No matter who you ask — clinicians, researchers, financial analysts — the HIV landscape is hot and getting hotter every year.
Fueled by significant advances in treatment and prevention as well as an exciting pipeline, the global drug market for HIV treatment and prevention is expected to quickly reverse pandemic-related supply-chain challenges and declines in new prescriptions. In fact, current projections suggest an HIV market growth from just over $30B to an estimated $50B by 2030.
While it’s often assumed that HIV is a greater problem elsewhere in the world, market analysts note that North America continues to dominate drug demand because of the increasing prevalence of HIV infection among the US population. Today, an estimated 1.2 million people in the United States are living with HIV, 13% of whom are unaware they are infected.
With such a robust clinical need, Medscape Medical News reached out to several HIV experts and researchers to learn more about the drugs they favor, the advances and challenges in HIV prevention, and their expectations for what the future holds.
“There have been huge advances and changes since the advent of integrase inhibitors [INSTIs], and because HIV is such a rapidly evolving virus, we still have a constant need for new medications and new interventions,” Lina Rosengren-Hovee, MD, MPH, assistant professor and infectious disease physician and epidemiologist at the University of North Carolina at Chapel Hill, told Medscape Medical News.
“In the last 5 to 10 years, the biggest advances have been the increased tolerability of ART [antiretroviral therapy] and switching our preferred regimens to the integrase backbone,” she said.
Among the numerous combinations for people starting ART for the first time, Monica Gandhi, MD, director of the Gladstone Center for AIDS Research at the University of California San Francisco and medical director of Ward 86, San Francisco General Hospital HIV Clinic, said she and her colleagues lean toward the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) and nucleoside RT inhibitor 3TC (lamivudine). “The idea that you can make things easier for people — going from three-drug to two-drug therapy — we’re simplifying therapy,” she said.
The ability to take a single tablet has likewise been a game changer both for clinicians in the field and the patients they treat.
“What was previously a very complicated and side effects-ridden set of treatments that required upwards of 20 to 30 pills per day has now been simplified to an extremely well-tolerated single tablet regimen capable of reducing viral load to undetectable levels,” Raphael J. Landovitz, MD, professor of medicine and co-director of the Center for HIV Identification, Prevention, and Treatment Services at UCLA-Health told Medscape Medical News.
A Personalized Approach Is Best
Longitudinal data highlighting different side effect profiles of newer agents and combinations continue to emerge, helping clinicians move from a one-size-fits-all to a more personalized approach to treatment, which may ultimately improve outcomes.
“When I select a regimen for a patient, we always have an open conversation about the different drug types, number of drugs and regimen, the side effects, and delivery modality,” Rosengren-Hovee explained. “The most important thing is to have that open dialogue with a patient and tailor the regimen to their needs and desires.”
It’s also essential to consider factors that will boost or hinder adherence, especially when it comes to the new long-acting injectables.
In January 2021, the US Food and Drug Administration (FDA) approved the first long-acting injectable for monthly dosing — CAB-LA (a combination of the INSTI cabotegravir and the non-nucleoside reverse transcriptase inhibitor [NNRTI] rilpivirine) — subsequently green-lighting a bimonthly regimen in February 2022. But as Medscape Medical News reported earlier this year, cost could be a deal-breaker.
“Ironically, we have had a greater ease getting authorization from the pharmacy and Medicare…and Medicaid patients than privately insured patients,” said Gandhi. She recently held a webinar with HIV providers from around the country, and only 30% of participants indicated they had started their patients on long-acting agents, she explained.
“It’s so new that it’s not on every private insurance plan and people don’t know how to use it yet. Patients have to be virally suppressed before you start it, so there are absolutely barriers,” she said.
Data from a study examining patient and physician preferences for long-acting ART also underscore that insurance coverage and medication costs are among the largest barriers to uptake. Additionally, compared with oral ART, switching patients to long-acting agents requires regular viral-load monitoring, which tasks administrative staff to reconfigure clinic flow, incorporate text messaging/phone reminders for adherence, and procure the medication itself.
“There’s a fair bit of complexity associated with its use,” explained Landovitz. “It’s not approved for people who are unsuppressed, so you can’t deploy it as an initial treatment. And then there’s the decision to be made whether tolerability should be probed or tested [monthly],” he said.
Equally important is comfort level, especially “as we move toward a model where we want to encourage primary care doctors whose sole focus and maybe even interest may not be HIV care and treatment. This doesn’t really fall under the [umbrella] of simple, straightforward, and easy to use,” said Landovitz.
HIV Prevention Paradox
In December 2021, the FDA approved CAB-LA PrEP based on findings from the HPTN083 and HPTN084 clinical trials, which were later published in the New England Journal of Medicine and The Lancet. In both trials, CAB-LA demonstrated superiority over oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), conferring reductions in HIV acquisition risk by 66% to 88%.
Despite its effectiveness, many of the challenges encountered by clinicians and patients exploring the use of CAB-LA for primary treatment are the same as those for PrEP, including cost, insurance coverage, and the need for viral load testing to ensure patients have not seroconverted while on prophylaxis.
“The CDC recommends getting [regular] viral loads; ironically that’s six viral loads a year for someone not living with HIV compared to one or two for people who are living with HIV, and it’s quite a barrier to get viral loads that often,” said Gandhi.
There’s also the question of drug resistance when patients have breakthrough infections.
“Our group has done a lot of work around this question of whether or not cabotegravir PrEP failures have resistance to cabotegravir and possibly other integrase inhibitors that might compromise the efficacy of first-line treatments,” Landovitz explained.
While Landovitz and his team continue to study this issue, he mentioned that the resistance rate, while low, is “very real,” noting that his personal clinical approach in these cases is to leverage a treatment regimen that doesn’t rely on an integrase inhibitor for first-line ART. For example, a tenofovir FTC-boosted protease inhibitor-based regimen or one that combines tenofovir FTC second generation and a reverse transcriptase inhibitor such as doravirine.
However, when it comes to another prevention option — post-exposure prophylaxis (or PEP) — experts Medscape Medical News spoke with were divided.
Rosengren-Hovee said most folks who need PEP are going to present to urgent care or the emergency room (ER) because the treatment window is small. (It must be dosed within 24 to 72 hours following exposure.) So, she typically defers to ER doctors unless patients have questions.
On the other hand, Landovitz believes that PEP has been underutilized.
“We see a lot of people who come in for a discussion about PrEP who’ve actually had an exposure within 24 to 72 hours,” he said. “So, I am a firm believer that if such exposure took place that the right strategy is a seamless PEP to PrEP transition, ie, PEP someone for 4 weeks and then deescalate them to a PrEP regimen without hiatus.”
For practitioners interested in following Landovitz’s lead, the CDC recommends a regimen for healthy adults and adolescents comprising single-tablet TDF 300 mg + FTC 200 mg once daily plus raltegravir 400 mg twice daily or DTG 50 mg once daily.
Hindsight Is 20-20
Regardless of which strategy clinicians select for preventing HIV in individual patients, the need to get as many patients as possible on HIV-prevention regimens cannot be overemphasized, that is, if goals to end the HIV epidemic are to be realized.
“UNAIDS has estimated that 10 million people need to get on PrEP worldwide over the next 2 to 5 years,” Gandhi said, also noting that on July 28 of this year, the World Health Organization formally incorporated CAB-LA into recommendations for HIV PrEP
This push for a global roll-out will undoubtedly help push more at-risk people onto preventive medicines with one possible notable exception: the US population.
This past August, a decision by a Texas district judge reversing a provision in the Affordable Care Act that requires employers to pay for PrEP has left many flabbergasted. Aside from the potential clinical implications, Rosengren-Hovee also points to what many have failed to consider when devising these judgments: money.
“Economically, it’s a disaster…not to cover preventive services that can save employers millions of dollars in costs for diseases that are easily preventable,” she emphasized.
The decision also challenges any national efforts that have been undertaken to meet people at highest risk for HIV where they are.
Last December, US Senator for Minnesota Tina Smith (D-Minn) co-sponsored such an effort with the PrEP Access and Coverage Act of 2021. Intended to expand access to PrEP and PEP in high-risk communities by ensuring accessibility and affordability of HIV prevention medications, regardless of a person’s health insurance status, the Texas decision might ultimately overturn any future efforts to move the bill past Congress, where it initially stalled due to a lack of bipartisan support.
“I am very concerned about Judge O’Connor’s judgment on the requirement of private health plans to cover preventive services like PrEP without cost-sharing,” Senator Smith told Medscape Medical News in a written email statement.
“I’ve heard from too many people in Minnesota and across this country about the excessively burdensome high costs of HIV drugs, which results in too many going without this lifesaving preventative medication,” she added.
The Senator continues to push her colleagues on both sides of the aisle, noting that President Biden’s fiscal year 2023 budget included a proposal to establish a national PrEP program.
“We will work with the Biden Administration and national HIV stakeholders to flesh out details of this program and incorporate those components into a reintroduced version of this bill next Congress,” she wrote.
What‘s in the Pipeline?
While the country awaits funding for a national prevention program, heavily treatment-experienced patients with multidrug resistance have renewed hope.
Lenacapavir, a first-in-class capsid inhibitor with no known cross-resistance to other existing drug classes, is currently under clinical review by the FDA. Approved by the European Union in August, 52-week results from the ongoing phase 2/3 CAPELLA trial presented at the 2022 Conference on Retroviruses and Opportunistic Infections demonstrated sustained rates of virologic suppression and clinically meaningful immunologic recovery in 83% of patients taking lenacapavir in combination with other ART agents.
Although the investigational new drug application was placed on hold in February due to safety concerns about the storage vial, it’s since resumed and is expected to be completed by late December 2022. Still, lenacapavir does not come without its challenges.
“The problem with it, of course, is it’s a subcutaneous injection that’s administered at 6-month intervals, so what do you pair it with to get a fully suppressive regimen?” Landovitz said.
“I’m not sure that it offers any advantages,” he added.
Among other agents under development, none appear to have garnered as much enthusiasm as oral islatravir, which is being studied in a once-daily combination with doravirine 100 mg in previously untreated adults with HIV and as a switch option in virologically suppressed adults.
Although both oral and implant formulations for ART and PrEP were placed on clinical hold last December due to FDA concerns over declines in total lymphocyte and CD4+ cell counts in study participants, the agent’s manufacturer (Merck) recently announced the resumption of a new phase 3 clinical program based on lower once-daily islatravir doses. The ongoing phase 2 trial assessing once-weekly oral dosing of combination islatravir and Gilead’s lenacapavir in treatment-experienced, virologically suppressed adults will also resume with a lower islatravir dose.
However, studies evaluating once-monthly islatravir for PrEP have been discontinued.
Despite their disappointment over the cessation of the PrEP trial, Landovitz, Gandhi, and Rosengren-Hovee are all looking forward to seeing what types of results Merck’s new nucleoside reverse transcriptase translocation inhibitor candidate MK-8527 garners; a phase 1b study is about to commence.
On the flip side, those waiting for the HIV vaccines might have to wait a bit longer.
“We’ve had a really hard time figuring out the details of how the immune system reacts to HIV,” Rosengren-Hovee explained. “Once we have a little bit more work done in that area, we can really start developing targets that we can use for therapeutic vaccines,” she said.
Still, the one thing that all of these experts agree on is that it’s an exciting time to be an HIV clinician and scientist.
Ghandi, Landovitz, Rosengren-Hovee, and Smith have reported no relevant financial relationships.
Liz Scherer is an independent journalist specializing in infectious and emerging diseases, cannabinoid therapeutics, neurology, oncology, and women’s health.