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Combination ART: are two drugs as good as three? Comment
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Lancet Jan 5 2018
*Mark A Boyd, David A Cooper
Faculty of Health and Medical Sciences, University of Adelaide,
Adelaide, SA 5112, Australia (MAB); and Kirby Institute, University
of New South Wales, Sydney, NSW, Australia (MAB, DAC)
The first 10 years of the development of antiretroviral therapy (ART) were characterised by a series of studies that led to the conclusion that triple therapy was the minimum required to induce and maintain full suppression of HIV replication. Early reports of using monotherapy with a nucleoside reverse transcriptase inhibitor (NRTI) had shown only transient decreases in p24 antigen and arrest of HIV disease progression.1 Studies of dual NRTI therapy showed more robust responses, but again these responses were temporary and unsustained in most individuals in the studies.2
The breakthrough came in 1996, at the XI International AIDS Conference in Vancouver, Canada, during which a set of studies that included antiretroviral drugs in two new classes (HIV protease inhibitors and non-NRTIs) added to two NRTIs were reported and had dramatic responses. Using the newly available and far more sensitive molecular amplification technology,3 the studies showed that these triple combination ART regimens could suppress and maintain HIV replication in plasma to very low concentrations, at which selection of resistance did not occur.4, 5 This outcome was accompanied by reconstitution of CD4-positive T cells and arrest of HIV disease progression. The triple ART era was born.
Since then, the use of three drugs has been the dominant framework in bringing new ART combinations to market. Nonetheless, there have been hints that the use of two drugs might be sufficient. For example, the ACTG 5142 study6 examined the use of efavirenz and ritonavir-boosted lopinavir, both given either as triple therapy combined with two NRTIs or together as dual therapy as an NRTI-sparing strategy. The time to virological failure was longer in the efavirenz group than in the lopinavir-ritonavir group but was not significantly different to the NRTI-sparing group. It should be remembered that the use of three drugs was not successful in the case of triple NRTIs. The ATCG 5095 study7 found that the triple combination of abacavir plus zidovudine plus lamivudine was substantially inferior to a triple combination of efavirenz plus two or three NRTIs. In retrospect, perhaps the pertinent lesson from these studies was that successful combination ART should be selected from drugs from two independent ART classes rather than simply containing three drugs.
Over the past 6 years, numerous studies examining various dual ART combinations in either viraemic patients or as a switch strategy have been done, many of them in underpowered pilot studies. A systematic review and meta-analysis8 of a set of selected randomised trials found that efficacy did not differ between the use of two and three drugs ART (excluding a-priori studies that included maraviroc as a component; most regimens contained a protease inhibitor). However, the analysis suggested that dual therapy was associated with selection of greater degrees of resistance at virological failure and poorer performance in people with a baseline viral load of more than 100 000 copies per mL.
In 2017, outcomes of some well powered studies shed more light on the risks and benefits of dual versus triple therapy as a switch strategy for people who have successfully achieved and maintained full virological suppression on conventional triple therapy. Results of the LATTE-2 study9 showed that the use of a two-drug ART regimen of 4-weekly injectable cabotegravir and rilpivirine successfully maintained virological suppression in people with HIV who had achieved full virological suppression using three drugs (oral cabotegravir plus abacavir-lamivudine). After 96 weeks of injectable therapy, no participant receiving the 4 weekly injections had virological failure.9
In The Lancet, Josep M Llibre and colleagues report on the SWORD 1 and 2 studies.10 These studies represent two identical randomised controlled, open-label, non-inferiority studies that examined a switch to oral dolutegravir and rilpivirine in participants who had at least 24 weeks of full virological suppression using conventional triple therapy. After 48 weeks, 95% (485 of 511) of participants who maintained the triple therapy and 95% (486 of 513) of participants who switched to dual therapy continued to have successful virological suppression (adjusted treatment difference of -0⋅2%, 95% CI -3⋅0 to 2⋅5), demonstrating non-inferiority within a predefined margin of -8%. These results make a convincing case for the use of dual therapy as a maintenance strategy.
The question of whether dual therapy can be used in people with viraemia (either in those patients naive to ART or having had virological failure) remains open. The GEMINI 1 and 2 studies (NCT02831673 and NCT02831764) in which triple therapy comprising dolutegravir plus tenofovir disoproxil fumarate and emtricitabine is being compared with dolutegravir and lamivudine as initial ART in people with a screening viral load of 500 000 copies per mL or lower have been enrolled and are underway. Other possibilities deserve exploration. For example, the use of tenofovir alafenamide combined with a once-daily integrase inhibitor would form a compact two-drug regimen that would effectively treat both HIV and hepatitis B, a good option for people living in low-income and middle-income countries. The once-weekly nucleoside translocation inhibitor in early human development (MK-8591) combined with a drug from another class offers another intriguing future possibility.11 All in all, 30 years since the emergence of ART, the potential pipeline for a variety of effective dual therapy options appears rich.
IAS: Single Doses as Low as 0.5 mg of the Novel NRTTI MK-8591 Suppress HIV for At Least Seven Days - (07/26/17)
IAS: Weekly Oral MK-8591 Protects Male Rhesus Macaques against Repeated Low Dose Intrarectal Challenge with SHIV109CP3 - (07/23/17)

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