New Drug Strategy VIR-576, HIV Entry Inhibitor Against gp41 Fusion) Shows Promise Against HIV
Experimental agent disrupts mechanism virus uses to enter cells, scientists say|
Posted: December 22, 2010
By Amanda Gardner
WEDNESDAY, Dec. 22 (HealthDay News) -- Scientists are reporting early but promising results from a new drug that blocks HIV as it attempts to invade human cells.
The approach differs from most current antiretroviral therapy, which tries to limit the virus only after it has gained entry to cells.
The medication, called VIR-576 for now, is still in the early phases of development. But researchers say that if it is successful, it might also circumvent the drug resistance that can undermine standard therapy, according to a report published Dec. 22 in Science Translational Medicine.
The new approach is an attractive one for a number of reasons, said Dr. Michael Horberg, director of HIV/AIDS for Kaiser Permanente in Santa Clara, Calif.
"Theoretically it should have fewer side effects [and indeed had minimal adverse events in this study] and there's probably less of a chance of mutation in developing resistance to medication," said Horberg, who was not involved in the study.
Viruses replicate inside cells and scientists have long known that this is when they tend to mutate -- potentially developing new ways to resist drugs. "It's generally accepted that it's harder for a virus to mutate outside cell walls," Horberg explained.
The new drug focuses on HIV at this pre-invasion stage. "VIR-576 targets a part of the virus that is different from that targeted by all other HIV-1 inhibitors," explained study co-author Frank Kirchhoff, a professor at the Institute of Molecular Virology, University Hospital of Ulm in Ulm, Germany, who, along with several other researchers, holds a patent on the new medication.
The target is the gp41 fusion peptide of HIV, the "sticky" end of the virus's outer membrane, which "shoots like a 'harpoon'" into the body's cells, the authors said. The launch of this peptide is a first step in the virus's bid to inhabit host cells.
Although there are two other drugs on the market, maraviroc and T-20, which also prevent the virus from entering cells, they don't target fusion peptides. That makes this trial the first time that scientists have seen that fusion peptides are a worthwhile target in the fight against HIV/AIDS.
VIR-576 caused some diarrhoea, but no other major side effects, the tests suggested.
And given that fusion peptides also provide a point of entry for many other viruses, from measles to Ebola and hepatitis B and C, scientists theorize that the strategy could be turned against these illnesses as well.
The 18 patients with HIV in this small phase I/II trial took either 0.5, 1.5 or 5 grams of VIR-576 a day for 10 days via injection.
Those taking the highest dose saw a 95 percent reduction in their average viral load, the amount of HIV in the blood, without developing severe adverse effects.
"They were getting results that are similar to maraviroc and T-20 and certainly comparable to what's seen with intracellular drugs," Horberg said.
But the same factors that have limited the use of maraviroc and T-20 are also likely to get in the way here as well, namely the cost and the fact that they must be given by injection (because of the large size of the molecule), he warned.
The needle-vs-pill hurdle is something patients and doctors have to contend with in many settings, not just HIV, Horberg said. For example, "we all know that insulin works great [in diabetic patients] but the hard part is convincing patients to actually take it."
Hoping to get around the problem, the researchers are now searching for a smaller molecule to do the same job.
"The next big step is to use the structure of VIR-576 and its viral target (the fusion peptide) to generate small molecule inhibitors that act by the same mechanism but are orally available," Kirchhoff said. "We will start to test the first compounds next year, but how long it will take such drugs make it to the market is impossible to say."
"The bottom line is, yes, any time that you can find a new mechanism to attack the virus -- and certainly if you can prevent the virus from getting into the host cells -- that's a really good thing. But this isn't near prime-time," Horberg concluded.
Novel HIV Drug Promising in Small Study
Published: December 22, 2010
A novel anti-HIV compound -- derived from a substance occurring naturally in the human body -- appears to be safe and efficacious at blocking the virus, researchers said.
In a small clinical trial, the compound, dubbed VIR-576, reduced viral loads by about 95% at its highest dose, according to Frank Kirchhoff, PhD, of the University Hospital of Ulm in Ulm, Germany, and colleagues.
At the same time, adverse effects were few and mainly involved injection site reactions, Kirchhoff and colleagues reported online in Science Translational Medicine.
It's the first time that a derivative of a naturally occurring compound has shown efficacy in treating HIV, Kirchhoff said in an interview. And, he said, it operates by a mechanism that differs from all other antiretroviral drugs.
* Note that in order to infect host cells, many enveloped viruses insert a hydrophobic fusion peptide into the host cell membrane. This study shows that VIRus-Inhibitory Peptide which bonds to the gp41 fusion peptide of HIV-1 appears to prevent the virus from entering target cells and reduces viral load.
* Note also that this short study is a proof of concept that may lead to a new class of drugs.
The compound is derived from a small peptide that, Kirchhoff and others reported in 2007, blocks the action of the fusion peptide of the HIV envelope protein gp41. The fusion peptide anchors the HIV virion to the membrane of the target cell, one of the earliest steps in infection.
While two approved drugs also target HIV cell entry, they use different mechanisms, the researchers noted. Maraviroc (Selzentry) blocks the CCR5 receptor used by some strains of HIV to enter the target immune cells, while enfuvirtide (Fuzeon) blocks one of the last stages of fusion by preventing the creation of an entry pore for the virion.
To test VIR-576, the researchers enrolled 18 treatment-naive, asymptomatic HIV-positive volunteers in a short-term dose-escalation phase I/II study. The participants had plasma HIV RNA levels of at least 10,000 copies per milliliter and a CD4-positive T cell counts of at least 350 cells per milliliter.
They were randomly assigned to three groups, based on dosing -- 0.5, 1.5, and 5.0 grams daily in a continuous infusion for 10 days -- and baseline virological, immunological, and disease characteristics were similar in all three groups.
The researchers found that the average viral load fell by:
* 0.061 log10 copies per milliliter with the low-dose treatment
* 0.303 log10 copies per milliliter with the medium dose
* And 1.233 log10 copies per milliliter with the 5.0-gram dose
The declines are similar to those seen in short-term monotherapy with a range of other anti-HIV drugs now approved for combination use, the researchers noted.
Over the short treatment period, there was no observable change in CD4 count. When treatment was stopped, the viral loads rebounded to baseline levels within two weeks, Kirchhoff and colleagues reported.
Two participants in the low- and medium-dose groups had moderate allergic reactions that disappeared when treatment was stopped. Other adverse effects were generally transient and mild to moderate and included constipation, headache, and fever.
Interestingly, side effects did not appear to be dose-related since, with the exception of high bilirubin found in two patients, they were less severe in the high-dose group.
The drug is not ready for prime time, Kirchhoff said, for two reasons -- it must be delivered intravenously and it is expensive. He said the researchers are trying to develop a small molecule with a similar effect in order to overcome those drawbacks.
He added that many other viruses -- including measles, mumps, influenza, and hepatitis B and C -- use a similar mechanism to initiate infection, so that fusion peptide inhibitors may be a fruitful approach to therapy beyond HIV.
The study was supported by the Ministry of Science and Innovation, the State of Lower Saxony, and the Deutsche Forschungsgemeinschaft. Kirchoff and several other authors hold a patent on the molecule under study. The lead author, Wolf-Georg Forssmann, MD, PhD, is a shareholder and chief executive officer of VIRO Pharmaceuticals, which is developing the molecule.