Page 41 - HIVMED_v21_i1.indb

Page 15 of 39 Guideline

• A resistance test that shows no drug resistance may • The patient previously developed resistance to other
prevent having to switch unnecessarily to a second-line InSTIs (e.g. RAL).
therapy. • The ART regimen may not contain any fully active NRTIs.
• A resistance test may permit recycling of some first-line • Accidental exposure to sub-therapeutic levels of DTG
NRTIs (e.g. TDF), if they are shown to be susceptible. This (e.g. RIF-based therapy was commenced without the
is particularly useful if one wants to carry through TDF DTG being given twice daily).
(or ABC) to a second-line DTG-based regimen.
• A resistance test will identify drug resistance that may be Guide for interpreting a resistance test
important to identify should the patient require a third-
line ART in future. Current commercial tests have been licensed for specimens
with a VL of at least 1000 ribonucleic acid (RNA) copies/mL.
Dolutegravir-based therapy: Because resistance to DTG in Nevertheless, many in-house assays can detect VLs of 500 RNA
first-line therapy is extremely uncommon, we do not copies/mL – 1000 RNA copies/mL. In general, most commercial
recommend resistance testing unless the patient has been on HIV resistance tests detect mutations if they are present in
a first-line DTG-based regimen for more than 2 years, > 10% – 20% of the HIV subpopulations in the sample.
provided that they were not exposed to a scenario where a ° Common pitfall: Performing a resistance test in
drug–drug interaction would have substantially decreased patients with a low or undetectable VL. Commercial
DTG concentrations (e.g. RIF-based TB therapy without assays may not be successful in samples where the VL
increasing DTG dosing frequency to 12 hourly). (Other rare is < 500 copies/mL – 1000 copies/mL.
62
indications for performing a resistance test before 2 years
include patients who were infected with HIV whilst receiving A key concept in interpreting resistance tests is archived
PrEP – see section 11). Because of the extreme rarity of first-line resistance. After reverse transcription from its RNA
DTG-based resistance mutations, we suggest switching from a template, HIV inserts a DNA copy of itself into the host
DTG-based first-line regimen to a second-line regimen only if genome. Some of the cells that HIV infects are extremely
resistance testing shows DTG resistance. long-lived, and essentially provide an ‘archive’ of HIV
variants over time. Thus, mutations that are known to have
been present at one point in time can be assumed to be present for
Second-line therapy
the lifetime of the patient, even if they are not visible on the
Non-dolutegravir-containing regimens
patient’s latest resistance test.
• Resistance testing is recommended upon failure of
a second-line therapy. This enables clinicians to A second key concept is that of the wild-type virus, which is
individualise a treatment regimen for a third-line ART. the naturally occurring HIV strain free of drug resistance
• For PI-based regimens, sufficient resistance mutations to mutations. In most cases, this form of the virus replicates
cause virological failure typically take at least 2 years to more efficiently than viral strains that have acquired
develop; therefore, in most cases, we recommend only resistance. Therefore, when drug pressure is removed, the
performing a resistance test after the patient has been on a wild-type forms of the virus will predominate, even though
PI-based regimen for at least this duration. Exceptions the resistant strains have been archived and can become
include exposure to sub-therapeutic PI drug levels as a predominant again later if the drug pressure subsequently
result of drug–drug interactions (e.g. not doubling the dose changes in ways favourable to these strains.
of LPV/r when using RIF-based TB treatment). Patients on • A prominent exception to this is the signature mutation of
PI-based therapy with a VL of 50 copies/mL – 500 copies/ EFV and NVP, namely K103N, which imposes no
mL pose a challenge as resistance testing is generally not significant fitness cost on the virus. Even after these drugs
possible. Such patients should remain on the same regimen are stopped, the K103N strains may persist at detectable
with 2–3 monthly VL testing. If the VL rises to > 500 levels for several years.
copies/mL, then resistance testing should be performed, • Resistance testing should therefore only be performed
whereas if the VL re-suppresses to < 50 copies/mL, then when the patient is still taking his or her ART regimen, or
the patient may revert to 6–12 monthly VL testing.
up to a maximum of 4 weeks after discontinuation (see
worked examples in Box 1).
Dolutegravir-based therapy: We do not recommend • The absence of any identified resistance mutations
performing resistance testing for DTG-based second-line implies that non-adherence is the cause of a raised VL.
therapies within 2 years where at least one active NRTI is • This does not exclude the possibility of archived resistance,
present. For instance, if the patient’s first-line NRTIs were however, which may only become detectable once the
FTC and TDF, and the patient was changed to 3TC and AZT, patient is back on ART that suppresses the wild-type strain.
then the strain of HIV can be assumed to be fully susceptible • Any significant drug resistance mutations identified by
to AZT.
resistance testing can be assumed to be present for the
lifetime of the patient, even if subsequent resistance
Scenarios in which to consider resistance testing when failing testings fail to show these mutations (as a result of
on a DTG-containing regimen include the following: worsened adherence or an ART switch, for instance).

http://www.sajhivmed.org.za 33 Open Access