AIDS Treatment Update, Issue 58, October 1997
Edward King

There was early optimism that people who developed resistance to saquinavir might still have a good chance of responding to a second protease inhibitor. However, this is gradually being replaced by a more pessimistic view that many people who have failed on one protease inhibitor may be less likely to experience a good and lasting response to a subsequent protease inhibitor.

The upshot has been that fewer clinicians now recommend saquinavir to people who are considering which protease inhibitor to take first. When first-line saquinavir is prescribed, it is increasingly given in combination with ritonavir which increases saquinavir levels in the body to a very large extent (but variably from person-to-person).

However, many people with HIV are already taking saquinavir - some surveys suggest that it is the most widely used protease inhibitor in the UK - and for these individuals the issues are somewhat different than for people who are deciding whether to start taking the drug. We asked several British clinicians to explain what factors individuals should consider when deciding whether to stay on saquinavir or to switch to a different regimen. We also report on the improved `soft gel' formulation of saquinavir, likely to be licensed in the USA this month.

>>Singling out saquinavir?

As we reported in issue 56/57, saquinavir has been singled out for criticism by many (but not all) doctors and activists, and by the recent US draft treatment guidelines, as the least suitable choice of protease inhibitor to use first.

However, the doctors we interviewed did not believe that saquinavir should be viewed any differently from the other protease inhibitors when assessing how well someone is responding to treatment. "I can see no need for special rules for patients taking saquinavir. Therapy decisions should be guided by the same principles as for any other protease inhibitor," said Professor Tony Pinching of St Bartholomew's Hospital.

The first such principle is that there is no need to change a regimen that is working successfully.

Much of the concern over saquinavir has been based on comparisons between different trials of protease inhibitors. These suggest that a smaller proportion of people taking saquinavir-based combinations achieve viral load reductions to below the limit of detection, compared with people taking combinations that include indinavir, ritonavir or nelfinavir.

However, some people do achieve undetectable viral load with saquinavir; in a study presented at the ICAAC conference in Toronto last month, 43% of previously untreated people taking the current formulation of saquinavir plus AZT and 3TC for 16 weeks achieved viral load below 400 copies/ml. Before they started treatment, these people had average CD4 count of 401 and an average viral load of 63,000.

Our respondents argued that there was no need for someone who is experiencing a good response to saquinavir (or any other protease inhibitor) to change therapy. HIV is unlikely to develop resistance to saquinavir while its replication is being kept at very low levels.

However, Dr Graeme Moyle of the Chelsea & Westminster Hospital suggested that it might be prudent for such individuals to have more frequent measurements of viral load - such as every two months - to enable therapy to be changed very promptly should their viral load start to increase.

>>Detectable viral load

But what should people do if their viral load remains at detectable levels despite several months of treatment while they are taking a saquinavir-based combination? Likewise, what is the best course of action for people who do achieve `undetectable' viral load after starting a new regimen, but who later find that their viral load bounces back up above the limit of detection?

The doctors we consulted had different perspectives on these questions, but they each said that their advice to people taking saquinavir would be the same as for people taking one of the other protease inhibitors.

While maintaining viral load below the limit of detection is accepted as the most desirable outcome, some doctors argue that having higher viral load despite therapy should not automatically be seen as grounds for changing treatment.

"If you're not achieving suppression to below detection, you might decide to try switching to a new regimen. That's an understandable response, but it's not the only choice", said Professor Pinching. "You might decide to hang in and see if your viral load is stable, or if there is a trend for it to be rising. There's a danger that people end up agonising unnecessarily about their test results when in fact they are experiencing very good responses to therapy, and the priority should be to allow them to get back to normal life."

Dr Moyle, on the other hand, proposed that anyone who has detectable viral load while taking a protease inhibitor reliably (i.e. not missing doses) should promptly modify their therapy, in order to minimise the risk of developing r esistance.

>>Switching options

If you do decide to modify your therapy, there are two options: to switch to a new regimen containing a different protease inhibitor, or to intensify your current regimen. Saquinavir levels can be boosted by taking it with cheap grapefruit juice (see Drugs and your diet), with ketoconazole, with ritonavir or with nelfinavir.

Dr Moyle recommended treatment intensification by continuing on saquinavir, and adding ritonavir. The main rationale for using this combination is the substantial increase in saquinavir levels caused by its interaction with ritonavir. "Since you're getting up to forty times the exposure to saquinavir compared with the standard dose, that may be enough to overcome any HIV strains that have already developed low level resistance to saquinavir."

The standard advice when modifying therapy is to change more than one drug. However, Dr Moyle suggests that "If your viral load is still only very low, such as a few thousand copies/ml, you can probably get away with intensifying your treatment just by adding ritonavir. But if your viral load is higher I would change one of your reverse transcript-ase inhibitor drugs at the same time."

When prescribing saquinavir and ritonavir together, Dr Moyle gives 400 mg of each drug twice daily, which have now been taken by 120 people for over a year in one trial. (The standard doses when not used together are 600 mg twice daily for ritonavir, and 600 mg three times daily for saquinavir.) It may also be less important to take saquinavir with food to improve its absorption; taking it within two hours of a meal may suffice.

>>Is it safe to boost saquinavir?

Professor Pinching noted that saquinavir levels can be boosted about 5- to 10-fold by taking it with the anti-fungal ketoconazole, but he expressed concern about how little is known about the safety of the saquinavir/ritonavir combination. "I think we find ourselves in uncharted waters on toxicity when we boost saquinavir levels so dramatically. We don't know how safe it is to be exposed to high levels of saquinavir, and the extent of the increase is also very variable from patient to patient. If people have active viral replication and have already developed low level resistance to saquinavir, I'm worried that by only increasing their saquinavir levels we may simply accentuate the selection of the resistant virus." He argues that people who are not happy with their response on saquinavir might be better advised to switch to a new regimen containing a different protease inhibitor, rather than adding ritonavir.

Professor Jonathan Weber of St Mary's Hospital was less concerned about the safety of high-dose saquinavir. He pointed out that animals have been given enormous doses of saquinavir without any significant side-effects, and one of his patients who took a massive saquinavir overdose during an early trial also noticed no adverse effects.

Professor Weber added that research among people with extensive saquinavir treatment at St Mary's, also presented at last month's ICAAC conference, has suggested a way of identifying who will respond well to adding ritonavir. It involves using experimental resistance tests to look for one of the characteristic HIV mutations that are associated with resistance to saquinavir. "We have found that people who have not developed the resistance mutation at codon L90M seem to respond quite well if you add ritonavir. It's possible that their lack of response and their lack of resistance to saquinavir are because they weren't absorbing it, and if you boost the levels with ritonavir they'll do well. But if that resistance mutation is present, you only get a transient response to adding ritonavir. In those cases it might be better to switch to a different regimen, perhaps using nevirapine or nelfinavir."

Nelfinavir is currently available through Roche on a named patient basis, in which people who have failed to respond to, or who are intolerant of, the licensed protease inhibitors receive priority. However, last month the scheme was expanded and now nelfinavir will also be supplied for people whose viral load responses to saquinavir have been less than expected, regardless of whether they have yet tried indinavir or ritonavir. In test-tube studies, nelfinavir boosts levels of saquinavir, although to a lesser extent than ritonavir.

>>A role for delavirdine?

The NNRTI drug delavirdine has also been reported to boost saquinavir levels by approximately five-fold when used in combination. It may offer another option for intensifying a saquinavir-based regimen.

Like nevirapine, delavirdine is not yet licensed in Europe. Both drugs are available through expanded access schemes run by their their manufacturers.

>>Key conclusions

- Decide whether to stay on or switch from saquinavir-based combinations for the same reasons as for other protease inhibitors

- Some doctors recommend modifying therapy if you do not achieve or cannot sustain undetectable viral load

- If you do change therapy, the options are to switch to a different protease inhibitor-based regimen, or to stay on saquinavir and intensify the effects, usually by adding ritonavir

- Try to change to at least two new drugs, unless your viral load is very low

BOX - Europe faces wait for Fortovase

Saquinavir's manufacturer, Roche, hopes that the improved version of the drug, known as the `soft gel' formulation or Fortovase, will be approved for prescribing in the USA this month. Studies have shown that Fortovase is better absorbed, resulting in nine-fold higher levels of saquinavir in the blood compared with the same dose of the current Invirase formulation. The first trial results, released last month, suggest that triple therapy including Fortovase leads to reductions in viral load that are comparable to rival protease inhibitors - after 12 weeks of therapy, 77% of recipients had viral load below 400, and 23% had viral load below 40.

However, Fortovase is unlikely to be widely available in Europe for many months. Full approval may not be gained until as late as June 1998, since the authorities are reportedly treating Fortovase as if it were an entirely new drug, rather than a new form of saquinavir.

However, supplies of Fortovase may be made available to people currently taking Invirase earlier in 1998. Roche is currently drawing up guidelines on how people who are taking Invirase should be switched to Fortovase. They are likely to suggest that people who have undetectable viral load can simply switch from the old formulation to the new, and that people with low but detectable viral load should change another of their drugs at the same time.

People currently taking Invirase whose viral load is higher are likely to be advised to switch to an alternative regimen that includes saquinavir/ritonavir, or that doesn't include saquinavir at all. Fortovase will not be recommended for people who have failed on saquinavir in the past because such individuals may already have developed HIV strains that are resistant to saquinavir, and these strains will also be resistant to the new formulation.

Studies are testing Fortovase either as a twice- or three times daily drug. It has caused few side-effects in early trials; it may therefore be an attractive new combination component for people who have achieved undetectable viral load using a more difficult combination and want to see whether they can sustain their viral load response with an easier regimen.

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