Drug companies, WHO trying to streamline current HIV regimens

June 2004

Nearly two dozen antiretroviral agents are now available for treating HIV, and many more are in the pipeline.

“What had been a death sentence, is now, for those people who can secure those drugs, a manageable, chronic condition,” said Jeffrey L. Sturchio, PhD, vice president of external affairs, human health, Europe, Middle East and Africa at Merck & Co. in Whitehouse Station, N.J.

Most of the research in drug development over the past few years has concentrated on reverse transcriptase and protease. “Virtually all of the agents that we have inhibit either reverse transcriptase or protease in some way,” said Sturchio at the International Conference on Emerging Infectious Diseases in Atlanta. “The other four stages in the cycle are the entry of HIV into the cell, its integration into the cell’s genome, the virus budding from the cell and then going off with a new mature virion to infect other cells.”

One of the challenges of chronic HIV/AIDS therapy is how to simplify and make therapy more convenient, so patients will remain on treatment.”

Improving what’s available

Much recent discussion has centered on trying to find better agents in the classes of drugs that are available. “The goal is to help people stay on therapy, and eventually have once-a-day simple therapies,” Sturchio said. For example, the 3 by 5 Initiative from WHO is calling for four fixed-dose combinations.

Proposed fixed-dose combinations include a backbone of zidovudine/lamivudine (AZT/3TC, Retrovir, Epivir, Combivir, GlaxoSmithKline) or stavudine (d4T, Zerit, Bristol-Myers Squibb)/3TC, each with either nevirapine (Viramune, Roxane Laboratories) or efavirenz (Sustiva, Bristol-Myers Squibb). “Some of those exist now,” Sturchio said. “But I think that the pharmaceutical industry – both research-based and generic – is working to find ways to improve the availability of these kinds of combinations and others that might be helpful.”

Tolerability and reducing toxicity is a major concern. Current regimens are being experimented with to reduce the toxicities: structured treatment interruptions, dose changing and delaying therapy.

Resistance

The greatest challenge, however, is managing resistance.

In the United States, there are now patients who have HIV that is already resistant to many available agents when they first present. “This is a very troubling development,” Sturchio said. “And no one knows what the public health implications are for using inadequate regimens or in resource-constrained settings, such as Africa, where most of WHO’s efforts with the 3 by 5 Initiative will be focused.”

Similarly, with limited regimens available in these countries, “what will happen when people begin to become resistant to those regimens and there are no alternatives?” Sturchio said.

Another major emerging challenge is improving patient access to these vital medicines. “Every day, around the world, there are more people who are HIV-infected,” Sturchio said. “The numbers are not getting better. There are now more than 40 million people infected, in countries like China, India, Russia, the Caribbean and Eastern Europe. It is really a race as to who will win: the virus or us. So, improving access to HIV therapy is critical.”

New targets, plus a coordinated approach

Recent research on HIV entry inhibitors, integrase inhibitors and inhibitors for assembly and budding is promising. “In the case of entry inhibitors, this would be a way of starting earlier,” Sturchio said. “Because of the nature of combination therapy, the more tools that clinicians have to fight HIV, the better it will be for patients.”

Merck continues its discovery and development efforts to find new drugs. “We are highly committed to finding an HIV vaccine,” Sturchio said. “But we also need to do what we can to facilitate access to medicines. In addition, we need to work in public-private partnerships to help build the infrastructure and achieve the broader goals in the public-health community for HIV/AIDS prevention and treatment.”

Merck is working to help Botswana transform its approach to HIV, in partnership with the Bill & Melinda Gates Foundation and Botswana’s government. “This is a project that covers the entire spectrum of prevention, care, treatment and support,” Sturchio said. Both Merck and the Gates Foundation have pledged $50 million each over five years. “We are also donating our medicines for use in the project,” Sturchio said.

However, improving access in a sustainable way requires more than knowledge, affordability, organization, education and supply. “One also has to coordinate all these factors,” Sturchio said. “Botswana is a good example of coordinating efforts.”

The government’s antiretroviral treatment program in Botswana began in January 2002. “Nearly 25,000 patients are enrolled, and more than 14,000 patients are already on therapy,” Sturchio said. “There are also efforts to encourage people to come forth for voluntary testing and counseling. Patients are now entering this program at the rate of about 1,000 a month. It is currently the largest government-sponsored treatment program on the continent of Africa.”

“By finding common ground and finding solutions, we’ll be able to make a world of difference in the lives of those who are living and working with HIV/AIDS,” Sturchio concluded.

For more information:

• Sturchio JL. Antiretroviral development: current status and emerging challenges. Presented at the International Conference on Emerging Infectious Diseases. Feb. 29-March 3, 2004. Atlanta.