In March 2007, a group of community activists, many living with HIV and hepatitis C virus (HCV), gathered with researchers, doctors, regulators, and representatives from Abbott, Roche, Schering, and Tibotec, in Sitges, Spain, at a meeting held by the European AIDS Treatment Group (EATG).
The meeting addressed a critical issue: the clinical development of novel HCV therapies for HIV/HCV coinfected people, who have urgent need for new treatments. It was a unique opportunity for stakeholders to discuss how coinfected people will gain access to experimental HCV therapies through well-designed clinical trials.
Hepatitis C is highly prevalent, progresses more rapidly, and causes significant morbidity and mortality among HIV-positive people. In Western Europe, an estimated 500,000 people are HIV-positive; 30% are coinfected with hepatitis C. In the United States, more than a million people are living with HIV, and 25-30% (250,000 to 300,000) also have hepatitis C.
HCV-associated end-stage liver disease is a now a leading cause of death among HIV-positive people in Europe and the United States. HIV accelerates hepatitis C progression; coinfected people may develop serious liver damage within a decade. The risk for cirrhosis is twice as great, and the risk for liver failure is six times greater for coinfected people vs. those with HCV monoinfection. Although some centers in Europe and the United States are performing liver transplants in HIV-positive candidates, medical management of transplant recipients is complex, and access to transplantation remains limited.
HCV is treatable, regardless of HIV status, but there are serious limitations to the current standard of care. Coinfected people are less likely to respond to treatment, and more likely to experience severe, potentially treatment-limiting side effects than their HCV monoinfected counterparts.
Several promising HCV therapies are currently in the pipeline; some have already entered phase III. HIV/HCV coinfected people are excluded from participation in these studies. Companies often cite safety issues-such as uncharacterized pharmacokinetic profiles, and potential drug-drug interactions- as the rationale for excluding HIV-positive people. HCV treatment trials in coinfected people are launched only after agents have been approved for HCV monoinfection.
Currently, there are no regulatory requirements or recommendations for studying novel HCV therapies in HIV-positive people prior to their approval for treatment of HCV monoinfection, but guidelines may be coming soon.
Since the Sitges Meeting, the European Agency for the Evaluation of Medicinal Products (EMEA) has begun work on draft guidelines on HCV drug development. In the United States, a dialogue between industry, regulators, clinicians, researchers and community members began in October 2006, when the Food and Drug Administration (FDA) Antiviral Advisory Committee met to address development of products for the treatment of hepatitis C infection. The agency has not yet released their recommendations.
The Sitges Statement was created at the end of the meeting, when all participants were asked to state their primary concerns about HCV drug development, trial designs, and access for coinfected people. A draft was circulated to all participants for comments; these were incorporated and then a final document, as follows, was approved by the signatories. Signatories and their affiliations are listed at the end of the Statement.
The meeting was co-planned by Joan Tallada, Director of El Grupo de Trabajo sobre Tratamientos del VIH (GTT) and Tracy Swan, Coinfection Project Director at Treatment Action Group (TAG).
The Sitges Statement
Community activists, doctors, researchers, company representatives and members of regulatory agencies, concerned about the life expectancy and the quality of life of people living with HIV and HCV, hereby declare that:
Collaboration between the community, regulatory agencies and industry is a crucial part of the HCV drug development process. The community is an important stakeholder, and must be given the opportunity to provide input into HCV drug development. We want to participate in:
The development of regulatory guidance for HCV drug development
- We believe that regulators with experience in HIV drug development and treatment need to be involved in the development of regulatory guidance for new HCV drugs.
The development of industry-sponsored clinical trials
- We ask to meet regularly with sponsors of novel HCV therapies, and to participate in designing clinical trials, and oversight of these trials via Data Monitoring and Safety Boards (DSMBs) of these trials.
The development of research networks
- We support building additional research networks, public- private partnerships, investigator-initiated studies and registries of data from multi-center collaborations to bring HCV therapies forward quickly and explore new therapeutic paradigms before and after their approval.
- We encourage creating networks of investigators with expertise in treating HCV coinfection to study novel HCV therapies in coinfected people.
We believe that the health care needs of different populations and the patient perspective must be considered part of the HCV drug development process. Studies should include people with the most urgent need for new HCV therapies.
Trials of novel HCV therapies in HIV/HCV coinfected people should begin before approval is granted for their use in HCV monoinfection, once results from Phase 2B studies are known, and there are indications from earlier toxicology, pharmacokinetic and drug-drug interaction studies that the specific agent, or agents, under investigation will not have the potential for significant drug-drug interactions, or other toxicities relevant to HIV.
It is clear that combination therapy will be necessary to avoid HCV drug resistance. We need to consider the most expeditious methods for co-developing drugs; this may depend on the outcome of early monotherapy studies of each agent. Since safety is paramount, we believe that in vitro and in vivo drug interaction studies must be conducted early, to facilitate pre-approval multi-agent trials and studies in persons likely to be using other medication, such as coinfected persons, and transplant recipients.
We support trials that look at methods to delay, or reverse fibrosis progression as well as trials to eradicate HCV. It is important that trials in different populations consider different outcomes for different patient populations (SVR vs. histological improvement or averting/delaying transplantation). We also support investigation into alternative and complementary therapies for HCV.
We ask that all possibilities are explored for conducting pre-approval studies of HCV therapies in the highest -prevalence population, people who use drugs. We encourage studies in people using methadone, buprenorphine, naltrexone and heroin substitution prior to approval.
In addition, we ask that sponsors design studies that:
- Enroll sufficient numbers of women to yield information on potential gender-specific side effects of new HCV treatments,
- Include TDM [therapeutic drug monitoring] in studies of persons with advanced liver disease
- Accelerate pediatric research
When possible, trials should include:
- Characterization of resistance
- Non-invasive assessments of liver damage, to see if they can be validated as an alternative to biopsy
- Assay standardization
Research to optimize the current standard of care must continue. Studies on management of side effects and models of care, especially those that will continue to explore the use of multidisciplinary care, are a priority. Interferon will still be part of HCV treatment for the next few years, but it may be possible to find a less toxic alternative to ribavirin.
We have seen high rates of liver-related mortality in the last few years. Since it will take time for new drugs to become available, we must raise awareness of the need for donor organs, promote policies to increase organ donation, and remove obstacles to transplantation for HIV-positive and coinfected people. Organ transplantation, and access to the highest-quality care and treatment, must be provided to HIV-positive and coinfected people throughout Europe.
Signatories
Massimo Puoti, Università di Brescia, Italy
Raymond Schinazi, Emory University, USA
Bruce Polsky, St. Luke’s-Roosevelt Hospital Center, USA
Tracy Swan, TAG, USA
Wim Vandevelde , BoD EATG, Portugal
Carmen Tarrades, Int. Community of Women Living with HIV/AIDS, UK
Miguel De Melo, TRT-5, France
Jose Maria Miro Meda, Hospital Clínic Universitari, Spain
Diego García Morcillo, FEAT, Spain
Joan Tallada, gTt / EATG, Spain
David Ananiashvili, Georgian Plus Group, EATG, Geórgia
Stephan Dressler, EATG / ECAB, Germany
Svilen Konov, HIV i-Base, UK
Luis Mendao, GAT/EATG, Portugal
Christophe Palaggi, UKCAB, UK
Siegfried Schwarze, Projekt Information e.V., Germany
Maxime Journiac, EATG, France.
Ana V. Balkandjieva, Expert Board on HIV/AIDS, Bulgarian MoH, Bulgaria
Zddenek Kurka, Credum, Czech Republic
Lucia Maria Stirbu, Terre des homes, Romania
Giancarlo Condoleo, I-CAB / LILA, Italy
Annette Piecha, Germany
Maria José Clemnet Ferrazzano, ABD, Spain
Udiarraga García Uribe, Asociación Itxarobide, Spain
Juanse Hernández Fernández, Grupo de Trabajo sobre Tratamientos del VIH, Spain
Esther Inés Rodrigo, Comité C. Anti-Sida Comunidad Valenciana, Spain
Ane Lasa Garmendía, ACASGI, Spain.
Ana Maria Lopez Zuñiga, Asociacion Lucha Contra El SIDA T4, Spain
María Lorenzo Brañanova, Spain
Paki Lucha Linares, ACASGI, Spain
Marta Pastor, Comisión Antisida de Bizkaia, Spain
Ramón Querol, ARPAONG & ASAUPAM, Spain
Javier García-Ogara Ornilla, Itxarobide, Spain
Begoña Bautista, Spain
Olle Karlström, EMEA, Sweden
Fernando De Andrés, AEMPS/EMEA, Spain
Laura Knipmeyer, Schering-Plough, USA
Clifford Brass, Schering-Plough, USA
Frank Duff, Roche, USA