New drugs, new data hold promise for next decade of HIV treatment
Potency, tolerance are chief focus
Antiretroviral research presented recently at the 9th Conference on Retroviruses and Opportunistic Infections, held Feb. 24-28, 2002, in Seattle, demonstrates that investigators and pharmaceutical companies continue to strive for the next highly potent and easily tolerated anti-HIV drug. Among the new approaches are entry inhibitor drugs, non-peptidic protease inhibitors, and second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs). New studies also looked into potency against multidrug-resistant virus and medication regimens that are simpler to take and have fewer side effects.
Continued research into better HIV treatment will be crucial to keeping the epidemic’s death rate from increasing in light of evidence that antiretroviral drug resistance is rising dramatically. According to research by the Centers for Disease Control and Prevention of Atlanta, the presence of antiretroviral drug resistance among recently diagnosed, untreated HIV-infected individuals in five cities increased from 3.8% in 1998 to 9.0% in 2000.1
"The more drugs we can give patients in simpler formulations, the better," says Richard Pollard, MD, professor of internal medicine at the University of California - Davis Medical Center in Sacramento. "Now we have several different options for developing a whole regimen that is once a day, and that’s clearly the goal for many of us," Pollard says.
"I think it’s an exciting time right now because we’re starting to see companies develop drugs that will be either active against multidrug-resistant viruses or have multiple actions," says Doug Mayers, MD, international head of the therapeutic area of virology for Boehringer Ingelheim in Ridgefield, CT.
Another reason for optimism is the early evidence of success with compounds based on chemokines that can block the virus, including SCH-C, an entry inhibitor created by Schering-Plough Research Institute of Kenilworth, NJ. "I think the entry inhibitors are an interesting class of drugs," Mayers says. "They showed activity that looks pretty good, but the concerns are going to be that we use those receptors for immune function, so the consequences of blocking them are unclear."
Chemokines block key receptors
It was discovered in 1996 that three chemokines produced naturally in the body are capable of stimulating the immune system and blocking HIV. This led to an investigation into reproducing a chemokine antagonist that blocks key receptors of the virus, with the goal of blocking HIV’s initial entry into cells. Schering-Plough’s SCH-C is a new class of CCR5 antagonists that works by binding to CCR5 and blocking the entry of HIV-1 isolates that use the CCR5 receptor for infection.
Research presented at the retroviruses conference offered some evidence that SCH-C will increase CCR5 receptor expression and may have potency against HIV-1.2,3 In March, the Institute of Human Virology in Baltimore began Phase I clinical trials using SCH-C as treatment. Schering-Plough, along with the Aaron Diamond AIDS Research Center in New York City and ViroLogic in San Francisco, also presented a study of SCH-D, a small-molecule antagonist of CCR5 and an even more potent compound that is in preclinical development.4
Although the initial research offers hope that the virus will not shift to a different receptor when the CCR5 receptor is blocked, it’s unclear whether this will remain the case. "Whether blocking any one of the receptors or even two of them will give you a durable response or whether the virus will just shift around them or use a different receptor is unclear," Mayers says.
Bristol-Myers Squibb Co. of Wilmington, DE, is developing a nucleoside reverse transcriptase inhibitor (NRTI), called DPC 817, that shows potential for use in highly active antiretroviral therapy regimens for patients who are resistant to older NRTI agents.5 DPC 817 has shown activity against drug-resistant virus in non-human test subjects, but there are no clinical data so far, Pollard says.
New PI can be given once a day
Bristol-Myers Squibb also has a new protease inhibitor (PI), called atazanavir (Zrivada), that has the longest half-life of any PI on the market, Pollard says. "So it can be given once a day," Pollard says. "It seems very potent, and studies have compared it to nelfinavir."
However, the research, which was presented at earlier international meetings, suggests that atazanavir may be most useful as a first-line treatment and not for treatment of patients with multidrug-resistant virus, Pollard adds. "Mostly because of its ease of administration, it’d be attractive as initial therapy, where patients would take two pills of atazanavir and then a couple of nucleosides for a regimen that has four pills a day." Pollard notes that some of the new studies about drugs early in development look promising, including investigation into entry inhibitors. "And there’s interesting data on integrase inhibitors," he says.
Research into the use of integrase inhibitors still is preliminary. An abstract presented at the conference found potent in vitro integrase inhibition with the use of S-1360, an integrase inhibitor developed by Shionogi & Co. Ltd. of Osaka, Japan.6 Shionogi & Co. and Shionogi USA Inc. of Florham Park, NJ, have the oral drug under clinical development in the United States.
Another potential antiretroviral is BCH-13520, a new heterosubstituted nucleoside analog that has shown potential as an inhibitor of wild-type and resistant HIV-1, according to in vitro studies.7 Data presented at the retroviruses conference showed that the compound, which is an NRTI, retains good activity against a wide variety of viruses, including those resistant to other nucleoside analogs. It also demonstrated that resistance is slow to develop in vitro, and the level of resistance associated with it is low.
Research presented at the retroviruses conference about other antiretroviral drugs includes the following:
• Tenofovir: Approved in October by the Food and Drug Administration (FDA), tenofovir, manufactured by Gilead Science Inc. of Foster City, CA, is an acyclic nucleotide analog that has demonstrated strong potency against HIV. In a study presented at the retroviruses conference, the drug also showed potency against hepatitis B virus (HBV) in co-infected patients.
Fighting the No. 1 cause of death
In a small 24-week study, tenofovir resulted in a dramatic decrease in HBV, both in wild-type and drug-resistant virus.8 "In patients who have HIV, the No. 1 cause of death now is liver failure, and it’s a result of hepatitis B infection," says John Milligan, PhD, vice president of corporate development for Gilead Science Inc. "Some of these patients have controlled the HIV infection, but they have uncontrolled HBV," Milligan adds. "So tenofovir is an additional way to control both hepatitis B and HIV infection with a single tablet."
Currently, the only approved antiviral for HBV treatment is lamivudine, but lamivudine-resistant HBV has rendered that option less desirable in many cases. Interferon, which is used to treat hepatitis C, can be used with HBV, but it’s also a less-than-ideal solution, Milligan says. "Hepatitis B is more difficult to cure with interferons," Milligan says. "With hepatitis B, historically you’ve had to give higher doses of interferon, and the side effects are so severe that it’s difficult for patients to stay on it."
Gilead Science researchers also presented information about GS 7340, a pro-drug of tenofovir that has highly potent activity against HIV and HBV.9 "This pro-drug GS 7340 is delivered into the blood intact," Milligan says. "It is then taken up at the macrophages of lymphocytes more selectively and concentrates a greater amount of tenofovir in it." The goal is to deliver a more potent version of tenofovir that can be taken in lower doses, resulting in better antiviral activity and fewer side effects, Milligan says. "It’s all preclinical, and we’re hoping to start clinical trials soon," he adds. "I think there’s a great need to improve therapy for HIV patients," Milligan says. "It’s clear that everybody wants a once-a-day drug so that patient adherence is maximized, and that way we can keep patients healthier for longer periods of time."
• Stavudine: Bristol-Myers Squibb presented data about a new formulation of stavudine, showing that a one-capsule, once-daily extended release formulation was as potent as the current formulation through 24 weeks of combination therapy. "The company has put the drug in beadlets inside a capsule, and once it gets into the gastrointestinal tract, the capsule comes off and it’s absorbed out of the beadlets, so it takes a longer time for the drug to be released," Pollard explains. A Phase II/III study compared virologic response between subjects who received stavudine in the twice-a-day formulation vs. once a day, and the results look identical in safety, activity, and immunologic effect, Pollard says.
New drug boosted with ritonavir
• Tipranavir: Boehringer Ingelheim also is moving in the direction of formulating a single-dose antiretroviral. Tipranavir, which is in the new class of non-peptidic protease inhibitors, has demonstrated consistent potency in a single dose of tipranavir (TPV) that is boosted with ritonavir (RTV).10 The boosted TPV also appears to maintain viral suppression among patients who have decreased susceptibility to other drugs, including PIs and NRTIs.
When TPV is used as a single drug, it induces liver enzymes, but this effect appears to not be a problem with the combination of TPV/RTV, Mayers says. "At this point, the drug has been tested with all other currently available drugs," Mayers says. "It’s a very innovative Phase II program where we let people get a genotype and then their physician selects the best drugs and best-boosted PI from the resistance data."
Then the patients in the study are randomized to receive either the physician-selected best regimen, including any expanded access agent that is available, or a combination that includes TPV/RTV as a substitute for another boosted PI, Mayers says. "The problem is, we need to do some final dosage adjustment to get the most powerful dose that gives the best drug level," Mayers adds. The combinations being considered are 500 mg TPV/100 mg RTV, 500/200, and 750/200. Starting this spring, there is a Phase II study in the United States and Europe that compares the various dosage levels, Mayers says. "Then we’ll meet with the FDA to make a final dose selection, and it will move to Phase III, which may start at the end of the year," Mayers says.
• TMC 125: This next-generation NNRTI, under development by Tibotec-Virco of Durham, NC, will soon be evaluated in a Phase II-B study for further evaluation of antiviral activity, safety, tolerability, and finding a dosage. The most recent data on TMC 125 showed promising antiviral activity in HIV patients infected with NNRTI-resistant virus and failing NNRTI therapy.11
The Phase II-A study, presented at the retroviruses conference, involved 16 patients, all of whom had NNRTI and NRTI mutations and most of whom had a PI mutation. After seven days of treatment, TMC 125 continued to show viral load decreases, indicating potency despite the presence of drug-resistant virus.
1. Bennett D, Zaidi I, Heneine W, et al. Prevalence of mutations associated with antiretroviral drug resistance among recently diagnosed persons with HIV, 1998-2000. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Poster 372-M.
2. Riley J, Wojcik L, Xu S, Strizki J. Genotypic and phenotypic analysis of in vitro generated HIV-1 escape isolates to the CCR5 antagonist SCH-C. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Poster 397-T.
3. Xu S, Wojcik L, Strizki J. Antagonism of the CCR5 receptor by SCH-C leads to elevated beta-chemokine levels and receptor expression in chronically treated PBMC cultures. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Poster 398-T.
4. Chen Z, Hu B, Huang W, et al. HIV-1 mutants less susceptible to SCH-D, a novel small-molecule antagonist of CCR5. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Poster 396-T.
5. Erickson-Viitanen S, Schinazi RF, Mellors J, et al. DPC 817: a cytidine nucleoside analog with activity against AZT- and 3TC-resistant viral variants. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Poster 385-T.
6. Yoshinaga T, Sato A, Fujishita T, Fujiwara T. S-1360: in vitro activity of a new HIV-1 integrase inhibitor in clinical development. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Abstract 8.
7. Bethell RC, Allard B, De Muys JM, et al. BCH-13520, a new heterosubstituted nucleoside analogue, is an effective inhibitor of drug-resistant HIV-1. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Poster 386-T.
8. Cooper D, Cheng A, Coakley D, et al. Anti-HBV activity of tenofovir disoproxil fumarate (TDF) in lamivudine (LAM) experienced HIV/HBV co-infected. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Abstract 124.
9. Lee W, He G, Mulato A, et al. In vivo and in vitro characterization of GS 7340, an isopropylalaninyl phenyl ester prodrug of tenofovir; selective intracellular activation of GS 7340 leads to preferential distribution in lymphatic tissues. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Poster 384-T.
10. McCallister S, Sabo JP, Mayers D, et al. An open-label, steady-state investigation of the pharmacokinetics (PK) of tipranavir (TPV) and ritonavir (RTV) and their effects on cytochrome P-450 (3A4) activity in normal, healthy volunteers. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Abstract 1182.5.
11. Gazzard B, Pozniak A, Arasteh K, et al. TMC125, a next-generation NNRTI, demonstrates high potency after 7 days therapy in treatment-experienced HIV-1-infected individuals with phenotypic NNRTI resistance. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 24-28, 2002. Abstract 4.