August 2, 2010

Conquering HIV, hepatitis C requires ongoing research, expert says

Publish date: Aug 1, 2010
By: John Jesitus

Key Points
  • More than a dozen drug candidates under development for HCV
  • Researchers are applying combination modalities established in cancer and HIV to HCV
Atlanta — Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may be out of the public eye, but curing these unseen epidemics requires ongoing research, says an expert who spoke at the 2010 annual meeting of the Society for Investigative Dermatology.
 
Although more than two dozen HIV drugs can alleviate suffering and prolong life, "The epidemic is not over," says Raymond Schinazi, Ph.D., D.Sc., professor of pediatrics, Emory University School of Medicine and Atlanta VA Medical Center. "We also know that more than 1 million people have been infected with HIV in the United States," and an estimated 60 million will be infected worldwide by 2015, he says, adding that only 28 percent of those who need treatment actually get it.
 
Before the advent of modern treatments in 1985, HIV had a 73 percent mortality rate, Dr. Schinazi says. But by 2008, more than 94 percent of people infected with HIV who receive Western standard-of-care treatment survive at least five years.
 
"More than 90 percent of HIV-infected subjects are taking one or more drugs invented at Emory University," he says. Examples include Atripla (efavirenz 600 mg, emtricitabine 200 mg, tenofovir-DF 300 mg; Bristol-Myers Squibb/Gilead), 3TC (beta-2',3'-dideoxy-3'-thiacytidine, also called Lamivudine; GlaxoSmithKline), Truvada (tenofovir-DF 300 mg/emtricitabine 200 mg, Gilead) and Viread (tenofovir-DF 300 mg, Gilead). As a professor of pediatrics, Dr. Schinazi says, "Probably the most important accomplishment is the fact that maternal-to-fetal transmission today is history. We rarely see it in the United States, although it still occurs in Africa" and elsewhere.
 
Hepatitis C
 
For hepatitis C virus (HCV), "We only have two drugs — ribavirin and interferon (IFN). Both are relatively toxic," Dr. Schinazi says. About 280 million people worldwide are infected with HCV. "There are 3 to 4 million infections per year globally, and we expect more than 800,000 U.S. patients to develop HCV-related cirrhosis this decade," he says.
 
Up to one-third of those with HCV are coinfected with HIV, Dr. Schinazi says, adding that coinfection complicates treatment because physicians must consider dangerous drug interactions. Both viruses share routes of transmission, which are all very dynamic.
 
"The number of patients with HCV treated in the United States is very small compared to the number of chronic carriers," Dr. Schinazi says. Treatment failures are common, he says, because the current standard of care does not work well against certain HCV genotypes. Only 30 to 60 percent of patients achieve sustained virological response (SVR, or a cure) on currently available HCV therapies, all of which require intravenous administration, he says.
 
Up-and-coming drugs
 
More than a dozen drug candidates are under development for HCV (Sarrazin C, Zeuzem S. Gastroenterology. 2010 Feb;138(2):447-462. Epub 2009 Dec 16. Review), Dr. Schinazi says. These include small molecules and interferon-related therapies.
 
"There are various classes of compounds, including nucleoside and non-nucleoside polymerase inhibitors, cyclophilin inhibitors, protease inhibitors (PIs) and, more recently, the very potent NS5A inhibitors," he says.
 
However, Dr. Schinazi says, only two candidates are in Food and Drug Administration phase 3 trials: telaprevir (Vertex) and boceprevir (Merck/Schering-Plough). "These PIs are having a remarkable effect on viral load in persons infected with HCV," he says. NS5A inhibitors also show promise in reducing viral load, though they're only in phase 1/2.
 
HCV drug candidates often fail, Dr. Schinazi says, due to side effects such as anemia, gastrointestinal issues, body composition changes or dermatologic side effects. Telaprevir can cause severe rashes, he notes, a fact which "probably should have been picked up in earlier development. Unfortunately, it wasn't," which has required investigators to cut the treatment duration from six or 12 months to 12 weeks.
 
HIV updates

People infected with HIV also can experience various dermatologic manifestations. Some, such as psoriasis, are associated with declining CD4 T cell counts, Dr. Schinazi says. Others — eczema/dermatitis, Kaposi's sarcoma, warts — occur despite adequate treatment. Still others, such as lichen planus, occur commonly with HIV-HCV coinfection.

Nevertheless, modern HIV therapies have simplified the complex multi-pill regimens of the 1980s and 1990s into a single pill with three active ingredients (Atripla, Truvada), which frequently achieves strong virus suppression. Meanwhile, Dr. Schinazi says, researchers are applying the combination modalities that have been established in cancer and HIV to HCV.

Researchers also must address HIV's persistence, he says. Even after extensive treatment, the virus rebounds without continued treatment, or when resistance develops. Additionally, persons on successful long-term treatment can experience "blips" wherein viral load climbs from undetectable levels to detectable levels. "Even one virus is enough to light the fire again and cause problems with reinfection (Pierson T, McArthur J, Siliciano RF. Annu Rev Immunol. 2000;18:665-708)," Dr. Schinazi says.

Researchers believe HIV's persistence stems at least partly from anatomical and cellular reservoirs of virus (in areas such as the gut or the brain) where current drugs cannot penetrate effectively, and from ongoing low-level replication. Accordingly, Dr. Schinazi says eradicating HIV will require systematic study of drug penetration into various compartments and its impact on local viral replication.

"Tissue macrophages are a major reservoir for HIV, in addition to the active and memory CD4+ T lymphocytes in the peripheral circulation," he says. En route to developing therapies that can eradicate HIV, Dr. Schinazi says, "We must develop systems to measure virus below current detection levels." Additionally, he says that researchers need preclinical tools that can identify and validate specific biochemical targets and rapidly screen drug candidates, perhaps using cell lines and/or primary cell assays.

Study details

In a recent study, Dr. Schinazi and his coauthors showed that after highly active antiretroviral therapy, viral "sanctuaries" persisted, with the highest levels of viral DNA and RNA found in the spleen, lymph nodes and gastrointestinal tract (North TW, Higgins J, Deere JD, et al. J Virol. 2010 Mar;84(6):2913-2922. Epub 2009 Dec 23).

For eradicating latent integrated HIV, he says the "shock and kill" strategy involves activating the virus and then stimulating it, leading to cell death (Hamer DH. Curr HIV Res. 2004 Apr;2(2):99-111). "The challenges are, how do we specifically kill the cells that are latently infected and deliver the drugs or deadly punch to initiate the cell apoptosis?" Dr. Schinazi says. Other potential approaches involve using anti-TNF-alpha treatment. "That will also be tested in the animal system we have developed."

In combating HCV, Dr. Schinazi says researchers have an advantage, because this virus does not establish latency. "Theoretically, we can eradicate this virus much more easily than HIV." Here, a promising drug candidate under development is a nucleoside developed at Emory in conjunction with Pharmasset, called R7128 (Roche). "The advantage of this nucleoside is that even when there is resistant virus, it is still active," he says.

In clinical testing, investigators combined R7128 (500 mg to 1,500 mg daily) with IFN and ribavirin for 28 days. "Preliminary results showed we had 85 percent rapid virological response in four weeks," Dr. Schinazi says. Researchers then combined the drug in doses of 500 mg or 1,000 mg daily with a PI (R7227, Roche; 100 mg or 200 mg daily) in an attempt to develop an IFN/ribavirin-free regimen.

"By day 14 there was a nearly five log10 drop irrespective of the dose (Gane EJ, Stedman C. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: Safety, pharmacokinetics, and virologic results from INFORM-1 [abstract]. J Hepatol. 2008;50 (Suppl. 1): Abstract 1046, S380). Unfortunately, the PI caused some toxicity, so the dose has now been reduced to 100 mg daily, with a protease booster, a bit like we do with HIV," Dr. Schinazi says.

"This is where the future lies — the INFORM study demonstrated that two compounds with different targets can achieve tremendous viral reduction," he says. With HCV, "Cures are already possible with IFN and ribavirin. We just need to improve the SVR." He predicts that in the next year or so, drug combinations will provide SVR for more than 90 percent of patients with HCV.

Disclosures: Dr. Schinazi is founder and major shareholder of Pharmasset, Idenix and RFS Pharma. He also receives royalties from 3TC and LdT.

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