6.0 Therapy after more than one previous failure ('salvage' therapy)
6.1 Definition of salvage
The definition of 'salvage' therapy varies. Here, it is taken to mean treatment following exposure to multiple drugs and, usually, all classes of antiretroviral agents. However, many so-called 'salvage studies' have been carried out in patients who are naive with respect to one class of drugs. Unfortunately the definition of salvage becomes a moving target as more classes of drugs (eg. nucleotides, fusion inhibitions) enter the market place.
The reasons for drug failure are complex. Most studies of salvage therapy to date have not distinguished between virological failure due to poor adherence and failure due to other mechanisms such as poor pharmacokinetics. In individuals who have been poorly adherent to previous therapy but have not developed resistant virus, subsequent treatment may be effective if adherence is improved. Enhanced adherence counselling and directly observed rather than self administrated therapy results in significantly better surrogate marker responses, demonstrating the importance of adherence.(1,2)
Low blood levels of PI's, either because of poor absorption or unforeseen pharmacokinetic interactions, may also lead to failure without the development of resistance to PI's.
6.2 Measuring the success of salvage regimens
Suppressing viral load to below detectability (i.e. to below 50 copies/ml) at 24-48 weeks has become an accepted measure of success in antiviral therapy. This criteria may be useful in determining success in highly antiretroviral experienced patients in whom the potency of subsequent regimens in attenuated become of the presence of resistant virus. However, data from a number of large clinical endpoint studies show that much more modest declines in viral load correlate with improvement in clinical outcome. Viral load reductions of greater than 0.5 log10 copies/ml may be responsible for clinical improvement and may imply that such a regimen is worth pursuing. 3
Many salvage studies have been of short duration with little follow-up data, making it hard to judge whether or not any viral suppression will be maintained in the long term. In late disease, the immediate risk of death is much more closely associated with the CD4 count than with the viral load and thus, perhaps, a more important criterion in salvage studies is the degree to which the CD4 count rises.
6.3 Principles of optimising salvage success
Despite these difficulties, both cohort and clinical controlled studies identify a number of general principles to consider when deciding upon a salvage regimen. Firstly, salvage will have the greatest likelihood of success if individuals are naive to one class of drugs. For historical reasons, this is most likely to be the NNRTI class and it seems to be particularly important to give these agents whenever possible as part of a fully suppressive regimen to avoid the rapid emergence of resistance. New classes of drugs such as nucleotides 4 and fusion inhibitions 5 are being introduced and such drugs may be used together in salvage patients to optimise the chance of success.
Secondly, improved outcome is more likely with the use of drugs within classes to which the patient has not been exposed and to which resistance is unlikely or proven to be absent. Recycling some nucleosides might be a useful strategy in this regard.
Thirdly, salvage therapy is more successful at reducing the viral load to undetectable levels in those who commence at a lower viral load (e.g.
Fourthly, resistance testing is strongly recommended in all cases where there are difficult choices to make concerning the most beneficial treatment. A number of retrospective and prospective studies demonstrate that responses to drugs in failing regimes can be predicted by the genotype or phenotype. These tests are clearly useful at first failure 6,7,8 but data on salvage patients is still evolving and has been conflicting. 9,10 A resistance result suggesting that the virus remains sensitive to a particular drug does not guarantee a long term response as drug exposure history is an important factor. Although responses in viral load are likely to be very small when using a drug to which the virus is resistant, some clinicians believe that using a number of such drugs together might have a cumulative benefit which out weights the potential toxicity. 11
Finally plasma drug concentrates may influence therapy outcome. Patients in the VIRADAPT study 12 had the best virological response in those who had optimal drug concentration as well as genotyping to guide future choices. The use of therapeutic drug monitoring and the relationship to drug levels to the viral IC5O have led to the theoretical possibility of optimising drug levels for a particular patients dominant viral strain 13 and PI boosting using the ability of Ritonavir to inhibit CYP450-3A4 is one strategy used to try and increase plasma drug concentration of PI's above the IC5O of resistant viruses. 14 Whether long term toxicity will be increased by such a strategy is unknown. Hydroxyurea is no longer recommend to enhance intracellular nucleoside levels but interest has now focused on Mycophenolate.
6.4 Salvage therapy in PI-experienced patients
Both cohort data and clinical controlled trials suggest that 60–70% of subjects who are experiencing failure of single agent PI-based therapy and who are NNRTI naive will achieve viral load reductions to below 400 copies/ml at 16 weeks by switching to appropriate (i.e. new) NAs plus two PIs and an NNRTI 15,16. The two PIs most commonly used in such studies are ritonavir, saquinavir and Lopinavir/ritonavir. The primary reason for their efficacy is probably improved pharmacokinetics, although it is possible, in some cases, the dose of ritonavir used, that is 400mg may have additional direct antiviral effects (i.e. if cross resistance to saquinavir is absent from the viral population).
Individuals who experience failure of ritonavir or indinavir as their initial therapy are less likely to respond virologically to the introduction of ritonavir/saquinavir than those who took nelfinavir as their first PI.
A proportion of individuals exposed to nelfinavir only will harbour virus with a codon M30N mutation and not the L90M associated with Saquinavir cross resistance, which will continue to be sensitive to other PI's. Thus, most clinicians would recommend a rapid change from nelfinavir, once failure has occurred, to a dual PI-containing regimen. Interestingly, in one small study despite the median time to virological failure prior to changing being 48 weeks 17 over 60% of patients achieved a viral load reduction to below 400 copies/ml. In a number of cohort studies the newly licensed protease inhibitor, Lopinavir enhanced with low dose Ritonavir in combination with either Efavirenz or Nevaripine, has reduced viral loads to below detectable limits in NNRTI na•ve PI experienced patients. 18,19
Thus far there are no head to head comparisons for this regime with other dual PI treatments.
Amprenavir may retain activity after prior PI failure. From one study of 108 patients, Amprenavir maintained viral sensitivity in patients failing the other 4 licensed PI's in half to three quarter of isolates. 20
6.5 Salvage therapy in NNRTI-experienced patients
There are few data to guide the appropriate choice of salvage therapy in patients who are NNRTI experienced. As class resistance between NNRTI's and PI's is unlikely, it would be logical to suppose that a good response might be obtained with a dual PI combination in those previously na•ve to this class of drug, particularly if suitable nucleoside analogues to which the virus harboured by the patient is sensitive, can be found.
6.6 Salvage therapy in patients with multiple class resistance
ACTG398 was a prospective study evaluating treatment options in heavily pre-treated patients. The study compared a regimen of Amprenavir plus a second PI versus Amprenavir alone. All patients received Efavirenz, Abacavir and Adefovir. The four arms included Amprenavir alone, Amprenavir plus Nelfinavir or Indinavir or Saquinavir soft gel. Approximately half of the patients were NNRTI na•ve and these experienced patients performed better than the NNRTI patients. (43% vs 16% for A number of approaches have been tried in this situation with varying success combining large numbers of drugs (five or more)
6.7 Structured treatment interruption
STI is a popular concept with many patients and some clinicians at present with few scientific data and no controlled trial data as yet to support it. The use of this can be considered in three different situations. Immunological responses to HIV are mostly completed shortly after seroconversion. In particular strong CD4 helper responses directed against HIV, which may be important in sustaining CD8 cytotoxic responses are present. Such responses disappear within a few months, either because the cells involved develop anergy or because they are deleted.
Immediate treatment at seroconversion appears to preserve these responses. In a small cohort of 14 patients, all of whom have been treated for more than 8 months and had viral loads which were undetectable, had a series of treatment interruptions with the concept that renewed viral replication would reinforce the immune responses to HIV. So far in 7 of these patients the viral load was low or absent following several interruptions. 22
In chronic disease single interruptions have resulted in rapid rebound of plasma viral load to pre-treatment levels with appearance of strong CD8 but not CD4 responses to HIV. The most mature study examining repeated treatment interruptions has failed to show any consistent effect on viral load following cessation of therapy although in a minority, after about 4 cycles of STI the plateau of viral load was at a lower level than that prior to treatment.23
Continuing cycles of treatment interruption might be associated with reduced toxicity and there would be important cost implications for resource poor countries. Potential dangers of such an approach include the development of resistance because of sub-optimal treatment when stopping drugs because of different half lives of drugs and the impact on adherence. This group of patients whom otherwise expect the CD4 count to continue to rise, if no STI was performed.
In some patients with an undetectable viral load who have achieved a high CD4 count STI might be used to allow a period off drug until the CD4 has fallen again to levels at which treatment would be recommended. This should only be undertaken as part of a clinical trial because it is all yet an untested hypothesis.
6.8 Structured treatment interruption (2)
STI has also been used in patients failing virologically 22 patients who had STI prior to salvage from a mean of 20 weeks had a CD4 mean fall of 88 cells and 3 developed AIDS. Most patients virus reverted to wildtype and 11 subjects who used a new class of antiretroviral achieved 24
Finally STI might be useful for discontinuation of toxic and ineffective therapy but in most individuals, a prompt fall in CD4 count mean (often around 100 cells) and rise in viral load indicates that the drugs still have some effect in so called failing regimens. After a variable time off therapy wild type virus which usually has enhanced replication fitness in the absence of drug becomes the dominant quasi species in the plasma although minority resistant species are likely still to be present in proviral DNA. In general when such individuals have restarted on treatment, this has been with different drugs to those discontinued and therefore the value of treatment interruption has been impossible to assess. The disadvantages in terms of falls in CD4 count are clear cut.
6.9 Viral fitness
The concept that some viral mutations replicate less well (particularly some PI and 3TC mutations) than wild type virus has been used to explain the improved results seen in cohort studies in late disease with high viral loads and low CD4 counts on PI containing regimes when compared with dual therapy. Similarly the short term maintenance of CD4 count improvements in patients continuing on regimes which allow continuing viral replication (the so-called disconnect syndrome) might be explained in a similar way. Viral fitness is, of course, relative and is usually measured by comparing growth rates of 50/50 mixtures of mutant and wild type virus in the presence or absence of drug. Clinically the most important comparison is likely to be the replication rate of mutant virus in the presence of drug compared with wild type virus without drug.
Thus an alternative approach to mega-HAART or treatment interruption in late disease would be using a PI and/or 3TC containing regime in a deliberate attempt to reduce viral fitness and maintain a CD4 count rather than an attempt to make the viral load fall below detectable limits. Controlled trial data is needed to validate this approach.
6.10 New Therapies
New drugs are being developed that may be from the same class as existing compounds or a new class altogether. Drugs from existing classes may offer advantages in terms of demonstrating activity against resistant viruses. Outside of clinical trials (eg. named patient or expanded access) the use of these drugs in salvage should be considered carefully as it may be better to wait for effective combinations of such compounds to be available and until then maintain patients on a "failing regimen" rather than using new drugs in a regimen with no other "active" drugs and allowing resistance to develop.
6.11 Stopping therapy long term
Most drug therapy discontinuations have been associated with a rapid rise in viral load and fall in CD4 cell count. Thus, for the majority of individuals, continuation of therapy is possibly associated with a better prognosis than discontinuation. However, it is most important to weigh up the risks of continuing any medication (potential toxicity) against the benefits (potential for improved outcome).
6.12 Recommendations for subsequent virological failure (third or more regimen)
- Test for genotypic resistance; phenotypic assay or virtual phenotype may be necessary if genotype difficult to interpret.
- Change as many drugs as possible.
- Introduce a new class if possible, but not if chance of success by combining new class with other drugs is small. May be better to defer change until new treatment options available.
- Structured treatment interruption is not recommended as standard of care; needs to be evaluated in clinical trials.
- Mega-HAART or recycling of nucleoside analogues may be of value to some patients.
- Consider stopping all drug treatment if toxicity outweighs any likely benefit.
- An viral load
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