Patients Intolerant to NNRTI
Patients who develop severe adverse events to nevirapine and Efavirenz should be treated with ritonavir boosted protease inhibitors (IDV/r, SQV/r, LPV/r) combined with 2NRTIs.Nelfinavir as a sole PI along with 2NRTI may be used in case of lack of storage facility for ritonavir or if patients canโt afford a ritonavir boosted PI or while providing treatment during
pregnancy.
Selection of Dual Nucleoside "Backbone" as Part of InitialCombination Therapy
Six nucleoside/nucleotide
HIV-1 reverse transcriptase inhibitors (NRTIโs)are currently available in India. Lamivudineis a common second agent in these combinations because of its tolerability. Though lamivudine has a low genetic barrier to resistance (a single mutation M184V/I causes high levelresistance), this mutation renders the virus less fit and delays development of thymidine-associated mutations (TAMs) which are responsible for ZDV and d4T resistance.38
The choice of another NRTI to be combined with lamivudine depends on cost, adverse event profiles and availability of fixed dose combinations, which potentially improves adherence. Another important issue would be the sequencing potential and availability of other NRTIโs to be used in future regimens. Randomized controlled trials have shown no difference in the potency between zidovudine + lamivudine and stavudine + lamivudine along with a PI.39,40 However, stavudine is significantlyassociated with long-term adverse events and is recommended only as an alternative in patients who cannot be initiated on ZDV(due to anemia) and cannot afford tenofovir. A combination of Zidovudine + lamivudine is recommended NRTI backbone for majority of the patients.
Another strategy may be to start with stavudine + lamivudine backbone (in patients who are anemic) and then switch to zidovudine + lamivudine at 12-24 weeks, when hemoglobin improves. However, no randomized controlled trials have been undertaken to assess this strategy.
Tenofovir is an NtRTI with once daily convenience and a good safety profile. When combined with lamivudine it has shown comparable efficacy with other NRTI backbones.41 However, there is very limited data on the use of tenofovir in the developing world. Other non-thymidine based backbones using ABC and ddI have the advantage of not being associated with long-term adverse events like lipodystrophy and dyslipidemia.42,43 When NVP based regimens are contemplated, consideration should be given to using fixed dose combinations (FDCs) of ZDV+ 3TC +NVP and d4T + 3TC + NVP which improves adherence due to low pill burden. It also reduces prescription errors and in a large observational cohort from India has shown effectiveness and tolerability.44
Though boosted protease inhibitors based regimens are extremely potent as first line therapy, they are only recommended in patients who canโt tolerate both NVP and EFV. Boosted PI based regimens are costly, complex, with high pill burden, associated with long term adverse events like dyslipidemia and
diabetes . The advantage for boosted PI based regimens is their high genetic barrier to resistance and patients failing these regimens usually do not have PI resistant mutations.