Download Indications for HIV drug resistance testing

Indications for HIV drug resistance testing
General introduction
Resistance testing can be performed either by determining the genotype or the phenotype of the
virus.
The genotype refers to the amino acid sequence of the viral protein that is targeted by a drug.
With the currently available drugs these target proteins are the reverse transcriptase, the protease,
the integrase or the envelope glycoproteins. Viruses with a sequence comparable to those of viruses
found in untreated patients are considered to be wild type. Genetic differences (mutations) are
considered to be drug resistance mutations if the presence of these mutations reduces the antiviral
efficacy of a particular drug. The genotypic analysis is currently confined to protease and reverse
transcriptase as no validated envelope assay is yet available.
The phenotype refers to the characteristics or properties of the virus. Phenotypic assays for drug
susceptibility determine the amount of drug needed to inhibit viral growth in tissue culture.
Phenotypic assays are more complex and labour intensive than genotypic assays.
The Belgian Aids Reference Laboratories (ARL) perform only genotypic analysis.
HIV genotypic analysis consists of two distinct steps: the laboratory work to determine the nucleic
acid sequence and the translated amino acid sequence and the drug resistance interpretation which
includes comparing the amino acid sequence to a reference consensus sequence and composing a
list of mutations together with their biological and clinical significance.
The results of both genotypic and phenotypic tests are complex and require virological and clinical
expert interpretation if they are to be used successfully to help guide physicians in their use of
antiretroviral therapy. Therefore, HIV genotyping for drug resistance will only be performed on
patients who are registered in an AIDS Reference Centre (ARC) or who are followed by a physician
closely collaborating with an ARC or ARL.
Indications for genotyping
Drug-exposed patients
Resistance testing is indicated in case of virological failure when treatment change is being
considered. Virological failure is characterized by: (1) a confirmed detectable viral load (two
independent consecutive samples) after an undetectable measurement; (2) a stable detectable or
rising viral load after the initiation of treatment; (3) detectable viral load 6 months after treatment
initiation.
In such cases of virological failure, resistance testing is indicated presuming that the patient is
effectively taking his medication at the time of the sampling. If the sample is collected without the
presence of selective pressure, the chances are high that wild-type will be detected instead of the
mutant. Mutant viruses display often a reduced replication capacity in comparison to wild-type and
therefore they are rapidly overgrown by the wild-type. However, they remain as minor variants and
can rapidly re-emerge in a subsequent regime causing therapy failure.
Drug naive patients
Testing for resistance to antiretroviral drugs is indicated before initiating therapy. However, it should
be taken into account that if the infection took place more than 6 months before the blood sample
was taken, the resistant virus may not be detected due to the expected predominance of wild-type
virus in the absence of drug selection. Therefore, the earliest sample available should be tested.
Special populations
Pregnant women
Genotyping is indicated at the start of ART (anti-retroviral therapy) and whenever virological failure
is suspected.
Paediatric patients
Genotyping is indicated in case of virological failure. There are no differences in regard to the
management of adults.
Remarks
The clinical usefulness of drug resistance testing is limited by the following factors:
1. The relationship between drug resistance and clinical failure is complex. Drug resistance is
not the only cause of treatment failure. Non adherence, the use of insufficiently potent
treatment regimens, pharmacokinetic factors that decrease the levels of one or more drugs
in a treatment regimen, and potentially other factors, also contribute to treatment failure.
Conversely, a drug may have some benefit even in the setting of resistance, because of
some, although limited, residual effect of some drugs and because many drug-resistant
variants have a reduced replication capacity compared to drug-susceptible variants.
2. An important limitation of either geno- or phenotyping is the unreliability of the tests to
detect minority HIV-1 variants. This limitation can complicate the interpretation of
resistance tests particularly in patients with complicated treatment histories. Therefore
treatment and resistance history have always to be taken into account.
3. HIV-1 exists in each infected individual as a complex quasispecies in which many different
subpopulations of drug-resistant variants co-exist. Also subpopulations that are no longer
actively replicating will remain archived in latently infected cells. The complexity of this
quasispecies may influence the success of therapy in ways that cannot be predicted by any
single drug resistance test.
Genotyping can be determined in other, exceptional circumstances after permission of the director
of the laboratory. Please contact the ARL.
HIV-2 resistance of envelope glycoproteins resistance testing can also be requested but are at
present insufficiently validated. Please contact an ARL for further information.
Retrospective analysis can be performed on archived samples at the ARL. Please contact the
laboratory for availability of sample.
Contact
Université Libre de Bruxelles, Hôpital Erasme (Cliniques
Universitaires de Bruxelles)
Marie-Luce Delforge
Tel.: +32 (0)2 555 57 83
Laboratoire de Référence SIDA
Université Libre de Bruxelles, Hôpital Universitaire Erasme
Laboratoire de Virologie
Route de Lennik, 808
1070 Bruxelles
Click here to visite the ARL website.
Instituut Tropische Geneeskunde
Katrien Fransen
Tel.: +32 (0)3 247 63 32
e-mail : [email protected]
AIDS-Referentielaboratorium
Instituut voor Tropische Geneeskunde
Departement klinische wetenschappen
Nationalestraat 155
2000 Antwerpen
Click here to visite the ARL website.
Université de Liège, Centre Hospitalier Universitaire de
Liège
Marie-Pierre Hayette (Director)
Tel.: +32 (0)4 366 24 54
Dolorès Vaira
e-mail: [email protected]
Tel.: +32 (0)4 366 24 48
Christiane Gérard
Tel.: +32 (0)4 366 75 39
Laboratoire de Référence SIDA
Université de Liège
Domaine Universitaire du Sart-Tilman
Laboratoire de Microbiologie Clinique
Niveau 2 - Bât. B23
4000 Sart-Tilman via Liège 1
Tel. ARL: +32 (0)4 366 75 39
Vrije Universiteit Brussel
(Section: Universitair Ziekenhuis Brussel)
Denis Pierard
e-mail: [email protected]
AIDS Referentie Laboratorium
VUB, UZ-Brussel
Laboratorium voor Klinische Biologie
Laarbeeklaan 101, 1090 Brussel
Tel.: +32 (0)2 477 50 01
Click here to visit the ARL website.
Vrije Universiteit Brussel (Section: Universitair Medisch
Centrum Sint-Pieter)
Sigi Van den Wijngaert
Tel.: +32 (0)2 535 45 31
AIDS Referentie Laboratorium
Universitair Medisch Centrum Sint-Pieter
Hoogstraat 185
1000 Brussel
Tel.: +32 (0)2 535 45 30
Universiteit Gent, Universitair Ziekenhuis Gent
Chris Verhofstede
Tel: +32 (0)9 332 51 61
e-mail: [email protected]
AIDS Referentie Laboratorium
Universiteit Gent
Laboratorium voor Bacteriologie en Virologie
Blok A, 3de verdieping
De Pintelaan 185
9000 Gent
Tel.: +32 (0)9 332 51 61
Fax: +32 (0)9 332 38 41
Click here to visit the ARL website
Université Catholique de Louvain, Cliniques Universitaires
Saint-Luc
Patrick Goubau
Tel.: +32(0)2 764 54 92
e-mail: [email protected]
Université Catholique de Louvain, Cliniques Universitaires
Saint-Luc
Laboratoire de Référence SIDA
Unité de Microbiologie
Avenue Hippocrate 5492
1200 Bruxelles
Tel.: +32 (0)2 764 54 92
Fax: +32 (0)2 764 54 22
Click here to visit the ARL website.
Katholieke Universiteit Leuven, Universitaire Ziekenhuizen
Leuven
Marc Van Ranst
Katholieke Universiteit Leuven, Universitaire Ziekenhuizen
Leuven
Zone Medische Diagnostiek, Activiteitencentrum AIDS
Referentie Laboratorium
Gasthuisberg - CDG8
Herestraat 49
3000 Leuven
Tel.: +32 (0)16 34 79 08
Fax: +32 (0)16 34 79 00
Scientific Institute of Public Health (IPH, WIV-ISP)
André Sasse (scientific secretariat)
Tel.: +32 (0)2 642 50 39
e-mail: [email protected]
Institut Scientifique de Santé Publique - Wetenschappelijk
Instituut Volksgezondheid
Public Health and Surveillance - Infectious Diseases Unit
Rue Juliette Wytsmanstraat 14
1050 Brussels
Click here to visit the IPH main website. The IPH’s Infectious
disease web pages can be found here.
Last update
18/11/2014