Antiretroviral Therapy in 2016: Expert Guidance on Choosing a Drug Regimen
April 7, 2016
In 2016, we'll continue to see new options for antiretroviral therapy (ART), including more single-tablet regimens (STRs) and simpler regimens for people with treatment experience and drug resistance. In this article, I'll discuss my choices for initial therapy, options for simplification and switching, and drugs in the pipeline.
Although there are many options for first-line therapy, in actual practice we use only a few of them. The treatment guidelines from the U.S. Department of Health and Human Services (DHHS) list six "recommended" regimens; five of them contain integrase inhibitors. In trial after trial, the integrase inhibitors are either as good as or better than older regimens, with clear safety and tolerability advantages. When I talk about starting therapy with a treatment-naïve patient who has no baseline drug resistance, the choice of initial regimen generally comes down to four: two STRs and two 2-tablet regimens. Let's start with the STRs. If taking one pill a day is important to you, you'll probably be choosing between Genvoya and Triumeq.
Genvoya, which includes the integrase inhibitor elvitegravir, is similar to Stribild except that it contains tenofovir alafenamide (TAF) rather than the original version of tenofovir, tenofovir disoproxil fumarate (TDF). TAF gets more tenofovir into cells with lower levels in the blood. As a result, it appears to have less kidney and bone toxicity than TDF. In fact we haven't seen any toxicity yet, though it will take time to know whether TAF is completely safe from a kidney and bone standpoint, or just safer than TDF. As I write this, Genvoya is the only approved agent that contains TAF, but that will change soon, as I discuss below. Since Genvoya has advantages over Stribild without any disadvantages or difference in cost, there's no reason to use Stribild anymore unless your insurance company just hasn't gotten around to approving Genvoya yet. The downside is that they both contain cobicistat, a booster that interacts with many other medications. In particular, be aware that cobicistat interacts with fluticasone, including Flonase, a widely used nasal steroid spray that's now available without a prescription.
Triumeq is another effective STR. Like Genvoya, it includes an integrase inhibitor (dolutegravir). Unlike Genvoya, it doesn't need a booster, which means there are fewer drug interactions. Dolutegravir has a higher barrier to resistance than the other two integrase inhibitors. Fortunately, resistance is uncommon with any integrase inhibitor, and extremely unlikely to happen if you're taking your meds. But so far we haven't seen any resistance in people taking dolutegravir as part of a complete regimen for initial therapy. Unlike other STRs, Triumeq contains abacavir/lamivudine as its nucleoside "backbone." There is still a lingering debate about whether abacavir increases the risk of heart attack. Current guidelines recommend avoiding abacavir (including Triumeq) if you have heart disease or a lot of risk factors for heart disease. Pre-screening for abacavir hypersensitivity with an HLA-B*5701 test is necessary before starting Triumeq. (See more information on Triumeq under Prezcobix plus F/TAF.)
If taking an STR isn't a priority, let me mention two other regimens you could consider. I discuss them assuming the new TAF-containing version of Truvada (currently referred to as F/TAF) will be approved on schedule in April.
Tivicay plus F/TAF: The problem with the two STRs I discuss above is that each involves a minor compromise. Triumeq has dolutegravir (available separately under the brand name Tivicay), everyone's favorite integrase inhibitor, but it requires taking abacavir, which has some disadvantages over tenofovir, especially now that TAF is available. Genvoya contains F/TAF, everyone's favorite new nucleoside backbone, but requires the cobicistat booster, which has drug interactions. If you want to avoid the compromise altogether, you could take the two-pill combination of F/TAF plus Tivicay (using Truvada plus Tivicay until F/TAF is approved). When I ask my HIV colleagues what they would take if they were HIV-positive, this is often the one they mention.
Prezcobix plus F/TAF: Protease inhibitors (PIs) used to be the drugs with the highest pill burden and the most side effects, but that's no longer the case. Two PIs, darunavir and atazanavir, are now coformulated with the cobicistat booster (Prezcobix and Evotaz, respectively), which means you can take a PI-based regimen with just two pills per day. They have a few more side effects than integrase inhibitors, but are still well tolerated, and without all the metabolic toxicity that used to come with the older PIs. Of the two, darunavir (either Prezista/Norvir or Prezcobix) is generally preferred over atazanavir (either Reyataz/Norvir or Evotaz) because of its better toxicity and tolerability profile. It's almost impossible to become resistant to PIs, even with poor adherence. I sometimes choose them when adherence is uncertain: in patients with substance abuse or mental health issues, those who miss a lot of clinic appointments, those with no prior experience taking chronic medications, or the very young. There's always the option of switching to an STR later, once it's clear that nonadherence isn't a problem. In fact, the combination of Prezcobix and F/TAF is being developed as an STR. While I mentioned only F/TAF as the NRTI backbone, Prezcobix can also be combined with Truvada or Epzicom. Dolutegravir-based regimens, including Triumeq, look like they may have the same resistance advantage, although we don't have the many years of experience with dolutegravir that we have with PIs. Still, if a patient with poor adherence insists on an STR, I choose Triumeq.
We're seeing a lot of data from "switch studies" these days. Drug companies obviously want you to switch from older drugs to their newer ones. Let's talk about when and why you might consider a switch. (Note that this discussion assumes you have an undetectable viral load on your current regimen and no prior drug resistance.) People on older regimens often worry that their combination is no longer "recommended," but the guidelines make it clear that what's no longer recommended for a person starting therapy may be fine for someone who's already taking it without problems. Let's discuss some specific examples.
Complera: It's not on the recommended list because of lower effectiveness at high viral loads and low CD4 counts, the food requirements, and the need to avoid acid-reducing drugs. But it's well tolerated and effective for those who take it correctly. There will be a new TAF-containing version of Complera coming out soon, and it will make sense for someone taking Complera to switch to the new version if possible.
Stribild: As I mentioned above, there's no reason not to switch to Genvoya.
Truvada: People taking Truvada can switch to F/TAF after it's approved (in combination with a third agent).
Atripla: While I no longer start this regimen because of its neuropsychiatric side effects, I've tended to leave people on Atripla if they're doing well, which means no sleep problems, disturbing dreams, depression, dizziness, or "cloudy thinking." However, unlike Complera, Truvada, and Stribild, there will be no TAF-containing version of Atripla. Many argue that a young person with healthy bones and no evidence of kidney toxicity has no reason to switch from TDF to TAF, but I'd prefer to use the safer form of tenofovir to avoid long-term toxicity. I'm now presenting this to my long-term Atripla patients as another reason to consider a switch. They can switch to one of the other STRs, or, if they love their wild efavirenz dreams, they can switch to F/TAF plus Sustiva.
Prezista/Norvir: If you're taking it once a day, there's no reason not to switch to Prezcobix simply to reduce the number of pills you take. If you're taking it twice a day because of darunavir resistance, Prezcobix is not an option.
Reyataz/Norvir: There's no reason not to switch to Evotaz to reduce pill burden.
Viramune: For toxicity reasons, Viramune is no longer recommended for initial therapy. But since all Viramune toxicity occurs in the first few weeks to months of treatment, it's not necessary to switch if you've been doing well on it for years, unless you'd prefer to be on an STR.
Older Protease Inhibitors
I can't think of a reason to use any PI other than the two I've mentioned. But if you're a creature of habit, you're happy with what you're taking, have no diarrhea, lipid problems, or blood sugar problems, and you don't mind the extra pills, you could choose to stay the course.
Before talking about new drugs, let's discuss some simplification options for treatment-experienced people taking what we used to call "salvage regimens." A recent study showed that in treatment-experienced people with drug resistance, switching to a two-pill combination of Genvoya and Prezista was more effective than remaining on the existing, multi-pill combination. However, this regimen isn't for everyone: People who enrolled in this study could have no integrase mutations, no darunavir mutations, and no more than 3 thymidine analog mutations (TAMs). An unstudied regimen that might also work in this situation would be Triumeq plus Prezcobix, but if you have drug resistance there are advantages of the F/TAF backbone in Genvoya over the abacavir/lamivudine backbone in Triumeq.
At double the usual dose, Tivicay is sometimes active against virus that's resistant to Isentress and elvitegravir, the integrase inhibitor in Stribild and Genvoya. The more mutations you have, the less likely you are to respond to Tivicay, so don't stay on other integrase inhibitors if they're not keeping your viral load suppressed. Integrase genotypes will tell you whether Tivicay still has activity.
Doravirine, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), has activity against common mutations that cause resistance to the existing NNRTIs (Viramune, Sustiva, and probably even Intelence).
Finally, there are new drugs in development with entirely new mechanisms of action. Fostemsavir blocks entry of the virus into the cell by interfering with the attachment of the virus to the CD4 receptor, and ibalizumab is a monoclonal antibody that binds directly to the CD4 receptor. BMS 955176 is a maturation inhibitor that disrupts the final processing of viral proteins. These drugs have promise for people who have run out of other options.
Other NRTIs, integrase inhibitors, and protease inhibitors are also being developed, including long-acting drugs that can be given by intermittent injections. For example, the combination of the integrase inhibitor cabotegravir and a long-acting version of rilpivirine (Edurant) is being given by intermittent injection in clinical trials, and cabotegravir is also being studied as an injectable PrEP agent.
Joel Gallant is medical director of specialty services at Southwest CARE Center in Santa Fe, New Mexico, adjunct professor of medicine at the Johns Hopkins School of Medicine, and clinical professor of medicine at the University of New Mexico. He treats patients and conducts clinical trials on the treatment of HIV infection. He is a past chair of the HIV Medicine Association and is on the Board of Directors of the IAS-USA. He is a member of the IAS-USA Antiretroviral Guidelines panel and the IDSA/HIVMA HIV Primary Care Guidelines panel. He authored 100 Questions and Answers about HIV and AIDS and has an interactive question and answer blog at hivforum.tumblr.com.
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