- For patients with a detectable VL on second-line therapy for < 2 years, intensified adherence counselling and support are required rather than a switch to a third-line therapy.
- For a patient on a second-line regimen for > 2 years with two or three VL measurements > 50 copies/mL within a 6-month period despite adherence interventions that have been assessed to be satisfactory (see text), then a resistance test should be performed. (Note: A resistance test can only be performed if the VL > 500 copies/mL.)
- The choice of the third-line regimen should be made in conjunction with an HIV expert.
Management of patients with a detectable viral load on second-line therapy and initiation of third-line therapy
As outlined in the prior module, there should be documented PI or DTG resistance before switching to a third-line regimen. Resistance tests should be interpreted by an expert in conjunction with a full ART history. In many patients failing second-line regimens, there are no PI (or DTG) mutations. In these patients, improved adherence is required rather than switching to a third-line regimen. If side-effects interfere with adherence, then consideration should be given to switching to a more tolerable regimen, provided that this regimen is predicted to be effective based on the treatment history (see Module 13).
Figure 5 outlines the indications for performing resistance testing in second-line ART regimens.
FIGURE 5: Indications for performing resistance (genotype) testing in second-line antiretroviral therapy.
(ART, antiretroviral therapy; DTG, dolutegravir; LPV/r, ritonavir-boosted lopinavir; PI, protease inhibitor, VL, viral load)
In a patient who has been on a second-line regimen for > 2 years, if there are two or three VL measurements > 50 copies/mL in a 6-month period despite adherence interventions, and adherence is assessed to be satisfactory (e.g. 100% pharmacy claims over 6 months), then a resistance test should be performed (resistance test can only be done if VL > 500 copies/mL). If a patient who has been on second-line therapy for < 2 years is found to have a detectable VL, then a resistance test should not be performed; rather, the same regimen should be continued and adherence counselling and support intensified. The regimen may be switched if there are significant side-effects. It is unlikely that significant resistance to the PI or DTG will have developed within 2 years. The exceptions include: a patient who in error was not prescribed LPV/r double dosing with concurrent RIF use, and subsequently demonstrates a detectable VL; and a patient who has been taking an incorrectly low dose of medication. Such patients should be eligible for resistance testing even if they have been on second-line therapy for < 2 years.
Specific adherence counselling should be provided for patients preparing to start third-line ART, with a clear discussion that this regimen is likely to be their last option for the foreseeable future.
A third-line regimen including a combination of DRV/r and other drugs decided upon based on resistance testing, results in virological suppression in the majority of patients, provided that adherence is optimal.74,75,76,77
For most patients who require third-line therapy (experience virological failure on a second-line LPV/r or ATV/r regimen with a low-, intermediate- or high-level resistance to the PI, i.e. Stanford score > 14), we recommend the third-line regimen outlined in Table 17. However, the final decision will be based on treatment history and resistance test results for the individual patient.
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|TABLE 17: Third-line regimen recommended for the majority of patients failing protease inhibitor-based second-line therapy.|
|Second-line regimen failing||Third-line regimen advised|
|PI-based second-line therapy||TDF 300 mg daily, 3TC 300 mg daily, DTG 50 mg daily (given as TLD)
DRV/r 600 mg/100 mg twice daily
|3TC, lamivudine; DTG, dolutegravir; DRV/r, ritonavir-boosted darunavir; TDF, tenofovir disoproxil fumarate; TLD, tenofovir disoproxil fumarate + lamivudine + dolutegravir fixed-dose combination (TDF + 3TC + DTG FDC).|
There are exceptions:
- In patients with renal impairment, replace TDF + FTC with ABC + 3TC, or AZT + 3TC. The choice between ABC and AZT will depend on Hb (anaemia: do not use AZT if Hb < 8 g/dL) and resistance testing.
- If the AZT Stanford score is lower than the TDF score, then use AZT + 3TC rather than TDF + FTC.
- Patients with a DRV score of 0 on Stanford score (and no DRV mutations, see Module 5) can take DRV/r 800 mg/100 mg once daily.
- Patients with prior virological failure on RAL and/or with a DTG score > 0 on integrase resistance testing should receive DTG 50 mg twice daily.
- In patients with extensive resistance (e.g. DRV score > 29 and NRTI score > 29), consider adding RPV or ETR (provided the score for these drugs is < 30) or maraviroc (MVC) (provided the virus is CCR5-tropic on the tropism test).
- We generally advise the continuation of NRTIs in the third-line regimen, even if there is documented NRTI resistance.
- 3TC (or FTC) resistance with the M184V mutation impairs viral replication. Another NRTI (generally TDF, but based on resistance testing) should be added. This is not essential if there are more than two other active drugs in the regimen.78
- Because most patients are not receiving an NNRTI at the time of failing second-line therapy when a genotype resistance test is typically performed, prior NNRTI mutations related to first-line NNRTI failure may be archived at this time. Therefore, it is difficult to be certain from a (this) genotype performed at second-line ART failure, whether ETR/RPV are still active; however, data from South Africa suggest that the majority of patients who have failed NVP or EFV have viral susceptibility to ETR/RPV.79
- In the SAILING trial, in treatment-experienced patients, a DTG regimen proved superior to RAL and fewer patients in the DTG arm developed treatment-emergent InSTI resistance. Consequently, we no longer recommend use of RAL in third-line therapy unless DTG is not tolerated or otherwise contraindicated or unavailable. We also recommend switching patients currently using RAL in third-line therapy to DTG, due to its higher barrier to resistance.14 If such patients have a suppressed VL, then they can be switched to standard dose DTG (50 mg daily), but if they are not virologically suppressed, then we suggest a resistance test with a request for integrase sequencing, before switching. If there are InSTI mutations present that are associated with reduced susceptibility to DTG, then the DTG dose should be 50 mg twice daily.
- WOCP should be counselled about the potential risk and benefits of DTG and be allowed to make an informed decision regarding the use of DTG and contraception.
- MVC (a CCR5 blocker) is a consideration in third-line therapy; however, it is currently extremely costly and can only be used after a tropism test demonstrates that the patient’s circulating virus has sole tropism for the CCR5 co-receptor. We advise only considering this when there is intermediate- or high-level resistance to all PIs, all NNRTIs and all NRTIs, and DTG does not demonstrate full susceptibility.
- If viral suppression is not achieved on third-line therapy, then there is still benefit in continuing failing ART, because of the residual partial activity and ‘crippling’ effect of such ART. ‘Crippling’ describes the fact that mutant viruses often have less replicative capacity. Provided that the VL can be maintained at < 10 000 copies/mL, the CD4+ count will usually be maintained or even increase.59
The choice of regimen will be guided by resistance test results and should include DRV/r with two NRTIs (generally 3TC or FTC with the NRTI with the lowest Stanford score). In patients failing a second-line DTG regimen who have not failed a PI/r previously, it can be assumed that DRV/r is fully active and can be used at 800 mg/100 mg daily. Based on the results of the EARNEST, SELECT and SECOND LINE trials, it can be concluded that a DRV/r regimen with two NRTIs will be an active regimen even if there is documented resistance to the two NRTIs.60,61,72 However, decisions regarding third-line therapy do need to be individualised in consultation with an expert, taking into account treatment history (which drugs and classes the patient previously failed) and previous and current resistance test results.
RAL may still be active in patients with DTG resistance – it depends on the specific resistance mutations in the integrase gene – but it is usually not necessary to include it in the regimen. ETR and RPV are other drugs that can be considered depending on resistance test results and treatment history.