Strategies for Third-Line Therapy

One area of HIV therapy research that has been inadequately addressed is strategies around third-line therapy regimens. Third-line therapy is usually defined as a regimen for an individual who has developed resistance to at least one drug in all three classes of HIV therapies [nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors] or has failed two treatment regimens. Third-line regimens are also termed by some as mega-HAART, giga-HAART, salvage therapy and multi-drug rescue therapy.

Most third-line regimens consist of four or more drugs, the theory being that not all of the virus in a patient is going to be resistant to all of the drugs. By using many drugs with different mechanisms of blocking HIV reproduction, it may be possible to achieve a potent therapy. Multi-drug regimens also increase the risk of side effects and make it more difficult to manage drug interactions. The use of therapeutic monitoring, using an experimental diagnostic test that measures the amount of drugs in the blood, may ensure adequate drug levels are achieved and mitigate side effects associated with higher blood drug levels.

The most obvious third-line option includes several new drugs that may be active against multi-drug resistant HIV that are FDA-approved or are still in early development. These include: fusion inhibitors T-20 (pentafuside) and T-1249; nucleotide analogue tenofovir, which, in general, can be considered an NRTI as it shares some of the same resistance patterns; new protease inhibitors including atazanavir (Zrivada), tipranavir and TMC 114; existing protease inhibitors enhanced by the addition of small doses of ritonavir, which increases their ability to overcome partially resistant virus; new NRTIs including DAPD, alovudine and ACH-126,443; new NNRTIs including capravirine, TMC125 and DPC961; CCR5 inhibitors including Schering C (SCH 351125) and UK-427,857; entry inhibitors including PRO 367; attachment inhibitors including PRO 542; and integrase inhibitors including S1360.

It is probably advisable for people considering a third-line regimen to get a resistance test. For most of these drugs, the only method of access is by participating in clinical trials, while some provide drugs to people through expanded access programs. Currently, there is a very limited expanded access program for T-20 and one planned for atazanavir by the end of the first quarter 2002.

There is still much debate about the role of structured treatment interruptions (STIs) as part of a third-line regimen. Several studies have shown STI in third-line situations do trigger a reversal of resistance when using standard resistance tests, but drug resistant HIV can be detected using a more sensitive test. Still, there is often a period of renewed activity from drugs that had previously failed. It is unclear how long the benefits last once therapy is restarted after an STI. One major concern with STIs is that there is often a rapid drop in CD4+ cell counts and an increase in viral load, both of which can be very significant after stopping therapy. Furthermore, after restarting therapy there is a slow increase in CD4+ cells, with some people never returning to their pre-STI cell counts.

Immune-based therapies have not adequately been studied as part of third-line regimens. There are some data showing that the use of GM-CSF (granulocyte colony stimulating factor, Leukine) may have some benefit.

Several studies report that even when regimens appear to "fail" -- defined as a return of measurable viral load despite treatment -- there is usually still a lasting benefit for people who remain on treatment. It is likely that viral load tests do not tell the whole story of how the body responds to HIV drugs. Early results of research into the "fitness" of the virus suggest that HIV is not able to replicate as well after it becomes resistant to certain drugs. Thus, one reasonable choice might simply be to stay on whatever regimen patients have been using. As long as patients remain clinically well and don't suffer a rapid further decline of CD4+ cells, it might be wise to not worry excessively about drug "failure."

The article concluded, "There is a definite need to evaluate the optimal strategy in putting together a third-line regimen and the various clinical trial networks and pharmaceutical companies need to make this issue a priority."

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