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Page 20 of 39 Guideline

informed decision regarding the use of DTG and problems rather than resistance. If DTG resistance is
contraception. If they choose not to use DTG in a second-line demonstrated, then we advise a regimen of two NRTIs +
therapy, then DRV/r should be used in its place. DRV/r, with the two NRTIs selected based on the resistance
test results.
Failed first-line regimen of two nucleoside reverse
transcriptase inhibitors + dolutegravir Patients currently established on protease
The second-line regimen to commence in patients who have inhibitor-based second-line therapy
failed a first-line approach of two NRTIs + DTG is provided Viral load < 50 copies/mL
in Table 15.
Clinicians can consider switching of patients currently on
a second-line PI/r regimen to a DTG regimen, particularly
If patients experience virological failure on a first-line DTG-
based regimen, then we do not recommend switching to a if patients experience GI side effects of PIs. This switch
second-line therapy unless a resistance test is performed that may also simplify the regimen and reduce pill burden.
demonstrates DTG resistance. This is because DTG is a very However, before such a switch is made, we advise a careful
robust drug and resistance is very rare when used in triple- review of the treatment and resistance (genotype test)
drug combination first-line therapy. Therefore, it is far more history to ensure that there is at least one fully active NRTI
likely that a VL > 50 copies/mL is attributed to adherence to accompany DTG in the new regimen. If this cannot be
assured, then we advise maintaining the current PI/r
regimen – although a switch to an alternative PI/r can be
TABLE 15: Recommended second-line regimen in patients who have failed a first-
line regimen of two nucleoside reverse transcriptase inhibitors + dolutegravir. considered to improve tolerance. If continuing a PI is not
Failing first-line regimen Advised second-line regimen possible, then a switch to a DTG-based second-line
Two NRTIs + DTG Only switch to second-line regimen if the resistance test regimen without an assured active NRTI could be
shows DTG resistance and the second line should be two
NRTIs (selected based on resistance test) + DRV/r considered with close VL monitoring. Refer to Table 16 for
DTG, dolutegravir; NRTI, nucleoside reverse transcriptase inhibitor; DRV/r, darunavir/ritonavir. our advice when considering switching a patient on a PI/
r-based regimen to DTG in a second-line therapy where
TABLE 16: Switching from a boosted protease inhibitor to dolutegravir in second- the VL is < 50 copies/mL.
line antiretroviral therapy when the viral load is < 50 copies/mL.†
First- and second-line regimen: Second-line options
Prior antiretroviral therapy BOX 3: Boosted protease inhibitor + two nucleoside reverse transcriptase
exposure inhibitors is an option in second-line therapy even if there is resistance to both
nucleoside reverse transcriptase inhibitors.
First-line TDF + 3TC (or FTC) + • Can continue the same regimen or switch to
NNRTI AZT + 3TC + DTG. Because boosted PIs are robust drugs (i.e. resistance develops slowly) in PI-naive
and second-line AZT + 3TC + PI/r patients, it is very likely that virological suppression will be achieved with good
adherence, even if the two nucleoside reverse transcriptase inhibitors (NRTIs) used
First-line AZT (or d4T) + 3TC + • Preferably stay on the same regimen. in second-line therapy are compromised by NRTI resistance mutations. This is
NNRTI • If resistance testing was performed at first-line supported by the findings of the Europe-Africa Research Network for Evaluation of
and second-line TDF + FTC + PI/r failure and showed full susceptibility to TDF, Second-line Therapy (EARNEST) , Second-Line Effective Combination Therapy
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then can switch to TDF + 3TC (or FTC) + DTG. (SELECT) (in resource-limited settings) and SECOND-LINE trials, which showed
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• If no resistance test was performed, but there good virological suppression rates of second-line LPV/r and NRTI regimens, even in
is intolerance to all boosted PIs, then consider patients with significant NRTI resistance. These trials demonstrated that without
switching to TDF + 3TC (or FTC) + DTG with the use of a resistance test to decide which NRTIs to use in second-line therapy
close virological monitoring (3 monthly) for with ritonavir-boosted ritonavir (PI/r), virological outcomes were good and similar
the first year. to a boosted PI + RAL regimen. In addition, those patients with more extensive NRTI
Note: See Box 2 and 3 for more information. TDF, tenofovir disoproxil fumarate; 3TC, resistance at first-line failure were more likely to achieve virological suppression in
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lamivudine; FTC, emtricitabine; NNRTI, non-nucleoside reverse transcriptase inhibitor; AZT, second-line therapy.
zidovudine; PI/r, ritonavir-boosted protease inhibitors; DTG, dolutegravir. PIs, protease inhibitors; RAL, raltegravir; NRTI, nucleoside reverse transcriptase inhibitor;
†, ABC is interchangeable with TDF in this table. LPV/r, lopinavir/ritonavir.
BOX 2: Choice of boosted protease inhibitor in second-line antiretroviral therapy.
If a boosted PI is used in second-line therapy, then this is our recommendation in the order of preference:
1) DRV/r 800 mg/100 mg daily
2) ATV/r 300 mg/100 mg daily
3) LPV/r 400 mg/100 mg twice daily
The first choice PI is DRV/r 800 mg/100 mg daily. The once-daily rather than twice-daily dosing can be used in patients who are PI-naive. The once-daily dosing may facilitate
adherence and be better tolerated.
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Darunavir is better tolerated than LPV/r. It has a similar risk of GI intolerance and lipid abnormalities when compared with ATV/r, but does not cause hyperbilirubinaemia like ATV.
Darunavir/ritonavir also has a high genetic barrier to resistance.
Darunavir/ritonavir 400 mg/100 mg daily has also been evaluated in switch studies for patients who are suppressed on a PI/r and who have not previously failed a PI. This lower
dose of DRV/r retained virological suppression in the vast majority of patients in two trials 33,34 and in a similar proportion to those who continued LPV/r in one of these trials.
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Clinicians could consider switching second-line patients who are suppressed on a PI/r to this dose, particularly if cost is an issue.
Darunavir/ritonavir cannot be co-prescribed with RIF and the alternatives to this in second-line therapy are DTG 50 mg twice daily (see above regarding one fully active NRTI),
double-dose LPV/r or switching RIF to rifabutin (see section 18).
Based on clinical trials demonstrating superior tolerability, if DRV/r cannot be used, then we suggest that ATV/r 300 mg/100 mg daily is preferred over LPV/r. 70,71 The benefits of
ATV/r over LPV/r include improved tolerance in terms of GI side effects, a more favourable lipid profile and once-daily administration. Drawbacks of ATV/r are the following: it
cannot be used with RIF-based TB treatment, and there are important drug interactions with drugs that reduce stomach acidity such as PPIs. An alternative PI/r rather than ATV/r
should be used in the following situations:
• Patients who do not tolerate ATV/r (e.g. cosmetically unacceptable jaundice).
• Patients receiving RIF-based TB treatment: the alternatives to this in second-line therapy are DTG 50 mg twice daily (see above regarding one fully active NRTI), double-dose
LPV/r or switching RIF to rifabutin (see section 18).
Lopinavir is the third choice PI/r. It is co-formulated with RTV in a heat-stable tablet (Aluvia). Lopinavir/ritonavir is an option with RIF when double-dosed. Darunavir/ritonavir and
ATV/r can never be co-administered with RIF-based TB treatment.
DRV/r, darunavir/ritonavir; ATV/r, atazanavir/ritonavir; GI, gastrointestinal; LPV/r, lopinavir/ritonavir; PI, protease inhibitor; PI/r, ritonavir-boosted protease inhibitors; DTG, dolutegravir; NRTI,
nucleoside reverse transcriptase inhibitor; RIF, rifampicin; TB, tuberculosis; PPI, proton pump inhibitor; RTV, ritonavir.
http://www.sajhivmed.org.za 38 Open Access