CROI 2012: Treating HIV During Pregnancy Also Lowers Risk of Transmitting Hep C to Baby

March 16, 2012

by Tim Horn

For women living with HIV and hepatitis C virus (HCV) coinfection, using HIV antiretroviral (ARV) therapy during pregnancy may lower the risk of transmitting both viruses to their infants, according to encouraging new data presented Tuesday, March 6, at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Most research on mother-to-child transmission (MTCT) of hepatitis C was done before there was widespread access to combination ARV therapy among pregnant women living with HIV and HCV. In earlier years of the HIV pandemic, up to 19 percent of babies born to mothers living with HIV/HCV coinfection acquired HCV, versus 2 to 5 percent of babies born to mothers with HCV alone. Although combination ARV treatment has been proved to reduce MTCT of HIV, little has been known about the effects of modern-day HIV treatment combinations on MTCT of HCV.

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CROI 2012: Prometheus Index Predicts Hepatitis C Treatment Response

Jim Kling

March 14, 2012 (Seattle, Washington) — In patients monoinfected with hepatitis C virus (HCV), a modification of the Prometheus index reliably estimates the probability of achieving a sustained virologic response with pegylated interferon plus ribavirin therapy, according to research presented here at the 19th Conference on Retroviruses and Opportunistic Infections.

This finding, presented at a poster session by José Medrano, MD, a clinical investigator at Hospital Carlos III in Madrid, Spain, could help patients and physicians decide whether to proceed with currently available therapies or to wait for novel therapies that are in development and will likely be available in the near future.

The Prometheus index — which incorporates interleukin (IL)28B variants, HCV RNA level, HCV genotype, and liver fibrosis — has been used to successfully predict sustained virologic response in patients coinfected with HIV and HCV.

To determine the ability of the index to predict response to treatment in HCV-infected patients, Dr. Medrano and colleagues conducted a multicohort study at clinics in France and Spain. The study involved 422 interferon-naïve patients who had undergone elastometry in the previous 12 months to assess liver fibrosis, serum HCV RNA measurement, HCV genotyping, and IL28B testing. The team excluded patients who had discontinued therapy because of adverse effects or who had poor drug compliance.

Of the 422 patients, 245 were coinfected with HIV and HCV and 177 were monoinfected with HCV.

The team found that the Prometheus index was worse at predicting treatment outcome in HCV monoinfected patients (area under the receiver operating characteristic [AUROC], 0.77; 95% confidence interval [CI], 0.70 to 0.84) than in HIV/HCV coinfected patients (AUROC, 0.87; 95% CI 0.83 to 0.92; P = .01).

The team then developed a new index that incorporated HIV status and HCV-1 subtype. They confirmed that a number of variables were independently associated with a failure to achieve sustained virologic response in HCV monoinfected patients: liver stiffness; HCV RNA level; IL28B favorable allelic variants (CT/TT; odds ratio [OR] 5.241; 95% CI, 3.097 to 8.870; P < .01); HCV genotypes 1 to 4 (OR, 9.128; 95% CI, 4.156 to 20.047; P < .01); and HIV-positive status (OR, 1.554; 95% CI, 0.929 to 2.599; P = .09).

The Prometheus index can be used in its current form to predict responses in HCV monoinfected patients, but clinicians "must know that prediction will be less accurate than in HIV/HCV coinfected patients," Dr. Medrano told Medscape Medical News.

The results might find application in settings with limited resources. "You could limit antivirals, which are very expensive, to patients with a lower probability of a virologic response," Dr. Medrano said.

The Prometheus index is available for the iPhone, iPad, and Android phones, but the modified Prometheus index is still being developed and will require further validation, he explained.

The index could help physicians and patients decide whether to pursue antiviral therapy now or to wait for new drugs on the horizon, according to Dawn Fishbein, MD, medical director of SAIC-Frederick's Partnership for HIV/AIDS Progress in Washington, DC, who attended the session.

"The side-effect profile [of currently available drugs] is enormous. It's important when we talk to a patient to say: 'This is the prediction of how you're going to respond now, so perhaps you should wait for newer treatments or you should do treatment now'," Dr. Fishbein told Medscape Medical News.

Dr. Medrano and Dr. Fishbein have disclosed no relevant financial relationships.

19th Conference on Retroviruses and Opportunistic Infections (CROI): Abstract 761. Presented March 7, 2012.

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CROI 2012: HIV/HCV Coinfection News from CROI 2012 [VIDEO]

[Liz Highleyman, Douglas Dieterich, and Kenneth Sherman, CROI 2012 interview, Seattle, March 8, 2012. Video footage courtesy of IFARA]

Provided by HIVandHepatitis.com

Published on Monday, 12 March 2012 00:00 Written by Gregory Fowler

Hepatitis C was a major topic at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) last week in Seattle. Liz Highleyman from HIVandHepatitis.com spoke with Douglas Dieterich and Kenneth Sherman about advances in the field, with a focus on HIV/HCV coinfected patients.

The attention this year was apt, since an estimated one-third of people with HIV are coinfected with hepatitis C virus (HCV). Dieterich and Mark Sulkowski presented the first data on sustained virological response (SVR) using the recently approved HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek) plus pegylated interferon/ribavirin in HIV/HCV coinfected patients.

Researchers also discussed drug-drug interactions between HCV direct-acting antivirals (DAAs) and antiretroviral agents, as well as interferon-free combinations that may be available in the future.

3/12/12

Source
L Highleyman, D Dieterich, and K Sherman. HIV/HCV Coinfection News from CROI 2012. IFARA interview, Seattle, March 8, 2012.

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CROI 2012: Pipeline Asset Update for Daclatasvir (DCV; BMS-790052)

Pipeline Asset:
Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir, also known as BMS-790052 or DCV, is the first NS5A replication complex inhibitor to be investigated in hepatitis C clinical trials.

Current Phase of Development:
Phase III

Meeting or Publication:
Conference on Retroviruses and Opportunistic Infections (CROI)

Study Title:
Assessment Of HIV Antiretroviral Drug Interactions with the HCV NS5A Replication Complex Inhibitor BMS-790052 Demonstrates a Pharmacokinetic Profile Which Supports Coadministration with Tenofovir, Efavirenz and Atazanavir/Ritonavir

Presentation Number:
Poster Number 618

Date/Time of Presentation:
Thursday, March 8, 2012 from 2:00 – 4:00 PST

Study Objective:
To evaluate the potential for drug-drug interactions (DDI) between daclatasvir (DCV) and HIV antiretrovirals (ARVs) in healthy subjects prior to beginning clinical trials in HIV-HCV co-infected patients, establishing dosing modifications, if needed.

Study Conclusion:

Daclatasvir (DCV) plus tenofovir (TDF) had no clinically relevant drug-drug interactions.

A dose adjustment for daclatasvir is necessary when administered with atazanavir boosted with ritonavir (ATV/r) and when administered with efavirenz (EFV). A daclatasvir dose adjustment of 30 mg QD with atazanavir plus ritonavir (300/100 mg QD) and 90 mg QD with efavirenz (600 mg QD) is expected to generate daclatasvir exposure similar to that for 60 mg of daclatasvir administered alone.

Safety profiles were unremarkable in all three ARVs. No unexpected safety signals were observed. See full safety analysis in adverse events section below.

Table 1: Daclatasvir and tenofovir gave similar C_max and AUC_tau for each drug relative to administration alone (See Table 1)

Table 2: Daclatasvir and atazanavir/ritonavir

• Dose-normalized increases in daclatasvir maximum plasma concentrations (C_max) and area under the concentration-time curve in one dosing interval (AUC_tau) were observed when dosed with ATV/r (See Table 2):
  • Geometric mean ratios (GMR) for Cmax and AUCtau of daclatasavir 20 mg when coadministered with atazanavir/ritonavir vs. daclatasvir 60 mg alone were below the predicted estimations. Non-normalized GMR for Cmax and AUCtau for the adjusted doses were less than 1.0 with atazanavir/ritonavir
  • Dose normalized (60 mg DCV) C_max and AUC_tau were 35% and 110% higher, respectively, when daclatasvir was co-administered with atazanavir/ritonavir
  • Based on linear pharmacokinetics, extrapolated doses of daclatasvir 30 mg once daily with atazanavir/ritonavir are estimated to give AUC_tau similar to the daclastasvir 60 mg dose administered alone
  • Exposure of atazanavir was similar to historical data

Table 3: Daclatasvir and efavirenz

• Dose-normalized decreases in daclatasvir maximum plasma concentrations (C_max) and area under the concentration-time curve in one dosing interval (AUC_tau) were observed when dosed with efavirenz (See Table 3):
  • Geometric mean ratios (GMR) for Cmax and AUC_tau of daclatasavir 120 mg when coadministered with efavirenz vs. daclatasvir 60 mg alone were above the predicted estimations. Non-normalized GMR for C_max and AUC_tau for the adjusted doses were significantly greater than 1.0 with efavirenz
  • Dose normalized (60 mg DCV) Cmax and AUCtau were 17% and 32%, lower, respectively, when daclatasavir was co-administered with efavirenz.
  • Based on linear pharmacokinetics extrapolated doses of daclatasvir 90 mg once daily with efavirenz are estimated to give AUC_tau similar to the daclastasvir 60 mg dose administered alone
  • Exposure of efavirenz was similar to historical data

Adverse Events:

Most Common Adverse Events (>25% in Any Study) by System Organ Class and Treatment:

^aCombined data from studies AI444032, AI444033 and AI444034 (exposure 4–7 days); ^bAll subjects initially received EFV with DCV 60 mg (9 days) then 120 mg (5 days); ^cInter-study incidence range 33% to 45%; ^dInter-study incidence range 25% to 40%

Overall:

• No serious adverse events occurred in any study
• 2/17 subjects enrolled to AI444034 discontinued for adverse events (treatment-unrelated myalgia, day 15; treatment-related dizziness, nausea and panic attack, day 7) and were not included in the evaluable population for DDI assessment
• 1/21 subjects enrolled to AI444033 discontinued for adverse events (vomiting and syncope on daclatasvir alone considered treatment related) and was not included in the evaluable population for DDI assessment
• Events in the most common classes on daclatasvir alone (GI and nervous system) occurred at similar rates in subjects receiving tenofovir alone

Daclatasvir (DCV) Background:

Daclatasvir (DCV) or BMS-790052 is an investigational, potentially first-in-class, highly selective hepatitis C virus replication complex inhibitor with broad genotypic coverage and picomolar potency in vitro.

Daclatasvir is one of several molecules Bristol-Myers Squibb is studying for the potential treatment of hepatitis C. The portfolio of investigational compounds, which also includes an NS3 inhibitor, an NS5B nucleotide polymerase inhibitor, and PEGInterferon Lambda, fits into the company’s overall R&D focus on diseases where there is unmet medical need.

Future studies are warranted to evaluate daclatasvir in HCV/HIV coinfected patients. Further DDI studies for daclatasvir plus boosted darunavir and daclatasvir plus lopinavir are planned.

Study Background:

These three open-label studies in healthy subjects evaluated steady-state pharmacokinetic interactions between daclatasvir and representative antiretroviral agents: nucleoside/tide reverse transcriptase inhibitors (or NRTI; tenofovir disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (or NNRTIs; efavirenz), and boosted protease inhibitors (or boosted PIs; atazanavir/ritonavir).

Three open-label studies in healthy subjects were evaluated for this assessment:

• DCV + ATV/r: 14 healthy subjects received daclatasvir 60 mg, once daily on days 1 – 4; and then received daclatasvir 20 mg, once daily plus atazanavir/ritonavir 300 mg/100 mg, once daily, on days 5 – 14
• DCV + EFV: 15 healthy subjects received daclatasvir 60 mg, once daily on days 1 – 4; then received daclatasvir 60 mg, once daily plus efavirenz 600 mg once daily on days 5 – 13; then received daclatasvir 120 mg plus efavirenz 600 mg once daily on days 14 - 18
• DCF + TDF: 20 healthy subjects received daclatasvir 60 mg, once daily, or tenofovir 300 mg once daily or both for seven (7) days in a 3x3 crossover design

Key Inclusion Criteria:

• Men and women, 18 to 49 years of age, inclusive
• Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, vital signs, ECGs, and clinical laboratory determinations
• Body Mass Index (BMI) of 18.0 to 32.0 kg/m2, inclusive

Key Exclusion Criteria:

• Any significant acute or chronic medical illness
• Current or recent (within 3 months of study drug administration) gastrointestinal disease indicated as clinically relevant by the Medical Investigator
• Smoking more than 5 cigarettes per day
• Recent (within 6 months of study drug administration) drug or alcohol abuse as defined in DSM IV, Diagnostic Criteria for Drug and Alcohol Abuse
• History of cardiac conduction abnormalities
• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations beyond what is consistent with the target population
• Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, HIV viral load, or HIV-1, -2 antibody
• Pregnancy or lactation

Request for More Information and Media Interviews:
Investors: John Elicker, 609-252-4611, john.elicker@bms.com
Media: Cristi Barnett, 609-252-6028, cristi.barnett@bms.com

Supporting information:
The abstract and the presentation can be viewed on the CROI website.

Source

CROI 2012: NATAP Updates and Slides

19th Conference on Retroviruses and
Opportunistic Infections
Seattle, WA March 5 - 8, 2011

Provided by NATAP

1. CROI: GS-7977 + Ribavirin in HCV Genotype 1 Null Responders: Results from the ELECTRON Trial - (03/7/11)
   
   
2. CROI: PHARMACOKINETIC INTERACTION BETWEEN THE HCV PROTEASE INHIBITOR BOCEPREVIR AND RITONAVIR-BOOSTED HIV-1 PROTEASE INHIBITORS ATAZANAVIR, LOPINAVIR, AND DARUNAVIR - (03/7/11)
   
   
3. CROI: The Pharmacokinetic Interactions of HCV Protease Inhibitor TMC435 with Rilpivirine, Tenofovir, Efavirenz or Raltegravir in Healthy Volunteers - (03/7/11)
   
   
4. CROI: Evaluation of NS3 Amino Acid Variants in a Phase 1b Study of GT 1 Infection with the HCV Protease Inhibitor, MK-5172 - (03/7/11)
   
   
5. CROI: Influence of the HCV Protease Inhibitor Boceprevir on the Pharmacokinetics of the HIV Integrase Inhibitor Raltegravir - (03/7/11)
   
   
6. CROI: Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: SVR12 Interim Analysis - (03/7/11)
   
   
7. CROI: Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients - (03/7/11)
   
   
8. CROI: HCV PI Boceprevir Lowers Levels of Three Key HIV PIs - written by Mark Mascolini - (03/7/11)

CROI 2012: UNC researchers make key HIV discovery

Published Thu, Mar 08, 2012 03:36 PM
Modified Thu, Mar 08, 2012 03:36 PM

By Jay Price - jprice@newsobserver.com

CHAPEL HILL -- Researchers at UNC-Chapel Hill have discovered what could be a vital step toward a cure for HIV.

By giving patients a drug normally used for treating some kinds of lymphoma, scientists have managed to make dormant, hidden HIV viruses reveal their presence.

That’s crucial if scientists want to find a way to target and completely eliminate the virus from the body, said Dr. David Margolis, a professor of medicine, microbiology and immunology, and epidemiology, who led the study.

Margolis spoke by telephone this afternoon from Seattle, just before presenting the findings at the 19th Conference on Retroviruses and Opportunistic Infections.

HIV is the virus that causes AIDS. In recent years, patients have been able to hold it at bay with elaborate cocktails of antiretroviral drugs.

Even though these regiments halt the progress of the disease, the virus remains, hiding in certain cells, and can turn active again if the drug regimen ends.

Researchers thought that a crucial step toward purging the body of HIV was finding a trigger to luring the virus from its hiding place. That’s what the UNC team did, for the first time.

The next steps in the research include a fuller exploration of the lymphoma drug’s effects on the virus, Margolis said.

The findings from that research will determine the next directions for research.

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AIDS Cure Quest Advances as Merck Cancer Drug Attacks Hidden HIV

By Simeon Bennett - Mar 8, 2012 3:00 PM ET

The 30-year quest for an AIDS cure advanced as scientists succeeded for the first time in attacking HIV in its hardest-to-reach hideouts with a cancer drug made by Merck & Co.

In a trial among six men with HIV, researchers led by David Margolis at the University of North Carolina at Chapel Hill used a dose of Merck’s Zolinza to rouse the virus from inside certain immune-system cells, where it evades regular AIDS drugs. That’s a crucial step toward eliminating the virus from the body. The findings were presented at a conference in Seattle today.

While no patients were cured, the trial shows that Zolinza, or similar drugs, may have the potential to purge the virus, Margolis said. He said he expects to hear from the U.S. Food and Drug Administration within “a couple of weeks” on approval for an additional test using more doses of Zolinza.

“What people want to know is when can someone go to a doctor and be handed a pill and be cured,” Margolis said by phone. “That’s decades away. Think of it more in terms of curing cancer. I think in 10 years someone with HIV infection could go to a specialist and get a complicated treatment and have some likelihood of a prolonged remission of their HIV.”

Mysterious Virus

HIV was first observed in the U.S. as a mysterious, deadly illness among gay men in 1981. Since then it’s killed more than 30 million people globally, making it the world’s deadliest infectious disease.

The hunt for a cure has gathered pace because of improvements in the drugs used to control HIV, such as Gilead Sciences Inc. (GILD)’s once-daily pill Atripla, the world’s top-selling AIDS treatment.

While those drugs reduce HIV to undetectable levels in the body, they don’t completely clear it. The virus hides in certain cells, where it switches off the normal process of replication. That enables HIV to avoid detection by the medicines, which are designed to block steps in its reproduction.

Studies have shown that when patients who have the virus under control stop treatment, latent HIV reactivates and comes roaring back, forcing victims to resume daily pill therapy.

“It’s sort of like the virus is a rabbit at the bottom of a hole, but it needs a boost to get it out of the hole,”Margolis said. “It doesn’t fall in the hole very much, but when it does, it’s stuck there.”

Fine Line

Margolis and colleagues have been looking for ways to reactivate the virus without switching on the so-called resting CD4 T-cells in which it’s hiding. Arousing those cells may trigger a dangerous over-stimulation of the immune system that can cause lasting damage.

In the trial, the researchers recruited volunteers who were taking AIDS drugs to subdue the virus, then added Zolinza to see if they could reactivate latent HIV. It worked, with no serious side effects. The scientists saw an average 4.8-fold increase in HIV’s genetic fingerprints, showing the virus was awake and active inside the cells.

In theory, that means the drug has kick-started HIV’s normal process of replication. That could spur an immune-system attack that kills the host cells, or result in the virus exiting and killing the cells in search of new ones to infect. AIDS drugs patrolling the body would prevent it from doing so, and with nowhere left to go, the virus would die.

If that were to happen on a large enough scale, most latent HIV could be eradicated, enabling patients to stop their regular treatment without the virus rebounding -- a cure.

Next Trial

The study wasn’t designed to see whether Zolinza depleted the number of CD4 cells harboring HIV because the doses of the drug were too low, Margolis said. That’s the objective of the next trial now being considered by the FDA.

“We need to make some progress, we need some signal that we can potentially alter or disturb latently infected cells, and this study suggests that might be possible,” said Sharon Lewin, a professor at The Alfred Hospital in Melbourne. She’s also running a trial using multiple doses of Zolinza to target latent HIV and expects to have results from 10 patients later this year, she said.

Zolinza, also known as vorinostat and SAHA, was approved in 2006 for use against a rare type of blood cancer. The drug earned Merck $15 million in 2008, the last year the Whitehouse Station, New Jersey-based company disclosed sales of the medicine. Laboratory tests had shown it could purge HIV from cells in dishes, but the real challenge was to achieve the same result in humans.

“The study gives us hope because it provides an idea that’s worth exploring further,” said Daria Hazuda, Merck’s head of infectious diseases research, and one of the main developers of Isentress, an AIDS drug that generated $1.36 billion for Merck last year. “It’s a very important first step, but we’re still a long way away,” Hazuda said by telephone today.

Forcing Replication

The drug targets an enzyme called histone deacetylase, or HDAC, that helps HIV go to sleep in cells by interfering with its ability to replicate. By blocking HDAC, Zolinza would reactivate the virus, forcing replication.

This is Margolis’s second attempt at flushing out latent HIV. In 2005 he published a paper in The Lancet journal showing that Depakote, an approved treatment for bipolar disorder made by Abbott Laboratories, reduced the number of infected resting cells by as much as 84 percent when combined with Roche Holding AG’s AIDS drug Fuzeon, in a study involving four patients. Subsequent research by Margolis and others contradicted those findings.

Today’s results, the first to show that a mechanism known to keep HIV dormant could be successfully targeted in humans, were presented at the Conference on Retroviruses and Opportunistic Infections in Seattle.

To contact the reporter on this story: Simeon Bennett in Geneva at sbennett9@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

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CROI 2012: Interferon decreases HIV-1 levels, controls virus after stopping antiretroviral therapy

March 7, 2012

A multi-institutional team of researchers, led by The Wistar Institute, has announced the results of a clinical trial that shows how the immune system can engage in fighting HIV infection if given the right boost. In their study, HIV-infected volunteers suspended their daily antiretroviral therapy to receive weekly doses of interferon-alpha, an antiviral chemical produced by the human immune system. The study provides the first clinical evidence for a means of reducing the persistent amount of HIV in patients and the ability to control HIV without continued antiretroviral therapy.

Wistar's Luis J. Montaner, D.V.M., D.Phil., today presents their findings of the first clinical strategy able to harness host control and decrease HIV reservoir measures, at the 2012 Conference on Retroviruses and Opportunistic Infections in Seattle, Washington. HIV reservoirs are populations of cells that harbor HIV-1, enabling the virus to persist as a chronic infection.

"Our data shows that our human immune response can be made to control HIV in persons who have otherwise lost that ability and, if sustained by natural interferon production, it establishes proof-of-concept that a functional cure is theoretically possible," said Montaner, a professor at Wistar and director of the Institute's HIV-1 Immunopathogenesis Laboratory. "And while we still have much to pursue with this early clinical finding, I firmly believe this gives us hope that one day we can control—and eventually eradicate—HIV in absence of antiretroviral therapy."

The trial showed that interferon-alpha when used as a drug (Peg-IFN-α2A) sustained control of HIV in 9 of 20 patients while also decreasing measures of HIV reservoirs in patients otherwise dependent on antiretroviral therapy (ART). No other clinical strategy to date has shown an impact on decreasing integrated HIV DNA levels in HIV-infected humans.

Click here to see video clip …

Luis Montaner, D.V.M., D.Phil., discusses how the immune system can engage in fighting HIV infection if given the right boost. In a recent study, HIV-infected volunteers suspended their daily antiretroviral therapy to receive weekly doses of interferon‑alpha, an antiviral chemical our bodies produce naturally. The study provides the first clinical evidence for a means of reducing the persistent amount of HIV in patients and the ability to control HIV without continued antiretroviral therapy. Montaner presents his results March 7 at the 2012 Conference on Retroviruses and Opportunistic Infections. Credit: The Wistar Institute

"While our data may not immediately change clinical practice, it identifies the first strategy that shows a clinical response where both viral replication and HIV reservoir indicators are observed to be reduced in absence of current chemotherapy," Montaner said. "This is the type of response HIV cure research aims to achieve."

The study analyzed 20 patients over a period of 24 weeks. Remarkably, 45 percent of these patients were able to sustain viral control under 400 copies per mililiter and a similar frequency showed more than 50 percent reduction in circulating HIV reservoirs, as measured by the laboratory of Una O'Doherty, M.D., at the University of Pennsylvania. According to the researchers, these results show that our immune system, which is targeted by the HIV-1 virus, can mount a defense to HIV infection, if given the right stimulation.

"In previous studies, we have seen that when people suspend ART, their viral loads begin to creep upward while their white blood cell count gradually drops," Montaner said. "We expected to see the same thing during this trial, but we were, frankly, surprised to see patients maintain the gains made through ART using only interferon that modulates our body's response rather than acting directly against HIV as all current HIV drugs do."

"When someone is first infected with HIV-1, the immune system is overwhelmed, and the natural release of interferon into the bloodstream is ineffective as cells that produce it are quickly impaired," Montaner said. "But in our study, conducted at a later stage of chronic infection in an individual, we saw that adding interferon to a recovered immune system can have a dramatic effect in directing responses against HIV-1 to both control and reduce its detection within places we know it can hide."

Patients were recruited in partnership with local HIV/AIDS clinical treatment programs, including the University of Pennsylvania, Drexel University, and the Philadelphia Field-initiating Group for HIV Trials Philadelphia (FIGHT). The trial followed the progress of 20 men and women of various ethnicities as they started on either of two different doses of interferon on ART, discontinued ART, and maintained interferon treatment for up to 24 weeks. The trial lasted either 24 weeks or until either their HIV-1 levels rose or CD4 T cell counts dropped to a pre-determined level, at which point they would resume ART. Surprisingly, at midpoint (12 weeks), 45 percent (9 out of 20) of the patients still controled viral replication, and those that dropped out still compared favorably to the controls. Eight patients remained in the trial during the entire 24 weeks. Both dosage arms achieved similar results.

"It is exciting to show control against HIV-1 can be regained by way of stimulating natural mechanisms," Montaner said. "Our findings also open the way to determine if we can move this clinical research strategy towards a cure based on the decrease in HIV reservoirs we observed."

Interferon-alpha is a chemical naturally manufactured by the human immune system to "interfere" with the ability of viruses to replicate within cells. Since human interferon does not persist long enough in the body to serve as a useful antiviral drug, pharmaceutical researchers modified it by adding polyethelyne glycol (PEG) to the interferon molecule, making it last longer in the bloodstream with less toxicity. This "pegylated" form of interferon was approved in 2008 to treat hepatitis B and C infections.

Provided by The Wistar Institute

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Also See: CROI 2012: Penn, Wistar researchers thwart HIV without antiviral drugs

CROI 2012: Penn, Wistar researchers thwart HIV without antiviral drugs

Wistar's Luis Montaner led the immune- therapy study.

Posted: Thu, Mar. 8, 2012, 3:01 AM

By Marie McCullough

Inquirer Staff Writer

For the first time, researchers have shown that they can suppress the AIDS virus by bolstering patients' immune systems, while taking them off standard antiviral drugs.

The small, six-month-long study, led by scientists at the Wistar Institute and the University of Pennsylvania, put patients on interferon, an old drug with nasty side effects. Interferon by itself had not worked against HIV, the virus that causes AIDS, in previous studies. The researchers can only speculate about why their protocol - which initially gave antivirals and interferon together - was effective.

Still, the study offers tantalizing evidence that an immune system damaged by HIV can nonetheless be prompted to control the virus on its own - without the powerful antiviral drugs that keep the microbe from reproducing.

While antivirals have transformed HIV infection from a death sentence into a manageable disease, they are costly, must be taken for life, and can spur the virus to develop drug resistance.

The new study was "designed to answer the question: Is it possible to control the virus with immune therapy? The answer is yes," said Wistar immunologist Luis Montaner, who presented the results Wednesday at an international AIDS conference in San Francisco. "There have been a lot of false hypotheses, so people are very jaded. But I firmly believe this gives us hope that one day we can control HIV in the absence of" antiviral therapy.

Virologist Satish Pillai, an AIDS researcher at the University of California San Francisco who was not involved in the study, called the findings "really amazing." The implication, he said, is that the body has natural defenses against the virus that are just waiting to be tapped by the right therapy.

At the National Institutes of Health, which funded the study, AIDS expert Carl W. Dieffenbach had a more reserved reaction.

"It's an important first step, so I don't want to damn it with faint praise," said Dieffenbach, director of the division of AIDS. "But I don't want to oversell it, either. While I suspect that the response to interferon was far more than we would have expected, we can't be sure."

Interferon, a drug based on a protein naturally produced in the body, is used to treat hepatitis C and some cancers. Side effects include flulike symptoms, hair loss, and depression.

In the new study, 20 patients took antiviral drugs plus interferon for five weeks, then interferon alone for up to 24 weeks. Any patient whose "viral load" - the amount of virus in the blood - surged above a low threshold was immediately put back on antivirals.

Based on previous studies in which patients tried taking breaks from antiviral treatment, the researchers predicted HIV would surge within about a month in all but a few of the patients.

Instead, nine patients - 45 percent - suppressed the virus on interferon alone. Three patients kept HIV in check for 12 weeks, while six patients were still suppressed at the end of the 24-week study.

Even more encouraging, sophisticated DNA tests showed that seven patients had a significant decrease in the amount of HIV hiding in their T cells, the immune cells that the virus invades and hijacks to reproduce. Normally, this reservoir of "integrated" HIV would start churning out more virus copies as soon as antivirals were stopped.

"Generally, we've assumed the integrated HIV is silent and invisible" to the immune system, said Una O'Doherty, a transfusion medicine specialist in the University of Pennsylvania's pathology department who conducted the DNA tests. "Maybe it's not invisible."

Interferon was shelved for HIV long ago, when antivirals revolutionized therapy. So why did it suppress the virus in the new study?

Montaner speculated that the key was the five weeks of overlapping treatment. Perhaps the antivirals gave interferon a chance to prime the immune system for defensive action, much like a vaccine primes the system to prevent infection.

UCSF's Pillai, who had studied interferon in patients co-infected with HIV and hepatitis C, believes the drug boosts "restriction factors" - immune-system chemicals that help neutralize or divert viruses.

In any case, the quest for therapies that work on the immune system - as opposed to the virus - is growing. At least seven companies and many academic labs are pursuing vaccines, gene therapies, or other immune boosters that would suppress HIV without necessarily eradicating it, a so-called functional cure.

Cure is a heady term, but it is theoretically possible, as a patient living in Berlin has shown. He has been free of the virus since 2008, following a bone-marrow transplant to treat leukemia, because the marrow came from one of the rare Northern Europeans who has a natural genetic resistance to HIV infection.

For Montaner's team - 14 scientists from seven institutions, including Philadelphia Fight, which helped enroll research subjects - the next step is finding funding for a larger trial.

"When the study was started, it was expected by most people to fail," he said. "Now, everyone is intrigued and hopeful."

---

Contact Marie McCullough

at 215-854-2720 or mmccullough@phillynews.com.

Source

Also See: Small US trial looks at body's ability to fight HIV

CROI 2012: HCV PI Boceprevir Lowers Levels of Three Key HIV PIs

Provided by NATAP

19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle

Mark Mascolini

Boceprevir, the recently licensed HCV protease inhibitor (PI), lowered concentrations of three ritonavir-boosted HIV PIs--atazanavir, darunavir, and lopinavir--in a pharmacokinetic study that enrolled 39 healthy volunteers [1].

The FDA advises that "healthcare professionals who have started patients infected with both chronic HCV and HIV on Victrelis [boceprevir] and antiretroviral therapy containing a ritonavir-boosted protease inhibitor should closely monitor patients for HCV treatment response and for potential HCV and HIV virologic rebound" [2].

In a letter to healthcare professionals, the manufacturer cautioned that "these drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by potentially reducing the effectiveness of these medicines when coadministered [3]." The statement stressed that "Merck does not recommend the coadministration of Victrelis [boceprevir] and ritonavir-boosted HIV protease inhibitors."

Boceprevir and telaprevir, another HCV PI, won FDA approval in 2011 for use with pegylated interferon and ribavirin in adults with genotype 1 chronic HCV and compensated liver disease. Neither boceprevir nor telaprevir is licensed for use in people coinfected with HCV and HIV.

In work reported separately by NATAP, a placebo-controlled trial of boceprevir plus pegylated interferon and ribavirin for 100 people coinfected with genotype 1 HCV and HIV logged undetectable HCV RNA levels in 39 of 61 people (64%) randomized to boceprevir and 10 of 34 (29%) randomized to placebo at week 48 [4]. All study participants had an HIV load below 50 copies when the trial began.

The pharmacokinetic study involved 39 healthy volunteers between 19 and 55 years old [1]. No one had HIV infection, and none tested positive for hepatitis B surface antigen or HCV antibodies. Everyone took boceprevir at the standard dose of 800 mg three times daily on study days 1 to 6 then took no drugs for 4 days. On days 10 to 31 study participants took 300/100 mg of atazanavir/ritonavir once daily, 400/100 mg of lopinavir/ritonavir twice daily, or 600/100 mg of darunavir/ritonavir twice daily. On days 25 through 31, they also took the standard dose of boceprevir.

Taking boceprevir with an HIV PI lowered trough concentrations by an average 49% for atazanavir, 43% for lopinavir, and 59% for darunavir. Average area under the concentration-time curve (AUC) fell 35% for atazanavir, 34% for lopinavir, and 44% for darunavir. Respective average drops in peak concentrations were 25% for atazanavir, 30% for lopinavir, and 36% for darunavir.
Taking atazanavir with boceprevir did not alter boceprevir AUC. But lopinavir cut boceprevir AUC 45%, and darunavir lowered boceprevir AUC 32%.

The FDA also issued online guidance about these findings for patients and patient advocates [5]. The agency cautioned that HIV-positive people taking boceprevir with an HIV PI should not stop taking any of their drugs without first talking to their clinician.
In a separate study involving 24 healthy volunteers, boceprevir did not affect levels of the integrase inhibitor raltegravir [6].

References

1. Hulskotte E, Feng HP, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 771LB.

2. US Food and Drug Administration. FDA drug safety communication: important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs. February 8, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm291119.htm.

3. Reddy SSK. Merck & Co, Inc. Important drug warning. February 6, 2012. http://www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdf.

4. Sulkowski M, Pol S, Cooper C, et al. Boceprevir + pegylated interferon + ribavirin for the treatment of HCV/HIV-co-infected patients: end of treatment (week 48) interim results. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 47.

5. US Food and Drug Administration. Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitor drugs--drug interactions. For patients and patient advocates. http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm291389.htm.

6. de Kanter C, Blonk M, Colbers A, Fillekes Q, Schouwenberg B, Burger D. The influence of the HCV protease inhibitor boceprevir on the pharmacokinetics of the HIV integrase inhibitor raltegravir. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 772LB.

Source

CROI 2012: Interferon-Free Hepatitis C Tx Hits Snag

By Michael Smith, North American Correspondent, MedPage Today

Published: March 07, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

SEATTLE -- Results in a hard-to-treat patient group have clouded the future of a closely watched agent that acts directly against hepatitis C.

Action Points

• This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Despite impressive results during treatment of hepatitis C virus with the investigational compound PSI-7977, all but one of the patients relapsed almost immediately after treatment stopped.
• The drug was being given in combination with ribavirin, one of the standard hepatitis C drugs, but without the other standby, pegylated interferon.

Despite impressive results during treatment with the compound dubbed PSI-7977, all but one of the patients relapsed almost immediately after treatment stopped, according to Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand.

The drug was being given in combination with ribavirin, one of the standard hepatitis C drugs, but without the other standby, pegylated interferon, Gane told reporters at the annual Conference on Retroviruses and Opportunistic Infections.

Among researchers and clinicians, there has been intense interest in the compound, a nucleotide analog, because of the potential to eliminate interferon, whose side effects make treatment difficult for many patients.

"The holy grail is treating people without interferon," commented David Thomas, MD, of Johns Hopkins University in Baltimore, who was not part of the study but who chaired a press conference at which details were presented.

But he told MedPage Today the results being presented here are disappointing, especially since the drug appeared to be remarkably effective in patients with relatively easy-to-treat disease.

In earlier results from the phase II ELECTRON study, patients with genotypes 2 and 3 of the virus were completely cured after just 12 weeks of therapy with PSI-7977 combined with ribavirin, Gane noted.

But researchers were also testing the combination in 10 patients with genotype 1 hepatitis C who had previously not responded to standard therapy with ribavirin and interferon, and in 25 genotype 1 patients who had not yet been treated, Gane said.

The initial responses in both groups were similar to those seen in genotypes 2 and 3 -- a quick drop to undetectable levels of virus followed by complete suppression throughout the 12-week treatment period, Gane said.

But all but one of the so-called null responders relapsed, with hepatitis C levels rising sharply within days of stopping the drug, Gane reported. Data on the treatment-naïve patients is not complete yet and will be reported in the next few months, he added.

"It's still a drug we're excited about, but these data put some limits on its use," Thomas said.

"The drug was curing [patients with] genotypes 2 and 3 in 12 weeks with just ribavirin," he said, but that doesn't appear to be possible in the hardest-to-treat subgroup.

Now, he said, the researchers have to do "a lot of hard work" to figure how to overcome the obstacles.

Any new study in genotype 1 null responders will either be longer in duration, or will add another direct-acting agent, or both, Gane said. But the researchers and the drug's manufacturer haven't settled on what they'll do.

Gane said the researchers will offer the relapsed patients a rescue protocol with PSI-7977 and another medication, but, again, they haven't decided what that drug will be.

The study was supported by Giliad.

Gane reported financial links with Gilead, Janssen-Cilag, Novartis, Pharmasset, and Vertex.

Thomas reported financial links with Gilead and Merck.

Primary source: Conference on Retroviruses and Opportunistic Infections
Source reference:
Gane E, et al "100% rapid virologic response for PSI-7977 + ribavirin in genotype 1 null responders (ELECTRON): early viral decline similar to that observed in genotype 1 and genotype 2/3 treatment-naïve patients" CROI 2012; Abstract 54LB.

Source

Also See: CROI 2012: PSI-7977/ribavirin combo achieved rapid response in HCV genotype-1

CROI 2012: New Hepatitis C Drugs in Clinical Practice [VIDEO]

Published on Wednesday, 07 March 2012 00:00
Written by Gregory Fowler
Provided by HIVandHepatitis.com

New therapies are leading to a "huge sea change" in the way infectious disease doctors are thinking about hepatitis C, Douglas Dieterich suggested at a press conference at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) this week in Seattle.

New therapies are leading to a "huge sea change" in the way infectious disease doctors are thinking about hepatitis C, Douglas Dieterich suggested at a press conference at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) this week in Seattle.

Joining Dieterich on the panel, David Thomas drew similarities to the state of HIV treatment in the 1990s before the advent of HIV protease inhibitors and effective combination therapy.

Mark Sulkowski emphasized the need for guidelines for treating HIV/HCV coinfected patients, noting that new week 12 sustained virological response data presented at the meeting "truly are cutting-edge." The latest data, he said, allay concerns about post-treatment relapse, while Dieterich noted that worries about worse side effects among coinfected people have not been confirmed.

Finally, Edward Gane expressed optimism about seeing interferon-free regimens within the next 5 years.

3/7/12

Reference
Press conference. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 6, 2012.

Source

CROI 2012: PSI-7977/ribavirin combo achieved rapid response in HCV genotype-1

Posted on InfectiousDiseaseNews.com March 6, 2012

SEATTLE — An interferon-free, experimental nucleotide analogue, PSI-7977, plus ribavirin for 12 weeks achieved rapid on-treatment response in hepatitis C virus genotype-1 patients and was well tolerated in this population, according to presenter Edward Gane, MD.

Gane, a hepatologist at Auckland City Hospital in New Zealand and principal investigator for the ELECTRON study, presented findings from a phase 2, multi-arm study aiming to assess the uridine nucleotide analogue, PSI-7977, combined with ribavirin currently in phase 3 development.

“Results on genotype-2 and genotype-3 patients were presented at the Liver meeting last fall, which demonstrated 100% rapid virologic response rates with interferon-free PSI-7977 plus ribavirin,” Gane said during a press conference today. “Following these results, we enrolled additional patients who were genotype-1 treatment-naive and null responders.”

For the current study, Gane and colleagues assigned 400 mg PSI-7977 plus ribavirin to 10 null responders and 25 treatment-naive patients with HCV genotype-1. Researchers compared early on-treatment data with data from treatment-naive patients with HCV genotype-2 and genotype-3 included in the ELECTRON study.

“Treatment-naive patients just completed treatment,” Gane said. “Therefore, results will not be available until next quarter and will be presented at the Liver meeting in Europe.”

However, overall data, thus far, indicate that patients achieved rapid treatment response, and among all participants, HCV RNA remained undetectable at 4 weeks and throughout the treatment regimen.

Of the nine null patients who have reached the 4-week treatment time point, eight patients relapsed. The one responder was a young, white woman who had the IL28 gene, a favorable predictor for response to interferon-based treatment, according to Gane.

“The majority of null responders have relapsed post-treatment. Further treatment options in this very difficult to treat group will either be longer duration of PSI-7977 plus ribavirin or the addition of another direct-acting antiviral,” he said.

For more information:

• Gane E. #54LB. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle.

Disclosure: The researchers report no relevant financial disclosures.

Source

CROI 2012: Results from Investigational Studies with VICTRELIS™ (boceprevir) Presented at the Conference on Retroviruses and Opportunistic Infections to Understand Potential Use in Patients Coinfected with Chronic Hepatitis C and HIV-1

SEATTLE, March 6, 2012 – Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from two different investigational studies conducted to better understand the potential use of VICTRELIS^™ (boceprevir), the company’s oral HCV NS3/4A protease inhibitor, in treating patients coinfected with chronic hepatitis C virus (HCV) and HIV-1. These data are being presented for the first time today at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Results were presented from a 12-week post treatment interim analysis of a Phase IIb clinical study evaluating the investigational use of VICTRELIS in combination with peginterferon alfa-2b and ribavirin for the treatment of chronic HCV genotype 1 infection in adult patients coinfected with HIV-1 (n=100). In the study, a higher percentage of patients receiving VICTRELIS in combination with peginterferon alfa-2b and ribavirin had undetectable hepatitis C virus (HCV-RNA) 12 weeks after treatment ended (sustained virologic response-12¹ or SVR-12) than patients receiving peginterferon alfa-2b and ribavirin alone.

Additionally, Merck announced results as part of a late-breaker poster session [Poster #771] from a pharmacokinetic study evaluating drug interactions between VICTRELIS and ritonavir-boosted HIV protease inhibitors in 39 healthy volunteers. In this study, concomitant administration of VICTRELIS with ritonavir (Norvir^®) in combination with atazanavir (Reyataz^®) or darunavir (Prezista^®), or with lopinavir/ritonavir (Kaletra^®) resulted in reduced exposures of the HIV medicines and VICTRELIS. These drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by potentially reducing the effectiveness of these medicines when co-administered. Merck does not recommend the co-administration of VICTRELIS and ritonavir-boosted HIV protease inhibitors.

"In light of the differing results in these data sets, Merck recognizes it is important to continue to study VICTRELIS in combination therapy in this difficult-to-treat patient population," said Eliav Barr, M.D., vice president, Project Leadership and Management, Infectious Diseases, Merck Research Laboratories. "Our collaborative studies with the French National Agency for Research on AIDS and Viral Hepatitis² (ANRS) and the AIDS Clinical Trial Group (ACTG), which is funded by the U.S. National Institute of Allergy and Infectious Diseases, will provide greater insight into the potential role of VICTRELIS in treating patients with chronic HCV genotype 1 infection who are coinfected with HIV-1."

Indications and usage for VICTRELIS
VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (P/R), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:

• VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.
• VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
• VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than a 2 log viral load decline by treatment week 12) to peginterferon alfa and ribavirin therapy.
• Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin

The safety and efficacy of VICTRELIS alone or in combination with peginterferon alfa or ribavirin has not been established in patients coinfected with HIV and HCV.

Interim SVR-12 Results from Phase IIb HCV-HIV Coinfection Study
One hundred (100) adult patients with previously untreated HCV genotype 1 infection, on an optimized antiretroviral regimen and with stable HIV-1 disease (HIV-RNA less than 50 copies/mL; CD4 cell counts equal to or greater than 200 cells/mm³) were randomized into the study. Two patients randomized to the treatment arm receiving VICTRELIS in combination with peginterferon alfa-2b (P) and ribavirin (R) did not receive VICTRELIS. Thus, the interim analysis was based on 98 patients who received at least one dose of study drug: 64 patients in the arm receiving VICTRELIS plus PR, and 34 patients in the control arm receiving PR alone. All patients treated in the study received a 4-week lead-in with PR alone followed by VICTRELIS plus PR or placebo plus PR for 44 weeks, for a total treatment duration of 48 weeks. Preliminary 24-week on-treatment data from this study were presented at the Infectious Diseases Society of America annual meeting in October 2011. Final study completion will be at week 72, or 24 weeks after the end of all treatment.

The interim analysis showed that 60.7 percent (n=37/61) of patients receiving VICTRELIS in combination with PR achieved SVR-12 compared to 26.5 percent (n=9/34) of patients receiving PR alone, a treatment difference of 34.2 percent. Three (3) patients in the VICTRELIS plus PR arm had not reached 12 weeks post treatment and were excluded.

Three (3) patients in treatment arms receiving VICTRELIS plus PR and four (4) patients in the PR control arm experienced HIV breakthrough (HIV viral load greater than 50 copies/mL at two consecutive visits). Preliminary safety data for VICTRELIS in combination therapy in HCV/HIV-1 coinfected patients demonstrated a profile similar to that previously observed in patients with HCV mono-infection.

The most common clinical adverse events with a difference of equal to or greater than 10 percent for the treatment arm receiving VICTRELIS plus PR compared to the PR control arm, respectively, were: anemia (41 vs. 26 percent), pyrexia (fever) (36 vs. 21 percent), asthenia (weakness) (34 v. 24 percent), decreased appetite (34 vs.18 percent), diarrhea (28 v. 18 percent), dysgeusia (bad taste) (28 vs. 15 percent), vomiting (28 vs. 15 percent), flu-like illness (25 v. 38 percent) and neutropenia (19 vs. 6 percent). Serious clinical adverse events occurred in 17 percent and 21 percent of patients in the two treatment arms, respectively. Dose modification for any study drug due to a clinical adverse event occurred in 28 percent and 24 percent of patients, respectively, and study discontinuation due to a clinical adverse event occurred in 20 percent and 9 percent of patients, respectively.

About the Phase IIb coinfection study
The primary objective of this ongoing randomized, multicenter, double-blinded Phase IIb study is to compare the efficacy of 800 mg of VICTRELIS three times daily in combination with peginterferon alfa-2b (P) 1.5 mcg/kg weekly plus ribavirin (R) 600 to 1,400 mg/daily to therapy with PR alone in adult patients coinfected with chronic HCV genotype 1 and HIV-1. Patients were randomized in a 2:1 ratio to the treatment arm with VICTRELIS plus PR or the PR control arm, respectively. Patients were stratified by cirrhosis (yes/no) and baseline HCV-RNA (less than 800,000 IU/mL vs. equal to or greater than 800,000 IU/mL). The majority of patients were non-cirrhotic (95 percent), white (82 percent) and male (69 percent), with a median age of about 43 years. Most patients had high HCV-RNA (88 percent) at baseline and HCV genotype 1a infection (65 percent).

Antiretroviral regimens for HIV-1 that included non-nucleoside reverse transcriptase inhibitors (NNRTIs), or zidovudine, stavudine or didanosine were not permitted. Ritonavir-boosted HIV protease inhibitors could be included in antiretroviral regimens for HIV-1. Patients with detectable HCV-RNA and less than a 2 log HCV-RNA decline at treatment week 12 or detectable HCV-RNA at treatment week 24 were considered treatment failures and discontinued all HCV treatment.

Primary pharmacokinetic drug interaction study results
The study was a single-center, three-arm, open-label, drug-interaction study in 39 healthy adults. Patients received 800 mg of VICTRELIS three times daily on Days 1-6. Following a 4-day "washout" period, patients received either 300 mg of atazanavir/100 mg of ritonavir once daily, 400 mg of lopinavir/100mg of ritonavir twice daily, or 600 mg of darunavir/100 mg of ritonvair twice daily on Days 10-31. From Days 25-31, patients also received 800 mg of VICTRELIS three times daily. Blood samples were collected for the pharmacokinetic assessment of the HIV medicines and VICTRELIS.

In the study, co-administration of VICTRELIS reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir and darunavir by 49, 43 and 59 percent, respectively. Mean reductions of 34 to 44 percent and 25 to 36 percent were observed in AUC and Cmax of atazanavir, lopinavirand darunavir. Co-administration of ritonavir-boosted atazanavir with VICTRELIS did not alter the exposure of VICTRELIS, but co-administration of VICTRELIS with lopinavir/ritonavir or ritonavir-boosted darunavir decreased the exposure of VICTRELIS by 45 and 32 percent, respectively. These drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by potentially reducing the effectiveness of these medicines when co-administered.

Important safety information about VICTRELIS
All contraindications to peginterferon alfa and ribavirin also apply since VICTRELIS must be administered with peginterferon alfa and ribavirin. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS and concomitant ribavirin.

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

Anemia and/or Neutropenia – The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared to peginterferon alfa and ribavirin alone and/or may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.

Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.

The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with peginterferon alfa and ribavirin were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for peginterferon alfa and ribavirin alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50 percent), anemia
(45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.

Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

# # #

¹ SVR-12, the primary endpoint of the interim analysis, is defined as achievement of undetectable HCV-RNA at the 12 week post-treatment visit.

² ANRS HC27 BOCEPREVIR pilot study; clinicaltrials.gov identifier: NCT01335529.

VICTRELIS^™ is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Norvir^®, Reyataz^®, Prezista^® and Kaletra^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Revatio^® and Adcirca^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Please see Prescribing Information for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and Medication Guide for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.

Source

CROI 2012: Telaprevir sustained high response rates in treatment-naive HIV patients

Posted on InfectiousDiseaseNews.com March 6, 2012

SEATTLE — Significantly higher response rates were observed with telaprevir combined with peginterferon alfa and ribavirin compared with placebo for the treatment of chronic hepatitis C virus genotype-1 infection in treatment-naive HIV patients.

Douglas T. Dieterich, MD, professor of medicine in the division of hepatology at Mount Sinai School of Medicine in New York, presented findings from a 24-week interim analysis of patients assigned telaprevir (Incivek, Vertex Pharmaceuticals).

“The numbers are impressive — 74% for treatment arm vs. 45% in the control arm,” Dieterich said during a press conference today. “This is a huge leap forward in treatment for HCV and HIV patients.”

Patients were grouped into the following treatment regimens:

• Part A: Patients received no concurrent antiretroviral therapy.
• Part B: Patients were on ART and also an efavirenz-based regimen or on an atazanavir plus ritonavir-based regimen.

Of the 62 patients included in the study, 44 reached week 24 of treatment and are, therefore, included in the current analysis. The mean age of the patients was 46 years; 88% male, and 27% black. Subtype 1a was confirmed in 68% and cirrhosis in 3.3%.

Although CD4 cell count percentage remained unchanged by week 24, absolute CD4 cell counts decreased overall.

At week 24, undetectable HCV RNA levels occurred in 86% of patients assigned treatment and no ART vs. 33% among those assigned placebo; in 75% of patients assigned to treatment who were also on an ART plus efavirenz-based regimen vs. 50% of those assigned placebo; and in 67% of patients assigned to treatment who were also on ART plus atazanavir/ritonavir-based regimen vs. 75% of those assigned placebo.

One patient in the efavirenz-based regimen group and one patient in the atazanavir/ritonavir group achieved HCV RNA breakthrough on telaprevir, according to the researchers.

Compared with placebo, 10% or more of patients assigned to treatment groups experienced vomiting, abdominal pain, nausea, dizziness, depression and pruritus. Both bilirubinemia and hyperbilirubinemia were more common among patients in the atazanavir/ritonavir group.

For more information:

• Dieterich D. #46. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle.

Disclosures: The researchers report no relevant financial disclosures.

Perspective

There is a lot of exciting work on hepatitis being presented at CROI. This is the first time that we will have data on cure rates in HIV/HCV coinfected persons treated with new protease inhibitors; a few first-ever in man releases of data.

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CROI 2012: Boceprevir regimen led to high rates of undetectable HCV RNA in HCV/HIV

Posted on InfectiousDiseaseNews.com March 6, 2012

SEATTLE — A boceprevir plus pegylated interferon and ribavirin combination resulted in significantly high rates of undetectable hepatitis C virus RNA at weeks 4, 8, 12, 24 and 48 in patients coinfected with hepatitis C virus genotype-1 and HIV.

“The [sustained virological response] 12 data being presented today is an endpoint that is currently being determined by regulatory authorities to represent a solid sustained virologic response metric,” Mark Sulkowski, MD, of Johns Hopkins University School of Medicine, said during the meeting. “Our data suggest that boceprevir plus pegylated interferon and ribavirin had a sustained virologic response rate of 60.7%, with three patients negative at 4 weeks.”

From November 2009 to December 2010, patients were randomly assigned in a 2:1 fashion to 1.5 mcg/week pegylated interferon plus 600 mg/day to 1,400 mg/day ribavirin and 800 mg boceprevir (Victrelis, Merck) three-times daily (n=64) or to placebo plus pegylated interferon and ribavirin (n=34). The median age of the patients was 43 years; 69% male, and 82% white.

Treatment duration was 44 weeks. Primary outcome measure was an achievement of SVR (undetectable plasma HCV RNA) by week 24 of treatment.

Overall, 61% of patients assigned to the boceprevir arm completed treatment vs. 32% of those assigned placebo by week 48. Compared with an undetectable HCV RNA rate of 29.4% in the placebo arm, the rate was 63.9% in the boceprevir arm.

Treatment failure occurred in 9% of those assigned boceprevir vs. 53% of those assigned placebo. Patients included in the boceprevir arm were more likely to experience adverse events, including a decreased appetite, anemia and neutropenia. HIV RNA virologic failure occurred in two patients in the placebo arm and in three patients in the boceprevir arm.

“Our data suggest that the boceprevir regimen was well tolerated in these patients with HCV/HIV coinfection,” Sulkowski said.

For more information:

• Sulkowski M. #47. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle.

Disclosure: The researchers report no relevant financial disclosures.

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Hepatitis C Patients Relapse on Gilead’s Experimental Medicine in Study

By Ryan Flinn - Mar 6, 2012 11:46 AM ET

Gilead Sciences Inc. (GILD), which paid $10.8 billion to buy Pharmasset Inc. (VRUS) for its hepatitis C pill, said the number of patients who relapsed after they stopped taking the treatment has increased.

Eight of nine patients with the most-common form of the virus in the U.S. had a relapse within four weeks after stopping use of the medicine, GS-7977, and ribavirin, according to research presented today at the Conference on Retroviruses and Opportunistic Infections in Seattle. The patients in the study weren’t helped by prior therapies.

Gilead announced last month that six patients relapsed, sending shares down the most in 11 years. A longer duration or combination with other therapies may help these patients, said researcher Edward Gane, deputy director and hepatologist of the New Zealand Liver Transplant Unit at Auckland City Hospital.

“It’s clear the treatment options for this very difficult to treat group will either be longer duration of 7977 plus ribavirin, or alternatively, the addition of another direct acting antiviral,” Gane said at the meeting.

Last year, Pharmasset reported data on PSI-7977 showing that 40 patients with genotypes 2 and 3 who received the therapy were responsive after 12 weeks. About half the patients had been followed up to 24 weeks, and they were all cured.

Hepatitis C is a viral infection that can lead to swelling of the liver. As many as 170 million people globally carry the virus, which is transmitted through exposure to infected blood, and more than 350,000 die from related illnesses each year, according to the Geneva-based World Health Organization.

Gilead declined 1.4 percent to $45.59 at 11:41 a.m. New York time.

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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HIV Main Focus of Retrovirus Conference

By Michael Smith, North American Correspondent, MedPage Today

Published: March 02, 2012

SEATTLE -- HIV is usually the main focus -- as the name suggests -- of the Conference on Retroviruses and Opportunistic Infections.

And this year will be no exception, according to Scott Hammer, MD, of Columbia University in New York City, co-chair of the scientific program committee.

"Other retroviruses come into play," he told MedPage Today, "but the bulk of the meeting is HIV and its related complications, both opportunistic and non-opportunistic."

But if the overall focus is not much changed, this year's meeting will narrow its gaze to three main areas, Hammer said:

• Preventing HIV infection, a topic that has included both good news and bad in the past year
• Treating the major co-infections, tuberculosis and hepatitis C
• Examining the potential for curing the infection

That last is "not fantasy, it's good science," Hammer said, although for years researchers and clinicians thought the best they could do was make HIV a chronic disease.

Now, though, many leading scientists think it may soon be possible to reach into the reservoirs where HIV hides in the body and eradicate the virus, although exactly how remains a matter of active investigation.

It's unlikely that this meeting will see any reports of a breakthrough in the area – "there aren't going to be any show-stoppers," as Hammer puts it – but he's expecting some incremental progress.

On the other hand, meeting-goers are likely to get more information on using anti-retroviral drugs to prevent HIV infection in the first place, Hammer said.

That field has been spurred by results from several trials, showing that treating people at risk of infection and also treating partners of infected people reduces the risk of infection.

But other trials – some looking at using anti-retroviral drugs in vaginal gels, for instance – have reported disappointing results, so that the overall picture remains unclear, Hammer noted.

"There's a lot of excitement, but also a lot of discussion points," he said.

For instance, the annual N'Galy-Mann lecture, which recognizes important epidemiological or clinical research, will be given this year by the husband-and-wife team of Quarraisha Abdool Karim, PhD, of the Centre for the AIDS Program of Research in South Africa (CAPRISA) and Salim Abdool Karim, MBChB, PhD, of the University of KwaZulu-Natal in Durban, South Africa.

The pair were investigators on the CAPRISA 004 trial, which showed for the first time that a microbicide gel could reduce the risk of infection for women.

Hammer also said he expects to learn more about the prospects for a vaccine, as researchers report on the so-called correlates of risk associated with protection during the RV-144 vaccine trial conducted in Thailand.

That trial, again for the first time, showed a small but significant benefit for a vaccine candidate and researchers want to know why, in the hope that they can tweak some factors and get a better result.

Hammer said he also expects to get some data on new agents and new combinations of agents that are in the clinical trials process, including the so-called quad pill and the integrase inhibitor dolutegravir.

The other major theme will be ways of dealing with some of the major diseases that march in step with HIV – tuberculosis (TB) and hepatitis C.

Hammer said he's looking forward to hearing more about new direct-acting agents against hepatitis C, which present their own challenges when they are used in people with an HIV co-infection.

But the novel agents – two of which have already been approved – have the potential to increase hepatitis cure rates, while reducing the toxicity that complicates therapy and the time it takes to treat the virus.

TB remains a major challenge, especially in resource-poor regions where appropriate treatment of people with co-infection is often difficult to obtain. Meeting attendees will hear about community-based approaches to treatment in Africa.

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