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Page 14 of 39 Guideline

TABLE 9: Antiretroviral drug resistance mutations.
CD4 lymphopenia Drug Key mutations selected
+
despite suppressed VL
3TC or FTC Selects for M184V, which compromises both 3TC and FTC and slightly
impairs the activity of ABC but increases susceptibility to AZT and TDF.
TDF Selects for K65R, which compromises TDF and ABC but increases
+
CD4 count previously susceptibility to AZT. Tenofovir disoproxil fumarate also selects for
CD4 count failed normal, but has now K70E, which causes low-level resistance to TDF, ABC and possibly 3TC/
+
to increase FTC.
decreased
ABC Selects for L74V, which compromises ABC. May also select for K65R,
which compromises TDF and ABC but increases susceptibility to AZT.
Selects for Y115F, which decreases its susceptibility.
Consider OIs (e.g. TB), AZT Selects for TAMs, which may ultimately compromise all NRTIs.
Clinically well Clinically unwell malignancies (e.g. lymphoma), d4T Selects for TAMs, which may ultimately compromise all NRTIs.
autoimmune disorders
(e.g. SLE), medications EFV or NVP Selects for K103N, which causes high-level resistance to EFV and NVP.
(e.g. corticosteroids) Also selects for Y181C and other NNRTI mutations, which cause
resistance to EFV, NVP, RPV and ETR.
Likely
immunological RPV Selects for several mutations, including E138K, which compromise its
susceptibility.
discordant
response to ART PIs Multiple mutations are usually required before seeing a decrease in
susceptibility, especially for LPV and DRV, and cross-resistance
between the PIs is common. ATV selects for I50L, which causes
+
ART, antiretroviral therapy; CD4 , cluster of differentiation 4; OIs, opportunistic infections; high-level resistance to ATV but not to other PIs.
SLE, systemic lupus erythematosus; TB, tuberculosis; VL, viral load. RAL Selects for Q148H/K/R, Y143C and N155H, which cause resistance to
FIGURE 2: Suggested approach to patients with low CD4 counts despite a suppressed viral RAL and, in certain combinations, to DTG too.
+
load on antiretroviral therapy.
DTG Very rarely selects resistance if InSTI-naive, provided that it is coupled
with at least one other fully active drug. In patients with prior RAL
° Common pitfall: Confusing an ‘immunological exposure, mutations such as Q148H may cause decreased DTG
susceptibility when combined with additional mutations.
discordant response to ART’ with treatment failure. 3TC, lamivudine; ABC, abacavir; ATV, Atazanavir; AZT, zidovudine; d4T, stavudine; EFV,
There is no role for changing ART if the VL is efavirenz; ETR, etravirine; DTG, dolutegravir; FTC, emtricitabine; InSTI, integrase strand
suppressed. transfer inhibitor; LPV, lopinavir; NVP, nevirapine; PIs, protease inhibitors; RAL, raltegravir;
RPV, rilpivirine; TAMs, thymidine analogue mutations; NRTIS, nucleoside reverse
transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitor; TDF,
tenofovir disoproxil fumarate.
Figure 2 shows the outline of the suggested approach to
+
patients with low CD4 counts despite a suppressed VL on TABLE 10: Recommendations for resistance testing.
ART. Regimen DTG-based therapy NNRTI-based PI-based therapy
therapy
10. Resistance and genotyping First-line Recommended if the patient Not routinely Not routinely
recommended
has been on regimen for >
regimen
recommended (rare
2 years
scenario)

Key points Second-line Recommended if the patient Recommended (rare Recommended if the
regimen has been on regimen for > scenario) patient has been on
2 years regimen for > 2 years
ÿ Adherence is the key to prevent drug resistance. DTG, dolutegravir; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease
ÿ Resistance testing in patients failing a DTG-based therapy inhibitor.
is unnecessary in the majority of cases and should only be
undertaken if specific criteria are met.
ÿ Resistance testing may not detect archived mutations to 1. Pre-exposure prophylaxis received in the previous
6 months
particular drugs if the patient is not receiving these drugs 2. History of sexual exposure to a person with known drug-
at the time of resistance testing.
resistant HIV or known to have failed an ART regimen.
Overview Resistance testing at treatment failure
As a result of transcription errors and recombination, HIV Resistance testing is generally only possible if the VL is
that is replicating can accumulate mutations, leading to > 500 copies/mL. Patients with two or more consecutive
drug resistance. Durable viral suppression by ART is VL results of 50 copies/mL – 500 copies/mL are, however,
required to limit the chances of developing drug resistance. still considered to have a virological failure (see section 8).
Intermittent drug adherence, as opposed to a total lack of
ART, provides a greater opportunity for resistance to Recommendations for resistance testing are summarised in
develop, by exposing replicating virus to sub-therapeutic Table 10.
ART drug concentrations.
First-line therapy
Antiretroviral drug resistance mutations are summarised in Non-nucleoside reverse transcriptase inhibitor-based
Table 9.
therapy: A resistance test at failure of first-line therapy is not
routinely recommended. The EARNEST and SELECT trials
When to perform a resistance test showed that without the use of a resistance test to decide
Baseline resistance test which NRTIs to use in second-line therapy, virological
A baseline resistance test is not generally indicated. We outcomes were good and equivalent to a boosted PI + RAL
recommend a baseline resistance test to guide first-line regimen. 60,61 However, where funds permit, resistance testing
regimen choice only in the following situations: will offer some advantages:

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