For more than 20 years, Merck has sought to make a difference in the fight against HIV and AIDS. We see our core role as discovering and developing innovative treatments for the disease. Today we market four antiretrovirals (ARVs): CRIXIVAN® (indinavir sulfate), STOCRIN® (efavirenz),1 ATRIPLA® (efavirenz 600 mg/emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg)2 and ISENTRESS® (raltegravir). Since our HIV products first reached the market in 1996, we have worked to expand access to them, particularly for patients in countries that are the poorest and hardest hit by the pandemic. Today, we continue our efforts to address the impact of the disease in resource-scarce settings.
Research & Development into HIV and AIDS Treatments
Merck has had an intensive broad-based HIV and AIDS clinical research program since 1985 that has sought to address both treatment and prevention. In addition to our own research efforts, we have entered into partnerships with other researchers and scientific organizations to help accelerate the search for new treatments and possible cures.
Timeline of Merck's Research Efforts
In 1988, Merck scientists established the role of protease in the HIV lifecycle, were the first to publish the crystal structure of HIV protease shortly thereafter, and were among the first to discover and develop medicines for the treatment of HIV and AIDS.
In 1996, Merck introduced CRIXIVAN, a protease inhibitor, which was followed by the introduction in 1999 of STOCRIN, a non-nucleoside reverse transcriptase inhibitor.
Merck's work in the early phase of HIV research played an important role in collaboration with others in defining the principles for combination ARV treatment to suppress the virus to undetectable levels, which continues to be the gold standard for treatment today.
In 2006, a partnership between Merck, Bristol-Myers Squibb and Gilead to develop a once-daily single tablet regiment to simplify HIV treatment resulted in the U.S. approval of ATRIPLA. ATRIPLA is marketed by Bristol-Myers Squibb and Gilead in the United States, Canada and Europe. Merck is working to register and distribute ATRIPLA in 94 developing countries around the world where convenient treatment options are critical to patient compliance and adherence to therapy.
In 2007, Merck's efforts to address the growing problem of multi-drug resistance led to the U.S. approval of ISENTRESS, the first integrase inhibitor and the first ARV treatment to target the integrase enzyme, which is essential for HIV replication. ISENTRESS offers patients who have exhausted other treatment options an important therapy that targets the HIV virus in a new way.
ISENTRESS in combination with other ARV agents for the treatment of HIV has been shown to be effective at both reducing viral load to undetectable levels (below 50 copies/mL) and raising CD4 cell count in many treatment-experienced patients living with HIV.
Given the resistant nature of HIV, continued research into new therapies is critical. That is why Merck remains focused on developing new treatments for millions of individuals who are already infected with HIV. Key areas of focus include promising new ARV mechanisms, agents with improved tolerability and combinations that allow optimal compliance.
Given the high-risk nature of pharmaceutical research and development however, setbacks are common. In September 2007, Merck announced that vaccination in a phase II clinical trial of the Company’s investigational HIV vaccine (V520) was being discontinued because the vaccine was not effective. The study, known as the STEP trial, was co-sponsored with the National Institutes of Health (NIH) and the HIV Vaccine Trials Network (HVTN). The STEP study was designed to evaluate two primary efficacy endpoints: whether the vaccine prevented HIV infection; and whether the vaccine reduced viral levels in those who developed infection. In an interim analysis, the vaccine did not reduce the incidence of infection nor did it reduce viral levels. In October 2007, the National Institute of Allergy and Infectious Diseases (NIAID) announced that a second clinical trial being conducted in South Africa, known as Phambili, would be discontinued.
Merck, NIAID and HVTN moved quickly to disseminate broadly the available information from the two trials. The first detailed review of STEP data occurred on November 2007, at a special open scientific session of the HVTN in Seattle where data suggested that those who received the vaccine might have an increased susceptibility to acquiring HIV infection. Study volunteers were promptly counseled about this risk. Study sponsors, including Merck, have ensured that volunteers who developed HIV infection during the study have access to medication and medical care, based on the health systems in each country.
It will take some time before researchers understand why the vaccine did not work and why there was a trend toward more cases of infection in volunteers who received the vaccine. Understanding STEP is important for the study volunteers, investigators and for the entire field of HIV vaccine research, and Merck remains deeply committed to analyzing the data and sharing it as broadly and as quickly as possible.
Merck is also collaborating with NIH and HVTN to implement a fair and rigorous scientific evaluation of STEP results and to enable external investigators to gain access to specimens and data from this study in an effort to advance the search for an effective HIV vaccine.
The news was incredibly disappointing to Merck and the external community, which viewed V520 as one of the most promising HIV vaccine candidates in mid-stage studies. Hundreds of Merck employees have been involved in Merck's HIV vaccine development program during the past 20 years and had made extraordinary efforts and significant sacrifices to try to develop an AIDS vaccine. Sadly, the development of a successful HIV vaccine remains one of the most challenging tasks facing modern medicine.
Preventing HIV through Microbicides
Reflecting the company's ongoing commitment to finding new ways to prevent and treat HIV and AIDS, in March 2008, Merck granted the International Partnership for Microbicides (IPM) a non-royalty-bearing, non-exclusive license to develop, manufacture and distribute a novel ARV compound (L'644) for use as a vaginal microbicide in developing countries to help protect women from HIV. The compound, the fourth we have granted to IPM, is a member of a class of ARV molecules known as fusion inhibitors, which inhibit HIV infection by preventing the virus from fusing with the surface of target cells, an early step in the HIV infection process, potentially representing a novel way to block infection. Merck is also collaborating with IPM to advance early stage product development research efforts. This recent agreement follows a similar IPM-Merck agreement announced in 2005.
Scientists believe that a safe and effective microbicide could provide women in the developing world with a powerful new tool to protect themselves from HIV that would complement existing prevention methods. Women currently comprise nearly half of the adults living with HIV and AIDS globally; in sub-Saharan Africa, women and girls account for almost 61 percent. It is estimated that even a partially effective microbicide could prevent 2.5 million HIV infections over a period of three years.
Treatments for Children Living with HIV
Access to affordable HIV diagnostics and treatment for children is an urgent global health priority. According to UNAIDS, there are approximately 2.1 million children under the age of 15 living with HIV worldwide, while the number of children living with HIV increased by approximately 1 million between 2001 and 2007. In 2007 alone, an estimated 370,000 children under the age of 15 became newly infected with HIV, via mother-to-child transmission or later contact with the virus, and 280,000 children died of AIDS. The course of HIV infection is faster and more aggressive in children, so it is critical that pediatric patients (aged 15 and younger) be provided with antiretroviral therapy (ART) as soon as treatment guidelines indicate, depending on individual clinical and immunological assessments.
As part of the Company's ongoing commitment to the fight against HIV and AIDS, Merck has developed the following pediatric formulations for its ARVs. Of those being treated with Merck ARVs as of December 2008, there were an estimated 111,471 children using pediatric formulations, representing 17 percent of all patients on Merck ARVs.
ISENTRESS: In 2007, Merck initiated in collaboration with the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Human Development, and the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Group a Phase I/II, multi-center, open-label, noncomparative study to evaluate the safety, tolerability, pharmacokinetics and antiretroviral activity of ISENTRESS in children and adolescents. The trial is enrolling patients ranging from two to 18 years of age in the United States with plans to open in several other countries in Latin America, Asia and Africa. The study will take place in two stages. The first stage is designed to collect intensive pharmacokinetics and short-term safety data in order to make a dose selection. The second stage will provide data on safety and efficacy at the selected dose with chronic use over 48 weeks, and will include collection of additional pharmacokinetics data. Preliminary results from the trial were presented at the 9th International Workshop on Clinical Pharmacology of HIV Therapy in New Orleans, Louisiana, in April 2008. Preliminary results suggest a dose of 8 mg/kg twice daily in HIV-1 infected adolescents (12 to <19 years and 6 to <12 yrs) was generally well tolerated. However, further pharmacokinetics and safety data are needed, and continued exploration of the appropriate dose of ISENTRESS in HIV-infected adolescents and younger children is warranted. For further details on this trial, please visit www.clinicaltrials.gov
STOCRIN: Indicated for the treatment of HIV-1 infection and has pediatric indications (for patients aged three to 17 years) in many countries, particularly in the developing world. For those countries for which Merck has the right to distribute STOCRIN under our agreement with Bristol- Myers Squibb, we are currently marketing four formulations: STOCRIN oral solution, STOCRIN 50mg, STOCRIN 200mg and STOCRIN 600mg. The oral solution, hard capsule and tablet formulations (50 mg, 200 mg), and a 600 mg tablet formulation, are prequalified by the World Health Organization (WHO).
CRIXIVAN: Indicated for the treatment of HIV-1 infection and has pediatric indications in many countries, particularly in the developing world. CRIXIVAN has not been evaluated in children under three years of age.
Merck is also working in partnership with the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) Partnership for Pediatric AIDS Treatment to identify scientific and technical solutions to improve access to ARV treatment for children living with HIV and AIDS in resource-limited settings. Participating in this effort is the U.S. Government, multilateral organizations such as The United Nations Children's Fund (UNICEF) and The United Nations Joint Programme on HIV/AIDS (UNAIDS), research-based pharmaceutical companies and generic drug companies. The partners have committed to work toward identifying scientific obstacles to treatment, share best practices and take concrete, practical steps to address barriers to access. For more information, please click here.
Stakeholder Engagement to Advance Merck's R&D Efforts
Merck embraces a mission to communicate, interact and collaborate openly with scientific leaders in the field to advance science. In the United States, for more than a decade, Merck has had an established physician advisory board that includes international and national scientific leaders. This advisory board meets with Merck on a regular basis to discuss and advise Merck on HIV research and development strategy, emerging scientific issues and clinical program design. At the international level, Merck has also established a similar advisory board with international scientific and clinical leaders worldwide to gain input on emerging challenges in HIV care in developing countries.
Long-term Business Strategies and Models
Registering our ARVs and WHO Pre-qualification
Merck is committed to rapid registration of our ARVs, including in those countries most affected by HIV and AIDS. Currently Merck ARVs are registered or available through import in more than 147 countries, including 98 countries in which Merck sells our ARVs at a price at which we make no profit or at significant discounts. Within less than eight months since its first approval, Merck's newest ARV — ISENTRESS — received regulatory approval in more than 50 countries. Since then, an additional 15 countries have been added, and Merck is in the process of filing ISENTRESS in 29 additional countries around the world. Furthermore, in one of the largest access programs ever, since September, 2006 we have made ISENTRESS available to more than 9,000 patients in more than 25 countries still awaiting regulatory approval.
As of February 2009, ATRIPLA has been registered or is available in 51 of the 94 countries where Merck has rights to market the triple combination ARV under our agreement with Gilead. This includes the majority of countries that are most heavily affected by HIV.
As of March 2009, STOCRIN had been registered or is available through pre-licensed sales or import authorization in 120 countries. Seventy-six of these countries, or 63 percent of the total, are in countries where STOCRIN is sold at a price at which Merck makes no profit or at a significantly discounted price.
To increase the transparency of the Company's product registration status, we are disclosing registration for our four ARVs and we plan to update this information every six months:
ATRIPLA (
PDF*)
CRIXIVAN (
PDF*)
ISENTRESS (
PDF*)
STOCRIN (
PDF*)
STOCRIN, CRIXIVAN and ATRIPLA have received WHO prequalification. Merck is committed to working with WHO for the pre-qualification of ISENTRESS. As it is required by the pre-qualification process, Merck is awaiting the inclusion of ISENTRESS in the WHO's Expression of Interest and will be ready to submit the necessary documents. WHO prequalification verifies that medicines meet the requirements of quality, safety and efficacy of UN agencies, including UNICEF and the Pan American Health Organization, and is an important step toward providing global access.
Pricing HIV and AIDS Medicines
Since 2001, Merck has had a tiered pricing policy whereby the Company provides our HIV medicines in the least developed countries and those hardest hit by the AIDS pandemic at not-for-profit prices. The offer extends to the governments of these developing countries as well as to international donor agencies, nongovernmental organizations (NGOs), charitable organizations and private-sector employers.
This ARV pricing policy applies to all of Merck's ARVs (CRIXIVAN, STOCRIN, ATRIPLA and ISENTRESS). For each product, Merck offers our lowest price — a price at which Merck does not profit — to the world's least developed countries and those countries hardest hit by the HIV and AIDS pandemic as measured by adult HIV prevalence. Countries with a higher degree of economic development and/or lower prevalence rate receive significantly discounted prices, within a price band. The prices at which patients and countries can obtain their ARVs are based on their relative level of economic development, relative burden of disease, the degree to which the governments are committed to treating its HIV infected population and the value that the Merck ARV has in the local marketplace and treatment regimen. For the most economically developed countries, Merck applies competitive, market-based principles for the purpose of pricing our ARV products.
Below is a summary of the pricing policy for each of Merck's ARVs:
ISENTRESS: Countries on the United Nations Conference on Trade and Development (UNCTAD) least developed countries list will receive ISENTRESS at the lowest, attainable price (this applies also to the public sector in the 12 non-UNCTAD countries in sub-Saharan Africa). Countries in the medium category will receive ISENTRESS at significantly discounted prices. Price bands will guide pricing in both the public and private sectors in these countries.
STOCRIN and CRIXIVAN: Countries on the UNCTAD list of least developed countries receive the lowest prices – prices at which we make no profit —plus all other countries that had received Merck's lowest prices under our previous ARV pricing policy. All customers — whether public or private — receive these prices. For STOCRIN 600mg, Merck's not-for-profit price to the customer is $0.65 per day, or $237.25 per year. The not-for-profit price of CRIXIVAN is $1.64 per day, or $600 per year. There are 84 countries in this category.
For middle-income countries, Merck makes STOCRIN and CRIXIVAN available at significantly discounted prices within a price range, the ceiling of which is $1.80 per day ($657 per year) and $2.82 per day ($1,029 per year), respectively.
ATRIPLA: In the least-developed countries and those hardest hit by the epidemic, Merck sells ATRIPLA at $1.68 per day, or $613 per year, a price at which we make no profit. There are 81 countries in this category. In middle-income countries, Merck sells ATRIPLA at significantly reduced prices, at $2.83 per day, or $1,033 per year.
For country classifications by product, click here. ( PDF*)
Price Decreases Over Time
Merck is committed to decreasing the manufacturing costs of our ARVs based on efficiencies in manufacturing and supply, and / or reductions in the costs of active ingredients.
Since 2000, Merck has lowered the not-for-profit price of STOCRIN more than 95 percent, from an introductory price of US$10/day in 1998, to US$.65/day now in least developed countries. Since 1996, Merck has lowered the not-for-profit price of CRIXIVAN by 84 percent, from an introductory price of US$12/day in 1996, to US$1.64/day currently in least developed countries.
Manufacturing and Licensing of HIV and AIDS Medicines
Merck is committed to seeking additional ways to reduce the cost of our ARVs for people living in the world’s poorest countries and those hardest hit by the pandemic, including through working with external manufacturers and suppliers to achieve incremental efficiencies.
In addition, to date Merck has granted royalty-free licenses of our ARV efavirenz to five South African generic manufacturers, of which four are currently on the market (see box). All but one licensee donates a percentage of efavirenz net sales to the Msizi (Cares) Trust, a charitable trust established to further the fight against HIV and AIDS in South Africa through the provision of preventative and education programs.
Compulsory Licensing
In November 2006, the government of Thailand announced that it had issued a compulsory license for Merck's ARV STOCRIN. Merck was disappointed that the Thai Ministry of Public Health (MOPH) chose to invoke a compulsory license without consulting with the company. Merck is working constructively with the MOPH to improve access to STOCRIN , and believes that the Ministry can achieve its access objectives for HIV and AIDS patients without resorting to compulsory licenses. We continue to work with the new Thai administration in broader discussions about sustainable health care reforms.
In May 2007, the Government of Brazil issued a compulsory license for STOCRIN. Merck was profoundly disappointed by the decision, which was made after several weeks of negotiations between the government and the Company. While we remain flexible and committed to exploring a mutually acceptable agreement with the Brazilian government to help the country sustain its objective of universal access to treatment.
Initiatives and Public/Private Partnerships
Despite Merck's efforts to develop and implement effective philanthropic and business strategies to help remove barriers to access, challenges remain due to the complex and multi-faceted nature of the problem. Improving access requires more than simply making our medicines and vaccines available at reasonable prices.
We believe that truly to address – and, ultimately, solve— the issue of access in developing and middle income markets, the international community must pool its resources and expertise to strengthen health care infrastructure, ensure adequate financing for health, and help to build local health care capacity through training and support. Pharmaceutical companies alone cannot solve these immense public health problems. Sustainable solutions will come from comprehensive approaches that draw on the expertise of all stakeholders.
For this reason, a key element of Merck's HIV access strategy is promoting and participating in public/private partnerships with governments, multilateral organizations, community-based organizations, other corporations and nongovernmental organizations to address specific health and development challenges beyond those which Merck has immediate and direct control.
Merck has applied our experience with the MECTIZAN® Donation Program to programs and partnerships around the world that are helping to prevent and treat HIV and AIDS. While many include financial or in-kind support, Merck also seeks to leverage our expertise and the skills of our employees to contribute in additional meaningful ways. For a summary of our HIV and AIDS partnerships, please click here.
The content on this page was last modified on September 15, 2009.
Merck & Co., Inc., Whitehouse Station, NJ, USA, and Schering-Plough Corporation, Kenilworth, NJ, USA, are now one company. We have combined our global operations under the name Merck & Co., Inc. We are working to update our corporate responsibility Web site to reflect our new, combined, global organization.
1 Efavirenz is marketed by Bristol-Myers Squibb under the tradename SUSTIVA® in the United States, Canada and six European countries (France, Republic of Ireland, Germany, Italy, Spain and the United Kingdom). Efavirenz is commercialized by Merck through its affiliate MSD under the tradename STOCRIN® in all other countries within the European Union and many countries outside of the United States.
2 ATRIPLA is marketed by Bristol-Myers Squibb and Gilead in the United States, Canada and Europe. Merck and Gilead are working to register and distribute ATRIPLA in 94 developing countries around the world.
PDF*)