Dear Researchers: Fewer Side Effects Please

Although it’s commonly known that HIV is a manageable condition, serious side effects from antiretrovirals can substantially limit or greatly affect a person’s quality of life. While toxicities, pill burden (the number of cumulative pills one has to take), and the possibility of developing drug resistance are significantly lower with newer drugs than those approved in the 1990s and the first decade of this century, most ARVs (including the latest drugs) still have significant toxicities in long-term use, can cause life-threatening conditions, and carry side effects that severely impact quality of life and limit treatment options.

Although ARVs are essential to living a healthy and longer life with HIV, there is a widespread belief that they are harmless, with little to no negative effect on those taking them. Many leaders in the HIV sphere downplay the side effects and complications people living with the virus experience. But that only prevents a greater demand for more tolerable drugs.

This sentiment is particularly damaging when it comes from those in positions that influence public opinion. Dr. Robert Redfield, director of the Centers for Disease Control and Prevention, told the Washington Blade in March the side effects of ARVs are “close to that of water” and that the medications allow for a high quality of life.

In researching, testing, and approving HIV drugs, certain criteria are essential. By today’s standards, the ability to virally suppress HIV quicker and better than (or at least as well as) other approved ARVs, once-a-day dosing, and limiting side effects are the main criteria to demonstrate “superiority” over other ARVs on the market. Several of the “new” therapies approved last year by the U.S. Food and Drug Administration for HIV treatment were fixed-dose combinations of previously approved drugs that satisfy the need for viral suppression and once-a-day dosing. However, these therapies and/or their components are linked to many adverse events, even life-threatening ones, and therefore do not fulfill the criteria for limiting side effects.

Side effects, both bothersome and serious, can be temporary or have long-lasting consequences. These include diarrhea, lipodystrophy, fatigue, bone pain and/or disease, nausea, and depression. Symtuza, Delstrigo, and Trogarzo (all of which are among the drugs approved in 2018) and some of their components are also linked to complications such as immune reconstitution inflammatory syndrome, and liver and kidney disease. Some of these conditions are related to a higher risk of cardiovascular disease.

Despite FDA approval, the extent of the effects of Trogarzo are largely unknown due to the speed of its approval. The drug was approved for those with limited treatment options based on a 24-week, single-arm (not compared to other drugs) study of 40 patients. Most HIV drugs are studied in thousands of individuals and compared to numerous other HIV drugs before receiving FDA approval. The process used to approve Trogarzo, called fast track designation, was created early in the U.S. HIV pandemic to make drugs available quickly for those in desperate need. Although very necessary for some individuals, fast track designation severely limits our knowledge of the effects of a drug.

As long as HIV medications have to be taken indefinitely — from both a personal and a public health standpoint (the latter because treatment prevents transmission of HIV) — there needs to be greater regulatory attention to ensure that adverse events are rigorously limited and not affecting adherence. Priority in publicly sponsored clinical trials and National Institutes of Health-funded grants should be given to therapeutics that are specifically designed with a great attention to reduce side effects. This would provide pharmaceutical and biotechnology companies that develop ARVs a strong incentive to invest the research and development dollars, time, and effort in making drugs that have much less of a negative effect on health and quality of life.

Some drugs by their very nature are thought to produce fewer toxicities and thus much fewer side effects. ABX464, a Rev inhibitor currently in phase 2a studies, BIT225 a Vpu inhibitor in phase 2, and baricitinib, a Jak inhibitor being studied as a functional cure, all demonstrate superior toxicity profiles to current regimens. Although baricitinib is associated with some serious side effects, such as shingles in those who have been prescribed the drug for rheumatoid arthritis, it is an anti-inflammatory, and lowering HIV-related inflammation is essential for lowering the risk of many comorbidities, including heart disease, HIV-associated neurological disease, and nonalcoholic fatty liver disease.

Another new drug in early development thought to have low toxicity is the RNA helicase DDX3 inhibitor being developed by a European pharmaceutical company, First Health Pharmaceuticals. DDX3 inhibitors are being considered for a list of infectious diseases including HIV, hepatitis C, Ebola, dengue, and Zika, as well as for several forms of HIV-related cancers. Thus far, these compounds have been found to have low toxicities both in vitro and in vivo testing. The DDX3 inhibitor for HIV is being studied as both a therapeutic and part of a functional cure, but like ABX464 and BIT225, it still hasn’t received any funding from the NIH.

RNA helicase DDX3 inhibitors target RNA helicase DDX3, a human protein that is hijacked by HIV and is essential for the replication of HIV and the assembly of active viral material to enable HIV to replicate. In addition to offering low toxicity, a major advantage of targeting a human protein versus targeting HIV itself is that drug resistance cannot occur as with current therapies where HIV can mutate to overcome attack. This lack of resistance has been observed during in vitro studies where there was no selection of mutated resistant strains long after treatment at active doses. DDX3 inhibitors have been shown to be active against all strains of HIV.

New drugs with reduced side effects and toxicity that improve quality of life and drug adherence for those who suffer with persistent ARV side effects should be prioritized in the HIV pipeline when considered for federal support. Only when this becomes the standardized norm will we see more drugs developed from conception that possess these qualities.