Severe Malaria Treatment in the United States at the Precipice

The American Society of Tropical Medicine and Hygiene (ASTMH) shares the concerns of Drs. Krey and Travassos about treatment of severe malaria in the United States. Since the announcement by Eli Lilly and Company that they would discontinue production of quinidine, we have been discussing with the Centers for Disease Control and Prevention (CDC) and U.S. Food and Drug Administration (FDA) how together we can best insure that patients with severe malaria in the United States have rapid access to highly efficacious treatment. The CDC and FDA have been working together to address this issue and facilitate the availability of IV artesunate to patients with severe malaria. We anticipate the CDC and FDA will soon provide additional information on this important issue.

Quinine and quinidine are less effective than artesunate for treatment of severe malaria, and continued production of quinidine was not feasible for Eli Lilly and Company. The long-term goal for all groups is that artesunate is available directly for hospitals in the United States for treatment of severe malaria. There has been progress in this area. La Jolla Pharmaceuticals has received orphan drug status for LJPC-0118 (artesunate) from the FDA and plans to file a New Drug Application for LJPC-0118 in the 4th quarter of 2019. http://lajollapharmaceutical.com/2019/07/la-jolla-pharmaceutical-company-receives-orphan-designation-from-fda-for-ljpc-0118-artesunate-for-the-treatment-of-malaria/

The CDC has also published updated guidelines on how to treat severe malaria, available at https://www.cdc.gov/malaria/diagnosis_treatment/artesunate.html. These guidelines address some of the issues raised in the opinion piece by Drs. Krey and Travassos, including oral treatment to give prior to receiving artesunate, and use of a nasogastric tube for medication if oral treatment is not possible. Artesunate treatment can be provided with a phone call to the CDC at CDC Malaria Hotline (770-488-7788) Monday-Friday 9am-5pm Eastern time, or 770-488-7100 outside of these hours.

We concur that the required transport time from the CDC creates an additional time hurdle that is a concern, and strongly support FDA approval of a new formulation of artesunate as soon as possible, as we outlined in a letter to the FDA in June 2019. We appreciate that the FDA is working to facilitate the availability of IV artesunate, and appreciate the work the CDC has done to create an interim solution that makes the most effective drug for severe malaria available to patients.

ASTMH take seriously the concerns of clinicians about the treatment of severe malaria in the United States and is working together with our key partners to insure that patients get the needed treatment in a timely fashion, and that, in the long term, an FDA-approved medication is available in hospitals for treatment of severe malaria in the United States.

Chandy C. John, MD, MS
President, American Society of Tropical Medicine and Hygiene

Helping severely ill patients gain timely access to life-saving treatments is a public health priority that the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) routinely work together to address.

In the U.S., there are approximately 300 annual cases of severe malaria that should be treated with intravenous (IV) antimalarial medications, but the only FDA-approved IV antimalarial, IV quinidine, was recently discontinued by its manufacturer. Since it became unavailable, CDC and FDA have ensured that U.S. patients with severe malaria have access to IV artesunate, a front-line antimalarial, through the FDA’s expanded access program, which provides access to unapproved treatments outside of a clinical trial when there are no comparable or satisfactory therapies available to treat a serious or life-threatening disease or condition. The program allows CDC to provide IV artesunate for all U.S. cases of severe malaria, and while CDC and FDA have taken this important step to make IV artesunate available nationwide, the agencies recognize concerns about timely access.

CDC has clinicians and Quarantine Station Officers on call 24 hours a day to provide IV artesunate. IV artesunate is positioned in 18 quarantine stations across the country (Fig. 1), strategically located at airports with high flight volumes. From April 1 to August 27, 2019, CDC supplied 121 courses of IV artesunate to more than 100 hospitals nationwide for patients with severe malaria. The median delivery time was 5.7 hours, ranging between 1.4 to 17.2 hours. Delivery times are affected by distance from a distribution site, mode of transport and the time the request is made. CDC monitors the distribution of IV artesunate and works to make improvements in its system on an ongoing basis.

Hospitals should have a preparedness plan for patients with suspected malaria. This includes plans for timely diagnosis and treatment of malaria, a stock of oral antimalarials and a transportation plan to pickup IV artesunate from the nearest airport or quarantine station. CDC published guidelines on how to treat severe malaria while awaiting IV artesunate, including administering oral medications via nasogastric tube or pretreatment with antiemetics depending on the patient’s needs.

FDA remains committed to facilitating and expediting the development and review of drugs for the treatment of severe malaria, including continued use of expanded access and is working with manufacturers interested in bringing forth new treatment options for patients with malaria, including severe malaria.

References:
• FDA - Expanded Access
• CDC - Malaria
• CDC – Availability of Intravenous Artesunate for Treatment of Severe Malaria in the United States

We strongly agree with Krey and Travassos (1) that hospitals throughout the United States (US) may well face difficulties in providing timely, effective therapy for cases of complicated malaria following the discontinuation of quinidine gluconate, the only FDA-approved treatment for severe malaria.
Data from the Centers of Disease Control (2) indicate that hospitals in every state could potentially encounter a patient with severe malaria. For example, although most of the 2,078 malaria cases (68.2% P. falciparum) reported during 2016 were from New York City (265 cases) and 14 other jurisdictions each reporting > 50 cases, at least one case was reported from all 50 states. Approximately one of every 7 reported cases (306 of the total 2,078) was categorized as severe malaria (2).
Our experience brings into focus the likelihood that a case of complicated malaria will be encountered in the clinical setting. Of 37 patients diagnosed with malaria by the Mount Sinai Health System laboratories between September 16, 2017 and September 16, 2019, P. falciparum was found in 33 (89%), amongst whom 5 (15%) had a parasitemia of 5% or greater observed in at least one peripheral blood smear.
Global political and climatic changes make it likely that malaria cases seen in the US will continue to rise. As summarized by Conn and colleagues (3), major cuts to malaria control programs in Latin America have been followed by a resurgence in cases, notably in Brazil, Colombia, Peru, and Venezuela. In 2016, these 4 countries were responsible for almost 80% of the 875,000 malaria cases reported in the region. Venezuela, in particular, has one of the most rapidly rising rates of malaria in the world, as well as a massive exodus of its population due to political instability (4).
The emergence in Latin America and elsewhere of widespread resistance in P. falciparum to most antimalarial drug classes, including aminoquinolines, antifolates, and most recently artemisin-based combination therapies presents an additional obstacle to effective management (3, 5). Some lineages of P. falciparum exhibit resistance to almost all currently available antimalarials, and P.vivax chloroquine resistance is rising (5).
We support the recommendation that manufacture of quinidine gluconate be resumed, plus extension of the expiration date for any remaining quinidine inventories, pending approval and more widespread availability of alternatives such as intravenous artesunate. It is critical that clinicians be cognizant of current constraints on management of uncomplicated and complicated multidrug-resistant malaria while approved therapeutic options are limited.

References
1. Krey RA, Travassos MA. Severe Malaria Treatment in the United States at the Precipice. Ann Intern Med. 2019; 171:362-363.
2. Mace KE, Arguin PM, Lucchi NW, Tan KR. Malaria Surveillance — United States, 2016. MMWR Surveill Summ. 2019; 68:1–35.
3. Conn JE, Grillet ME, Correa M, et al. Malaria Transmission in South America—Present Status and Prospects for Elimination. Towards Malaria Elimination - A Leap Forward, Sylvie Manguin and Vas Dev, IntechOpen, DOI: 10.5772/intechopen.76964.
4. Grillet ME, Hernández-Villena JV, Llewellyn M, et al. Venezuela's humanitarian crisis, resurgence of vector-borne diseases, and implications for spillover in the region. Lancet Infect Dis. 2019; 19: e149-e161.
5. Menard D, Dondorp A. Antimalarial Drug Resistance: A Threat to Malaria Elimination. Cold Spring Harb Perspect Med. 2017; 7:a025619.