This strategy of intensification may help enhance the viral activity of the nucleoside regimen, while sparing addition of other drug classes (protease inhibitors). Discontinuation of efavirenz will prevent development of additional NNRTI resistance mutations. Continuing efavirenz in the setting of viral replication and in the presence of the K103N mutation is unlikely to contribute to viral activity, as this mutation selects for high level NNRTI resistance. Stopping efavirenz may, in theory, preserve future NNRTI options, as drugs in development are being designed to be active against viruses with the K103N NNRTI mutation, but in vitro are less active against viruses with multiple NNRTI mutations. While this strategy risks development of further resistance to the NRTI class, this risk is offset by the benefit of preserving future classes of drugs. It is difficult to predict whether susceptibility to abacavir is still present, however there is little to lose as abacavir shares a similar mutation pattern to the AZT/3TC regimen failed previously. If abacavir is used, close attention should be paid to abacavir hypersensitivity, which can occur in up to 5% of patients and is manifested by multi-system involvement with symptoms including rash, fever, nausea/vomiting, malaise, gastrointestinal, and/or pulmonary symptoms. Another related option is to D/C efavirenz and continue d4T/ddI dual-therapy. Although two-drug therapy would not be considered standard-of-care according to published antiretroviral therapy guidelines, in this case it may be possible to maintain partial suppression with two nucleosides. Using a 2 or 3 nucleoside regimen allows delaying use of other antiretroviral agents until new drugs (tenofovir, fusion inhibitors, possibly 2nd generation NNRTIs) are available.

PROs:
Adding third NRTI may enhance viral activity, preserves future NNRTI options, does not sacrifice other ARV classes

CONs:
Risk of additional development of NRTI resistance, monitor for abacavir hypersensitivity and mitochondrial toxicity

This approach is most consistent with currently published guidelines and is perhaps the most aggressive approach. The major concern is the early use of the patient's one remaining therapeutic class (protease inhibitors). If this aggressive approach is chosen, many panel members would discontinue the current regimen, either simultaneously or in stages (e.g. discontinue the efavirenz first and observe virologic response. If no virologic rebound and viral load is stable, then discontinue the d4t/ddI to observe virologic response) before switching. This allows “re-staging” of the patient to determine baseline viral load and CD4 off medications, plus his immune system may be able to partially control virus in the absence of medication. If rapid viral rebound occurs and CD4 count drops to below 300-350 cells/mm3 occurs, a new HAART regimen containing a protease inhibitor should be restarted. Protease inhibitor options include but are not limited to ritonavir/indinavir, ritonavir/saquinavir, or ritonavir/lopinavir (Kaletra™).

PROS:
Most aggressive, likely to attain complete viral suppression

CONS:
Risks exposing patient to protease inhibitor class, but without new drugs he has not used yet, patient may be able to maintain partial suppression on a nucleoside regimen and delay protease inhibitors, additional protease inhibitor side effects/complexity/pill burden

SIDE EFFECTS:
Side effects should be closely monitored for. If abacavir is started, the patient must be educated on symptoms of abacavir hypersensitivity and how to contact their provider if they experience symptoms. Abacavir hypersensitivity can occur in up to 5% of patients and is manifested by multi-system involvement with symptoms including rash, fever, nausea/vomiting, malaise, gastrointestinal, and/or pulmonary symptoms. Additonally, peripheral neuropathy, pancreatitis, and mitochondiral toxicity (e.g. lactic acidosis) are possible with the combination of d4T and ddI. Heavy alcohol use should be avoided to decrease the risk of pancreatitis. Protease inhibitors are frequently associated with GI side effects, particularly common with ritonavir. Hepatotoxicity, lipid abnormalities, hyperglycemia/insulin resistance, and fat redistribution abnormalities are also associated with protease inhibitors. Indinavir has the potential for causing nephrolithiasis and patients should drink at least 1.5L of fluid per day.