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An Historic Turning Point Arrives for HIV Therapy

October 2007

The Conference on Retroviruses and Opportunistic Infections (CROI) in the US and the International AIDS Society (IAS) conference elsewhere are two of the most important annual HIV science gatherings each year. This year's meetings, held in Los Angeles and Sydney Australia, included literally thousands of posters and presentations, on topics spanning the HIV science spectrum, from antiretrovirals to opportunistic infections and microbicides. This issue of PI Perspective will cover some of the most important stories from this year's meetings, from new anti-HIV drugs, new research on older anti-HIV drugs as well as areas like cardiovascular disease and lipodystrophy.

The Big Story

The International AIDS Conference in Vancouver in 1996 ushered in the era of Highly Active Anti-Retroviral Therapy (HAART). Data presented there from several groups introduced a new paradigm in the treatment of HIV disease, where long-term suppression of HIV replication was possible and the concept of "undetectable" viral became the new goal of treatment. Dramatic drops in death and serious illness associated with HIV/AIDS were seen throughout the late 1990s. Despite the obvious benefits, however, drug side effects and the development of resistance made it clear that still better drugs were needed.

As we rightly celebrated each advance in HIV care and treatment there was one group for whom the picture wasn't as bright. Sometimes called salvage patients, these were people with extensive resistance to available anti-HIV drugs. This sometimes included people who had begun with AZT monotherapy in the late 1980s, and had cycled through round after round of helpful, but not fully suppressive drug therapy. One of the challenges they faced was the inherent conflict between the requirements of the new treatment paradigm and the erratic and difficult-to-predict drug development process. Success with treatment was believed to require that a patient take three active drugs at the same time. But with their health and lives in the balance, people had to take each new drug as it became available, often without enough other fully active drugs to support the new drug -- a situation called serial monotherapy.

When the protease inhibitor Prezista (darunavir) was approved toward the end of 2006, following upon the approval of Fuzeon a few years before, the possibility for something better began to emerge. The introduction of this new drug was important in two ways. First, studies showed it was one of the most effective drugs to date in treatment experienced people, with over 60% of people taking it able to achieve undetectable viral loads. Second, it was approved just as three other new drugs were far along enough in their development that they were becoming available through expanded access programs. This meant that rather than the dead-end of serial mono-therapy, people might be able to construct truly viable regimens with two or three new, active drugs.

Expanded Access Times Three

With this in mind, Project Inform, along with other advocates, argued successfully for the companies with expanded access drugs to allow other experimental agents to be used alongside theirs, when safety and drug interaction concerns were adequately understood. Typically when a drug is offered to people in expanded access programs, they are only allowed to use it with already approved drugs. This agreement, by all three companies (Pfizer, Merck, and Tibotec), to permit the use of other experimental drugs in their expanded access programs is a good example of treatment advocacy in action. It also offers a hint of the good that might be done when pharmaceutical companies cooperate and not just compete.

It isn't just the number of new drugs, but the qualities of the drugs themselves. Two are entirely new types of drugs, from new classes. This is crucial for treatment experienced people, who may harbor a large degree of resistance to the older classes of anti-HIV drugs. They are the CCR5 antagonist, Selzentry (maraviroc) and the integrase inhibitor Isentress (raltegravir). The third drug is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) called etravirine. Unlike the other NNRTIs, which have a high degree of cross-resistance, etravirine works against HIV that has developed resistance to other drugs from this class, like Sustiva (efavirenz) and Viramune (nevirapine).

Following up on the success of Prezista, the data presented at the CROI and IAS conferences on both Selzentry and Isentress show that achieving an undetectable viral load is now possible for many people who may have never been able to. In one study of Isentress, over 90% of people taking along with two other active drugs had undetectable viral loads after 6 months. While the numbers for Selzentry weren't quite as striking, they were impressive nonetheless -- with around 2 out of 3 people achieving viral loads below 400 copies.

Little data on the third new drug, etravirine, were available at the time of the CROI meeting, but results presented at the more recent IAS meeting showed convincing evidence that it works well in most people who have developed resistance to the older NNRTIs. The pivotal studies that will be used to secure FDA approval, called Duet 1 and Duet 2, showed that etravirine works best against HIV that has fewer NNRTI associated mutations. If one or fewer NNRTI mutations were detected at baseline, 60-75% of people taking etravirine achieved HIV levels below 50 copies. When three NNRTI mutations were present, that number dropped to 45%; with 4 only 25% reached the goal. When five NNRTI mutations were detected, only 15% of people achieved HIV levels below 50 copies. Still these are promising results for people who can no longer take NNRTIs due to resistance and the drug clearly fills an unmet and important need. When its success is considered alongside the results shown by Prezista, Selzentry and Isentress, it's clear that this an entirely new era in the treatment of HIV.

Introducing the session at CROI where some of these results were first presented, Dr. John Mellors remarked that he didn't think it was an exaggeration to say that this marked an important milestone for the treatment of drug-resistant HIV. Project Inform shares that view -- the stars have indeed aligned and people with HIV, perhaps as never before, and most importantly even heavily treatment experienced and drug-resistant have reason for a renewed sense of hope. All of these drugs are being studied mostly in treatment experienced people. When they are approved, it will likely be restricted to people with significant experience with other HIV drugs. It is difficult not to speculate, though, on how these drugs will also affect the treatment of people just beginning therapy. At the very least, people will soon have many new and improved options that will almost certainly lead to new paradigms at every stage of HIV treatment.

Both Isentress and Selzentry are already being further studied in less treatment experienced people. In fact, intriguing early results from one study (presented last year) of Isentress in people taking HIV drugs for the first time suggested that it might have unrivaled potency as first line therapy. A longer term follow-up of this study presented at IAS showed long-term success and continued powerful suppression of HIV. We will follow this research closely. Data were presented in Sydney comparing Prezista to the gold standard Kaletra in people taking HIV drugs for the first time. This study was the first head-to-head comparison where any drug was able to prove superiority to Kaletra. In contrast, however, results from a study comparing Selzentry to Sustiva as first line therapy, showed that Selzentry didn't quite match up.

A note or two of caution is warranted. The data seen thus far on these drugs is very encouraging, but much more is needed. In each case, only several hundred people have taken the drugs and not for very long. The drugs appear to be potent and safe. Only long-term study, along with clinical use will allow us to fully understand the strengths and weaknesses of each of these new treatments.

Of particular importance is the concern around resistance, especially with Isentress and Selzentry, as they are from new classes. While research to understand resistance to these new drugs has been done, it is fair to say that this is the question that is the least understood at the moment.

While lab tests can help us know what to look for around drug resistance, clinical trials and real world use is needed to fully understand how prone to resistance these drugs are. There are two main factors involved in HIV drug resistance. The first is how much HIV needs to change, or mutate, to evade a drug. This is sometimes referred to as the genetic barrier to resistance -- the more mutations that need to develop, the higher the genetic barrier. The second factor is a drug's potency -- how well it reduces viral replication. Simply put, the less HIV replicates, the fewer opportunities it has to develop mutations and grow resistant to the drugs.

Too often, HIV drug resistance is talked about only in terms of the genetic barrier. While the genetic barrier is a vital factor, it fails to tell the whole story. The drug Sustiva (efavirenz) -- widely used in first line therapy -- offers a good example. HIV can develop resistance to Sustiva with a single change in its genetic code (called a point mutation). So, it has a very low genetic barrier to resistance. However, it is also quite potent -- meaning it is able to reduce HIV levels very well. If you just looked at the genetic barrier, you might predict that resistance to Sustiva would develop quite rapidly. When you also factor in its potency, it is easier to understand how so many people have stayed on it for so long.

Of course, there is a third important factor in the durability of any drug regimen: adherence. Resistance to any HIV drug is less likely to develop the more consistently people can take it. Accurately predicting adherence is tricky, as many factors influence the ability of people to stick to their regimens. Two crucial drug-specific (in contrast to personal issues like depression) factors that influence adherence are ease of use, and tolerability. All of these new drugs are taken twice a day, and have good safety and tolerability profiles so far.

Final Thoughts

With all of this in mind, there is little doubt that this is a truly rare moment. People with highly drug-resistant HIV have a number of powerful, well tolerated new drugs to build effective regimens around. In the third decade of this pandemic, this is the fist time we have had this many new drugs available at the same time. It may very well be the only time we do.

The goal of undetectability has been out of reach for too many people for too long. In talking with people around the country, we have been hearing from heavily treatment experienced people able to achieve undetectable viral loads for the first time ever. While these hopeful stories need to be backed up by controlled scientific studies and real world, they are hopeful nonetheless.

If you are a person with drug resistant HIV, it's crucial to make the most of this opportunity. This doesn't necessarily mean that you should start taking one, two, three or all four of these new drugs. It does mean working closely with your health care team, including an experienced HIV medical provider, to evaluate the options available to you and build a drug regimen that is the most likely to work for you. The goal of therapy for everyone now should be to reduce viral levels to undetectable, whenever possible. That goal is more possible for more people than ever before.

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