One World, One People.

Monday, December 17, 2007

Rapid Impact Packages

The Rapid Impact Packages (RIP)have been introduced by the global network for neglected tropical diseases (NTD), with the aim of helping to reduce the prevalence of soil transmitted helminthiasis, filariasis, river blindness, and trachoma in the third world countries. These disease currently ravage the under served and poverty stricken populations of the third world. This is a blister pack combination of 4 drugs donated by pharmaceuticals and NGOs' to countries in Asia, Africa and South America. Some of the drugs are currently not yet free abut are being made available at a subsidized cost. The list of diseases and their cures included in the rapid impact packages are as follows.

1. Onchocerciasis (River Blindness) - Ivermectin - currently being donated by Merck. Cost 0 cents.

2. STH (Soil Transmitted Hemlminthiasis - includes ascariasis, trichuriasis and hook worm infestation)- Albendazole- GSK - 2 cents.

3. Trachoma - Azithromycin- Pfizer - o cents.

4. Lymphatic filariasis- Ivermectin- Merck - 0 cents

5. Schistosomiasis - Praziquantel- Med Pharm- 8 cents.

This 50 cents still proves to be a lot for many third world countries, especially those with poor governance and ongoing civil and military conflicts. The PUSH fund has been established to try and overcome this deficit. Let us combine to make this a success.

Kala Azar

Injectable Paramomycin for Visceral Leishmaniasis (Kala Azar) in India

Sunder, S et al. N Engl J Med 2007;356:2571-81 (www.nejm.org)

Background Visceral leishmaniasis (kala-azar) affects large,rural, resource-poor populations in South Asia, Africa, andBrazil. Safe, effective, and affordable new therapies are needed.We conducted a randomized, controlled, phase 3 open-label studycomparing paromomycin, an aminoglycoside, with amphotericinB, the present standard of care in Bihar, India.

Methods In four treatment centers for visceral leishmaniasis,667 patients between 5 and 55 years of age who were negativefor the human immunodeficiency virus and had parasitologicallyconfirmed visceral leishmaniasis were randomly assigned in a3:1 ratio to receive paromomycin (502 patients) at a dose of11 mg per kilogram of body weight intramuscularly daily for21 days or amphotericin B (165 patients) at a dose of 1 mg perkilogram intravenously every other day for 30 days. Final curewas assessed 6 months after the end of treatment; safety assessmentsincluded daily clinical evaluations and weekly laboratory andaudiometric evaluations. Noninferiority testing was used tocompare 6-month cure rates, with a chosen margin of noninferiorityof 10 percentage points.

Results Paromomycin was shown to be noninferior to amphotericinB (final cure rate, 94.6% vs. 98.8%; difference, 4.2 percentagepoints; upper bound of the 97.5% confidence interval, 6.9; P<0.001).Mortality rates in the two groups were less than 1%. Adverseevents, which were more common among patients receiving paromomycinthan among those receiving amphotericin B (6% vs. 2%, P=0.02),included transient elevation of aspartate aminotransferase levels(>3 times the upper limit of the normal range); transientreversible ototoxicity (2% vs. 0, P=0.20); and injection-sitepain (55% vs. 0, P<0.001);> B, as compared with those receiving paromomycin, nephrotoxicity(4% vs. 0, P<0.001),> 0, P<0.001),>

Neglected Tropical Diseases

From 1975 to 1999 only 13 drugs from 1393 new chemical entities (NCE) marketed, were for neglected tropical diseases (NTD). Over the past 30 years, number of drugs for NTD are 10, 18 if you consider Malaria, and 21 if you consider TB. This represents a lamenting 1% of all the NCE (1556) launched till 2007. Today majority of the worlds population lives under poverty, struggling for basic access to health care. Diseases such as malaria, TB, HIV, Kala Azar, sleeping sickness and soil transmitted helminthiasis cause extensive morbidity and mortality destroying the very social and economic fabric of the country. But all is not lost, work from orgnaizations such as medicine sans frontier, institute of one world health and drugs for neglected diseases initiative is bringing back much needed attention to this domain. Kala Azar is one such example, where the IOWH pioneered the efforts to bring a cheap and relatively safe alternative treatment Paramomycin to India in the treatment of patients with the disease, thus giving hope to thousands of patients, especially children affected by the parasite (In India 40-60% of patients with Kala Azar have resistance to first line agent sodium stibogluconate).

When the Market Fails, the Poor Pay

The story of Kala Azar illustrates the inequities in global health care.

By Mrinal M. Patnaik M.D., William M. Stauffer, M.D., M.S.P.H., Ann Campagna, M.D.,
Carol I. Stauffer, M.S.W., M.P.H., and Patricia F. Walker, M.D.

During the last 50 years, world leaders have begun to recognize their responsibility in addressing health issues that disproportionately affect poor and disenfranchised populations, particularly in the developing world. Yet progress on the prevention and treatment of diseases such as measles, polio, malaria, tuberculosis, and HIV has been slow. Nonetheless, most health care professionals in the United States are at least aware of these diseases. Few, however, are familiar with a category of forgotten diseases responsible for the continued suffering of many individuals around the world.

Frequently referred to as “neglected” tropical diseases, they affect only the poorest of the poor. They also exemplify the inequity in our market-driven health care system: More that half of the world’s people still struggle to obtain access to basic health care. Although some enjoy the fruits of economic prosperity, most live in poverty with challenges posed by illiteracy, a poor health care infrastructure, and disease.

Four of these neglected diseases are visceral leishmaniasis (Kala Azar), African and American trypanosomiasis, and amoebiasis (E. histolytica). Lack of awareness of the magnitude of suffering caused by these diseases is reflected in the funding available for research, control, diagnosis, and treatment. For example, of the nearly 1,400 drugs brought to market between 1975 and 1999, only 13 targeted tropical diseases, and virtually none were developed for the neglected ones. This lack of investment perpetuates a vicious cycle of disease feeding poverty and poverty feeding disease.

Worldwide, these 4 diseases account for approximately 17 million to 19 million infections and 200,000 to 300,000 deaths annually. Kala Azar, the poster-child for neglected diseases, kills nearly 200,000 people each year in rural parts of India.1,2 Similarly, African trypanosomiasis (sleeping sickness) remains endemic in areas of sub-Saharan Africa; Chaga’s disease or American trypanosomiasis infects nearly 16 million people in Latin America; and E. histolytica can be found in virtually all slums and refugee camps in the developing world.

During the last few years, Minnesota has seen a steady influx of immigrants from around the world, including from countries in Asia, Africa, Europe, and Latin America. As immigrants access local health care systems, it is now imperative that health care providers at least familiarize themselves with these neglected diseases and acknowledge the social and health inequities they represent. We share the story of Kala Azar to illustrate the quandaries and challenges associated with neglected diseases and to show how one dedicated person can make a world of difference.

Profiting from Neglected Diseases
Leishmaniasis is a vector-borne disease, transmitted by sand flies and caused by a protozoan parasite (Figure 1). The visceral form gained the surname Kala Azar, meaning “black fever” in Hindi, because of its tendency to discolor its victim’s complexion during advanced stages. Of the nearly 500,000 annual cases of visceral leishmaniasis in 88 countries where it is endemic, more than 90% are concentrated in India, Bangladesh, Nepal, southern Sudan, and northeastern Brazil.^1,2 The situation is particularly disastrous in the northern Indian state of Bihar (on the Ganges plains), often referred to as the “heartland of Kala Azar.” The typical patient with Kala Azar has chronic fevers, weight loss, and massive hepatosplenomegaly (Figure 2). Many die from intercurrent infections.

Although sodium stibogluconate has been used to treat Kala Azar since the 1950s, a combination of subtherapeutic doses of antimonials, inadequate prescribing, poor patient compliance, substandard drug quality, lack of knowledge, and an inadequate health care infrastructure have led to increasing drug resistance.^3,4 In the 1990s, a dose of 20mg/kg/day given for 30 days (total dose of 600mg/kg) had an efficacy rate of 83% to 86%.⁵ A month’s course costs about $40 U.S.^5,6 Since the mid 1990s, the efficacy of antimonials in Bihar has declined to between 36% and 69%.^7-9 This increasing drug resistance has directly increased both the number of cases of and deaths from Kala Azar.

The HIV/AIDS epidemic has further driven a global resurgence in the incidence of visceral leishmaniasis and quickened the emergence of drug resistance. Most of the global hot spots for leishmaniasis are also struggling to cope with HIV/AIDS. Although the United States has been spared this dreadful co-infection, other developed nations have not remained immune. Of the 1,700 cases of leishmania-HIV co-infections reported in 1998 to the World Health Organization (WHO), 1,440 were from the Mediterranean region.¹⁰ Spain reported 835 cases, Italy 229, France 259, and Portugal 117, illustrating the fact that this truly is a global phenomenon.

In the 1960s, it was discovered that amphotericin B, a polyene anti-fungal agent, along with its lipid formulations, were extremely effective in treating Kala Azar.^11-14 However, even conventional amphotericin B is much more expensive than antimonials, costing approximately $150 for a month’s treatment. The drug also requires expertise to administer and manage its side effects.⁶ The lipid formulations of amphotericin, which is expensive even by U.S. standards, have the added benefit of much greater tolerability and fewer adverse effects. A recent 3-armed study from Bihar, compared amphotericin B (1mg/kg/day on alternate days for 30 days) with amphotericin B lipid complex (Abelcet at 2mg/kg/day for 5 days) and liposomal amphotericin (AmBisome at 2mg/kg/day for 5 days).¹⁵The study showed that the overall cure rates of the 3 drugs were between 92% and 96%, with the only difference being in the marked reduction in the adverse-effect profile with the lipid formulations.¹⁵ The lipid formulations cost between $2,000 and $5,000 for a 5-day course.⁶ The average monthly household income for a family in Bihar is $25, rendering these lipid formulations as merely theoretical treatment options. The inability of almost all patients with Kala Azar to procure effective therapy because of cost is manifest in human lives.

In the early 1990s, as a Kala Azar epidemic was devastating large populations in southern Sudan, a discovery was made that not only curbed the epidemic but also sparked an idea for providing medications for neglected diseases. Doctors without Borders set up treatment centers in Sudan. A large number of patients came to these health posts, which were few and far between. Poor hygiene measures among patients resulted in massive outbreaks of dysentery. In a desperate attempt to control the dysentery, doctors tried combining half doses of antimonials with paramomycin, a cheap aminoglycoside antibiotic known to be effective against protozoan parasites, particularly E. histolytica. To their surprise, not only did this combination reduce the incidence of dysentery, it was also synergistic in the management of Kala Azar, cutting treatment time and reducing drug toxicity.

Just as the potential of paramomycin was coming to light, the drug’s sole manufacturer, the now-defunct Pharmacia, decided to cease production of the medication. The drug’s patent had expired, and manufacturing it was no longer commercially viable. This is a sad, but all-too-common, scenario. A pharmaceutical company ceases production of a life-saving medication because it can no longer profit sufficiently.

Another drug almost removed from the market was eflornithine, often referred to as the resurrection drug, because of its ability to “resurrect” and cure comatose patients with African trypanosomiasis, a neglected disease that kills approximately 60,000 people per year. Its maker, Aventis, was unable to make a profit—leaving no other effective medication to treat this deadly disease. However, shortly before the manufacturer stopped producing eflornithine, it was discovered to be very effective in reducing facial hair in women, thus hailing its own resurrection in the U.S. drug market. Because lifestyle pharmaceuticals promise ever-increasing profits for their manufacturers, this particular life-saving medication was spared for the estimated 500,000 impoverished Africans who acquire trypanosomiasis each year.¹⁶

A $10 Solution
The silver lining in the Kala Azar story came when Victoria Hale, Ph.D., a San Francisco pharmacist, visited the state of Bihar and witnessed the devastation caused by this disease. Hale enlisted the help of Phillippe DesJeux, Ph.D., M.D., a former WHO leishmaniasis expert, and others to start the first nonprofit pharmaceutical company in the United States, the Institute for OneWorld Health.

After procuring the rights to paramomycin, the company collaborated with the International Dispensary Association, a not-for-profit drug-supply agency based in the Netherlands, to make paramomycin available for a phase III clinical trial in India. The trial, which was completed in 2004, compared paramomycin favorably with conventional amphotericin B.¹⁷ Results from the study of 667 patients treated showed that it was equally efficacious when compared with conventional amphotericin (95% cure rate) and had significantly fewer adverse effects (9% with paramomycin versus 67% with amphotericin). The drug is likely to be made available to the Indian population at a cost of $10 a month. OneWorld Health since has embarked on developing drugs for other neglected diseases.

The availability of paramomycin is not the solution for Kala Azar, but it does offer some respite. As has happened with more publicized diseases such as HIV, the global community needs to advocate for treatment of this and other neglected tropical diseases. In the case of Kala Azar, the Indian government, in conjunction with nongovernmental organizations and international bodies such as the WHO needs to develop a comprehensive plan to address this disease. Such a plan must consist of vector-control programs, continued development of cheap and effective drugs, and expanded use of existing medications through subsidies or creative production such as what OneWorld Health has accomplished.

One World, One People.

Monday, December 17, 2007

Rapid Impact Packages

Kala Azar

Neglected Tropical Diseases

Blog Archive

About Me

Millenium Development Goals

When the Market Fails, the Poor Pay

By Mrinal M. Patnaik M.D., William M. Stauffer, M.D., M.S.P.H., Ann Campagna, M.D.,
Carol I. Stauffer, M.S.W., M.P.H., and Patricia F. Walker, M.D.

Published in Minnesota Medicine, March 2007.

Global Apathy

Time to get our priorities in place.

Please Help Make a Difference.

One World, One People.

Monday, December 17, 2007

Rapid Impact Packages

Kala Azar

Neglected Tropical Diseases

Blog Archive

About Me

Millenium Development Goals

When the Market Fails, the Poor Pay

By Mrinal M. Patnaik M.D., William M. Stauffer, M.D., M.S.P.H., Ann Campagna, M.D.,Carol I. Stauffer, M.S.W., M.P.H., and Patricia F. Walker, M.D.

Published in Minnesota Medicine, March 2007.

Global Apathy

Time to get our priorities in place.

Please Help Make a Difference.

By Mrinal M. Patnaik M.D., William M. Stauffer, M.D., M.S.P.H., Ann Campagna, M.D.,
Carol I. Stauffer, M.S.W., M.P.H., and Patricia F. Walker, M.D.