HCV Fall Issue: Gilead's Islands - The Road to Treatment Access

The Treatment Action Group’s Hepatitis/HIV Project collaborates with activists, community members, scientists, governments, and drug companies to make safer, more effective and less toxic treatment for viral hepatitis available. The Project forges coalitions with activists worldwide to demand universal access to hepatitis care and treatment. 

The following HCV related articles were printed online in the fall issue of "TAGline"

NEWS ON THE FIGHT TO END HIV/AIDS, VIRAL HEPATITIS, AND TUBERCULOSIS

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Gilead's Islands - The Road to Treatment Access

The Road to Treatment Access
Generic drug registration, licensing, and a trip to Gilead’s islands

By Karyn Kaplan and Tracy Swan

So far, Gilead has registered and licensed sofosbuvir in only one middle-income country, Egypt, where Gilead is selling it to the government for US$300 per month. Prices will be much higher—and unaffordable—for uninsured Egyptians, who must pay for their own medication; according to the World Bank, Egypt’s per capita annual GDP is US$3,314, but the expected private-market price will be US$9,000 for a 12-week course....

Gilead’s “Egypt price” sounds like a bargain—but it isn’t. Sofosbuvir can be mass-produced, at a profit, for far less than Gilead is charging anywhere. According to Andrew Hill, PhD, of the University of Liverpool and colleagues, three months of sofosbuvir could be mass-produced at a profit, and sold for as little as US$105. In September 2014, Gilead announced licensing agreements for generic sofosbuvir in 91 LMICs. The countries that are not included in these licenses must buy higher-priced sofosbuvir from Gilead. Limiting the countries where generic sofosbuvir can be sold will make it difficult for producers to reduce the price, because they cannot achieve economies of scale....

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A Drug by Any Other Name
The basics of generic medications, bioequivalence, and the push for good manufacturing practices
By Tim Horn

Securing access to generic drugs to treat HIV, hepatitis C virus (HCV), and tuberculosis (TB) is now one of the most prominent strategies of global health care and treatment activism. The ongoing development, regulatory approval, and evaluation of generic drugs are dependent on activism. This requires a basic understanding of the science and policies of generics, particularly the practices that must be followed to help ensure equivalence and quality control.

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For information about ongoing HCV treatment access advocacy and to get involved in campaigns, please visit www.hepcoalition.org.

Of Interest @ NATAP

Costs of telaprevir-based triple therapy for hepatitis C: $189,000 per sustained virological response - (09/29/14)

J&J makes a splash in hep C with a $1.75B deal for Alios

Investment Commentary

J&J makes a splash in hep C with a $1.75B deal for Alios

September 30, 2014 | By Damian Garde

Johnson & Johnson ($JNJ) is taking a deep dive into antivirals, trading $1.75 billion for private biotech Alios BioPharma to get its hands on a midstage treatment and some early assets that could expand its share of the blockbuster hepatitis C market.

The handsome deal is an all-cash transaction that will bring J&J a wide pipeline of nucleotide analogs, or nucs, oral treatments that stop viral infections by blocking their ability to reproduce.

Continue reading....

France uses tax to put pressure on hepatitis C drug prices

France uses tax to put pressure on hepatitis C drug prices

By Natalie Huet

PARIS Tue Sep 30, 2014 7:38am EDT
(Reuters) - France will tax drugmakers whose costly hepatitis C drugs threaten to throw off course its healthcare budget, the government has said, heaping pressure on pharmaceutical companies like Gilead Sciences to cut their prices.

The Socialist government said it had designed a "progressive contribution scheme" ensuring all patients can access new and more effective treatments against the liver-destroying virus, while limiting the burden of these drugs on state finances.

The government will selectively tax drugmakers when the total cost to the state from their hepatitis C drugs exceeds a certain amount each year, Health Minister Marisol Touraine said, as she unveiled the country's 2015 social security budget bill on Monday.

If social security spending on hepatitis C drugs exceeds 450 million euros ($567 million) in 2014, the makers of those drugs will be taxed based on the revenue they had reaped in excess of that cap, the ministry said in a presentation.

In 2015, the tax will apply beyond a 700 million euro cap, it added.

Details of the new tax should be presented to lawmakers in October and a vote on the budget is due by the end of the year.

Some 200,000 people in France are infected with hepatitis C and treatments for the virus could cost the state-run healthcare system as much as 1 billion euros this year, according to reports in newspapers Le Monde and Les Echos.

The ministry declined to comment on any estimates.

LOWER CURE RATES

With its move, France is raising pressure on U.S. biotechnology company Gilead, which obtained regulatory approval for its hepatitis C drug Sovaldi in Europe last January, but is still negotiating its official price in France with representatives of the economy and health ministries.

A representative for Gilead in Europe could not immediately be reached for comment. Gilead has argued that Sovaldi's price is comparable to older medicines that require longer treatment duration with much lower cure rates and nasty side effects.

Sovaldi cures well in excess of 90 percent of patients in as little as eight weeks of treatment. But its price has fueled sharp criticism from governments and private insurers alike.

Sovaldi currently costs around 56,000 euros ($70,000) in France and $84,000 in the United States for 12 weeks of treatment. The U.S. price works out to as much as $1,000 per pill.

Sovaldi is on track to be one of the world's biggest-selling drugs, set to rake in close to $12 billion in revenue in 2014 - its first full year on the market - according to forecasts compiled by Thomson Reuters Cortellis.

Rivals Merck & Co and AbbVie are also racing to develop next-generation hepatitis C treatments that cure most people of the virus in a shorter timeframe.

Hepatitis C virus, or HCV, is spread through blood, often via contaminated needles, and causes cirrhosis and liver cancer. Approximately 150 million people in the world live with the infection, most of them in low and middle-income countries.

(Editing by Andrew Callus and David Holmes)

Upcoming/Recruiting HCV Clinical Trials - Sofosbuvir Based Including Ledipasvir/Sofosbuvir

Clinical trials on this page are not a complete list; to learn more about HCV trials or to find out if a study is enrolling patients in your area, please click here. View additional hepatitis trials updated in the last 30 days @ ClinicalTrials.gov

For additional information visit HCV Advocate News and Pipeline for trial updates;

AbbVie
Bristol-Myers Squibb (BMS)
Gilead
Merck
Tibotec / Janssen
**Quick Reference Guide*

Simeprevir/Sofosbuvir/Ribavirin

Not yet recruiting
Efficacy and Safety Study of Simeprevir in Combination With Sofosbuvir in Subjects With Chronic Genotype 4 Hepatitis C Virus Infection
Conditions: Chronic Hepatitis C; Genotype 4 Chronic Hepatitis C
Interventions: Drug: Simeprevir; Drug: Sofosbuvir Sofosbuvir/Ribavirin
ClinicalTrials.gov Identifier: NCT02250807
Sponsor: Janssen Infectious Diseases BVBA

Simeprevir/Sofosbuvir

Not yet recruiting

Efficacy and Safety Study of Simeprevir in Combination With Sofosbuvir in Subjects With Chronic Genotype 4 Hepatitis C Virus Infection

Conditions: Genotype 4 Chronic Hepatitis C
Drug: Simeprevir
Drug: Sofosbuvir
Phase 3

ClinicalTrials.gov Identifier: NCT02256176

Sponsor: Janssen R&D Ireland

Recruiting

Sofosbuvir/Ribavirin - Adolescents and Children

Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children With Genotype 2 or 3 Chronic HCV Infection

Conditions: Hepatitis C Virus Infection
Drug: SOF
Drug: RBV
Phase 2

ClinicalTrials.gov Identifier: NCT02175758

Sofosbuvir/Ribavirin 

Not yet recruiting
DAA-based Therapy for Recently Acquired Hepatitis C II (DAA = Directly Acting Antiviral)
Condition: Hepatitis C
Intervention: Drug: Sofosbuvir and ribavirin
ClinicalTrials.gov Identifier: NCT02156570

Recruiting
Efficacy and Safety of Sofosbuvir+Ribavirin in Genotype 2 HCV-infected U.S. Veterans With Cirrhosis
Condition: Hepatitis C Virus Infection
Interventions: Drug: Sofosbuvir; Drug: RBV
ClinicalTrials.gov Identifier: NCT02128542

Recruiting
Safety and Efficacy of Sofosbuvir Plus Ribavirin in Treatment-Naive Adults With Chronic Genotype 1 or 3 HCV Infection
Condition: Chronic HCV Infection
Interventions: Drug: Sofosbuvir; Drug: RBV
ClinicalTrials.gov Identifier: NCT02074514

Sofosbuvir/GS-5816

Recruiting

Comparison of Sofosbuvir/GS-5816 Fixed Dose Combination for 12 Weeks With Sofosbuvir and Ribavirin for 24 Weeks in Adults With Chronic Genotype 3 HCV Infection (ASTRAL-3)

Condition: Hepatitis C Virus Infection
Drug: SOF/GS-5816
Drug: SOF
Drug: RBV
Phase 3

ClinicalTrials.gov Identifier: NCT02201953

Ledipasvir/Sofosbuvir and Vedroprevir With or Without Ribavirin
Recruiting
Ledipasvir/Sofosbuvir Fixed-Dose Combination and Vedroprevir With or Without Ribavirin in Treatment-Experienced Participants With Chronic Genotype 1 HCV Infection and Cirrhosis
Condition:
Hepatitis C Virus Infection
Interventions:
Drug: LDV/SOF; Drug: VDV; Drug: RBV
ClinicalTrials.gov Identifier: NCT02226549

Ledipasvir/Sofosbuvir - Adolescents and Children

This study is not yet open for participant recruitment
Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination in Adolescents and Children With Chronic HCV-Infection

Condition: Hepatitis C Virus Infection
Drug: LDV/SOF
Phase 2

ClinicalTrials.gov Identifier: NCT02249182

Ledipasvir/Sofosbuvir

Recruiting
Efficacy and Safety of Oral Regimens for the Treatment of Chronic HCV Infection
Condition: Chronic Hepatitis C
Interventions: Drug: LDV/SOF; Drug: RBV
Phase: Phase 2
ClinicalTrials.gov Identifier:
NCT02202980
Other IDs: NCT02202980
GS-US-337-1468

This study is not yet open for participant recruitment
Safety and Efficacy of Ledipasvir/Sofosbuvir (LDV/SOF) Fixed Dose Combination (FDC) for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic HCV Infection
Condition:
Hepatitis C Virus Infection
Intervention:
Drug: LDV/SOF
ClinicalTrials.gov Identifier: NCT02251717

Recruiting
Ledipasvir/Sofosbuvir Fixed-Dose Combination on Cerebral Metabolism and Neurocognition in Treatment-Naive and Treatment-Experienced Participants With Chronic Genotype 1 HCV Infection
Condition:
Hepatitis C Virus Infection
Interventions:
Drug: LDV/SOF; Drug: Placebo to match LDV/SOF
ClinicalTrials.gov Identifier: NCT02219685

This study is not yet open for participant recruitment
Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination in Adolescents and Children With Chronic HCV-Infection
Condition:
Hepatitis C Virus Infection
Intervention:
Drug: LDV/SOF
ClinicalTrials.gov Identifier: NCT02249182

Enrolling by invitation
Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination ± Ribavirin in Subjects With Chronic Genotype 1 HCV Who Participated in a Prior Gilead-Sponsored HCV Treatment Study
Condition:
HCV Infection
Interventions:
Drug: LDV/SOF; Drug: RBV
ClinicalTrials.gov Identifier: NCT01987453

Recruiting
Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination and Sofosbuvir + Ribavirin for Subjects With Chronic Hepatitis C Virus (HCV) and Inherited Bleeding Disorders
Condition:
Chronic HCV Infection
Interventions:
Drug: LDV/SOF; Drug: Sofosbuvir; Drug: Ribavirin
ClinicalTrials.gov Identifier: NCT02120300

HIV Co-infection
Sofosbuvir/Ledipasvir

Not yet recruiting
Pilot Study to Assess Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-dose Combination in Treatment Experienced Subjects With Hepatitis C Virus (HCV) Genotype 1 - HIV Co-infection
Conditions: Viral Hepatitis C; HIV
Intervention: Drug: Sofosbuvir/Ledipasvir fixed dose
ClinicalTrials.gov Identifier: NCT02125500

HIV Co-infection
Simeprevir and Sofosbuvir

Not yet recruiting
A Study of the Safety and Effectiveness of Simeprevir and Sofosbuvir for Patients With HIV and Hepatitis C
Conditions: Hepatitis C, Chronic; HIV CDC Category A1
Intervention: Drug: Sofosbuvir + Simeprevir
ClinicalTrials.gov Identifier: NCT02206932

Achillion in prime position to develop its own all-oral hepatitis C treatment

Investment Commentary
Source - The Pharmaletter.com

Achillion a good candidate for collaboration or takeover based on hepatitis C candidate, says Edison     
US-based Achillion Pharmaceuticals (Nasdaq: ACHN) is in a prime position to develop its own all-oral hepatitis C treatment as it is the only standalone biotech company with drug candidates in three key classes for the indication, says Edison Equity Research, which has valued the company at $1.42 billion, or $14.5 per basic share.

The firm's all-oral, once-a-day, interferon- and ribavirin-free single pill hepatitis C treatment could be as competitive as current market leader, US biotech major Gilead Sciences’ (Nasdaq: GILD) SOF/LDV fixed-dose co-formulation.

Achillion’s offering is showing promising efficacy in early stages of development, and additional efficacy and safety data in more patients from later stage clinical trials will add value to the pipeline, and Edison believes this could lead to a possible corporate partnership deal.

The company has discovered inhibitors of three key enzymes of HCV replication: nucleotide NS5B polymerase, NS5A and NS3/4A polymerase. Early studies have shown the candidates to be equally as potent, if not more, than candidates developed by competitors including Gilead. More Phase II trials will give greater proof of the drugs’ efficacy and safety profile, and will lead to Phase III confirmation trials required for market approval.

This makes Achillion a prime candidate for a big pharma company still interested in the hepatitis C market but lacking the necessary components to create a competitive oral drug for the indication. Idenix, in possession of drug candidates in two key classes, was acquired by pharma giant Merck & Co (NYSE: MRK) for $3.9 billion, highlighting the importance of these drugs to big pharma.

Based on this, Edison has derived a valuation of $1.42 billion or $14.5 per share, and says a major value inflection point would be a positive Phase II result of the combination of ACH-3422 and ACH-3102, which is similar to Gilead’s SOF/LDV fixed-dose co-formulation.

Review article: the management of cirrhosis in women

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Review article: the management of cirrhosis in women

1. A. M. Allen and
2. J. E. Hay^*

Article first published online: 28 SEP 2014

DOI: 10.1111/apt.12974

View Full Text Article @ Alimentary Pharmacology & Therapeutics

Abstract

Background
There are differences in the predisposition, natural history of liver disease, complications and treatment response between men and women.

Aim
To review clinical differences in cirrhosis between men and women and to address unique management issues of fertility, pregnancy and contraception in this patient population.

Methods
PubMed and MEDLINE were searched using the terms ‘cirrhosis’ and ‘chronic liver disease’, each cross-referenced with specific liver diseases, as well as terms such as ‘cancer’, ‘hepatocellular carcinoma’, ‘smoking’, ‘liver transplantation’, ‘metabolic bone disease’, ‘fertility’,’ pregnancy’ and ‘contraception’.

Results
Pre-menopausal status is protective in viral hepatitis C and non-alcoholic steatohepatitis. However, smoking, especially in combination with alcohol, is a stronger risk factor for cirrhosis and malignancies in women with chronic liver disease compared to men, although they are less likely than men to develop hepatocellular carcinoma. Women with cirrhosis have more osteopenic bone disease than men and require active management. Successful pregnancy is possible in well-compensated cirrhosis or with mild portal hypertension, although the maternal and foetal mortality and morbidity are higher than in the general population. The maternal risk correlates with liver disease severity and derives mostly from variceal bleeding. The choices for contraception in compensated cirrhosis are generally the same as for the general population. Women with cirrhosis are disadvantaged by the current MELD system of organ allocation, at least in part due to body size.

Conclusion
The management of women with chronic liver disease is unique in regards to counselling, screening for complications, fertility and pregnancy.

Discussion

Differences in liver disease between men and women

Sex-based differences in gene expression and in a wide range of hepatocyte functions translate into differences in natural history of liver disease between men and women[4] affecting aetiology, clinical course, treatment response and complications. While men are most likely to have hepatitis C and alcoholic cirrhosis, women have predominantly autoimmune hepatitis and primary biliary cirrhosis (PBC).[1, 5] Although generally the management of cirrhosis is similar regardless of gender, some differences in natural history highlighted below may support a gender-based approach to counselling, treatment and follow-up.

Viral hepatitis

Women clear acute hepatitis C at a higher rate than men. In chronic hepatitis C, the female gender has long been associated with decreased progression to fibrosis,[6, 7] which is slower in pre-menopausal women than in men and post-menopausal women.[8] Most women with hepatitis C cirrhosis are post-menopausal. Women generally have a lower prevalence of additional risk factors for fibrosis – alcohol, smoking and iron overload. Furthermore, animal studies have shown that oestrogens protect hepatocytes from oxidative damage, inhibit secretion of pro-inflammatory cytokines (IL-1, IL-6 and TNFα) and suppress hepatic fibrosis in mice.[9] Hormone replacement therapy (HRT) is potentially beneficial in decreasing fibrosis progression.[10] Moreover, the likelihood of sustained virologic response (SVR) to interferon-based treatment is higher in pre-menopausal women than their post-menopausal counterparts and men.[11] It remains to be determined if the impact of hormonal status on SVR remains significant in the era of direct-acting antiviral agents. However, it is reasonable to conclude that the pre-menopausal status is prime time for initiating therapy while the rate of fibrosis progression is low.

Although sex-based differences in the natural course of chronic hepatitis B are less clear, female sex confers an advantage in some aspects of hepatitis B infection. As in hepatitis C, fibrosis progression is slower in women than men.[7] Women are more likely to clear hepatitis B surface antigen and to undergo e-antigen seroconversion.[12] Moreover, reactivation after e-antigen seroconversion is less likely in women.

Alcoholic liver disease

Women are at greater risk than men for developing alcoholic liver disease and cirrhosis. Unlike chronic viral hepatitis, women with alcoholic liver disease experience more rapid fibrosis progression than their male counterparts, even after abstinence.[7] The female susceptibility to alcoholic liver disease is increased for multiple reasons, including higher blood alcohol levels due to smaller volume of distribution and lower gastric metabolism. Increased gut permeability in female rats compared to male rats results in higher endotoxin levels to which female Kupffer cells have increased sensitivity, resulting in increased oxidative damage. Furthermore, female rats fed alcohol have differential gene expression from male rats and fail to upregulate hepato-protective genes of compensatory pathways involving oxidative stress and inflammation.[13] Chronic alcohol ingestion alters the hormone environment in blood and liver in both men and women, but the exact role of female hormones in the aetiology of alcoholic liver disease remains unknown.[13] Several other recent studies have suggested that smoking, especially combined with alcohol, is a stronger risk factor for fibrosis and cirrhosis in women with liver disease compared to men.[3, 14, 15]

Non-alcoholic fatty liver disease

As in chronic hepatitis, pre-menopausal status seems to be a protective factor in the rate of nonalcoholic steatohepatitis (NASH)-related fibrosis progression. Among NASH patients, men and post-menopausal women have a greater likelihood of fibrosis than women <50 years.[16] Therefore, reproductive age represents an opportune time for counselling and life style changes before the risk of fibrosis increases. Hormone replacement therapy has been found to be protective against non-alcoholic fatty liver disease (NAFLD) after menopause. In addition, of 4338 women in 3rd NHANES survey from 1988 to 1994, oral contraceptive users had less NAFLD than non-users.[17]

Sex-based differences in complications of cirrhosis
Cancer risk

It is known that male gender is a risk factor for hepatocellular carcinoma (HCC) in all populations.[18, 19] Men with cirrhosis have two to three times higher risk of HCC compared to women, with larger discrepancies found in medium-risk European populations. In USA, the incidence of HCC between 1992 and 2004 was 6.7 cases per 100 000 men and only 2 per 100 000 women.[20] Although the increased risk of male gender may be explained by higher exposure to risk factors, such as hepatitis B or C, there is some evidence that oestrogens may reduce the risk of carcinogenesis-induced inflammation and the subsequent development of HCC in women. The beneficial effects of female hormones is suggested by data from Taiwan showing that the risk of HCC was inversely related to the number of full-term pregnancies, age at natural menopause and use of hormone replacement therapy; the risk was increased in women who underwent oophorectomy during pre-menopausal years.[21] Despite this overall reduced risk of HCC, women have been shown to be as susceptible as men to the effects of alcohol as a risk factor for HCC.[22, 23] Therefore, women with cirrhosis, irrespective of the underlying liver disease, are at risk of developing hepatocellular cancer and should follow similar screening guidelines as men. Once HCC develops, the management strategies and survival rates between sexes are similar.[2, 24]

Women with cirrhosis are at least as susceptible as men to develop nonliver-related malignancies. In a Danish nationwide cohort study of 11 000 cirrhotics followed for 5–7 years, incidence of tobacco and alcohol-related cancers was higher in women than men.[25] A large Italian study of 1400 female cirrhotics with digestive tract cancers showed an increase in liver, oral and pharyngeal cancers, but not pancreas, colon or stomach.[26]

Early studies suggested that the risk of breast cancer may be increased in alcohol-related cirrhosis [25] and in PBC, but larger recent studies in patients with PBC have refuted this finding.[27-29] The risk of other gynaecologic cancers does not appear to be increased. Therefore, the recommendations for breast and gynaecologic health in women with cirrhosis follow the guidelines used in the general population.

Metabolic bone disease

Patients with cirrhosis of all aetiologies should be screened for osteoporosis irrespective of gender.[30] The major risks for bone loss are chronic cholestasis (commoner in women) and cirrhosis itself but additional, albeit lesser, risk factors for bone loss in women with cirrhosis are steroid therapy, female gender and post-menopausal status. In chronic cholestatic liver disease in particular, osteoporosis and fracturing are common. Thus, all female cirrhotics should undergo assessment of bone mineral density at the lumbar spine and hips. In addition to adequate calcium and vitamin D supplementation and weight-bearing exercise, correction of all reversible factors contributing to bone loss must be addressed. For the debilitated patient, appropriate physical therapy should be initiated.

Although there are no clinical trials in patients with cirrhosis, bisphosphonates are the preferred agents for the treatment of hepatic osteoporosis or advanced osteopenia. Therapy should be strongly considered prior to LT, to reduce the risk of bone loss and fracturing post-transplant. In patients with oesophageal varices, oral bisphosphonates are generally avoided. Intravenous pamidronate or zoledronic acid may be given every 3–12 months. Hormone replacement therapy remains an option for post-menopausal patients.

Portopulmonary hypertension

Portopulmonary hypertension (PPH) is an uncommon complication of cirrhosis which seems to occur more frequently in women.[31] Of 34 patients with PPH and 141 controls, the two identified independent risk factors for PPH were female gender and autoimmune hepatitis.[32] Therapy for PPH is the same for men and women.

Unique issues for women with cirrhosis

The unique issues for women with cirrhosis relate to reproduction and hormone therapy. The US prevalence of cirrhosis in women of reproductive age is only 0.045%,[33] which represents approximately 27 000 women. Autoimmune hepatitis is the most common underlying liver disease, while a few patients have primary sclerosing cholangitis (PSC), Wilson's disease, alpha 1- antitrypsin deficiency and chronic viral hepatitis. Pregnancy is rare in decompensated disease, but is increasingly encountered in patients with compensated disease and mild portal hypertension. Issues that concern women of reproductive age with cirrhosis or after LT include their fertility, maternal and foetal risks associated with pregnancy, and risks related to breastfeeding. Unfortunately the optimal management of cirrhotics in the modern era of obstetrics remains poorly defined, but some guidance can be provided.

Fertility

The patient of child-bearing age with compensated cirrhosis and minimal portal hypertension commonly maintains regular menstrual periods and preserved fertility. If pregnancy is undesirable, then contraception must be offered. However, in decompensated cirrhosis, hypothalamic pituitary dysfunction leads to anovulation, amenorrhoea and infertility. Menstrual history is important, as conception is very unlikely with primary or secondary amenorrhoea. A high percentage of females listed for LT have amenorrhoea.[34] Assisted conception has been attempted [35] but with little success: three conceptions in two women with compensated autoimmune cirrhosis, resulted in two early miscarriages and one healthy baby whose mother died of hepatic decompensation 12 months after delivery. Similarly, assisted conceptions in pre-cirrhotic autoimmune hepatitis had complications; it is not recommended in decompensated disease.

Pregnancy in cirrhosis
Maternal outcomes

Pregnancy does not alter liver function in most patients with cirrhosis except in autoimmune hepatitis, where the course is unpredictable; flares can develop in about 50% of cases, either during pregnancy or in the post-partum period.[36, 37] In a study of 33 pregnancies in 21 women with cirrhosis due to autoimmune hepatitis, severe adverse maternal outcomes occurred in seven pregnancies, leading to two LTs, three deaths (two variceal bleeds and one decompensation) and two severe decompensations.[35] Risk factors for poor pregnancy-related outcomes in autoimmune hepatitis include persistent clinical disease or decompensated cirrhosis, poor compliance with therapy and relapse during a previous pregnancy.[34, 37]

The main maternal risk associated with pregnancy in cirrhosis is from portal hypertension. In a normal pregnancy, portal blood flow increases and drives more blood into the portosystemic collateral circulation.[33, 38] These changes exacerbate the pre-existing portal hypertension in cirrhosis and result in maternal complications in 30–50% of patients. There is a high risk of variceal bleeding in 20–45% of patients, especially in those with pre-existing varices; this risk is greatest in the second trimester and during delivery. Post-partum haemorrhage occurs in 7–10% of patients. Splenic artery aneurysm rupture can be a rare (2.6% of patients), but fatal complication. Occasionally, hepatic encephalopathy, ascites, spontaneous bacterial peritonitis and hepatic failure may occur.

Based on sparse data, maternal mortality is estimated at 10–18%. In a study of 33 pregnancies in patients with cirrhotic autoimmune hepatitis, three deaths occurred within 1 year of delivery.[35] Maternal prognosis correlates with severity of the liver disease. In 62 pregnancies in 29 cirrhotic patients, there were no complications in patients with preconception MELD score less than 6 but a MELD score of 10 or higher, was associated with liver-related complications in 10% of patients (3 variceal bleeds).[39]

Foetal outcomes

Cirrhosis in pregnancy is associated with worse foetal outcomes compared to the general population. There is a higher rate of prematurity (26–64%) and early spontaneous foetal loss (15–20% vs. 3–6% in the general population). Considering the additional foetal loss from maternal death, variceal haemorrhage and therapeutic abortion, the live birth rate is only 57–58%.[39] More recent data are shown in Table 1. A MELD score of 10 or higher predicts increased foetal prematurity and decreased live birth rate.[39]

Table 1. Foetal risk in cirrhosis

	Cirrhotic AIH[35], N = 33	Non-cirrhotic AIH[35], N = 48	All cirrhotics[39], N = 62
N, number of pregnancies
Live birth rate	57%	83%	58%
Prematurity	26%	17%	64%
Perinatal mortality	0%	0%	0%
Congenital abnormalities	Perthe's (1)	Cerebral palsy (1)	Cerebral palsy (2)
			Learning difficulties(1)

General management of the cirrhotic pregnancy

Optimal management of the pregnant patient with cirrhosis requires coordinated care from the hepatologist, endoscopist and high-risk obstetrician. Preconception counselling about foetal and maternal risk is essential. In order to minimise the risks, the liver disease should be stable, compensated, and the portal hypertension optimally controlled. If LT is imminent, pregnancy should be postponed until 1 year post-transplant. Treatment of liver disease should be continued and tailored to minimise teratogenicity. Azathioprine and/or prednisone therapy for autoimmune hepatitis must be maintained throughout pregnancy; flares should be treated as in the non-pregnant patient. Chelating agents in Wilson disease must be maintained in pregnancy to avoid a flare of disease; foetal outcomes are satisfactory with zinc, trientine and D-penicillamine, although rare embryopathy may occur with the latter. Antiviral agents for hepatitis B (most commonly tenofovir or lamivudine) should be continued throughout the pregnancy. Treatment for hepatitis C is associated with high rate of teratogenicity and must be avoided during pregnancy. Ursodeoxycholic acid must be maintained during pregnancy in PBC[40] and can be used during the second and third trimesters to treat worsening cholestasis in PSC.

An ultrasound examination of the splenic artery should be performed in early pregnancy, to exclude pre-existing splenic artery aneurysm. Dietary sodium restriction to reduce fluid retention and portal pressure is recommended.

Management of portal hypertension

Preconception screening for varices is essential for optimal care. If no varices are identified, screening should be repeated in the second trimester. In the event that small varices have developed, beta blocker therapy should be started. Close foetal monitoring is important, as foetal bradycardia and intrauterine growth retardation may occur with beta blocker use. There are no studies comparing use of beta blockers vs. variceal band ligation in this setting.

Medium-large oesophageal varices noted before conception, without history of haemorrhage, can be controlled with either beta blockers or endoscopic therapy. As the varices will likely increase during pregnancy, it seems reasonable to proceed with variceal band ligation. Anecdotal data support prophylactic band ligation for high-risk varices as a safe and effective method before and during pregnancy.[38]

Large varices with previous gastrointestinal bleeding should be ligated to obliteration, preferably before conception, and treated during pregnancy as required. For failure of endoscopic therapy or for large varices with very well preserved hepatic function, a shunt may be considered before pregnancy. In the older literature, definitive surgical therapy for varices has been shown to improve foetal and maternal outcome.[41, 42] Although initially more risky, surgical shunts are less likely to occlude in pregnancy and any TIPSS intervention exposes the baby to significant radiation. However, more recently TIPSS has been used with success. Pregnancy is not advised prior to LT in patients with borderline liver function or with decompensated cirrhosis. If no preconception screening is performed, endoscopic evaluation is recommended in the second trimester. Thrombocytopenia (platelet count of <110 × 10⁹ cells/L), but not MELD score, predicted the presence of varices on screening endoscopies during the second trimester.[39]

Management of the acute variceal bleed

Endoscopic management is similar to that of the non-pregnant patient. Serial endoscopies for variceal band ligation to obliteration should be performed. Use of adjunctive medications during the bleeding episode is limited. Vasopressin is contraindicated due to risk of placental ischaemia and potential teratogenicity. Octreotide use is controversial; although it is a category B drug, it causes splanchnic vasoconstriction and may precipitate placental ischaemia and abruption. Placement of TIPSS will expose the foetus to considerable radiation and its use must be weighed against the mother's status.[43]

Perinatal care

Recent data[44] on the impact of cirrhosis on maternal health during labour and delivery show a high rate of Caesarean section, preterm delivery, abruptio placentae and need for maternal blood transfusion compared to the general population (Table 2). During hospitalisation for delivery, 6.5% of patients experienced variceal bleeding, 10% ascites and 1.1% hepatic encephalopathy. In addition, there was a higher risk of venous thromboembolism, pregnancy-induced hypertension, peripartum haemorrhage and infection. Patients with cirrhosis have worse outcomes than liver transplant recipients.

Table 2. Impact of cirrhosis during labour and delivery[44]

	Patients with cirrhosis (n = 187)	General population
a  More in decompensated than compensated cirrhosis (also placenta previa). b  Sepsis, pre-eclampsia with DIC.
Caesarean section ratea	50%	26%
Preterm laboura	38%	7%
Abruptio placentae	5.6%	1.1%
Maternal transfusiona	12.8%	0.6%
Maternal death rateb	1%

Caesarean section is recommended in patients with large oesophageal or gastric varices, to decrease the risk of variceal rupture during vaginal delivery.[40] The risk of vaginal delivery in patients with small varices and a mature cervix is unknown. Assisted vaginal delivery can be employed to keep second stage short. Post-partum haemorrhage and bacterial infections can be reduced with correction of coagulopathy and prophylactic antibiotic use.

Contraception

Few data exist on the effects of contraception in patients with cirrhosis.[45, 46] Although uncommon, unplanned or dangerous pregnancies may occur[39] and the safety of termination in cirrhosis is unknown. Tubal ligation is recommended after completion of child-bearing.

The choices for contraception are generally the same as those for the general population. Combined oral contraception (COC) has 99% efficacy, but has traditionally been discouraged in chronic liver disease due to concern about cholestasis and the risk of HCC. No link between oral contraception and HCC has been confirmed.[47, 48] A WHO study in 1989 found no association between HCC and COC. Widespread use of COC in women with hepatitis B and C in Asia has not led to an increase in HCC, perhaps even reduced its incidence. Indeed history of oral contraceptive use was an independent factor associated with survival in females treated for HCC in the setting of hepatitis B.[49]

In 2008, the WHO expert Working Group reviewed available data on hormonal contraceptive use and concluded that for women with mildly decompensated cirrhosis, there should be no restriction on use of any hormonal contraceptive methods, although in severe decompensated cirrhosis, hormonal contraception should not be used.[50] Present-day preparations, oral or transdermal, have even lower-dose oestrogen and are likely to be even safer. Progesterone-only preparations are safe in patients with liver disease with minimal hepatic effects. Depot medroxyprogesterone acetate is given once every 3 months with excellent efficacy.[51] Intrauterine contraceptive devices are the most effective form of birth control, without increase risk of infections in liver transplant recipients or HIV-infected patients. In patients with compensated disease without coagulopathy or significant thrombocytopenia, bleeding should not occur. Barrier methods (condoms and spermicidal preps) can be used safely but are less effective.

Hormone replacement therapy

Hormone replacement therapy has been used safely in PBC and chronic active hepatitis [52, 53] and may be protective against fibrosis in hepatitis C[8] and risk of HCC in viral hepatitis.[10] The presence of compensated cirrhosis is not a contraindication to HRT, but the same precautions and contraindications considered in the general population apply to patients with cirrhosis.

Access to and survival with LT

Women have less muscle mass and lower serum creatinine than men, thus may be disadvantaged for LT by the MELD system. The Organ Procurement and Transplantation Network (OPTN) database of the United Network of Organ Sharing (UNOS) shows that in 2013, 38% patients on the liver waiting list were female, consistent with the estimated prevalence of <40% cirrhosis in the USA occurring in women. Over the past 10 years, 34.5% liver allografts have been transplanted into female recipients, both before and after the introduction of the MELD system. In 2008, Moylan and colleagues published data showing that women were less likely to receive a LT within 3 years of listing both before and after MELD; in addition they were more likely to die or become too sick to transplant in the MELD era.[54] Several other studies have confirmed this gender-based disparity in LT.[55, 56] From the UNOS database of 2002–2007, 40 393 patients were listed for LT of which 36% were female; as expected, women had lower serum creatinine and lower MELD score than the men; they were also less likely to receive a LT within 90 days (22.7% vs. 27.5%) and had a higher 3 month mortality.[57] A further study expanded this Scientific Registry of Transplant Recipients (SRTR) data both pre- and post-MELD and showed that the disparity in LT rates between females and males has actually increased in the MELD era, especially for women with higher MELD scores, who are most likely to have a survival benefit; this disparity is geographically widespread but magnified in some areas.[58] Further analysis of wait-list mortality in the MELD era has shown that women have a 19% increased mortality compared to men with the same MELD scores, with at least some of this difference correlating with the shorter height of the women.[59] The reasons for gender disparity in access to LT from the waiting list are not entirely understood but may include deeming an organ too large for a small-size candidate.

Survival rates after LT at 1, 3 and 5 years are similar in men and women. While this may seem satisfactory, note should be made that the indications for LT in women are conditions which generally have an excellent outcome, such as autoimmune hepatitis and chronic cholestatic disease. This may be offset by the fact that more women undergo LT for fulminant hepatic failure. In addition, female survival is further reduced by the poorer outcomes of women transplanted for hepatitis C. In 2002, survival data of over 11 000 LT recipients transplanted from 1992 to 1998 showed that hepatitis C infection impairs both graft and patient survival and that this effect was greatest in female patients.[60] An extended study of this SRTR data (1999–2008) confirmed poorer survival of female recipients with hepatitis C, who have a 14% greater risk of death at 5 years than men with hepatitis C.[61] A more recent multicentre cohort study of 1264 HCV-infected patients (24% of which were women) showed that recipient female gender was associated with advanced recurrent hepatitis C, graft loss and mortality.[62] The reasons for worse HCV-disease progression after LT in women compared to men is not well understood and does not seem to be explained by age, increase in living donor LT, less HCC, more rejection or donor sex. The increased efficacy of the new antiviral agents will hopefully eliminate this disparity.

Conclusions

Although the current management of liver disease and associated complications is similar in men and women, there are significant sex-based differences in aetiology, natural progression and treatment response that deserve better understanding and may optimise future management of women. Female sex, and particularly the pre-menopausal status, is a protective factor in viral hepatitis and NASH, but a risk factor in alcoholic liver disease. Women with cirrhosis have more osteopenic bone disease and PPH than their male counterparts. Their risk of HCC is less than men but still occurs in all aetiologies of cirrhosis and requires screening. Smoking and alcohol use potentiates increasing fibrosis and cirrhosis in women with chronic liver disease, more so than in the male population, and also increases their risk of HCC and upper aerodigestive cancers. The mechanisms of this gender effect are unknown but demand further study, especially with regard to use of hormonal therapy in these women. Women with chronic liver disease must be strongly counselled against smoking and alcohol use.

Successful pregnancy is possible in inactive, compensated cirrhosis, but is still high risk and demands careful counselling about maternal and foetal risk. Active management of varices is essential before and during pregnancy. Contraception must be discussed with women of child-bearing age to avoid unwanted and potentially dangerous pregnancies.

Women listed for LT are disadvantaged by the present system of organ allocation. Lower muscle mass and subsequent lower creatinine does not entirely account for this disparity. Further study is needed and the necessary adjustments made to eliminate the preferential allocation of organs to men resulting in higher female mortality. Hopefully, the introduction of more effective antivirals for hepatitis C will greatly improve the transplant outcome for both men and women with hepatitis C. With their poor post-LT prognosis without treatment, antiviral therapy should be strongly considered for women with HCV-cirrhosis, before LT or in the early post-transplant period.

Authorship

Guarantor of the article: J. Eileen Hay.

Author contributions: J.E.H designed the research study, A.M.A and J.E.H collected and analysed the data and wrote the manuscript. All authors approved the final version of the manuscript.

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