Paradigm Shifts in Antiretroviral Therapy

Every so often, a paradigm shift occurs in medicine.

In HIV antiretroviral management, the first shift, at least arguably, occurred when it was shown in several trials that a combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) was better than monotherapy.^1-3 A second shift occurred when the addition of low doses of ritonavir to another protease inhibitor (plus 2 NRTIs) demonstrated greater potency and substantially lower risk of drug-limiting mutations compared with an “unboosted” protease inhibitor (plus 2 NRTIs).⁴ Still a third occurred when efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), was shown to have greater virologic potency than a boosted protease inhibitor, when either was added to 2 NRTIs.⁵

I believe that a fourth shift occurred within the last year or so, when the US Department of Health and Human Services (DHHS) revised their guidelines such that 4 of the 5 “preferred” regimens for initial therapy included an integrase strand transfer inhibitor (INSTI).⁶

Of course, there have been other advances as well. Single tablet, 3-drug, fixed dose, once-daily regimens are available for the NNRTI and INSTI classes, and likely will be available for the protease inhibitor (PI) class within the next year or so. All of these regimens include 2 NRTIs, combined with 1 active drug from another class. Furthermore, all of the DHHS preferred regimens for initial therapy include 3 active drugs, of which 2 are NRTIs. But are 3 antiretroviral drugs necessarily any better than 2? Imagine comparing a 2-drug regimen, including 2 very potent and well-tolerated antiretrovirals with one of the current DHHS preferred or alternate regimens. Already we are getting intriguing hints that certain 2-drug regimens are likely to be as good as “standard” 3-drug regimens with the added advantage of potentially fewer side effects. And when the results of several of the planned larger trials comparing 2-drug regimens with 3-drug regimens are published in the next couple of years, I believe that we will be on the verge of a fifth paradigm shift.

All of which begs the question: Why are 2 NRTIs plus 1 drug from another antiretroviral class considered “standard of care”? One might think that the answer would be that regimens containing 2 NRTIs plus 1 drug from another class have been shown to be more potent than regimens containing 1 NRTI plus 1 drug from another class. But the reality is that those data do not exist to any great extent. I am forced to conclude that the reason we still use, and the reason that the DHHS guidelines still recommend, 2 NRTIs plus 1 drug from another class is purely historic. In other words, the sequence of events, involving multiple clinical trials over the last 3 decades, was that 2 NRTIs were better than 1, and that a PI plus 2 NRTIs were better than 2 NRTIs. And the rest, as the saying goes, is history. But all of that is likely to change.

At the recent 15^th European AIDS Conference in Barcelona, the presentation that created the most “buzz” was the one by the Fundacion HUESPED research group from Buenos Aires.⁷ In that presentation, Dr. Pedro Cahn showed that the combination of dolutegravir (an INSTI) plus lamivudine (an NRTI) was extremely potent, such that all 20 previously antiretroviral-naïve participants were able to achieve a viral copy number of <50 copies/mL within 8 weeks, and stay at <50 copies/mL through 24 weeks. Of course, the trial was small and not randomized, but the rapidity of the viral response stunned those in attendance. Partly as a result, multiple clinical trials are being proposed that involve combining dolutegravir with one of two ritonavir-boosted PIs or an NNRTI, or lamivudine, each of which will be compared, in large randomized trials, with one of the more “standard” regimens. And while it is possible that one of the standard regimens will be shown to be “better” than one of the 2-drug regimens, my prediction is just the opposite: specifically that the 2-drug regimens will be at least as potent, and likely better tolerated, than the 3-drug regimens. And then, the era of 2-drug regimens will be upon us.

Remember, you read about it first here.

References:

1. Eron J, Benoit S, Jemsek J, MacArthur RD, et al. The safety and efficacy of lamivudine (3TC)/zidovudine combination therapy vs. zidovudine monotherapy and lamivudine monotherapy in therapy-naive, HIV-positive patients with CD4 cell counts of 200-500/mm3: a randomized, double-blind, multicenter, controlled trial. N Engl J Med. 1995;333:1662-1669.
2. Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS clinical trials group study 175 study team. N Engl J Med. 1996;335:1081-1090.
3. Saravolatz LD, Winslow DL, Collins G, et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. N Engl J Med. 1996;335:1099-1106.
4. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346:2039-2046.
5. Riddler SA, Haubrich R, DiRienzo G, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358:2095-2106.
6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Accessed 14 NOV 2015.
7. Figueroa MI, Sued O, Patterson P, et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naïve patients: first results of the PADDLE Trial. Abstract LBPS4/1, 15th European AIDS Conference, 21 – 24 OCT 2015, Barcelona, Spain.