New paradigms in HIV therapy

Near 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). 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 non-nucleoside 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 will your disease be suppressed, but you won’t transmit it to your partner.”

But there are limitations. Patients must first be virologically suppressed on a stable ARV regimen with no previous treatment failure, so this combination can’t be used as a first-line therapy or in treatment-resistant patients. There also is some inconvenience. “You have to come in to see your health care provider; it can’t be self-administered,” Dr. Daar said. In addition, “if you skip an injection, you’re at pretty big risk for developing resistance. Both drugs have pretty long half-lives, but one is significantly longer than the other. Skipping a dose translates into using monotherapy, and we know that always selects for resistance.”

Other products are in the pipeline, including a subcutaneous agent that could be given at home once every six months. “That would be a home run, but we know you can’t do this with one drug, so you need to find another you can give every six months,” Dr. Daar said. “That’s the challenge: finding drugs that have promise to be long-acting, then figuring out how to pair them.”

Treatment Resistance

Today’s ARV regimens are more effective and easier to take than ever, but there is still a small percentage of people living with HIV who are heavily treatment-experienced and are resistant to multiple classes of drugs (AIDS 2020;34[14]:2051-2059). “The proportion of people with HIV who have two or fewer drug classes available to them has declined significantly since 2000, and represents about 1% of the population today,” Dr. Bedimo said. “This group includes patients who are highly adherent but were started on nonsuppressive regimens that led to selection of highly resistant HIV—fortunately, this is a smaller group—and a somewhat larger group of patients who do not have multidrug resistance, but are nonadherent to therapy due to various challenges and still have viremia.”

There is also a pediatric cohort among treatment-resistant patients. A 2019 study of young people who recently transitioned from pediatric to adult HIV care found that 56% of participants had at least one incident of unsuppressed viremia in the year before the transition (Clin Infect Dis 2020;71[1]:133-141).

“Some of these new therapies may be able to reduce the treatment-resistant population further,” Dr. Bedimo said. “For the second group—those with nonadherence issues—we can try to simplify the pill burden, reduce frequency of dosing with long-acting injectables, or if vascular or renal tolerability is an issue, try to find agents that mitigate the impact to these organs. As our population ages, they have other non-HIV medications they have to take, so we also need to mitigate potential drug-drug interactions.”

For adherent patients who have failed second-line regimens and beyond, the challenges are even greater. “We can use past and current genotypic and phenotypic resistance and ART history in designing a new regimen,” Dr. Bedimo said. “These patients should be on at least two, and preferably three, fully active agents, but partially active drugs may be used when no other options are available as they can partially suppress progression even if they don’t totally suppress viremia.”

He cited several novel agents that either have been recently approved or are in the pipeline, as possible options. They include the monoclonal antibody ibilizumab (Trogarzo, TaiMed Biologics), approved in March 2018 for heavily pretreated adults with HIV, administered intravenously every two weeks and used in combination with other ARV drugs; and fostemsavir (Rukobia, ViiV Healthcare), a first-in-class HIV attachment inhibitor approved in July 2020, for people with extensive drug resistance. It’s a twice-daily oral therapy also used with other ARV drugs.

“New mechanisms of action and additional long-acting regimens are also coming soon,” Dr. Bedimo noted. For example, in early August, data on Gilead’s twice-yearly, long-acting injectable lenacapavir, the first HIV capsid inhibitor, were reported at the 11th International AIDS Society Conference on HIV Science in July. The phase 2 Capella study found that lenacapavir in combination with an optimized background regimen produced sustained virologic suppression in 81% of heavily pretreated patients at week 26. In the phase 2 Calibrate study (theprogramme.ias2021.org/Abstract/Abstract/2211), it also produced high rates of virologic suppression in treatment-naive patients in combination with emtricitabine/tenofovir alafenamide (F/TAF).

“The group of people who need new options for treatment because of side effects or underlying resistance is not a huge number, but for those who are dealing with it, it’s their life,” Dr. Daar said. “These new options offer huge promise for these people, and it’s rewarding to see that companies have invested in developing treatments for them.”

By Gina Shaw