An HIV Protein and Telomerase Inhibitor Join Forces Against Cancer

Posted on January 13, 2011 by Kristine Novak, PhD, Science Editor

Researchers have found a way to specifically kill liver cancer cells and stop tumor growth. In the January issue of Gastroenterology, Guangming Chen et al. report that fusion of a natural inhibitor of telomerase to an HIV protein stops proliferation of hepatocellular carcinoma (HCC) cells and growth of liver tumors in mice.

Cancer cells, especially HCC cells, overexpress the enzyme telomerase, which allows them to extend their chromosome ends and proliferate indefinitely. Telomerase has been investigated as an anti-cancer target because it is required for long-term proliferation of cancer cells and is inactive in most healthy cells. Chen et al. fused part of the protein LPTS—an endogenous blocker of telomerase—to the HIV Tat protein, which allowed the fusion protein (called TAT-LPTS-LC) to cross cell membranes and induce telomere shortening, cell crisis (white arrows in figure) and apoptosis of HCC cells (red arrows in figure). TAT-LPTS-LC also reduced the tumorigenicity of HCC cells in mice.

TAT-LPTS-LC shortens cancer cell telomeres

to induce cell crisis and apoptosis.

Chen et al. observed the inhibitory effects of TAT-LPTS-LC only in telomerase-positive cells—normal cells were not affected and the fusion protein caused no signs of toxicity in the mice. This might be because normal cells already express LPTS, whereas cancer cells lose it, which allows them to replicate indefinitely; LPTS is reduced or absent in 40%–50% of cases of HCC and other tumor samples.


LPTS (also called PinX1) was the first natural telomerase inhibitor identified. Chen et al. note that although TAT-LPTS-LC suppresses tumor growth effectively, its effects in mice took several weeks, rather than inducing an immediate response. Combinations of telomerase inhibitors and chemotherapeutic drugs might be used to reduce this lag phase and cause rapid and sustained tumor cell death.

Read the article online:
Chen G, Da L, Wang H, et al. HIV-tat–mediated delivery of an LPTS functional fragment inhibits telomerase activity and tumorigenicity of hepatoma cells. Gastroenterology 2011;140:332–343.
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Fibrosis in Patients with HIV and Hepatitis C

Posted on December 16, 2010 by Kristine Novak, PhD, Science Editor

HIV infection does not speed the progression of fibrosis in patients with Hepatitis C, according to findings from Richard Sterling et al. in the December issue of Clinical Gastroenterology and Hepatology.

Sterling et al. compared liver biopsies taken from more than 300 patients with HIV/HCV co-infection and more than 200 with only HCV infection. They found that fibrosis progressed in 20% of HIV/HCV co-infected patients over time (10% by 1 stage and 10% by 2 or more stages)—this was not significantly different than progression in patients with only HCV infection (22%; 17% by 1 stage and 5% by 2 stages). Patients’ baseline features—such as inflammation or steatosis—were not associated with progression, nor were numbers of T cells, levels of HIV RNA, or any particular therapeutic regimen for HIV infection.

Previous studies reported that fibrosis progressed more rapidly in HIV/HCV co-infected patients, and that all co-infected patients—even those without significant liver damage—should receive anti-HCV therapy. However, most of these studies were either retrospective, based only on estimates of disease duration, or in patients that had received anti-HCV therapy, so disease progression was poorly defined. Before the study of Sterling et al., there were no direct comparisons of co-infected patients who were matched with patients with HCV alone.

Limitations to the study include referral bias and self-selection for subjects that were willing to undergo a second biopsy. Furthermore, the authors were not able to account for alcohol use between biopsies and did not have accurate data on alcohol use in those with HCV alone. Although Sterling et al. did not associate any particular anti-HIV therapy with fibrosis, the specific regimen for each patient was not controlled, and the authors did not account for compliance or change in anti-HIV therapies between biopsies.

The authors recommend that all co-infected patients be repeatedly assessed for disease severity by liver biopsy analyses at periodic intervals. Because a significant proportion of patients with HIV and HCV did not have increasing liver damage, decisions on whether to begin HCV therapy should depend on patient compliance and likelihood of response, rather than concerns about rapid disease progression. Sterling et al. conclude that it is reasonable to defer HCV therapy in patients with mild disease until better therapies for HCV are available.

Changes in fibrosis about patients co-infected with HIV

and HCV and those infected with only HCV.

Read the article online:

Sterling RK, Wegelin JA, Smith PG. Similar progression of fibrosis between HIV/HCV–infected and HCV–infected patients: analysis of paired liver biopsy samples. Clin Gastroenterol and Hepatol 2010;8:1070–1076.

Read a related review:
Price JC, Thio CL. Liver disease in the HIV-infected individual. Clin Gastroenterol and Hepatol 2010;8:1002–1012.

Read the complementary Gastroenterology article:
de Vries­–Slujis TEMS, Reijnders JGP, Hansen BE, et al. Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus. Gastroenterology 2010;139:1934–1941.

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Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir †

Hepatology
Early View (Articles online in advance of print)

Fumitaka Suzuki1,*,‡, Yoshiyuki Suzuki1, Norio Akuta1, Hitomi Sezaki1, Miharu Hirakawa1, Yusuke Kawamura1, Tetsuya Hosaka1, Masahiro Kobayashi1, Satoshi Saito1, Yasuji Arase1, Kenji Ikeda1, Mariko Kobayashi2, Kazuaki Chayama3, Naoyuki Kamatani4, Yusuke Nakamura5, Yuzo Miyakawa6, Hiromitsu Kumada1

Article first published online: 18 JAN 2011
DOI: 10.1002/hep.24058
Copyright © 2011 American Association for the Study of Liver Diseases

Abstract

Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (−1.63 ± 0.92 vs. −0.48 ± 0.75 g/dL, P = 0.001) and week 4 (−3.5 ± 1.1 vs. −2.2 ± 0.96, P = 0.001), as well as at the end of treatment (−2.9 ± 1.1 vs. −2.0 ± 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 ± 14% vs. 65 ± 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 ± 17% and 54 ± 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724). Conclusion:ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes. (Hepatology 2011)

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Also See: Evaluating patients for genetic variations impacts adherence to antiviral therapy

P66 SVR with telaprevir, peginterferon alfa-2A and ribavirin in HCV patients with well-characterised prior null response, partial response, viral breakthrough or relapse after peginterferon+ ribavirin

Gut 2010;59:A37-A38 doi:10.1136/gut.2010.223362.92

G Dusheiko 1, T Berg 2, J M Pawlotsky 3, P Ferenci 4, S Zeuzem 5, A J Muir 6, F Poordad 7, M L Shiffman 8, J Heathcote 9, H Reesink 10, N Adda 11, J G McHutchison 6

Abstract

Introduction Study107 is an open-label rollover study of telaprevir (T) with peginterferon+ ribavirin (PR) in genotype-1 HCV patients who did not achieve SVR following PR treatment in telaprevir Phase 2 studies.

Method Null responders (<1-log10 HCV RNA decrease at week-4 or <2-log10 at week-12), partial responders (=2-log10 decrease at week 12, detectable at week 24), patients with viral breakthrough and relapsers from PROVE1/2/3 PR arms were eligible for treatment. Initially all patients received T 750 mg q8h plus PR at standard doses for 12 weeks, followed by 12 weeks of PR (T12/PR24). Protocol was amended to allow partial responders, viral breakthroughs and relapsers with undetectable HCV RNA at weeks 4 and 12 (eRVR) to receive T12/PR24. Partial responders, viral breakthroughs and relapsers with detectable HCV RNA at week 4 and/or week 12 and null responders received an additional 24 weeks of PR (T12/PR48).

Results Of 117 patients included in an ITT analysis, 97 (83%) had baseline HCV RNA=800 000 IU/ml, (69) 59% had genotype subtype 1a, 44 (38%) had cirrhosis or bridging fibrosis, and 9 (8%) were black. Viral breakthrough and relapse rates occurred in 25%, 23% of prior null responders; 10%, 22% of prior partial responders; 13%, 0% of prior viral breakthroughs; and 0%, 4% of prior relapsers.

Conclusion Patients with prior relapse, breakthrough and partial response exhibited high SVR rates after 24 weeks of telaprevir-based regimen. High SVR rates were also observed in patients with previous null response after 48 weeks of therapy.

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Trends in all cause and liver-related hospitalizations in people with hepatitis B or C: a population-based linkage study

Published on: 2011-01-25

Previous studies have reported an excess burden of cancer and mortality in populations with chronic hepatitis B (HBV) or C (HCV), but there are limited data comparing hospitalization rates. In this study, we compared hospitalization rates for all causes and viral liver disease in people notified with HBV or HCV in New South Wales (NSW), Australia.

Methods: HBV and HCV notifications were linked to their hospital (July 2000-June 2006), HIV and death records.

Standardized hospitalization ratios (SHRs) were calculated using rates for the NSW population. Random effects Poisson regression was used to examine temporal trends.

Results: The SHR for all causes and non alcoholic liver disease was two-fold higher in the HCV cohort compared with the HBV cohort (SHRs 1.4 (95%CI: 1.4-1.4) v 0.6 (95%CI: 0.6-0.6) and 14.0 (95%CI: 12.7-15.4) v 5.4 (95%CI: 4.5-6.4), respectively), whilst the opposite was seen for primary liver cancer (SHRs 16.2 (95%CI: 13.8-19.1) v 29.1 (95%CI: 24.7-34.2)).

HIV co-infection doubled the SHR except for primary liver cancer in the HCV/HIV cohort. In HBV and HCV mono-infected cohorts, all cause hospitalization rates declined and primary liver cancer rates increased, whilst rates for non alcoholic liver disease increased by 9% in the HCV cohort but decreased by 14% in the HBV cohort (P <0.001).

Conclusion: Hospital-related morbidity overall and for non alcoholic liver disease was considerably higher for HCV than HBV.

Improved treatment of advanced HBV-related liver disease may explain why HBV liver-related morbidity declined. In contrast, HCV liver-related morbidity increased and improved treatments, especially for advanced liver disease, and higher levels of treatment uptake are required to reverse this trend.

Author: Heather GiddingGregory DoreJanaki AminMatthew Law
Credits/Source: BMC Public Health 2011, 11:52

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How ZymoGenetics Coulda Been a Contender: The Big Break That Came Too Late

Luke Timmerman 1/25/11

ZymoGenetics, if it had stayed an independent company in Seattle, would be worth tens of millions of dollars more today than what it was in September when it agreed to be acquired by Bristol-Myers Squibb (NYSE: BMY).

Bristol clearly scored a big break with its new ZymoGenetics assets on December 21, about two months after it closed the books on its $885 million acquisition of the venerable Seattle biotech.

If it had still been an independent biotech, the value of ZymoGenetics would have soared that day when Cambridge, MA-based Vertex Pharmaceuticals announced that, essentially, it had failed to make ZymoGenetics’ lead drug candidate obsolete. On that day, Vertex (NASDAQ: VRTX) said it was unable to eradicate one of backbone components of hepatitis C therapy in a high profile clinical trial.

Vertex is blazing a new trail in the field with a potent new oral pill that generates unprecedented cure rates when given in combination with two standard treatments—pegylated interferon alpha and ribavirin. Vertex was hoping to raise the bar even higher, to find out if its lead molecule, telaprevir, could be combined into a new cocktail regimen that Vertex hoped would kick old-school interferon into the dustbin of history. Doctors and patients have been yearning for a way to get rid of interferon, which causes nasty flu-like symptoms that make patients feel awful for months, which discourages most patients from seeking treatment today.

ZymoGenetics, knowing this well, had developed a genetically modified version of interferon, which it called pegylated interferon lambda. This new form of interferon was designed to kill the hepatitis C virus just like the older version of interferon, but without the flu-like side effects. Results from early clinical trials were so promising that ZymoGenetics was able to entice Bristol to sign a $1.1 billion partnership to co-develop the drug in January 2009.

But many on Wall Street weren’t impressed. They had fallen head over heels for Vertex’s new molecule, insisting that ZymoGenetics and Bristol were wasting their time with a new type of interferon. Vertex, they said, was coming along with a cocktail approach of new oral pills that would get rid of interferon, meaning any improvement on old-school interferon would soon be irrelevant. While many doctors, and companies like Vertex still hope it will be possible to do this, the latest clinical trial failure makes it clear that interferon will be part of the standard treatment regimen for years. That means the drug Bristol acquired from ZymoGenetics has a chance to integrate itself into a new standard of care, at a moment when awareness has never been higher among an estimated 6 million U.S. and European patients with this liver-damaging condition.

Former ZymoGenetics CEO Doug Williams, who recently took a new job as head of R&D at Weston, MA-based Biogen Idec, acknowledged in a recent interview that the failure of Vertex’s combination trial would have been a positive turn of events for ZymoGenetics and its pegylated interferon lambda program. He stopped short of saying that Wall Street would have perceived the development in a way that would have boosted ZymoGenetics’ stock price.

“Certainly some will people would have come off the fence and perhaps started to believe that interferons will be really hard to get rid of,” Williams says. “I’m certainly of the mind that it will be extremely difficult to get rid of interferon, and achieve [cure rates] currently seen.”

He added: “I gotta believe it would have been viewed as a net positive, but the degree to which it would have been reflected in the stock price, I don’t think anybody can say that.”

David Miller, the president of Biotech Stock Research in Seattle, who criticized ZymoGenetics for selling the company at a bargain price, said he believes investors would have given the company credit. An estimated 6 million patients in the U.S. and Europe have hepatitis C, and many of them are expected to start seeking treatment in 2011, now that a new wave of protease inhibitors like Vertex’s telaprevir and Merck’s boceprevir are being primed to hit the market later this year. The existing interferons from Roche and Merck made up a combined market worth more than $2 billion in 2009, even before the more-effective protease inhibitors came along to spur more interest in hepatitis C therapy.

ZymoGenetics could have seen its stock climb another $2 to $3 a share if it had still been an independent company when the Vertex news hit the wire on December 21, Miller says.

“Smart money was moving toward ZymoGenetics,” Miller says. The latest clinical trial failure of the no-interferon regimen, Miller says, “would have been huge for ZymoGenetics. People were starting to understand that interferons aren’t going anyway anytime soon. This press release (from Vertex) would have cemented that.”

Now that doctors are getting accustomed to seeing hepatitis C cure rates in the neighborhood of 70 to 75 percent of patients who take the combo regimen of the Vertex drug, plus interferon and ribavirin, it’s unlikely they will ever sacrifice even a few percentage points of effectiveness just to get rid of interferon’s side effects, Williams says. That means the bar is high for any oral pill cocktail regimen that aspires to get rid of interferon. It’s certainly possible that the combination of doses, and schedules, could coalesce to make that happen, but it will take years to figure out in clinical trials, Williams says.

Given that was what ZymoGenetics management was betting on with their new interferon, and that its thesis was essentially validated on December 21st, I had to ask Williams if he regrets selling the company for less than a billion dollars. He said no.

“I don’t look back on these sorts of decisions,” Williams says. “You make the decision you have to make at the time with the information you have available to you at the time. I feel we made the right decision at the right time.”

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Survival following transplant surgery for liver cancer not impacted by HIV-positive status

25. January 2011 08:43

French researchers determined that infection with human immunodeficiency virus (HIV) impaired results of transplant surgery for liver cancer, with more HIV infected patients dropping off the transplantation wait list. The team found that overall survival and recurrence-free survival was not impacted following liver transplantation in patients with controlled HIV disease. Details of this single center study—the largest to date—are published in the February issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).

More than 40 million individuals are infected with HIV; of these roughly two to four million and four to five million are also carriers of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. With the introduction of highly active antiretroviral therapy (HAART) in 1996 the survival of patients with HIV infection has improved dramatically and now end-stage liver disease has become the principal cause of death among HIV- positive patients co-infected HBV or HCV. Prior studies have shown that 25% of liver-related mortality in HIV-positive patients is attributable to hepatocellular carcinoma (HCC), or liver cancer.

"Liver transplantation is the optimum treatment for HCC and can also be considered for controlled HIV-positive patients with liver cancer," said René Adam, MD, PhD, from Hospital Paul Brousse in France and lead author of the current study. "Our study showed that HIV infection impaired the results of liver transplantation on an intent-to-treat basis but exerted no significant impact on overall survival and recurrence-free survival following transplantation."

The research team analyzed data from 21 HIV-infected and 65 HIV-negative patients with HCC who were listed for liver transplantation between 2003 and 2008. All HIV-positive patients were treated with HAART and had not experience any AIDS event or opportunistic infections prior to being place on the wait list.

Researchers observed a trend towards a higher drop-out among HIV-positive wait listed patients (23%) compared to patients without HIV (10%). Patients with HIV who dropped out had significantly higher alpha-fetoprotein (AFP) levels at the time of listing than those who received a transplant—98 μg/L versus 12 μg/L, respectively. A similar difference in AFP levels was not found in HIV-negative patients—18 μg/L in those who dropped out versus 13 μg/L for those who underwent liver transplantation. Only one HIV-positive patient who did not have increased AFP levels while on the wait list dropped out due to progression from controlled HIV to AIDS.

Medical evidence indicates a major predictive factor for HCC recurrence post-transplantation is an increase in patient's AFP level of more than 15 μg/L per month while on the waiting list. "Our study confirmed the importance of this preoperative factor (AFP levels), as all HIV-positive patients who dropped out displayed a rise in AFP levels," Dr. Adam concluded. "There is clearly a critical need for more effective neoadjuvant therapy in HIV-positive patients with HCC, however there are no objective arguments to contraindicate liver transplantation in this group if strict criteria are used for selection and patients are closely monitored until surgery."

Source Hepatology

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Evaluating patients for genetic variations impacts adherence to antiviral therapy

25. January 2011 08:39

In two recent studies, researchers have identified two functional variants in the inosine triphosphatase (ITPA) gene that protect patients with hepatitis C virus (HCV) against anemia brought on by antiviral treatment. The ability to identify those patients protected against treatment-induced anemia will ensure completion of antiviral therapy and successful elimination of the virus. Full findings of these studies appear in the February issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

Chronic HCV affects up to 170 million individuals worldwide and is a leading cause of end-stage liver disease. While HCV is curable with treatment of pegylated interferon (pegIFN) and ribavirin (RBV), many patients have difficulty tolerating these antiviral drugs. Prior studies have shown that 9% to 22% of patients enrolled in phase III trials of pegIFN plus RBV require modification of their dose due to hemolytic anemia brought on by the drugs. A reduction in RBV limits treatment efficacy, thus impacting the viral clearance success rate.

Alessandra Mangia, M.D., from Casa Sollievo della Sofferenza Hospital in Italy, and colleagues evaluated the association between ITPA variants and anemia in a cohort of 238 Caucasian patients treated with variable pegIFN and weight-based doses of RBV. The research team found that the ITPA variants were strongly and independently associated with protection from anemia, but did not provide an increase in sustained virological response.

"When anemia develops only four weeks after the start of treatment, physicians are required to immediately reduce ribavirin dosages. This early reduction will affect the overall duration of treatment which, with the combination of pegIFN and RBV, lasts 24 weeks for patients infected with HCV genotypes two and 3 (G2/3) and 48 weeks for patients with HCV genotype one (G1) infection. Currently, only the use of the drug erythropoietin (EPO)—an expensive drug that due to its high cost cannot be reimbursed in several countries—might prevent unsuccessful antiviral treatment in these cases," explained Dr. Mangia.

"Our findings demonstrated that ITPA variants are strongly associated with protection from week four anemia and help us in selecting in advance who will need early ribavirin dose reduction and possibly supportive EPO treatment. This may lead to a more rational use of economical resources and to an individualized use of supportive EPO treatment," concluded Dr. Mangia. "Patients with a genetic profile that included the two ITPA variants may be safely administered higher doses of RBV, increasing the likelihood of HCV elimination after treatment—an important finding given that to achieve viral clearance high dosages of RBV need to be used in the early phases of treatment."

A related study led by Fumitaka Suzuki, M.D., from Toranomon Hospital in Japan found similar results in its cohort of 61 Japanese patients with HCV. Patients in this study received a triple therapy of pegINF, RBV and the protease inhibitor, telaprevir. Dr. Suzuki and colleagues found that ITPA variants impacted blood levels; however a sustained virological response could be achieved with careful monitoring of anemia and prompt adjustment of RBV dose. The authors suggest that future investigation of the influence of ITPA gene variants on RBV-induced anemia are needed on larger scales and on patients of various ethnicities.

SOURCE Hepatology

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