Programme 3: Strategic studies and clinical trials based on interventions and without direct commercial interest
Chair: Daniel Podzamczer
Co-Chair: Antonio Rivero
The main objective of the programme Strategic studies and clinical trials (based on interventions and without direct commercial interest) will be to perform investigator-driven interventional studies and clinical trials addressing strategic issues relating to hot aspects of clinical management of HIV-infected patients such as antiretroviral therapy, co-morbidities, viral hepatitis co-infection and eradication/cure for hepatitis C. This ambitious programme will be conducted by clinical investigators with a great expertise in these fields and several of them internationally recognized.
Specifically, the objectives of the Programme divided in 4 work packages (WP) are:
- WP1. Interventional and strategic studies addressed to optimize the utilization of ART, including pharmacokinetics, pharmacogenomics, pharmacoeconomy, resistance, tropism and anatomic reservoirs. The aim of this WP is to optimize the utilization of antiretroviral regimens assessing different strategies in naïve and experienced scenarios, with the best cost-efficiency relationship.
- WP2. Interventional and strategic studies addressed to minimize the impact of toxicity of ART, immune reconstitution inflammatory syndrome (IRIS), and aids and non-aids events (cardiovascular diseases, neurocognitive disorders, cancers, etc). This WP broadly aims to design and to develop studies addressed to improve the tolerability of antiretroviral therapy and to reduce the impact of non-aids events related to HIV infection.
- WP3. Interventional studies of safety and proof of concept of drugs for intensification, eradication and immunogens for potential preventive or therapeutic vaccine candidates. To assess different eradication/cure strategies including mobilization of HIV reservoirs, testing vaccine candidates in humans that have been developed (including animal toxicology and efficacy) in the immuno-pathogenesis programme (P4) or by external institutions or companies, and evaluation of immumodulatory effects of different strategies such as modification of bacterial translocation.
- WP4. Intervention studies to optimize the treatment of hepatitis C and B, including the efficacy of different therapeutic regimens, pharmacokinetic, pharmacoeconomic studies and resistance to antiretroviral drugs. In addition, studies that analyze the evolution of hepatitis C and B in patients coinfected with HIV or the results after liver transplantation, among others. On the other hand, WP4 from 2018 will include intervention studies on diagnosis, prevention and treatment of sexually transmitted infections. With this we intend to improve the prevention and management of this growing epidemic of sexually transmitted infections in individuals infected with HIV.
The studies that are included in Programme 3 are characterized by:
- they are needed for an optimal utilization of therapy against HIV, HCV, HCB or for the initial development of candidates for HIV eradication or for HIV vaccines;
- it is usual that this type of studies are not promoted by pharmaceutical companies although they can be co-financed by them.
- may generate changes in the approved indications or at least in the guidelines;
- may support patents of the new vaccine candidates developed in the P5 programme;
- these studies benefit from a network structure for their expertise in the design and rapid development and recruitment, and
- they are focused on issues like simplification of ART including dual therapies, intensification studies, clinical testing of our own vaccine candidates like MVA-B or dendritic cells and hepatitis C in HIV co-infected patients in which the Spanish investigators have previously done widely internationally recognized contributions.
The ultimate objective of this programme is to achieve the best tools for the management of HIV infection as a chronic infection including a potential cure and thus with aim of benefiting HIV infected individuals and public health.
Work Package 1 (WP1): Interventional and strategic studies addressed to optimize the utilization of antiretroviral treatment (ART), including pharmacokinetics, pharmacogenomics, pharmacoeconomy, resistance and tropism
Leaders: José María Miró and Esteve Ribera.
The aim of this WP is to optimize the utilization of antiretroviral regimens assessing different strategies in naïve and experienced scenarios, with the best cost-efficiency relationship.
Specifically, studies are being focused on:
- Hyperacute infection for HIV (<30 days after exposition)
- Advanced ARV naive patients
- Different strategies in simplification strategies (several dual therapies)
- Rescue therapy with an alternative dual regimen
- Pharmacokinetic studies
- Assessment of drug concentrations and antiviral activity in reservoirs such as CSF or genital fluids
- Pharmacoeconomics of three ARV regimens
Description of work
The WP1 currently include 14 clinical trials or interventional studies addressed to optimize the utilization of new ART regimens (including integrase inhibitors) in naïve and experienced patients with innovative studies on immune reconstitution, cardiovascular risk, pharmacokinetics, pharmacoeconomy, impact on viral reservoirs including CSF, resistance and tropism. The background is the important contributions of the research groups in the optimization of the ART.
The opportunity and the hypothesis is that several aspects remain to be improved mostly in advanced patients and in the simplification studies and in improving the efficiency. Several of these projects are continuation of projects already started in the late phase of the former RIS and some are new projects. There is one trial in very advanced naïve patients, comparing the immune-reconstitution induced by a darunavir-boosed ART regimen vs. dolutegravir-based ART regimen with interesting microbioma and bacterial translocation sub-studies. There are five simplification trials, one very interesting pilot study evaluating the efficacy and safety of Atripla® given three-times per week vs. daily in suppressed patients. Three trials exploring dual therapies such as dolutegravir plus lamivudine, raltegravir plus lamivudine or darunavir boosted plus lamivudine in comparison with the classical triple ART therapy. Another switching trial evaluates the benefits of replacing PI-regimens with a dolutegravir-based regimen in terms of maintaining viral suppression plus an improvement in lipid profile and cardiovascular risk. On rescue therapy, there is one trial evaluating the combination of boosted-dolutegravir plus maraviroc in failing patients with R5 virus. On viral reservoir there are two studies evaluating the impact of ART in hyper-acute HIV infection (Fiebig I-II stages) in one and the second is evaluating the role of dolutegravir-based ART in viral reservoir in patients previously treated with boosted-protease inhibitors. On pharmacokinetics there are three important studies, one developing a very original methodology of estimating plasma levels of drugs measuring the concentration in the hair, the second addressing the CSF levels and CSF viral replication in patients with dual therapy with atazanavir-boosted ritonavir plus lamivudine, and the third looking for the concentration of TAF in seminal cells and seminal plasma, that would have important implications for PrEP. There is one study about pharmacoeconomics of three common ART regimens. Overall, the results of these studies will have an important impact in future strategies and guidelines for ART.
Work Package 2 (WP2):Interventional and strategic Studies addressed to minimize the impact of toxicity of ART, IRIS, and aids and non-aids events
Leaders: Esteban Martínez and Mar Masià
This WP broadly aims to design and to develop studies addressed to reduce the risk or the impact of complications associated with HIV.
- Use of non-antiretroviral drugs to prevent or to manage comorbidities.
- Use of tools (diagnostic procedures and/or scores) to predict the risk of comorbidities and to guide interventions on prevention or therapy.
- Assessment of subclinical disease and subsequent development of inteventional studies to change the natural history of comorbidities.
- Studies on primary and secondary prophylaxis of comorbidities.
- Studies addressed to decrease the risk of IRIS
Description of work
The WP2 currently includes 10 studies addressed to reduce the risk or the impact of complications associated with HIV.
One study evaluates changes in CPE score in patients treated with regimens with different penetration into CNS. This is a controversial topic which will be appropriately addressed in this clinical trial. Four studies evaluate different aspects of cardiovascular risk, markers of inflammation, and subclinical atherosclerosis. One includes patients with high cardiovascular risk in whom an intensive intervention including tobacco quit, lipid-lowering drugs and diet is compared with a standard strategy. Another study prospectively evaluates different inflammatory markers and lipid fractions in different groups of ARV-naïve patients. The third one assesses the role of inflammatory markers and their association with subclinical atherosclerosis determined by carotid intima-media thickness (cIMT). Another study assesses the influence of vitamin D supplementation in atherosclerosis progression through longitudinal measurement of the cIMT and surrogate biomarkers of atherosclerosis and immune status in virologically-suppressed HIV-infected patients with vitamin D insufficiency. HPV infection and the risk of anal cancer is being evaluated in two studies. In one of them, the natural history of this infection is being addressed, as recent studies have suggested that spontaneous regression of anal HSIL may occur in a number of cases, which might avoid aggressive interventions. In the other study, a new marker mRNA-E6/E7 is assessed as a tool in the screening of this complication observed in HIV-infected MSM. The use of the new integrase inhibitor-based regimen elvitegravir in post-exposure prophylaxis is the subject of one study. As HIV infection is now a chronic disease with a long survival, several co-morbidities seem to be increased in HIV-infected patients related to immunoactivation and chronic inflammation. Malignant neoplasms are one of these co-morbidities. A randomized, open-label multicenter study not yet initiated will address the impact of an expanded screening programme in the detection of non-AIDS neoplasms in adult patients with HIV infection vs the standard screening recommended by the guidelines.
Work Package 3 (WP3): Interventional studies of safety and proof of concept of drugs for intensification, eradication and immunogens for potential therapeutic or preventive vaccine candidates
Leader: Felipe García
To assess different eradication/cure strategies including mobilization of HIV reservoirs, testing vaccine candidates in humans that have been developed (including animal toxicology and efficacy) in the immuno-pathogenesis programme (P4) or by external institutions or companies, and evaluation of immumodulatory effects of different strategies such as modification of bacterial translocation.
The WP3 (Interventional studies of tolerance and proof of concept of drugs for intensification and eradication and immunogens as vaccine candidates in healthy volunteers or HIV infected patients) contains 13 research projects focusing: on intensification, different modalities and approaches potentially leading to HIV eradication and on safety and immunogenicity of potential therapeutic and preventive vaccine candidates, developed in the P5 research programme. Intensification and eliminating the potential residual replication is a necessary condition to pursue the hope of eradication. Mobilizing the reservoirs with or without CTL stimulation with a therapeutic vaccine is the way to proceed forwards, in the field of HIV eradication. Finally, the RIS has obtained the best results ever in humans with a therapeutic vaccine (based on monocyte derived dendritic cells primed ex-vivo with heat inactivated autologous virus) and also has his own viral vector (MVA-B) produced in GMP conditions and proved to be safe and immunogenic, in healthy volunteers. Consequently, we are in a good starting position to have an important impact in these two fields (eradication and vaccine development).
Finally, as HPV infection has evolved a cause of a growing number of anal cancer in MSM co-infected with HIV, two studies are evaluating different aspects related to this infection: a vaccine and the study of microbiota as its role in the screening of anal cancer.
Description of work
The ongoing or future studies to be conducted in this area are:
- Eradication. 1) Immunotherapy against HIV with a therapeutic vaccine plus interferon to modify the viral reservoir and eventually achieve the remission without antiretroviral therapy. 2) Antiretroviral activity and impact of dasatinib on viral reservoir in patients with chronic HIV-1 infection. 3) An open phase I study to evaluate the safety and effectiveness of vaccines HIVconsv administered in combination with romidepsin in viral control after discontinuation of antiretroviral therapy in early treated HIV-positive patients. 4) Impact of dasatinib added to antiretroviral therapy on viral reservoir in patients with acute/recent HIV-1 infection. 5) Phase IIa, double-blinded placebo-controlled randomized study to evaluate safety and effectiveness of the combination of a therapeutic vaccine (MVA-B) plus 3BNC117 bNAb with Romidepsin in chronic HIV-infected patients under stable combined antiretrovial therapy.
- Vaccine candidates. 1) Safety and immunogenicity of therapeutic vaccine candidates ChAdV63.HIVconsv and MVA.HIVconsv Chad63.HIV in individuals with recent HIV-1 infection and viral suppression after early antiretroviral therapy. 2) iHIVaRNA. A Phase I Open Label Dose Escalation Study to Evaluate Safety of iHIVARNA-01 in Chronically HIV-infected Patients Under Stable Combined Antiretroviral Therapy. 3) iHIVARNA Phase IIa therapeutic TriMix / mRNA based Vaccine in Chronic HIV-1 Infected Patients Receiving Antiretroviral Therapy. This is a randomized, parallel, double-blinded, controlled clinical phase IIa study of 70 antiretroviral treated chronic HIV-1 infected volunteers.
- Immune modulation. 1) Immunomodulatory effects of nutritional intervention on immune recovery of patients with late HIV infection. 2) A Phase I/II randomized, double-blind, placebo controlled study of REpeated low-dose Fecal microbiota REStoration in HIV infection (REFRESH Study). The aim of this study is to evaluate the safety and tolerance of low and repeated doses of fecal microbiota and to evaluate its influence on inflammation markers and CD4 cells activation. 3) Study of changes in bacterial translocation and immune activation in patients infected with HIV after change to a supplemented mediterranean diet: Prospective randomized study of two arms.
Work Package 4 (WP4): Interventional Studies to optimize treatment of hepatitis C and B, including pharmacokinetics,pharmacoeconomics and resistance. Diagnosis, prevention and management of sexually transmitted infections and other pathogens
Leaders: Juan Pineda and Joaquín Portilla
Address relevant issues related to the treatment and evolution of hepatitis C and B in patients coinfected with HIV, such as regimens with direct antiviral agents (DAA) or results after liver transplantation, among others. Improve the prevention and management of STIs, a growing epidemic in patients infected with HIV and other population groups.
- To evaluate the efficacy and safety of AAD regimens in HIV / HCV co-infection in real life, with a specific focus on:
- Shorter durations of the DAA treatment.
- Comparisons of DAA regimens to rescue failures to IFN-free DAA combinations.
- The selection of therapy based on the presence of basal or selected virological failure mutations.
- To evaluate the clinical outcome and changes in liver function in individuals with cirrhosis after a sustained viral response (SVR) with AAD.
- Analyze the effect of chemotherapy and other treatments on the outcome of hepatocellular carcinoma in HIV infection.
- Evaluate the prognosis of patients infected with HIV after liver transplantation (HT).
- To analyze the efficacy of DAA in acute HCV infection and the risk factors for HCV reinfection after SVR.
- Evaluate the course of HIV / HBV coinfection under treatment by applying HBsAg levels to monitor and predict seroconversion.
- To evaluate the short-term changes in hepatic steatosis (HE) after changing the EFV plus two nucleosides to RAL plus the same pair of nucleosides.
- To assess the influence of long-term ART in HD and associated metabolic disorders in HIV infection.
- Address the diagnosis, prevention and treatment of STIs, mainly in high-risk groups such as MSM.
Description of work
WP is aimed at addressing unresolved problems in the treatment of relevant liver diseases in HIV-infected patients in Spain. In the rapidly changing scenario of HCV treatment, it is unrealistic to design independent clinical trials because the use of DAA in real life is ahead of trial results. Prospective cohorts of patients coinfected with HIV / HCV in treatment with IFN free of DAA will give timely answers to questions not addressed by the trials. In this regard, several cohort studies are ongoing within the previous RIS. One study aims to evaluate the efficacy and safety of AAD regimens among patients coinfected with HIV / HCV in real-life conditions. This multicenter cohort has included more than 1000 patients coinfected with DAA regimens without INF. Within this cohort, the relapse rates of short-term AAD regimens, such as SOF / LDV for 8 weeks, will be assessed in two studies and aims to examine comparisons between AAD regimens to rescue virological failures to free AAD combinations of IFN.
This is a growing problem with scarce information in HIV / HCV coinfection. There are conflicting results about the effect of basal variants associated with HCV resistance (VRA) in SVR to DAA. To clarify this problem, the utility of the baseline or post-virological RAV to select the therapy will be evaluated in another study. Finally, the specific population of patients with cirrhosis is analyzed to estimate the incidence of decompensation and to measure changes in the parameters of liver function during and after treatment with AAD.
Hepatocellular carcinoma is increasingly being detected among HIV-infected patients, including HCV carriers after SVR. However, there are few data on the treatment of them. A study is investigating the effect of current treatment modalities on the evolution of HC in HIV infection.
Liver transplantation (HT) is the only option for patients with end-stage liver disease (ESLD) and a poor expectation of survival. Changes in the TH policy among HIV-infected patients in Spain have been driven by data generated by an ongoing cohort study of the previous RIS and that currently analyzes the long-term prognosis of HT in HCV / HIV and HBV / HIV patients, the efficacy and safety of direct-acting antivirals against HCV to treat HCV recurrence in post-HT and the risk of developing neoplasms (de novo cancer) in the long term (10 years).
Acute HCV infection (CHC) is being detected in outbreaks among men who have sex with men (MSM). The AHC treatment approach is unclear. The main problem is the risk of reinfection after SVR that will be evaluated in a study.
The course of co-infection with HBV in treatment (HEP-RIS18) will be studied. New tools to monitor and predict anti-HBs seroconversion will be applied to an open prospective cohort of patients co-infected with HIV / HBV who receive anti-HBV drugs, particularly HBsAg levels compared to HBV DNA.
Fatty liver disease (FLD) often affects patients infected with HIV. Progression to steatohepatitis is a potential cause of end-stage liver disease. A randomized clinical trial, initiated within the previous RIS, assesses short-term changes in steatosis after changing ART. Based on the preliminary data from this study, the effect of different ART regimens on the long-term evolution of steatosis and associated metabolic disorders will be evaluated.
The STD study has recently been added to this WP. New ideas and projects will surely be presented in the coming months.