On the evening of May 5, during the National Conference on Women & HIV held in Pasadena this year, Women Alive hosted an educational satellite symposium called "Antiretroviral Resistance: Implications for Women with HIV." This well-attended forum was one of the first of its kind, in which experts explained useful, though difficult, data and research concepts to an audience of women living with HIV and struggling with treatment decisions. Moderated by our own Treatment Advocate, Nina Marks, and translated into Spanish by Jenny Güembes, four presentations were given on different topics concerning anti-retroviral drug resistance.

Resistance occurs when HIV is able to change the make-up of its genes in a way that allows it to by-pass the effects of treatments. Resistance is one of the main reasons that drugs and drug combinations fail. There are some specific reasons why some women living with HIV are at unique risk for developing resistance.

With all the old, new and upcoming drugs now available, when to start or stop taking them can feel like Russian Roulette. Especially as we now know that the combination you first use will affect every other option available for the rest of your life. This is a very scary thought. But there are preventable problems, and logical sequencing of drugs, when we apply the knowledge now available to us during the two-hour session, experts explored the following aspects of antiretroviral resistance.

Basic Science

What exactly is antiretroviral resistance and why do we care about it? How is it measured? Why does it happen? These questions were answered by Risa Denenberg, R.N., N.P., M.S.N. from Riker's Island, Montefiore Medical Center in New York.

Resistance is a biological strategy of adaptation to the environment in order to survive. Simply put, resistance is the ability of HIV to change its genetic material so it can continue making copies of itself in the body despite combination antiretroviral therapy. It does this by mutating.

Resistance is caused by many things. One is monotherapy (use of only one drug). This increases the probability of resistance because it kills off a strain of the virus that's been replicating, allowing a mutation to have a fuller field to replicate in and to take over. Interruptions in treatment can also cause resistance. As can internal environmental factors such as vaccinations, which may stimulate viral reproduction and therefore mutations.

Resistance can be monitored by regular viral load tests. If your viral load is going up, most likely resistance is occurring. One big reason we want to keep our viral load low is that it gives HIV a lower chance of replicating, mutating and creating resistance.

Another term we've been hearing is cross-resistance. This is a predictable resistance to a drug you've never even taken. Certain drugs behave the same way in the body in their response to resistance. The actual mapping of HIV resistance to Reverse Transcriptase Inhibitors can be observed in the lab with what is called an HIV Genotyping Test. (Not enough is know about Protease Inhibitors now in order to map the actual site of resistance.) This is genetic mapping which locates specific sites where HIV mutates during replication. These are translated in the lab results as numbers. This test is not widely available and can be very expensive.

State-of-the-Art-Therapies & Likelihood of Resistance

Kevin Robert Frost, the Director of Clinical Research and Information for the American Foundation for AIDS Research in New York City presented this part of the symposium. He began by explaining with regret that most of the data he was presenting was collected in men.

The goal of therapies is to shut off viral replication, which stops resistance. Combination therapy means two or three drugs which ideally target HIV at different points in its life cycle. This is now considered the only acceptable standard of care. Monotherapy has been shown to cause resistance and is never recommended.

The big questions is; What combination will work best, yet leave you the most options open when you need to change therapy? This is where the prevention of resistance comes into play as does drug combining decision making.

Here are the current options available to us by category:

1. Nucleoside Reverse Transcriptase Inhibitors (NRTI's). They work early in the HIV life cycle. The familiar names are AZT, ddI, ddC, D4T, 3TC. These drugs can be further broken up:
   • D4T and AZT are in a chemical class called Thymidine Nucleoside Analogs. These drugs work mostly on active cells.

   • DDI, 3TC and DDC are Non-thymidine Nucleoside Analogs. They work in resting cells.

   • Drugs which cross the blood-brain barrier to protect the nervous system. The three that do this are d4T, AZT and 3TC.

2. Non-nucleoside Reverse Transciptase Inhibitors (NNRTI's) -- They work at the same point of the HIV life-cycle as the NRTI's, but they work differently upon that point. The two which are currently available are Delavradine and Nevirapine. Audience members said that tests had been done which showed that Nevirapine also crossed the blood-brain barrier.

3. Protease Inhibitors (PI's) - These work at a very late stage in the HIV life-cycle. The generic names are Saquinavir, Indinivar, Ritonavir and Nelfinavir.

These drugs still leave much to be desired. They are far from perfect with difficult and often life-threatening side effects in addition to extremely complex dosing. We know very little about drug interactions or the long-term effects. And of course, they are all way too expensive. "We don't know a damn thing about a lot of this stuff in women and we've got to figure that out."

Sequencing Therapies for Long Term Care

Sequencing is the order in which anti-HIV drugs are taken over time to manage cost, efficacy, side-effects, viral load, resistance levels and ability to preserve future options. Pat Kloser, Associate Professor of Clinical Medicine and Medical Director of AIDS Service at the University of Medicine and Dentistry in New Jersey was the third presenter.

She began by pointing out some of the major problems with today's drug therapies, beginning with compliance. We are told to take a lot of pills a day, don't miss doses, take some with food, some with no food, some with fat, some with no fat, one with gallons of water, some twice a day, some three times a day. It's very, very tough.

These factors must also be considered when deciding on a drug therapy regimen and sequencing.

Another treatment consideration is; How long have you been infected? The longer you've been infected, the more likely your chances for having resistant virus. Also, the more reasonable it is to be on a regimen with the maximum number of drugs and the most potent combinations. So what happens if a triple drug therapy fails? Change at least two of the drugs. Don't add a protease inhibitor to a failing regimen. Substitute drugs with a different profile. The chart to your right provides examples of choices for long term treatments with some of the progressive drug possibilities.

How to Preserve Options

What if you simply can't tolerate a drug? There are many possible side-effects with all the drugs. Some may be too debilitating to allow you to function. Other considerations are cost, and can you manage it? And, do you want to take it? You must think carefully before deciding on a drug regimen because once you start, you are married to it. Therefore, you must have the ability to be compliant. And if you have problems with the drugs, you must communicate those to your doctor so you can work as a team to individualize your treatment and do what is best for your health and your life.