More potent, easier-to-use drugs are on the horizon

Studies tout durability of some PI combinations

Clinicians soon will hear a great deal more about new antiretroviral drugs, including new classes of drugs such as nucleotide reverse transcriptase inhibitors (RTI) and pyrophosphate reverse transcriptase inhibitors (PPRTI). Pharmaceutical companies also are focusing on making current treatments more potent, easier to administer, and durable for the long haul.

For example, at the 7th Conference on Retroviruses and Opportunistic Infections, held Jan. 30 - Feb. 2, 2000, in San Francisco, researchers presented an abstract on Triavir, a combination tablet formulation with three nucleoside reverse transcriptase inhibitors (NRTIs): abacavir, zidovudine (AZT), and lamivudine (3TC). The study found that the three separate drugs work as well when taken in one pill every 12 hours as when they’re taken simultaneously as separate pills.1

In other research presented at the conference, investigators demonstrated the high potency and durability of the twice-daily combination of the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine when combined with AZT and 3TC.2

"The therapy is quite active in patients with greater than 100,000 viral copies, and even in a few folks with greater than 500,000 copies," says Richard Pollard, MD, an investigator for the study and professor of internal medicine, microbiology, immunology, and pathology at the University of Texas Medical Branch in Galveston. Boehringer Ingelheim Pharmaceuticals Inc. of Ridgefield, CT, which is part of Boehringer Ingelheim GmbH International of Ingelheim, Germany, sponsored the research and is the company that developed nevirapine.

The research showed that 45% of patients taking the triple-drug combination of nevirapine, zidovudine, and lamivudine achieved suppression of HIV below the limit of detection at one year. These were 171 antiretroviral-naive patients who were randomized to receive the nevirapine combination or a placebo plus zidovudine and lamivudine. By contrast, 3% of the placebo plus AZT/3TC group achieved suppression to undetectable levels at 12 months.2

Nevirapine was developed as a twice-a-day drug, but many clinical studies have used it as a once-a-day drug, Pollard adds. "So the message is that it’s a fairly easy drug to give, and it’s very potent."

More than 1,000 HIV drug trials under way

While the retrovirus conference showcased a plethora of promising studies, clinicians will see many more in the next five years. There are more than 1,000 clinical trials under way involving drugs to treat HIV/AIDS patients. (See related story on current clinical research, p. 57.)

Adefovir dipivoxil, which is part of the new RTI class of antiretrovirals has been studied in 20 clinical trials and is being studied for the treatment of patients who are infected with both HIV and hepatitis B.

Tenofovir disoproxil fumarate, an acyclic nucleotide analogue that’s similar to adefovir, is in phase III trials that will administer one dose daily vs. a placebo to patients who have plasma HIV-1 RNA levels between 400 and 10,000 copies/mL.

An in vitro study of a PPRTI drug was presented at the retroviruses conference by U.S. Department of Veterans Affairs researchers.

Laboratory tests show that two foscarnet (PFA) prodrugs, MB-PFA and EB-PFA, are highly active against a panel of drug-resistant HIV strains, including those resistant to NRTIs like zidovudine and lamivudine.

"The prodrugs act on the HIV reverse transcriptase at a different place than the NRTIs and the NNRTIs," says Karl Hostetler, MD, professor of medicine at the University of California - San Diego and a researcher at the U.S. Veterans Affairs Medical Center of San Diego in La Jolla.

If the drug succeeds in clinical trials, it could be an ideal salvage therapy because of its potency against drug-resistant virus, Hostetler says.

Hostetler and co-investigator John W. Mellors, MD, director of AIDS research at the VA’s Pittsburgh Health Care System, have been working on this new class of drugs for more than 10 years.

The researchers took an old drug called phosphonoformate, which had weak activity against HIV, and found a way to increase its potency. "We had the idea that we could disguise phosphonoformate as a naturally occurring lipid, fat material, so the fat would help promote its entry into the cell," Hostetler says.

"We designed it so that every cell would have the ability to take this little molecule apart and release it within the cell interior," he adds. "And we believe that is how it works and why it shows 50 times greater activity in HIV-infected cells than the free phosphonoformate compound."

The drug will be easy to make, could be taken in pill or liquid form, and could be relatively cheap to manufacture because it has no expensive materials, Hostetler says.

VA funding dries up

Their research already has prompted clinicians to call them and ask if they are taking volunteers for clinical trials. But the researchers’ main problem now is obtaining funding for clinical trials because the VA has not expressed any interest in funding further research, Hostetler says.

"If we had a backer right now and enough money, it’d be 18 months to two years before we’d start clinical trials," he says.

The protease inhibitor (PI) ABT-378 is one of the new drugs in the most advanced stages of development. Several studies about ABT-378, developed by Abbott Laboratories in Abbott Park, IL, were presented at the retroviruses conference.

Studies focused both on treatment of naive patients and on patients who already had failed PI therapy. "What we found was that patients who came into the study with significant test-tube resistance to ABT-378 — even up to 20-fold — responded equally well to ABT therapy as did the patients who came into the study with nonresistant virus in the test tube," says Dale Kempf, PhD, senior project leader of antiviral research at Abbott Laboratories’ Pharmaceutical Products Division.

Kempf explains that ABT-378 works well clinically — even in patients who have PI resistance — because it has a high pharmacokinetic barrier that keeps the virus from replicating.

"There will come a point at which the virus becomes so resistant in the test tube that it’s able to overcome the high dam put forth by ABT-378, so what we’re doing now is studying other patients who have an even more highly resistant virus to PIs," Kempf says.

The treatment-naive study looked at a regimen of ABT-378 with a low dose of ritonavir combined with stavudine (d4T) and 3TC. At 72 weeks, the combination proved potent, with a viral load below 400 copies/mL in 98% of patients on treatment and below 50 copies/mL in 96% of patients.3

"We saw a very impressive suppression of HIV RNA," says Roy Gulick, MD, MPH, assistant professor of medicine at Weill Medical College of Cornell University in New York. Gulick was a lead investigator on the study.

Patients on triple-drug therapy often will have trouble taking the drugs over time because they may be experiencing unpleasant side effects or they may find their regimen to be too complicated, Gulick notes. "So they miss doses and this leads to viral breakthrough."

But with the ABT-378 study, only one person out of the 100 enrolled dropped out because of side effects, he says.

Also, the combination proved to be more convenient to patients because the capsules only needed to be taken twice a day, once with breakfast and once with dinner, Gulick adds.

"On the pro side, the combination therapy with ABT-378 and ritonavir certainly looks to be a very active drug against the virus, providing impressive virologic activity and durability of effect," Gulick says.

Still, clinicians may side with the school of thought that it is better to start with a regimen that spares PIs, and the long-term side effects of PIs are only now just being described, he adds.

"The field is growing, and what we’re really talking about now is treating people with antiretrovirals for years and years," Gulick says. "We want strong drugs that are well-tolerated over the long-term and easy to fit into people’s lives."

Now that PIs have been available for almost five years, there are more studies with long-term data showing the durability of that class of antiretrovirals.

For instance, the PIs ritonavir and saquinavir showed sustained viral suppression after 144 weeks, which was the longest study on PI therapy.4 About 85% of the 141 participants had undetectable HIV RNA levels during their three years of therapy, and 53 patients remained on the dual-PI therapy after three years.

"The study looks at people who were studied previously, had interrupted their treatment, and then went on to various doses of saquinavir and ritonavir," explains William Cameron, MD, lead investigator and professor of medicine at the University of Ottawa and Ottawa Hospital in Ottawa, Canada. The study was sponsored by Abbott Laboratories, manufacturer of ritonavir (Norvir).

"What the analysis means to me is that the majority of patients responded to ritonavir and saquinavir alone without any of the nucleoside drugs," Cameron adds.

References

1. Yuen G, et al. The bioequivalence of a fixed dose triple-NRTI combination tablet containing abacavir, lamivudine, and zidovudine. Abstract 98. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco; Jan. 30-Feb. 2, 2000.

2. Pollard R. Factors predictive of durable HIV suppression in randomized double-blind trial with nevirapine (NVP), zidovudine (ZDV), and lamivudine (3TC) in treatment-naive (ARV-n) patients with advanced AIDS. Poster 517. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco; Jan. 30-Feb. 2, 2000.

3. Gulick R, King M, Brun S, et al. ABT-378/ritonavir (ABT-378/r) in antiretroviral-naïve HIV+ patients: 72 weeks. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco; Jan. 30-Feb. 2, 2000.

4. Cameron DW, Xu Y, Rode R, et al. Three-year follow-up and conditional outcomes survival analysis of ritonavir plus saquinavir therapy in HIV infection. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco; Jan. 30-Feb. 2, 2000.