More photos »

Access to newer and adapted medicines: The challenge remains

HIV/AIDS is a chronic disease requiring life-long treatment with different ARV combinations for people who develop drug resistance and side effects over time. In MSF’s longest-running ART program, in Khayelitsha, South Africa, approximately 22% of patients on treatment for 5 years needed to be switched to a second-line drug combination due to resistance. In MSF’s HIV project in Kigali, Rwanda, 16.6% of patients needed to switch to an alternative regimen (median ART duration, 1.5 years) due to side effects related to stavudine (d4T), one of the ARVs most commonly used in first-line drug combinations in developing countries. A further study of a South African cohort found that within 3 years on ART, 21% of patients who had started a d4T-based regimen needed to be switched because of toxicity. In 2006, WHO recommended a move away from d4T to less toxic combinations based on either AZT or tenofovir (TDF). This recommendation however has significant pricing implications.

High prices for newer ARVs

The need for access to less toxic first-line ARV combinations and for options when resistance develops is urgent, yet high prices caused primarily by monopoly control remain a critical barrier. Because of increased global patenting as a result of World Trade Organization (WTO) rules in key generics-producing countries such as India, Brazil, and Thailand, prices are not likely to drop as dramatically as the 99% reduction seen for today’s most commonly used first-line ARV regimen, from >$10,000 per patient per year in 2000 to $87 today. National treatment programs will be faced with uncomfortable choices about whether to treat a greater number of patients on more affordable ARV combinations, or fewer patients on less toxic but more expensive combinations.

For example, changing a patient’s regimen from the most commonly used d4T-based first-line ARV combination to a less toxic option involves, at best, almost doubling the cost, if substituting with AZT. Switching to a TDF-based regimen would require a price increase ranging from 4- to 11-fold. A model applied to MSF’s ART project in Epworth, Zimbabwe estimates that replacing d4T with a TDF-based regimen for all patients from 2008 to 2014 (based on today’s prices) would increase ART costs from $2 million to $8.5 million. However, the situation may not be as grim as these numbers suggest, since the study did not take into account reductions in overall costs linked to TDF usage, such as reduced requirements for biological monitoring or management of d4T toxicities, as well as the fact that TDF prices have decreased and will continue to drop as increased quantities of the drug are used.

In a study of the cost-effectiveness of switching from d4T to TDF in South Africa, savings on d4T toxicity management were estimated to offset about 20% of the cost of TDF, based on a price of $17/month (the current lowest price in the public sector). The analysis found that changing to TDF would be highly cost-effective if the price were lowered to about $13/month, and would be cost-neutral for the government at $6/month.

According to estimates, switching a patient who has developed drug resistance from d4T-based first-line ARV combination to a new second-line regimen involves at least a 9-fold cost increase. In some middle-income countries not able to access generic products, up to a 17-fold cost increase would be seen over the most affordable first-line combination (Figure 1).

Keeping the door open for affordable ARVs

Because countries with manufacturing capacity such as India, Brazil, and Thailand did not begin granting pharmaceutical patents until recently, multiple producers were able to compete for the market, which helped bring prices down dramatically. Indeed, India has been called the “pharmacy of the developing world,” and MSF sources >80% of its ARVs from India. The lack of patents on individual ARV compounds also allowed for the development of FDCs, which represent an innovation that has simplified HIV/AIDS treatment and helped facilitate global treatment scale-up.

However, newer medicines are likely to be patented in these countries, preventing the competition that leads to lower prices. This means the battle for access to newer drugs will have to be fought in different ways. Public health safeguards enshrined in the WTO TRIPS (Trade-related Aspects of Intellectual Property Rights) Agreement allow countries to overcome patent barriers by issuing compulsory licenses (CLs) to open the market to competition despite a patent. CLs issued by Thailand and Brazil since January 2007 have had a major savings impact on national HIV treatment programs. In Brazil, a CL issued for EFV brought the price down by nearly 70%, from $576 to $190 per year, leading to savings of $30 million from March to December 2007 alone, and a further projected savings of $237 million by 2012. Similarly, a CL issued by Thailand for lopinavir/ritonavir brought the drug price down by 55-75% in middle-income countries.

Further TRIPS safeguards allow countries to design patent laws that limit the scope of patents in the interest of public health. India’s Patents Act of 2005, for example, has strict criteria as to which innovations deserve patents and includes a provision allowing any interested party to oppose a patent. Civil society and others have filed multiple oppositions against ARV patents, and in June 2008 for the first time such an opposition was successful, when the Indian patent office rejected a patent for the pediatric syrup formulation of NVP.

Diving into the patent pool

The July 2008 decision by UNITAID to in principle establish a patent pool is a groundbreaking development, which may hold the key for access to affordable newer ARVs in the future. MSF, together with Essential Inventions, originally proposed the patent pool concept to the UNITAID board in June 2006, in response to difficulties in accessing newer ARVs. A patent pool is a mechanism whereby a number of patents held by different entities, such as companies, universities, or research institutes, are made available to others for production or further development. The patent holders receive royalties paid by those who use the patents. The pool manages the licenses, patent negotiations, and royalty payments.

A patent pool could facilitate, for example, the development of pediatric formulations or much-needed FDCs for less toxic first- and second-line treatments. Patents on individual compounds typically stand in the way of producing FDCs, a barrier that a patent pool would help circumvent. A patent pool can also help speed up the availability of generic versions of new medicines, because the development can start well before the 20-year patent term expires. At the same time, it will help to increase the size of the potential market because companies that produce drugs under license from the patent pool will be able to export them to any of the countries designated by the pool’s licenses.

Critical to a patent pool’s success, however, is the patent holders’ willingness to include their patent rights in the pool. UNITAID is setting up a task force to design their proposed patent pool. The recently adopted WHO Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property also recommends exploring the feasibility of patent pools.

Newest ARVs not adapted for resource-poor settings or pediatric patients

Therapeutic advances for HIV have been seen over the last 2 years, with the approval of new drugs from older classes, as well as entirely new classes. However, these new ARVs are targeted primarily for developed-country markets and are often not designed to meet the specific needs of populations in resource-poor countries, where 90% of HIV-positive people live.

For example, some of these drugs have monitoring requirements that make their use impractical in resource-limited settings, or they lack essential data for target populations in developing countries, such as pregnant women or patients who also take TB drugs. A further example is the lack of knowledge about drug interactions between antimalarials and ARVs; 80% of HIV-positive individuals live in malaria-endemic regions.

Furthermore, the specific ARV needs of children with HIV must be urgently met. Of the 22 ARVs approved by the US Food and Drug Administration (FDA) for adults, 8 are not approved for use in children, and 9 do not have any pediatric formulations. Although one new drug (tipranavir) was approved in late June 2008 for use in patients 2-18 years old, most of the recently approved ARVs, some with entirely new mechanisms of action (maraviroc, etravirine, darunavir), lack safety and efficacy data for children. This situation exists despite the fact that the FDA has included obligations and incentives encouraging submission of data for pediatric use since 1997, and the European Agency for the Evaluation of Medicinal Products (EMEA) followed suit in January 2007. EFV was approved by the FDA for use in adults in 1998, but dosing for children under 3 years of age has not yet been established.

Generic manufacturers have been at the forefront of developing adapted pediatric formulations, and today several pediatric FDC tablets are finally available. In countries with the manufacturing capacity, the lack of patents on individual compounds has facilitated the development of these FDCs. Nevertheless, the fact that the first WHO-prequalified pediatric FDC became available a full 6 years after the adult equivalent is distressing. This lag highlights the urgent need to systematically include pediatric studies in the ARV development process, and to ensure that formulations adapted for children are developed at the same time as those for adults.

Access to newer, safer, better adapted, and cheaper ARVs requires:

• Price reductions for less toxic first-line ARV combinations (TDF- and AZT-based)
• Development of affordable, adaptable options for adults and children when resistance develops to first-line regimens
• Support for countries’ use of TRIPS safeguards such as compulsory licenses and the creation of pro-public health patent laws
• Establishment of a patent pool to foster competition and facilitate the development of needed FDCs for adults and children
• Development and adaptation of HIV drugs and diagnostics for resource-limited settings
• Systematic inclusion of pediatric studies in the development of ARV formulations

Continue reading: Program indicators of quality and continuity of care »