'Still could fail'

While a handful of companies are testing or have tested potential HIV vaccines in human volunteers, none of these trials has generated nearly the excitement of the latest announcement from officials at Merck. After shifting its vaccine screening program into overdrive some four years ago, Merck may now have something to show for its efforts. TAG's Mark Harrington was one of a very limited number of activists invited to the company's closed-door presentation late last month, and there remain many unanswered questions. But in an era where news of potential therapeutic break-throughs is harder and harder to come by, we thought it prudent and perhaps even inspiring to briefly summarize the few hard facts currently at hand.

Late last month Merck announced that is has begun human trials of a new experimental HIV vaccine which has generated quite a bit of excitement within the scientific community. The trial, which began just a few weeks ago, is first being conducted to assess safety in healthy, uninfected adult volunteers.

While full details of the vaccine and the research protocol are being withheld until their presentation at the April Keystone meeting in Colorado, the company held a special meeting with a handful of community AIDS activists at its Whitehouse Station, NJ headquarters several weeks ago. It has also presented its preliminary data to the AIDS Vaccine Advisory Committee of the National Institutes of Health.

According to what little information is available about the vaccine, it has apparently been shown capable of preventing laboratory monkeys exposed to a virulent strain of HIV from getting sick. Most of the unvaccinated control monkeys, by contrast, died or developed AIDS.

The vaccine does not, however, prevent infection with HIV. In this experiment the monkeys became infected with HIV but somehow were able to keep the virus in check. While the monkeys, to date, reportedly show no signs of disease, it must be noted that the follow-up observation period in this preclinical study is still rather short. At this time, no one can say just how long the apparent protection from the vaccine will last. It is not at all unlikely that the monkeys will eventually get sick and die -- even after an initial disease-free period.

But even if the vaccine ends up merely post-poning the onset of disease, it could still represent a major advance in control of the AIDS epidemic. If, for example, the use of the vaccine results in lower blood levels of HIV, this may translate into a greatly reduced likelihood of transmitting the virus. And if it can keep HIV-infected individuals alive longer without the need for complicated oral antiretroviral regimens, the vaccine might offer both a new hope for impoverished regions of the world (considering, of course, that it is made available through some sort of subsidized distribution program) as well as lend a new lease on life for persons currently enslaved to -- or failing because of -- the intricate requirements of current anti-HIV therapies.

Traditionally, vaccines have worked by stimulating the immune system to produce antibodies to the virus in question. But in HIV infection, the ability of vaccines designed to stimulate the production of anti-HIV antibodies have met with mixed success or outright failure (e.g., the AIDSVax product of the VaxGen Corp., currently in Phase III studies in Thailand, Tanzania and the U.S.).

The Merck vaccine is said to designed to stimulate the cellular arm of the immune response rather than the one mediated by antibody responses. Most viral infections, perhaps with the notable exceptions of hepatitis B and rabies, are brought under control by the cellular arm of the immune system with or without the assistance of an antibody response. By revving up the activity of the body's killer T-cells, the boosted cellular immune response is then capable of attacking the virus by destroying the cells it has already infected. Merck had earlier attempted a similar approach through the use of so-called "naked DNA." Naked DNA involves the injection of bits of the HIV genes directly into an individual. Unfortunately, the killer T-cell responses generated by this approach were not quite up to the job.

By fine-tuning this earlier approach, Merck appears to have come up with a much more immunogenic product this time. The key, it appears, turns out to be the addition of an adenovirus "vector" to the mix. A common component to many gene therapy and vaccine research programs, the adenovirus is a virus capable of causing the common cold. Careful tinkering with the adenovirus, however, renders it incapable of causing illness but, apparently, makes it a very useful component to an effective vaccine. Other possible viral vectors which are under investigation by various vaccine manufacturers include canarypox, vaccinia, salmonella, Venezuelan equine encephalitis virus (VEE), modified vaccinia virus Ankara (MVA), bacillus Calmette-Geurin (BCG), herpesvirus vector, and yellow fever virus,

The use of this adenovirus greatly facilitates the delivery of the naked DNA genes directly into the targeted immune cells. The approach which Merck found the most effective was the familiar "prime-boost" succession of immunizations. The immune system is first "primed" with an injection of just the naked DNA vaccine. Once this has been done, the "booster" injection of the adenovirus-engineered product is administered. As a result, the levels of killer T-cells capable of attacking HIV are greatly increased.

Despite all the excitement surrounding the announcement, Merck is not the first company to pursue this "partial protection" vaccine strategy. Scientists at Harvard University have also reported similar success with such an approach -- although they are using a different vaccine construct (see the January 2001 TAGline). Similarly, research collaborative teams at Emory University/NIAID and Yale University/Aaron Diamond Research Center have also presented similar results with their approaches.

But the Merck product is the first of these to actually enter human clinical trials. The Yale/Aaron Diamond vaccine, however, may also be soon to move into human trials.

Part of the excitement over the Merck announcement stems from the company's long history of vaccine research and development. Merck is one of the world's largest and most experienced vaccine manufacturers (along with SmithKline and Pasteur Merieux).

Even as Merck plays down expectations for its newest vaccine strategy, it is not ruling out the possibility that the vaccine might still prove to be protective in humans. Part of this speculation derives from the fact that the challenge dose in the laboratory animals was much greater and much more virulent than what a human to human inoculum would typically entail. But at the current time, this possibility is purely speculative.

In fact, Merck appears to be quite concerned that even the snippets of information that have been allowed to leak out up to this point may result in undue expectations and inevitable disappointment. Even it the vaccine were to prove successful, Merck officials caution, it would still not be available for years. And it is still very possible that the vaccine could simply fail.

One additional possible benefit to this partial protection approach -- whether with the Merck candidate or the Harvard, Emory or Yale construct -- is the additional application to individuals already infected with HIV. Simply put, if any of these vaccines do eventually prove capable of augmenting the body's natural immune defense against the virus, they might be reasonably expected to be useful as treatment.

And Merck seems amenable to just such a two-pronged development strategy. The company has said that it is quite willing to test whether the vaccine might be useful for the treatment of people already infected with HIV. In fact, a recent company announcement reported that Merck will put the vaccine into HIV-positive people within the next three months. For now all we can do is watch and wait. Fingers crossed. ¤

Dear Sirs:

We are writing as a coalition of AIDS treatment advocates, educators, and service providers to request that GlaxoSmithKline immediately withdraw from participation in threatened legal action regarding the importation of generic antiretroviral medications in Ghana and South Africa.

Specifically we refer to your threats of legal action against Cipla for selling Duovir, its generic form of Combivir, in Ghana (Wall Street Journal, 1 December 2000), and in Uganda (Glaxo-Wellcome letter to Cipla, 20 November 2000), and the announcement by the Pharmaceutical Manufactur-ers Association of South Africa of its intent to bring suit against the South African government on March 5 (Reuters, 15 January 2001).

As you are not doubt well aware, two-thirds of the world's 34 million HIV infected people live in Africa, the world's poorest continent. UNAIDS estimates that 4.2 million (20%) of South Africa's population of 39.7 million, 820,000 (8.3%) of Uganda's 21 million people, and 340,000 (3.6%) of Ghana's 19 million people are infected with HIV. The per capita income in South Africa is $3,160 per year (although most of the HIV infected population earns far less than that, if they are lucky enough to be employed at all), while the per capita income in Ghana is just $390 per year, and that in Uganda is $320.

We believe that threatening lawsuits to prevent people in poor countries-already staggering under the weight of the AIDS pandemic, excessive debt to western banks, poverty, and underdevelopment-from accessing life-saving antiretroviral medications is simply unacceptable from a moral and humanitarian point of view.

GlaxoSmithKline has several other options before it which would enable it to help increase, rather than decrease, access to antiretroviral medications among infected people in developing countries:

Immediately implement, without regard to negotiations with host countries, steep discounts in the prices of antiretroviral drugs to affordable levels. Match the generic offering price (for example, with Cipla, the retail price-not their best price-appears to be $1.72/day for Duovir - just twenty-eight cents lower than Glaxo's own announced discount to $2.00/day for Combivir in Rwanda, Senegal, and Uganda). Provide antiretroviral drugs in donation programs, which may presumably confer some tax benefits for your company. If you choose not to undertake the expense of providing discount antiretroviral drugs to poor countries where they are most desperately needed, permit generic manufacturers to manufacture and distribute them in your stead.

None of these steps would affect your markets in rich countries, which are where your profits come from. According to your own spokesman, quoted in the Wall Street Journal, Africa represents less than one percent of GlaxoSmithKline's revenues or profits. We doubt that you are earning significant profits in Ghana, in Uganda or in South Africa on overpriced medications which few can afford.

We appreciate Glaxo's efforts to develop new treatments for HIV, and we recognize that you have invested significant resources in the development, testing, approval, distribution, and marketing of antiretroviral medications. However, what use are these discoveries for the 95% of the world's HIV infected population which cannot afford them at current prices? Can you really maintain that 30 million people must die because they cannot afford your drugs? We recognize that it is not up to industry alone to resolve the issues of health care infrastructure, political leadership, and social mobilization which responding to the AIDS pandemic necessitates.

However, it is also important for drug companies not to stand in the way of saving the lives of people for whom the price of drugs is often the main, and sometimes the only, obstacle to treatment.

Since Glaxo, along with four other global pharmaceutical companies, announced in May 2000 their intent to provide steep discounts on anti-HIV medications to developing countries, many press releases have been issued, but how many discounted pills have reached anyone in Africa or elsewhere in the developing world? How many lives have been saved?

Over two million people around the world have died of AIDS since that announcement, and now you, along with 39 other companies, are going to court in order to stop the South African government, with the world's worst epidemic, from obtaining life-saving therapies by means established as legal under the TRIPs clause of the World Trade Organisation treaty. The TRIPs clause allows the granting of a compulsory license in cases where there is a national emergency. How could you deny that AIDS constitutes a national emergency in countries such as Ghana and South Africa?

We appeal to you to immediately cease and desist from using the court systems in Ghana, Uganda, South Africa, and elsewhere in the developing world to prevent HIV infected people from accessing life saving antiretroviral medications.

Yours truly,
[several pages of signatures] ¤

An international coalition of 65 activist groups and over 100 AIDS activists, educators, health care workers and service providers from six continents and many countries around the world today called on GlaxoSmithKline, one of the world's largest drug companies, to withdraw threatened lawsuits in Ghana, Uganda, and South Africa which are intended to block people with AIDS (PWAs) in those countries from having access to generic anti-AIDS medications.

The coalition, led by the Health GAP Coalition, Treatment Action Group (TAG), and Gay Men's Health Crisis (GMHC), took this action because in November 2000, Glaxo threatened to sue Cipla Ltd. of India, a generic pharmaceutical manufacturer, if Cipla continued to sell its generic Duovir, a combination of the AIDS drugs AZT and 3TC (marketed by Glaxo as Combivir).

In addition, Glaxo has joined forty other drug companies in suing the South African government for a 1997 law intended to broaden access to cheap generic drugs in South Africa.

The activists wrote, "We believe that threatening lawsuits to prevent people in poor countries-already staggering under the weight of the AIDS pandemic, excessive debt to western banks, poverty, and underdevelopment-from accessing life-saving antiretroviral medications is simply unacceptable from a moral and humanitarian point of view."

Instead, the activists suggested that Glaxo:

• Immediately reduce antiretroviral drug prices to levels affordable in poor countries;
• Match the best generic offering price (Cipla's Duovir sold for $1.72 retail in Ghana);
• Provide free antiretrovirals in drug donation programs; and/or
• Allow poor countries to permit generic manufacturers to make or import the drugs.

TAG Senior Policy Director Mark Harrington said, "We are announcing today a Global Day of Solidarity on March 5, the day when the Pharmaceutical Manufacturers Association of South Africa's lawsuit against legal generic drug access comes before the court in South Africa. On that day, some groups will take direct action against drug companies, pharmaceutical trade organizations, or the U.S. Trade Representative, which has just brought action against Brazil for manufacturing generic antiretrovirals. The program in Brazil is reaching over 85,000 people with AIDS and has saved thousands of lives. No other program - whether the UNAIDS Accelerating Access initiative or the much-touted, but so far insignificant, discounts announced by five big drug companies last May - are reaching significant numbers of people with HIV in the world's poorest countries."

The March 5 Global Day of Solidarity was initiated by South Africa's Treatment Action Campaign (TAC), a grassroots advocacy organization which has been struggling to make anti-AIDS drugs available to South Africa's estimated 4.2 million people living with HIV. ¤

Note: the March 5 Philadelphia march was postponed to March 12 due to the snowstorm; and the trial was postponed to April by the judge so that TAC could become part of the case as a friend of the court.