Friday, Dec. 1, is the 19th Worlds AIDS Day.

In the years since the Joint United Nations Programme on HIV/AIDS (UNAIDS) declared the first World AIDS Day in 1988, much has changed. The theme of that first World AIDS Day, “Communication,” reflected how little many people knew about the virus at the time and how much the virus was still associated with what were perceived to be the margins of society: gay men, intravenous drug users and sex workers.

It had only been in June 1981 (in an article published by the Centers for Disease Control and Prevention by medical researchers at UCLA) that the presence of a new syndrome was reported, with otherwise healthy gay men showing up with pneumocystis pneumonia and then Kaposi’s sarcoma, ailments usually effecting only the already sick and the elderly. It wasn’t until the next year that it became clear that what was being seen was a communicable disease, not entirely limited to the gay community. By September 1982, the CDC had reported almost 600 cases of what came to be known as HIV/AIDS, with 243 deaths.

By 1984, the virus responsible for AIDS had been discovered independently in labs in the United States and France, and the secretary of Health and Human Services in the Reagan administration, Margaret Heckler, was holding out hope that a vaccine would be discovered within two years.

It’s 20 years after her hoped-for vaccine deadline, and while we still don’t have a vaccine, our knowledge and treatment options for the disease have come a long way. Nonetheless, the focus for this year’s World AIDS Day, as it is for each of the days from 2005 to 2010, is on keeping the promise that has been made to the world and not just managing the virus but putting an end to it. In particular, the World AIDS Campaign, which took over World AIDS Day from the United Nations, hopes to emphasize accountability of governments to take seriously their own commitments to stop the spread of the pandemic, and especially the promise that world leaders made to themselves and to their people to end AIDS by 2015.

According to estimates by the United Nations, there are roughly 40 million people living around the world with HIV/AIDS. Of those 40 million, 2.3 million are children and 4 to 5 million are people who became newly infected in the last year.

The virus killed 3 million people last year, and the pandemic shows little sign of slowing down. It has, in fact, become a major scourge in the developing world, where 95 percent of all people with HIV/AIDS reside, most of them dying before their 35th birthdays. For instance, there were 3 million new cases in Sub-Saharan Africa in the last year, bringing the number of infected people there up to 26 million, or 7 percent of the entire adult population.

The numbers are somewhat better for the United States: Estimates are that around 1.2 million people are infected with HIV or about 0.5 percent of the adult population, with another 45,000 people becoming infected, on average, each year. Estimates are that about 140,000 people are infected in California, with about 4,500 new infections per year. Of those infected, the CDC estimates that almost a quarter don’t realize they are HIV positive.

When the HIV virus was first discovered, there were no available treatments. This was partly because the virus was a new kind of enemy. Not only does it attack the immune system itself (the very thing that treatments of other diseases attempt to stimulate and recruit to help in fighting off sickness) but it also is a different kind of virus that “works” in a different way.

Most viruses, like the cold or flu viruses, have to inject their entire DNA – that double-spiral structure that most of us remember from biology class – into the cell they’re infecting. They then trick the cell into splitting the double spiral into two and turning it into two new spirals that are then split again and again.

But HIV is a retrovirus. What this means in simple terms is that the genetic code it inserts into the cells it infects is a much simpler single strand of RNA, a strand that because of its simplicity is harder to destroy. It then gets the cells it attacks, the cells of the immune system, to make two-stranded DNA out of this single strand, killing the cells in the process.

In “normal” viruses, because a new double strand has to be matched up in the infected cell, the virus stays more or less the same over time, so the virus remains a relatively stable target. Because the retrovirus starts off with a single strand, there is no matching, no way for the infected cells to keep the virus attacking them the same. This has made fighting HIV more difficult because it has meant that the virus is more likely to mutate. While the flu virus might come in a new version every year, the HIV virus comes in slightly mutated versions all the time. This has been one of the difficulties in developing a vaccine and has also led to the rise of some drug-resistant strains.

But the very process of the virus’s replication in the body’s immune cells has also opened the way for some treatments. In order for HIV to reproduce, it makes use of three different viral enzymes, reverse transcriptase (to convert from RNA to DNA), integrase (takes the newly formed DNA and integrates it into the infected cell) and protease (allows new copies to break off and break out to infect more cells). Because HIV works only by copying itself and affects the body by using and killing its immune cells in the process, the key to treatment has been to attack the process through blocking the necessary enzymes.

The first effective treatment for HIV was zidovudine, better known as AZT, introduced in 1986. It was the first of the (nucleoside analog) reverse transcriptase inhibitors. By 1991, other (non-nucleoside analog) reverse transcriptase inhibitors, drugs like Viramune, Rescriptor and Sustiva, had been introduced that attacked the same enzyme but more quickly and in a different way, also preventing the virus from replicating. Quick to follow were protease inhibitors, like Crixivan, Viracept and Kaletra, drugs which did nothing to prevent the virus from replicating but kept it from going on to infect other cells after it had infected one.

But even with new and different types of drugs available, until the mid ’90s most treatment options consisted of one drug and one type of drug at a time. It was in the mid ’90s that researchers and physicians realized that the strategy of monotreatment was increasing the prevalence of drug-resistant strains of HIV. As AZT, for instance, might be very effective in killing off one form of the virus in a patient, it only meant that other strains, less sensitive to that particular drug, would increase in numbers in the body. Switching to another drug or even type of drug at that point would just change the balance of which resistant strain had the upper hand without knocking out the virus altogether.

To effectively combat a virus, which scientists were then discovering replicates from the moment of exposure rather than spends up to a decade in latency, required more than one drug – more than one type of drug – at once. Thus were introduced the first of the combination therapies, or drug cocktails, also called HAART (Highly Active Antiretroviral Therapy). While the therapies were themselves much more effective than treatments with only one drug at a time, they had and continue to have their drawbacks. And they never lived up to the fanfare with which they were initially greeted. For instance, their introduction at the AIDS conference in Vancouver in 1996 led Andrew Sullivan to talk about the twilight of the epidemic. Though things have certainly gotten better, we are not yet seeing the end of HIV/AIDS.

With more drugs come more interactions between them and with other medications that HIV-positive people might be taking. Instead of the side effects of one drug, there came the side effects of two or more drugs together. And, not of least concern from a treatment perspective, more drugs meant more pills to take each day, sometimes pills that have to be taken at different times; some with food, some without.

With the complexity of the drug regime, increased by the number of different medications, came the increasing likelihood that people would fail to take their medications correctly, leading right back to the possibility of drug-resistance and even cross-resistance, the resistance of the virus not just to a drug that’s being or been tried but sometimes to others of the same class.

For these reasons, much of what has occurred since the introduction of combination therapies has been a matter of fine tuning combination therapies and their component parts – looking for combinations that work well together – and more simplified regimes with fewer pills and fewer chances to forget to take them. This has led to, for instance, drugs like Truvada, a once-daily pill containing two different nucleoside reverse transcriptase inhibitors, and Combivir, a twice-daily pill containing a combination of two different nucleoside reverse transcriptase inhibitors.

In addition to having to be taken only once or twice a day, these treatments have no food restrictions, allowing them to be easily combined with once-daily protease inhibitors, like Sustiva and Kaletra, each of which have certain food restrictions.

Atripla, a once-a-day regime, was approved by the FDA this year on July 12, combining efavirenz (Sustiva), tenofovir (Viread) and emtricitabine (Emtriva). Atripla has revolutionized HAART therapy, making the one pill, once a day, a reality. It is usually used as an initial therapy option for those who do not have a drug-resistant virus and can tolerate the drug’s side effects. For those lucky enough to be on treatment plans that have fewer restrictions, compliance becomes much easier and the risks of resistance decrease.

Combination therapies like these have led many people to a stage never imagined in the early days of the epidemic: undetectability, the point at which the presence of the virus can’t be detected in the bloodstream. While not a cure – being below the detectable level doesn’t mean the virus is gone, nor does it mean that it can’t come back or that it can’t be passed to others – for those who have become undetectable it has meant the virus is doing little damage during that time, not replicating quickly and not damaging the immune system.

Aside from advances in combination therapies, a relatively new class of injected drug has recently been introduced: the fusion or entry inhibitors, of which Fuzeon is the first to be approved. Unlike the other drugs that have been developed, which interrupt the replication process, fusion inhibitors work by preventing the virus from ever opening up immune system cells. Since they can’t “fuse” with the cells they attempt to attack, they can’t insert their genetic material and the process of replication and destruction never gets underway.

The initial results for fusion inhibitors look very promising. Since they are a new class of drug, they aren’t yet affected by resistance in people who have been on drug regimes sometimes for two decades. In the clinical trials done in the development of Fuzeon, when added to an aggressive treatment regime it doubled the likelihood that patients would become undetectable.

There’s some hope that another new class of HIV medications will soon be available. Merck is currently in Phase III trials of an integrase inhibitor taken twice daily, currently called MK-0158. As its name suggests, it is supposed to work by suppressing the availability of the enzyme integrase, and so preventing the HIV genetic material from becoming a part of the host cell, interrupting the replication process.

Like fusion inhibitors, if successful, integrase inhibitors would not be subject to resistance since they would be a new foe for the virus to face. Merck is currently increasing access to the investigational medication in hope that it might help some patients even as the testing of its efficacy is completed. If integrase inhibitors work, they would be another strong tool in breaking the cycle of HIV replication in the body.

All in all, according to the Treatment Action Group, as of last year at this time, there were 112 anti-HIV medications in development, with about 43 of them either protease or reverse transcriptase inhibitors, 30 of them fusion inhibitors with many of them attempting to stop fusion in different ways than Fuzeon, and 39 integrase inhibitors and other new types of drugs, including ones that prevent HIV from fully developing and others that attack the virus itself in various ways. Although it’s almost certain that many of these proposed drugs will not be as effective as hoped or will have side effects that make them unfeasible as treatment, the very fact that so many drugs are in development and that so many of them are of new types holds out hope for continued treatment even for those who have developed resistance to drugs currently available.

Even as the pandemic has continued to expand, our treatment options have increased through the years. In the early days of the epidemic, a positive test result was often looked upon as a death sentence, and magazines for gay men were filled with ads for viatical settlement companies, companies that would buy a dying man’s life insurance policy for ready money.

In the intervening years, first AZT and now a handful of different combinations of antiretroviral and other drugs have come to mean that for many people HIV is a manageable disease, and the ads have changed from viatical settlements to pharmaceutical companies.

However, drug cocktails have their share of side effects, from lipodystrophy and facial wasting to diarrhea, nausea, lack of appetite and/or susceptibility to other ailment. These side effects combined with the high costs of the drugs, the necessity of following a complicated regime that for many can mean multiple pills taken at different times throughout the day for the rest of one’s life and the development of drug-resistant strains has meant that treatment is unfeasible, too expensive or impossible for some, both in the developed and especially in the developing world. In spite of the progress that has been made in simpler combined regimes and the reduction of costs and development of generic drugs for those who can’t afford brand name therapies, this alone is not enough to stop the suffering caused by AIDS.

The real hope for most is the same one that Secretary Heckler held out in 1984: a vaccine that would prevent new HIV infections, combined with treatment for those already infected.

There’s little doubt that we have come a long way in the quarter century of the epidemic, from knowing no more than that a mysterious illness was affecting gay men in New York, Los Angeles and San Francisco to our present state of knowledge about prevention and treatment of the virus.

However, no matter how many advances we make in treatment, the real hope for the eradication of the HIV/AIDS pandemic is the development of a vaccine. The search for a vaccine has continued for two decades now, occasionally looking as if the goal was just beyond the horizon. So how close are we really to a vaccine?

One thing that is certain is that the globalization of the pandemic and the increased awareness of the truly horrific effects of HIV/AIDS on individuals throughout the world – and even whole countries in the developing world – has increased investment and effort in the search for a vaccine. In 2000, according to data collected by the AIDS Vaccine Advocacy Coalition (AVAC), the total investment in the search for a preventive vaccine for AIDS was only $327 million, with $272 million of that total coming from the U.S. government, $20 million coming from philanthropic and charitable investment, and the remainder coming from various other governments.

While the estimated numbers for 2006 still show the majority of global funding coming from the United States government, there has also been an amazing increase in overall commitment and especially in investment from the private sector. The estimate for 2006 predicts that governments will spend about $704 million ($663 million from the U.S.), with another $77 million coming from philanthropic and charitable organizations, such as the Bill and Melinda Gates Foundation. And, if this year is like last, another $75 million can be expected from pharmaceutical and biotechnology companies. Compared to the $195 million a day the Department of Defense estimates the Iraq war costs or the $1.1 to $1.2 billion that the Global HIV Vaccine Enterprise estimates is actually needed to find a vaccine soon, this is not a huge amount of money. It is, however, a demonstration that there is more interest in a vaccine from more sectors than there has been in the past.

Apart from the increased, if still insufficient, financial investment in the search for a vaccine, there has been a blossoming of vaccine trials. There are currently more than 30 separate vaccine trials being undertaken in 27 countries throughout the world. One of these, the STEP study (www.stepstudies.com), which is working on a vaccine developed from an inactivated cold virus already shown to be harmless in animals and humans, has one of its locations in Los Angeles. The STEP study continues to recruit volunteers to test the effectiveness of the vaccine against HIV. The most advanced and widespread of these is a trial in its third phase that involves more than 16,000 volunteers in Thailand.

While the increasing number of trials holds out the hope that one of the vaccines being tested will be the one that finally stops the spread of HIV, the trials themselves are not without their difficulties. For one, since a few of the vaccines being tested either contain or trigger HIV antibodies, they can lead to false positives on HIV tests which themselves test not for the virus but for antibodies to it, requiring different tests that look for the virus itself. This, along with the stigma attached to being sexually active or being part of an “at risk” population even among gay and bisexual men, and the unfounded fear that vaccines might themselves lead to infection, has cut into the number of available volunteers for some trials.

In addition to the trials already underway, any one of which might turn out to be the magic bullet against HIV, new candidates are suggested every day. In October, Yong Kang, a virologist at the University of Western Ontario in Canada, began the process of gaining FDA approval of trials for a new type of vaccine. Other vaccines have either been developed from partial sections of the DNA of the HIV virus or from other viruses like the STEP study’s cold virus-based vaccine (not unlike the way the smallpox vaccine was developed from the virus that caused cowpox). However, Kang’s vaccine uses an entire dead HIV virus together with another piece of its genetic code (more like the way the polio virus works). According to Kang, this new vaccine – and new type of vaccine – has stimulated the immune systems of macaque monkeys to recognize and fight the HIV virus. His hope is that it will be able to do the same in human subjects and that it will work not only for prevention but also in those who are already infected with HIV. Of course, it remains to be seen whether those results will translate into anything meaningful in the human immune system, since macaques aren’t affected by HIV.

In spite of the number of ongoing trials, the news on the vaccine front is, at best, ambiguous. Any one of the vaccines being tested, or some combination of them, might just be the key to preventing the spread of HIV. But at the same time, most of these trials are still several years away from any definite results.

On the encouraging side, there has been a recent success in the development and delivery of the HPV (human papillomavirus, responsible for genital warts and cervical cancer) vaccine, partly because, according to AVAC, much of the infrastructure and delivery methods for the HPV vaccine will be ready and in place – especially in developing countries where HIV is spreading most rapidly – when and if an HIV vaccine becomes available. And, of course, the very fact that an HPV vaccine has been developed holds out some hope for the possibility of an HIV vaccine. At the same time, the same evolution of the virus that can lead to drug resistance in some HIV-positive people also makes the design for a vaccine more difficult, since the vaccine faces a changing target.

Another Canadian virologist, Earl Brown of the University of Ottawa, said in response to Kang’s proposed virus: “Don’t count your chickens. [HIV] has a way of ducking the immune system, plus it’s attacking the immune system.” It’s for this reason that 20 years of vaccine research hasn’t yet given us a surefire vaccine.

Whether we can count on the vaccine egg to hatch or not, a vaccine isn’t the only egg in the prevention basket. Besides the strategy of safer sex, education and clean needles for intravenous drug users, there are new strategies much closer to release.

Similar to the prophylactic or preventative use of HIV medications to prevent the transmission of HIV from positive mothers to their unborn infants in as many as 98 percent of cases, and the use of antiretroviral medications in those who have had an exposure to the virus to prevent infection, there is hope for pre-exposure prophylaxis (PrEP) for the prevention of HIV infection in people at risk for infection. While this strategy might result in otherwise healthy people suffering some of the side effects of HIV medications, it shows promise for the prevention of infection in high-risk groups and for those who have had trouble practicing safer sex. Definitive results of the effectiveness of this strategy are expected in 2009.

2009 is also when results are expected in trials of another newer preventive strategy for infection: microbicides. Microbicides work against the virus the way that spermicides work to prevent pregnancy; they kill the virus before it can get into the body to cause an infection. So far, most trials for microbicides have focused on preventing the transmission of HIV in heterosexual encounters, using vaginal microbicides. This reflects the shift in focus as the AIDS epidemic has become a worldwide pandemic. However, there are also more limited trials of rectal microbicides that show promise for the reduction, if not out-and-out halting, of HIV transmission in sex between men. Together with studies about the efficacy of male circumcision and the treatment of genital herpes in reducing new infections, the use of microbicides holds out hope for an increasingly effective battery of preventive measures.

The bad news is that a vaccine doesn’t seem to be just beyond the horizon, even if the results from the massive Thai trials expected in 2010 and the STEP study expected in 2011 look promising. The good news is that new preventive techniques combined with the methods we already have and the treatments that continue to be developed may be able to slow the spread of the virus until we get to the vaccine.