**4.5. Synergistic enhancers of anti-retroviral drug action**

Certain compounds such as pharmacokinetic boosters and virostatics, are being evaluated for their role in potentiating the action of anti-retroviral drugs. The property of pharmacokinetic boosting is exclusively exploited for protease inhibitors which are metabolized and cleared from the body by the cytochrome P-450 CYP3A4 enzyme. The effect of protease inhibitors can be boosted if they are co-administered with compounds that inhibit this enzyme. The protease inhibitor ritonavir with the propensity to inhibit the cytochrome P-450 CYP3A4 enzyme, when co-administered with another protease inhibitor not only enhances its bioavailability, but also acts synergistically to minimize the dosage of both agents [24]. The combination of lopinavir boosted by ritonavir has been identified to provide maximum benefits with minimal adverse effects and hence is approved by the FDA and marketed as a fixed dose combination pill under the name, kaletra. Cobicistat is another unrelated compound which is a potent inhibitor of the cytochrome P-450 CYP3A4 enzyme without having any inherent anti-retroviral activity. As it is also capable of boosting the beneficial effects of integrase inhibitors, it is approved for use along with the fixed combination of elvitegravir, emtricitabine and tenofovir under the trade name, striblid [18, 25].

Virostatics is an abbreviation for the combination of antiviral (viro) and cytostatic drugs (static). This combination intends to reduce viremia by inhibiting HIV replication with antiretroviral drug and simultaneously reducing the number of the viral target cells (normal CD4 T-cells), using the cytostatic drug. It has been observed that the antiviral drug didanosine functions synergistically with hydroxyurea, an inhibitor of cellular proliferation to achieve viral load reduction. As this strategy depends on hydroxyurea induced immunosuppression for reduction of viremia, more knowledge has to be gained on its practicality, with respect to didanosine resistant HIV mutants and flare-up of opportunistic infections [26, 27]. The antiparasitic / anti-inflammatory drug leflunomide is also found to have similar synergistic effect to inhibit HIV replication when used along with nucleoside reverse transcriptase inhibitors [28, 29].
