AIDS Treatment Update, Issue 63, March 1998
Keith Alcorn

>>Switching after protease failure

Doctors tend to define treatment failure in three ways. Everyone agrees that treatment is failing if there is a sustained fall in your CD4 count. Increasingly, treatment is also said to have failed if it has not suppressed viral load to `undetectable' by 12 to 16 weeks (although if it is still falling, many doctors would suggest waiting longer before making any change). Those who are most cautious about resistance may also define `failure' as any point at which viral load becomes detectable, because this indicates a growing risk of drug resistance.

The following general guidelines are now widely accepted when changing therapy:

1. Never add one drug to a failing regimen; it is advisable to switch to at least one other new drug at the same time.

2. Examine your treatment history and consider which drugs you are most likely to have developed resistance to. For example, 3TC resistance develops easily, so if you have taken 3TC before there is little hope of re-using it. But resistance to d4T or ddI is rare, so there may be more reason to retain these drugs.

3. Choose new drugs which are the least likely to be affected by cross-resistance. For example, if you have taken an NNRTI drug such as nevirapine before, your HIV may also be cross-resistant to other NNRTIs.

4. Try to assemble a combination that has a good chance of suppressing your viral load to below the limit of detection. If your viral load remains detectable 16 to 24 weeks after starting such a regimen, discuss with your doctor whether to modify your regimen.

>>What to switch to

The most potent anti-HIV regimens consist of combinations of at least three drugs which contain at least one PI or an NNRTI.

In the UK, many doctors consider NNRTI-based triple combinations to be a reasonable alternative to PI-based combinations for people starting therapy for the first time. However, there have been no formal trials comparing the effectiveness of NNRTI-based combinations versus PI-based combinations. There is little evidence of any kind on the effectiveness of NNRTIs among people who have already taken a PI-based combination.

The alternative is to switch to a new combination that includes at least one different PI. But HIV strains that have developed resistance to one PI are often cross-resistant to other PIs, at least in test-tube studies, which may reduce your chances of a good response.

Only one substantial, randomised study, known as ACTG 333, has looked at what happens when you switch from one PI to another. It enrolled people who had been on saquinavir (in its current `hard gel' formulation) for at least 48 weeks before switching to either indinavir or the new, soft gel saquinavir formulation. Viral load falls were modest in both groups after eight weeks on the new drug, disappointing the trial researchers who had hoped for better responses among those switching to indinavir. However, it is worth noting that people in this study changed their PI without switching at least one other drugs at the same time, a practice which is not now recommended.

At the Fifth Conference on Retroviruses and Opportunistic Infections last month, there were several reports of attempts at salvage therapy.

One popular approach has been to use both ritonavir and saquinavir (RTV/SQV), with or without additional nucleoside analogue reverse transcriptase inhibitor (NRTI) drugs, as salvage therapy for people whose first PI regimen is failing. The effects of this regimen seem to be unpredictable. In a French study, about 40% of 101 ritonavir- or indinavir-experienced people who switched to RTV/SQV plus NRTIs achieved viral load below 200 copies/ml after six months (abstract 425). Other studies reported that this regimen was also effective for around 50% or more of saquinavir- or nelfinavir-experienced people (abstracts 423, 427).

Other PI combinations now being studied in trials - but not yet tested as salvage therapy - include nelfinavir with either indinavir, saquinavir or ritonavir.

Attempts to use nelfinavir, the most recently approved PI, as part of salvage therapy regimens have generally been disappointing. For example, in one report 16 people who failed on saquinavir switched to nelfinavir, but none had viral load below 400 copies/ml after 12 weeks. Eleven subsequently switched to indinavir, nevirapine and two NRTIs, but only three had viral load reductions below 400 copies/ml that lasted beyond 20 weeks. It is worth noting that all of the group had taken an average of four nucleoside analogues before switching to nelfinavir, making it virtually impossible to put together new combinations of three or four drugs. This may have reduced the effectiveness of nelfinavir and indinavir in this group (abstract 422).

Better results were seen among 36 people who switched to indinavir/nevirapine/3TC plus either AZT or d4T, having failed after less than one year of saquinavir treatment. All had a viral load of at least 100,000 copies when they switched. 31 achieved viral load below 400 copies/ml after 24 weeks (abstract 428).

>>`Recycled' & unlicensed options

If you have already used most or all of the licensed anti-HIV drugs, your treatment choices may be limited to two options:

- `recycling` drugs you have taken before - using currently unlicensed drugs

There are few data on the effectiveness of `recycling'. In one report in Chicago, 12 people who had previously taken all the NRTIs and three PIs started a six-drug combination of two new drugs - nelfinavir and nevirapine - plus `recycled' d4T/3TC/ddI/saquinavir. After 12 weeks, nine of the twelve participants had viral load below 400 copies/ml. However, the practicalities of such intensive regimens, including side-effects, compliance, drug interactions and so on, mean that their long-term usefulness remains in doubt.

There is no firm evidence yet of the value of any currently unlicensed drugs in salvage therapy. The table opposite examines how cross-resistance to current treatments might affect drugs in advanced development.

>>Resistance tests

Several presentations at the conference suggested that in future new tests for drug resistance may have a role in guiding treatment choices. For example, saquinavir-experienced people who had a specific resistance mutation (known as a codon 90 mutation) were less likely to respond to subsequent treatment with nelfinavir (abstract 422).

However, these tests also have major shortcomings. In particular, they may only be accurate at detecting whether or not HIV has developed resistance to the drugs that you are currently taking, rather than any drugs you have taken in the past. Even then, they are difficult to interpret, and may not detect low levels of resistance.

>>Box: Better responses to prompt switches?

Several studies have suggested that it may be important to identify PI failure promptly and to switch to a new regimen as soon as possible, to maximise your chances of benefit from a second PI.

Resistance to PIs is usually associated with the gradual appearance of mutations in HIV protease, one after the other. The longer you remain on a PI to which resistance is developing, the greater the number of mutations you may accumulate.

An Australian study of people who had failed on saquinavir suggested that people who had developed more than one resistance mutation were less likely to respond to a second PI than people who had developed only one mutation. This implies that switching from saquinavir at the first sign of viral rebound may offer the best chance of benefiting from a salvage regimen (abstract 396).

In practical terms, this means it may be important to have frequent viral load tests, even if your viral load has been `undetectable' for many months, and to get the test results back as quickly as possible.

Table: Unlicensed drug options for salvage therapy (see print or web version for fully formatted table)

Drug Class Likely impact of cross-resistance Getting it

Abacavir (1592U89) NRTI May be effective against AZT and/or 3TC-resistant HIV. Not effective against HIV that is resistant to multiple NRTIs Named patient basis from Glaxo Wellcome (probably from April)

Adefovir Nucleotide May be effective against most types of resistant HIV. Also active against CMV Available via the ADHOC trial (see issue 58)

Delavirdine NNRTI Ineffective against NNRTI-resistant HIV Named patient basis from Pharmacia & Upjohn

Efavirenz (DMP-266) NNRTI Effective against some, but not all, delavirdine and nevirapine-resistant strains Named patient basis from DuPont-Pharma

Nelfinavir PI Potentially cross-resistant to other protease inhibitors Named patient basis from Roche (see page 7)

Saquinavir (soft gel) PI Potentially cross-resistant to other PIs. Ineffective against HIV that is resistant to saquinavir in its current formulation Named patient basis from Roche (see page 7)

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