Are We Standing in Our Own Way on the Path to a Cure for HIV/AIDS

PROFILE

Are we standing in our own way on the path to a cure for HIV/AIDS

lthough there are many reasons to celebrate the life-extending benefits from antiretroviral tAherapeutics (ART) for HIV/AIDS and the ability to chronically manage patients’ disease for decades, the majority of people around the world living with the virus do not have access to ART and those that do, have over decades developed life-threatening side effects. Our inability to identify a cure to HIV lies not only in the as-of- yet failure of the medical research community to identify and develop appropriate means of ridding the body of the virus but also government and industrial policies that promote public opinion exclusively focused on chronic management scenarios instead of broadly exploring innovation for cure.

“An inconvenient truth” (Davis Guggenheim) mates of the magnitude of the global forced government policy for early epidemic. As the majority of Ameri - and expanded access to experimental There are approximately 37 million cans are not rountinely tested for HIV, drugs, the medical community and people living with HIV and 39 million the virus can go years without being society are struggling with the fact have died of AIDS-related diseases diagnosed in an HIV positive person. that we are barely managing the HIV since the start of the epidemic in 1981. With these statistics it is no wonder epidemic and AIDS crisis. For years we As of March 2015, only 15 million that every day an estimated 5,600 have been locked into thinking of people have access to treatments for people globally become newly infected solutions in terms of a chronic disease HIV. It is estimated that one fifth of with the virus. Importantly, the statis - with life-long treatment. The past 30 people infected with HIV in the USA tics we are analysing are biased for years in which anti retroviral drugs have not been diagnosed and only populations who can or are willing to (ARV) have been identified and treat - half the patients with access to ART in access HIV testing/treatment programs ment modalities have been refined the USA take prescribed medication. and where government policies or are remarkable in their success in pro - Durable suppression of HIV is only cultural beliefs allow the health status longing the lives of people infected achieved in 25% of the patients who of individuals to be revealed. with HIV. These years also have the are linked to medical care and inconvenient truth that they reflect receiving ART. The etiologies for these Despite the research on HIV and AIDS with one exception, the Berlin patient, statistics are hotly debated but as from academic institutions, industry failure to discover a cure or achieve concerning as these numbers are, and advocacy groups and dedicated sustained viral suppression without they are likely to be gross underesti - efforts of AIDS treatment activists that ever changing drug regimens.

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Cocktails, cascades and a industry that adjudicates and ranks conundrum research proposals submitted to gov - At this time, decision makers speak of ernment and private foundations. A an ‘HIV Care Continuum’, underwritten majority of those who served in peer as policy by a United States Federal review have been in lockstep with the initiative and supported by the Center dogma that a cure was not possible for Disease Control (CDC) and the and they put the ‘thumbs down’ on National Institutes of Health (NIH). priority scores that determine grant This four-part recommendation funding for hypotheses for the eradi - includes comprehensive HIV testing cation of HIV. Simply put, if one could and diagnosis, linking and maintaining not state a hypothesis for a cure, then all HIV positive individuals to a health - specific research objectives could not Dr. Harold Charles Smith care provider, providing all HIV be articulated in a funding proposal positive patients with life-long access for testing opportunities to cure HIV. to ART and ensuring that for each to advocating that ‘everyone be given Eventually word got out and such patient, viral loads remain suppressed. ART immediately after diagnosis’. The ideas no longer were submitted for The impracticality of this manage - recommendations go further to consideration or they were couched ment model as a solution to the global include pre-exposure prophylactic as being for therapy. In that way, KOL’s AIDS pandemic can be appreciated in ART treatment (PrEP) for HIV negative and rank and file scientists them - both social and economic considera - individuals who are at high risk of selves influenced capitalisation and tions. In fact, while the ink is still wet infection. We now are faced with the development of new concepts. I on the HIV Care Continuum initiative, conundrum of an expanded and hasten to add that in this era gone by, we already know that its goals are not global epidemic with a need to supply had academic scientists inadvertently broadly achievable due to significant ART and access to medical care for found a cure to HIV, it is unlikely that attrition from care and treatment decades on a planetary scale. Given they would have suppressed findings dubbed as the ‘care cascade’. the improbability of this course of simply based on government or foun - action, discovering a cure to HIV/AIDS dation funding priorities. But cure has Two potential limitations of the new has to become an overriding priority. the potential of being a disruptive policy are the magnitude of chemical technology for the pharmaceutical production that will be necessary to A challenge to the industry and Wall Street. So it is not meet the global demand for ARV (i.e. imagination for those who clear how industries would manage how do we produce this quantity of could make a difference the impact of a cure on sales of life- chemistry, for that many people, for Key opinion leaders (KOLs) have in long ART that have held reliable billion all years that their disease will need to recent years said that they now “dare dollar profits from the sales of so-called be managed) and an inadequate to imagine” a cure yet others say we ‘block buster’ drugs. mechanism in place that can ensure cannot go there because ‘there be long term compliance (i.e. uninter - dragons’ in charting a course to cure, “A rose by any other name rupted access to healthcare and ART i.e. a cure is not possible. The HIV would smell as sweet” to a diverse global community with community is encouraged by talk (William Shakespeare) disparate education, infrastructure, about HIV eradication but are con - cultural and religious beliefs). The fused over the course that is being Many members of the drug discovery limitations of this model will be exac - prescribed. The negative outlook and drug development communities erbated by the recent announcement toward curing HIV/AIDS actually has remain astonished by the about-face from the World Health Organization held back adequate funding for cure that is now referred to as ‘cure (WHO) that they have reversed research by actively discouraging it for research’. The past structure leaves their policy from one of ‘don’t treat many years as ‘intellectually unsound’. many scientists uncomfortable with with ART until individuals become There is a peer review system com - the direction for and implementation significantly immune-compromised’ prised of experts from academia and of this change in emphasis. The many

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years of the chronic therapeutic man - before the recent glasnost on cure FDA-approved ARVs can have serious agement mindset has left the map for research. A vaccine strategy that is side effects that will almost certainly ideation with many information voids. capable of neutralising one or multiple manifest in chronically treated patients. The years required for exploration strains of HIV and does so for have been squandered. Confusion is extended periods of time has not For decades the efficacy of a new drug a typical symptom of deep shock that been achieved. Clearly there is prece - candidate has been assessed pre-clin - may explain why eradication research dent in other diseases that justifies ically by the ability of HIV to evolve has become mired in a debate over continued pursuit of a broadly drug resistance to it in the laboratory. what the word ‘cure’ means? Recent neutralising vaccine strategy. These This policy is based on the premise media blitzes have tragically rushed to endeavors have yielded a fascinating that if a drug is interacting with an be first to proclaim (define) a cure that understanding of the acquired important viral target, the virus will turned out not to be. Trying to define immune system relative to HIV that figure out a way to become drug- cure as what can or cannot be achieved may yet triangulate investigators resistant. Said in a different way, all has been distracting. We certainly will toward a curative vaccine strategy. ARVs that have been brought to know a cure when we find the overt market are already known to select evidence in someone like the Berlin “There are approximately 37 for minority subspecies of HIV and patient. million people living with therefore they have anticipated ‘use HIV and 39 million have died until dates’ (i.e. not curative). The We have to accept and stop arguing of AIDS-related diseases since industry and venture capital firms about whether a cure can only be the start of the epidemic in demand this proof and failure to ‘functional’ (no replicating virus 1981. As of March 2015, only establish it evokes silence in the room. detectable but genetic analysis will 15 million people have demonstrate the presence of HIV access to treatments for These policies certainly will become genomes) or what most would under - HIV know as antiretroviral fodder for future debates on how to stand to be an absolute cure (the therapy (ART).” eradicate HIV. Would a new drug that complete elimination of HIV genetic is curative be able to satisfy these material from the patient’s body). Will Otherwise, cure research includes a criteria? The Berlin patient was cured a cure be achievable for everyone reversal on the epidemic-long policy of HIV while treating him for his who has HIV or only possible for endorsed by government and indus - cancer. Certainly cancer eradication is certain strains of the virus? Will a cure try to restrict innovation to new not without significant side effects only be achievable for patients with classes of drugs that interact with and risks. One has to wonder whether particular genetic backgrounds? Can a proteins and functions encoded solely taking a toxic drug for 6 months to a cure be achieved that enables an ART- by HIV. We know that HIV encoded year might not be worth the potential free future or will there be a remission functions must co-opt cellular and of a life-long cure for HIV/AIDS? If the period that requires maintenance biochemical infrastructure and raw answer to this question is yes, then it boosts over time? While one might materials in order to replicate the evokes concern that the rubric we speculate about the answer to these virus. However, therapeutic strategies have been following for drug approval questions, a cure in any form MUST to thwart the virus by targeting path - may be responsible for why a cure has be acceptable, no matter how limited. ways in the cell are discouraged and never been found in the 30 years of sidelined with speculation that they ARV development? Learning from the past but might be fraught with adverse effects. encumbered by it The development of many experimen - Given the industry-wide position of Eradication of HIV and prevention of tal ARV compounds has in fact been ‘well tolerated’ new drugs, it is curious new infections with the use of an HIV suspended by the systematic and that there has been lightning-fast vaccine is a logical and appealing cure industrial application of these criteria. uptake of the concept known as strategy that has been evaluated for ‘shock and kill’. The premise is that many years. In fact, this has been the This position only makes sense if one viral reservoirs (cells infected by HIV only ‘cure talk’ that was tolerated chooses to ignore the fact that most but not shedding virus) are the major

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reason why ART cannot eradicate HIV. be preserved and the biotech industry In this strategy, viral reservoirs are should be facilitated under a mandate forced to express HIV so that the to bridge the valley of death for the body’s inflammatory and immune development of ideas for eradication responses can identify and eliminate as a matter of government policy. them. The drugs being evaluated in Government relationship with the clinical trials are known as histone pharmaceutical industry and taxation deacetlylase inhibitors (HDACi) and policies need to change such that are a class of drugs that induce gene Timothy Ray Brown, the Berlin Patient, resource allocations are incentivised expression by changing the structure Speaks to the ACTG for the development of new ideas for of human chromosomes. Although eradication. Society should demand these drugs have clinical applications versities, due to their non profit tax of governments, foundations and HIV as mood stabilisers, anti-epileptics, status and professed need to protect advocacy groups to demonstrate the anti inflammatory and anti-cancer their intellectual freedom, largely do political will to create a new fund, one treatments, they are fairly toxic, and not see it as their responsibility to do of military budget proportions, for the their effect is not limited to viral more than basic science, patent their discovery of a cure(s) for HIV/AIDS so genes. The use of HDACi treatment in ideas and wait for an industrial part - that we can truly win a global war on HIV HIV patients has been pushed ner. Faculty and their students are rather than manage the engagement. through to clinical trails despite generally discouraged by institutional significant concern and skepticism in policy from participating in contract Dr. Harold C. Smith, Ph.D. is the founder, CEO and President of the scientific community. The public research for drug development and OyaGen, Inc, a biotechnology company in Rochester, NY USA media has hastily portrayed HDACi as cannot participate in commercialisa - dedicated to the discovery and development of novel therapeutic a ‘cure’ drug because in clinical trials it tion. Venture capital will not invest in approaches and eradication strategies for HIV/AIDS based on induced expression of HIV (viremia) new ideas unless there is a clear path APOBEC host cell, viral restriction factors. He also is a tenured full from viral reservoirs in patients whose (flip) to an industrial partner. Conse - professor in biochemistry and biophysics at the University of viral loads would have otherwise been quently ideas for cure (and therapeu - Rochester, School of Medicine and Dentistry where he conducts suppressed by the ART they were tics) at an early stage of development basic research on HIV and RNA biology and mentors undergradu - receiving. Further studies will deter - and the biotech companies bold ates and graduate students in research and critical thinking. mine whether the activation of viral enough to push them forwards are https://en.wikipedia.org/wiki/Harold_Smith_(scientist) reservoirs with HDACi, or by any other struggling in a financial ‘valley of death’. means, will safely destroy all viral The HIV-positive population will reservoirs, prevent the induced viremia continue to grow unless everyone from forming new reservoirs and pro - takes responsibility for discovering a vide, potentially in combination with cure and the monopoly on resources ARV, a cure? is dispersed.

Links in the chain of responsibility “When you come to a fork in the New findings from university and road, take it” biotech labs have been largely por - (Yogi Berra) trayed as academic and ignored by the HIV media, KOLs and pharmaceu - It is essential that new research ideas Dr. Harold Charles Smith, Ph.D. tical industry. These new ideas are the and innovative approaches for cure Founder, CEO and President background noise for a select cast of are rapidly reviewed and diverse and OyaGen, Inc speakers invited to HIV conferences. divergent proposals become ade - Tel: 1 (585) 697 4351 Federal and foundation research quately funded so that they can be [email protected] grants are very difficult to get and vetted, not lost in endless KOL www.oyageninc.com typically only support incremental debates in the media and at meetings discoveries. Moreover, research uni - on HIV/AIDS. Biotechnology needs to