Salvage therapy is an approach taken when previous anti-HIV treatments fail to achieve desired goals, which include undetectable viral load, CD4 cell levels above 200 cells/mm³, and the prevention of HIV disease progression. It is one of the most difficult situations to face as a patient, and one of the most problematic challenges for healthcare providers. Though sometimes euphemistically referred to as "management of treatment-experienced patients," many HIV positive people, having already exhausted the benefits of at least a couple of drug combinations, think of their next regimen as salvage or "rescue" therapy.

A few physicians argue that due to cross-resistance among different drugs within the same class, people with HIV infection have only one good shot at treating it, and that any treatment regimen beyond the first is therefore salvage therapy. Others see salvage therapy as literally the end of the line -- when an individual's HIV has developed extensive resistance to all currently available treatments. But most providers consider salvage therapy to be somewhere in between these extremes. Understanding that the term can refer to different treatment situations is important. Nevertheless, most of the information in this article will be relevant for anyone changing a drug regimen, no matter where that person is on the treatment path.

Individualized Care

Salvage therapy is one of the most difficult topics to write about because every statement must be qualified in relation to an individual's personal treatment history. Although this should be the case with any medical decision, choices about HIV treatment should be tailored for each person. As therapeutic options become more limited, the stakes are arguably higher. More than at any other time in a person's treatment history, salvage therapy requires highly individualized care.

It is important for people to keep their own treatment history file that includes CD4 cell count, viral load, and resistance test results, together with a list of drugs previously used, medication allergies, past side effects, and adherence levels (frequency of taking doses as prescribed). As antiretroviral therapies become more effective, it is clear that we now need to plan for 30 years or more of treatment. Keeping complete treatment records is especially important when changing providers or hospitals.

Whether an individual has failed an initial regimen, has been HIV positive for many years and has used all the available drugs, or has been recently infected with a multi-drug-resistant HIV strain, the approach will be similar. It involves looking at five or six key areas, each of which must be addressed to optimize the chances of success with a subsequent regimen. This highly individualized approach is not based on new science, and in fact has changed very little over the past three or four years.

Why Treatments Fail

Although the range of antiretroviral therapies has expanded, the basic principles of HIV treatment have been understood for some time and remain fairly constant. Apart from a few exceptions, such as recent research on viral fitness (replication capacity), most of the approaches discussed in this article are not new or recently discovered.

John Mellors, M.D., of the University of Pittsburgh outlined the foundations of HIV therapy in a keynote speech opening the 1999 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco. The multidisciplinary approach he described was also stressed at the Workshop on Management of Treatment Experienced Patients held in San Diego, California, this past September.

Both lectures emphasized that there are only a limited number of known reasons why treatment might fail: drug resistance, inadequate drug potency, suboptimal drug levels, poor adherence, and drug toxicity. At least one -- and possibly a combination -- of these factors are responsible for the failure of each treatment regimen used in the past, whether it was the first or the fifth combination. To avoid repeating the same mistakes with salvage therapy, it is important to understand why each previous treatment attempt failed.

Resistance

Drug resistance is recognized as the reason most combination regimens fail, but how resistance develops is still often misunderstood.

The medical explanation for the development of resistance is that ongoing viral replication occurs in the presence of a drug regimen that does not adequately suppress the virus. This means that if a person has a detectable viral load (over 50 copies/mL) while on treatment, enough new virus is produced each day for resistance to develop by chance due to random viral mutations (genetic changes). Once resistance develops by chance, however, if a person continues to take the drugs to which HIV is no longer susceptible, the resistant virus will continue to replicate until it becomes established as the majority strain.

Resistance, therefore, does not cause a treatment to fail, but rather develops if one or more of the other key factors related to treatment failure are present. If a combination regimen is not potent enough, if drugs are poorly absorbed, if adherence is not perfect, or if the drugs are not effective due to pre-existing resistance, a person may not achieve or maintain a viral load under 50 copies/mL. Then, as a result of continuing treatment with a detectable viral load, viral mutations may develop and resistance can follow.

However, studies show that if viral load is reduced to an undetectable level (usually below 50 or 25 copies/mL, depending on the assay) and all other factors related to treatment success are taken into account, then a combination regimen will continue to work and the virus is much less likely to develop further resistance. Individuals who achieve and maintain undetectable viral load levels with any drug combination, first-line or salvage, are in the best position to see their viral load remain this low for many years. The magnitude of the drop in viral load -- even if it is reduced by hundreds of thousands of copies -- is not as important as getting viral load as low as possible. Some studies suggest that it may be beneficial to aim for a viral load below 5 copies/mL; ongoing research should clarify whether this is important for long-term health.

Another important concept is that resistance rarely acts like an on-off switch. Think of resistance more as being on a continuum, with completely sensitive or even hypersensitive virus at one end and completely resistant virus at the other. In between these two extremes, other factors come into play. For example, HIV generally slowly accumulates mutations that gradually limit how effective protease inhibitors (PIs) are against the virus. But even with extensive resistance, the drugs still can have some clinical benefit. If a person with drug-resistant HIV discontinues treatment and viral load increases further, this is evidence that the drugs were providing some anti-HIV activity. Since resistance is on a continuum, increasing the dose or concentration of a drug often can overcome resistance -- although doing so may also increase drug toxicity.

Resistance Testing

Resistance tests are used to identify drugs that are not effective against an individual's specific strains of HIV. There are two main types of resistance tests. Genotypic tests look for genetic changes in a person's virus and match these mutations against a database of known mutations that in clinical trials have been associated with resistance to different drugs. Phenotypic tests look at how viral replication is affected when increasing concentrations of different drugs are added to an individual's HIV in a test tube. A third variation called a "virtual phenotype" compares genotypic results with a large database of phenotypic results.

Both genotypic and phenotypic tests only detect resistance once it is relatively extensive. The tests are less sensitive to minority drug-resistant strains of HIV that are present in the body at low levels. For the most reliable results, the viral load should be above 1,000 copies/mL and the individual should currently be taking anti-HIV therapy. While several studies have shown that resistance tests can help physicians select an optimal drug regimen, other studies have not shown a dramatic benefit in terms of clinical outcome. This is likely because as a person's HIV becomes more resistant, there are fewer effective treatment options available. Resistance tests can tell which drugs are no longer active, but someone whose virus is no longer sensitive to any drugs will not be able to construct an effectively suppressive regimen.

Experts have begun to recognize the value of resistance tests at every important change in a person's HIV disease progression. Julio Montaner, M.D., of the University of British Columbia in Vancouver has referred to the combined history of all of an individual's worst resistance profiles over time as "virtual resistance." Compiling such a profile involves blood tests when HIV is originally diagnosed and before starting treatment, a complete history of all drugs a person has taken, and viral load test results for the periods during which those drugs were used. It also requires knowing the exact timing of previous resistance tests and what drugs were being taken at the time of these tests.

Short-term treatment benefit has been observed when resistance testing is used in conjunction with therapeutic drug monitoring (TDM) to ensure optimal drug levels (discussed below). Long-term TDM data for anti-HIV medications are not yet available.

Drug Potency

Potency refers to the strength of drugs in a combination regimen -- how effective they are at reducing viral replication and maintaining a response. On a basic level, drug potency refers to how much of a viral load reduction a drug generates by itself. The greater the potency of each drug in a combination, the greater the magnitude and durability of viral load reduction.

Anti-HIV drugs are approved only when they show a clear antiretroviral effect; even the newest drugs that have been studied for use in salvage therapy must show this effect. For example, results from a recent study of the fusion inhibitor T-20 (enfuvirtide, Fuzeon) showed that T-20 added to the best available existing choice of therapy produced a 1.7 log reduction in viral load, while the best existing regimen alone produced only a 0.7 log reduction. The European/Australian segment of this study (TORO 2) showed slightly less of an effect (1.4 log and 0.6 log reductions with and without T-20, respectively) in people who had more resistance to existing drugs before they started the study. From this, it appears that T-20 can produce an approximate 1 log reduction in viral load, although this will of course vary among individuals.

The reason combination antiretroviral therapy includes three or more drugs is largely linked to the issue of potency. The potency of a regimen is determined not only by the activity of each drug, but also by the combined activity of the regimen as a whole. The overall potency of a combination regimen must be strong enough to reduce viral load from baseline to an undetectable level and to maintain this response for months and, ideally, years.

If a single drug could produce a 5 log or 6 log reduction in viral load on its own, it could theoretically be used without other drugs in a combination (although resistance is more likely when a drug is used alone). However, existing drugs produce viral load reductions only of about 0.4 to about 2.5 logs. Therefore, at least three highly suppressive drugs are generally required to reduce viral load from baseline to an undetectable level. By definition, people who require salvage therapy do not have three potent drugs available, so regimens with larger numbers of drugs -- sometimes up to nine -- may be needed to achieve adequate potency. Even drugs that are not very potent by themselves can still contribute some antiretroviral activity to a combination.

Potency depends not only on the effectiveness of a drug itself and the other drugs it is used with, but also on the specific virus it is used against. A few drugs can be more effective against drug-resistant virus than against wild-type (nonmutated) HIV, but in general, resistance and previous treatment experience render new drugs less potent. For example, studies have shown that the recently approved nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir DF (TDF, Viread) produces an average 0.6 log viral load reduction in treatment-experienced people compared with a 1.1 log drop in those who are treatment-naive. Tenofovir may therefore contribute more potency as part of a first-line regimen than as part of a salvage regimen.

Suboptimal Drug Levels

A third important reason for treatment failure is suboptimal drug levels in the body. Suboptimal drug levels may be due to inadequate dosing, but may also be related to individual differences in pharmacokinetics (drug absorption, metabolism, and excretion). How drugs are absorbed in the body is highly individual, and blood drug levels are subject to significant variation among different people taking exactly the same dose. For some drugs used for conditions other than HIV this is not a problem, because their generally low toxicity means the drugs can be given in sufficiently high doses to allow for this variability. But this is not the case for most anti-HIV medications. Due to the toxicity of antiretroviral drugs, the highest tolerable dose may be only just above the minimum dose required to avoid resistance.

Many antiretroviral drugs are metabolized in the liver by the cytochrome P450 (CYP450) enzyme system. Some people naturally metabolize drugs more slowly or more rapidly than others. For example, those with existing liver damage often have impaired drug metabolism. People who metabolize drugs faster than average run the risk of developing resistance due to suboptimal drug levels. Those who metabolize drugs more slowly than average may experience increased side effects due to high drug levels. Among people who metabolize drugs quickly or do not achieve adequate concentrations in the body for other pharmacokinetic reasons, even perfect adherence will not ensure safe levels.

In addition, drugs that are metabolized by the CYP450 pathway can interact. When multiple drugs that use the same pathway are present, metabolism may be slowed, leading to higher drug levels. In other cases, certain drugs can stimulate CYP450 metabolism, leading to more rapid drug processing and lower levels. Every recent medical conference on AIDS has included reports about drug interactions, often involving medications that have been licensed for many years. Some foods and herbal remedies (for example, grapefruit juice and St. John's wort) can also affect drug metabolism.

Peak and trough levels and area under the curve (AUC) are important concepts in understanding drug levels. The peak level is the highest drug level in the body after taking a dose. The trough level is the lowest drug level between doses, usually reached right before the next scheduled dose is taken. On a graph, the line that joins peak and trough levels is a curve; therefore, the amount of drug exposure over a dosing interval is represented by the "area under the peak/trough curve," or AUC.

It is best to have a constant therapeutic drug level in the body over time, since high levels can cause increased side effects and low levels can promote resistance. Several new antiretroviral drug formulations are designed to last longer in the body and achieve steady drug levels with a single daily dose.

Sometimes low drug levels and resulting drug resistance can be overcome with higher doses. Increasing drug dosages can produce a stronger antiviral effect, but also heighten the risk of side effects. For example, it is well known that the first studies of AZT (zidovudine, Retrovir) -- which used three or four times the current accepted dose -- led to side effects that were very difficult to tolerate. What is less well known is that AZT monotherapy at these high doses produced about a 4 log reduction in viral load. Using such high doses as part of salvage therapy is not common, but may be useful on an individual basis (though only in consultation with a physician).

With regard to T-20, it should be noted that maximum dose cut-offs for efficacy or tolerability were not reached in the registrational studies due to supply problems and the difficulty of asking subjects to inject the drug more than twice per day. There may therefore be a subgroup of people using T-20 in the context of salvage therapy who could benefit from the potentially greater antiviral activity of higher doses.

Drug Boosting

One way to increase the antiretroviral activity of a drug is to add another medication that "boosts" the blood level of the first drug. As discussed above, this works because certain medications inhibit drug metabolism in the liver.

Ritonavir (Norvir) is used most often to boost the levels of other PIs. Numerous studies have shown that using ritonavir to boost indinavir (Crixivan) can overcome indinavir resistance; however, as blood levels of indinavir increase, so too does the incidence of side effects. The new PI Kaletra includes a small amount of ritonavir in the pill to increase levels of lopinavir. The added ritonavir boosts lopinavir well above the minimum concentration needed to inhibit 50% or 95% of viral replication (called the IC 50 or IC 95 , respectively; IC refers to the "inhibitory concentration" as determined in laboratory tests). This is one of the reasons Kaletra has proven to be so effective against HIV that is resistant to older PIs. Lopinavir itself has a resistance profile similar to that of other PIs, but boosting with ritonavir can overcome this resistance.

As another example, a recent study suggested that using a low dose (300 mg) of hydroxyurea (Hydrea) twice daily could enhance the activity of ddI (didanosine, Videx) while reducing ddI toxicity. It has also been suggested that mycophenolate (mycophenolic acid, CellCept; used in organ transplantation) can similarly increase the potency of abacavir (Ziagen) and a few other nucleoside reverse transcriptase inhibitor (NRTI) drugs, although clinical benefit from this approach has not been clearly shown in recent studies.

Therapeutic Drug Monitoring

Therapeutic drug monitoring (TDM) refers to measuring the levels of medications in the body. The goal of TDM is to help achieve optimal drug levels on an individualized basis. The technique can provide protection against excessively low or high drug levels, and thereby improve virological outcomes and reduce toxicity. TDM is most useful with PIs and may also be used with non-nucleoside reverse transcriptase inhibitors (NNRTIs); however, it is not recommended for NRTIs due to current technological limitations. Results from a large European trial (named ATHENA) of subjects taking their first antiretroviral regimen showed that TDM led to lower rates of treatment discontinuation and higher rates of virological response. Some clinicians believe TDM may be beneficial for people taking salvage regimens as well.

By helping to optimize treatment, TDM can lead to the use of very different dosing regimens in different individuals. For example, indinavir/ritonavir is often dosed at 400 mg/100 mg twice daily in France, where TDM is widely used. (The typical dose in the U.S. is 800 mg indinavir with 100 or 200 mg ritonavir twice daily.) People in the Netherlands using the original formulation of saquinavir (Invirase) with the benefit of TDM received "double dosing" and avoided the early failures seen in the U.S. due to suboptimal drug levels. And in the UK, a patient whose damaged liver allowed only extremely slow metabolism of efavirenz (Sustiva) was given a low dose of 200 mg twice weekly prior to a liver transplant.

Such individualized dosing is possible only when drug levels can be monitored and adjusted on a person-by-person basis; it is not possible simply to guess drug levels. Further research needs to be done in this area, however, as optimal drug levels are not precisely understood and drug level tests have not been standardized.

Scientific opinions about TDM differ considerably between Europe and the U.S., as does access to it. Countries in Europe with leading research programs on drug metabolism already have laboratories that can analyze blood drug levels in people receiving antiretroviral therapy. In the Netherlands TDM is part of the standard of care; all people starting anti-HIV regimens that include a PI or an NNRTI have their levels of these drugs measured. In France TDM is not universal, but it is widely used, especially for people receiving salvage therapy. In the UK TDM is available to a wide range of people, mainly those using PIs. Use varies by clinic, and some offer TDM to all patients; due to the efforts of treatment advocates in the UK, the additional cost of the tests is covered by drug manufacturers.

Availability of TDM in the U.S. has increased over