Speaking at the 15th International AIDS Conference earlier this month, Jim Yong Kim, director of the department of HIV/AIDS at the World Health Organization, listed recent global HIV efforts and said there is "real hope that treatment can become a reality for people living with HIV/AIDS in poor countries."

But he also said that while the number of people receiving treatment in developing countries might have doubled, that doubling is from such a small base that "we can only hang our heads in shame."

Thus the battle against HIV/AIDS is neatly summarized.

At this year's conference, held in Bangkok, Thailand, it was noted that for all the effort, 6 million people have died from AIDS since the 2002 meeting in Barcelona, Spain, and another 10 million became infected. There were more red flags. The World Health Organization (WHO) reported that its ambitious "3 by 5" plan to treat 3 million HIV-infected people by 2005 was behind by about 60,000 people. There was a report from the United Nations that Thailand, once hailed for quashing its rising infection, has let things slip, and now its HIV rate is marching upward again, with infections in gay men, migrant workers, fishermen and young people, among other groups, all on the rise.

And if the goal is treatment for all who need it, the data point to there being a long way to go. While an estimated 54 percent of people who need HIV treatment in the Americas receive it, in poorer sections of the world the figures are disheartening: Coverage drops to 9 percent in Eastern Europe and Central Asia, falls to 5 percent in Southeast Asia and dips further to 4 percent in Africa.

Not good.

The positive is the global effort Kim mentioned. Besides WHO's 3 by 5 plan, President Bush pledged $15 billion in funding over five years. Today there are 20 drugs approved worldwide to fight HIV.

But the reality is that against a shifting nature of HIV, that might not get the job done.

HIV Drugs: More Is Never Enough

Ian Lloyd, managing editor of Pharmaprojects, a firm that tracks global pharmaceutical research and development, puts the number of antiretroviral compounds in active development at 186. That covers drugs that "stop the virus' life cycle or attack the virus," Lloyd said, but does not include "all the vaccine projects" or "a very small number of immunostimulatory drugs."

The most popular antiretroviral drugs remain reverse transcriptase inhibitors and HIV protease inhibitors. However, those 186 drugs in development stem from 48 methods of action, or pharmacological strategies, which is an improvement from the 38 strategies in development in 2001. But it's still a far cry from 1997's 69 strategies, and while 186 sounds comforting, in 1997 there were 4.03 drugs in development for every strategy, compared to 3.87 now.

"It would be OK to have fewer drugs in development than we did a while ago if we had a broader range of strategies, but the number of strategies has not improved, and that is not good news," Lloyd said.

Why that fall-off since 1997?

"A large number of companies decided to quit the area around that time," Lloyd told BioWorld Financial Watch. "At that time, there was pressure to supply drugs into poor countries and that made [drug makers] wonder how much money they could make."

Also, with drugs approved and more in pipelines around the world, in 1997 "there was a feeling that this area is fixed, it's covered," he said. That soon proved not to be the case, and drug makers "realized it isn't enough, because, for starters, we don't know how long people can take the drugs [due to] toxicity. Also, resistance is rising, just as it happened with [antibacterial drugs]."

The slippery, mutational nature of HIV suggests that there might never be enough HIV drugs on the market.

"In order to keep on top of what is effectively a moving target, we need more drugs with different strategies as part of the armory," Lloyd said. He referenced the 20 approved drugs and said he heard at the conference that those drugs "work out to be 1,333 potential tripled-drug combinations," which seems like a lot.

It's not. Lloyd pointed out that "if someone gets resistance to a protease inhibitor, it's possible they might be resistant to all protease inhibitors. Also, people don't always respond to [combination regimens]." Factor in those elements and 1,333 "is not as impressive as it sounds."

The Effect Of HIV Drug Generics

Generics, as elsewhere in the drug world, loom as a potential hornets' nest. WHO has approved use of 3-in-1 generic pills, and a study conducted in 21 countries by Doctors Without Borders has shown they are effective in keeping the disease at bay. The generic combination drugs cut down on the number of pills patients pop each day, which increases adherence, and generics have helped drive down the cost of treating HIV to an estimated $140 per person per year, in some cases.

But it's also been reported, by the New York Times and others, that the Bush administration is adamant that its funding be used for brand-name HIV drugs, because generics have not been reviewed by the FDA.

Not to mention that generic competition could scare drug companies out of the space. Lloyd said a Pfizer Inc. representative made a presentation at the AIDS conference and said that if patent rights aren't protected, HIV drug makers would no longer have an incentive and, thus, would stop chasing HIV drugs.

"So the challenge is finding a balance between those two positions," Lloyd said.

Better patient adherence is necessary, though, and companies are responding. Vertex Pharmaceuticals Inc. and GlaxoSmithKline plc received approval in October for Lexiva (fosamprenavir calcium), and its flexibility - it can be administered once or twice a day, and with no food or water restrictions - should benefit patients.

Gilead Sciences Inc. in March announced it was seeking approval of a co-formulation of its two HIV drugs, the antiretrovirals Viread (tenofovir disoproxil fumarate) and Emtriva (emtricitabine), into a single pill taken once daily with other antiretrovirals. The FDA granted the application priority review. The idea is for the drug to compete directly with Combivir, which is a mixture of AZT (zidovudine) and Epivir (lamivudine), made by GSK.

Taking it a step further, in May Gilead said it was exploring combining Viread and Emtriva with Sustiva (efavirenz), marketed by Bristol-Myers Squibb Co. and Merck & Co. Inc. Again, the idea is to reduce the number of pills patients need to take, thereby upping compliance.

Pacific Growth Equities research analyst Greg Wade, for one, doesn't see generics as being much of a threat - or not a threat unique to HIV drugs, anyway.

"Generics will hurt products in the U.S. like they always hurt branded drugs," he said, "but I don't think that it will be any different from what we've seen to this point.

"More specifically," he said, "it's a competitive environment, and physicians and patients are most interested in therapies that have both long-term efficacy and safety. It's been shown that the long-term tolerability of some of those older therapies [that have come off patent] have not been as good as some of the newer agents."

The HIV drug market, Wade said, "will continue to support the drugs that have the best long-term safety and efficacy, and as drugs are developed with those characteristics, they will be successful and have an advantage."

Boiling the sector down further, Wade likes Gilead. Viread has more than a 20 percent market share, and he thinks "there is an opportunity for good growth for [Gilead's] HIV franchise, overall," he said. While the Viread/Emtriva co-formulation product might take away stand-alone sales of the drugs at first, in the long-term it should boost sales for both.

Viread brought Gilead $193.1 million in the first quarter, and Emtriva added $12 million, but there's more behind Viread and Emtriva. Early in the first quarter, Gilead submitted an investigational new drug application for GS 9005, a protease inhibitor, in HIV.

Although Wade favors Gilead, he said it's "not prudent" to consider the HIV space overall as a good or bad investment.

"Each company has its own issues that will make it a success or failure," he said. "We like Gilead and its prospects for the specific nature of what they have done."

The HIV Mountain Ahead

Antiretroviral drugs have made strong strides against the disease, but data throw cold water on any exuberance - HIV is running rampant. As Pharmaprojects' Lloyd put it, all the drugs developed since the virus was identified are "a great achievement for pharma," but globally, HIV is "clearly, completely out of control."

Estimates by WHO and UNAIDS suggest 1 million adults and children were living with HIV in North America at the end of 2003. Eastern Europe and Central Asia had an estimated 1.3 million infected individuals at that time. Move to South and Southeast Asia and that estimate rose to 6.5 million. In sub-Saharan Africa, that figure was a crushing 25 million at 2003's close.

Drug users and homosexual males no longer are the first in HIV's targets. Today the person at the highest risk of catching HIV is "a poor married woman in a Third World country," Lloyd said. "Seventy percent of new infections are in those women."

At the conference, "there was a big thing about leadership," Lloyd said. "For prevention and education, it has to come from the top." He added that in areas such as China and parts of Eastern Europe, "a disgust and prejudice" against those infected with HIV prevails, and that stigma is preventing those who need help from being able to get it.

"Many countries are in denial of it," he said. "Basically, they are putting their head in the sand, and that's one of the biggest hurdles."

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