What Is the State of the Art in HIV Treatment and Prevention?

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With eight new HIV drugs approved so far in 2018, it's been a busy year in the world of HIV clinical research. Now, with several new regimens nearing late-stage trials, a new generation of HIV antiretrovirals may soon be entering the marketplace.

Thankfully, three researchers presenting at IDWeek 2018 in San Francisco summarized the latest clinical research for a packed audience of infectious disease specialists. Susan P. Buchbinder, M.D., of the San Francisco Department of Health, summed up current research on long-acting antiretroviral candidates for treatment and prevention.

"Over the next four to five years were going to have several other potential agents entering the field," said Buchbinder. "The future is bright; there are lots of possibilities."

As well, Judith Currier, M.D., with the UCLA Division of Infectious Diseases shared the latest research on novel drug candidates that might improve the standard of care for patients with highly drug resistant infections. Finally, cardiologist Priscilla Hsue, M.D., with UCSF shared new research on the link between inflammation and HIV, and she offered tips on what HIV physicians can do to help their patients limit inflammation.

Sony Salzman is a freelance journalist reporting on health care and medicine, who has won awards in both narrative writing and radio journalism. Follow Salzman on Twitter: @sonysalz.


Susan P. Buchbinder, M.D., at IDWeek 2018 (Credit: Kenyon Farrow)

Long-Acting Antiretrovirals for Treatment

Patients who struggle with adherence and pill fatigue may soon be able to take advantage of long-acting injections of antiretrovirals. Cabotegravir is an experimental integrase inhibitor with a long half-life. The drug can also be co-formulated with rilpivirine (Edurant), a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI).

Cabotegravir injections were effective and well-tolerated in a Phase IIb trial called LATTE-2, with the vast majority of patients indicating that they would be happy to continue their injections. Now, it's being studied in two Phase III trials called FLAIR and ATLAS.

While injectable cabotegravir is often described as a good option for patients who have trouble with pills, Buchbinder cautioned that this drug might not actually be an ideal candidate for poorly adherent patients because it takes a long time for the drug to leave a patient's system, requiring them to take antiretrovirals to cover the so-called sub-therapeutic tail.


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Long-Acting Antiretrovirals for Prevention

Long-acting antivirals are also being evaluated as pre-exposure prophylaxis (PrEP). Two trials -- one in men who have sex with men and another in sub-Saharan African women (HPTN083 and HPTN084, respectively) will evaluate how well injectable cabotegravir stacks up against oral PrEP.

Meanwhile, pre-clinical research is ongoing for implantable devices that would deliver PrEP slowly over months and years, similar to the currently available birth control implant.

"The advantage of an implantable is you can remove it when needed, there's more consistent drug release so you can allow a lower dose per day, it avoids the 'tail,' and it can remain in place for years," said Buchbinder.


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Other Experimental Prevention Trial

According to Buchbinder, other prevention research is underway that make use of novel interventions.

"There's a long history of using antibodies to protect from infections," she said, adding, "There's a breadth and potency of [broadly neutralizing antibodies] in development." An investigational anti-HIV antibody called VRC01 is currently being tested in the Antibody Mediated Prevention (AMP) studies, for which results are expected as early as next year.

Another prevention therapy, the antiretroviral dapivirine formulated in a vaginal ring, was found in two Phase III trials to reduce the risk of HIV 56% for women who used the ring relatively consistently and 75% for women who used the ring perfectly. The dapivirine ring is awaiting a regulatory decision in Europe but has not yet been submitted in the U.S. Eventually, it could be combined with contraceptive hormones, Buchbinder said.


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HIV Entry Inhibitors for Drug Resistance

"The good news," said Currier, "is that multi-class HIV drug resistance is really becoming less common, particularly in high resource settings where effective antiretroviral care has been in use for years."

Even better news is that two HIV entry inhibitors have demonstrated broad efficacy for treatment-experienced patients. The first, ipilimumab (Yervoy), was approved in March based on promising Phase III data and is administered intravenously.

The second, fostemsavir, isn't far behind in clinical development, and in a Phase III trial it suppressed viral load in about half of patients with multi-drug resistance. Fostemsavir's oral formulation would ease treatment burden for patients and care centers.


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Long-Acting Antiretrovirals for Drug Resistance

Islatravir is a nucleoside reverse transcriptase inhibitor (NRTI) currently in Phase II trials.

"What's exciting about it is its antiviral activity seems to be very potent," Currier said. "It can be given once a day and less frequently. I think it needs to find a partner to team up with for long-acting options for treatment-experienced patients, and there are trials of this drug going on right now in combination with doravirine [Pifeltro] and 3TC [lamivudine, Epivir]."

Yet another exciting research program involves a totally different class of drugs called capsid inhibitors, Currier said. Unfortunately, she added, these programs are still in preclinical stages, though promising activity was presented at CROI 2017.

"There's no human data yet, but I think because of its novel mechanism of action, it would be something we could pair with other drugs for treatment-experienced patients," she said.


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The Latest on HIV and Inflammation

Scientists have long understood that HIV can lead to chronic inflammation, or an overreaction of the body's own immune system. Though the risk of inflammation goes down with antiretroviral treatment, in some patients, inflammation persists.

Statins -- cholesterol-lowering drugs that help reduce inflammation among people with cardiovascular disease -- have been studied as a way to potentially reduce inflammation and decrease the risk of heart attacks and strokes among people with HIV.

A trial called the SATURN study hinted at the protective benefit of statins among people with HIV, but didn't shed light on changes to the specific inflammatory pathways thought to be important in HIV, Hsue said. An ongoing trial called REPRIEVE will be helpful in addressing this question, she added.

Though there's a lot of conjecture, supported by strong theoretical rationale, about the role of inflammation in HIV -- such as the idea that proinflammatory cytokine IL-1beta is involved in HIV-related inflammation -- we still need more research to understand better the link between specific inflammatory pathways and HIV, Hsue said.

This could take a while, she said, reminding the audience that "the inflammation hypothesis in the general population has taken 20 years to establish."