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Glossary

 SALVAGE THERAPY         Dr John Goode

Today there at least 16 anti-HIV drugs to choose from including those available in trials or open access programmes. Many people with HIV will have already used two or three different combinations and the next combination choice could be salvage therapy.

Second, third or salvage combinations are one of the most difficult challenges facing people living with HIV/AIDS and their treatment providers. This article will look at why certain combinations are no longer effective and strategies for developing new combinations using mega-HAART and drugs from access programmes.

The first shot at combination treatment is the most important. Medical professionals who are well experienced in HIV medicine and who have developed a good partnership with their patients should develop this first combination.

Why treatment fails?

Drug resistance

Resistance is the ability of HIV to overcome the effects of a drug. Resistance has been seen with every anti-HIV drug. If someone shows resistance to a drug, it does not mean that every strain of HIV in the person's body is resistant, so there might still be some merit to taking the drug, especially if there are no other treatment options. Drugs are used in combination to discourage resistance. Once resistance develops that resistant viral strain may continue to replicate until it becomes the majority strain.

Studies have shown that when the viral load remains at undetectable levels (less than 50 copies per ml.) that combination will continue to work and be less likely to develop resistance, possibly for many years.

Resistance testing is to measure resistance of HIV to anti-retroviral drugs. Resistance testing can aid in anti-retroviral drug selection but has certain limitations.

1. Resistance testing identifies drugs that should be avoided, but not necessarily the drugs that are most likely to be active.
2. Testing should be done in the presence of the anti-retroviral agents in question, as discontinuation of therapy often results in the proliferation of wild type virus that could suggest susceptibility. The time between discontinuation of HAART and the shift from resistant strains to wild type virus is usually 2-8 weeks, though there is considerable variation depending on the specific mutation.
3. Interpretation of results in people who have received prior antiretroviral agents is difficult. Resistance to previously used drugs may be present even if resistance assays indicate susceptibility.
4. A viral load greater than 500 - 1000 c/ml is usually required.
5. Results are more accurate with failure of early regimens.

There are two types of resistance tests: genotypic and phenotypic tests. The most commonly used test is the genotypic test, because results are available more quickly, the test is less expensive and is more readily available. Genotype testing looks for genetic changes in a person’s virus. Phenotype testing examines how viral replication is affected when increasing concentration of different drugs are added to a person’s HIV in a test tube. A potential advantage of phenotypic tests is that results are more easily interpreted.

WEAK COMBINATIONS

The goal of effective treatment is to slow viral replication to undetectable limits; this requires at least three drugs. Weak drug combinations mean that the strength of the drugs in the combination is inadequate at reducing viral replication and maintaining that reduction. The greater the strength of each drug in a combination the greater the extent and durability of viral load reduction.

In studies of the fusion inhibitor T20 (enfuvirtide) when used in combination with an unchanged combination showed a viral load decrease of 1.2 and 1.5 log but only a 0.6 log decrease when used as monotherapy.

INADEQUATE DOSING

Inadequate dosing maybe due to the incorrect amounts of drugs been given but may also be due to individual differences in how the body metabolises a drug, which tissues the drug penetrates and the excretion of the drug. Drug absorption varies significantly from person to person. Because of the toxicity (the undesirable side effects of drugs which can range from annoying to life threatening) of the anti-HIV drugs the highest tolerable dose may be only just above the minimum dose required to avoid resistance.

Most anti-HIV drugs are metabolised by the liver. People with liver damage or disease may metabolise drugs more slowly. Whereas people who metabolise drugs faster are more likely to develop resistance because they are unable to achieve adequate therapeutic levels. Also drug interactions may effect drug metabolism.

The ideal situation is to achieve the optimal drug levels for each person. The use of Therapeutic Drug Monitoring (TDM) which measures the amount of drug in the body may help to accomplish this. TDM is most useful with the protease inhibitors but may also be used with the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Studies using TDM have shown a higher rate of viral load reduction and a lower rate of treatment discontinuation.

TDM may result in very different dosing regimens in different people but it is only possible when drug levels can be monitored and adjusted on an individual basis. Currently TDM is not widely available in Ireland whereas it is part of the standard of care in the Netherlands.

Preliminary studies are showing that the combination use of resistance testing with TDM are providing better treatment responses.

Adherence: The extent to which a patient takes his/her medications according to the prescribed schedule (also called "compliance"). Nonadherence may jeopardise the effectiveness of a drug and lead to drug resistance.

There are a number of reasons why people are non-adherent with combination treatments. One study showed how people missed one or more doses:

Adherence can be difficult with combination treatment. Information about the full extent of the dosing requirements of each drug within a combination is essential along with support from treatment providers / treatment centres or a support group. Designing a strategy for near perfect adherence when taking a salvage combination can be as beneficial as having access to new drugs.

Side Effect: Any unwanted effect of a drug or treatment (also called an "adverse event"). Some side effects are minor; others can be life threatening.

Side effects often lead to discontinuation of treatment. Side effects vary from a simple rash to serious liver problems. Although drugs are designed to work against HIV they sometimes interfere with other ways in which the body works. The current HIV drugs are far from perfect and some do cause side effects. Most side effects reduce and disappear with time.

Salvage Treatment: A drug combination that is used after other combinations have failed. Often, salvage treatment is used to refer to regimens designed to combat highly resistant HIV. Also called rescue therapy.

Salvage treatments will be considered here under the following headings:

1. Treatment interruptions before starting salvage treatment
2. MDRT or Mega-HAART
3. New drugs (expanded access)
4. The modest approach – sustaining the status quo

There are a number of reasons for taking a pre-salvage break. There is of course the psychological benefit of not having to take drugs with a possible break from side effects and allowing a respite period to be better able to cope with the next drug regime.

During a treatment break there could also be a reversion to wild type virus. This may occur because of an increase in a small surviving population of drug-sensitive HIV that had been suppressed by treatment or a type of reverse mutation of drug-resistant HIV to a wild-type once the drug pressure is removed. Either way it is assumed that the wild-type HIV is more fit (replicates more quickly).

Wild-Type Virus: HIV that has not developed any mutations – this is usually, but not always, the virus that you are first infected with.

Recent studies confirm that resistant virus does not routinely revert to a more drug-susceptible wild type during pre-salvage break, and that reversion to wild type does not relate with salvage success (Ruiz 2002). Also studies have shown that CD4 cell count drops during treatment breaks can be steep and unpredictable.

It is important that if deciding to take a treatment break then more frequent monitoring is needed with possible prophylaxis to protect against opportunistic infections (OIs), particularly if the CD4 count is at risk of going below 200-100 cells/mm^3.. Economically the financial saving from the antiretroviral combination during this break period should cover the cost of additional monitoring tests.

One hope with treatment breaks or STIs (structured treatment interruptions) is to produce an ‘autoinoculation’ with one’s own virus that would help to jog the immune system into recognising HIV as clearly as it did when first infected. A good immune response against HIV might put the virus into remission by itself and eventually allow antiretroviral treatment to be discontinued. But studies to date have only given clues to the possible value of STIs while suggesting some of the distinct disadvantages. Most recently STIs are promoted not as immune boosters but as breaks from drug side effects.

HAART (Highly-Active Anti-Retroviral Therapy): Combination anti-HIV therapy, usually involving a protease inhibitor. Combinations of drugs have been found to be highly suppressive of HIV, and this strategy helps delay or avoid the development of treatment-resistant viral mutants.

Mega-HAART: Drug combinations that use 5 or more anti-HIV drugs, usually 2-3 protease inhibitors.

MDRT: multiple drug rescue therapy.

MDRT calls for as many antiretrovirals as a person can tolerate. Some studies have used as many as 9 drugs. Most people within these studies had run out of drug choices with multiple resistance to all drug classes and CD4 counts as low as 20 cells/mm³.

Safety and tolerability are concerns when dealing with MDRT and TDM (therapeutic drug monitoring) is an essential component to confirm levels of each PI and NNRTI with the ability to individualise doses.

Studies presented at Barcelona showed that aiming for undetectable viral load in treatment experienced people is both realistic and sustainable (Montaner). Using aggressive MRDT approaches with highly resistant HIV has produced survival benefits similar to those seen in treatment-naïve people using normal HAART.

NEW DRUGS

Expanded Access: A general term for methods of distributing experimental drugs to patients who are unable to participate in ongoing clinical trials and have no other treatment options. Specific types of expanded-access mechanisms include parallel track, treatment IND (Investigational New Drug), and compassionate use.

For those who continue to experience a rising viral load with MDRT (Mega-HAART) the use of new drugs may provide their best hope. Some drugs in development hold great promise but will produce better results if they are supported by other effective drugs in a combination regimen. (BETA 2002).

Apart from the development of new drugs within the same classes i.e. the PIs, NNRTIs, NRTIs there are new classes of drugs in the pipeline.

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