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Drug Failure and Salvage Therapy

Fall 1998

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Let's begin with a quiz. Which of the following statements best describes someone who is experiencing drug failure?

A) Patient A had not taken any antivirals in the past and had a viral load of 100,000 copies/mL prior to beginning highly active antiretroviral therapy (HAART). His viral load was undetectable for more than a year after starting HAART therapy, but has since rebounded. For six months, his viral load has been stable at 2,000 copies/mL.

B) Patient B has been on HAART for six months and her viral load is undetectable, according to a lab that uses the first generation PCR test (not capable of detecting less than 400 copies/mL of HIV-RNA). Her lab then acquires the second generation test (capable of detecting down to 50 copies/mL of HIV-RNA), which shows that she has a detectable viral load of 200 copies/mL.

C) Patient C has taken many antiretrovirals in the past and is not able to achieve an undetectable viral load result while on his most recent combination. His viral load after six months of therapy is 20,000 copies/mL -- down from 700,000 copies -- but his T-cells (CD4 count) keep on going up.

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So who is experiencing drug failure? That depends on who you ask. Some researchers and primary care physicians would argue none of the above while others might argue all of the above. One reason for this discrepancy might be that "drug failure" embodies two distinct terms: "virologic failure" and "clinical failure." Yet, people who experience virologic failure aren't necessarily experiencing clinical failure, or vice versa. The United States Public Health Service (USPHS) has published an official definition of virologic failure in its Guidelines on the Use of Antiretroviral Agents, published and updated almost every month. According to the USPHS, virologic failure is characterized by any of the following:

  • if viral load does not decrease by more than 0.5 to 0.75 log during the first four weeks after initiating therapy;

  • if viral load does not decrease by more than 1 log after the first 8 weeks of therapy;

  • if viral load does not go below the level of detection (<400 copies/mL) within four to six months of starting therapy;

  • if viral load rebounds above the level of detectability.

Based on these criteria, it was recently estimated that the number of people experiencing virologic failure while on HAART is as high as 70%.

The rate of virologic resistance among patients who have their viral load checked using the newest PCR test is expected to be even higher. Research results from studies using the newest test were recently submitted to the FDA for review and are expected to be approved soon. In clinical trials, a sizeable number of patients who were undetectable using the standard PCR assay (less than 400 copies/mL) were found to be detectable using the second PCR assay. The USPHS has not yet examined the potential use of the newest "ultra-sensitive" PCR test but is likely to do so once it is approved. In turn, the guidelines regarding when to switch therapy may become even more strict than they currently are.

The term clinical failure refers to continuing disease progression (i.e., experiencing an opportunistic infection) while on HAART, and the term immunological failure refers to the decrease of CD4 count while on HAART. While many patients who experience virologic failure also experience clinical and/or immunological failure, there have been several documented exceptions to this rule. For example, some patients who experience virologic failure as defined by the USPHS may also continue to see a rise in their T-cells. For such patients, continued monitoring may be acceptable, at least until their HIV rebounds to levels greater than three times the lowest stable viral load measurement (e.g., if viral load increases from 4,000 copies to greater than 12,000 copies). Some doctors, may want their patients to wait even longer before switching therapies, especially in the presence of an increasing or stable CD4 cell count.

The primary problem with virologic failure is that HIV is no longer being maximally suppressed. In turn, this means that HIV is replicating, albeit much more slowly, and is likely to produce a large multidrug-resistant population of the virus. The relevance of increasing T-cells in the presence of virologic failure has also been called into question. According to Dr. Doug Richman of the University of California at San Diego, very high levels of T-cell recovery may actually signify impending failure; with more T-cells in the blood, HIV has more targets to attack as it escapes drug suppression.

Even as the eradication hypothesis dwindles, many researchers argue that the goal of HAART remains the same: Patients on HAART who manage to keep their viral load down stand the best chance of leading the longest, healthiest lives. In turn, the need for salvage therapies will likely increase dramatically over the next several years.


When to Switch

As with drug failure, many doctors and researchers view salvage therapies differently. For starters, there are opposing views regarding when one combination should be dropped and another should be initiated.

According to proceedings from the International Workshop on Salvage Therapy for HIV Infection held this past April in New Orleans, many researchers and physicians agreed that patients experiencing any degree of virologic failure should be switched from their "failing" regimen to another, more potent one. As discussed above, it is generally believed that the longer a patient stays on a treatment that allows some viral replication, the more likely drug-resistant strains of HIV will accumulate. On the other hand, some researchers and physicians made it clear that switching at such an early stage does not always pay off, especially with so few "unique" drugs to choose from. In turn, some recommend waiting to see if there is a trend in viral load increases and T4 cell decreases before switching to a salvage regimen.

It has been suggested that drug resistance assays will make it much easier for patients and their doctors to choose HAART regimens more carefully. Not only will these tests help determine whether or not resistant strains of HIV are present before initiating therapy, but they may also be of incredible value in deciding which therapies to switch to after failure has occurred. At the present time, it is highly recommended that a patient experiencing failure drop the entire regimen and switch to an entirely new regimen of drugs (though this is not always possible). With resistance testing, it may be possible to determine which drug(s) is causing the regimen to fail, ultimately allowing a selective switch over a universal one.


What to Switch to

By far, the most frustrating issue in terms of salvage therapies is cross-resistance -- when HIV that is resistant to one drug is resistant to other drugs in the same class. While many of the nucleoside analogues boast fairly unique resistance patterns, often allowing for successful switches, their antiviral potency is somewhat limited. Protease inhibitors and non-nucleosides are much more potent, but tend to cause a significant amount of cross-resistance to each other. As a result, the long-term benefits of salvage therapies tend to be short-lived.

Of course, the success of salvage therapy is highly dependent on a patient's prior antiviral experience. For example, someone who has never tried a non-nucleoside analogue may benefit significantly by switching from a protease inhibitor-based combination to a non-nucleoside-based combination. Some patients who are failing their first HAART combination have also been shown to benefit greatly from switching to a second combination. Options as easy as these, however, are more difficult to come by for patients with extensive prior protease inhibitor and non-nucleoside analogue experience.

In the absence of protease inhibitors and non-nucleoside analogues with truly unique resistance profiles (although several are currently in the drug development pipeline), researchers have been experimenting with drug combinations consisting of four or more compounds -- mega-HAART, if you will -- in an attempt to find acceptable salvage regimens.

Salvage therapies that combine ritonavir with the first saquinavir formulation (Invirase®) have been the most extensively studied to date. According to an analysis presented at the 5th Conference on Retroviruses and Opportunistic Infections in January 1998, Dr. Joel Gallant of the Johns Hopkins Hospital in Baltimore found that 12 out of 17 (70.5%) patients failing indinavir who switched to ritonavir, saquinavir and two new nucleoside analogues achieved undetectable viral load for at least 33 weeks. At the salvage therapy conference in New Orleans, Dr. Keith Henry of St. Paul's Regions Hospital reported similar findings in patients who were failing nelfinavir: 24 weeks after switching to ritonavir/saquinavir, 17 out of 24 (71%) patients were undetectable (less than 500 copies/mL; Chiron's Quantiplex bDNA assay). Other studies have shown however, that patients with extensive protease inhibitor experience -- loosely defined as two or more protease inhibitors in the past -- are much less likely to experience viral load reductions similar to these; only 5% of heavily pretreated patients typically see their viral load fall below the level of detection upon switching to ritonavir and saquinavir.

For patients who have failed multiple protease inhibitors (including ritonavir, saquinavir, and indinavir), preliminary data suggest that a combination of six drugs -- saquinavir, nelfinavir, nevirapine, d4T, ddI, and 3TC -- reduces viral load significantly. At the retrovirus conference, Dr. Cassy Workman of Australia found that this combination, which used a nelfinavir dose of 1000 mg three times daily (750 mg doses are standard), helped 9 out of 12 patients with an extensive history of failing protease inhibitors achieve undetectable viral loads for at least 12 weeks. Similar results from a study conducted by Dr. Schlomo Staszewski of Germany -- using between six and eight different drugs -- were reported at the salvage therapy conference: 90% of patients with extensive antiviral experience achieved a 2 log (99%) reduction in viral load upon starting therapy with six or more drugs.

As for hydroxyurea's role in salvage combinations, some data presented at the 12th World AIDS Conference suggests that it is an effective base from which to build salvage therapies. However, hydoxyurea's side effects reared their ugly head in at least one salvage therapy study; 25% of patients with extensive antiviral experience and low CD4 counts (<100 cells) enrolled in one study were forced to go off the drug due to severe neutropenia (loss of particular white blood cells called neutrophils) or bone marrow failure.

Several salvage therapy studies involving new antivirals -- including abacavir, adefovir dipivoxil, amprenavir, and efavirenz -- are either underway or expected to open soon. Unfortunately, these compounds do not appear to be much different from those already approved and may not radically improve salvage therapy options. Looking further down the pipeline, however, many "second generation" antivirals -- drugs specifically designed with resistance in mind -- are now entering phase II clinical trials and are expected to expand both first-line and salvage treatment options considerably. But even in the absence of new drugs to choose from, salvage therapy research consisting of recycled and/or multidrug combinations continues to yield impressive results.


Tim Horn is the Executive Editor of The PRN Notebook, published by Physicians' Research Network in New York.


Back to CRIA Update Fall 98 Contents Page

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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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.
 
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