Basic Science Programme / Research on ART resistance

Lead Research Organisation: MRC/UVRI Uganda Research Unit on AIDS

Abstract

In the past few years there has been an increase in access to anti-retroviral therapy (ART) of HIV infection in resource limited settings. Studies are also underway to find the most cost effective approaches to deliver ART to different populations in such settings. One of the major challenges of delivery of ART is the development of drug resistance. MRC/UVRI is therefore conducting different studies to investigate the development of resistance under the different delivery settings in our population infected with HIV subtypes A and D. We also participate in national activities aimed at prevention, monitoring and surveillance of HIV drug resistance. These include surveillance of drug resistance in recently infected individuals and in those on treatment in research projects and public HIV care programmes. All these efforts will contribute to better understanding of how resistance develops and how we can prevent it. Methods to test for drug resistance involve extracting the viral genetic materials from patient blood participating in a number of cohorts that we support and performing a number of laboratory experiments including sequencing using different machines to detect the genetic sequences combined with a number of mathematical analyses.

Technical Summary

Overall aim: To provide information on the nature and frequency of ART resistant mutants occuring in rural and urban setting under various ART delivery routes. Specific objectives: 1) To describe ART resistance in COLTART and DART participants 2) To describe ART resistance among recently infected individuals 3) To participate in national ART prevention and monitoring activities including hosting the National ART drug resistance reference laboratory 4) Introduction of the use of DBS in drug resistance monitoring
Background: There are efforts to study the most cost effective modes of ART delivery in resource limited settings such as the recently concluded Dart trial. Understanding the effect of these approaches on viral suppression and ART drug resistance in these communities infected with HIV subtypes A,C and D is of importance. In addition, as a contribution to the prevention and monitoring of ART drug resistance, we are participating in a number of studies including looking at the frequency of resistant viruses in recently infected individuals and those on treatment. We also host the national HIV drug resistance reference laboratory.
Laboratory methods: Viral loads are measured by Roche Amplicor v1.5 assay for baseline samples (lower limit of detection 400 copies/ml), and the Roche ultra-sensitive assay for other samples (lower limit of detection 50 copies/ml). Viral RNA is extracted from cryo-preserved serum using QIAamp Viral RNA Mini Kit. Reverse transcription and first round PCR is done using QIAGEN OneStep RT-PCR Kit and subsequent sequencing of a consensus contiguous region of the pol gene by an in-house sequencing method, using a Beckman capillary sequencer or an ABI capillary sequencer. Mutations at baseline are identified by reference to the WHO consensus list for surveillance of transmitted drug resistance and mutations at later time points by reference to the most recent IAS-USA classification. Subtype was inferred from the pol sequences using the REGA HIV subtyping algorithm. We are also introducing the use of DBS in drug resistance
Public health application: Better understanding of the effectiveness of the different ART delivery approaches and prevention of HIV drug resistance development.

Publications

10 25 50

 
Description Harmonize routine medical records to facilitate routine HIVDR Early Warning Indicator abstraction at ART facilities
Geographic Reach National 
Policy Influence Type Citation in other policy documents
Impact We are not able to easily capture early warning indicators for HIV drug resistance in order to intervene early enough
 
Description Relevance of virological monitoring in patient management
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Currently we show no differences in drug resistance development in the different HIV subtypes we have Laboratory monitoring only can lead to good virological response though there is more resistance development in patients who continue on drugs when there is virological failure
 
Guideline Title The revised 2018 HIV treatment guidelines
Description Use of Integrase strand inhibitors (Dolutegravir) as first line due to high Pre-Treatment HIVDR to NNRTIs in the country.
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Uganda and other countries where HIV pre-treatment drug resistance is above 10%, have adopted Dolutegragir ased regimens as the preferred first line ART regimen in women >50 years, adolescent and adult men; and as an alternative second line in the above eligible groups.
 
Guideline Title The revised 2018 HIV treatment guidelines
Description Use of PI based regimens as first line for HIV infected infants especially with prior PMTCT exposure.
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Due to the high prevalence of pre-treatment drug resistance especiallt to NNRTIs and to some extent NRTIs, the ministry rolled out use of Lopinavir pellets as first line for HIV positive infants <3 years country -wide in 2016
 
Guideline Title The revised 2018 HIV treatment guidelines
Description Viral Load monitoring at 6 and 12 months after ART initiation instead of 18 months.
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact We are not able to get viral load data at 6 and 12 months which is used as an early warning sign for the development of HIV drug resistance
 
Description Efficacy and drug resistance development in patients on tripe Nucleosides
Amount £291,543 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 08/2006 
End 02/2009
 
Description MRC Research Grant (The emergence and impact of HIV resistance associated mutations under the public health approach to ART: Implications for resource limited countries)
Amount £1,000,000 (GBP)
Funding ID G0600044 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2007 
End 05/2011
 
Description Surveillance of HIV drug resistance
Amount £150,000 (GBP)
Organisation PharmAccess Foundation 
Sector Charity/Non Profit
Country Netherlands
Start 06/2008 
End 05/2010
 
Description Dart Drug resistance 
Organisation Medical Research Council (MRC)
Department MRC Clinical Trials Unit
Country United Kingdom 
Sector Public 
PI Contribution Analysis of Data and publications
Collaborator Contribution Analysis of Data and publications
Impact Publications and abstracts
 
Description Dart viral load 
Organisation Joint Clinical Research Center, Kampala
Country Uganda 
Sector Academic/University 
PI Contribution Viral load testing and publications
Collaborator Contribution Viral load testing and publications
Impact Viral load testing, publications and sharing of information
 
Description Dart virology substudies 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided sequence data, participated in the presentation of data and publications
Collaborator Contribution Training of staff and in publications
Impact Training, other capacity building and publications
Start Year 2006
 
Description HIV Drug resistance surveillance 
Organisation PharmAccess Foundation
Country Netherlands 
Sector Charity/Non Profit 
PI Contribution We have conducted molecular virology experiments
Collaborator Contribution Training and network
Impact Information of transmitted HIV drug resistance and publications
Start Year 2008
 
Description Ministry of Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Policymakers/politicians
Results and Impact We have presented information on the development of drug resistance to the Ministry of Health officials

In the context of Dart the ministry of health is aware of the efficacy of the drug regimens The ministry is aware of the prevalence of mutations in drug naice patients and in recently infected people
Year(s) Of Engagement Activity 2008