Publications

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

Dr Edward Maina

Kenya

EDCTP portfolio: Career Development Fellowships

Dr Edward Maina aims to detect how much of the inducible HIV-1 virus is left after ART through a longitudinal, descriptive study, looking for ways to describe and reduce this latent reservoir of HIV-infection.

Inducible, replication- competent latent HIV-1 as an impediment to HIV/AIDS cure

In 2014, the Joint United Nations Program on HIV/AIDS (UNAIDS) issued treatment goals for HIV, the 90-90-90 target. The 90-90-90 target specifies that by 2020, 90% of individuals living with HIV will know their HIV status, 90% of people with diagnosed HIV infection will receive antiretroviral treatment (ART), and 90% of those taking ART will be virally suppressed. However, achieving viral suppression will not lead to an HIV-free society by 2030. Although tracking progress towards the 90-90-90 target is important, the challenge of achieving an HIV-free society depends also on detecting the inducible virus and expunge it.

The challenge

Although ART can suppress HIV-1 infection to undetectable levels of plasma viraemia, HIV DNA integrates and persists in resting CD4+ T cells. Latent HIV-1 genomes that encode replication-competent virus can resurface once ART is discontinued. This is believed to be the largest impediment to a cure by ART alone. The vast majority of HIV-infected individuals currently live in sub-Saharan Africa where fully suppressive ART is expanding rapidly. A large number of patients is expected to achieve viral suppression. To date, there have been no systematic studies to quantify the latent reservoir in virally suppressed HIV-infected patients in Africa.

Dr Maina proposed to detect how much of the inducible virus is left in the human body after ART through a longitudinal, descriptive study. He aims to: document the antiviral cocktail in a-viraemic HIV-1 patients, viral suppression and incidences of rebound; measure the size of the latent HIV reservoir in virally suppressed HIV-infected individuals; and examine the immunological correlates of the latent reservoir.

The project

Data generated through this study will provide a clear framework for high-burden countries to reduce gaps at each stage of the HIV care continuum, maximise linkage, retention and health outcomes. These data may also inform strategies to reduce HIV-1 reservoirs, inflammation and activation which persist despite ART. The study results may also enable identification of eligible candidates for latency reactivation treatment once one becomes available.

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

In 2014, the Joint United Nations Program on HIV/AIDS (UNAIDS) issued treatment goals for HIV, the 90-90-90 target. The 90-90-90 target specifies that by 2020, 90% of individuals living with HIV will know their HIV status, 90% of people with diagnosed HIV infection will receive antiretroviral treatment (ART), and 90% of those taking ART will be virally suppressed. However, achieving viral suppression will not lead to an HIV-free society by 2030. Although tracking progress towards the 90-90-90 target is important, the challenge of achieving an HIV-free society depends also on detecting the inducible virus and expunge it.

Although ART can suppress HIV-1 infection to undetectable levels of plasma viraemia, HIV DNA integrates and persists in resting CD4+ T cells. Latent HIV-1 genomes that encode replication-competent virus can resurface once ART is discontinued. This is believed to be the largest impediment to a cure by ART alone. The vast majority of HIV-infected individuals currently live in sub-Saharan Africa where fully suppressive ART is expanding rapidly. A large number of patients is expected to achieve viral suppression. To date, there have been no systematic studies to quantify the latent reservoir in virally suppressed HIV-infected patients in Africa.

Dr Maina proposed to detect how much of the inducible virus is left in the human body after ART through a longitudinal, descriptive study. He aims to: document the antiviral cocktail in a-viraemic HIV-1 patients, viral suppression and incidences of rebound; measure the size of the latent HIV reservoir in virally suppressed HIV-infected individuals; and examine the immunological correlates of the latent reservoir.

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.

Data generated through this study will provide a clear framework for high-burden countries to reduce gaps at each stage of the HIV care continuum, maximise linkage, retention and health outcomes. These data may also inform strategies to reduce HIV-1 reservoirs, inflammation and activation which persist despite ART. The study results may also enable identification of eligible candidates for latency reactivation treatment once one becomes available.

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