Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis.

Lead Research Organisation: Makerere University
Department Name: Infectious Diseases Institute

Abstract

Cryptococcal meningitis (CM) is a major causative agent of fungal meningitis worldwide. In sub-Saharan Africa, cryptococcal meningitis is the most common cause of meningitis in adults and causes 20-25% of AIDS-related mortality. The excessive early mortality from cryptococcosis is in large part due to the high cost, toxicity, and relatively limited repertoire of available anti-fungals, which have changed little in the last 30 years. For these reasons, the identification of new anti-fungals effective for the treatment of fungal meningitis must be a high priority. One problem with many current anti-fungal drugs is that they penetrate poorly into the brain. This is a particularly difficult problem in treating fungal meningitis, which is an infection around the brain.

New research suggests that sertraline, one of the most widely prescribed antidepressants in the world, has anti-fungal activity against Cryptococcus. The findings are the result of investigations testing sertraline against Cryptococcus neoformans in culture, in a mouse model of infection, and in studies of it's mechanism of action which appear to be inhibiting protein synthesis in the Cryptococcus yeast. Sertraline is known to be well-tolerated and is effective as an antidepressant. Preliminary investigations of sertraline in a mouse model of systemic cryptococcal infection revealed that it combats infection with efficacy similar to fluconazole, an oral anti-fungal drug used commonly for fungal disease since 1990. Most importantly, the combination of sertraline and fluconazole was found to work better than either drug alone. Sertraline is concentrated in the brain (average of 22-fold over blood levels), and thus may be an ideal oral medicine to add to standard therapy for cryptococcal meningitis.

Despite these promising initial studies, no studies have been conducted in actual humans. This study seeks to help answer these questions. The research team, based in Uganda, plans to determine whether the addition of sertraline to standard therapy for CM will result in more rapid clearance of the fungal infection. An This project will have two phases. An initial pharmacokinetic dose finding and safety study was conducted Aug 2013-Feb 2014 which has informed the sertraline dosing choices, confirmed the general tolerability, and provided preliminary data that the rate of clearance of yeasts from the cerebrospinal fluid (termed early fungicidal activity) is approximately 25% faster over the first two weeks than current standard therapy.

This proposal is for support of a multisite, Phase III study to determine whether sertraline improves survival in comparison to placebo. All research participants will receive standard anti-fungal therapy of amphotericin + fluconazole as induction therapy.

The implications of this research are clear. Since strong safety data already exists, investigation into the use of sertraline as anti-fungal is greatly accelerated. If sertraline proves to be effective in treatment of Cryptococcus in humans, it would be immediately available for use, essentially creating a shortcut from bench to bedside. This would result in huge cost savings compared to bringing an entirely new drug to the market. Sertraline could have the potential to revolutionize cryptococcal care in Sub-Saharan Africa as it is an existing low cost, generic medicine made by >=25 manufacturers worldwide.

Technical Summary

This is a phase III randomized trial to evaluate the early fungicidal activity of sertraline when added to standard amphotericin-based therapy for cryptococcal meningitis. The primary objective is to determine whether adjunctive sertraline will improve survival through 18-weeks as compared to standard therapy alone. Secondary objectives include comparing the adjunctive sertraline groups and control group for early fungicidal activity, pharmacokinetics, microbiologic susceptibilities, safety, incidence of immune reconstitution syndrome or relapse, and potential cost-benefit.

Cryptococcal diagnosis will be made via CSF cryptococcal antigen (CRAG) at time of lumbar puncture (LP) with confirmation by CSF culture. After informed consent, subjects who meet eligibility requirements will be able to enter study.

Phase III Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at either 200mg or 400mg/day doses. We will use a permutated block randomization in a 1:1:1 allocation (n=160 per arm).
CSF from the LPs at diagnosis, day 3, day 7, day 10, and day 14 will be collected for quantitative cryptococcal CSF cultures. Quantitative cultures will be used to calculate the rate of clearance (early fungicidal activity) over 14-days and compared between study arms.

Subjects will be followed for up to 18 weeks to assess for secondary endpoints. An 18-week duration of study participation is chosen as ~90% of the mortality in the first 5 years after cryptococcal meningitis occurs in the first 18 weeks.

Planned Impact

The primary beneficiaries of the research would be HIV-infected persons living with AIDS who develop cryptococcal meningitis in resource limited areas. Cryptococcal meningitis causes 20-25% of AIDS-related mortality in sub-Saharan Africa, and treatment options are often limited. This research, if successful, would demonstrate a new adjunctive ORAL therapy for cryptococcal meningitis with an existing off-patent, generic (low cost) medication.

Sertraline was originally manufactured by Pfizer, Inc. (Trade name: Lustral, Zoloft); however, this is now a generic medication manufactured by at least 25 manufacturers worldwide. Sertraline is available worldwide, including in numerous Sub-Saharan African countries in retail pharmacies.

Publications

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Atherton RR (2018) Detection of Mycobacterium tuberculosis in urine by Xpert MTB/RIF Ultra: A useful adjunctive diagnostic tool in HIV-associated tuberculosis. in International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

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Bahr NC (2016) GeneXpert MTB/Rif to Diagnose Tuberculous Meningitis: Perhaps the First Test but not the Last. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

 
Description Membership on Guidelines committees
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Team members on this grant funding have been involved in reviewing the Cryptococcal guidelines for WHO and Uganda.
 
Description Membership on committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Increased Cryptococcal antigen screening in public health facilities,
 
Description Alliance for Global Health and Science.
Amount $35,000 (USD)
Funding ID Phenotypic and Kinetic changes in CD4+T cells associated with Anti-retroviral therapy initiation in HIV associated Cryptococcal Meningitis 
Organisation University of California, Berkeley 
Sector Academic/University
Country United States
Start 12/2016 
End 12/2017
 
Description High Dose Oral Rifampicin to Improve Outcomes from Adult Tuberculous Meningitis: A Double-blinded Randomised Controlled Phase III Trial (HARVEST trial application) 
Organisation Bandung Islamic University
PI Contribution We have collaborated with individuals from the University of Bandung in Indonesia, University of Minnesota, University of Durban in Kwazulu Natal, Radboud University in the Netherlands to apply for global health trials research funding for a clinical trial in Uganda, Indonesia and South Africa on improving TB meningitis.
Collaborator Contribution We have collaborated on writing a grant application which was submitted in mid February 2018.
Impact Grant application to the MRC
Start Year 2017
 
Description High Dose Oral Rifampicin to Improve Outcomes from Adult Tuberculous Meningitis: A Double-blinded Randomised Controlled Phase III Trial (HARVEST trial application) 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have collaborated with individuals from the University of Bandung in Indonesia, University of Minnesota, University of Durban in Kwazulu Natal, Radboud University in the Netherlands to apply for global health trials research funding for a clinical trial in Uganda, Indonesia and South Africa on improving TB meningitis.
Collaborator Contribution We have collaborated on writing a grant application which was submitted in mid February 2018.
Impact Grant application to the MRC
Start Year 2017
 
Description High Dose Oral Rifampicin to Improve Outcomes from Adult Tuberculous Meningitis: A Double-blinded Randomised Controlled Phase III Trial (HARVEST trial application) 
Organisation Radboud University Nijmegen
Country Netherlands 
Sector Academic/University 
PI Contribution We have collaborated with individuals from the University of Bandung in Indonesia, University of Minnesota, University of Durban in Kwazulu Natal, Radboud University in the Netherlands to apply for global health trials research funding for a clinical trial in Uganda, Indonesia and South Africa on improving TB meningitis.
Collaborator Contribution We have collaborated on writing a grant application which was submitted in mid February 2018.
Impact Grant application to the MRC
Start Year 2017
 
Description High Dose Oral Rifampicin to Improve Outcomes from Adult Tuberculous Meningitis: A Double-blinded Randomised Controlled Phase III Trial (HARVEST trial application) 
Organisation University of KwaZulu-Natal
Country South Africa 
Sector Academic/University 
PI Contribution We have collaborated with individuals from the University of Bandung in Indonesia, University of Minnesota, University of Durban in Kwazulu Natal, Radboud University in the Netherlands to apply for global health trials research funding for a clinical trial in Uganda, Indonesia and South Africa on improving TB meningitis.
Collaborator Contribution We have collaborated on writing a grant application which was submitted in mid February 2018.
Impact Grant application to the MRC
Start Year 2017
 
Description High Dose Oral Rifampicin to Improve Outcomes from Adult Tuberculous Meningitis: A Double-blinded Randomised Controlled Phase III Trial (HARVEST trial application) 
Organisation University of Minnesota
Country United States 
Sector Academic/University 
PI Contribution We have collaborated with individuals from the University of Bandung in Indonesia, University of Minnesota, University of Durban in Kwazulu Natal, Radboud University in the Netherlands to apply for global health trials research funding for a clinical trial in Uganda, Indonesia and South Africa on improving TB meningitis.
Collaborator Contribution We have collaborated on writing a grant application which was submitted in mid February 2018.
Impact Grant application to the MRC
Start Year 2017
 
Description Hiccup circus 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Ugandan meningitis clinical research team held a social circus in an informal settlement in Kampala to engage the public on the topic of HIV- associated meningitis and share the aims of current meningitis clinical trials. A pre-event focus group with the community advisory board helped identify key messages for the event. Dramatisation of meningitis and lumbar puncture (LP), patient testimonials, a Q&A session with the researchers, and circus performances, were used to share key messages relating to safety of LP, HIV management, early meningitis recognition and the clinical research process.
Year(s) Of Engagement Activity 2018
 
Description Science Cafe 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact 25 Ugandan journalists attended a 3-hour discussion led by Drs. Rhein and Kambugu about HIV-related meningitis on 25th November 2015. This activity was part of the Science Café, a recurring event that is intended to connect HIV experts and Ugandan health journalists with the goal of increasing awareness about HIV and improving health literacy among the Ugandan Public. The Cafés are organised by The Health Journalists Network in Uganda (HEJNU) in partnership with the AIDS Vaccine Advocacy Coalition (AVAC). Several journalists from a variety of backgrounds, including print, radio, and television were present for this lively, fluid, and interactive conversation. The journalists reported increased awareness of meningitis, cryptococcal disease, the role of HIV in meningitis. Dr. Rhein also discussed current research topic and the audience expressed excitement in the fact that cutting edge research was being performed in Uganda. The event led to several stories about cryptococcal meningitis in local and national newspapers and radio.
Year(s) Of Engagement Activity 2015
 
Description Symposium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The activity involved giving a talk during the Center for AIDS Research (CFAR) East African regional symposium organized by the University of California, San Francisco.
The talk involved presenting an update on the clinical trial to the participants and providing a background to the project.
The information provided an opportunity for learning activities, important questions were raised regarding the project and there was increased awareness about cryptococcal disease, the focus of this project.
Year(s) Of Engagement Activity 2017
URL http://cfar.ucsf.edu/event/8th-ucsf-east-africa-collaborative-scientific-symposium
 
Description VIdeo 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We put together a short instructional video on how to use the cryptococcal Antigen (CrAg) Lateral Flow Assay (LFA) as part of the screening procedures for the trial
found at https://www.youtube.com/watch?v=0RwN3p7XirQ
We also put together an educational film entitled: Mulalama (Taking Water) -- short film aimed at educating the Ugandan public about the safety of lumbar punctures (known in Uganda as "taking water").
Year(s) Of Engagement Activity 2016
URL https://www.youtube.com/watch?v=dVqyj4sgDDA&t=3s