed two medications:
-- abacavir (trade name Ziagen) and
-- lamivudine (Epivir), both from the "nucleoside reverse transcriptase inhibitor" class (NRTI) of antiretroviral treatments. The NRTI class of drugs inhibits the reverse transcriptase enzyme that the virus needs to copy its RNA to DNA, in the process of commandeering the cell's machinery. The term "nucleoside" denotes the structure of the compound, meaning that it mimics one of the nucleoside units of DNA and interferes with the enzyme by that mimicry.
Patients also were given a third medication from one of three classes:
-- a "nonnucleoside" reverse transcriptase inhibitor (nNRTI), efavirenz (Sustiva)
--an NRTI, stavudine (Zerit) or
-- a protease inhibitor combination (PI), amprenavir/ritonavir (Agenerase and Norvir). Protease inhibitors interfere with the enzyme that HIV needs to snip apart the protein it creates in reproducing itself. Such snipping is the final step in producing the working proteins that constitute the virus.
At the end of 48 weeks, at least 75 percent of patients in each of the three groups had viral load measurements of less than 400 copies/mL in these abacavir/lamuvidine containing regimens.
The group of patients using abacavir and lamivudine in combination with an nNRTI (efavirenz) experienced the greatest decline in viral loads, with 75 percent of patients having viral loads of less than 50 copies/mL at the end of 48 weeks.
Among patients in the nNRTI group with initial viral loads of 100,000 copies/mL or more, 86 percent had 48-week viral loads of less than 400 copies/mL and 77 percent had viral loads of less than 50 copies/mL after 48 weeks of treatment.
Patients were switched to a different class of antiretroviral treatment under any of three circumstances: their viral loads failed to reduce to the target level of 400 copies/mL by week 24; their viral loads reduced to 400 copies/mL but rose to more than 1265 copies/mL (as measured at two consecutive visits) after week 24; or if they developed side effects from the medications.
"While patients in the nNRTI group had the greatest reduction in viral loads to less than 50 copies/mL, all three groups showed impressive changes in their viral loads," said Bartlett. "The 96-week results will give us a clearer picture of which group sustains their reduced levels best over time."
A common problem in controlling viral loads is the HIV virus' ability to become resistant to one or more drugs in a patient's regimen, said Bartlett.
Drug resistance can also develop when patients fail to adhere to their medication routine as prescribed, added Bartlett. If patients develop intolerable side effects from medication, they may not use the treatments as prescribed, providing the HIV an opportunity to develop resistance to the drugs, he said.
In this study, 38 percent of patients in the nNRTI group and 35 percent of patients in both the PI and NRTI groups experienced moderate to severe side effects, said Bartlett. The most commonly reported side effects were allergic reactions, hypertriglyceridemia (elevated concentration of the fatty molecules triglycerides in the blood), nausea, rash, diarrhea and sleep disorders.
"Side effects are one of the major reasons why patients fail to consistently take their medications as prescribed," said Bartlett. "If we can reduce patients' viral loads using drugs that are tolerable over an extended period of time, then we will have made great strides toward making HIV a chronic disease and helping our patients maintain a high quality of life."
This study was supported by funding from GlaxoSmithKline. Bartlett has served as a paid consultant to and has received speaking honoraria from GlaxoSmithKline. He holds no financial interests in GlaxoSmithKline.
Joining Bartlett in this research were Gisela Herrera, M.D., of SEMECO in San Jose, Costa Rica; Nestor Sosa, M.D., a private-practice physician in Panama City, Panama; Allan Rodriguez, M.D., of the University of Miami; and Judy Johnson, Qiming Liao, Ph.D. and Mark Steven Shaefer, all of GlaxoSmithKline in Research Triangle Park, N.C.