Which HIV Treatment Regimen to Start With

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Today, HIV-positive patients have access to dozens of powerful medications that can keep the virus at bay. Three classes of drugs have emerged in the last five to 10 years as treatment mainstays: non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and integrase inhibitors.

With so many potent medications to choose from, clinicians have embarked on several long-term clinical trials to compare the safety, tolerability and effectiveness of available treatments. Recently, many of these large studies have yielded results that have significantly impacted our understanding of the best first-line treatment.

In a symposium at ICAAC/ICC 2015 in San Diego, University Health Network clinician Sharon Walmsley, M.D., offered her insights on "What to Start With for 2015."

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Everyone Should Start

Last year, the results of the aptly named START study upended previously held ideas about which patients should begin treatment. Previously, guidelines suggested that HIV-positive patients with robust, functioning CD4+ cells (immune lymphocytes) should wait. Only once patients' CD4+ count dropped below 350 cells/mm3 would they be recommended for treatment. The START study asked, "should we wait?" and the answer was definitive. Patients who started on highly active antiretroviral therapy (HAART) right away were healthier than patients who were told to wait until their CD4+ was less than 350 cells/mm3. Because of this important trial, HAART should be offered to any newly diagnosed patient.

Questioning the Gold Standard

For decades, the NNRTI efavirenz, when combined with other medications to make the combo-drug Atripla, has been considered the gold standard of care. It is still true today that the combination drug efavirenz/emtricitabine/tenofovir disoproxil fumarate is the most effective medication available -- no other medication has surpassed it on efficacy measures.

Yet, recent data show that it is not as well tolerated as some other drugs, and if patients can't or won't stay on medication because of side effects, then strong efficacy does not matter. In fact, due to a small but alarming number of patients who have experienced risks of suicide on efavirenz-based combinations, experts agree that this drug should be moved to a second-tier choice of the best medication to start with.

Integrase Inhibitors and Drug Resistance

Recent efficacy data on integrase inhibitors has been strong, and this class of drugs is quickly emerging as a preferred first-choice for treatment. Integrase inhibitors are better tolerated over time. For example, in a long-term study that compared the integrase inhibitor raltegravir (Isentress) to efavirenz, over time raltegravir proved superior because of its better side-effect profile.

However, there is a concern with integrase inhibitors, as the price of failing with these drugs might be virological resistance. It's clear that if patients are failing on an integrase inhibitor, they should switch medication immediately to avoid building up additional virological mutations. Drug resistance is a real problem for some integrase inhibitors, but one, dolutegravir (Tivicay, DTG), seems less prone to resistance than others.

Dolutegravir Tips the Scales

Dolutegravir, approved in the United States in 2013, is an integrase inhibitor that has never led to virological resistance in any study of patients who have taken the drug as a first choice and then failed on treatment. The drug's outstanding performance on drug resistance was demonstrated in two large trials: the SINGLE and the FLAMENGO.

Considering dolutegravir, integrase inhibitors have a distinct advantage as a first-line option. They are extremely well tolerated by patients, and the proportion of patients who have had to stop treatment because of any adverse event is about 1% to 2% in any clinical trial.

Choosing a Treatment Backbone

Integrase inhibitors are not prescribed as monotherapy. Even though evidence has now emerged supporting integrase inhibitors as a first-line choice, clinicians must still pick the best backbone treatment for their patients. There are two options to chose from: the combination of tenofovir/emtricitabine (Truvada) or abacavir/lamivudine (Epzicom, Kivexa).

Yet neither of these combinations is without its problems. Tenofovir/emtricitabine has been associated with renal disease and osteoporosis, while abacavir/lamivudine has been associated with cardiovascular disease -- although this connection is debated.

For a patient with other comorbidities, such as kidney, heart or bone disease, these safety profiles present a problem. Unfortunately, dropping these backbone drugs is not really an option, because integrase inhibitors won't be as effective. But there is a new formulation of tenofovir entering the market soon that will hopefully reduce the bone and kidney risks.

So Where to Start in 2015?

Today, the vast majority of patients should consider the combination of an integrase inhibitor with two "nukes," such as the combo drugs tenofovir/emtricitabine or abacavir/lamivudine. The specific drug a doctor picks within the class will depend on desired coformulation and dosing schedule, and potential drug-drug interactions.

New treatment guidelines say that two nukes and the protease inhibitor darunavir (Prezista) could also be a first choice for some patients. This option would be best for someone with more advanced disease, because many integrase inhibitors studies have tested only with relatively healthy patients, so the effects on a sicker patient population are not well understood. This combination might also be best for patients who have trouble adhering to medication.