Some existing drugs work on resistant HIV
Not all protease inhibitors are equal
HIV clinicians increasingly are confronted with failing combination drug therapies. Patients do well for weeks with the virus remaining suppressed, and then suddenly their viral load begins to rise. So physicians search through the current arsenal of medications to find combinations that will again fully suppress HIV.
Pharmaceutical companies are on the brink of offering clinicians a slew of new pharmacological weapons that are designed specifically to defeat drug-resistant HIV.
Here is a sample of some of the new and existing antiretroviral drugs that have been shown to be effective against drug-resistant virus:
• Amprenavir: Currently available, amprenavir has shown a smaller degree of susceptibility to protease inhibitor (PI)-resistant virus than four other PIs.
In vitro data presented at the 39th Interscience Conference on Antimicrobial Agents and Che mo therapy (ICAAC), held in September in San Francisco, showed that 22 (24%) of 92 virus samples isolated and cultured from patients had eightfold resistance to amprenavir. Nearly all of the patients had been previously treated with at least one PI, and the median number of PIs they had taken was three.
By comparison, the study found that 43% of the isolates showed a similar level of resistance to indinavir; 63% were resistant to ritonavir; 61% were resistant to nelfinavir; and 53% had resistance to saquinavir.
"We like to think [amprenavir] will have benefit in a second-line therapy, and maybe even more benefit if you boost its levels by adding ritonavir as well," says Eric Furfine, PhD, senior research investigator with Glaxo Wellcome in Research Triangle Park, NC.
Amprenavir, which was developed by Vertex Pharmaceuticals in Cambridge, MA, is manufactured by Glaxo Wellcome. The drug was approved by the Food and Drug Administration (FDA) in mid-1999.
Its most common side effects are an early onset of nausea, diarrhea, vomiting, rash, and perioral paresthesia. On rare occasions, the drug also has been associated with severe and life-threatening drug interactions, including Stevens-Johnson syndrome, spontaneous bleeding in patients with hemophilia A and B.
• DAPD: This is a dioxolane purine nucleoside reverse transcriptase inhibitor (NRTI) that has shown in vitro activity against drug-resistant strains of HIV, according to research presented at ICAAC.
A new drug, DAPD is a different-looking mole cule chemically and structurally from other NRTIs, says Bruce McCreedy, PhD, vice president for cli nical virology and diagnostics for Triangle Phar maceuticals in Durham, NC.
Triangle Pharmaceuticals is developing DAPD, which currently is in the preclinical phase of development and probably is a couple of years away from FDA approval.
"DAPD has shown very good activity against a variety of HIV-resistant isolates," McCreedy says. "Because of its different structure, it does have in vitro activity in the lab against resistant HIV, especially against HIV that has resistance to AZT and 3TC."
This means DAPD could be a potent drug for patients who have failed combination therapies of AZT and 3TC. However, the drug will need to undergo extensive clinical research before this can be proven, McCreedy says.
"We’ve done extensive preclinical work to characterize its in vitro resistance profile," he explains. "We’ve been doing the dose range-finding trials to determine what the optimum dose of DAPD might be in HIV-infected patients, including patients who harbor resistant forms of HIV," he adds.
DAPD is a guanine derivative, as is abacavir.
• Lamivudine: A commonly prescribed NRTI, lamivudine shows promise of having antiviral activity in patients who have a mutated HIV strain that is resistant to other NRTIs.
Five clinical trials, involving patients receiving initial treatment with an NRTI combination of either lamivudine plus zidovudine or lamivudine plus stavudine, showed that 92% of patients exhibited the M184V mutation, which is associated with a reduction in susceptibility to lamivudine. However, although the mutation emerged, patients continued to maintain low HIV RNA levels after a third NRTI or a PI was added to the lamivudine-containing combination, according to research presented at the Third International Workshop on HIV Drug Resistance and Treat ment Strategies held in June in San Diego.
Lamivudine, developed by BioChem Pharma of Laval, Quebec, and manufactured by Glaxo Wellcome, is generally well tolerated. Its most commonly reported side effects include head ache, nausea, malaise, fatigue, nasal congestion, runny nose, and diarrhea. In some cases there have been lactic acidosis and severe hepatome galy with steatosis with the use of nucleoside analogues alone or in combinations that include lamivudine.
• Tipranavir: The first of a new class of non-peptidic protease inhibitors, tipranavir is active against HIV strains that are highly resistant to four commonly used protease inhibitors: indinavir, ritonavir, nelfinavir, and saquinavir.
Developed by Pharmacia & Upjohn of Peapack, NJ, tipranavir was effective against 90% or 96 out of 107 strains of HIV that were resistant to PIs, according to research presented at the Third International Workshop on HIV Drug Resistance and Treatment Strategies.
Researchers speculate that tipranavir is immune to these PI-resistant strains because it is not a peptidic PI, as are the other protease inhibitors. Tipranavir binds in a flexible manner to the protease-active site.1 Tipranavir studies also have shown that the drug is well tolerated, with the main side effects related to gastrointestinal problems, including diarrhea. The drug is in Phase II clinical studies.
In addition, Glaxo Wellcome is working on a second-generation protease inhibitor program that is focused on treating resistance, Furfine says.
The program’s basic strategy is to make mole cules that are so potent against HIV that even if there is some resistance, they still will have enough potency to be effective, he explains. PIs already are the most potent class of HIV drugs.
Although the company is years away from clinical trials, the laboratory work so far shows that researchers can synthesize molecules that have significantly improved activity against wild-type virus and retain significant activity against viruses that are highly cross-resistant to the currently available PIs. Wild-type virus is a strain of virus most similar to what an HIV patient would have before taking any antiretroviral drugs.
The company’s also developing new non-nucleoside reverse transcriptase inhibitors and NRTIs, again with the focus on improving potency, Furfine says.
1. Larder B, Bloor S, Hertogs K, et al. Tipranavir is active against a large selection of highly protease inhibitor-resistant HIV-1 clinical samples. Abstract presented at the Third Inter national Workshop on HIV Drug Resistance and Treatment Strategies. San Diego: June 1999.