CONTACT: Tim Stephens
PHONE: (650) 725-8047 or 723-6911
EMAIL: [email protected]
EMBARGOED FOR RELEASE at 9 a.m. U.S. Eastern Time on Tuesday, Feb. 3, to correspond with presentations by Sarah Palmer and Jody Lawrence at the 5th Conference on Retroviruses and Opportunistic Infections, held at the Sheraton Chicago Hotel and Towers Feb. 1-5.
CROSS-RESISTANCE DULLS PROMISE OF NEW AIDS DRUGS; ëRESCUE THERAPIESà SOUGHT
STANFORD ó HIV strains that have developed resistance to a wide range of antiviral drugs constitute the gravest challenge now facing AIDS researchers in the battle against this deadly virus. Two new studies by researchers at Stanford offer mixed news to physicians and patients pinning their hopes on new compounds coming through the drug-development pipeline.
In one study, laboratory tests showed that many of the experimental drugs being developed by pharmaceutical companies, while potentially useful against nonresistant HIV, do not work against HIV strains resistant to currently available drugs.
The test-tube study did identify some promising new drugs for fighting highly resistant HIV strains. But it also reinforced concerns about cross-resistance ó the tendency for a viral strain that develops resistance to one drug to show resistance to all other drugs in the same class.
A second study ó a clinical trial focusing on currently available drugs ó confirmed that cross-resistance occurs not just in the test tube but also in patients.
The findings of both studies will be reported Tuesday, Feb. 3, in poster presentations at the 5th Conference on Retroviruses and Opportunistic Infections, held in Chicago. Postdoctoral fellows Sarah Palmer and Jody Lawrence will present the test-tube results and clinical findings, respectively. Palmer and Lawrence work in the Center for AIDS Research at Stanford under Dr. Thomas Merigan, Becker Professor of Medicine and director of the center.
ìIt is frustrating that so many of these new drugs are not going to work for patients who are harboring resistant viruses,î Palmer said.
Clinicians today have little to offer HIV-infected patients whose virus has developed resistance to multiple drugs, Lawrence noted. Such patients provide a sobering counterpoint to the remarkable treatment successes doctors have achieved since 1996 using powerful new combinations of antiviral drugs. In recent years, researchers led by Merigan have isolated viral strains resistant to virtually all of the drugs so far approved by the FDA for treating HIV infection.
ìWe have a situation where the glass is half full and half empty: About 50 percent of patients do very well on the new drug therapies, [but] we think it is important to understand what is happening in the other group,î Merigan said.
His team is attacking the problem from several angles.
ìWe are studying resistance both genotypically, looking at the genetic mutations that make the virus resistant, and phenotypically, looking at how the virus responds to drugs in cell cultures,î Merigan said.
ìWe are also conducting clinical trials, trying to find new combinations of drugs to fight these highly resistant strains,î he said.
AIDS researchers often refer to such treatments, tailored for HIV-infected patients who are failing to respond to potent drug regimens, as ìrescue therapy.î
Weapons at hand
The pharmaceutical arsenal lined up against HIV consists of two broad categories of drugs: those that inhibit the viral enzyme reverse transcriptase (RT) and a newer class of drugs that inhibit the protease enzyme.
The RT inhibitors include nucleoside analogs, which mimic the enzymeÃs cellular substrate; similar compounds with an additional phosphorus component; and non-nucleoside compounds that inhibit the RT enzyme through a completely different mechanism.
A patient on a typical drug regimen would receive two RT inhibitors and one protease inhibitor. Physicians monitor patientsà responses to treatment by measuring the amount of virus (ìviral loadî) in the blood. The greater the suppression of viral load, the more durable the patientÃs response to treatment is likely to be.
PalmerÃs study looked at two strains of HIV isolated from patients who had high viral loads despite drug therapy. One strain, MNR, had four genetic mutations that made it resistant to RT inhibitors. The other strain, MDR, had seven mutations conferring resistance to RT inhibitors and seven additional mutations conferring resistance to protease inhibitors.
Palmer grew the viruses in cell cultures and ìchallengedî them with experimental anti-HIV compounds ó new drugs recently developed by pharmaceutical companies and not yet approved for use in patients. She tested the MNR strain against six RT inhibitors and found it highly resistant to the new nucleoside analogs. This strain was partially susceptible to two phosphorylated compounds, however, and was completely susceptible to one non-nucleoside RT inhibitor.
The other virus, MDR, was tested against both RT and protease inhibitors. It showed resistance to two RT inhibitors and to five experimental protease inhibitors, but was sensitive to one protease inhibitor and to the same three RT inhibitors as the MNR strain.
Drug companies do not usually do this kind of testing, Palmer said.
ìIt is important for drug companies to test new compounds against highly resistant viral strains, because a lot of patients harbor these strains,î she said.
Palmer said she is particularly concerned about the protease inhibitors, because the only one she found to be effective against the MDR strain requires further development to make it clinically useful. Drug company researchers will have to improve the compoundÃs solubility so that it can be effectively absorbed by patients, she said.
Clinical confirmation
LawrenceÃs study looked at the clinical effectiveness of currently available protease inhibitors in patients with resistant HIV. Her study involved switching patients from a protease-inhibitor-containing drug regimen that was failing to suppress their viral load to a regimen containing a different protease inhibitor. The purpose was to see if the virus showed cross-resistance in actual patients as opposed to cell cultures.
ìWe needed to confirm that the cross-resistance we observe in vitro correlates with clinical effectiveness,î Merigan said.
Although retrospective studies have found apparent clinical cross-resistance in HIV, LawrenceÃs study is one of the few prospective trials to address the issue. The 16 patients in her study had large amounts of HIV in their blood despite having received at least six months of treatment with the protease inhibitor saquinavir (Invirase or Fortovase) in combination with RT inhibitors.
Initially, the researchers changed the regimen to include the protease inhibitor nelfinavir (Viracept). They also gave some patients different RT inhibitors in an effort to ensure that each patient received the most effective drug cocktail possible.
ìWe wanted to see if nelfinavir could be used for rescue therapy in patients who had been on saquinavir and had experienced a rebound in their viral load,î Lawrence said.
Most of the patients experienced a transient reduction in viral load on the new regimen. After three months, however, 14 of the 16 had just as much virus in their blood as they had before the trial began. Ten of those patients then switched to another protease inhibitor, indinavir (Crixivan), plus the non-nucleoside RT inhibitor nevirapine (Viramune). This combination appeared to have a more durable effect, but after six months only three patients (30 percent) continued to have virus levels below the limit of the assay for measuring viral load.
LawrenceÃs findings confirm a prevailing concept in the treatment of HIV infection, which holds that the most effective approach is to hit the virus as early as possible with the most potent drugs available.
ìAlthough we can find effective drug regimens for some patients who fail on the first regimen, all indications are that the first attempt is really our best shot at suppressing the virus,î Lawrence said.
Additional well-designed prospective studies are needed to evaluate potential rescue regimens for patients with drug-resistant virus, Lawrence said. One such trial is under way now at Stanford, using a drug regimen based in part on PalmerÃs in vitro study of experimental drugs.
ìWe [at Stanford] have a lot of patients who harbor highly resistant viral strains, and I would like to give these patients some hope that in the future there could be a rollover treatment for them,î Palmer said.
MeriganÃs lab is funded by grants from the National Institute of Allergy and Infectious Diseases. The groupÃs clinical studies, including LawrenceÃs, are also funded in part by grants from the pharmaceutical companies Hoffman-La Roche Inc., of Nutley, N.J., and Agouron Inc., of San Diego.
###
RSS