Programme 2: Cohort-Based clinical research
Chair: Santiago Moreno
Co-Chair: Juan González
Despite the enormous progress made on clinical research in recent years, there are multiple areas in which further investigation is needed. Clinical aspects of HIV-infection are continuously evolving as a consequence of the changing epidemiology, the innovation in therapy, and the emergence of new clinical conditions, which are becoming frequent in patients despite successful antiretroviral treatment.
The aims of this program are to describe the contemporary, evolving clinical picture of the HIV epidemic in Spain, to study disease progression and mortality and its major determinants (including host and viral factors), timing of and response to ART, and associated co-morbidities and coinfections. As the focus for the Program and as a continuation of previous activities developed within the RIS, we have prioritized areas with the greatest clinical implication, which are briefly summarized in the following paragraphs.
HIV-infection in children and vertically infected adults
In Spain, perinatally acquired HIV-1 infection has become a chronic disease of childhood. Our HIV-infected adolescent population comprises a mixed group, but fundamentally of perinatally infected adolescents who are now surviving into adulthood. The transfer of these patients to the Adult Clinical Unit is usually difficult. HIV perinatally infected adolescents have differential social, psychological, clinical, immunological, neurological and virological characteristics from patients infected through other routes. At present, it is not known how ART will affect the health and the survival of these children, as well as the success of transferring pediatric patients to adult units.
HIV drug resistance and molecular epidemiology
HIV drug resistance due to transmitted mutations are associated with a higher risk of virological failure to first line ART. In Spain, thanks to RIS, we have data of primary resistance in patients newly diagnosed with HIV that allow to guide treatment. Sequence data from routine resistance testing offer unique opportunities to characterize TDR and, also, distribution of non-B subtypes. Surveillance and vigilance of TDR in Spain, and the description of the molecular epidemiology of HIV in Spain are of utmost importance to contribute to preventive and public health measures aiming to limit spread and transmission of HIV.
Diagnostic delay, disease progression, response to ART and mortality
ART has transformed HIV disease from a fatal disease to a chronic condition. The gap in life expectancy among treated HIV-positive individuals and the general population is closing. Recently diagnosed asymptomatic HIV-infected patients approach the life expectancy of non-infected individuals and patients with persistently high CD4 cells counts on long-term ART reach same mortality rates as the general population. As deaths are fortunately rare events, it is essential to study its incidence and distribution in multicentre cohort collaborations with unified data collection procedures.
Aging and co-morbidities
The advent of ART has dramatically shifted patterns of morbidity and mortality in HIV-infected persons from AIDS defining diseases to the so-called non-AIDS-defining events (NADEs). Intriguingly, many of the medical co-morbidities seen now in HIV-infected patients are remarkably similar to those seen in individuals of older age. Although some information has been generated, data on the epidemiology of NADEs are still scarce and little is known about its pathogenesis.
Coinfections with Hepatitis C virus (HCV), Hepatitis B virus (HBV), Human papillomavirus (HPV) and other Sexually Transmitted Infections (STI)
In Spain, before the era of direct antiviral therapy against HCV, coinfected patients benefited less from ART than HIV monoinfected patients. However, the eradication of HCV infection is associated with a significant decrease in the overall morbidity and mortality of coinfected patients. Nowadays, with the new direct acting antivirals (DAA), it is possible to eradicate HCV in all patients. In Spain, still 20-25% of HIV-infected patients have active HCV infection representing the main risk factor for morbidity. The rapidly changing scenario of HIV and HCV and its treatment requires continuous monitoring of trends. Similarly, HIV/HBV infected patients may have an increased risk of liver related mortality compared with patients with HBV infection alone. There remains controversy about whether chronic HBV infection affects the natural history of HIV infection. HR-HPV is the etiologic agent of anal carcinoma (AC) and HPV-HIV coinfection is very frequent in MSM. In Spain, as in most parts of the world, no guidelines exist regarding screening, follow up and treatment of HPV-associated anal SIL in HIV positive MSM. Interesting initiatives for better diagnosis and treatment of anal HPV infection and AIN are emerging from collaborative studies in our research network.
Work Package 1 (WP1): HIV-infection in children and vertically infected adults (CoRISpe and FARO Project).
Leaders: Marisa Navarro and Maria Isabel González
In Spain, HIV infection in children has become a chronic infection thanks to antiretroviral treatment and there are few new diagnoses in HIV children. The pediatric population followed in our country is reaching adolescence and transferring to adult units for follow-up. The new diagnoses are due to children born outside our countries and to adolescents who acquire HIV through a behavioral mechanism.
To Know the epidemiology of pediatric HIV in Spain and the changes that may appear is a priority to improve prevention measures. Deepening the knowledge of all clinical, immunological and virological aspects of the HIV adolescents and young adults patients who acquired HIV at the pediatric age is a great interest to establish strategies for improvement in all aspects related to the health of this population. In this way, there is a network platform linked to the RIS that allows to investigate the pediatric HIV population, this is CoRISpe. CoRISpe group the centers with patients under follow-up in pediatric units and who have patients registered in the national follow-up cohort of HIV children and adolescents. The pediatric HIV patients , after transition to adult units, continue to be followed prospectively by the CoRISpe structure, in the transition CoRISpe cohort “The FARO project”. CoRIspe are linked to the RIS Biobank.
The objetives of this WP are:
- To evaluate the clinical features, the immunovirological status and the associated comorbidities, as well as ART strategies in CoRISpe patients (newly infected children, adolescents and young adults).
- To determine the HIV reservoir, the inflammatory and immunosenescence situation, and the immune function of pediatric patients.
- To assess the current situation and the evolution of all HCV-HIV coinfected pediatric patients.
- To evaluate vertically infected adolescents and young adults that have been transferred into adult clinics. To evaluate stigma, quality of live, drug abuse and sexual health in these patients, comparing with other populations.
- To evaluate the evolution of the neurocognitive profile and neuroimaging findings of HIV vertically infected patients and the sleep quality in this population.
- To analyze the clinical situation and the development of comorbidities of perinatally HIV exposed-uninfected children and the characteristics of newly diagnosed pediatric patients.
- To describe and to compare the characteristics of different populations, mainly, localized in developing countries, as well as, to share and join data with different countries.
Work Package 2 (WP2): HIV Drug Resistance & Molecular Epidemiology
Leaders: Federico García and Eva Poveda
The main objective of WP2 is the surveillance of the prevalence of HIV variants harboring drug resistance mutations to the current drugs used for the treatment of HIV-infected patients in Spain. Since the presence of drug resistance mutations have a negative impact on the response to antiretroviral therapy the information generated in this WP is essential to know which is the situation in our country, and to establish the adequate recommendations for drug resistance testing in patients with HIV infection before treatment initiation. Moreover, this WP describes the molecular epidemiology of HIV infection in Spain, investigating which are the characteristics of HIV variants circulating in Spain. Finally, the WP aims to use phylogenetic tools (i.e. phylogeographic, phylodynamic) to investigate transmission nodes and patterns in Spain, using this information to promote the use of public health measures to optimize strategies for prevention and diagnosis to limit HIV transmission.
Research in this WP is on the following directions:
- Surveillance of drug resistance mutations in Spain, including all drugs currently used for the treatment of HIV infection.
- Contribute to the Spanish HIV Treatment Guidelines for drug resistance testing recommendations before treatment initiation.
- Update annually the National Guidelines for the interpretation of HIV Drug Resistance.
- Describe the molecular epidemiology of HIV in Spain, by means of phylogeographic and phylodynamic studies, to contribute to preventive and public health measures aiming to limit spread and transmission of HIV.
- Establish collaboration with other Programs and WP of RIS:
- Programme 1-WP2. Continuum of Care and New Infections Estimates, by providing estimates of genetic variability on pol gene of newly infected patients.
- Programme 1-WP3. Cohort of people starting PreP, by monitoring resistance in this special population.
- Programme 4 - Immunopathogenesis of HIV infection, to provide data on HIV genetic evolution on the viral latent reservoir.
- Contribute with the data of our country in the European and WHO drug resistance and molecular epidemiology surveillance programs.
You can download: Antiretroviral resistance guidelines. Update 2019
Work Package 4 (WP4): “Aging and Non-AIDS Defining Events”
Leaders: Felix Gutierrez and Paco Vidal
The widespread use of cART has dramatically shifted patterns of morbidity and mortality in HIV-infected persons from AIDS-defining diseases to the so-called non-AIDS-defining events (NADEs) whose aetiology is probably multifactorial as they have been related to ART-toxicity, older age, low CD4 cell counts, immune activation in spite of effective cART, and lifestyle issues. Intriguingly, many of the medical co-morbidities seen now in HIV-infected patients are remarkably similar to those seen in individuals of older age. Moreover, patients with HIV present marked similarities to those accumulated with age in the uninfected elderly.
Overall, the purpose of this work package is to investigate the epidemiologic and clinical profile of non-AIDS defining events (NADEs) and comorbidities, and aging in the Spanish HIV-infected population; to investigate the pathophysiological mechanisms involved, and to search for potential biomarkers of clinical utility. This will be done in the framework of CoRIS and interacting with other programs and work packages of the Spanish AIDS research Network.
The objectives of this WP are as follows:
- To investigate the incidence, risk factors and outcomes associated with the occurrence of NADEs in newly diagnosed HIV-infected patients.
- To determine the relationship of NADEs with older age, uncontrolled replication of HIV and co-pathogens (eg. HCV, CMV), immune dysfunction, immune activation and inflammation, and antiretroviral therapy.
- To evaluate the usefulness of biomarkers of inflammation, metabolomics, immune dysfunction, oxidative stress, coagulation, immunosenescence, and tissular fibrosis, as predictors of advanced age and NADEs.