AIDS SOCIETY OF INDIA

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Management of first-line ART regimen failure

be designed for the patient. The goal of second-line ART is to achieve optimal virological suppression (PVL <50 or <400 copies/ml at 6 months post initiation). Potent regimens are needed toachieve this goal

NNRTIs (NVP, EFV) used in the first-line regimen have a low genetic barrier to resistance (a single mutation leads to high level resistance). These mutations (K103N, V106M, Y181C, G190A)emerge rapidly and confer cross-resistance between the NNRTIs.110When a patient fails a first-line regimen of 2 NRTIs+1 NNRTI, resistance to NNRTI should be expected and the other NNRTIs cannot be used in the second-line regimen. Thus a protease inhibitor (PI) based regimen is recommended.

PI based regimes are recommended to be boosted with ritonavir (except nelfinavir). Ritonavir is a potent inhibitor of the CYP2503A4 enzyme in the liver and gut, the major pathway for metabolism of PIs. Concomitant use of low dose ritonavir increases Cmax, Cmin and AUC concentrations of the other PIs thus increasing drug exposure. Also doses can be reduced and schedules can be altered with co-administration. Use of non-boosted PIs in constructing a second-line regimen is not recommended.

Another reason a boosted PI is recommended is because some NRTI (used in the first-line) cross-resistance is expected. A potent boosted PI needs to be given with 2 NRTIs to address NRTI cross-resistance and make the second-line regimen more robust. Three boosted PIs are currently available in India: lopinavir/ritonavir, saquinavir/ritonavir and indinavir/ritonavir. LPV/r has better antiretroviral effects as compared to SQV/r and IDV/r,though this difference was driven by greater discontinuations in the in SQV/r and IDV/r arms due to inconvenience and adverseevents.111,112 A new formulation of SQV (500 mg) will be soon available which will make the pill burden similar with all the three boosted PIs (3 cap/tab bid). All the three are also associated with significant short-term GI intolerance and long termdyslipidemia and insulin resistance. However there is evidence to suggest that the low dose ritonavir used to boost PIs itself causes rise in total cholesterol LDL cholesterol total/HDL cholesterol ratio and triglycerides which is amplified further by the concomitant PI.113 IDV/r is associated with clinically insignificant indirect hyperbilirubinemia and nephrolithiasis. Finally, the genetic barrier to resistance is highest with LPV/r.114 Concomitant use of rifampicin is not recommended with all the boosted PIs.

Which 2 NRTIs need to be used with the boosted PI depends on which NRTIs were used in first-line therapy. If lamivudine was used in the first-line, then the virus is expected to develop resistance, due to its low genetic barrier. M184V is the mutation associated with lamivudine resistance. Some studies have shown that this mutation renders the virus less fit.115 In spite of resistance it may have some residual antiviral activity and this may be continued in the second-line regimen for replication advantage. However this may not be significant if full virologic suppression is achieved. This mutation also delays development of TAMs(see below), which may be another reason to keep it in the second-line regimen using one of the thymidine analogs. M184V partially compromises the activity of abacavir and didanosine; however this may be clinically in significant.

If zidovudine or stavudine has been used, some thymidine analog mutations (TAMs- positions 41, 67, 70, 210, 215, and219) may be expected. Greater the number of TAMs or a unique pathway (41,210,215) is associated with broader NRTI cross-resistance. TAMs can accumulate if the failing regime is continued. If all TAMs accumulate then it signifies multi-NRTI resistance. It is interesting to note that M184V delays the accumulation of TAMs.116 Hence the choice of second-line NRTIs depends on the number of TAMs accumulated. With a combination of M184Vand 3 or more TAMs abacavir activity is compromised.

Genotypic drug resistant testing helps identify these mutations and can help optimize the choice of drugs to be used in a second-line regimen. In one meta-analysis, evidence for benefit of antiretroviral drug resistant testing was sparse and limited to small short-term improvements of virological response.117 In India access to genotypic testing is extremely limited and when available is expensive. Expert advice is also advised for interpretation of drug resistant testing reports.

Table 11 lists the recommended second-line regimens for patients failing first line ART regimen in India. However, second-line regimens have the following disadvantages:

• They are more expensive
• High pill burden
• Difficult to adhere to
• Current formulation of ritonavir needs refrigeration; recently a tablet formulation of lopinavir/ritonavir has been approved that does need refrigeration.
• Long term complications, particularly lipid abnormalities and insulin resistance, which may correlate with increased cardiovascular risk for HIV-infected patients.

It is also important to emphasize that patient involvement and discussion is important before initiation of second-line regimen.

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