Salvage therapy

Christian Hoffmann and Fiona Mulcahy

The term "salvage therapy" is not clearly defined in HIV medicine. It is currently used to refer to varying situations. Some speak of salvage only if all drug classes have failed, whereas for others it applies to second-line therapy onwards. No consensus on a definition has been reached at multiple conferences. Here, we define salvage as the therapeutic approach when at least one PI-containing regimen has failed. Moreover, the concept is constantly being shifted further back in the therapy career of patients. Today, many clinicians talk about salvage when there is resistance to at least two or three antiretroviral drug classes. Viruses with multiple resistances are in turn termed MDR ("multi-drug resistant") viruses. In the last few years, significant progress has been made for these patients. T-20, tipranavir, darunavir, maraviroc, raltegravir and etravirine are also still effective in the presence of numerous resistances (see also "HAART 2007/2008"). This provides hope for the future. In addition, it changes the aim of therapy. These days, even in intensively pre-treated patients, an attempt should be made to reduce the viral load to below the level of detection (Youle 2006).

Nevertheless, there are many problems. Salvage studies are becoming increasingly more difficult as patients with MDR viruses are becoming less frequent (Lohse 2005). Homogenous patient populations are scarce as each one has an individual history of therapy, a different distribution of resistances and therefore varying prerequisites. In large HIV centers, often more than 50 different combinations are used. This makes it difficult to test new salvage substances in Phase II/III trials. It is also hard to find the correct study design: as the single use of an experimental drug in a failing regimen is ethically questionable, the appropriate ART must always be optimized (=OBT, optimized background therapy). If the OBT is too good, the effect of the new drug may be hidden, as many patients achieve a good viral suppression just on OBT. If the OBT is too poor, the effect of the new drug may only be temporary or too weak - the window through which the efficacy of a new salvage drug can be seen is small.

Background

First: it should not be forgotten that patients with MDR viruses, who often have a long therapeutic history, and who now presumably find themselves once again on a precipice, need encouragement. It is important not to deny anyone hope. Although some studies have shown that patients with MDR viruses have a worse prognosis than patients without resistances (Hogg 2005, Zaccarelli 2005), data are not unequivocal. In the GART Study, the risk of progression for patients with more than six resistance mutations was not increased in contrast to patients with less than twomutations, (Lucas 2004). Despite MDR viruses, the risk of developing AIDS with good CD4-cell counts is relatively small (Ledergerber 2004). MDR viruses have a weaker ability to replicate and are probably less aggressive (Prado 2005).

Furthermore, progress is continuing. New classes of drugs will arrive. So, for MDR, simply - be patient!

Until then, one should accept that even today there are patients in whom one has to say goodbye to the primary aim of therapy of reducing the viral load to undetectable levels - especially if despite better compliance the only response to intensification of therapy is more side effects. Sometimes it is better to step back and wait for new options (see below). If possible, these patients should be managed in large centers, in which the new possibilities are usually available sooner, and where there is more experience with complex salvage regimens. A single new medication should ideally not be used alone - use as many effective substances as possible! It usually takes years to progress from virological to immunological, and finally to clinical treatment failure (see also "Principles of Therapy").

It is, however, important that patients with MDR viruses are very carefully observed and undergo regular (monthly) full body examination - something that is often neglected today in the long discussions about blood values and resistance testing for many HIV patients. Loss of weight, B-symptoms, oral candidiasis, OHL, and cognitive worsening are early signs of disease progression that should not be missed.

The following is a discussion about a few salvage therapy strategies, which when used alone or in combination, are promising.

• Salvage with lopinavir/r, tipranavir/r, darunavir/r and T-20

• Double PI regimens

• Mega-HAART, with or without treatment interruptions

• Utilizing NNRTI "hypersusceptibility"

• Salvage through recycling

• Just waiting, and even simplifying ART

• Experimental salvage drugs

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