HIV-associated cryptococcal meningitis causes 15% of HIV-related deaths annually in low and middle income countries (LMICs) with no sign of numbers of cases reducing despite roll out of antiretroviral therapy (ART). Indeed, approximately 50% of HIV-associated cryptococcal meningitis cases in LMICs are now ART experienced.

Meningitis

Effective and safe treatment options for resource limited settings are extremely limited, with the current gold standard (two weeks amphotericin B deoxycholate -AmB- and flucytosine) aspirational for most LMICs. Mortality in routine care is approximately 70% with the most widely used therapy (fluconazole monotherapy).

Our projects aim to drive down this mortality: DREAMM, ACTA, TRIP, AMBITION.

DREAMM

Driving down HIV-associated meningo-encephalitis deaths in Africa.

  •   Dates: April 2016 – ongoing
  •   Principal Investigator: Angela Loyse
  •   Locations: Tanzania, Cameroon and Malawi
  •   Funding: EDCTP and ANRS

Project summary

This project aims to implement more effective testing and treatment pathways for meningo-encephalitis in Africa.

Meningo-encephalitis is one of the major causes of HIV/AIDS related deaths in Africa. It places a high burden on the limited healthcare resources available.

There are three phases to the trial: an audit which will determine current mortality rates, availability of diagnostic tests and essential medicines; the training of clinical and laboratory personnel in testing and administering of medicines; and the implementation phase.

Technical Details

This project is known as the DREAMM (Driving Reduced AIDS-associated Meningo-encephalitis Mortality) project and is backed by Institut Pasteur and Centers for Disease Prevention and Control.

Audit

The audit phase will determine current HIV-associated meningo-encephalitis mortality rates and availability of diagnostic tests and essential medicines in routine care.

Training (laboratory and clinical)

In the training phase key clinical and laboratory personnel will be trained on the latest point of care diagnostic tests and safe administration of essential medicines for HIV-associated meningo-encephalitis such as amphotericin B deoxycholate. They will disseminate this knowledge to their hospital counterparts.

Implementation

Optimised laboratory and patient pathways will be implemented in order to reduce the time from patient presentation to diagnostic testing and administration of effective, microbiologically-driven treatment.

Important sub-studies include a health economics evaluation study to determine the cost of the intervention and routine care costs. A new semi-quantitative cryptococcal antigen lateral flow assay (CrAg LFA) (CryptoPS, Biosynex, Strasburg, France) will be evaluated uniquely for the diagnosis of patients with meningo-encephalitis. New, point of care (POC) polyvalent tests (CrAg/HIV) and (CrAg/Streptococcus pneumoniae) will also be evaluated. Lastly, nanopore technology (MinION, Oxford Nanopore Technology, Oxford, UK) will be optimised for the diagnosis of HIV-associated meningo-encephalitis in African low and middle income countries (LMICs).

Dr Angela Loyse is working in partnership with the respective African Principal Investigator leads: Dr Sayoki Mfinanga, Dr Charles Kouanfack and Dr Cecilia Kanyama as well as their hospital counterparts.

Muirgen Stack is the project manager and Dr Sile Molloy the epidemiologist/senior project manager.

Contact: Muirgen Stack - This email address is being protected from spambots. You need JavaScript enabled to view it.

TRIP

Implementation of cryptococcal antigen screening and enhanced Antiretroviral Therapy in advanced HIV patients accessing routine care in Dar es Salaam, Tanzania.

  •   Location: Tanzania
  •   Principal Investigator: Dr Sayoki Mfinanga
  •   Funding: EDCTP

Project summary

This project, known as TRIP, is an EDCTP-funded follow-on study to the Lancet published REMSTART study which was the first study to show a mortality benefit of cryptococcal antigen screening in combination with enhanced antiretroviral therapy.

TRIP is led by Dr Sayoki Mfinanga, Chief Research Scientist and Director of the Muhimbili Research Centre of the National Institute for Medical Research, Tanzania, who is rolling out the screening and enhanced ART adherence in 18 rural and urban clinics within routine care.

Dr Mfinanga is assisted by our team at St George's (Loyse, Harrison, Robb, Molloy) and close collaborators at Liverpool School of Tropical Medicine (Jaffar).

Contact: Sayoki Mfinanga - This email address is being protected from spambots. You need JavaScript enabled to view it.

ACTA

Developing novel treatments for HIV-associated cryptococcal meningitis in Africa.

  •   Dates: June 2013 – July 2017
  •   Principal Investigator: Professor Thomas Harrison
  •   Locations: Tanzania, Cameroon, Malawi, Zambia
  •   Funding: MRC & ANRS

Project summary

This project aims to significantly reduce the mortality rate from HIV-related cryptococcal meningitis in Africa by developing novel treatments which can be implemented in resource-limited settings.

Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. In developed countries, the current standard for initial treatment of HIV-associated cryptococcal meningitis is two weeks of amphotericin B-based therapy. However, in many settings in Africa, amphotericin B is not available or not used due to its requirements for in-hospital care and close monitoring.

This trial will compare three different treatment regimens to find out which is the most effective in resource-limited settings.

Technical Details

This trial is known as ACTA (Advancing Cryptococcal meningitis Treatment for Africa). A phase III randomised, controlled trial, comparing the best oral treatment, a combination of fluconazole and flucytosine, with a one-week amphotericin B-based strategy, and with the standard of two weeks amphotericin B, in resource-limited settings where implementation of two weeks of amphotericin B would be difficult to sustain, and therefore would not be used unless shown to be superior to more readily implementable alternatives. Additionally, fluconazole and flucytosine will be compared as additional drugs to be given with amphotericin B, in the two amphotericin B treatment strategies. The results were presented at IAS 2017.

Contact: Dr Sile Molloy - This email address is being protected from spambots. You need JavaScript enabled to view it.

AMBITION

Testing novel treatments for cryptococcal meningitis in Africa using Ambisome.

  •   Dates: June 2016 – Ongoing
  •   Principal Investigator: Dr Joseph Jarvis and Professor Thomas Harrison
  •   Locations: Tanzania, Botswana, South Africa, Zimbabwe
  •   Funding: Gilead Investigator Initiated Award (Phase 2) EDCTP (Phase 3)

Project summary

The aim of the trial is to identify an effective and sustainable treatment for cryptococcal meningitis in resource limited settings, specifically testing the use of Ambisome.

Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. The current standard for initial treatment in developed countries is two weeks of amphotericin B-based therapy. This trial will investigate whether a modified form of amphotericin B, known as AmBisome, which is known to be effective in treating this condition, can be given in higher doses and shorter courses and would be as effective.

Technical details

AMBITION-cm: AMBIsome Therapy Induction OptimizatioN

Intermittent high dose AmBisome® for cryptococcal meningitis induction therapy in sub-Saharan Africa: An Adaptive Randomised Controlled Non-inferiority Trial.

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 effective in the treatment of cryptococcal meningitis. Its use has been limited by the high cost of therapy, but recent data suggest that due to its lower toxicity, higher doses of AmBisome® can be given safely and much shorter courses may be effective in the treatment of cryptococcal meningitis.

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 the costs of two weeks of conventional amphotericin B, and provide a convenient, safe and effective 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.

The study consists of two steps. The first step will test 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 in step one will then be continued in the larger step two trial along with the standard 14-day course to determine whether or not it is as effective as the standard treatment in terms of preventing deaths from cryptococcal meningitis.

Contact: Dr Sile Molloy - This email address is being protected from spambots. You need JavaScript enabled to view it.


Last Updated: Tuesday, 03 October 2017 09:25