Abstract
More than 20 years ago, there was a revolution in the treatment of HIV-infected patients and it was soon understood that combined treatment was needed to reduce morbidity and mortality associated with this infection. Years later, the treatment paradigm in the overwhelming majority of therapeutic guidelines was the use of three-drug regimens: two nucleos(t)ide reverse transcriptase inhibitors (nucs) and one-third drug [previously a nonnuc or a protease inhibitor, currently the most consensual as a first-line, an integrase inhibitor (INI)]. Over the past 2 years, a novel therapeutic approach has been widely studied with promising results: if simplified two-drug regimens seem to have the same efficacy (noninferiority), why use three or four drugs? This is the big question. The scientific evidence of the success of those therapeutic schemes is increasing in the medical literature. The NEAT 001 [1] study showed noninferiority of ritonavir-boosted darunavir (DRV/r) with raltegravir versus DRV/r and two nucs in treatment naïve patients with CD4+ less than 200 cells/ml and HIV-1 RNA less than 100 000 copies/ml. Similar results were showed on the GARDEL study [2], in which drug-naïve patients on ritonavir-boosted lopinavir (LPV/r) and lamivudine (3TC) had similar virological suppression, lower toxicity and better tolerability compared with a three-drug regimen (LPV/r and two nucs). Equally successful results were presented by the ANDES study [3] DRV/r and 3TC versus DRV/r and two nucs. Moreover, the ACTG A5353 [4] showed virologic suppression rates greater than 90% at 24 weeks in naïve patients under dolutegravir (DTG) and 3TC even with HIV-1 RNA up to 500 000 copies/ml. More recently, the GEMINI 1 and 2 studies [5] showed noninferiority in virologic suppression of previously INI-naïve patients under DTG and 3TC with failure rates below 1% and no evidence of resistance mutations to those antiretroviral drug classes. A new systematic review and network meta-analysis, performed on a large scale comparing the use of DTG and 3TC in HIV-1 drug-naive patients versus three-drug regimens, seems to be yet another example that the therapeutic paradigm may, safely, change. Radford et al. [6] constructed a network of 14 randomized clinical trials with more than 10 000 treatment-naïve patients and analyzed it using a Bayesian methodology. In this way, Radford et al. [6] evaluated virological suppression at week 48 of three-drug regimens versus DTG and 3TC including patients with HIV RNA more than 100 000 copies/ml, as well as CD4+ T-cell count progression and safety by quantification of adverse effects. The results appear to be once again promising as DTG and 3TC behaves as well as the classical three-drug regimens evaluated with similar virologic suppression, immune recovery, and number of adverse effects at 48 weeks. In particular instances, the two-drug regimen performed even better than standard three-drug regimens, as was the case of virologic suppression at 48 weeks compared with efavirenz and disoproxil fumarate/emtricitabine. As suggested by earlier studies and by the meta-analysis published in this issue of AIDS[6], two-drug regimens appear to be equally effective compared with classic regimens, and undoubtedly represents a trend in the future of HIV treatment worldwide. Indeed, a few international guidelines already consider certain dual therapies including boosted protease inhibitor and 3TC or an INI, recommended to specific HIV-treatment groups [7,8]. The use of two-drug regimens will significantly avoid a number of disadvantages brought by standard schemes. The long-term side effects of standard treatments, including increased cardiovascular disease and bone and renal toxicities [9–11], are important issues to be considered towards such simplified schemes. Moreover, simplified schemes are also less prone to adverse drug–drug or pharmacokinetic interactions commonly seen in HIV-infected patients that have to treat other clinical conditions, including concomitant infections and malignancies [12–14]. Financial costs are expected to reduce in simplified HIV treatments, both at individual and population levels. It has been estimated that between US$ 500 million and US$ 3 billion would be saved in antiretroviral treatment costs in the United States in 5 years should a simplified DTG and 3TC regimen starts in HIV drug-naïve patients and as a switch from standard regimens to maintain virological suppression among treated people [15]. In resource-limited settings such as Brazil, where DTG-containing regimens are already the standard-of-care and where a universal public health system provides HIV therapy to large amounts of people for free (currently over 600 000 patients) [16], the impact on the country's health economy would be unprecedented. Such cost-effectiveness is expected to reach multiple nations, both resource-rich and limited, with the dissemination of simplified DTG-containing schemes. Acknowledgements No funding has been received for writing this article. Conflicts of interest F.D. has received honoraria for speaking or advising and research grants from Bristol-Myers Squibb, AbbVie, Gilead, Janssen, Merck and ViiV. M.A.S. has received honoraria for speaking from BioMérieux and has been supported by research grants from Merck in the form of subcontracts.
Published Version
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