[Ip-health] A drug priced out of reach in Africa could save lives from a neglected killer
Shailly.GUPTA at geneva.msf.org
Wed Aug 8 09:32:45 PDT 2018
A drug priced out of reach in Africa could save lives from a neglected killer
By Patrick Adams and Cameron Nutt
August 8, 2018
Mulago Hospital in Kampala, Uganda, treats crypto patients, some of whom have lost their eyesight, hearing, or both. AP Photo/Rebecca Vassie
When it comes to controlling the AIDS pandemic, Botswana is in many ways a model for the world. Last year, the country became one of the first to achieve ambitious United Nations goals<http://www.unaids.org/en/resources/documents/2017/90-90-90> for universal access to timely, high-quality treatment of HIV, doing so years before the United States is projected to reach the same targets.
But even in Botswana, a collective failure of the global fight is on stark display: an inability to protect the poorest individuals with HIV from an infection called cryptococcal meningitis<https://www.cdc.gov/fungal/global/cryptococcal-meningitis.html>, or "crypto" as it's commonly known.
One of the biggest reasons, say infectious disease experts, is the lack of access in Africa to a key component of the crypto treatment regimen, a 60-year-old antifungal drug called flucytosine that should cost a few dollars a pill but is now vastly more expensive than that.
Crypto is a fungal infection of the membranes around the brain and spinal cord. Though far less well-known than tuberculosis, the leading killer of people living with HIV/AIDS, it is a close second, accounting for as much as 20 percent<http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0005575> of HIV-related deaths worldwide. That represents hundreds of thousands of individuals who, for any number of reasons, fall through the cracks along the cascade of care - the journey from an HIV diagnosis to suppression of the virus - or who come in for testing only after they've fallen ill<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655523/>.
Even in places like Botswana, where most people with HIV now have access to antiretroviral therapy<https://www.cdc.gov/hiv/basics/livingwithhiv/treatment.html> (the standard treatment for HIV infection), crypto remains a menace. Antiretroviral drugs can restore an immune system weakened by HIV, allowing it to fend off so-called opportunistic infections<https://www.cdc.gov/hiv/basics/livingwithhiv/opportunisticinfections.html> like crypto. Yet as a 2017 study<https://www.ncbi.nlm.nih.gov/pubmed/28505328> found, the incidence of crypto in Botswana is "almost identical" to estimates from before antiretroviral therapy became widely available across the region.
Over the past decade, we've spent time with physician-researchers at hospitals across sub-Saharan Africa as they conducted studies on crypto and cared for those bedridden by the disease (P.A.) and as they took care of patients struggling to afford effective treatment in the United States (C.N.).
In Uganda's Mulago Hospital, many crypto patients had lost their eyesight, others their hearing. Some had been robbed of both<https://www.npr.org/sections/goatsandsoda/2016/02/21/465538409/a-2-test-might-have-helped-this-man-with-hiv-avoid-daily-spinal-taps>. All suffered agonizing, unrelenting headaches, a hallmark symptom produced by the buildup of cerebrospinal fluid in the skull. Despite receiving relatively high-level care provided as part of the studies they were taking part in, most of the patients died.
Tragically, this is typical of crypto in sub-Saharan Africa, where the disease is fatal in 70 percent of patients even after they reach referral hospitals in capital cities. (For the sake of comparison, patients infected with Ebola during the disastrous recent epidemic in West Africa died at roughly the same rate). By contrast, in wealthy regions such as Western Europe<https://journals.lww.com/aidsonline/Fulltext/2009/02200/Estimation_of_the_current_global_burden_of.12.aspx>, crypto kills under 10 percent of patients. The difference is largely a function of access to flucytosine, a drug the World Health Organization considers essential<http://www.who.int/medicines/publications/essentialmedicines/en/> to every health care system in the world.
First developed as an anti-cancer agent, flucytosine was being used as early as the 1960s<https://jamanetwork.com/journals/jama/article-abstract/341469?redirect=true> to treat crypto and other fungal infections. In the decades since, repeated studies<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797641/> have demonstrated its safety and efficacy. The most recent, a randomized controlled trial<https://www.nejm.org/doi/full/10.1056/NEJMoa1710922> conducted in hospitals in Cameroon, Malawi, Tanzania, and Zambia, found that when flucytosine was used in combination with another drug called amphotericin B, deaths among patients enrolled in the study fell by a staggering 65 percent compared to the standard of care in sub-Saharan Africa.
"And it's not like survivors are a burden to society," Dr. David Boulware, an infectious disease specialist at the University of Minnesota who heads up research on crypto at Mulago, told us. "If you can treat the infection, people go back to work, they're functional, they do great."
Yet where the need is greatest, flucytosine remains entirely out of reach<https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(13)70078-1/fulltext>. In no African country has the drug been registered, a costly and often cumbersome process<http://apps.who.int/medicinedocs/en/d/Jh2994e/7.2.html> that must be initiated by the manufacturer in order for the drug to be sold and distributed. That's because at its current price, the demand for flucytosine is deemed insufficient to generate a profit, and also because governments and donors have been content to settle for a substitute: fluconazole, a far inferior antifungal drug made by the pharmaceutical giant Pfizer.
(Widely shamed<https://www.wsj.com/articles/SB954790745715846990> for pricing Diflucan, its brand-name version of fluconazole, out of reach<https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)74314-2/fulltext> of patients at the height of the AIDS epidemic, Pfizer has donated the drug to affected countries for free since 2000. Boulware and others say fluconazole, too, is becoming increasingly scarce, and that Pfizer's Diflucan donation program has "outlived its PR value.")
In the United States, brand-name flucytosine (Ancobon) is for sale at an exorbitant price - more than $2,000 per day<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885648/>, up from $6 per pill a decade ago, or approximately $30,000 for a full two-week regimen. The increase comes courtesy of Valeant Pharmaceuticals International, the drug company so synonymous with its strategy of indiscriminately raising the prices<https://www.nytimes.com/2015/10/05/business/valeants-drug-price-strategy-enriches-it-but-infuriates-patients-and-lawmakers.html> of old drugs (such as the lifesaving<https://www.npr.org/sections/health-shots/2017/08/09/542485307/47-hospitals-slashed-their-use-of-two-key-heart-drugs-after-huge-price-hikes> heart medicines nitroprusside and isoproterenol) that it's announced plans for a kind of makeover: a new name<https://www.nytimes.com/2018/05/08/health/valeant-name-bausch-drugs.html>, a new website<https://www.bauschhealth.com/news-room/our-perspective/artmid/714/articleid/11/welcome-to-bausch-health>, and a new logo.
Researchers say the escalation in the cost of flucytosine is likely already limiting access<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885648/> to the drug in the U.S. - unless, that is, you happen to be a cat. A July 2018 price quote from the online veterinary pharmacy Diamondback Drugs<https://www.diamondbackdrugs.com/drug/flucytosine/> says that oral flucytosine is currently available for the treatment of crypto in felines<http://catexpert.blogspot.com/2014/07/cryptococcosis-in-cats.html> for just $1.59 per 250 milligram capsule. Compare that to the $92.21<https://www.uptodate.com/contents/flucytosine-drug-information?search=ancobon&source=search_result&selectedTitle=1~57&usage_type=default&display_rank=1#F171771> Valeant charges for the same amount of the same molecule - or the $82.07 that a handful of other companies now ask for a generic alternative - and it's easy to see why pharmaceutical costs are growing faster than any other part of the health care industry.
There has been progress. In early March, the World Health Organization updated its guidance for the treatment of crypto, recommending flucytosine as the cornerstone of all first-line options, and approved a generic version<https://extranet.who.int/prequal/medicine/3628> of the drug.
That leaves it up to Mylan, another pharmaceutical company with a penchant for profiteering on essential medicines (think EpiPen<https://www.statnews.com/pharmalot/2016/12/01/mylan-ceo-responsibility-epipen-price/>), to make the next move. The firm, which acquired the generic version of flucytosine in 2016 and promptly doubled the price (as described to us in an email from Doctors Without Borders' Access Campaign), first has to file for the drug's registration in each country. Mylan said in an email to us that it is "in the process" of doing so. But if the EpiPen and similar other fiascos tell us anything, it's that what pharmaceutical companies say and what they do can be very different<http://www.latimes.com/business/hiltzik/la-fi-hiltzik-mylan-generic-20161216-story.html> things.
Mylan has vowed to "do what's right<http://www.mylan.com/en/careers/life-at-mylan>, not what's easy," while Valeant (now Bausch Health) says it is "dedicated to advancing global health<https://www.bauschhealth.com/about-us/who-we-are>." But flucytosine puts the lie to those claims. If they're sincere, these companies can start by rolling back their prices for the drug to what it was a decade ago and registering it in countries where it remains unavailable - and desperately needed.
A headache, perhaps, for their shareholders. But nothing like a fungal infection of the brain.
Patrick Adams is a freelance journalist based in Atlanta. Cameron Nutt is a fourth-year student at Harvard Medical School.
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