Over the past year there has been quite a lot of discussion about the risk of liver cancer following treatment with Direct Acting Antivirals like Harvoni® and Sovaldi®.
Here is a quick explanation and the latest thinking from the academic gurus.
First, the risk of Hepatocellular Carcinoma (HCC aka liver cancer) only starts to rise when patients develop cirrhosis, so for patients without cirrhosis there is little to worry about.
In patients with cirrhosis, and untreated Hepatitis C the annual risk of developing liver cancer is 3%. With SVR (cure) following treatment this risk falls to around 1%, so is much less.
In patients who have already had one HCC, treatment increases their short term risk of getting another one (this is probably one they already have but is simply too small to see) and demands very close monitoring both during and immediately after treatment.
So the bottom line is pretty simple. Treat before you get cirrhosis, but if you already have cirrhosis, you are still better off treating. If you have previously had an HCC you can still treat but need very close follow up.
Below you will find the text of a press release from EASL 2017. EASL is the European Association for Study of Liver Diseases and represents the best experts in the world telling it how they see it.
ILC 2017: Is direct-acting antiviral therapy for Hepatitis C associated with an increased risk of liver cancer? The debate continues
Eight studies being presented at The International Liver Congress™ 2017 demonstrate contrasting evidence on the potential link between direct-acting antiviral treatment for Hepatitis C and liver cancer
April 20, 2017, Amsterdam, The Netherlands: According to data from eight studies being presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, there remains continued debate on whether patients are at risk of developing liver cancer after achieving sustained virologic response (SVR) with a direct-acting antiviral (DAA) regimen for Hepatitis C virus (HCV). Investigators will present the results of their studies that show both sides of the argument – DAA therapy is associated with a higher risk of liver cancer compared with interferon-based therapy, versus there is no difference in liver cancer risk following cure with either therapy.
Whilst remarkable progress has been made in the development of successful antiviral therapies for HCV infection, some recent studies suggest that curing patients does not eliminate the risk of developing liver cancer. There also appears to be an unexpectedly high rate of liver cancer (also known as hepatocellular carcinoma [HCC]) recurrence in patients who previously had their tumour treated successfully and had received DAAs.
This claim was further supported by a Spanish study led by Dr Maria Reig and Dr Mariño, Hospital Clinic Barcelona, Spain in which patients with HCV and HCC who had previously been cured of HCC received DAA therapy. After a median 12.4 month follow-up, following treatment with DAAs, the rate of HCC coming back (recurrence) was 31.2% (24/77) and of those who received HCC treatment at recurrence, 30% (6/20) of patients presented progression in the immediate 6-month follow-up. This is an update of the study that will be published in the May 2017 issue of Seminars in Liver Disease, and is available here: https://www.thieme-connect.de/products/ejournals/html/10.1055/s-0037-1601349.
“Our study offers further support to previous findings that there is an unexpected high recurrence rate of hepatocellular carcinoma associated with DAAs, and that this association may result in a more aggressive pattern of recurrence and faster tumour progression,” said Dr Maria Reig, Barcelona Clinic Liver Cancer Group, Hospital Clinic Barcelona, Spain, and lead author of the study. “These data indicate that there needs to be further research conducted in this area, clarifying the mechanism for the association between liver cancer recurrence and DAA therapy.”
Identifying those patients at risk of liver cancer is essential, a task that Dr Etienne Audureau, Public Health, Henri Mondor University Hospital, Créteil, France, and colleagues attempted to achieve by developing a prognostic tool for HCC. They found that in patients with severe scarring of the liver due to HCV (compensated cirrhosis), failure to achieve SVR was the most influential factor in predicting liver cancer. In addition, risk factors for liver cancer differ according to SVR status. The investigators recommend that in patients with compensated cirrhosis, eradication of HCV should be achieved before liver function is impaired and people who have achieved SVR should be monitored for liver cancer after 50 years of age.
The mechanisms behind the development of liver cancer following HCV cure are not yet understood. One group of investigators led by Prof Thomas Baumert, Inserm Institute for Viral and Liver Diseases, University of Strasbourg, France, aimed to investigate if HCV infections produce epigenetic and transcriptional changes that persist after the infection is cured, and whether these epigenetic changes drive liver disease and HCC following cure. They found that the epigenetic and transcriptional changes are only partially reversed by DAAs and persist after HCV cure, suggesting that these changes are a driver for liver cancer that develops after HCV infection has been cured. The investigators concluded that these findings open a new perspective to develop novel biomarkers to identify patients at high risk of HCC and provide an opportunity to develop urgently needed strategies for HCC prevention.
On the other side of the debate, a systematic review, meta-analyses, and meta-regression study, by Prof Gregory Dore and Dr Reem Waziry from The Kirby Institute, UNSW Sydney, and colleagues, found no evidence for higher risk of HCC occurrence or recurrence following DAA treatment, compared with interferon-based HCV therapy. A total of 41 studies, including 26 on HCC occurrence and 15 on HCC recurrence (in total, n=13,875 patients) were included. In studies assessing HCC occurrence, average follow up was shorter and average age was higher in DAA studies compared to interferon studies; incidence was lower with longer follow-up and younger age. In studies assessing HCC recurrence, average follow up was also shorter. Ultimately, in the meta-regression analysis, no evidence in favour of a differential HCC occurrence or recurrence was found between DAA and interferon regimens, after adjusting for study follow-up and age.
“Recent studies have reported contradicting evidence on risk of hepatocellular carcinoma following direct-acting antiviral therapy; our aim was to bring some clarity to this,” said Prof Gregory Dore, Kirby Institute and lead author of the study. “These data show the higher incidence of HCC observed following DAA therapy can be explained by the shorter duration of follow-up and older age of participants, rather than the DAA treatment regimen.”
A Scottish study, led by Dr Hamish Innes, School of Health and Life Sciences, Glasgow Caledonian University, Scotland, found that the risk of liver cancer following SVR was not associated with the use of DAAs, but baseline risk factors. Furthermore, risk of HCC development was similar in patients taking interferon-free regimens versus interferoncontaining regimens, following a multivariate adjustment (IRR: 0.96, p=0.929) and no significant differences in HCC risk were found when treatment regimen was defined in terms of DAA containing regimens versus DAA free regimens. These data indicate that rather than the treatment regimens themselves, it is the baseline risk factors that determine risk of hepatocellular carcinoma.
Another interesting study in Japanese patients with HCV genotype 1 infection, found a reduced incidence of liver cancer following achievement of SVR after 12 weeks of therapy with an interferon-free regimen (ledipasvir plus sofosbuvir) to a similar degree as that obtained with an interferon-containing regimen (simeprevir with peginterferon plus ribavirin). This study, which was conducted by Dr Masaaki Korenaga, Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan, and colleagues, also found that unexpected development of liver cancer following SVR in patients without previous liver cancer could potentially be predicted by imaging procedures (computer tomography or enhanced magnetic resonance imaging).
Similarly, a Chinese study led by Dr George Lau, from the Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Centre, in Beijing, China, found no increase in the incidence of liver cancer in patients who achieved SVR12 with DAA compared to peginterferon plus ribavirin.
A Sicilian study conducted by Dr Vincenza Calvaruso, University of Palermo, Palermo, Italy, and colleagues, demonstrated that patients who achieved SVR with DAAs had a similar risk of developing liver cancer when compared to historical controls of patients with compensated cirrhosis who achieved SVR after interferon-based therapy. In addition, those who achieved SVR with DAAs had a lower risk of developing liver cancer than those patients whose HCV infection was not cured.
“The original observations made by researchers from the Barcelona Clinic Liver Cancer Group have sparked a huge number of studies aimed at verifying the potential association between DAA treatment and increased HCC recurrence after cure,” said Prof Francesco Negro, Divisions of Gastroenterology and Hepatology of Clinical Pathology, University Hospital of Geneva, and EASL Governing Board Member. “At this stage, there is no reason to alter treatment guidelines until the issue is definitively clarified. We cannot exclude, however, that we may have to revise post-SVR surveillance in some specific patient subgroups.”
- Ends -
About The International Liver Congress™
This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2017 will take place from April 19 – 23, at the RAI Amsterdam, Amsterdam, The Netherlands.
Here is the response from EASL to the recent Cochrane review. http://www.journal-of-hepatology.eu/pb/assets/raw/Health%20Advance/journals/jhepat/CochraneEASLJMP003.pdf
EASL, the European Association for the Study of the Liver, one of the world leading associations of liver specialists, feels compelled to express its serious concerns after the recent publication of a Cochrane Group systematic review entitled “Direct acting antivirals for chronic hepatitis C” by Jakobsen et al. After reviewing 138 clinical trials, including 25,232 participants, the authors conclude that: “Overall, direct acting antivirals (DAAs) on the market or under development do not seem to have any effects on risk of serious adverse events. […] we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.”
The inability of the authors of the Cochrane review to determine a clinical benefit of DAA-based treatment of hepatitis C unfortunately reflects their flawed methodological approach and their ignorance of the natural history of hepatitis C virus (HCV) infection and associated systemic diseases. The review examines the intervention in a clinical vacuum that fails to accept that DAA treatment to attain an SVR is a pivotal outcome of treatment, and does not accept the likelihood that an SVR will reduce the risks of long-term outcomes of hepatitis C.
With this deduction comes responsibility. The uncertainty created by the illconceived Cochrane group’s conclusions and the attendant press publicity could grievously affect policy making, and constrain the gathering momentum for diagnosis, testing and linkage to care of individuals with hepatitis C. It will create dangerous confusion in the mind of patients treated or about to be treated and their families. The World Health Organization (WHO) has published an authoritative Global Hepatitis Report, expressing its alarm at the burden of disease, and has promulgated critical targets for global elimination of hepatitis C by 2030. In the absence of a prophylactic vaccine, the Cochrane review jeopardises treatment as a necessary intervention to reduce the global morbidity, mortality and prevalence of chronic hepatitis C.
The primary endpoint in DAA investigational drug development trials has been the sustained virological response (SVR), i.e. undetectable HCV RNA 12 or 24 weeks after completion of treatment, which corroborates permanent elimination of the viral infection. The Cochrane review evaluated the effect of DAA treatments on several outcome measures, including hepatitis C-related mortality, all-cause mortality, serious adverse events, no SVR and health-related quality of life (HRQOL). Most of their conclusions are flawed.
- The report from 32 trials including 7115 participants indicates that a total of 1180/1692 (69.7%) patients in the DAA groups and 915/5194 (17.6%) patients in the control group had “no SVR” during the observation period. This can only be an error as the authors deduce that meta-analysis showed that DAAs “seemed to reduce the risk of no SVR (risk ratio=0.44, p <0.00001) […]“.
- It is inappropriate to have pooled the data to include 57 trials that included drugs that have been withdrawn or discontinued. These are experimental drugs that have been discarded for lack of safety or inferior efficacy and that have been superseded by more effective and safer drugs, making the review dated and ignorant of current clinical decisions and guidelines in the context of a rapidly progressing field. Including treatments that are not or no longer used, and/or overly heterogeneous introduces a bias in the meta-analysis.
- From 43 trials involving 15,817 patients, the authors report serious adverse events (SAEs) in 2.7% of DAA-treated patients versus 5.5% in the control group during the observation period. They conclude that there is no firm evidence that DAAs reduce risk of SAEs. However, the terminology is clouded as the authors fail to clearly indicate whether they consider drug-related SAEs or clinical SAEs, i.e. clinical events resulting from the natural history of HCV infection which would happen months to years after the period of observation of the clinical trials.
- The HRQOL analysis has missed many recent studies. Several systematic reviews have been performed which have shown significant improvement in quality of life parameters with DAA therapy. The results show improvement over interferon and ribavirin-based treatments and are an encouraging aspect of an SVR with chronic hepatitis C, that further support the use of the SVR as surrogate. Very detailed and comprehensive analyses have been compiled before, during and after treatment objectively demonstrating improved patient-reported outcomes.
- The major weakness of the Cochrane review is that results are only assessed at “maximum follow-up”. These are of course short-term results for a disease with a long clinically latent period. A meta-analysis should only evaluate the primary endpoint selected by the clinical studies. The trials were not designed or powered to capture long-term outcomes such as hepatitis C-related morbidity or all-cause mortality, but to establish whether infection, reflected by persistent viremia, could be safely and effectively terminated.
The risk of clinical liver outcomes increases with aging and duration of disease. It is the result of chronic production of viral antigens during ongoing infection which incite host immune responses. The resulting hepatic inflammation in turn triggers fibrogenesis, the basis of liver disease progression towards aggravating fibrosis, cirrhosis and, ultimately, decompensated cirrhosis and hepatocellular carcinoma. The harmful effects of chronic hepatitis C take years to develop in patients that generally remain asymptomatic for long periods of time. Thus, although there is variation in rates of progression of fibrosis, early disease does not indemnify an individual from subsequent progressive disease, that can be accelerated by various cofactors and comorbidities. The authors of the Cochrane review have unfortunately not considered the possibility, the necessity and feasibility of arresting progression of early stage disease to more advanced fibrosis, cirrhosis, decompensated cirrhosis, or the ultimate development of HCC.
Achieving SVR, i.e. eliminating the infection, removes the trigger, thereby halting or considerably slowing the progression of liver disease. Terminating active infection also alters the natural history of a number of HCV-induced extrahepatic morbidities, such as diabetes and renal insufficiency. This has been clearly demonstrated by long-term follow-up studies in patients with chronic hepatitis C cured of their persistent infection during the interferon era. An SVR is associated with normalization of serum aminotransferases and improvement or disappearance of liver necroinflammation and fibrosis in patients without cirrhosis. Hepatic fibrosis generally regresses and the risk of complications such as hepatic failure and portal hypertension is reduced in patients with severe liver disease. Recent data showed that the risk of HCC and all-cause mortality is significantly reduced (although not eliminated to zero) in patients with cirrhosis who clear HCV compared to untreated patients and non-sustained virological responders. For the first time, DAAs have allowed patients with decompensated cirrhosis access to anti-HCV therapy, improving their liver function and reducing the indications for liver transplantation in a large proportion of cases, with a major impact on transplant programs already evident. Moreover, the possibility to treat patients after solid organ transplantation with high infection cure rates has opened the door to the use of HCVpositive grafts, increasing transplantation rates, reducing on-list mortality and containing healthcare costs for management of patients on the transplant waiting list.
National and international regulatory authorities have accepted the primary endpoint of an SVR and demonstrable safety as evidence for DAA licencing. Because the complications of chronic hepatitis C take years to occur, depending on the stage of liver disease, and clinical trials with new DAAs with SVR as main endpoint last only a few months, the benefits in terms of clinical outcomes of achieving an SVR cannot be measured in these trials. The Cochrane group’s conclusion is therefore illogical and inappropriate, as it fails to respect the methodology this organization has developed. The Cochrane review also ignores the opportunity of reducing the risk of transmission from viremic individuals, particularly in highrisk groups. Overall, the Cochrane review displays a lack of understanding of hepatitis C and drug development in the context of a transmissible infectious disease with a long natural history.
The Cochrane review authors’ conclusion that “randomised clinical trials assessing direct effects of DAA are needed” suggests an ethical anathema of leaving patients untreated to accrue increasing hepatic fibrosis, in the face of treatments that are likely to arrest viral replication in the overwhelming majority. This conclusion evokes memories of the infamous Tuskegee study conducted by the United States Public Health Service, in which patients with syphilis were left untreated to observe the natural history even after advent of and proven efficacy of penicillin. This unethical approach is unacceptable in a context where: (i) the HCV treatment landscape has markedly altered with the introduction of DAA-based regimens which in both clinical trials and real-world data have shown remarkable SVR (i.e. infection cure) rates in treatment-naïve and -experienced patients with or without cirrhosis across all genotypes; (ii) modelling has clearly demonstrated the benefits of DAA-based therapies in reducing long-term hepatitis C-related morbidity and mortality as compared to no treatment (individual benefit) and reducing HCV transmission (collective benefit). In summary, to arrive at such a flawed conclusion reflects the squandering of a vast amount of considerable time-consuming endeavour and significant public funding. The premise of the Cochrane review will be viewed as so egregiously mistaken that the conclusions will rightly be disregarded. As the findings do not assist or advance the field, they will not be pertinent to clinical decision making or guidelines.
EASL will continue to emphasize and reinforce the fight against HCV and to lend its support to the international efforts aimed at eliminating HCV, a major aetiology of severe liver and extra-hepatic diseases, complications and related mortality, by 2030. There is no precedent for a disease to be eliminated only 40 years after the discovery of its causal agent thus far. This chance cannot, and will not be missed.
This article was just published in the Lancet
The introduction of direct-acting antiviral (DAA) medicines in 2013 revolutionised the treatment of chronic hepatitis C virus (HCV) infection. The efficacy of DAA therapy is impressive—in many clinical trials HCV cannot be detected by sensitive laboratory assays in more than 90% of people who complete DAA therapy, and observational studies have documented similar results.1, 2 High efficacy combined with low rates of adverse events have led WHO to include DAAs in the WHO Model List of Essential Medicines.3 Several countries, including Australia, Georgia, Iceland, and Morocco, have started national DAA-based treatment programmes to eliminate HCV infection, and WHO has called for the expansion of HCV therapy with DAAs as part of its global hepatitis elimination strategy.4
HCV is an important contributor to global mortality, causing an estimated 399 000 deaths each year worldwide, and as HCV treatment expands, it is anticipated that mortality from HCV infection will decline.5 However, because the annual risk of death from HCV infection is low and the DAAs were introduced only recently, there are limited data on how these drugs affect mortality. Clinical trials that evaluate the efficacy of DAAs do not assess mortality as an outcome but rather a surrogate outcome called the sustained virological response (SVR). An SVR is defined as the absence of detectable HCV by nucleic acid testing of blood samples obtained 12–24 weeks after completion of HCV therapy. An SVR is deemed equivalent to a cure because once an SVR is achieved, it is maintained in more than 99% of patients, even after years of follow-up.6 Also, an SVR is associated with resolution of cirrhosis in about half of patients with cirrhosis followed-up clinical trials.7
However, documenting in a clinical trial that DAAs result in an SVR is not the same thing as showing that they reduce mortality or morbidity. A recent systematic review by Jakobsen and colleagues8 from the Cochrane Hepatobiliary Group sought evidence from clinical trials of HCV therapies to assess this issue. The authors reviewed randomised clinical trials that used SVR as the primary outcome in people receiving DAA therapy compared with those either not treated or treated with other regimens (primarily interferon-based therapy). Jakobsen and colleagues concluded that DAAs were effective in producing an SVR (relative risk 0·44, 95% CI 0·37–0·52); however, the analysis did not find a reduction in morbidity or mortality after DAA therapy. At first sight, this conclusion seems to contradict systematic reviews of observational data that show that people who have an SVR after treatment with interferon and ribavirin had a 50% (95% CI 37–67) reduction in overall mortality and 76% (95% CI 69–82) reduction in the incidence of hepatocellular carcinoma as compared with people who were treated but did not achieve an SVR.9, 10 The reduction in overall mortality was even greater (81% [95% CI 72–87]) when persons with an SVR were compared with those not treated.9 Other studies have shown improvements in extrahepatic manifestations of HCV infection and quality of life among people with an SVR after DAA treatment.11, 12 Data on the effect of DAA therapy are also beginning to be reported from national programmes that are scaling up HCV therapy. In England where HCV therapy increased by 48% in 2015, compared with 2014, there were reductions in the incidence of HCV-related cirrhosis (42%), liver transplantations (32%), and deaths (8%).13
Observational studies are biased towards showing an effect of treatment since treatment decisions are based on the likelihood of a successful outcome, and people achieving an SVR may be predisposed to a better outcome for reasons unrelated to the treatment. However, the magnitude and consistency of health benefits across studies and outcomes support the conclusion that HCV therapy resulting in an SVR substantially reduces mortality and morbidity.
How to explain these apparently contradictory results? An important difference between the studies reviewed by Jakobsen and colleagues is the duration of follow-up, which was short at an average of 34 weeks compared with an average of more than 5 years in the other reviews.9, 10 Simply put, the clinical trials included in the systematic review by Jakobsen and colleagues were not designed to answer the question posed by the authors about the effect of DAA treatment on morbidity or mortality. These studies generally followed up patients for only 24–48 weeks after the completion of DAA therapy, and the risk of HCV-related disease and death during such a short period is extremely low because the harmful effects of chronic HCV infection take years to develop. In fact, no morbidity was reported, and only 16 deaths occurred among the 2996 patients enrolled in all the DAA trials that were assessed by Jakobsen and colleagues. Thus, the statistical power to show a difference between the two groups is very low. In addition, the non-intervention groups in many of the studies included in Jakobsen and colleagues' systematic review did in fact receive HCV therapy, primarily an interferon-based regimen, which would minimise any mortality benefit of DAA therapy. Finally, Jakobsen and colleagues' study included early, less effective DAA regimens that were discontinued or withdrawn before marketing. They propose that, to resolve definitively whether DAA therapy reduces morbidity and mortality, randomised clinical trials with a non-treatment comparator group be done with clinically relevant outcomes such as death. Clearly, with the ready availability of safe and effective DAAs and ample evidence showing the health benefits of achieving SVR, such a study design is unethical and would be unacceptable to institutional review boards and harmful to patients' health. Several organisations, such as patients' groups and international hepatology associations, have expressed their concerns about the methods and conclusions of the Jakobsen review.14, 15, 16
People who are knowledgeable in the field of HCV therapy can readily ascertain the limitations of the approach taken in the systematic review by Jakobsen and colleagues and will be able to place their results in the proper context relative to other data that document the health benefits of DAA therapy. But for some patients, health-care providers, and decision makers who may be less knowledgeable about HCV therapy, this type of analysis, especially as reported in the mainstream media,17 could lead to conclusions that DAA therapy has no benefit, resulting in decisions to decline to prescribe or take DAA therapy or to decline to approve budgets for DAA treatment programmes, particularly in view of their expense. This would be a tragic outcome, as it would lead to preventable deaths. Public-health policy makers who must decide on budget allocations for HCV treatment cannot wait for perfect data on mortality endpoints, since the types of trials that would generate these data will never be done. Rather, they must assess available, albeit imperfect, data from observational studies and trials using surrogate outcomes that are reliably predictive of clinically important outcomes. Based on the fact that DAA therapy is safe and effective in achieving SVRs, that the SVRs are durable in most patients, that HCV-induced liver damage improves after SVR, and that observational data show a large reduction in morbidity and mortality, health-care decision makers and providers can take comfort that the evidence is strong in favour of treatment. A more definitive assessment of impact on morbidity and mortality will take time, but this should not be used as a reason for denying HCV therapy and delaying efforts to eliminate HCV infection.
About 1 in 5 patients taking Direct Acting Antivirals will get insomnia. Here is a post of mine from some years ago about how to manage it.
Insomnia is a common and often frustrating problem. Part of the reason it's frustrating is that, unless an accurate diagnosis of the root cause(s) is made, treatments tend to be temporary band aid solutions and rapidly lose their effectiveness.
Do you have an underlying medical problem?
There are a range of medical condition that can cause insomnia.
Chronic pain, sleep apnoea or a need to urinate frequently caused by an enlarged prostate gland can all cause insomnia.
Diseases like arthritis, cancer, heart failure, lung disease, gastroesophageal reflux disease (GERD), overactive thyroid, Parkinson's disease and Alzheimer's disease have all been implicated.
Mental health problems like stress, anxiety and depression can also cause problems.
Many of these issues are amenable to treatment, and by fixing the root cause, sleep patterns can return to normal.
Are your medications to blame?
- SSRI antidepressants
- ACE inhibitors
- Cholinesterase inhibitors
- H1 antagonists
Note that you should consult with your doctor before stopping any prescribed medications.
Are your daily habits contributing?
There are many habits and work patterns that promote poor sleep
- Not enough light at midday and too much light (device screens) at night
- Shift work - this scrambles your body clock (circadian rhythm)
- Eating late in the evening
- Fluids in the evening (we were all trained as children to wake up and not wet the bed)
- Excess caffeine, nicotine and other stimulant (ie Red Bull) consumption
- Using stimulants in the afternoon and evening
- Not getting enough exercise
- Too much alcohol - although alcohol is a sedative it prevents entry into deep sleep
Could your sleep hygiene be improved?
If you use your bedroom for other activities than sleep and sex you are missing the opportunity to program your thinking along the lines of go to bed, go to sleep.
You will sleep better if:
- You have got a good dose of daylight during the day, and less light at night
- Your bedroom is pitch black
- Your bedroom is quiet
- You bedroom is not too hot, not too cold
- You have a comfortable mattress
- You have a comfortable pillow - not too high or too low, too soft or too firm - get one that's just right (and remember they wear out over time)
- You have enough blankets so you're not too hot when you go to bed, but also don't wake up freezing when it cools off in the early morning
What can my doctor do for me?
For a start, any doctor worth his/her salt can discuss everything with you and look for root causes. It's always best to fix the source(s) of problems.
A simple plan (from Dr Margaret Hardy)
- Work out average amount of actual sleep per night from sleep diary
- Choose a regular wake-up time
- Set a regular bedtime by subtracting average sleeping hours from the planned wake-up time
- Review at weekly intervals and, if tired, increase time in bed by going to bed 30 minutes earlier
Your doctor can also provide medications including:
- Melatonin (which re-sysncs your body clock and is thus really good for shift work and jetlag
- First generation sedating antihistamines (promethazine, doxylamine)
- Benzodiazepines (temazepam, zopiclone, zolpidem and many others) which are good for short term (particularly stress related insomnia). Long term you become first tolerant (needing ever increasing doses) and then addicted (needed the medication or you won't be able to sleep)
- Antidepressants like amitriptyline and mirtazipine which are used (usually in low doses) not to treat depression but for their common sedating side effect. Their advantage over benzodiazepines is that tolerance is far less of an issue, so they can be used longer term.Don't despair. Most people can get
Don't despair. Most people can get a far better nights sleep with a few simple changes.
Talk to your doctor, or see one of our expert GPs online from the convenience of home.
Dr James Freeman
Yesterday the Guardian published an article called 'Miracle' hepatitis C drugs costing £30k per patient 'may have no clinical effect'
The problem with this sensationalist headline is that while it is reporting what was said by the Cochrane Collaboration what they looked at was trial specifically designed to test SVR rates, and not specifically designed to look at long-term outcomes.
Here is a commentary from Dr Andrew Hill and the study to which he refers which was presented at AASLD in 2015 and published in Clinical Infectious Diseases.
There is some really interesting stuff happening in the "reverse liver fibrosis" realm.
Here is state of the art in 2009 (great review of the mechanism) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702953/ where we had no clear candidates, and
Here is state of the art in 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703795/ where we have literally hundreds of candidates (coffee and milk thistle (silymarin) and resveratrol are in there), and
Here is the state of the art in 2016 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754444/ in an article called Promising Therapy Candidates for Liver Fibrosis
I like this bit from the conclusion:
Since both animal experiments and clinical studies have revealed that liver fibrosis, even early cirrhosis, is reversible, treating patients by combined therapies on underline etiology and fibrosis simultaneously might expedite the regression of liver fibrosis and promote liver regeneration.
Here is a copy of the generic hep c medication presentation given by Dr James Freeman at EASL 2017 today.
Mostly the presentation followed the slides.
The last words, with the last slide were "I want everyone to join the club, not the hep c buyers club, this club, the hep C cure club."
“The Liver Meeting”, or AASLD 2011, was taking place at the great, glass-fronted Moscone West Convention Center in downtown San Francisco. Almost 9,000 people were there – family doctors, hepatologists, gastroenterologists, academics, drug salesmen, public health officials – all networking, trudging the escalators, wandering the beige exhibit halls, trying to stay on top of an avalanche of medical information. Across five days in early November, no fewer than 2,200 liver-related scientific abstracts were being presented, at sessions that ran from 6.30am until 9pm. Specialists in hepatitis C, an awkward, under-recognised health problem, were used to finding their way to the back rooms, the less-glamorous receptions.
Many felt it was time the disease moved up the agenda. Since it was identified in 1989, “Hep C” or “HCV” to those who work on it, has only confounded those who underestimate it. Transmitted through blood, the virus is now thought to infect around 2.5 per cent of the world’s population, or 170 million people. Of those, around a quarter will develop liver cirrhosis, or cancer, within a decade or two. In the UK, deaths from hepatitis C have trebled since 1996 and more than 200,000 people are infected. No one knows what to do about the coming demand for liver transplants. For the past decade at least, scientists have used phrases such as “gathering storm” and “silent epidemic” to try to bring attention to the subject.
There has also been a torrent of new data to keep up with. Despite its orphan status, the sheer numbers of people infected with hepatitis C have made it the subject of hundreds of millions of dollars of medical research – particularly by pharmaceutical companies, working on a new generation of drugs. And AASLD, as the world’s premier liver event, has become the occasion when information on those drugs – known as “direct-acting antivirals” – is often shared for the first time. In recent years, hepatitis C delegates had got used to turning up to must-see presentations that were filled way beyond capacity.
One look at the 2011 programme told conference-goers that a session on the Sunday afternoon – “HCV: Refining the Use of Direct-Acting Antivirals” – was going to be mobbed. Room 2001, on the second floor of the convention centre, only held about 400 people. Dr Ed Gane, a 51-year-old hepatologist and transplant specialist from New Zealand, who was to give the fourth of six presentations in the session, arrived about 10 minutes before it was due to begin. “It was packed to the gunwales,” he told me. Conference staff began setting up a video link to adjoining rooms to cope with the spillover.
The cognoscenti were there to hear Gane. An unshowy, respected doctor, he had been working on hepatitis C since the early 1990s, and for the past year, had been carrying out a clinical trial of a particularly promising new drug developed by a small American pharmaceutical company called Pharmasset. The drug was known by its laboratory name, “PSI-7977”, and today, Gane was to give an update on the trial, called ELECTRON.
An article with the title: Importation of generic hepatitis C therapies: bridging the gap between price and access in high-income countries just made it into the Lancet print edition:
There is a PDF of it here
This article about the rationale for using generic hepatitis C medication has just been published in Liver International in their section "Debates in Hepatology".
James A. D. Freeman1 and Andrew Hill2
1 GP2U Telehealth, Hobart, Tas., Australia
2 St Stephens AIDS Centre, Chelsea and Westminster Hospital, London, UK
Liver Int. 2016; 36: 929–932. DOI: 10.1111/liv.13157
Hepatitis C, hepatitis B, HIV, TB and malaria are the five major causes of infectious disease death worldwide. In a breakthrough that rivals the invention of penicillin, drugs that cure hepatitis C, with minimal side effects and high success rates, have reached the market, but, in what must be one of the greatest tragedies of modern times, these life-saving medications are not being deployed on a mass scale. Pharmaceutical patents are gifted to private corporations by governments for the dual purposes of protecting R&D expenditure and encouraging innovation. Unfortunately the monopoly pricing power these patents provision currently lacks adequate checks and balances, is open to abuse, and is quite clearly being abused. The sort of legislative changes required to deliver on the original goals of pharmaceutical patents will take years or even decades to eventuate. Parallel importation of generic medication offers hope to the millions of patients with HCV unable to afford access to vastly overpriced originator medications. Doctors prescribing and monitoring patients taking generics can take comfort from the fact that the REDEMPTION trial results show, like the HIV generics that came before them, that HCV generics deliver robust clinical results.
Read the full article at: http://onlinelibrary.wiley.com/doi/10.1111/liv.13157/full
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