December 15, 2014
There was a time when some HIV experts proposed that we rip a page from the oncology playbook and take an induction-maintenance approach to HIV treatment. I thought these people were nuts, or else they were seeing patients very different from the men and women at our clinic, who more often than not were struggling to get to their appointments, keep their meds straight, and cut down on their crack use.
Now, I sing a different tune. Not because our patients have changed, but because our medications have.
The number of once-daily single tablet regimens for the treatment of HIV infection has tripled in the past couple of years, and unlike efavirenz/tenofovir/emtricitabine (Atripla), originally approved in 2006, these newer agents are as attractive as a switch option as they are initial therapy.
But not all simplification strategies trade down to a single pill. For some, the idea is to move from a particular antiretroviral therapy class or reduce the number of classes being taken. The table below highlights major studies that looked to switch virologically suppressed patients to a simplified regimen.
|GS-123||TDF/FTC + RAL||TDF/FTC/EVG/Cobi||✔|
|Strategy-NNRTI||TDF/FTC + NNRTI||TDF/FTC/EVG/Cobi||✔|
|Strategy-PI||TDF/FTC + PI/RTV||TDF/FTC/EVG/Cobi||✔|
|SPIRIT||2 NRTI + PI/RTV||TDF/FTC/RPV||✔|
|SPIRAL||2 NRTI + PI/RTV||2 NRTI + RAL||✔|
|SWITCHMRK||2 NRTI + LPV/RTV||2 NRTI + RAL||X|
|HARNESS||2 NRTI + 3rd Agent||TDF/FTC + ATV/RTV||✔|
|ATV/RTV + RAL||X|
|SALT||ATV/r + 2 NRTI||ATV/r + 3TC||✔|
|OLE||LPV/r + 2 NRTIs||LPV/r + 3TC||✔|
Some notables here include the STRATEGY-PI and STRATEGY-NNRTI trials, in which patients who changed to the fixed dose combination of elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild) maintained suppression of viremia just as well as those continuing on their pre-study therapy. Benefits of the switches were less gastrointestinal issues with the change from a protease inhibitor (mostly lopinavir/ritonavir) and improvement in neuropsychiatric symptoms for those coming off their non-nucleoside (mostly efavirenz).
The SPIRIT study looked at going from two nukes plus a protease inhibitor to the fixed dose combo of rilpivirine/tenofovir/emtricitabine (Complera). Again, low rates of virologic failure were seen, even among those with long-ago pretreatment HIV RNA levels of >100,000 copies/mL.
Not all switches are good. Years ago, in the STARTMRK trial, we learned that patient selection was just as important as regimen selection when messing with success. Participants entering that study with a prior history of virologic failure were more likely to fail a change from lopinavir/ritonavir to raltegravir than those without such a history. In contrast, in the STRATEGY and SPIRIT studies, entry criteria aimed to exclude those with resistance to the components of the substitution regimen.
In the HARNESS study, changing to atazanavir (Reyataz)/ritonavir + raltegravir was fairly disastrous, with high levels of failure and treatment-limiting adverse events. This seems to be due to an interaction between atazanavir and raltegravir leading to higher levels of the former, but there may well be a potency issue here too, as suggested by the virologic failure data mentioned above.
The clinical data is nice to have. I have warmed up to switching: I now offer this option to appropriate patients who have long been suffering with multiple pill bottles, copays, and quality-of-life-robbing low level side effects. In practice, we can feel secure in using the regimens found to be efficacious in switch studies. However, we must also make certain we do not handicap a simplified regimen by ignoring prior failures and possible resultant drug resistance. First, do no harm.
What are some other top clinical developments of 2014? Read more of Dr. Wohl's picks.
David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.
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