Strategies for Salvage Therapy
Enormous strides in HIV treatment have been made over the last several years. Fifteen approved anti-HIV drugs have saved thousands of lives and have helped many people return to mostly healthy, productive lives. Unfortunately, these drugs are not perfect. This is especially true for people who have used these drugs in the past and no longer respond to them. For these folks, new drugs -- along with, perhaps, improved ways to reap benefits from older ones -- are an absolute necessity.
People who have become fully or partially resistant to current drugs are searching for what is called salvage therapy. Like visitors to auto salvage yards where junked car parts are sold, people who need salvage therapy are seeking drugs in new classes, older drugs to recycle, and other treatment strategies that may slow HIV and make their bodies' immune systems run efficiently again.
What happens when someone becomes resistant to their anti-HIV drugs and runs out of options to keep viral load undetectable? Dr. Steven Deeks and his colleagues at the University of California San Francisco now have some data from a study to answer this question. Dr. Deeks found that, for HIV-positive people who are unable to keep their viral load undetectable (<500 copies/mL) because of drug resistance and limited treatment options, 41% would progress to AIDS within four years. The risk of progression to AIDS -- which includes life-threatening opportunistic infections -- was highest among people who were unable to keep their viral load at least somewhat lower than it had been before therapy was even started. In other words, keeping viral load at least partially suppressed is better than nothing at all.
Waiting in the Wings -- New Drugs
What are the latest drugs to be used in salvage regimens? In a closing lecture at February's 8th Conference on Retroviruses and Opportunistic Infections (CROI), Dr. Roy Gulick from Cornell University Medical Center provided a detailed overview of the newest anti-HIV therapies, both approved and in the pipeline. Dr. Gulick admitted that one of the major challenges in HIV research is the development of salvage therapies for people with drug-resistant HIV. His discussion focused on new drugs in each class that may have different resistance patterns than the older drugs, along with new classes of drugs that hit different targets in HIV's replication process. Fortunately, each scenario offers options for salvage therapy.
Protease inhibitors currently in phase II studies include tipranavir, mozenavir, and BMS-232632. All of these drugs have varying degrees of activity against strains of HIV resistant to currently approved protease inhibitors. Additional studies are definitely needed to determine how effective they will be for patients starting therapy for the first time or in need of salvage options.
DAPD, a nucleoside guanine analogue, may be effective against Retrovir (AZT) and Epivir (3TC) resistant virus and is in early human testing. In a small study, patients who had used AZT or Epivir, added DAPD (500mg twice a day) to their current regimen. Within two weeks, viral loads decreased by two logs from baseline levels.
Tenofovir DF, a nucleotide analogue, is now available through an expanded access program (see "Tenofovir Expanded Access" in this issue). The drug is active against many AZT and Epivir resistant viruses and may be even more active against strains containing the Epivir-associated resistance mutation, M184V. Tenofovir DF, administered once a day, appears to be safer and more potent than its cousin adefovir, which was denied FDA approval last year because of its causing kidney damage.
Early results from a study involving approximately 550 people who had tried and failed other anti-HIV drugs in the past have been reported. In this study, volunteers who had been on an anti-HIV drug combination for at least eight weeks and were not able to push their viral load to undetectable levels added either tenofovir DF or a placebo (sugar pill) to "boost" their current regimen. After 6 months, 22% of patients who added tenofovir DF were able to reduce their viral load to undetectable levels (less than 50 copies/mL), compared to only 1% of patients who added the placebo. In other words, tenofovir DF was active against HIV, even in people who had failed other anti-HIV drugs in the past.
Capravirine, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), has been shown to be effective against virus that is resistant to currently approved NNRTIs. Unfortunately, development is on hold due to a severe toxic problem seen in dogs. Another NNRTI, TMC-120, has been shown to be effective against the common NNRTI mutation, K103N. These drugs are in early development, and larger human studies need to be completed before we can know how effective they really might be.
And New Classes
New classes of anti-HIV drugs are particularly important for people who need salvage therapy. We already have a number of drugs that target HIV's protease and reverse transcriptase genes. What we need are drugs that target different parts of the virus and act at different points in HIV's lifecycle.
A veritable new field of research has opened up with the HIV entry inhibitor drugs. These compounds prevent entry, attachment, or fusion of HIV to the host cell. People are most familiar with the fusion inhibitor pentafuside (T-20) because it is furthest along in development. There is also a second-generation fusion inhibitor, T-1249, that doesn't seem to be cross-resistant to T-20 and appears to be 2 to 100 times more active.
Because pentafuside and T-1249 target proteins on HIV's outer shell, resistance will always be a problem. Luckily, researchers are developing drugs that target proteins on the outside of cells -- cellular proteins that won't become resistant nearly as quickly as viral proteins. These new drugs target the CXCR4 and CCR5 co-receptors on CD4+ cells. While they are still in the early stages of development, there is already a lot of talk about using these drugs in combination since they may be synergistic, meaning that they work better together than separately. Although they offer great hope, most, although not all of these drugs, must be injected, a possible barrier for people who are uncomfortable with needles. As exciting as the new attachment inhibitor field is for people who need salvage therapy, caution is warranted since these drugs are all in early stages of development.
Other classes of HIV drugs being investigated are only worth mentioning until further human studies are done: DC-sign inhibitors, regulatory protein inhibitors, uncoating inhibitors, assembly inhibitors, capsid protein polymerization inhibitors, RNAase H inhibitors, and integrase inhibitors. Even zinc finger inhibitors, thought to be useless, are back in development. And there are adjunctive therapies such as hydroxyurea and mycophenolic acid, which may make some current antivirals such as Videx (ddI), Zerit (d4T), tenofovir DF, and Ziagen (abacavir) even more effective.
Everything but the Kitchen Sink
One salvage strategy studied by Canadian researcher Julio Montaner uses a mega-HAART approach, employing between five and nine antiviral drugs in people who were heavily pre-treated with antivirals and at least partially resistant to most of them. Some consider mega-HAART a desperate approach due to the compounding toxicities of so many drugs. At the 3rd International Workshop on Salvage Therapy in HIV Infection last April, Montaner's data on three separate groups showed that mega-HAART kept virus at undetectable levels (below 400 copies/mL) in up to 44% of patients who had been on their regimen for as long as 57 weeks. Not surprisingly, there was a very high dropout rate because of side effects. For people who don't have new HIV drugs to choose from, recycling older drugs in the form of mega-HAART remains a promising possibility, although the probable side effects limit that promise.
Besides complicated strategies using drugs for salvage therapy, a method of not using drugs is being studied -- structured treatment interruptions (STIs), stopping and restarting antivirals. When a person stops treatment, the HIV that replicates most quickly and usually becomes dominant is "wild-type" virus -- HIV without resistance mutations. The idea behind stopping, then restarting therapy is that the response to the restarted treatment may last longer because wild-type virus is more susceptible to antivirals.
At the 8th CROI, Steven Deeks presented the results of a small study in salvage patients who went on a treatment interruption for an average of 20 weeks. As expected, viral loads increased while off treatment. But CD4 cells decreased substantially, and three of the 22 participants developed opportunistic infections while off therapy. Most -- but not all -- participants' CD4 counts went back up after restarting treatment. People who were able to introduce a NNRTI to their regimen after the treatment interruption did significantly better than those who didn't have a new class of drug to add.
STIs may have some role in the salvage setting and need to be studied further. But the risk of developing an opportunistic infection while off therapy and the possibility that restarting treatment may not increase CD4s to pre-STI levels make it clear that this strategy is particularly risky for salvage patients.
For years, patients have been hoping for better immune-based therapies. In the salvage setting, Interleukin-2 (IL-2) appears to be promising. ACTG 328 looked at people with CD4 counts between 50 and 350, some on HAART alone, others on HAART and IL-2. None of the study participants had taken a protease inhibitor before. After a year and a half of treatment, those using IL-2 had significantly higher CD4 cell counts compared to those not on IL-2. Although this wasn't a salvage study, it has implications for people who need salvage strategies.
There has been concern about using IL-2 in people whose HIV disease is further progressed. It was thought that IL-2 would stimulate HIV by pumping out new CD4 cells for HIV to infect. But it appears that IL-2 can be used effectively to boost CD4 production without necessarily increasing virus levels. ACTG 328 is the largest prospective randomized study of IL-2 in advanced HIV patients to show significant increases in CD4 counts. It remains to be seen whether these CD4 cells are functional, rather than just carbon copies.
Other immune modulators such as GM-CSF (colony stimulating factor) are also being studied in patients with higher levels of virus and lower CD4 counts. As with IL-2, the concern has been about stimulating more "food" for the virus. But if antivirals can keep virus levels low, but not necessarily undetectable, research can go forward with immune modulators.
Finding new ways to treat people who have used up all their treatment options remains a major challenge. In order to discover new drugs and develop useful strategies, randomized, controlled, studies in the salvage population must be conducted. But such trials are difficult to design. And pharmaceutical companies usually want to study their newest drugs in people who have never taken antivirals before because the resulting data looks better. Finally, salvage studies focus on drug failure, something that, for complicated reasons, almost no one wants to look at too closely. It may take time before more studies are done, but this is time that many people with AIDS simply don't have.
Matt Sharp has been living with AIDS for ten years. Now living in Chicago, he is an AIDS treatment activist with Survive AIDS (formerly ACT UP Golden Gate) and a member of the Coalition for Salvage Therapy, a group that advocates for treatments for people with AIDS in late stage.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.