• Despite recent financial problems in some Asian countries, the market potential for health care products in Asia is enormous. Such financial problems are neither catastrophic nor likely to adversely affect the markets for infectious disease treatments over the long term.
• Pharmaceutical and diagnostics firms can take advantage of the shorter regulatory procedures required in Southeast Asian countries by marketing products in these countries before doing so in other Asian nations. Also, early registration in a Southeast Asian country allows companies to collect real-world outcomes and effectiveness data that can be used for marketing by the time a product typically receives approval in Japan.
• Business strategies for pharmaceutical companies intending to enter the infectious disease markets in Southeast Asia must focus on several factors, including economics, epidemiology, available products, and expected innovations.
• Not all infectious diseases are good targets for pharmaceutical and diagnostics companies. As countries become better able to afford expensive HIV/AIDS therapies and HIV/AIDS becomes more prevalent, the market for such products will grow. However, incidence of malaria and cholera decreases in conjunction with economic growth. Therefore, as countries become more able to pay for treatment and vaccination for these diseases, they are less likely to require these measures.
Southeast Asia, which includes some of the fastest-growing economies in the world, is becoming an increasingly important market for medical products, including products for diagnosing and treating infectious diseases. Table 1 below lists pharmaceutical sales and market growth in selected Southeast Asian countries. (For the purposes of this article, Southeast Asia includes the following countries: Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar [formerly Burma], the Philippines, Singapore, Thailand, and Vietnam.) Although countries in this region are experiencing a rising occurrence of diseases common in Western nations (e.g., cancer, heart disease), much of Southeast Asia still must confront conditions typically occurring in developing nations (e.g., malaria, cholera).
The ability to pay for infectious disease diagnostics and therapies has not matched demand in Southeast Asia. Because many patients with infectious disease live in poor, rural areas, they and/or their local health authorities cannot afford the often costly diagnosis, treatment, and prevention plans that are available in wealthier regions and countries. Further, the very conditions that are often symptomatic of infectious disease prevalence (e.g., poor water quality, unsanitary living conditions) are found in countries that can least afford to diagnose and treat such diseases.
|Pharmaceutical Sales and Market Growth in Selected Southeast Asian Countries, 1995|
Sources: Pacific Bridge, Inc., and Decision Resources, Inc.
However, as strong economic growth continues to improve the quality of health care throughout Southeast Asia, this region’s ability to pay for more and better health care will increase. In this scenario, two questions remain. First, will economic growth translate into improved health care for rural populations that may be excluded from much of this growth? Second, will the increased living standards that are associated with economic growth change the epidemiology of diseases, thereby affecting the markets for infectious disease products? In the following sections, we examine some of the financial trends, epidemiological trends, current products, and products in development that will help determine the answers to these questions.
This report focuses on three diseases: HIV/AIDS, malaria, and cholera. A majority of the Southeast Asian population is at risk of contracting these diseases; thus, these conditions represent significant potential for additional health care demand beyond the heavy costs they have already imposed on the region’s health care delivery systems. Further, these three diseases illustrate the changing landscape for different diseases in Southeast Asia as economies develop and living standards improve. Whereas malaria and cholera are usually found in poor and rural locations, HIV/AIDS has spread throughout Asia and the world with little correlation to economic development. Thus, economic growth in Southeast Asia will affect the incidence and treatment of each type of disease differently, with varying consequences for the pharmaceutical and diagnostic markets.
Background—Effects of the Asian Financial Crisis
Despite recent financial problems in some Asian countries, the market potential for health care products in Southeast Asia is enormous. Although the staggering economic growth rates of the last decade are not sustainable, Asian countries will continue to post substantially higher growth rates than most Western countries. For example, despite its devastating currency problems, even Malaysia should exceed 4% gross domestic product (GDP) growth in 1998. Recent financial problems in Southeast Asia are neither catastrophic nor likely to adversely affect the markets for infectious disease treatments over the long term.
However, in the short term (a year or two), medical equipment imports will slow because manufacturers have less incentive to sell their goods at prices that government reimbursement bodies set before the currency declines. As a result, medical care will suffer in all areas, including in the treatment of infectious diseases. For example, Western drugs and pharmaceutical raw materials have become so expensive in Indonesia because of the local currency collapse that many medicines are not available. Those medicines that are available have experienced dramatic price increases or are available only on the black market.
Because such currency declines have diminished reimbursement prices for foreign manufacturers, some countries have raised their reimbursement rates to encourage more importation of necessary medical supplies. For example, Thailand has increased its reimbursement rates by 18%. Nevertheless, economic crisis has made it increasingly difficult for countries to pay for current health care costs, let alone increased costs. Therefore, some governments, including Malaysia and Indonesia, are encouraging the use of less expensive locally produced generic drugs. However, Southeast Asian manufacturers are having trouble keeping costs down because many of them rely on increasingly expensive imported raw materials.
Wile Asia’s current economic woes cannot be ignored, the fundamentals for long-term economic growth in the region are still in place. Government accounts are usually in surplus, savings rates are high, the workforce is large, and the skill of the labor force in Southeast Asia will continue to improve significantly in the 21st century. Further, the framework for strong health care markets remains in place, with growing populations, an increasing incidence of Western diseases, and expanded national insurance coverage.
Penetrating the Asian Markets
Penetrating the Southeast Asian market for infectious disease products requires careful planning and a well-devised strategy that considers other market competitors. For example, because of the plethora of HIV/AIDS diagnostic tests in Southeast Asia, only tests that are inexpensive or demonstrate superior quality or innovation will be able to capture market share.
Specific strategic nuances make the regulatory approval processes in Asia unique. For example, companies can take advantage of shorter regulatory procedures in Southeast Asia by marketing products there before doing so in other Asian nations. Product registration in Thailand and Singapore usually lasts six to nine months, and other Southeast Asian countries have registration processes that can be as short as three months. In contrast, Japan has particularly stringent regulatory procedures compared with Southeast Asian countries; thus, marketing products in Japan requires more time, patience, and money. The average time for approval is two to three years. This situation allows companies to generate revenues throughout Southeast Asia while still undergoing the registration process in Japan. Such early registration in other countries also enables companies to collect real-world outcomes and effectiveness data that can be used for marketing by the time a product typically receives approval in Japan.
Because medical products often require some subassembly, companies should consider outsourcing some manufacturing of materials in Asia to keep their production costs down—and thus to keep their prices competitive in Asian markets. Outsourcing is particularly common in the HIV diagnostics market, where materials are often manufactured in Asia.
Thailand and Singapore are particularly suited for subcontract manufacturing and have served as the location for many regional manufacturing plants. Thailand’s main advantages are the following: (1) inexpensive manufacturing costs (especially in light of recent currency fluctuations), (2) a skilled labor force, and (3) proximity to HIV/AIDS, malaria, and cholera epicenters domestically and in Southern China, Indochina, and India. Because of Singapore’s reputation as the leader in medical care and product manufacturing in the Asian health care industry outside of Japan, manufacturing performed in Singapore connotes quality products. This country’s reputation for stringent quality requirements gives its products credibility and promotes consumer confidence. Further, Singapore has a superior infrastructure compared with its neighbors, is one of the world’s major shipping ports, and is strategically located for easy distribution throughout Asia.
Finding satisfactory manufacturer and distributor partners in Southeast Asia can be challenging. Because the enforcement of patent laws is often lax in much of the region, medical companies must choose their partners carefully. Before contracting with a manufacturer or distributor, companies should know the legal individualities of each country involved and structure contracts accordingly. An often overlooked precaution is cultivating a close relationship before entering into contract talks; such relationships will improve the chances that both partners in the agreement are familiar with each other and are on good terms. They are particularly valuable in Asia where partnerships tend to emphasize personal associations.
On the other hand, despite the higher costs associated with manufacturing in the United States, such a strategy can be successful if costs are minimized; a product that is manufactured in the United States and receives FDA approval will connote high quality and garner superior credibility. Often, such products can command a premium that helps compensate for higher manufacturing costs. Therefore, companies must analyze the costs and benefits of this strategy based on the particular product. If a product treats or diagnoses an indication that requires products with a reputation for the highest quality, manufacturing in a country such as the United States may be worth the additional costs.
Epidemiology and Pathophysiology
The spread of HIV/AIDS has become one of Southeast Asia’s most pressing health problems. The Joint United Nations Program on HIV/AIDS (UNAIDS) estimates that of the 30.6 million HIV/AIDS cases worldwide, approximately 6 million have occurred in South and Southeast Asia. Although HIV was slow to arrive in Asia, in recent years, this disease has spread more rapidly throughout Asia than any other region. Between 1996 and 1997, the incidence of HIV/AIDS grew 16% faster in South and Southeast Asia (27.7%) than in sub-Saharan Africa (23.8%). By 2001, UNAIDS predicts, 25% of the world HIV/AIDS population will reside in Asia.
The principal mode of HIV/AIDS transmission in Southeast Asia is heterosexual contact. Widespread prostitution has been a primary factor in the rapid spread of the virus. Other modes of transmission include intravenous drug use, homosexual contact, and blood transfusions. In addition to increased prostitution, recent growth in the number of migrant workers has exacerbated the HIV/AIDS problem and helped to accelerate its spread throughout Southeast Asia.
Two factors have made Southeast Asia a particularly attractive market for HIV diagnostic tests: (1) the large number and rapid growth of HIV/AIDS cases, and (2) economic growth, which has spurred demand for more and better health care and health-related products. The combination of Southeast Asia’s booming economy over the last 20 years, the growing middle class, and the formidable HIV/AIDS problem has made this region the largest market of HIV diagnostic tests worldwide.
Enormous growth in health care infrastructure has helped the market for all diagnostic tests in Southeast Asia grow throughout the 1990s at approximately $30 million per year. In 1991, diagnostic tests generated $98.6 million is sales in Southeast Asia. By 1996, the market had grown 162% to $258.1 million. This growth in the diagnostics market resulted in large part from increased sales of HIV/AIDS-related diagnostics. Additionally, as mentioned earlier, the less stringent regulatory procedures in Southeast Asia than those in the United States and Japan make product registration easier for companies, allowing for a quicker return on their investment.
Two types of HIV diagnostic tests are currently on the Southeast Asian market: enzyme-linked immunosorbent assay (ELISA) tests and rapid tests. ELISA tests are the most widely used HIV diagnostics in Southeast Asia and are the most accurate. However, ELISA tests are fairly complicated, require laboratory support, and do not provide immediate results (i.e.: usually within two hours). Alternative rapid tests, which provide results in minutes and do not require laboratory support, are beginning to become available, but they often provide less accuracy than their ELISA counterparts. Many ELISA tests are available (produced by companies such as Abbott Laboratories, Organon, Roche Diagnostic Systems, and Sanofi Diagnostics Pasteur), usually at a cost of $1.20-1.60 per test, including materials, services, and other related costs.
Rapid tests include the HIVSPOT test, produced by Genelabs Technologies and available in Southeast Asia since the late 1980s. This test is difficult to use and interpret because reagent reconstitution is required; the reagent has a shelf life of only five days at room temperature and thus requires special equipment. HIVSPOT is manufactured in Southeast Asia directly through Genelabs’ Singapore office and through a distributor network.
In 1997, Beacon Diagnostics signed a $6.75 million distributor agreement with Sejati Technical Services of Kuala Lumpur for the distribution of its Ora-Screen Rapid Test, among other tests for infectious diseases. The test is saliva-based, provides results in 15 minutes, and offers virtually the same accuracy as blood-based tests. Sejati has exclusive distribution rights for Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam.
Agen Biomedical (Australia) markets the SimpliRED HIV test in Asia. This test is fairly easy to conduct and takes approximately five minutes to complete. Agen’s products are manufactured in Australia and marketed in Asia through distributors. The SimpliRED HIV test is available throughout much of Southeast Asia, despite being rejected by the Singapore regulatory agency in 1996.
Saliva Diagnostic Systems (SDS) has also begun to market a rapid test in Southeast Asia. Hemastrip HIV has been sold in various countries, mainly though exclusive distributorships. SDS has submitted Hemastrip for regulatory approval in China, Malaysia, India, and Thailand. It also recently established a manufacturing facility in Singapore, where it hopes to sell the test directly.
As mentioned earlier, compared with Japan—which has time-consuming, complicated, and costly regulatory requirements—Southeast Asia offers a speedy process. Further, pharmaceutical and diagnostics companies in the Japanese market often compete with innovative and expensive products. Purchasers in Southeast Asia are much more concerned with price than their Japanese counterparts. Therefore, companies looking to promote me-too products may find that marketing these competitively priced products in Southeast Asia can allow them to gain market share in this region.
Several treatment options for HIV/AIDS are available in Southeast Asia, including reverse transcriptase (RT) inhibitors, and traditional medicines. Combining several RT inhibitors or combining RT inhibitors with protease inhibitors has produced better clinical results than use of single therapies. However, because combination therapy is so expensive, patients in Southeast Asia more commonly are treated with single therapies. In Thailand, for example, Glaxo Wellcome’s AZT (also known as zidovudine and marketed as Retrovir) alone costs $657 per patient per year, while combination therapy costs a minimum of $8,000 per year for each patient.
After the United States and Europe, Asia is the largest market for HIV/AIDS treatments. As the number of people infected with the disease has increased and health care delivery systems have progressed, sales of HIV/AIDS therapies in Asia have increased markedly (from $100 million in 1995 to more than $200 million in 1997). Outside of the United States and Europe, the RT inhibitors AZT and Bristol-Myers Squibb’s didanosine (DDI; marketed as Videx) have the highest sales. Glaxo Wellcome recorded AZT sales of approximately $101 million in 1997, and Bristol-Myers Squibb booked approximately $41 million in DDI sales. The majority of these sales occurred in Southeast Asia, where these therapies are among the few affordable drugs for most HIV/AIDS patients. Sales of protease inhibitor drugs, however, are considerably smaller because they are expensive. In fact, no protease inhibitor drug has yet exceeded $10 million in sales outside of Europe and the United States.
Nonetheless, protease inhibitors are becoming increasingly available throughout Southeast Asia. In 1996, the Thai government approved the sale of two protease inhibitors: Abbott Laboratories’ ritonavir (Norvir) and Hoffmann-La Roche’s saquinavir (Invirase). However, at a cost of $4,000-7,000 per patient annually, these protease inhibitors are too expensive for the majority of HIV/AIDS patients in Thailand.
To address treatment cost issues, pharmaceutical companies, government agencies, and nongovernment health organizations have all helped reduce the price of HIV/AIDS treatments in Southeast Asia through subsidization programs. For example, Glaxo Wellcome is working with the Indonesian Association of Doctors to subsidize AZT for pregnant women infected with HIV. AZT’s market price is approximately $455 per pregnancy, making it too expensive for the majority of Indonesian HIV patients.
Even in wealthier countries such as Singapore, where the GDP per person is higher than in much of Europe, only approximately 30% of HIV/AIDS patients can afford prohibitively expensive drug cocktails. In response, a nongovernment organization called Action for AIDS has started a program to help HIV/AIDS patients pay for such treatments.
In Thailand, the government is attempting to make drugs available to as many HIV/AIDS patients as possible. Thus, the Thai Government Pharmaceutical Organization is currently working with ACIC Company of Canada to produce and sell AZT at below-market prices. Plans are also underway to manufacture DDI in Thailand. These domestically manufactured drugs, in combination with a low per capita income and standard of living, make the market for HIV/AIDS treatments in Thailand more price sensitive than markets in more developed countries and reduce demand for foreign-made pharmaceuticals.
A growing number of traditional therapies for treating HIV/AIDS are available in Southeast Asia. Because Western medicines are often unaffordable and not fully effective, HIV/AIDS patients are willing to try these traditional remedies. Although several herbal medicines have been shown to improve the immune system in animals and alleviate some symptoms in HIV/AIDS patients, such treatments have not gained widespread acceptance. The Thai Government Pharmaceutical Organization also has approved the manufacture of HIV/AIDS drugs based on five herbs. While these herbs boost the immune system, they are not thought to be a cure for HIV/AIDS. In the short term, Southeast Asia’s economic crisis may increase demand for traditional therapies because Western pharmacological therapies have become prohibitively expensive for many health systems and patients. Over the long term, however, traditional therapies will probably not capture market share from Western pharmaceuticals.
HIV/AIDS Prevention Programs
Because treating many HIV/AIDS patients in Southeast Asia with the most effective therapies is prohibitively expensive, slowing the increase in new infections is of paramount importance. Thailand offers perhaps the foremost example of effective prevention programs; 2.3% of the nation’s adult population is infected with HIV/AIDS. In recognition that prevention needed to focus on sexual activity, in the early 1990s, the Thai government instituted the “100 Percent Condom Program,” a national education campaign to promote the use of condoms. The program, which consisted of distributing condoms to brothels and a media campaign to promote condom use, has been a success, and condom use grew from only 10 million in 1986 to 150 million in 1996. A 1996 study concerning HIV and young men in Thailand demonstrated the following results in selected populations from 1991 to 1995:
• Prevalence of HIV infection dropped 42%.
• The percentage of men reporting sexual relations with a prostitute fell from 81.4% to 63.8% of the study population.
• Use of condoms in the most recent sexual contact increased from 61% to 92.5%.
• The percentage of men with a history of sexually transmitted disease fell from 42.2% to 15.2% of the study population.
This study showed the effectiveness of educational programs in changing sexual behavior. Other reports indicate a fourfold drop in HIV infections since 1990. No countrywide data exist to measure the effect of such prevention programs on Thailand as a whole. We believe it is reasonable to assume that although prevention programs will help slow the spread of HIV infection throughout Thailand and the rest of Southeast Asia, the results will not be as dramatic as in this study. Such results are difficult to maintain on a large scale because study participants often receive more attention than patients would receive in a typical treatment setting. Further, Thailand is the leader in HIV prevention; such prevention programs are not as comprehensive in the rest of Southeast Asia. Thus, HIV/AIDS prevention programs should help slow the spread of the disease, but not reduce overall incidence. HIV/AIDS will continue to significantly burden Southeast Asia’s health care systems and demand for related diagnostics and pharmaceuticals will increase.
Epidemiology and Pathophysiology
One of the three leading causes of morbidity and mortality in the developing world, malaria kills more people per year than any other communicable disease except tuberculosis. Annually, malaria infects approximately 300-500 million people worldwide and kills approximately 1-3 million people. Although accurate numbers are not available for all of Southeast Asia, more than 50% of the region’s population is at risk of malaria transmission. However, the World Health Organization estimates that malaria incidence may be as much as six to seven times higher than reported figures indicate, partly because most incidence estimates include only cases that have been confirmed with a blood test.
Malaria is transmitted to humans by Anopheles mosquitoes carrying one of four species of the Plasmodium protozoan parasite: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Of the four, P. falciparum, the most common and the most lethal, accounts for more than half of all infections.
Most malaria infections occur in rural and poor areas where local health care systems are underdeveloped. Although the majority of malaria cases (90%) are found in Africa, 75% (22-38 million cases) of all other cases are concentrated in only nine countries, including Cambodia, Indonesia, Thailand, and Vietnam. In fact, South and Southeast Asia account for more malaria cases than any other area in the world outside of Africa. In Asia, malaria is most prevalent in Southeast Asia, where it occurs in all countries except Singapore and Brunei.
To help control the spread of malaria, nine Asian nations formed the Asian collaborative Training Network for Malaria (ACTMalaria) in 1996. Coordinating the fight against malaria is necessary because frequent cross-border migration renders individual nations’ malaria control ineffective; migrants would eventually carry the disease back over the border from another less vigilant nation. Thus, the network should help to decrease the spread of malaria among participating nations by improving training and communication about malaria.
Although malaria is curable, serious complications can occur if it sis not diagnosed early. Malaria is typically diagnosed according to clinical symptoms (e.g., headaches, aching, lack of appetite, vomiting). Because many of these symptoms may result from conditions other than malaria, however, a definitive diagnosis requires demonstration of parasites in the blood through microscopic blood examinations. However, such examinations may not be possible in poor and rural tropical regions that lack the necessary medical equipment and trained personnel. Therefore, many patients are treated for malaria based on an empirical diagnosis only.
Newer testing methods are beginning to emerge as an alternative to microscopic blood examinations. For example, Becton Dickinson has developed the Parasight-F assay for P. falciparum malaria. Specifically designed for ease of use, this test can be implemented at all levels of health care centers, from hospitals to peripheral clinics. The Parasight-F assay is accurate to ten parasites per microliter of blood and screens in 11 minutes. Already used in peripheral treatment centers in Northern Thailand and Cambodia, this test allows health care providers in rural areas to identify patients who need radical malaria treatment and to conserve antimalarial drugs that are in short supply.
Like many other health care product manufacturers, Becton Dickinson believes that Asian market has great potential. While acknowledging that some Asian health care systems are underdeveloped, the company nevertheless has increased its R&D activities in Singapore. The underdeveloped state of some Asian health care systems means that medical staff in these systems will have greater educational needs than those in well-developed systems. However, if diagnostics companies such as Becton Dickinson can educate health care providers about the benefits to be gained from their diagnostic products, poorer health systems may be more willing to absorb the expense of purchasing diagnostic tests.
Despite numerous available pharmaceuticals, only approximately 100 million of the 300-500 million malaria cases worldwide are treated pharmacologically. This lack of pharmacological treatment probably results from a combination of deficiency of funds and the disease resistance that populations indigenous to malaria regions develop, making each infection less severe.
Choosing the correct drug must be based on the level of immunity that parasites have built up to particular drugs in the region targeted for treatment. Although chloroquine is becoming less effective against P. falciparum in Asia, rural clinics still widely use the drug because of its affordability. In chloroquine-resistant areas, alternative drugs typically include quinine, quinidine, and Hoffman-La Roche’s mefloquine (Lariam). However, malaria parasites are becoming resistant to these drugs as well. For example, mefloquine, once considered a breakthrough drug, is failing in 60% of life-threatening malaria cases in Cambodia and Thailand.
The derivatives of quinghaosu, Rhône-Poulenc Rorer’s artemether (Paluther) and Zydus Cadila’s artesunate (Falcigo), derived from a Chinese plant extract, have demonstrated effectiveness against most malarial parasites and are being used more commonly in Asia. These drugs are rapid-acting and have been shown effective against multidrug-resistant infections. In Vietnam, where malaria is becoming increasingly resistant to chloroquine, the Wellcome Trust Clinical Research Unit of the Center for Tropical Diseases concluded that artemether was a viable alternative to chloroquine. Also, combinations of already existing drugs, such as mefloquine and artemether, are also being tested throughout the region.
Glaxo Wellcome recently developed a new antimalarial drug called atovaquone (Malarone), which is the first new antimalarial drug to be developed since the 1940s. Glaxo Wellcome has tested the drug in both Thailand and the Philippines and has received approval in Myanmar. Unfortunately, this agent is quite expensive to produce, so the people who need it will not be able to afford it. In response, Glaxo Wellcome has developed a donation program through which various health organizations subsidize malaria treatment.
Another treatment option—known as chemoprophylaxis—involves preventing infection through drug treatment while a patient is in an area of potential exposure to malaria. This method is therefore prohibitively expensive for most affected countries. Patients should begin this program two weeks before entering a high-risk area and continue until four weeks after leaving the area. Therefore, tourists and necessary medical or military personnel are the target markets for chemoprophylaxis.
Clinicians in Southeast Asia typically treat malaria with regimens involving the medications we have described in the previous paragraphs. However, because malaria parasites continue to develop resistance to current drugs, the market for malaria treatment will most likely shift towards combination therapies of current drugs. Because little research is under way to develop new antimalarials, future treatment options will depend on such combination therapies. Marketing expensive breakthrough drugs to health care systems that cannot afford them is problematic. A recurring question is whether it makes good business sense to devote R&D resources to diseases whose patients may not have the means to pay for the result.
Because of malaria’s growing resistance to many current therapies, the malaria scientific research community has focused most of its interests on vaccine research in recent years—even drawing complaints from some health care providers that researchers should pay more attention to developing new therapies. Although the same resistance and adaptation that malaria has shown against drug therapies is also a problem for vaccine developers, some evidence suggests that a vaccine is possible. For example, researchers have induced protective immunity in every animal model of malaria, indicating that such immunity should also be possible in humans. Another sign of hope is that in areas with a high prevalence of malaria, patients who have been repeatedly infected with the parasite show a decreased reaction to each new infection and often show no sign of sickness.
Several vaccines are under development, including a genetically engineered vaccine from SmithKline Beecham and Walter Reed Medical Center and a vaccine from Aquila Biopharmaceuticals that has entered Phase I clinical trials. Despite these, and other, promising compounds, a malaria vaccine most likely will not be marketed in the near future because the development process is lengthy and none of the more promising products are in the later stages.
Epidemiology and Pathophysiology
Cholera is an acute intestinal infection that can result in rapid dehydration and death in severe cases. In its extreme manifestation, cholera is one of the most rapidly fatal diseases, sometimes killing within two hours if untreated. More often, patients with severe cases enter a state of shock within 4-12 hours of infection and may die within 18 hours to several days. Other symptoms include vomiting and altered consciousness. Complications of cholera include electrolyte imbalances, acidosis, and renal failure.
The majority of Vibrio cholerae infections can be categorized as one of two biotypes that classified as V. cholerae 01—classical and El Tor. However, in 1992, a new strain, V. cholerae 0139 Bengal, emerged in Bangladesh and India and has spread to ten Southeast Asian countries. The emergence of the Bengal strain complicated cholera control because prior immunity to the classical and El Tor strains does not protect patients from the Bengal strain. Therefore, the Bengal strain has affected endemic areas where inhabitants developed immunity to older strains, and this strain is rapidly displacing both the classic and El Tor biotypes. In endemic areas, cholera is primarily a pediatric disease, but it affects adults and children equally when newly introduced to a population.
Most patients infected with cholera do not become ill. Of those that do, 90% exhibit only mild or moderate cholera symptoms. In fact, most cholera infections are difficult to distinguish from other conditions that cause diarrhea.
Cholera is usually spread through water supplies but has also been found in food. Because more-developed countries tend to have superior water filtration systems and better sanitation in general, cholera primarily occurs in developing countries. For example, cholera is indigenous in every Southeast Asian country except Singapore. Vietnam experiences annual outbreaks and had more than 5,000 cases and 59 deaths from cholera in 1995. In 1997, both Malaysia and Indonesia suffered widespread outbreaks.
Although in endemic areas cholera can often be diagnosed according to clinical symptoms, definitive diagnosis can also be obtained through the use of dark-field microscopy on a fresh stool. Laboratory diagnosis is necessary for identifying the bacteria strain and therefore crucial for epidemiological purposes. Such diagnoses, however, require trained personnel with the appropriate equipment, both of which are often unavailable in endemic areas and therefore are not used frequently in Southeast Asia.
Despite its potentially fatal nature, cholera is simple to treat; typically, less that 1% of infections result in death. The most important part of treatment is rapid replacement of fluids. Except in the most severe cases, which require intravenous fluid replacement, care providers can administer fluid replacement orally using a glucose electrolyte solution. Although not necessary, a single dose of antibiotics (most commonly tetracycline) has been found to reduce the duration and volume of fluid loss. The classic and El Tor strains of cholera, however, have developed resistance to some antibiotics, including tetracycline. In response, doctors have begun prescribing quinolones, which appear to be more effective.
Treatments in development include a synthetic sugar compound from Synsorb Biotech that is in early-stage testing. The compound, which would be used for both prevention and treatment, attempt to attach itself to toxin molecules that eventually will be expelled from the body. The goal is to block the toxins from binding to intestinal tissue, thereby preventing diarrhea. Human testing of this compound is several years away.
Awareness of, and preparation for, cholera treatment is crucial to prevent the potential morbidity and mortality associated with infection. In well-prepared communities, the death rate from a cholera epidemic is usually less that 1%, whereas ill-prepared communities can suffer fatality rates as high as 50%. Care providers in endemic areas will quickly recognize the symptoms of cholera and begin treatment immediately—a crucial step in preventing serious complications. However, if cholera is not diagnosed quickly and treated, morbidity and mortality rates increase.
Because inhabitants of endemic areas have shown growing immunity to cholera strains, a major effort is under way to develop a vaccine for V. cholerae. Two types of oral cholera vaccines have demonstrated safety, immunogenicity, and effectiveness: an inactivated and an attenuated strain of V. cholerae 01. However, despite proven effectiveness in diminishing the incidence of cholera, these vaccines have not been widely used in Southeast Asia because of their high cost. (Current vaccines cost approximately $20-30.)
Because cholera is relatively inexpensive to treat, isolated treatment is often less expensive than mass vaccinations. Thus, most health care providers wait until patients become ill and then treat them with fluid replacement, rather than trying to prevent cholera infection beforehand with vaccines. However, the Ministry of Health of Vietnam has sponsored the development and production of an inexpensive, killed whole-cell vaccine to improve the affordability of cholera vaccines. The vaccine, which will sell for approximately $0.10 per dose, showed a 66% protective efficacy rate against 01 strains—higher than a Swedish vaccine tested in the 1980s that showed a 50% protective efficacy rate. Not only is the Vietnamese vaccine inexpensive, but it also has the potential to be the most efficacious vaccine available. The Vietnamese project is the first successful example of local production of a vaccine and should serve as proof to other developing Asian nations that such ventures are feasible.
To increase local production and use of vaccines, in 1997 the Vietnamese government borrowed $25 million from the Official Development Assistance source of South Korea to produce vaccines on a large scale. Under this agreement, the Institute for Health and Hygiene hopes to produce 10 million cholera vaccines over the next five years. The Ministry of Health is aiming to provide these vaccines free of charge to all people in high-risk regions after 2000.
Strategies for Targeting a Disease
Companies cannot simply rely on regional economic growth for product success; they must develop strategies for gaining market entry and market share. Business strategies for health care product companies intending to enter the infectious disease markets in Southeast Asia must focus on several factors, including economics, epidemiology, available products, and expected innovations.
Not all infectious diseases are good targets for R&D resources. Diseases such as malaria and cholera that occur most frequently in developing counties may not be attractive treatment targets because countries where such diseases are endemic often cannot afford innovative and expensive new treatments. The paradox is that as such countries’ economies develop, making them better able to afford new treatment and prevention products, incidence of diseases such as malaria and cholera will likely decrease. Thus, they also will be less likely to require treatment and prevention. Further, developments such as the Ministry of Health of Vietnam’s production of a cholera vaccine may spread to other countries, and vaccines may be developed for other indications. For pharmaceutical companies developing vaccines or therapies for infectious diseases, such events would make the market potential for products targeted for sale in these areas unprofitable and unattractive.
In contrast to the prevalence of diseases such as malaria and cholera, prevalence of HIV/AIDS has not been shown to dissipate in conjunction with economic growth. Thus, as countries become better able to afford expensive combination therapies, the market for such products will grow.
About the Authors
Ames Gross is president and founder of Pacific Bridge, Inc., a Washington, D.C.-based consulting firm that specializes in linking Western pharmaceutical and other health care companies with Asian partners as well as in conducting primary market research and building distributor networks in Asia. Pacific Bridge works with strategic affiliates throughout Asia that have been carefully selected for their expertise and track record of successfully helping U.S. medical companies to increase sales, establish joint ventures, and conduct market research. Mr. Gross has written extensively about Asian medical and business issues for journals in the United States, Europe, and Asia. He also frequently serves as a featured speaker at medical conferences and meetings. Before establishing Pacific Bridge in 1988, Mr. Gross gained broad experience and contacts in Asia while working at three major Wall Street firms—First Boston, Salomon Brothers, and Smith Barney—where he completed more than $500 million in Asian cross-border transactions. Mr. Gross holds a B.A. from the University of Pennsylvania and M.B.A. from Columbia University.
Timothy G. McDonald is an associate at Pacific Bridge, Inc. He holds a B.A. in international relations from Mary Washington College.