Antiretroviral update: 3 drugs are better than 1
NIH says RTIs work better with protease inhibitors
Results are in from the National Institute of Health’s "ACTG 320" study, and they confirm that adding a protease inhibitor (specifically, indinavir) to a dual regimen of reverse transcriptase inhibitors (here, zidovudine or stavudine and lamivudine) works better at controlling the AIDS virus than giving RTIs alone.
The nine- to 12-month study found that patients getting the triple therapy had half the number of AIDS-related diseases or death than those in the dual-therapy group.
The study confirms what antiretroviral researchers have been saying for months: The drugs work better when administered as a cocktail than when dosed alone.
At a meeting of the International AIDS Society in Atlanta last month, Victoria A. Johnson, MD, of the University of Alabama in Birmingham suggested that so-called "resistance" to the antiretrovirals might be caused by an ineffectual regimen or by a lack of patient compliance.
Johnson says resistance certainly plays some part in the failure of antiretroviral drugs, but that failure is probably more closely connected to such factors as using one drug instead of two or three. Combinations of antiretrovirals are better insurance against therapeutic failure because they’re more likely to suppress HIV replication to a maximal level.
Patients may stop taking their drugs
Non-compliance to an antiretroviral regimen can occur for many reasons patients may begin to feel better and stop taking their drugs, for instance, or the drugs may be too expensive. Whatever the case may be, non-compliance can result in a rebound effect with HIV.
Sometimes you can do everything right as far as drug therapy goes and still end up with a problem. One independent predictor of a poor outcome is the appearance of clumped-up T cells. Variants of HIV known as syncytium-inducing (SI) viruses cause the clumping. SI variants are especially virulent and often signal hard clinical times ahead for HIV patients.
Health care practitioners shouldn’t be dissuaded from using certain drugs just because they’ve had resistance problems in the past, Johnson says. They can still effectively halt the virus. But again, one of the best ways to prevent resistance from developing is to stick with a multidrug regimen instead of a monotherapy.
With multidrug regimens, one drug often will enhance the effect of the other. But this isn’t always the case. Lamivudine and zidovudine usually work well together. But there are some patients in whom the two drugs enhance only one thing: the development of resistance to both products.
The latest studies bolster support for multi-drug regimens in HIV. The protease inhibitor nelfinavir works far better at suppressing HIV when given with zidovudine and lamivudine. Given alone, it’s only a quarter as effective. The same is true with indinavir. When given with the new drug DMP-266, indinavir pulled viral loads down significantly in more than 80% of patients. When it was used alone, about half that number improved.
It appears vigilance is the only way to outsmart the AIDS virus. With resistance and supraviruses nipping at the heels of the antiretrovirals almost as soon as they hit the market, researchers are looking to a few new products to stay ahead.
ABT-378, another protease inhibitor, promises to make life easier for AIDS patients by allowing for daily or twice-daily dosing. The long-acting product is about 10 times stronger than ritonavir and works against strains of HIV resistant to that drug and to indinavir. Ritonavir, having perhaps outlived some of its usefulness as a first-line antiretroviral, can be used to potentiate ABT-378 even in doses as small as 50 mg.
A new reverse transcriptase inhibitor, code-named MKC-442, caused sizable drops in HIV RNA levels after just a week of twice-daily therapy. The drug is being studied in Germany, where researchers are determining how high it can be dosed before side effects kick in. So far, just one patient has experienced a rash.
A new broad-spectrum antiviral has entered Phase II studies. Adefovir dipivoxil is effective against HIV, CMV, HBV, and other herpes infections.
And finally, an old drug may be finding a ew use, if results of a Swiss study hold up. Hydroxyurea, when given with a combination of two other antiviral drugs, seems to help bring down total viral load. One drawback, though: Because hydroxyurea influences blood cell production and thus its efficacy in polycythemia vera CD4+ counts increased only minimally when the drug was used, even in comparison to a dual therapy.
HIV drug interaction alert: Rifamycins
Treatment for patients with AIDS and TB infections just got trickier. According to the Centers for Disease Control and Prevention in Atlanta, rifamycins (rifabutin, rifampin) and protease inhibitors interact with each other, sometimes dangerously. The rifamycins accelerate the metabolism of the protease inhibitors, leading to less active drug in the system. And the protease inhibitors inhibit the metabolism of the rifamycins, possibly leading to rifamycin toxicity.
How then, do you proceed with these patients? The U.S. Public Health Service says you’ve got three options, the last two untested in major clinical trials:
• Discontinue the protease inhibitors and initiate TB treatment with a six-month course of rifampin.
• Use a four-drug TB regimen that includes rifampin for two months. After drug susceptibility testing, continue the TB treatment using isoniazid and ethambutol, but not rifampin.
• Administer Indinavir as your protease inhibitor at a dose of 800 mg every eight hours. And for TB, administer a four-drug regimen for nine months using rifabutin 150 mg a day.
Meanwhile, it may have nothing to do with protease inhibitors, but Finnish researchers have found that rifampin effectively cancels out the effectiveness of triazolam, once again by revving up the P450 metabolic pathway.
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