THERAPY IN 2014
How does a doctor choose?
By Joel Gallant, MD, MPH
While development of drugs for HIV infection has definitely slowed over the last several years, treatment options continue to expand and improve, making antiretroviral therapy (ART) easier, better tolerated, and more convenient. In this article, I’ll discuss my own opinions on options for initial therapy, and what’s in the pipeline for treatment-experienced patients.
There’s a wealth of potential options for first-line therapy, but only a few combinations that we should actually be using on a regular basis. Speaking for myself, my “go-to” regimens for a patient starting antiretroviral therapy (ART) without baseline resistance consist of a small handful of combinations, listed here in alphabetical order:
- Prezista/Norvir or Reyataz/Norvir plus either Truvada or Epzicom
- Tivicay plus either Truvada or Epzicom
Of course, I have patients on many other first-line regimens. There’s no reason to switch therapy in someone doing well on Atripla, Viramune, or Isentress, for example. But I generally stick with one of the choices mentioned above if I’m starting ART for the first time. Here’s why:
Atripla is an effective medication that has served us well for many years, but the early and usually temporary neuropsychiatric side effects (vivid dreams, dizziness, mood and cognitive changes) have always been a drawback—one that we don’t have to put up with anymore using other combinations. It’s also clear that some people have lingering side effects: depression, difficulty focusing or concentrating, or sleep changes that persist long after the more intense early side effects have resolved. These changes may be subtle, and it can sometimes be impossible to know whether they’re caused by Atripla without making a switch. I leave people on Atripla if they’re doing well without side effects, but I don’t use it any longer in people starting ART.
Viramune becomes a fine drug after the first month or two, but it can have potentially serious and even life-threatening toxicities during the first few weeks, especially in people with high CD4 counts. Now that we’re starting ART when CD4 counts are high, Viramune isn’t a great choice for most people. But there’s no need to switch therapy in people doing well on Viramune unless they prefer to switch to a single-tablet regimen.
Isentress is a terrific drug: it’s effective, well tolerated, and has few drug interactions. Its only downsides are that it’s taken twice a day (unlike Tivicay and Stribild) and isn’t available in a single-tablet regimen (unlike Stribild). If you’re taking other twice-daily medications anyway, there’s no reason to switch, but for those who would prefer something more convenient, Stribild and Tivicay offer easier alternatives.
So how do I choose among my favorite regimens?
Stribild is a great choice for people who want an easy, single-tablet regimen, even if they have high viral loads or low CD4 counts. I avoid it in people with kidney disease or those who need drugs that can’t be taken with cobicistat, which is similar to Norvir in terms of drug interactions.
I sometimes use Complera in people with baseline viral loads below 100,000 and CD4 counts above 200 who want an easy, well tolerated, single-tablet regimen. Adherence is essential, of course, and it has to be taken with a meal. I avoid it in people who are taking proton pump inhibitors or H2 blockers to treat ulcers, heartburn, or reflux. I also use Complera as a “switch drug” in people on more complex regimens who want something simpler, provided they don’t have resistance to NRTIs or rilpivirine.
Prezista/Norvir or Reyataz/Norvir: I choose a PI for people whose adherence is uncertain: people with substance abuse or mental health issues, people who frequently miss clinic appointments, people with no prior experience taking long-term medications, the very young, or just the patient I don’t know well. PIs are also recommended for those starting ART during acute infection, before resistance test results are available. There’s always the option of switching to a single-tablet regimen later, once it’s clear that there’s no resistance and the patient can adhere to therapy. However, PIs continue to get easier. This year it should be possible to take a PI-based regimen with just two pills per day: either Prezista/cobicistat or Reyataz/cobicistat plus either co-formulated Truvada or Epzicom. Of the available PIs, Prezista has the fewest side effects. Reyataz can cause jaundice, kidney stones, and gallstones, and drugs that reduce stomach acid interfere with its absorption. I may choose Reyataz for people with severe sulfa allergies, since they may be more likely to develop a rash on Prezista.
Tivicay, the newest addition, looks like a terrific drug: potent, well tolerated, easy, and with few drug interactions. Its only drawback is that it’s not available yet in a single-tablet formulation, but that will soon change when the abacavir/3TC/dolutegravir pill (see 572-Trii) is approved. Abacavir still has its issues, which I’ve discussed in my Drug Guide comments, but it will be nice to have a single-tablet combination for people who can’t take tenofovir.
The choice of NRTIs
IN my list above, those taking a PI or Tivicay have to choose between Truvada or Epzicom as their NRTI “backbone.” For people without kidney disease or osteoporosis, I choose Truvada. I use Epzicom in people with kidney or bone disease, provided their HLA B*5701 is negative and they don’t have a lot of cardiac risk factors (hypertension, diabetes, high cholesterol, smoking, family history). The jury’s still out on whether abacavir really increases the risk of heart attack, but until we know for sure, I play it safe. Some people aren’t good candidates for any NRTI: the typical example is someone with kidney disease and either a positive HLA B*5701 or high cardiac risk. In such cases, I may use a “nuke-sparing regimen”—usually a combination of a boosted PI plus either an NNRTI or an integrase inhibitor. These haven’t been well studied, and the data we have so far have been disappointing, but sometimes we just have to “wing it” (using the best available data) to avoid NRTI toxicity, hoping that we’ll soon know more about how to appropriately use regimens that don’t include NRTIs.
Because there are now so few people with HIV that’s “untreatable” with approved drugs, pharmaceutical companies have lost interest in developing drugs for what we used to call “salvage therapy.” Most drugs in development are intended for first-line use, because that’s where the money is. That being said, there is some good news for people with extensive drug resistance.
At double the usual dose, Tivicay is sometimes active against virus that’s resistant to Isentress and elvitegravir (the integrase inhibitor in Stribild). But the more integrase mutations you have, the less likely you are to respond to Tivicay, so don’t stay on Isentress or Stribild if they’re not keeping your viral load undetectable. Get an integrase genotype test to find out whether Tivicay will still work. If it will, get off the integrase inhibitor to avoid accumulating new mutations, and use Tivicay only when you can combine it with at least one other active drug.
Because it achieves higher tenofovir levels within cells, the investigational prodrug of tenofovir—tenofovir alafenamide fumarate (TAF)—may be active against NRTI-resistant virus, including virus that’s resistant to tenofovir DF, the current version of tenofovir (Viread), which is included in Truvada, Atripla, Complera, and Stribild.
Finally, there are new entry inhibitors in development that block the attachment of the virus to the CD4 receptor. These attachment inhibitors might eventually offer promise to people who have run out of other options.
Another bit of good news for people with drug resistance is that their regimens may soon get simpler. For example, it may not be long before someone with resistance to NRTIs, NNRTIs, and PIs could take a regimen consisting of a single tablet combination of elvitegravir, cobicistat, emtricitabine, and TAF (“son of Stribild,” if you will) plus a single tablet of Prezista. That two-tablet “salvage” regimen would be a remarkable improvement over the kinds of regimens that many treatment-experienced patients are taking now. This is just one example of how the combination of new drug development and drug co-formulation may make things easier for people with drug resistance.