While chronic viral infections produce therapeutic challenges, in the areas of hepatitis B and HIV, advances in treatment are being reported which improve the outlook of those affected. For those with responsibility for developing and licencing new treatments it is imperative that priority is afforded to enabling individuals with the haemophilias to benefit from these advances.
Summary. Whilst virally attenuated clotting factor concentrates are now safe with respect to transmission of HBV and HIV there are many individuals with haemophilia who were infected many years ago by these viruses. New combination therapies are available for treating both these virus infections and efficacy rates are increasing. Although many of the clinical studies are initially undertaken in non-haemophilia individuals, consideration needs to be given as to the possible benefits of including those with haemophilia in the clinical assessment.
Chronic hepatitis B treatment update
Chronic hepatitis B virus (HBV) infections remain a major public health problem worldwide with approximately 350 million chronic carriers. These carriers are exposed to the risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) . HBV infection can be acquired via vertical, sexual or blood transmission. Approximately 10% of HIV infected patients are co-infected with HBV. HBV belongs to the hepadnavirus family. The replication of its genome requires a reverse transcription step. Viral persistence is mainly the result of the persistence of a stable closed circular element (cccDNA) in the nucleus of infected hepatocytes .
The goal of antiviral therapy is to prevent progression of liver fibrosis and development of HCC [2,3]. To achieve this goal, prolonged viral suppression is required. Two main classes of drugs have been approved including cytokines (pegylated interferon alpha) and nucleos(t)ide analogues (NUCs) which are viral polymerase inhibitors (lamivudine, adefovir, telbivudine, entecavir and tenofovir). The use of drugs with a high antiviral potency and high barrier to resistance (entevavir and tenofovir) is now recommended.
In patients with HBeAg-positive chronic hepatitis B, administration of pegylated interferon for 48 weeks results in viral suppression in approximately 40% of patients and in HBe seroconversion in 30% of patients. Administration of entecavir or tenofovir results in viral suppression in approximately 70% of patients and in HBe seroconversion in 20% after 1 year, while the rate of viral suppression continues to increase during prolonged treatment beyond 1 year. The end point of therapy in these patients is viral suppression and HBe seroconversion; in this situation, treatment cessation can be considered [2,3].
In patients with HBeAg-negative chronic hepatitis B, administration of pegylated interferon for 48 weeks results in viral suppression in approximately 60% of patients. Administration of entecavir or tenofovir results in viral suppression in 90% of patients after 1 year and this rate rises to >95% during prolonged treatment. In this category of patients, long-term antiviral therapy is needed to prevent rebound of viral replication. HBsAg loss, which would allow treatment cessation, is rarely observed in this group of patients [2,3].
The choice of first-line therapy is based on multiple criteria including the age of the patients, HBeAg/HBeAb status, viral load, viral genotype, results of HBsAg quantification, ALT levels and liver histology [2,3]. Depending on these criteria, a finite duration treatment with pegylated interferon may be considered, or a long-term antiviral therapy with NUCs. In patients with decompensated liver disease, pegylated interferon is contraindicated, and NUC administration has been shown to be effective . It is noteworthy that tenofovir is active on both HBV and HIV and therefore is often recommended for co-infected patients .
Prolonged antiviral therapy with entecavir or tenofovir results in very high rate of viral suppression which is associated with improvements in serum transaminase levels and in liver histology [6–9]. In treatment naive patients, antiviral drug resistance has not been observed with tenofovir and in only 1.2% of entecavir-treated patients over periods of >5 years [10–12]. In patients with previous treatment failure, the second-line treatment should be decided based on the cross-resistance profile of the drugs with the same objective of viral suppression .
Although there have been major breakthroughs in the treatment of chronic hepatitis B, major challenges remain . Compelling evidence connects high levels of viral replication to an increased time to HBV DNA undetectability during treatment, and an increased incidence of cirrhosis, hepatocellular carcinoma and liver-related mortality. Thus, the correct choice of a potent first-line therapy to achieve sustained long-term suppression of viral replication provides the best chance of preventing the progression of liver disease and prolonging survival . Most patients receiving treatment will need long-term treatment to meet these goals, and the development of antiviral resistance is a major concern in these cases. The correct choice of first-line treatment also provides the best chance of avoiding salvage therapy, which can be affected by cross-resistance. For economically challenged countries that have a high burden of disease, there is a need for initiatives that can deliver virological monitoring and the most efficacious drugs at affordable cost, enabling wider accessibility of antiviral treatment and improved patient management. In addition, new treatments that can eradicate the infection are needed. Although new oral medications such as tenofovir and entecavir potently suppress replication, if they are stopped, infection is often reconstituted from the cccDNA reservoir. One of the most important future challenges in the field of viral hepatitis is developing a mechanism to bring about long-term control of HBV infection by elimination of cccDNA and/or stimulation of effective protective immunity [15,16]. Since major progress has been made in the last decade allowing the control of viral replication in the majority of patients, clearance of HBsAg has become the next most desirable endpoint. Indeed, HBsAg loss could lead to treatment cessation and is associated with a decreased risk of HCC development. To meet this challenge, clinical trials are now ongoing with new schedules of combination therapy with NUCs and pegylated interferon, as well as with the combination of novel therapeutic vaccines.
HIV treatment update
A total of 34 million people were estimated to be HIV infected at the end of 2010, up 17% since 2001. This reflects still a large number of new infections, although the annual number of new infections fell by 21% between 1997 and 2010. It also reflects a significant expansion in access to antiretroviral therapy. Still 1.8 million people died from AIDS-related causes in 2010. The proportion of women infected is 50% globally but as high as 59% of people with HIV in sub-Saharan Africa.
One of the major challenges worldwide is tackling late infection. A high proportion of patients in all communities present with a CD4 count below 350 × 109/l, the level that all guidelines recommend starting treatment. We need to increase the opportunities to offer tests by working with colleagues to increase testing in patients with HIV indicator diseases and we need to make additional efforts to reduce stigma to encourage uptake of testing.
Combined antiretroviral therapy is very effective in terms of virological control, but the long-term toxicities are still a cause of major concern. The comorbidities our patients may have been not only due to therapy but also lifestyle and HIV itself.
A major focus over the last year was the treatment for prevention with many guidelines advocating that patients should have access to combination retroviral therapy (CART) to protect partners if they so wish. However, there are of course concerns about long-term toxicity when a patient does not need treatment for their infection. There has also been encouraging new data on pre-exposure prophylaxis (PREP) and those data have increased the focus on prevention.
There has also been new energy for researchers to increase efforts to find a cure, as the sustainability of treating the numbers of individuals infected with CART in the long term worldwide is a major cause for concern.
Accelerated access to new therapies
The pharmaceutical industry has made great strides over the years in the research and development of new medications which have improved the quality of life and extended the life expectancy of those with congenital and acquired coagulation disorders. This progress suggests that despite the fact that these coagulopathies are considered to be rare or ‘orphan’ diseases, there is financial benefit to pharma if an innovative new product can be developed for its treatment. These medications may not be the ‘blockbuster’ pharmaceuticals which provide ‘blockbuster’ profits to the industry, but they remain attractive due to the incentives offered by regulatory agencies when therapies for rare or orphan diseases are marketed. As an example, for the US FDA, incentives for orphan drug status include: tax incentives for conduct of clinical research; study design assistance from FDA; exemption from application filing fees; grants for phase I and II clinical trials; 7 years of marketing exclusivity after approval of the drug. On the other hand, diseases like HBV and HIV are well-known and widespread diseases, which are no longer considered eligible for orphan drug status per se but which have a great potential for pharmaceutical profitability. Because of the large potential and profitable markets for new medications for HBV and HIV, pharmaceuticals will focus all their efforts on creating an uncomplicated, efficient and unobstructed pathway for their research and development. Introducing special populations of patients into their clinical trials increases the possibility that unforeseen and unwanted complications or ‘safety signals’ may arise, which will ultimately delay, sidetrack, or even block drug development or approval. At a cost of billions of USD for research and development and a cost of 50–100 million USD for clinical trials, access of these trials to patients with the haemophilias and associated bleeding disorders could confound the complex toxicity profile for the new drug. For instance, if the haemophilia patient develops an alloantibody inhibitor or experiences increased bleeding events (HAART medications were associated with increased frequency and severity of intramuscular and visceral bleeds in haemophiliacs), or develops an intracerebral haemorrhage and dies while on a clinical trial, how will those serious adverse events be interpreted by regulatory authorities? A direct drug toxicity? A reflection of drug-induced alteration of the immune system? Drug-clotting factor replacement therapy interactions which influence the metabolism of either or both medications? Furthermore, traditional randomized controlled clinical trials with new drugs are difficult to perform in isolated rare disease populations since the limited number of subjects will not allow for appropriate biostatistical interpretation or analysis. The use of surrogate markers and Bayesian probabilities and the pharmaceutical commitment to conduct postlicencing surveillance studies focusing on long-term safety might accelerate the clinical trial process and the subsequent fast-tracking through the regulatory process; however, in reality, nine of every 10 new pharmaceuticals fail during development because of unacceptable toxicity or underwhelming efficacy and for those individuals with the rare disease awaiting a new effective and safe drug, the requirements for fast track approval are still regarded as impediments to their acquisition to promising drugs.
One possible strategy to accelerate access to new HIV/HBV drugs would involve the definition of a new disease state which integrates the use of the new drug in the rare disorder. For example, while HBV is no longer considered an orphan disease per se (in the USA <200 000 people or 1/1 500; in Japan<50 000 or 1/2 500; in Europe 1/2 000), HBV postexposure or reactivation in the postliver transplantation scenario is designated an orphan disease state and thus medications intended to treat or prevent that complication are eligible for fast-tracking through the FDA. Such a strategy for new drug accessibility could be proposed for those with haemophilia and associated blood diseases afflicted by HIV or HBV individually or who are coinfected. Alternatively, this orphan disease state in haemophilia could serve as a nested cohort for larger HIV or HBV population studies. This would reduce time and expense compared to performing separate randomized controlled trials even if they were feasible for haemophilia. In summary, accelerated access is desirable for those with haemophilia, who hope for promising new medications to treat their HIV/HBV. The pharmaceutical industry is risk averse due to the economics of drug development and the regulatory authorities, while trying to incentivize new drug development, still require stringent safety, toxicity and effectiveness data before approval. There may be ways to achieve accelerated access through creative clinical trial design, use of surrogate markers and creative application of biostatistical methods.
The effectiveness of lobbying efforts by patients and their local, regional, national or international advocacy groups cannot be underestimated in bringing this issue to the forefront and in reminding the pharmaceutical industry and the regulatory agencies that there are individuals with haemophilia and associated bleeding disorders who are desperate for accelerated access to new, promising drugs to treat their HBV and HIV and that many of these affected individuals are very willing to accept reasonable risks by participating in clinical trials.
The authors stated that they had no interests which might be perceived as posing a conflict or bias.