Reductive ART Strategies: Time to Rethink the Unthinkable?
Reductive ART Strategies: Time to Rethink the Unthinkable?
Individuals living with HIV thrive in the current era, having several potent, well tolerated options for initial combination antiretroviral therapy (cART), including fixed-dose combination (FDC), single-tablet regimens (STRs). Many individuals who were virologically suppressed on complex regimens are switching to these simpler combinations, though a group of patients remain bound to complex regimens that were selected in order to overcome extensive drug-resistance mutations, while avoiding adverse effects and/or drug–drug interactions. Critically, all STRs to date contain emtricitabine and tenofovir disoproxil fumarate (TDF), and an anchor antiretroviral drug. This implies the available STRs have overlapping contraindications and adverse effects such as the bone and renal consequences of TDF. Studies are evaluating whether tenofovir alafenamide fumarate (TAF) will be an effective and safer alternative to TDF, and the pharmaceutical industry has announced plans to co-formulate dolutegravir and abacavir/emtricitabine as the first TDF-sparing STR.
Novel two-drug combinations are being investigated for initial therapy as well, demonstrating various degrees of efficacy. Lopinavir/ritonavir and lamivudine showed encouraging results in the Study of Lopinavir/Ritonavir and Lamivudine Versus Standard Therapy in Naïve HIV-1 Infected Subjects (GARDEL), whereas the Maraviroc Once-daily with Darunavir Enhanced by Ritonavir in a New regimen trial (MODERN) (NCT01345630) of ritonavir-boosted darunavir 800/100 mg and maraviroc 150 mg daily was prematurely terminated due to inferior efficacy. Results of ritonavir-boosted darunavir and raltegravir (NCT01066962) are on the horizon.
The next wave of progress in HIV-1 therapeutics needs to further address barriers to long-term antiretroviral drug success in the large population of patients who are already virologically suppressed or become suppressed on conventional three-drug cART, including the once-daily STRs. One major barrier to success is long-term toxicities, which may be compounded by comorbidities as the patient population ages. Additional barriers include cumulative costs and treatment fatigue. Accordingly, there is a need for 'reductive ART strategies', which we define as ART with fewer than three antiretroviral drugs per day in patients who are virologically suppressed on conventional three-drug cART.
Most efforts towards reductive ART have focused on ritonavir-boosted protease inhibitor (PI/r) monotherapy, and the latest frontier involves exploration of long-acting antiretroviral drug formulations. Long-acting formulations generally evoke excitement for individuals living with HIV and providers because this strategy opens the door to monthly or even less frequent dosing, which would address treatment fatigue for many patients. On the contrary, memories of suboptimal outcomes with monotherapy and dual therapy in the first decade of ART and equivocal results from other trials feed inertia against reductive ART strategies. Therefore, we find ourselves at a crossroads when considering the possibility of reductive ART in the modern era.
Background
Individuals living with HIV thrive in the current era, having several potent, well tolerated options for initial combination antiretroviral therapy (cART), including fixed-dose combination (FDC), single-tablet regimens (STRs). Many individuals who were virologically suppressed on complex regimens are switching to these simpler combinations, though a group of patients remain bound to complex regimens that were selected in order to overcome extensive drug-resistance mutations, while avoiding adverse effects and/or drug–drug interactions. Critically, all STRs to date contain emtricitabine and tenofovir disoproxil fumarate (TDF), and an anchor antiretroviral drug. This implies the available STRs have overlapping contraindications and adverse effects such as the bone and renal consequences of TDF. Studies are evaluating whether tenofovir alafenamide fumarate (TAF) will be an effective and safer alternative to TDF, and the pharmaceutical industry has announced plans to co-formulate dolutegravir and abacavir/emtricitabine as the first TDF-sparing STR.
Novel two-drug combinations are being investigated for initial therapy as well, demonstrating various degrees of efficacy. Lopinavir/ritonavir and lamivudine showed encouraging results in the Study of Lopinavir/Ritonavir and Lamivudine Versus Standard Therapy in Naïve HIV-1 Infected Subjects (GARDEL), whereas the Maraviroc Once-daily with Darunavir Enhanced by Ritonavir in a New regimen trial (MODERN) (NCT01345630) of ritonavir-boosted darunavir 800/100 mg and maraviroc 150 mg daily was prematurely terminated due to inferior efficacy. Results of ritonavir-boosted darunavir and raltegravir (NCT01066962) are on the horizon.
The next wave of progress in HIV-1 therapeutics needs to further address barriers to long-term antiretroviral drug success in the large population of patients who are already virologically suppressed or become suppressed on conventional three-drug cART, including the once-daily STRs. One major barrier to success is long-term toxicities, which may be compounded by comorbidities as the patient population ages. Additional barriers include cumulative costs and treatment fatigue. Accordingly, there is a need for 'reductive ART strategies', which we define as ART with fewer than three antiretroviral drugs per day in patients who are virologically suppressed on conventional three-drug cART.
Most efforts towards reductive ART have focused on ritonavir-boosted protease inhibitor (PI/r) monotherapy, and the latest frontier involves exploration of long-acting antiretroviral drug formulations. Long-acting formulations generally evoke excitement for individuals living with HIV and providers because this strategy opens the door to monthly or even less frequent dosing, which would address treatment fatigue for many patients. On the contrary, memories of suboptimal outcomes with monotherapy and dual therapy in the first decade of ART and equivocal results from other trials feed inertia against reductive ART strategies. Therefore, we find ourselves at a crossroads when considering the possibility of reductive ART in the modern era.
Source...