Although there are many options for first-line therapy, in actual practice we use just a few. Recognizing this fact, the International Antiviral Society-USA (IAS-USA) took a minimalist approach last year, including only four regimens in the "recommended" category: Genvoya, Triumeq, Isentress + Descovy, and Tivicay + Descovy. All four are integrase inhibitor-based regimens, and all but one (Triumeq) contain TAF, the new version of tenofovir. The guidelines from the U.S. Department of Health and Human Services (DHHS) recommend either TAF or TDF, the original version of tenofovir, and still include one protease inhibitor (PI)-based option: Prezista + Norvir. In trial after trial, the integrase inhibitors are either as good as or better than older regimens, with clear safety and tolerability advantages. Once again, neither group included a non-nucleoside reverse transcriptase inhibitor (NNRTI) in their list of recommended combinations. In discussing initial options, let’s start with the single-tablet regimens (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 TAF rather than TDF. TAF gets more tenofovir into cells with lower levels in the blood. As a result, we haven’t seen any kidney or bone toxicity so far, though it will take time to know whether TAF is completely safe from a kidney and bone standpoint or just safer than TDF. Genvoya contains cobicistat, a booster that, like Norvir, interacts with many other medications. In particular, be aware that it interacts with fluticasone, including Flonase, a widely used nasal steroid spray now available without a prescription.
Triumeq is another effective STR. Like Genvoya, it combines an integrase inhibitor (dolutegravir) with abacavir (ABC) and lamivudine (3TC), the two ingredients of Epzicom. Unlike Genvoya, it doesn’t need a booster, which means fewer drug interactions. Dolutegravir has a higher barrier to resistance than the other two integrase inhibitors. 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 when dolutegravir-based regimens are used for initial therapy. There’s still debate about whether the ABC in Triumeq increases the risk of heart attack. Current guidelines recommend avoiding it if you have heart disease or several risk factors for heart disease. Pre-screening for ABC hypersensitivity with an HLA-B*5701 test is necessary before starting Triumeq. If taking an STR isn’t a priority, here are two other regimens you could consider.
Tivicay plus Descovy: The problem with the two STRs I discuss above is that each involves a minor compromise. Triumeq has dolutegravir (Tivicay), everyone’s favorite integrase inhibitor, but it requires taking abacavir (ABC), which has some disadvantages over tenofovir, especially now that TAF is available. Genvoya contains emtricitabine (FTC) and TAF, everyone’s favorite nucleoside backbone, but requires the cobicistat booster, which has drug interactions. If you want to avoid any compromise, you could take the two-pill combination of Tivicay + Descovy. When I ask my HIV colleagues what they would take if they were HIV-positive, this is the one they most often mention.
Prezcobix plus Descovy: PIs used to be the drugs known for their high pill burden and nasty side effects, but that’s no longer the case. Two PIs, darunavir and atazanavir, are now co-formulated with the cobicistat booster (Prezcobix and Evotaz, respectively), which means you can take a PI-based regimen with just two pills per day. Although these PIs have a few more side effects than integrase inhibitors, they’re still well tolerated and don’t have all the metabolic toxicity we saw with the older PIs. Of the two, darunavir (either as Prezista/Norvir or Prezcobix) is 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, or those with no prior experience taking chronic medications. 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 the drugs in Prezcobix and Descovy is being developed as an STR. Dolutegravir-based regimens, including Triumeq, look like they have the same resistance advantage and are generally better tolerated. Although we don’t have as many years of experience with dolutegravir as we do with PIs, we haven’t seen resistance yet.
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. But while people on older regimens sometimes worry if their combination is no longer “recommended,” the guidelines make it clear that what’s not recommended for someone starting therapy may be fine for someone who’s already taking it without problems. Let’s talk about when and why you might consider switching from a regimen that’s working...assuming you have an undetectable viral load on your current regimen and no resistance to any of the drugs you’ll be switching to.
Complera: Odefsey is gradually replacing Complera because it contains TAF instead of TDF. Neither is on the recommended list for initial therapy because they’re less effective at high viral loads and low CD4 counts and you have to take them with a meal, avoiding acid-reducing drugs. Still, Odefsey is well tolerated and effective if you take it correctly. If you’re on Complera, there’s no reason not to make the switch.
Stribild: Similarly, I can’t think of a reason not to switch from Stribild to the TAF-containing version, Genvoya.
Truvada: At the moment, there’s no reason not to switch from Truvada to the TAF-based version, Descovy (in combination with a third agent). That could change when generic TDF becomes available and the price goes down, but for now, there’s no increase in cost with the switch.
Atripla: I no longer start this regimen because of its neuropsychiatric side effects. Most of my patients who experienced those effects (sleep problems, disturbing dreams, depression, dizziness, or “cloudy thinking”) already switched to something else a long time ago, leaving just a handful who either tolerate it well or love the vivid dreams. However, there will never be a TAF-containing version of Atripla. This is a new reason for people to consider switching, usually to one of the other STRs. Those who look forward to their wild efavirenz dreams every night can keep them by switching to Descovy + Sustiva.
Prezista/Norvir: If you’re taking it once a day, there’s no reason not to switch to Prezcobix 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: Similarly, 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 almost 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 nucleoside analogs: No one should be taking didanosine (ddI, Videx) or stavudine (d4T, Zerit) anymore. In fact, they’re finally being taken off the market for that reason. I can’t think of a reason to use zidovudine (AZT, Retrovir, also found in Combivir and Trizivir) either.
Older protease inhibitors: There’s little reason to use any PI other than the two I’ve already mentioned, but if you’re a creature of habit, you’re happy with what you’re taking, have no diarrhea, have no problems with lipids or blood sugar, 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 were once called “salvage regimens.” A recent study showed that in some treatment-experienced people with drug resistance, switching to a two-pill combination of Genvoya and Prezista was better than staying on the existing, multi-pill combination. This regimen isn’t for everyone: People who enrolled in the 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 some situations would be Triumeq plus Prezcobix, though if you have drug resistance there are advantages of the FTC/TAF backbone in Genvoya over the ABC/3TC backbone in Triumeq. Some providers are also using rilpivirine to replace etravirine (Intelence) in order to simplify complex regimens. This is an untested strategy, but it allows the use of Odefsey (rilpivirine plus FTC/TAF) in combination with a protease inhibitor, integrase inhibitor, or both. A very small study suggested that the two-pill combination of Tivicay plus Edurant could be considered in treatment-experienced patients without resistance to either drug; the same is presumably true for the two-pill, three-class combination of Tivicay plus Odefsey.
At double the usual dose, Tivicay is active against some virus that’s resistant to Isentress and elvitegravir, the integrase inhibitor in Stribild and Genvoya. But 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 sometimes even Intelence and Edurant).
Bictegravir, an investigational integrase inhibitor, is being studied in an STR that also contains FTC and TAF.
Entry inhibitors. Two drugs that block entry of the virus into the CD4 cell look promising for people who have run out of other options. Fostemsavir blocks entry of the virus into the cell by interfering with the attachment of the virus to the CD4 receptor. Ibalizumab is a monoclonal antibody given by intravenous infusion that binds directly to the CD4 receptor.
Long-acting agents. The combination of the integrase inhibitor cabotegravir and a long-acting version of rilpivirine (Edurant) is being given by monthly intramuscular injection in clinical trials, and cabotegravir is also being studied as an injectable PrEP agent. MK-8591 is a long-acting nucleoside reverse transcriptase translocation inhibitor (NRTTI) that has the potential for either oral or injectable dosing. This approach won’t be right for everyone, though. One concern about long-acting agents is the danger of missing doses. For example, skipping a monthly injection of cabotegravir/rilpivirine could result in a month of gradually declining drug levels and the potential for two-class drug resistance. Also, if you’re already taking pills for other conditions anyway, andyou’re seeing your provider just twice a year, coming in for monthly injections in order to decrease your daily pill burden by one or two tablets might not seem like a lousy trade-off.
A hot new trend in HIV therapy is immediate initiation or “rapid start,” where ART is started right away, sometimes on the day of diagnosis. This approach is appealing not only because of the health and prevention benefits of ART, but also because people who are on treatment are more likely to remain engaged in care than those who are just told to come back for more clinic visits. Only certain regimens can be started without lab results. My short list would include Genvoya, Tivicay + Descovy, or Prezcobix + Descovy. Triumeq and other ABC-containing regimens are out because you need the HLA-B*5701 test first. TDF-based regimens require information on kidney function. You shouldn’t start NNRTI-based regimens (e.g. Atripla, Odefsey) without a baseline resistance test, and you need to know the baseline viral load and CD4 count before starting rilpivirine (Complera or Odefsey).
Another strategy being studied involves two-drug regimens instead of the three-drug approach we’ve been using for the last 20 years. I’ve discussed the long-acting cabotegravir + rilpivirine(Edurant) studies (which enroll people whose viral load is already suppressed on standard therapy). The two-drug combination of oral Tivicay + Edurant is also being evaluated. There are two ongoing trials of Tivicay + 3TC (lamivudine), which is attractive mainly because of the low cost of the generic 3TC component. Some researchers have so much confidence in Tivicay that they’ve been giving it by itself (“monotherapy”). I don’t recommend that approach, since we’ve already seen integrase resistance emerge with Tivicay monotherapy, which we’ve never seen when Tivicay is combined with other drugs.
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 on the Board of Directors of the IAS-USA and of the HIV Medicine Association (HIVMA), which he previously chaired. He is a member of the IAS-USA Antiretroviral Guidelines panel and the IDSA/HIVMA HIV Primary Care Guidelines panel. He is the author of 100 Questions & Answers about HIV and AIDS and has an interactive question and answer blog at hivforum.tumblr.com.