Last years XIII International AIDS Conference in Durban, South Africa, marked a paradigm shift. Held for the first time on the continent worst affected by AIDS, the conference focused the eyes of the world on the plight of the more than 30 million people living with HIV/AIDS in poor countries. Leading scientists, government agencies and activists all argued that it is no longer acceptable that the vast majority of people with HIV/AIDS are left without treatment. Thanks to determined advocacy by people living with HIV/AIDS, non-governmental organizations (NGO) and other pressure groups, the provision of affordable treatment, in particular, antiretroviral therapy (ART), is now a worldwide concern.
The public health importance of intellectual property rights first came to public prominence in May 1998 during the World Health Assembly, the annual gathering of member states of the World Health Organization (WHO). Activists in developed and developing countries began testifying to the negative impact of global trade agreements on access to drugs. Public concern was further amplified during the protests around the World Trade Organization (WTO) meeting in Seattle, December 1999 . Since then, activism has concentrated on the right of developing countries to produce and import affordable generic antiretrovirals.
But access to antiretroviral treatment, and indeed the prophylaxis and treatment of opportunistic infections, remains vastly insufficient in developing countries. Last year, only six developing country governments (Brazil, Argentina, Uruguay, Mexico, Chile and Costa Rica) were providing antiretroviral treatment for the majority of people for whom treatment is indicated .
The price of antiretroviral drugs has been dramatically reduced, largely thanks to public pressure and increased generic competition. As the cost of antiretrovirals comes down, treatment moves within reach of greater numbers of people living with HIV/AIDS. But cost is not the only issue. This paper begins by reviewing the essential role played by activism in challenging the view that antiretroviral treatment is not possible in developing countries. It then reviews existing experiences with ART in developing countries and explores the challenges of wider implementation that lie ahead.
Globalization and access to drugs
Patents are a determining factor for drug access. By granting a market monopoly, patents prevent competition and allow a producer to charge globally whatever price the Western markets will bear. It would be realistic and fair for the industry to sell critical medicines to the developing world at an affordable price. But rather than differentially pricing medicines according to a country's wealth, companies have aimed to maximize profits in developed countries without attempting to enter less lucrative markets [3-5].
The implication of patents on access to drugs is illustrated well by comparing the prices of the antifungal drug fluconazole in South Africa and Thailand. In South Africa, the drug is patented by Pfizer and is retailed at US$8.25 per 200 mg. In Thailand, fluconazole is not patented and is subject to market competition: a generic version of identical quality to the Pfizer drug costs only US$0.29 for 200 mg .
Patents are granted by public authorities and provide a limited period of market monopoly during which research and development costs can be recuperated. With the advent of the WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement) in 1995, member countries were obliged to codify certain standards of patent protection into national law. The deadline for implementation of the TRIPS Agreement depends on the level of development: most developing countries had until 1 January 2000; least-developed countries have until 2006.
According to the TRIPS Agreement, intellectual property rights should be protected "in a manner conducive to social and economic welfare, and to a balance of rights and obligations" (Article 7). The potential negative effects of patents have long been understood, and safeguards have been included in the TRIPS Agreement. One such safeguard is compulsory licensing, which allows national governments to revoke the monopoly privilege conferred by a patent and allow other producers to enter the market where it is in the public interest, such as for the protection of public health . Another safeguard is parallel importation, which allows governments to obtain the lowest priced patented drugs offered on the world market by importing from countries where the drug is sold at a lower price .
However, these provisions need to be written into national law  and many countries have been pressured to forsake these rights: at the bidding of the multinational pharmaceutical companies, the United States and some European countries have pressured developing countries into passing more restrictive legislation. The examples of South Africa and Thailand are discussed later.
Most HIV drugs were invented within the past 20 years and are patent protected in industrialized countries, which represent 80% of the worldwide pharmaceutical market . They have provided pharmaceutical companies with huge revenues since the first antiretroviral drug, zidovudine, came onto the market almost 15 years ago. A list of commonly used antiretroviral drugs and combinations is presented in Table 1.
The usual argument proposed in favour of patents, that patent protection is necessary to recover research and development costs, is not valid for many AIDS drugs. Much of the research and development of these drugs was carried out by public institutions using public funds [11,12]. Public institutes hold patents for didanosine, stavudine and zalcitabine. Public funds have been used in the discovery of the HIV protease enzyme, the development of assays to measure protease inhibition. and the development of saquinavir and efavirenz (see http://www.cptech.org/ip/health/aids/gov-role.html, accessed 11 July 2001). In addition, most antiretrovirals benefited from rapid approval from the US Food and Drug Administration, resulting in lower costs of development and longer market exclusivity .
In some countries, pharmaceuticals have traditionally not been covered by product patents. Brazil and India in particular have developed thriving industries that produce generic AIDS drugs at a fraction of the price of the patented products. [Further information is available from the Consumer Project on Technology (see www.cptech.org, accessed 14 March 2001) and Médecins sans Frontières (MSF) (see www.accessmed-msf.org, accessed 14 March 2001).] Once the World Trade Organization Agreements become ratified by all developing countries, this will no longer be possible, and new drugs will be patent protected worldwide for 20 years.
To mitigate the negative impact of the World Trade Organization Agreements on public health, NGO have called for action from the responsible governments and intergovernmental bodies [12-14].
Developing countries should be supported in their efforts to make full use of TRIPS safeguards, not pressured by Western governments and pharmaceutical companies into removing them. Both the United States and the European Commission have issued statements that they would not object to the use of TRIPS safeguards, but they have continued to push for more restrictive patent protection than required by TRIPS in bilateral and regional trade agreements. This practice should end if countries are to benefit from the safeguards within TRIPS.
The World Intellectual Property Organization (WIPO) should help governments offer the highest level of protection for public health while implementing laws that are TRIPS compliant. The WHO has a mandate to cooperate with countries, at their request, to analyse the public health implications and to mitigate the negative impact of international trade agreements . This mandate should be put into practice.
The TRIPS Agreement was formulated with the aim of balancing public and private interests. Without the support of the responsible bodies, this balance tips in favour of industry, at the expense of the world's poor. This has been the focus of powerful activism in South Africa and Thailand in the past few years.
South Africa taken to court by the multinationals
In 1997, the South African government passed legislation intended to reduce the price of medicines in South Africa through mechanisms such as generic substitution and parallel importation, practices that are extensively used in the United States and Europe. However, a group of 39 pharmaceutical companies filed a lawsuit against the government to block these provisions. The companies were backed by Western governments, particularly the United States, which threatened trade sanctions by placing South Africa on the US Trade Representative's 'Special 301' trade watch list in 1998, which it uses to punish alleged violators of intellectual property rights law .
South African and US AIDS activists protested against the US government and the pharmaceutical companies, demanding they drop their opposition to South Africa's attempts to improve access to medicines. Activists from ACT UP Philadelphia and the Health GAP Coalition invaded the office of the US Trade Representative and chained themselves to her table, disturbed Al Gore's political campaigning, and littered the streets between the office of Bristol-Myers Squibb and the US Trade Representative with blood-coloured fake money, a symbol of industry profittering at the expense of people living with HIV/AIDS (PWHA).
In response to activist pressure, the official US government position changed dramatically, culminating in an announcement at the WTO meeting in Seattle, December 1999, by President Bill Clinton of a new trade and patent policy "flexible enough" that "people in the poorest countries won't have to go without medicines they so desperately need" . South Africa was removed from the Special 301 list at the same time.
However, the pharmaceutical companies persisted in their lawsuit, and the first court hearing took place on 5 March 2001 . Activists all over the world rallied in support of the South African government, and the following month the pharmaceutical companies finally bowed to the public pressure, unconditionally dropping the case. This victory sends a powerful signal to other developing countries that it is possible to stand up to pressure from the pharmaceutical industry and allows the South African government to implement the contested legislation. However, the South African government has indicated that it has no plans to introduce an antiretroviral treatment programme, disappointing many of those who supported the government during the court case and highlighting the need for legal provisions to be linked with strong government leadership. Nonetheless, MSF with the support of the provincial government has been able to start a treatment programme in one province.
One year earlier, in March 2000, South African AIDS activists started to directly target the pharmaceutical industry when the Treatment Action Campaign (TAC), a prominent South African NGO advocating for improved access to medicines, began a campaign demanding that Pfizer either reduce the price of fluconazole to the levels in Thailand or issue a voluntary license to allow generics to be imported or produced in South Africa. Protests in South Africa and at Pfizer's New York headquarters eventually led Pfizer to announce in April 2000 that it would donate fluconazole to the South African government for a period of 2 years (essentially until the patent expires in South Africa). However, after months of fruitless negotiations, TAC decided to take matters into its own hands and imported generic fluconazole from Thailand, demonstrating that generics can offer an immediate solution to access problems, in contrast to slow and bureaucratic donation programmes.
Ultimately, an agreement between Pfizer and the South African government was signed on World AIDS Day, 1 December 2000. But by pre-empting generic competition and avoiding differential pricing, Pfizer's donation blocks the establishment of more sustainable solutions. Drug donation programmes are fraught with problems of sustainability, geographic and quantitative restrictions, indication restrictions, time restrictions, and delays in implementation, and may end up being more costly in the long run due to the diversion of resources required to manage the donation .
Confrontation and compromise in Thailand
Thailand is well known for its progressive HIV prevention strategy . The AIDS NGO movement has played a key role in lobbying for respect for human rights and access to compassionate care for all since the early 1990s .
The Thai Government Pharmaceutical Organisation (GPO) is a state enterprise that manufactures quality, low-cost generic drugs. The GPO began producing generic zidovudine in 1992, with a fall in cost of this drug of 83% between 1992 and 1996 . However, the Thai government has for a long time been under trade pressure from the US government to adopt restrictive patent laws [23,24]. The GPO's attempt to launch generic didanosine in early 1998 was blocked by the patent holder Bristol-Myers Squibb. Although the active substance of didanosine is not patented in Thailand, GPO production was blocked by a patent on a particular formulation held by Bristol-Myers Squibb (Thai Patent No. 7600).
In August 1998, the high price of didanosine became the focus of co-ordinated lobbying by a consumer group, academic pharmacists, PWHA and AIDS NGO to advocate for lower prices. Didanosine was developed by the US National Institutes of Health and licensed to Bristol-Myers Squibb. The licensing agreement contained a reasonable-pricing clause [25,26] that lobbyists felt had been overlooked.
In December 1999, activists demanded the Thai government issue a compulsory license to enable GPO production. The Thai government was faced with two options if it wanted to support generic production: issue a compulsory license or support the generic production of didanosine in powder form, thereby circumventing the formulation patent .
The US government backed the interests of pharmaceutical companies and warned the Thai government against the use of a compulsory license in January 2000 , despite Clinton's announcement of a more flexible trade policy the previous month . Demonstrations outside the US embassy in Bangkok, together with consumer group lobbying and activist pressure in the United States , forced the US government to relent [30,31]. But the initial warnings were hard to forget and the Thai government rejected the use of compulsory license . Thailand's unease was summarized by a senior official at the Commerce Ministry's Intellectual Property department, who said that "Thailand has committed to the international community not to use poverty and sickness as an excuse in international trade" .
As a compromise, the Thai government authorized the production of generic didanosine in powder form, which was not patented, and this is now available at about 50% of the Bristol-Myers Squibb price. Thai lobbyists remain unconvinced of the legality of the Bristol-Myers Squibb patent: AIDS ACCESS Foundation (a Thai NGO) and two people with HIV/AIDS have filed a plaint with the Thai Intellectual Property Court.
Co-operation between the GPO, people with HIV/AIDS and NGO continues and has led to the production of generic stavudine (price reduction, 85%), lamivudine and nevirapine. None of these drugs are patented in Thailand.
At the time of writing, the Thai Ministry of Public Health continues to purchase higher priced brand-named drugs. Price reductions by the industry have been accepted but will only benefit patients enrolled in limited Ministry of Public Health projects. GPO production operates on a small scale, supplying individual hospitals and MSF, but the Thai government has recently made a significant financial commitment to scale-up generic production.
Campaign achievements and unresolved problems: where next?
The WHO, the World Bank, the European Union, and many Western governments have all begun to address the impact of trade on public health. The right of individuals to receive antiretrovirals is recognized, and efforts are under way through the G8 and other national and international initiatives to explore ways to achieve this goal.
In response to increasing demands for equitable access to treatment and threats of generic competition, five major pharmaceutical companies in a UNAIDS-coordinated program (the Accelerated Access Initiative) announced price reductions in May 2000. Each country must negotiate its own price and, for those few countries that have so far negotiated a price, the discount is less than anticipated. So far, 11 countries have signed agreements with prices negotiated at around US$1000 per patient per year for non-nucleoside reverse transcriptase inhibitor-based triple therapy  (see www.unaids.org/whatsnew/press/eng/pressarc01/UNGASScare_250601.html).
Generic manufacturers have offered even better prices: in February and March 2001, two Indian companies, Cipla and Hetero, offered a triple combination therapy of lamivudine, stavudine, and nevirapine for around US$350 per patient per year to governments and NGO (Table 2) . This generic competition has resulted in a drop in the price of brand-name drugs (Fig. 1).
Faced with generic competition and fears of the increasingly negative media attention over their pursuits of patent rights, two multinational companies (Bristol-Myers Squibb and Merck) announced that they would sell their products at cost price in sub-Saharan Africa (Bristol-Myers Squibb) or low-income countries (Merck). However, the middle-income countries that are more likely to afford these prices were excluded by Bristol-Myers Squibb and given smaller discounts by Merck .
Generic production is the most direct and sustainable way to make drugs affordable. Countries where these drugs are patent protected should make maximum use of TRIPS measures such as compulsory licensing to import or allow production of generic versions. For this, they will need the technical support of international organizations like the WHO and WIPO, and freedom from Western trade pressure and pharmaceutical company court cases.
The most significant impact for PWHA themselves so far has been the sense of empowerment and increased confidence engendered through successful campaigning and international networking. However, giving such attention to access to antiretrovirals has raised expectations, while the vast majority of people still do not have access to ART and many will be unable to afford either generic or discounted drugs. Moreover, access to compassionate care and prevention and treatment of common opportunistic infections remains limited. Activists in Thailand and South Africa are now using their increased confidence and knowledge to campaign for access to cotrimoxazole prophylaxis for all PWHA, since coverage is still low .
Thus, PWHA in the developing countries live in hope for antiretroviral treatment, but are frustrated that basic treatment needs are unmet and left out of the debate .
The ethics of access to treatment
There is continuing disagreement among health professionals regarding provision of antiretroviral treatment in developing countries.
A major concern of public health is equitable access to treatment. For HIV treatment, this means two things. Firstly, treatment, whether of opportunistic infections or ART, should not unduly drain resources from other health priorities. Secondly, treatment should not be undertaken unless equitable access for the entire population can be achieved.
The international public health community previously sidestepped this dilemma, stating that ART was too complex and not cost-effective enough for widespread use in resource-poor settings, and that poor adherence could lead to the rapid spread of resistance [38-41]. Now that the use of antiretrovirals to reduce mother-to-child transmission has been accepted as a cost-effective and achievable goal in less developed countries , the ethical dilemma is obvious: prevention of mother-to-child-transmission is considered cost-effective but antiretroviral treatment of mothers is not.
PWHA and their families may feel that their rights and aspirations are ignored when treatment is withheld for these arguments. For clinicians, failing to provide the best possible available treatment for their patients acts against a fundamental professional ethic. There is thus a friction between public health considerations about equitable access and cost-effectiveness, and individual concern that if a life-saving treatment is available it cannot be withheld.
The message from the past year's activism was that if a life-saving treatment is considered not to be cost-effective, then every effort must be made to make it so. After years of not challenging prices, research now suggests that if prices are reduced far enough, ART becomes cost-effective . Activists have also challenged the priority afforded to considerations of cost-effectiveness by pointing out that the availability of treatment provides a powerful incentive for those in developing countries to come forward to be tested for HIV, which can provide vital support to prevention efforts. As Peter Piot, Executive Director of UNAIDS, said in his speech at the African Summit on HIV/AIDS, tuberculosis and other related infectious diseases, in Abuja, Nigeria, April 2001, care is inextricably linked with prevention (see www.unaids.org/whatsnew/speeches/eng/piot270401abuja.htm).
The combined force of these arguments means that the terrain is shifting: questions of whether ART should be provided at all are being replaced by questions of how and where. While health policy-makers everywhere should assure that a minimum level of key care interventions is provided for all PWHA, the goal should be to make ART part of a comprehensive HIV/AIDS care policy.
Experiences with ART in developing countries
Beginning in 1992, Thailand became the first developing country to make ART relatively widely available. Outcomes were poor due to inefficient regimens (monotherapy or dual therapy), poor patient compliance (resulting largely from lack of correct information), and lack of physician adherence to protocols (poor information and lack of teamwork across the continuum of care) [22,443]. As a result, the World Bank recommended the programme be scaled back , and Thailand is now proceeding more carefully and on a smaller scale.
Brazil provides the most extensive developing-country experience and this experience is overwhelmingly positive: mortality has been reduced by around 50%, and savings in terms of treatment of opportunistic infections and avoided hospitalizations are almost as great as ART expenses (see www.aids.gov.br/new_drug_policy.pdf, accessed 26 July 2001). A key factor in the success of this programme is the free distribution of antiretrovirals. Many of the drugs are manufactured domestically by Brazilian companies, bringing the cost of treatment down to US$1500 per year. Adherence rates are similar to those observed in industrialized countries , and efforts are under way to further improve adherence [47-49] and broaden treatment access among marginalized groups .
Limited information is available from other developing countries. The main examples are the UNAIDS programmes in Uganda [51,52] and Ivory Coast [53,54], the government initiative in Senegal [55,56] and anecdotal reports from clinical practice elsewhere [57-60]. The UNAIDS projects and the Senegal experience clearly show that implementation of ART is feasible and effective in resource-poor countries.
However, drugs in the UNAIDS projects were not free, and cost issues have impacted on treatment outcome. Prohibitive cost leads to delay in initiating therapy, prescription of suboptimal regimens, and non-adherence to treatment [61-64].
A common experience from all these countries is that the majority of patients start ART when already severely immune-compromised. Clinical management is challenging because such patients, at least initially, remain at high risk of severe opportunistic infections either due to new infections or immune reconstitution syndrome. Many opportunistic infections are difficult to diagnose or treat in resource-poor settings. Patients need to be encouraged to present earlier to avoid this high mortality and possible negative public perception of effectiveness of ART.
Beyond prices: challenges for implementation
The price debate is not over, and many groups will continue to push for further discounts. But the recent price reductions of antiretrovirals do open the way for discussion to progress on the feasibility of wider access. Political commitment on the part of the governments of both developed and developing countries is now needed to overcome three barriers: sustainable funding, adequate health care infrastructure, and simplified treatment protocols .
Donor funding for HIV/AIDS programmes has been dramatically inadequate , and an increase in donor funding (including for ART) is desperately needed. The Secretary-General of the United Nations, Kofi Annan, has recently promoted the creation of a Global AIDS and Health Fund, calculating that annual contributions of US$7-10 billion are required as part of the fund to combat HIV/AIDS (see www.un.org/News/Press/docs/2001/sgt2276.doc.htm, accessed 3 May 2001). But when the Fund was announced at the G8 meeting in Genoa in July, the contribution stood at a paltry 1.3 billion . There have been exchanges between the United States and the European Union about how this limited amount of money will be spent. The United States wants the money to buy brand-name drugs; the European Union says that the fund should not become a subsidy for the pharmaceutical industries . If the real purpose of the Fund is to save lives, then it should always buy the most affordable medicines and other health commodities.
Moreover, details about the governance of the Fund remain unclear , and it has been stressed that substantial investment in health systems will be needed to enable poor countries to increase prevention, treatment and research activities . This will require far more resources than have so far been committed.
Infrastructure is a major barrier to wide-scale implementation. The pharmaceutical industry has repeatedly emphasized that infrastructure problems are more important than price  and has used this to justify delaying price reductions. But high price acts as a disincentive to developing infrastructure. Moreover, to say that poor countries have poor infrastructures and so cannot cope with sophisticated treatments vastly oversimplifies the issue. There are enormous differences between the so-called developing countries and even within each individual country. The pharmaceutical industry is an important player, but its role should be to make affordable drugs, not to set public health policy.
In most developing countries, sufficient infrastructure already exists to begin using antiretrovirals in limited programmes. There is clearly an urgent need to start such projects as widely as possible to gain further appreciation of the obstacles that will need to be overcome before widespread provision of antiretrovirals is possible, and to build capacity, as well as for the obvious benefits to PWHA.
However, as long as price is an issue, only limited projects are possible, raising ethical issues of who will be included or excluded. PWHA in Zambia benefiting from such projects report feeling guilty because their friends are not so lucky . In Central America, many members of PWHA groups receive ART but their priorities evolve away from those who in the same countries or regions are still struggling for access . MSF's experience in Thailand shows that PWHA are cautious towards limited projects because of their potentially divisive nature.
Wider implementation of antiretroviral treatment in developing countries requires an assessment as to what extent Western standards of care must be met. Minimum requirements for laboratory testing in resource-poor settings need further exploration: there is no consensus and hardly any research or discussion on price [73-77]. Such considerations are vital in determining the feasibility of ART implementation in developing countries. Efforts should increase to simplify and adapt antiretroviral combination therapy and monitoring for use in developing countries .
Impressive mortality reductions have been observed only after the introduction of triple therapy , and highly active antiretroviral therapy (HAART) is cost-effective in Western settings [80-82]. But dual therapy is better than no antiretrovirals at all [82-84]. Experiences in Uganda and Ivory Coast confirm that patients fare better with dual therapy than with no therapy, but durability is limited. However, the modest benefits of dual therapy might not justify the costs and efforts of implementation . As prices fall, HAART will become an affordable and more cost-effective solution for many countries. Dual therapy will remain an option for individual patients who cannot access free drugs and who can afford two but not three drugs. Structured treatment interruptions have been suggested as yet another way to reduce cost  but uncertainty remains about the efficacy of interrupted therapy, and the long-term cost/benefits need further investigation.
Ultimately, guidance on ART implementation in developing countries cannot be based on single global (Western) standards. Treatment must be adapted to the patients and prevailing conditions of care .
Justified concerns about adherence and the development of resistance need to be addressed. There are some successes with pilot programmes using direct observed therapy in industrialized countries [87,88], but this is not practicable for developing countries because treatment is lifelong and usually requires more than one dose per day. Convincing patients to enter treatment programmes or prescribing without giving sufficient information can only lead to poor adherence and increased resistance. Patient motivation is the key to good adherence: patients must be able to decide freely whether or not to take ART, with realistic expectations and a clear understanding of the challenges to adherence in their own social situation. However, health care providers cannot reliably predict adherence and should not withhold treatment to patients who are motivated but are estimated to be poorly adherent .
Thanks to generic competition promoted through international activism, a price war has begun and the price of antiretrovirals has fallen dramatically. At the time of the Durban conference, US$2000 per year was being offered to developing countries for triple combinations costing US$10 000-15 000 per year in the United States. By March 2001, generic manufacturers had reduced this to below US$350. These prices must now be made available everywhere in developing countries, and further price reductions should be sought.
Antiretrovirals have focused international concern over the adverse impact of globalization on access to medicines in developing countries. The WTO TRIPS Agreement provides safeguards such as compulsory licensing and parallel importation, and governments of developing countries must be allowed to make maximum use of these provisions. It is morally reprehensible that pharmaceutical companies and governments of industrialized countries continue to pressure poor countries for more restrictions than required by international trade agreements.
The multinational pharmaceutical industries, for their part, should more fully engage in differential pricing and make reduced prices available without restrictions, or issue voluntary licenses to generic manufacturers.
Donor countries need to increase funding for HIV/AIDS, including antiretrovirals. Such funds would be best used to purchase low-cost generics, and the transfer of technology to support generic production. Political will is thus indispensable.
Experiences from the increasing number of treatment programmes in developing countries need systematic documentation. Research is needed to simplify treatment protocols and low-technology/low-cost testing methodology, but should not be a reason for delay in widening access to treatment.
Activism has played a crucial role in catalyzing change but cannot replace government action. In Brazil, the government has shown political commitment and has viewed civil society as an ally. While activism has been strong in Thailand and South Africa, the government response has been slower and achievements limited. Until recently, the dominant view was one of caution towards the use of ART in developing countries because of poor cost-effectiveness and the complexity of the treatments. Activism successfully challenged this view, pressing for price reductions that eventually triggered a policy shift in the WHO, UNAIDS, and other international bodies. There are encouraging experiences with ART in some developing countries, and policy-makers in other developing countries are now faced with the challenge of making ART part of a comprehensive HIV/AIDS care policy.
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Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
Antiretroviral therapy; ethics; activism; Africa; Asia; Latin America; non-governmental organization; patent; World Trade Organization