6 antiretrovirals

Antiretroviral: issue and access with a focus on Thailand Antiretrovirals: issues and access
with a focus on Thailand
Kate Shehan *
Boonyong Keiwkarnka **
Manirul Islam Khan ***
This paper seeks to introduce the reader to the objectives, functions and limitations of the three classes of antiretroviral medicines (ARV) and Highly Active Antiretroviral Therapy. It summarizes the technical, legal, financial, and adherence issues that governments in resource poor countries must consider when constructing policies related to ARV provision. Further, this paper will focus on Thailand to highlight the pressures faced by middle-income countries that have the means to produce, procure, and disseminate ARV drugs. These pressures, applied by western governments seeking to protect their economic interests via stricter interpretation of World Trade Organization laws, limit the capability of middle-income governments to provide necessary ARV drugs to their populations.
Key Words
Antiretroviral Therapy HIV/AIDS Drug Thailand An Overview of Antiretroviral Medicines
developed world, critical questions and conflicts related to ARVs remain. The ARV drugs remain expensive in As HIV/AIDS continues to wreak havoc on individuals, developed countries and prohibitively so in developing families, and societies, a new source of both hope and countries. The World Health Organization (WHO) frustration is under urgent development: antiretroviral conservatively estimates that of the 6 million people (ARV) therapy. The goal of ARV therapy is to help in developing countries in immediate need of ARV restore the immune system’s ability to produce essential therapy, only 23,000 have access to it. Half of these T lymphocyte (T4) cells, thus enabling more effective people live in one country, Brazil. Effective ARV therapy immune reconstitution. While these drugs have decreased requires stringent adherence, which proves problematic in morbidity and mortality, prolonged lives, and improved developing and developed countries alike. Due to less the quality of life for many people with HIV/AIDS in the cohesive health care infrastructures and the lack of Tulane University, School of Public Health and Tropical Medicine, USA Director, ASEAN Institute for Health Development, Mahidol University, Thailand Foreign Lecturer, ASEAN Institute for Health Development, Mahidol University, Thailand วารสารสาธารณสุขและการพัฒนา 2546 ปีท่ี 1 ฉบับท่ี 2
financial and technological resources, effective ARV Nucleoside and Nucleotide Analogs
therapy becomes extremely difficult to administer in resource poor settings. Hence, the recommendations for ARV therapy in resource poor settings differ from replication. Each of the seven nucleoside/nucleotide those in resource rich settings. Mutations, one of the analogs impedes the virus’ ability to replicate itself.
virus’ great weapons, arise naturally and from non- Upon integration into a replicating HIV DNA strand, adherence, resulting in resistance to the medicines.
any of the seven drugs obstructs further synthesis Further, the toxicity of ARV therapy results in complica- of the DNA strand. Hence, the HIV RNA is never tions, negative side effects, and an increase of chronic converted into HIV DNA. The nucleoside analog illnesses. Development of inexpensive, non-toxic, terminates the chain by preventing reverse transcriptase, effective, easily adhered to medicines for treating the HIV enzyme, from taking position in the DNA HIV/AIDS is critical to slowing the spread of HIV and strand. Unfortunately, nucleoside analogs are only alleviating the suffering of millions of people in the 21st effective when used in conjunction with other ARVs.
When used as a monotherapy, nucleoside analogs Following HIV infection, the immune system’s ability to generate new cells decreases, resulting in a) HIV quickly develops nucleoside analog resistance the depletion of cells carrying CD4, especially T4 b) positive clinical effects are not sustainable cells. CD4 and From March of 1987 through early c) nucleoside analogs do not delay the onset of AIDS 2003, the United States Food and Drug Administration d) each drug has individual toxic side effects (USFDA) had approved of 17 anti-HIV drugs approved for use by people infected with HIV (Table 1). Two Non-Nucleoside Reverse Transcriptase Inhibitors
additional drugs have been approved for use in salvage regimens where standard therapies have failed. T4 cells Non-nucleoside reverse transcriptase inhibitors are crucial for effective immune response; loss of CD4 (NNRTIs) are used in Highly Active Antiretroviral and T4 cells results in diminished immunological Therapy (HAART), the treatment regimen combining response and an increase in opportunistic infections.
two reverse transcriptase inhibitors and one protease Because HIV/AIDS results in multiple pathologies and inhibitor. Similar to nucleoside analogs, NNRTIs because single drug therapies quickly result in resistance, obstruct HIV replication and the conversion of HIV one drug will not provide adequate treatment for an RNA into HIV DNA. Unlike nucleoside analogs, individual with HIV. Highly Active Antiretroviral NNRTIs do not integrate into the DNA chain. Rather, Therapy (HAART) mobilizes multiple drugs and NNRTIs obstruct HIV replication by attaching to reverse transcriptase. Used as a monotherapy, NNRTIs do stunt reverse transcriptase, but drug resistant Table 1 USFDA Approved Antiretroviral Medicines
virus mutations develop soon after initiation. Used Nucleoside/Nucleotide Analogs Non-nucleoside compounds Protease Inhibitors
in combination with other drugs, NNRTIs do not (reverse transcriptase inhibitors) (non-nucleoside reverse
transcriptase inhibitors)
extend survival time, but they do delay the onset of symptoms. The main objective in NNRTI utilization Amprenavir(Agenerase) Saquinavir(Fortovase) is to delay the use of protease inhibitors, which often Delavirdine(Rescriptor) Saquinavir mesylate produce acute negative side effects.
Journal of Public Health and Development 2003 Vol. 1 No. 2 Antiretroviral: issue and access with a focus on Thailand Protease Inhibitors
3) by decreasing the number of virus replications, under the principle that fewer replications generate HIV is assembled within a cell and then breaks through the cell wall. At this point the virus obtains a human lipid envelope and HIV envelope proteins. HIV Highly Active Anti-retroviral Therapy (HAART)
is not replicable until after breaking through the cell wall, when the enzyme HIV protease cleaves the Gag The first antiretroviral, Zidovudine (AZT), was and Gag-Pol polyproteins into active subunits. Without introduced as a monotherapy in 1987. However, HIV protease-facilitated cleavage, the virus cannot replicate.
quickly outsmarts monotherapies by producing drug Protease inhibitors, constructed of amino acids, seek resistant mutations. Increasing the dosages of certain to inhibit protease cleavage by binding to the protease individual drugs in attempt to quell mutation production active site. If protease cleavage is obstructed, the virus is ineffective and often counter productive, due to will remain immature and noninfectious. Protease intensified negative side effects resulting from individual inhibitors present an avenue to fight HIV besides drug toxicity. For example, increased doses of nucleoside inhibiting reverse transcriptase. Theoretically, attacks reverse transcriptase inhibitors result in greater toxicity on HIV protease should not negatively impact normal but do not thwart resistance or increase the intended cell function. Unfortunately, approximately 15% of benefit. Conversely, higher doses of protease inhibitors those prescribed protease inhibitors cannot tolerate do achieve delayed viral resistance without increasing their negative side effects and must stop taking them; the toxicity. Due to the need to delay drug resistance, further, protease inhibitors do not suppress HIV replication HAART has replaced monotherapy as standard treatment.
in over half of those taking them from one to three years.
HAART employs numerous combinations of ARVs in the effort to suppress HIV replication. HAART works on Mutations and Their Significance
the principle that in order to become resistant to the therapy, the virus must produce individual strands of HIV reverse transcriptase is not capable of rectifying RNA that have mutated to resist all of the drugs in the or eliminating transcription errors that occur during regimen. Effective HAART decreases the viral load, and nucleic acid replication. These errors manifest themselves thus reduces the likelihood of transmission. By stunting as mutations. HIV reproduces between 1 and 10 billion virus replication, HAART prevents the emergence of drug times per day, there for, literally billions of HIV mutants resistant mutations. Combining protease inhibitors with can occur in an individual per day. A Darwinian model NNRTIs and nucleoside analogs in a HAART regimen may be applied to HIV replication in that during the is the most effective way to delay drug resistance.
course of viral replication, the fittest forms of the virus However, only approximately 50% of those on HAART survive. Resistant forms of the virus may exist prior to achieve undetectable viral loads (fewer than 50 copies treatment initiation or may evolve under selective of HIV RNA per microgram of blood) and significant pressure during treatment. The presence of drug resistant numbers of those infected with HIV are multi-drug HIV strains is a major reason for ARV treatment resistant. Because the transmission of multi-drug resistant failure. HIV therapy can attempt to counterbalance viral strains of HIV is well documented, strict adherence to complicated and specific HAART guidelines is imperative 1) by employing multiple drugs, which would require to minimizing drug resistance on both individual and the virus to develop several drug resistant mutations 2) by forcing the replication of strains with diminished Specialists remain unsure as to the most effective and least toxic drug combinations. Successful HAART วารสารสาธารณสุขและการพัฒนา 2546 ปีท่ี 1 ฉบับท่ี 2
therapy requires the consideration of many factors, toxicity and relieving patients of mentally strenuous including pregnancy and lactation status, age, co- drug intake schedules. However, contrary to early morbidities, previous use of injecting drugs, drug hypotheses, STI does not induce a boost in the immune resistance, viral load, previous ARV use, adherence response to HIV that could potentially enhance future issues, lifestyle, resource availability, side effects.
viral replication control. As of 2001, the US Department Balancing these complexities with resource availability of Health and Human Services recommends initiating in developing countries is extremely difficult. The WHO therapy when the number of T4 cells drops to 350/mL has considered these factors and established guidelines and viral load surges above 30,000/mL by DNA assay.
for prescribing ARVs in resource poor settings.
This suggests that otherwise healthy individuals should delay HAART initiation so as to avoid toxicity build up.
Medical Complications and HAART Initiation
Economic Considerations For Antiretroviral Therapy In
Drug toxicity induces negative side effects that Resource Poor Settings
complicate therapy. Doctors and patients must consider toxicity and side effects when considering HAART Only a fraction of the estimated 6 million people initiation. HAART can result in heart disease, diabetes, in developing countries who need antiretroviral therapy cancer, liver dysfunction and failure, kidney dysfunction have access to it. Increasing access to antiretroviral and failure, bone density loss, lactic acidosis, lipodystrophy, drugs tops the public health priority list. However, in fatigue, weight loss, increased heart rate, breathlessness, developing countries, where the needs are greatest and hair loss, increased blood acidity, peripheral numbness the resources scarce, policy makers must consider how and/or pain, muscle disease, yeast infections, and antiretroviral therapy will relate to broader health and inflammation of the pancreas. The lack of long-term country development issues, other interventions that research prevents physicians from knowing which must accompany ARV provision, realistic options given ARV regimens and combinations work the best. Some the economic situation, and which of the affordable physicians ascribe to an aggressive treatment policy options are the most efficient in meeting country health while others ascribe to a reactive treatment policy.
Skilled management of HAART is crucial to Widespread access to ARVs in developing countries patient well-being. Physicians and patients must will alter the socio-economic climate in three important collaborate to decide when to inititiate treatment, which areas: treatment costs, individual productivity, and drugs to use, and how long to implement treatment.
overall costs related to transmission rates. While ARV Specialists offer differing opinions regarding whether procurement would increase AIDS related treatment to initiate treatment sooner or later. Some physicians expenditures, this increase would be at least partially advocate early treatment initiation so as to beat increasing offset by the decrease in in-patient treatment for viral loads while others advocate later initiation so as opportunistic infections, unscheduled outpatient visits, to reserve the powerful and potentially toxic drugs and non-ARV drug needs. Antiretroviral therapy increases for use upon immune system failure. If initiation productivity by sustaining physical strength, decreasing begins prematurely, toxicity, negative side effects, and absenteeism at work, and reducing the need for recruitment the emergence of drug resistant strains threaten to and retraining. That people with access to ARVs can counterbalance the intended therapeutic benefits. Late continue contributing to their family’s basic and educational initiation may result in insurmountable disease progression.
needs holds profound social significance. Because ARVs Most doctors agree that Structured Therapy Interruptions decrease transmission rates, widespread access could (STI) are important to overall adherence by curbing ultimately reduce overall transmission, thereby diminishing Journal of Public Health and Development 2003 Vol. 1 No. 2 Antiretroviral: issue and access with a focus on Thailand HIV/AIDS related costs. Convexly, the availability of ARVs may contribute to disease transmission in that Several key issues must be addressed when both HIV positive and negative people may feel more considering ARV provision in resource poor settings.
compelled to take risks due to the availability of such One basic issue involves who will receive the treatment.
drugs. Further, ARVs extend potential transmission time The three main options differ significantly in terms of by increasing the life expectancy of those infected. Little cost and necessary infrastructure. Governments may data exists to quantify these conflicts. There for, governments choose to provide drugs to all people with HIV who struggle with the cost-benefit analyses of providing demonstrate commitment to an intense regimen.
ARVs without solid information regarding long-term Another option is to provide ARVs only to people who economic efficiency. This can result in governmental have been diagnosed with AIDS (as indicated by a commitment to HIV provision without assurance of its positive HIV test and the presence of an AIDS indicative economic advantage or in access denial based on the infection). Lastly, governments may choose to provide assumption that the cost of ARV provision far exceeds ARVs, most likely AZT, only to pregnant women so as the economic advantages of providing access to these drugs. While widespread access to ARVs is certainly Policy makers must also determine which drugs ideal, procurement, distribution, and adherence remain to provide and how to ensure adherence. While HAART is the most effective treatment, the prohibitively high Many policymakers and health professionals argue cost of new protease inhibitors precludes this as an that governments, pharmaceutical companies, and non- economically viable option in most resource poor governmental organizations should align to ensure the settings. Governments then face the difficult decision availability of ARV drugs to those living in resource of whether to purchase sub optimal drugs at a less poor settings. These arguments generally rest on political expensive price, or optimal therapy at a significantly and ethical grounds. Conversely, those who oppose the purchase of ARV drugs in extremely resource poor settings Antiretroviral drug production remains largely in generally argue that economic conditions in such settings the hands of pharmaceutical companies in the US and thwart rational, sustainable ARV drug purchase and Western Europe, although some middle-income countries, dissemination. Because ARV treatment is often a lifetime such as Thailand, are implementing programs to subsidize, commitment and drug resistant mutations are a grave produce, and distribute ARVs. The vast majority of consequence of non-adherence, drug provision countries must negotiate for feasible drug prices with other governments, organizations, and companies. Price Achieving heightened access to ARVs requires negotiations may prove more difficult for countries not only rational selection and use of drugs, but also with fewer HIV/AIDS cases. Conversely, countries improved affordability, sustainable drug financing, and with large numbers of AIDS patients in need of ARV accessible, quality health infrastructures. When making treatment may be able to secure better prices. While decisions regarding the purchase of ARVs, governments the cost of many ARVs has decreased in the past in resource-limited countries juggle political, legal, decade, buying sufficient supplies would still consume and budgetary pressures. Providing expensive ARV a formidable percentage of many countries’ national drugs to treat those with AIDS and developing health health budget. Pharmaceutical companies are concerned care infrastructures that can both ensure distribution that they will not receive an adequate return on the sustainability and assist patients with adherence may substantial resources that they allocate to research and divert extremely limited financial resources from other development. They are also concerned that reducing health programs and preclude the prevention and cure the prices for ARVs in developing countries will lead วารสารสาธารณสุขและการพัฒนา 2546 ปีท่ี 1 ฉบับท่ี 2
to re-sale of these less expensive drugs in developed for all 142 members of the World Trade Organization countries and that these price reductions will compel (WTO). The TRIPS Agreement sets minimum standards insurance companies and activists in developed countries for the protection of intellectual property, such as trade- to demand similar reductions. In order to confirm marks, patents, and copyrights. Previous to the Uruguay that developing countries continue to purchase ARVs, Round and TRIPS, many industrialized countries pharmaceutical companies are asking countries to sign recognized pharmaceutical patents and other drug extended contracts that may, in light of the trend for related intellectual property rights while approximately decreasing ARV prices, lock resource poor countries 40 developing countries did not provide patent protection into prices higher than existing market prices.
for pharmaceutical products. As a result, drugs protected Because countries at various stages of economic by patent in some countries could be copied by local development face various budgetary and technical manufacturers and sold freely and more cheaply in restrictions as well as differing epidemic stages, assessing other countries. All members of the WTO have had to ARV utilization from a strictly medical perspective is amend their intellectual property laws in accordance inadequate in assisting policymakers in countries with TRIPS. TRIPS grants those pharmaceutical companies considering purchasing ARV drugs. Further research that develop a product exclusive production and sales from an economic perspective is needed to clarify the rights to it. Hence, manufacturers that did not develop a drug may not produce or sell it. While TRIPS does not ban the copy of those drugs patented before January 1995, HIV/AIDS and Antiretroviral Therapy in Thailand
it does ban the copy of any drug patented thereafter.
While TRIPS was articulated to standardize the Thailand’s estimated HIV prevalence is 2.5% in a protection of intellectual property, developing countries population of 62 million. The Thai government reacted and NGOs have argued that TRIPS limits access to quickly and decisively to the emergence of the epidemic, essential ARVs by protecting the prohibitively high instituting social and health reforms that have assisted in price of patented drugs. However, some articles within stabilizing transmission rates. However, an estimated TRIPS provide allowances through which developing 1.5 million people are infected, and 30,000-50,000 countries can access ARV drugs. Article 8 allows new cases emerge each year. Most of these cases are governments to adopt measures that they deem necessary transmitted via heterosexual intercourse.
to protect public health. Article 31 states that governments can override patents by issuing compulsory licensing.
ARV Access Barriers in Thailand
Compulsory licensing allows governments and drug manufacturers to produce a generic version of a patented Trade laws are among the most crucial determinants drug, thus weakening monopolies held by patent holders.
of access to ARV drugs in developing countries. In May Member States “may use the substance of a patent without of 1999, WHO accepted the mandate to monitor the the authorization of the right holder, including use by health effects of trade laws; this mandate is detailed in the government or third parties authorized by the the Revised Drug Strategy, the WHO policy developed to government…the right holder shall be paid adequate ensure equal access to quality treatment and essential remuneration…taking into account the value of drugs. The most important trade law to date is The World authorization.” James Love, of the Consumer Project on Trade Agreement on Trade Related Intellectual Property Technology says that “[Compulsory licensing] is neither Rights (TRIPS). Negotiated during the Uruguay Round in conflict with TRIPS, the cornerstone of the WTO’s trade negotiations of the General Agreement on Tariffs provisions on intellectual property, nor any other and Trade (GATT) from 1986-1994, TRIPS is binding multilateral agreement on trade related intellectual Journal of Public Health and Development 2003 Vol. 1 No. 2 Antiretroviral: issue and access with a focus on Thailand property. We are urging countries to use provisions where the patent holder sells the identical drug at a lower in TRIPS for compulsory licensing so that people in cost. Parallel importing is widely employed by countries developing countries can have access to modern essential such as The United Kingdom to reduce the cost of drug therapies. In 1992, under a threat by the US to ban textile Although compulsory licensing is legal under imports, the Thai government passed a law prohibiting TRIPS, its implementation in developing and middle parallel imports until 1999. In response, the Thai income countries has been restricted by Western Europe government created the Pharmaceutical Patent Review and the US in order to protect their own economic Board (PPRB), which monitored all economic data interests. Pharmaceutical companies contend that reduction related to pharmaceuticals, including production costs.
of their TRIPS rights will decrease their incentive to The PPRB disbanded in 1998 under threats by the US devote resources to the research and development of Trade Representative Office to increase taxes on wood drugs for which compulsory licenses are issued. The United States regularly mobilizes compulsory licensing in its own domestic market, but has not approved of it Production of Generic ARVs in Thailand
in relation to essential medicines. Compulsory licensing can be used to alleviate a national emergency, but Because Thailand has limited ARV drug resources, developing countries and developed countries often in 1995 WHO advised Thailand to focus on the disagree as to what constitutes a national threat to prevention of perinatal transmission and the treatment public health. Developed countries have proved hesitant of opportunistic infections. The minimum wage in Thailand to consider AIDS a national public health threat. The US is less than $120 per month, and patented ARV triple has pressured foreign governments to adopt laws limiting therapy costs roughly $675 per month. Approximately compulsory licensing. Laws which are more restrictive 5% of people with HIV in Thailand can afford ARV than those internationally accepted standards delineated double therapy; HAART is even less accessible. The by TRIPS are called “TRIPS Plus”. One potent example Thai government has pursued the research and development of the US enforcing TRIPS Plus in Thailand involves of generic HIV-related drugs, including ARVs and the production of the anti-HIV drug didanosine (ddI).
drugs for the treatment of opportunistic infections.
In the midst of the South East Asian economic crisis, The Government Pharmaceutical Organization Thailand introduced a plan to produce and sell ddI in (GPO) manufactures more than 400 pharmaceuticals order to offer one low-tech double combination therapy, and supplies them to those health organizations supported AZT/ddI, at a price affordable to Thai people. In by the Ministry of Public Health. The GPO has an annual response, the US threatened trade sanctions severe sales volume of $100 million and focuses on those drugs enough to convince the Thai government to abandon the on the National List of Essential Drugs, which was plan. Invented by the US government, the anti-HIV drug ddI is licensed exclusively to US drug manufacturer In collaboration with the GPO, The Research and Bristol Myers Squibb. Hence, Thailand’s plan to produce Development Institute (RDI) conducts basic, pilot scale, and distribute ddl threatened American pharmaceutical and applied research to assist in developing new interests. The US government’s response limited access pharmaceutical products and augmenting existing to AZT/ddI in Thailand, thus decreasing the length and technologies. Since 1992, the RDI has been conducting quality of life for untold numbers of people with HIV.
bioequivalence studies and working on the formulation In the case of unfair pricing practices or national and production of generic HIV-related drugs. The generic public health emergencies, TRIPS allows parallel drugs produced by the GPO and RDI cost between one- importation, the importation of drugs from a country fifth and one-tenth of the cost of their patented equivalents.
วารสารสาธารณสุขและการพัฒนา 2546 ปีท่ี 1 ฉบับท่ี 2
While the sustainable production of low-cost, quality advancement, ARVs do increase life expectancies while HIV-related drugs offers a preferable alternative to procur- augmenting the quality of life for many people in ing expensive patented drugs, the Thai government developed countries. Developing countries have the right has faced pressure from foreign governments similar to and obligation to protect and enhance the health of their that applied when Thailand has considered employing citizens. This often conflicts with the commercial and the compulsory licensing and parallel importing rights economic interests of governments and pharmaceutical stipulated under TRIPS. Under US pressure, Thailand has companies in the developed world. The American and introduced tougher patent laws that limit the production European governments protect the interests of their phar- of generic drugs. In addition, the Safety Monitoring maceutical companies, resulting in pressure, limitations Program (SMP), a program started in 1989 under American and trade sanctions placed on middle income countries, influence, has slowed progress on the production of such as Thailand, that have the means to produce, procure, generic HIV-related drugs by introducing an interim and disseminate ARV drugs. The enactment of “Trips measure allowing a minimum two years of market Plus” by western countries disarms those governments exclusivity for all new drugs. During this time, doctors seeking to provide affordable, necessary medications to monitor the safety of the drug and researchers may those living with HIV. In engaging “Trips Plus” policies, not conduct bioequivalence studies. After completion of western governments reduce the length and quality of life the SMP, generic production can begin and prices for untold numbers of people with HIV in developing plummet. For example, in 1998, the price of fluconozole countries. The WHO, with its mandate to monitor the fell from $6.10/200 mg tablet to $0.60/200 mg effects of trade laws, should actively propose revisions tablet. In 2000, stavudine decreased from $2.20/40 mg to those laws that limit ARV accessibility in resource to $0.60/40 mg. Pharmaceutical companies abuse the poor settings. Members of the WTO must align to coun- interim period to ensure market exclusivity and to apply terbalance trade sanctions, encourage resource sharing, and discourage western governments from mobilizing “Trips Plus”. Western governments must shift their CONCLUSION
objectives from corporate and economic dominance to global health. Only when all stakeholders share the While toxicity, fallibility, and demanding regimens common goal of health for all will the true potential render antiretroviral therapy a frustrating medical บทคัดย่อ
บทความนี้นำเสนอข้อมูลเกี่ยวกับยาต้านไวรัส 3 ประเภท(เอ อาร์ ดี) และการบำบัดโดยใช้ยาต้าน ไวรัส โดยจะให้ข้อมูลเกี่ยวกับวัตถุประสงค์ หน้าที่ ตลอดจนข้อจำกัดของยาและการบำบัดโดยใช้ยาต้านไวรัส รวมทั้งสรุปว่าในการวางนโยบายเกี่ยวกับการจัดหายาต้านไวรัสนั้น รัฐบาลของประเทศที่ขาดแคลนทรัพยากร จะต้องพิจารณาประเด็นต่างๆ ได้แก่ประเด็นทางด้านเทคนิค กฎหมาย การเงิน และการยอมรับ นอกจากนี้ยัง มุ่งเน้นสถานการณ์ของประเทศไทย เพ่ือแสดงให้เห็นว่าประเทศท่ีมีรายได้ระดับปานกลางสามารถผลิต จัดหายาและ แจกจ่ายยาต้านไวรัสได้จะต้องเผชิญกับแรงกดดันด้านใดบ้าง แรงกดดันดังกล่าวเกิดขึ้นเพราะรัฐบาลของประเทศ ตะวันตกพยายามปกป้องผลประโยชน์ของประเทศตน โดยการตีความกฎหมายขององค์การการค้าโลกให้แคบขึ้น ซึ่งจะลดขีดความสามารถของประเทศที่มีรายได้ปานกลาง ในการจัดหายาต้านไวรัสให้ประชากรของตน คำสำคัญ
การบำบัดโดยใช้ยาต้านไวรัส ยาเอชไอวีเอดส์ ประเทศไทย Journal of Public Health and Development 2003 Vol. 1 No. 2 Antiretroviral: issue and access with a focus on Thailand References
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ANDREW B. SILVA, MD VIRGINIA HEAD AND NECK SURGEONS P.C. HERE’S WHAT TO DO IF A NOSE BLEED STARTS: Sit down or lay down with your head propped up on 2 or 3 pillows. Keep calm and remember many nose bleeds will stop all by themselves if you just rest for a few minutes. If you are driving or operating heavy or dangerous equipment stop. Put an ice pack on your nose . Get a thin washclot


Süddeutsche Zeitung, Am Wochenende, 13.03.2004, S. 4 Zwischen allen Fronten die Schweiz Wie der Soldat Max Waibel den Zweiten Weltkrieg verkürzte / Eine wahre Geschichte (von Alex Capus) Das ist die vergessene Geschichte des mutigen und ungehorsamen Schweizer Soldaten Max Waibel, der auf eigene Faust den Zweiten Weltkrieg um zwei Monate verkürzte, Tausende von Menschenleben rettete

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