Continued follow-up of the United Kingdom Collaborative HIV Cohort (UK CHIC) and the UK HIV Drug Resistance Database (UK HDRD), 2014-2019

The number of people living with the human immunodeficiency virus (HIV) in the UK continues to increase. Current treatment for HIV is very effective and, as a result, the life expectancy of a person living with HIV has increased substantially over the past 15 years. However, HIV remains extremely costly to the National Health Service and there are still many challenges that must be faced to ensure that people with HIV continue to live full and healthy lives. In particular, some people continue to experience side effects on treatment - these may be life-threatening, may lead to a reduction in quality-of-life, and may limit the drugs that patients can receive in the future. If patients are unable to take their treatment for periods of time, then virus may grow that is resistant to some of the currently available drugs. An increasing number of HIV-positive people are living to older age, which may also lead to an increase in the side effects that are seen as well as an increase in general age-related illness. In addition, many HIV-positive children are also surviving into adulthood - as yet, we have little information on the outcomes of this group as they switch their care to adult HIV clinics. A proportion of people with HIV in the UK are also infected with hepatitis C virus (HCV) which has implications for the timing and choice of treatments that can be used. Whilst HCV has traditionally been hard to treat in those who also have HIV, some of the newly available HCV drugs offer greater promise of a cure for HCV. However, a large-scale assessment of the use of these drugs in people also infected with HIV remains to be undertaken. There are therefore many questions that must be addressed to ensure that the outcomes of those living with HIV are optimised. In particular, although it is often said that people with HIV can expect to live a 'near-normal' lifespan, whether this will ultimately be possible is far from clear. In order to plan the need for health care services and to understand the need for new drugs, it is essential that any changes in the characteristics of the UK epidemic are monitored.
Since 2001, the UK Collaborative HIV Cohort (CHIC) Study has followed people with HIV in the UK, to monitor their use of treatments against HIV and their outcomes. The UK HIV Drug Resistance Database (UK HDRD) collects information on the results of any tests that are performed to determine whether the virus that infects these individuals has become resistant to any of the currently used treatments. The latest dataset includes data on >45,000 patients attending 16 clinics and is one of the largest such collaborations worldwide. This application is for continued support of the combined UK CHIC Study and UK HDRD until 2019 for the following reasons:

1. To study the outcomes of people with HIV in the UK, including a description of the drugs that are used and any resistance that may develop;
2. To better understand of how HIV spreads between and within subgroups of the population;
3. To assess whether new and infrequently encountered strains of HIV are likely to respond less well to treatment;
4. To describe the use of new treatments for HCV in study participants, and to describe the success of these treatments, particularly in people who may get re-infected with HCV on multiple occasions;
5. To describe the outcomes of HIV-positive adolescents who switch their HIV care from paediatric to adult services and to model the likely problems that might result as the HIV population ages;
6. To explore the extent to which genetic factors might contribute to the outcomes of HIV and its treatment;
7. To investigate the potential effects of treatment, side effects and resistance on life expectancy in HIV-positive people.

A secondary aim is to continue to ensure that the UK plays a leading role in international HIV cohort research through the provision of high quality data to international studies.

Whilst current combination antiretroviral (cART) regimens for HIV are extremely effective, there are many questions that remain to be addressed to ensure the optimal outcomes of HIV-positive people. In order to plan the need for health care services and to understand the need for new drugs, it is essential that any changes in the characteristics of the UK epidemic are monitored. These changes may arise from the changing demographics of the HIV-positive population, an increase in viral diversity, the introduction of new drugs, generic forms of existing drugs and changing treatment paradigms (e.g. a move towards earlier initiation of cART), as well as increased use of cART drugs as part of pre- or post-exposure prophylaxis against HIV. Surveillance of clinical and resistance outcomes is therefore required to inform national treatment policies. The primary aim of this application is to continue to expand and maintain the combined UK CHIC and UK HDRD database in order to answer a wide-ranging spectrum of questions relating to the clinical outcomes of those with HIV in the UK. The secondary aim is to continue to ensure that the UK plays a leading role in international HIV cohort research through the provision of high quality data and scientific input to major collaborative studies. The proposed research will be conducted in an environment at University College London that provides expertise in surveillance and audit studies, surveys of sexual behaviour, randomised trials, qualitative methods, mathematical modelling, behavioural and basic science research. UCL provides access to information technology and bioinformatics capability through the Farr Institute, with UCL Platform Technologies providing biobanks and informatic support. This setting therefore provides an ideal environment in which to conduct large-scale HIV cohort studies, with opportunities to translate study findings into interventions for those living with HIV and for wider public health benefit.

The primary non-academic beneficiaries of our research are those living with HIV in the UK, their treating physicians, and the National Health Service (NHS). Our findings will, however, also have relevance for such individuals in countries other than the UK. Whilst our clinical findings have greatest relevance for those in other resource-rich settings, our research around resistance and transmission of HIV will be of relevance to resource-limited settings, particularly as antiretroviral therapy is rolled out more widely.

There are currently almost 100,000 people living with HIV in the UK. Despite the benefits of cART, it is estimated that the lifetime costs of HIV are £366,777. Thus, HIV continues to place a significant burden on the NHS. Even when treated, HIV is associated with a significant impact on quality of life (Duracinsky M, JAIDS, 2012). The Terence Higgins Trust/Age UK 50-Plus study (tht.org.uk) found that compared with their HIV-negative peers, HIV-positive people aged over 50 reported twice as many (non-HIV) long-term health conditions, had mobility problems and difficulties with everyday tasks, were less economically active, were less likely to have a financial cushion for old age and were more reliant on benefits. Any findings that result in further improvements in the way that people living with HIV are cared for, will likely result in substantial benefits to this population in the UK as well as their ability to remain in full-time employment, resulting in economic benefits for the country as a whole. The HIV patient community may additionally benefit through the increased capacity for work that may result.

The planning of health care services and antiretroviral drug prescribing must also be based on evidence. Changes to the UK HIV epidemic may arise from the changing demographics of the HIV-positive population (particularly the ageing population), an increase in viral diversity, the introduction of new drugs and changing treatment paradigms (e.g. earlier initiation of cART), as well as increased use of cART drugs as part of pre- (PrEP) or post-exposure prophylaxis against HIV. Whilst many of the recently licensed antiretroviral drugs are vulnerable to resistance, there is limited information on acquired and transmitted resistance to these drugs. Although the availability of generic drugs provides a significant potential for cost savings, concerns that the use of such drugs may be associated with lower rates of cART adherence (and therefore higher rates of treatment failure and resistance development) must be addressed. In particular, the use of more expensive novel agents in place of generics must be justified based on evidence. The impact of earlier initiation of cART and the roll-out of PrEP on the incidence of transmitted drug resistance and transmission of HIV is unknown. Finally, large-scale datasets are required to guide the diagnostic implementation and use of next generation sequencing methods in clinical practice. The information that is provided by this study will have a huge impact, therefore, on national treatment and care policies for those living with HIV with obvious financial benefits to the NHS. Our studies of associations with genotype may also identify new potential therapeutic targets, and the identification of genetic markers for stratification of patient management.
Our results also have implications for the wider population at risk of HIV infection. In particular, our research on HIV transmission dynamics and the extent of bridging between the MSM and heterosexual epidemics will provide important information for the development of interventions to prevent the transmission of HIV. Through the input to mathematical models, our results will be of use of public health professionals. These models have already been applied at an international level and have been used to inform global policy for ART programmes through work with WHO.