Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. The current recommended treatment is a drug called amphotericin B deoxycholate. Treatment with amphotericin B requires 14 days of intravenous infusions given in hospital, making it difficult and costly to administer. It also causes many side effects, including kidney failure and low blood count, making close laboratory monitoring essential. The combination of the costs associated with prolonged hospital admissions, the difficulties in administration and the need for laboratory monitoring make amphotericin B treatment difficult in much of Africa. The only alternative currently available treatment is called fluconazole. Treatment with fluconazole is inadequate, and is associated with death rates of approximately 60%. A modified form of amphotericin B is available called liposomal amphotericin B (Ambisome). This is considerably less toxic than standard amphotericin B, and is known to be efficacious in treatment of cryptococcal meningitis. Its use has been limited by the high cost of therapy, but recent data suggest that much shorter courses of Ambisome may be effective in the treatment of cryptococcal meningitis. Due to its lower toxicity, higher doses of Ambisome can be given safely, and it also persists for a long time in the tissues, raising the possibility of delivering highly effective induction therapy with very few (1, 2, or 3) doses. A large reduction in the number of doses and duration of hospitalisation, together with reduced pricing of Ambisome, may result in cryptococcal meningitis treatment costs that are not more than those with 2 weeks of conventional amphotericin B, and provide a convenient, safe and efficacious alternative to conventional amphotericin B therapy. This study aims to define the most effective and most cost-effective schedules for Ambisome use in the treatment of cryptococcal meningitis. A currently ongoing study is testing the safety and effect on rate of clearance of cryptococcal infection of one, two or three dose Ambisome treatment regimens compared to the standard 14-day course. The shortest of these Ambisome regimens that is found to be safe and effective will be utilized in this proposed large clinical trial to determine whether or not it is as effective as the standard 14-day amphotericin B deoxycholate treatment in terms of preventing deaths from cryptococcal meningitis. If short-course Ambisome treatment regimens were shown to be of comparable effectiveness in the treatment of HIV-associated cryptococcal meningitis, the results of this study would lead to changes in international treatment guidelines, and provide an effective and practical treatment option for HIV-associated cryptococcal meningitis with the potential to prevent many thousands of deaths.

2.1 Unmet Clinical Need Bronchiectasis (BE) is a progressive respiratory (lung) disease characterised by cough, mucus and severe, recurrent bacterial chest infections with high rates of ill health, time off work and marked reductions in health-related quality-of-life. In almost half of cases, the cause of bronchiectasis is unknown (idiopathic) and treatment in these patients remains "best guess" or symptom driven. Bronchiectasis presents a huge challenge to patients and doctors because no effective treatment is available. Both the world's first national guidelines (authored by coapplicants of this proposal) and Cochrane "best evidence" review of Bronchiectasis confirms this situation, reporting that small single-centre studies with ill-defined patient groups have hampered the few attempts to study clinical interventions /drug trials, rendering them of unproven use. Previously the MRC sponsored UK trials in Bronchiectasis in the 1950s: Since then major developments have been sorely lacking. This partly reflects a feeling that BE is rare. However recent evidence is against this: In the UK and the US healthcare demands due to BE and mortality rates are increasing with 70,000+ hospital admissions in the UK 2011. Based on projections from US health insurance claims there are 100,000 US patients. We have limited UK data on how common this bronchiectasis is: Experts have however estimated 30-60,000 patients are affected in the UK but recent research suggests over 100,000 are affected. Whilst the small case series reported so far demonstrate that "unknown cause" (idiopathic) and post-infectious bronchiectasis are the leading causes, bronchiectasis can also complicate common lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) or immune problems e.g. Rheumatoid arthritis. Cystic Fibrosis is an inherited (genetic) form of bronchiectasis which like COPD associated bronchiectasis has different outcomes, microbiology and management needs from Bronchiectasis. Cystic fibrosis is rare (10,000 cases in the UK) yet has made significant gains through multicentre working and coordinating research. To date no large studies of the genetic causes of idiopathic bronchiectasis have been conducted as this requires large numbers of patients beyond that a single centre can provide. There is currently no registry of well characterised patients with Bronchiectasis anywhere outside the US. The US national registry was commenced recently and has 1200 patients that differ to UK patients. There is an urgent need to build a large cohort of UK patients with Bronchiectasis in which large enough studies can be undertaken; adding in a biobank is a key additional strength. Brief description of the Cohort and Partnership The cohort will comprise 3500 symptomatic adult patients with a High Resolution CT scans demonstrating bronchiectasis. Patients will be characterised on the basis of clinical history, clinical examination and detailed investigations that are already part of routine clinical care with yearly reviews. A DNA biobank (from a blood sample) will be collected and will form a world's first in bronchiectasis providing a unique resource allowing future genetic studies to identify underlying genetic causes & new targets for treatment. The partnership links 9 recruiting centres with established clinics & track records in Bronchiectasis research spread across the UK that have never had funding to work together. Additionally ground-breaking scientific partners with expertise in relevant areas will for the first time allow comprehensive mapping of the knowledge gaps. Future research will be able to use the strength of the assembled cohort; we can deliver a programme of clinical trials that address fundamental issues. We will therefore tackle three major unmet needs 1) Lack of expertise in the area, 2) Lack of a clinical evidence base 3) Basic science- attracting skilled scientists to work in the area.

The Liverpool University Drug Interactions group has over twenty years' experience in developing prescribing support resources in infectious diseases, demonstrated by our world-renowned HIV and Hepatitis drug interaction websites (www.hiv-druginteractions.org and www.hep-druginteractions.org) and associated Apps. In 2019, these websites had over 50,000 unique monthly visitors searching for >4.5 million interactions. Our websites are recommended in over 30 international treatment guidelines and many national guidelines. In response to the COVID-19 pandemic and to address the pressing need for prescribing support for studies and clinical situations where experimental COVID-19 therapies are being used, we have developed a static drug interactions website (www.covid19-druginteractions.org) providing information on the likelihood of interactions between the experimental agents and commonly prescribed co-medications. We now have to move to develop a fully interactive and searchable website resource with an associated App. The website will be constantly updated and populated with the latest information on experimental therapies with guidance given to clinicians for managing complex patients.

Stratified Medicine is a type of personalised medicine where treatments are directed specifically at people who are most likely to respond to them, often using detailed information about individuals. We believe that the treatment of patients with hepatitis C virus (HCV) would benefit enormously from this approach. About 300,000 people in the UK are infected with HCV, only half of whom have been diagnosed as carrying the virus. The virus has a high tendency to persist as the body's immune system is usually unable to clear infection. HCV infects the liver, causing liver cirrhosis (scarring), liver failure and liver cancer. HCV exists in different genetic forms called genotypes. In the UK, most infections are caused by either genotype 1 or 3, which occur at about equal frequency. Treatment for HCV has consisted of two drugs interferon and ribavirin. Approximately half of patients receiving treatment respond and are successfully cured of infection. Until recently, no additional drugs were available to treat those who failed treatment. The number of people who develop severe liver disease from HCV is expected to continue to rise over the next two decades. Those who develop liver failure can be given a transplant but the transplanted organ is rapidly infected with the virus and often becomes diseased within a few years. New drugs, which directly act against the virus (called DAAs), are being used in combination with interferon and ribavirin in NHS patients for the first time in the clinic in 2012. DAA drugs increase the cure rate to 70%. However, there are drawbacks: the drugs are very expensive costing in excess of £20,000 per patient; the virus can become resistant to new drugs, rendering them useless and increasing the frequency of resistant strains in the community; the first wave of new drugs are effective against genotype 1 but not genotype 3 strains; additional side effects can be associated with the new drugs, so that treatment may be stopped before the virus is eliminated. We have developed a team of experts in the clinical care of HCV patients, who will work with HCV scientists, in partnership with industry. Combining expertise in this way should serve to benefit patients. The group is already working well together collecting blood samples and information from 10,000 people across the UK into a single bio-bank, supported by government infrastructure. We aim to assess the genetic make up of both the virus and the infected person. We will also look at the way in which the immune system responds to the virus, and measure protein markers in the blood. We will assess these in patients receiving therapy and also in those with serious liver disease to try to work out in advance who will develop further complications of their disease. A unique feature of our group will be the ability to draw all these strands together. We will develop new technologies so that we rapidly obtain the host and viral sequence in thousands of infected people. In this way we hope to improve treatment options for patients so that the right therapies are given to patients who are most likely to benefit from them. We will focus our efforts especially on HCV genotype 3, which is a particular problem in UK patients, and also on patients with more serious liver disease, who are more difficult to treat with the new therapies. Ultimately we hope to predict the likelihood of treatment response in individuals, and possibly through our investigations develop new therapies. This could bring considerable cost-savings to the NHS and means that drugs are given to HCV-infected people who are most likely to respond to them.

Fungal infections are a growing problem, now killing more people than tuberculosis or malaria globally. Unfortunately fungi are also becoming resistant to the main anti fungal drugs we use to treat them. We have show that this is due to mass use of antifungals in agriculture. These are needed because fungi are the main pathogens that destroy crops. Furthermore global warming is increasing the threat of fungi across plant, animal and human health. To combat this, new types of antifungal therapies are coming into medical use, however we are already seeing equivalent antifungals being used in agriculture, known as "dual-use". We urgently need a holistic framework to ensure that we don't lose the efficacy of anti fungal drugs, both as medicines and as fungicides, whilst ensuring that we can continue to ensure that our food supplies are protected. In order to address the issue of antifungal resistance we have developed a Fungal One Health and Antimicrobial Resistance Network. One health refers to approaches that seek to balance and optimise the health of people, animals and ecosystems. The key challenges we face our to be able to understand the specific reasons why emergence of anti fungal resistance occurs within a one health context, to develop early warning systems that allow us to know when resistance in occurring or spreading, to identify the key hot-spots in the environment where anti fungal resistance is occurring, and have better understanding of where antifungals are being used most across one health. This will allow us to identify appropriate countermeasures that allow us to deliver judicious stewardship of antifungals so they can be used appropriately to enable food security and animal and human health, whilst ensuring that the risk of anti fungal resistance is minimised. In order to address these challenges and deliver appropriate countermeasures we have brought together a diverse range of scientists from across the relevant disciplines, as well as key stakeholders from relevant government departments, healthcare, agrochemical and pharmaceutical industries and end users such as farmers and patients. They will contribute to 4 working groups that focus on 1: the underlying causes of dual use anti fungal resistance, 2: surveillance of anti fungal resistance, 3: understanding the role of agricultural waste streams and water as hotspots for antifungal resistance, and 4: developing countermeasures such as anti fungal stewardship and other interventions to mitigate the risk of antifungal resistance. Our key aims will be to advance our knowledge of the underlying drivers of dual use antifungal resistance, how this occurs within the ecosystem, to develop surveillance systems and antifungal stewardship toolkits. We will develop policy documents and white papers, undertake outreach with end users, the public, governmental bodies and NGOs. The Network will train the next generation of multidisciplinary researchers in this area and develop pragmatic research proposals to enable us to fight the spread of anti-fungal resistance.