JAK Inhibitors

JAK of All Trades
Researchers look to JAK inhibitors as part of hiv treatment & eradication
by Jeannie Wraight

R research on three Janus kinase inhibitors (JAK inhibitors) explored the effect of this class of drug on both viral reservoirs and HIV-associated neurocognitive disorders (HAND). The central nervous system (CNS), which consists of the brain and the spinal cord, is believed to be a viral reservoir for latently infected CD4 cells. HAND occur in the CNS and is reported to effect 30–50 percent of people living with HIV.

There are three forms of HAND, which range from severe HIV-associated Dementia), with extremely debilitating symptoms, to mild: Asymptomatic Neurocognitive Impairment (ANI), with symptoms recognizable only on neuropsychological tests. People with a third, mid-range form of HAND (Mild Neurocognitive Disorder) can experience a loss of memory, and difficulty in concentrating, decision-making and/or maintaining attention. HAND can have a significant effect on a person’s ability to live a productive and independent life.

Chronic low grade inflammation and immune activation is often seen in people living with HIV and is believed to be responsible for numerous age-related comorbidities, including HAND. It also can be predictive of subsequent morbidity and mortality despite suppressive antiretroviral treatment. In other words- even if a person is virally suppressed on ARVs, low levels of inflammation can still occur that contribute to these conditions and which can be life-threatening and/or debilitating. Reducing or eliminating this inflammation may decrease the occurrence and/or severity of these conditions.

JAK inhibitors are a class of drugs that are used in the treatment of several different diseases, mainly to reduce inflammation. Ruxolitinib, tofacitinib and Baricitinib are JAK inhibitors that are currently in use for other indications and may hold some benefit in reducing HIV-related inflammation and thus HIV comorbidities. Researchers are looking at the effects of JAK inhibitors on reducing inflammation, as well as a functional HIV cure.

An ongoing AIDS Clinical Trials Groups (ACTG) study of Ruxolitnib as an add-on to ART is exploring whether this drug can decrease inflammation in people living with HIV. Ruxolitnib is FDA-approved to treat myelofibrosis, and has been shown to reduce inflammation which could help prevent or reduce HIV age-related diseases. The study hopes to determine whether a limited course of Ruxolitinib can reduce inflammation, in turn reducing the risk of HIV-related co- morbidities and at the same time “reset the immunologic balance in favor of less immune activation and inflammation” and have“an impact on HIV reservoir cells that are able to turn on after ART is stopped and infect other cells.”

Tofacitinib is approved in the U.S. to treat ulcerative colitis as well as moderate to severe active rheumatoid arthritis in patients who have had an inadequate response to, or who are intolerant of, methotrexate.

Baricitinib is a second-generation JAK Inhibitor that is approved in the EU and Japan for rheumatoid arthritis. FDA approval of Baricitinib for RA is pending in the United States.

Research conducted by Christina Gavegnano, Ray Schinizi and a team at Emory University has shown that JAK inhibitors may be beneficial in reducing the size of the HIV reservoir. An in vitro study published in 2017 found that tofacitinib and ruxolitinib reduced the frequency of cells which harbor integrated viral DNA in CD4 T cells, block seeding and maintenance of HIV reservoirs and prevented transmission of infectious particles to bystander activated T cells, as well as block expansion in primary monocytes/macrophages.

The most recent research by the Emory University team studied baricitinib in mice to determine its effect on HAND. Barcitinib’s ability to reverse HAND is due to its potent anti-inflammatory properties, and its ability to block HIV replication and reactivation in primary macrophages and microglia. The team hypothesized that blocking HIV inflammation with baricitinib in addition to reversing HAND, might lead to a purge of the viral reservoir and that this would result in a functional cure or elimination of HIV-1.

Researchers found that baricitinib crossed the blood-brain barrier and improvements in cognitive impairment were seen in the murine HAND model (SCID mice) with the introduction of Baricitinib. The groups also found that Barcitinib blocked:

• HIV replication in primary human macrophages and microglia-like cells
• HIV reactivation from macrophages harboring latent HIV
• HIV-induced activation of primary monocytes and macrophages

Despite this potential benefit, JAK inhibitors come with a degree of risk. This class of drug has been known to make it more difficult for the immune system to fight off infection. In addition, there is an increased risk of certain cancers, high cholesterol, high triglycerides, kidney dysfunction, and liver function abnormalities. Whether that risk is subverted with limited use as in the ACTG trial or other functional cure research studies of these drugs, is unclear from the studies’ description. Despite this possible risk and due to promising study results, JAK inhibitors are gaining momentum as a potential curative agent and more studies are needed to further explore it’s use in both decreasing or eliminating inflammation to treat conditions such as HAND as well as a potential curative agent.

Special thanks to Kelly Morgan for providing research on this topic.

Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.