HCV: new frontiers and controversies was the final session I attended, abstracts 179 to 181.  It built on the earlier workshop, HCV in the interferon-free era, blogged by Jane.  In the pathogenesis of acute infection, Ashwin Balagopal described a doubling time of 7.5 hours with 21 days to reach a viraemia of over 6 logs. HCV infects a minority of hepatocytes at 20-45% with about 100 copies of HCV RNA per hepatocytes. 1-3 trillion copies of RNA are made daily and rapidly cleared to maintain set point. 20-25% of people clear infection, usually within the first six months, and prior clearance of an earlier infection makes this more likely (as does being female, non-African and HIV negative).  In reminding us of ELITE controllers, he raised the vaccine option. 

IL28B is now known as interferon lambda 3 which can mutate to IFN L4 to which HCV binds differently. Evidence of immune response is also seen in that neutralising antibodies from people who have cleared HCV previously have an effect in a further clearance of infection.  

Greg Dore first defined terminology in his HCV treatment as prevention talk.  There are three approaches: eradication as in small pox, elimination in which the incidence is zero but on-going work is required (measles and polio) and epidemic control where incidence decreases over time. 

The dilemma in HCV treatment is whether to focus on the liver disease burden in older people (defined as over 35) or on HCV infection prevention in younger people. He presented data which indicated that 75% of people aged 15 to 19 years had ever injected, this rate falling to 25% over the age of 35. 

In discussing treatment as prevention in Australia in the 10% co-infected with HIV and HCV, he reported on the CEASE study: approximately 80% of co-infected people have been diagnosed, around 80% of those are linked to / retained in care but only about two thirds are / have received treatment.  Of the treated fraction, HIV RNA is suppressed in over 60%. 

He spoke of the harm reduction approach for PWID, noting that only 41% of countries have NSP programs and only 30% have opiate substitution programs.  HCV incidence in Australia was around 25% per annum in the 1990s falling to about 5% per annum in the 2000s.  The target groups for treatment as prevention are PWID, prisoners (12% of injectors are jailed annually with an incident HCV infection rate of 10% per annum), HIV positive MSM and pregnant women.  

He outlined the STOP C study of early and deferred treatment with sofosbuvir and GS5816 for 12 weeks planned for two medium to maximum security prisons in New South Wales. 

In abstract 181, HCV therapeutics: It's the virus stupid, Mark Sulkowski described the HCV life cycle and where the directly acting molecules fit.  He also spoke of the class cross resistance seen (in the low number of people who fail treatment) to date with telapravir and daclatatasvir and of the benefit in preventing failure in adding ribaviron. 

He define Perfectovir, introduced by Greg Dore in the preceding talk, as achieving SVR in > 90%, working for all genotypes, administered as a once daily pill and with no side effects.  He also thanked all the people who were in clinical trials which did not show benefit.  

Marion Peters had given a superb talk in the HCV workshop on HCV cirrhosis with early decompensation in which she demonstrated the usefulness of the Childs Pugh score as well as the MELD during treatment for assessing decompensation.  She had reminded us that the natural history of ESLD is that 5-7% of people decompensate annually.   In this the last talk of the conference, she was given the title of HCV therapeutics: big sticks with big stickers. In noting that SVR produced a 70% reduction in HCC and a 50% reduction in all cause mortality (renal and bone disease, cryoglobulinaemia, lymphoproliferative disease, CVD and cognitive impairment) as well as reducing portal hypertension. 

Cost effectiveness of staging determined treatment as opposed to treating all patients yielded a best result for immediate treatment of anyone with a Fibroscan score of > F1. The cost of treating T2DM, HIV, HER2 positive breast cancer and HCV with IFN RBV and a PI were about the same but the difference is that the costs with HCV treatment are all up front, not spread out over time.  A time delay in treatment (until people reached Medicaid age in the USA) meant two thirds had at least one other chronic disease which could complicate treatment.  

91 countries across the world to date have made deals of various sorts with pharma to access treatments for their populations.  The obvious inequities were discussed in question time.  

Marion Peters ended her talk saying that the problem is the patient load of HCV infection worldwide and that in its management of HCV, Australia could be considered the greatest country in the world. 

Ebola - not a retrovirus but an international emergency

Ebola did in months what HIV took years to do. There were over 23,000 cases and more than 9,000 deaths as of last week.  The emergency medical coordinator for Ebola in Liberia, Dr Gilles Van Cutsem, of Medecins Sans Frontieres (MSF), described the response to the challenge.  

Ebola is a RNA virus in the same family as Marberg and Lassa fever. The incubation period is 2-21 days with an early febrile stage, then overwhelming GI symptoms, shock and death or recovery.  

The case fatality rate is 30-90%, severity is related to a high viral load at presentation. Transmission is from human to human, via contact with infected fluids. It is not airborne. The animal host is thought to be bats.  

This epidemic is different from previous Ebola epidemics with more cases than all other epidemics combined; previous epidemics have been confined to rural or remote areas and gradually burned out. Now there are massive outbreaks in cities. 

The index patient was a three-year-old child probably infected by a bat in Guinea in December 2013. All family members died rapidly then it spread to distant family and other villages. The first epidemic spread through 500 km.

In March 2014 the second outbreak occurred with rapid spread through neighbouring countries of Liberia and Sierra Leone.  Then there was a third wave of epidemic involving the cities of Monrovia and Freetown and further spread. The hIghest risk of transmission is thought to be later in disease progression; a small infectious viral load only is needed. Five hundred health care workers in Liberia have died. 

The Lagos outbreak was well handled by the Nigerian Ministry of Health. The interventions were based on community education/mobilisation with distribution of protective kits, case/outbreak investigation and contact tracing (which must be rapid), home disinfection, safe transport of patients (for isolation and treatment) and safe burial (it takes six people many hours to ensure decontamination).  One hundred percent of cases on contact lists were traced in Liberia but this is much less in the surrounding countries; in Guinea, 16% of contacts are traced and there the incidence is not falling. 

Current case fatality has been estimated at 51% but the death rate is declining over time in most centres.  A decreased VL on presentation for care has become more common.  The reason for this is unclear; perhaps decreased viral fitness or perhaps a lower infective inoculum in cases because of behaviour change.  

A pregnant woman about to deliver presented to a MSF care station. She was otherwise  asymptomatic and was accepted into the unit only because delivery was very close. She was checked for Ebola because it was routine and found to have a high viral load.  She remained asymptomatic for 3 days.  

Health system closures mean that people are dying from other disease. MSF isolation capacity has been close to full and people died waiting outside the centres. WHO declared a public health emergency only in August 2014 despite several earlier calls for MSF for a response.  MSF had actually called for civil and military biohazard response - unusual for MSF, and the response is still slow and not coordinated. There is a real difficulty balancing patient care and outbreak control.  WHO called for coordination and community organisation on 18 February 2015.   

There is no functional global response to epidemics in countries with fragile health systems. The decreasing incidence in Liberia is largely due to the quality of the response.  The national case manager from Liberia spoke of the country's response - they trained all their HCW and provide training to those who come to help. If there is any next time, the situation should not repeat. 

There was a standing ovation.  

Prevention and Treatment

Prevention and treatment were discussed by H. Clifford Lane from the National Institute of Health.  The NIH was involved following a direct government to government invitation.  

Ebola represents HIV compressed into a couple of months.  Ebola is different from HIV in that  survival means immunity but there is no clear correlate of protective immunity.  There are two current vaccine candidates: recombinant VSV and recombinant chimpanzee adenovirus.  There are the usual vaccine side effects including transient reactive arthritis.  Antibody induction post vaccination has been demonstrated.  

He proposed a trial of a vaccine candidate with probable 50% efficacy and assuming a 1% incidence in Liberia, initially focussing on people at higher risk such as contacts, HCWs and burial teams.  A clinical endpoint study is feasible because of the relatively high mortality and short clinical course. 

Potential therapeutic approaches are neutralising antibodies, nucleoside or nucleotide analogues and agents related to cellular cytotoxicity. Currently there is a monoclonal antibody focused on glycoprotein, a drug called brincidovir, convalescent plasma and an antisense compound. 

An adaptive trial of an investigational intervention would be added to supportive/standard of care. If the experimental arm is effective, then it becomes SOC.  The fatality rate means only 

small sample numbers. Historical controls may not be effective because of changes in the virus over time (74% morality in mid 2014, now at 25%).  The FDA have agreed to easing their licensing  process in this situation.       

Dr Lane emphasised "doing things the right way" and not just "doing something"; compassionate studies muddy the water and complicate subsequent decision making.  Rigorous research programs by extension enhance the local healthcare systems and may improve coordination of the various countries and organisations working in Ebola affected areas. 

 

Three unintended pregnancies were reported in women using levonorgestrel implants while on an efavirenz based regimen.

Late breaker 86 reported that in only one woman was the level of efavirenz below the recommended therapeutic level.

The authors suggest that, if a depot gestagenic contraceptive is used, women should be informed of the small risk of pregnancy and advised that nevirapine or ritonavir boosted lopinavir may be safer choices in this setting.   

Clinical pharmacology of drugs used in PrEP was discussed by Marta Boffito from the Chelsea and Westminster Hospital London.  They measured drug concentrations in cervicovaginal fluid, rectal lavage fluid and in tissue from both sites.  

All data was not presented today. In cervicovaginal fluid, CCR5 is high and maraviroc is less protein bound than in plasma.  Raltegravir concentrates in cervicovaginal fluid, reaching steady state by 4 days; the half life is 17 hours in cervicovaginal fluid compared with seven hours in blood.

Both maraviroc and raltegravir had high concentrations when measured in rectal tissue in woman.  There is data in men but little was presented.  Dolutegravir was detected three hours after a single dose and had a half life of 13 hours.    

Injectable long acting rilpilvirine was trialed in two doses, 1200 and 600 mg.  Sampling of cervcocervical fluid, rectal fluid and tissue showed high levels in cervicovaginal fluid but low levels rectally.  There were high levels of drug at one month.  A higher BMI was associated with lower concentrations of rilpilvirine.  There were no reports of increased toxicity with any of the medications. 

When asked to express an opinion on the negative protection described in the FACTS 001 phase III trial of precoital tenofovir gel presented the day before, Marta thought that systemic PrEP was probably easier for users than local PrEP.  In that study of young women, mean age 23, many of them were living at home and questions of privacy were thought to be germane.