Publications

Funding for clinical research |drugs, vaccines, microbicides, diagnostics | HIV/AIDS, tuberculosis, malaria, other infectious diseases |sub-Saharan Africa

Dr George Kyei

Ghana

EDCTP portfolio: Senior Fellowships

Dr George Kyei is exploring new ways to enhance the ‘shock and kill’ approach to eradicate HIV from the body.

An innovative approach to HIV cure

Although the numbers of new HIV infections are in decline, around one million new infections occurred in Africa in 2017. In addition, millions of people living with HIV have to take antiretroviral drugs daily to keep HIV infection under control.

The need for daily treatment is a huge drain on resources, exposes people to powerful drugs throughout their lives, and increases the risk that drug resistance will arise due to lack of adherence to long-term treatment.

The challenge

These issues could be overcome if it were possible to cure rather than just control HIV infections. The main obstacle to cure is the persistence of HIV in a reservoir of quiescent T cells – HIV-derived DNA is integrated into the T cell genome but is dormant. One suggested approach to cure, known as ‘shock and kill’, is to reactivate these quiescent cells while patients are taking antiretroviral drugs, to eliminate residual HIV and enable patients to stop taking medication. However, to date, it has not proven possible to reactivate cells sufficiently to achieve eradication.

In his EDCTP Senior Fellowship, Dr George Kyei is testing new strategies to reactivate HIV replication in quiescent cells. In such cells, HIV replication is suspended because of the compact folding of DNA around HIV DNA integrated into the genome. Dr Kyei is screening a library of compounds that have the potential to unfold DNA, potentially kick-starting HIV replication.

Compounds showing the most promising DNA unfolding effects will be tested on resting T cells obtained from HIV patients taking antiretroviral drugs. To do this, Dr Kyei will monitor virus levels in a cohort of patients receiving antiretroviral therapy and select those in whom viral reproduction is being effectively suppressed by medication.

The project

As well as providing new data on the effectiveness of antiretroviral treatment in Ghanaian patients, Dr Kyei’s Senior Fellowship project could identify novel compounds that make it more likely that the shock and kill approach is successful. Achieving HIV cure would have a huge impact on management of HIV in sub-Saharan Africa. More immediately, the project will increase regional capacity for HIV cure studies, including training of graduate students, and establish a biobank of samples for future HIV-related research and training.

Impact


test the safety and efficacy of this new formulation in young children

Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

Although the numbers of new HIV infections are in decline, around one million new infections occurred in Africa in 2017. In addition, millions of people living with HIV have to take antiretroviral drugs daily to keep HIV infection under control.

The need for daily treatment is a huge drain on resources, exposes people to powerful drugs throughout their lives, and increases the risk that drug resistance will arise due to lack of adherence to long-term treatment.

These issues could be overcome if it were possible to cure rather than just control HIV infections. The main obstacle to cure is the persistence of HIV in a reservoir of quiescent T cells – HIV-derived DNA is integrated into the T cell genome but is dormant. One suggested approach to cure, known as ‘shock and kill’, is to reactivate these quiescent cells while patients are taking antiretroviral drugs, to eliminate residual HIV and enable patients to stop taking medication. However, to date, it has not proven possible to reactivate cells sufficiently to achieve eradication.

In his EDCTP Senior Fellowship, Dr George Kyei is testing new strategies to reactivate HIV replication in quiescent cells. In such cells, HIV replication is suspended because of the compact folding of DNA around HIV DNA integrated into the genome. Dr Kyei is screening a library of compounds that have the potential to unfold DNA, potentially kick-starting HIV replication.

Compounds showing the most promising DNA unfolding effects will be tested on resting T cells obtained from HIV patients taking antiretroviral drugs. To do this, Dr Kyei will monitor virus levels in a cohort of patients receiving antiretroviral therapy and select those in whom viral reproduction is being effectively suppressed by medication.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

As well as providing new data on the effectiveness of antiretroviral treatment in Ghanaian patients, Dr Kyei’s Senior Fellowship project could identify novel compounds that make it more likely that the shock and kill approach is successful. Achieving HIV cure would have a huge impact on management of HIV in sub-Saharan Africa. More immediately, the project will increase regional capacity for HIV cure studies, including training of graduate students, and establish a biobank of samples for future HIV-related research and training.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M