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EDCTP portfolio: Senior Fellowships

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Dr Georgia Schafer aims to develop a clearer picture of Kaposi’s sarcoma-associated herpesvirus in HIV-related disease.

Identifying the true burden of Kaposi’s sarcoma 

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TB is a major cause of death and ill-health in sub-Saharan Africa, particularly for those with HIV infections: a third of all HIV-related deaths are due to TB. However, because it is so common, TB is often presumed to be the cause of symptoms, leading to significant levels of misdiagnosis.

One infection that is common in sub-Saharan Africa and has pathological features similar to TB is Kaposi’s sarcoma-associated herpesvirus (KSHV). Despite 32,500 cases being identified in 2018, leading to 17,500 deaths, KSHV is relatively little studied and its exact contribution to HIV-related disease not fully understood.

The challenge

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In her EDCTP Senior Fellowship, Dr Georgia Schafer aims to work with well-defined cohorts of people living with HIV to determine the burden and characteristics of KSHV-related disease. As well as Kaposi’s sarcoma, a cancer of the skin, respiratory system and other organs, the virus can cause a range of other conditions.

KSHV can establish dormant or ‘latent’ infections, which can be reactivated, leading to extensive viral replication. A key hypothesis is that this ‘lytic reactivation’ is a key contributor to the risk of severe symptoms and death.

Dr Schafer has carried out studies showing that high KSHV viral load is a strong predictor of death in people with HIV. Among nearly 700 people hospitalised and investigated for TB, 31% had KSHV infections. The 6% with high KSHV viral load were at 6.5 times higher risk of death. Dr Schafer has also shown that variants in the receptor used by KSHV to gain access to cells, known as EPHA2, are associated with susceptibility to infection and risk of developing Kaposi’s sarcoma.

In her Senior Fellowship, Dr Schafer will undertake an intensive analysis of a new cohort of HIV patients. As well as screening for KSHV infections and investigating links between viral load and poor outcomes, she will also characterise EPHA2 variant status and subtype KSHV infections to see if any are associated with severity of disease.

The project

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Born in Germany, Dr Schafer has worked in South Africa for many years. She has established an extensive programme of research in cancer-causing viruses, including human papillomavirus (HPV), the main cause of cervical cancer. The EDCTP Senior Fellowship will allow Dr Schafer to strengthen her research presence in KSHV and KSHV-linked disease. The work should also highlight the importance of an underappreciated cause of illness in people living with HIV and may suggest new ways in which the burden of KSHV-related disease could be minimised.

Impact

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

Bringing antiretroviral drugs to children

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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

TB is a major cause of death and ill-health in sub-Saharan Africa, particularly for those with HIV infections: a third of all HIV-related deaths are due to TB. However, because it is so common, TB is often presumed to be the cause of symptoms, leading to significant levels of misdiagnosis.

One infection that is common in sub-Saharan Africa and has pathological features similar to TB is Kaposi’s sarcoma-associated herpesvirus (KSHV). Despite 32,500 cases being identified in 2018, leading to 17,500 deaths, KSHV is relatively little studied and its exact contribution to HIV-related disease not fully understood.

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In her EDCTP Senior Fellowship, Dr Georgia Schafer aims to work with well-defined cohorts of people living with HIV to determine the burden and characteristics of KSHV-related disease. As well as Kaposi’s sarcoma, a cancer of the skin, respiratory system and other organs, the virus can cause a range of other conditions.

KSHV can establish dormant or ‘latent’ infections, which can be reactivated, leading to extensive viral replication. A key hypothesis is that this ‘lytic reactivation’ is a key contributor to the risk of severe symptoms and death.

Dr Schafer has carried out studies showing that high KSHV viral load is a strong predictor of death in people with HIV. Among nearly 700 people hospitalised and investigated for TB, 31% had KSHV infections. The 6% with high KSHV viral load were at 6.5 times higher risk of death. Dr Schafer has also shown that variants in the receptor used by KSHV to gain access to cells, known as EPHA2, are associated with susceptibility to infection and risk of developing Kaposi’s sarcoma.

In her Senior Fellowship, Dr Schafer will undertake an intensive analysis of a new cohort of HIV patients. As well as screening for KSHV infections and investigating links between viral load and poor outcomes, she will also characterise EPHA2 variant status and subtype KSHV infections to see if any are associated with severity of disease.

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.

Born in Germany, Dr Schafer has worked in South Africa for many years. She has established an extensive programme of research in cancer-causing viruses, including human papillomavirus (HPV), the main cause of cervical cancer. The EDCTP Senior Fellowship will allow Dr Schafer to strengthen her research presence in KSHV and KSHV-linked disease. The work should also highlight the importance of an underappreciated cause of illness in people living with HIV and may suggest new ways in which the burden of KSHV-related disease could be minimised.

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