New Paradigms in HIV Therapy BY GINA SHAW
N
ear the end of the first act of Jonathan Larson’s iconic musical “Rent,” which opened on Broadway in New York City in 1996, a beeper goes off loudly. Mimi, an exotic dancer struggling with heroin addiction, tells her date (who unknown to her also has HIV), “AZT break!” Twenty-five years later, living with HIV no longer requires constant reminders to take multiple daily pills with potentially debilitating side effects. These and other advances represent a paradigm shift in HIV management, according to interviews with HIV experts. “The biggest news in HIV management isn’t just how good our therapies are—they are great. But we’ve been there for a long time,” said Eric Daar, MD, the chief of the Division of HIV Medicine at Harbor-UCLA Medical Center in Los Angeles. For virtually everyone who starts taking their HIV regimen as prescribed, their viral load will drop to undetectable levels within six months, maintaining their health and preventing transmission of the virus to sexual partners, Dr. Daar noted, citing data from the National Institute of Allergy and Infectious Diseases (bit.ly/3jHIDnV). What is new, he said, is how easy the latest drugs are to take. “Our current regimens are incredibly well tolerated, very safe, with limited drug-drug and drug-food interactions [JAMA 2020;324(16):1651-1669]. They also come in increasingly smaller and smaller single tablets that need to be taken only once a day, and we have several regimens, so those who are unlucky to have some side effects can usually go on to one of the others with all the same advantages. It just continues to get easier and easier for people to take these medications.” For most people with newly diagnosed HIV, clinicians should start by reviewing the latest information from the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents (updated June 2021; bit.ly/37TXbKi). The guidelines recommend starting treatment with two nucleoside reverse transcriptase inhibitors administered in combination with a third active antiretroviral (ARV) drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a nonnucleoside reverse transcriptase inhibitor, or a protease inhibitor with a pharmacokinetic enhancer. (See box for more details.) The latest guidelines removed raltegravir (RAL)-based regimens as initial therapy for most people because RAL has a lower barrier to resistance than bictegravir (BIC) and dolutegravir (DTG), and RAL-based regimens have a higher pill burden than other INSTI-based regimens. In addition, new study data (Lancet 2021;397[10281]:1276-1292) showed the risk for neural tube defects associated with DTG use during conception is much lower than previously understood, so women of childbearing age no longer need to choose RAL over DTG.
“We’ve known for several years that people whose viral load is already suppressed on a three-drug regimen can switch to two, but now it is possible even in people starting therapy for the first time,” Dr. Daar said. “Now, it’s open to debate just how big an advantage this is. Yes, fewer drugs mean smaller pills, fewer interactions and less toxicity, but most of the other first-line therapies have pretty small pills, few interactions and few side effects already. Cost is another issue. While that’s not necessarily defined by how many drugs are in a regimen, DTG/3TC did come in at a lower cost than other standard regimens.” A 2016 analysis found that DTG/3TC could save more than $500 million in antiretroviral treatment (ART) costs in the United States over five years (Clin Infect Dis 2016;62[6]:784-791). One of the most recent paradigm shifts in HIV therapy is the option for a long-acting regimen. In January 2021, the FDA approved cabotegravir and rilpirivine (CAB-RIL; Cabenuva, ViiV Healthcare/Janssen)—the first long-acting, once-monthly injectable HIV treatment. “This simplifies therapy in many ways,” said Roger Bedimo, MD, the chief of the Infectious Diseases Section at the VA North Texas Health Care System. “It addresses issues such as pill fatigue and the daily stigma of oral medications, and because it is administered by a health care provider, it offers ease of documenting adherence.” The once-monthly treatment cycle for CAB-RIL might even be extended to once every two months soon, Dr. Daar said. The FDA is considering a supplemental New Drug Application based on results from the phase 3b ATLAS-2M study. According to the data, the antiviral activity and safety of the antiviral combination administered once every two months was noninferior to once-monthly administration (Lancet 2020;396[10267]:1994-2005). “That’s pretty amazing,” he said. “Patients will go from multiple pills a day, every day, to coming in six days a year and being assured that not only
INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021
27
