AIDS Treatment Update, Issue 60, December 1997
Edward King

**Updated recommendations

The US guidelines continue to recommend the `hit early, hit hard' approach to anti-HIV therapy. They advise that anyone with a viral load greater than 10,000-20,000 should consider starting therapy, and that treatment should consist of two NRTI drugs (AZT/ddI, AZT/3TC, d4T/ddI or d4T/3TC) plus a potent protease inhibitor (indinavir, ritonavir or nelfinavir). As reported in AIDS Treatment Update issue 56/57, many British doctors are concerned that this may be an over-aggressive approach to therapy which may lead some people to use up their available treatment options too rapidly.

The changes to the draft guidelines reflect new information that has accumulated since the first draft was published in June 1997. For example, the combination of ritonavir/saquinavir, in combination with two NRTIs, is now also recommended as a possible first-line regimen, although the guidelines advise that not enough is yet known about the safety of this combination.

As before, the draft guidelines recommend that the aim of treatment should be to reduce viral load to below 500 copies/ml (the limit of detection of the most widely used viral load tests), and that a change in treatment should be considered if viral load remains above 500 at 4-6 months after starting treatment. More recently, an `ultra-sensitive' viral load test that can measure as low as 50 copies/ml has become available through some laboratories. One study has suggested that the effects of treatment may be longer-lasting if viral load is suppressed below 50 (see AIDS Treatment Update issue 59). However, the updated guidelines argue that not enough is known to base treatment decisions on the `ultra-sensitive' test, since the results may be very variable.

The information on changing therapy has also been updated. As reported in AIDS Treatment Update issue 59, recent studies have demonstrated that only a minority of people taking two NRTIs alone will achieve and sustain viral load below the limit of detection. For those who do achieve undetectable viral load on two NRTIs, the new draft suggests that they should nevertheless consider switching to a more aggressive regimen, since this may reduce the risk of their viral load rebounding to detectable levels.

The new draft sounds a gloomy note on the treatment options for people who experience a rising viral load despite treatment with a combination that includes a protease inhibitor (PI). The document notes that "It appears that viral strains that become resistant to one PI will have reduced susceptibility to most or all other PIs", because of cross-resistance. Even switching to a entirely new triple combination of two new NRTIs plus a new PI may offer only a "limited likelihood of success". To increase the chances of success, the panel say that "many experts would include 2 new PIs in the subsequent regimen".

**Estimates of disease progression

In issue 56/57, we published a table showing the estimated risk of disease progression among untreated people, depending on their viral load and CD4 count.

The US guidelines have now updated these estimates in the light of new evidence which suggests that the previous viral load levels may have been over-estimated in the statistical analysis.

The latest figures are shown in the table below. They now estimate that at any given viral load level, the risk of developing AIDS within three years may be higher than was previously believed.

TABLE: % OF PEOPLE WHO DEVELOP AIDS WITHIN 3 YEARS (ASSUMING NO TREATMENT) (for fully formatted table, see text or web edition) Viral load CD4 count Below 200 201-305 351-500 501-750 Above-750 Roche test Chiron test Below 200 Below 1,500 Below 500 ** ** ** 3.7 0 1,500-7,000 500-3,000 ** ** 2.0 2.0 2.0 7,000-20,000 3,000-10,000 ** 8.1 8.1 8.1 3.2 20,000-55,000 10,000-30,000 40.1 40.1 16.1 16.1 9.5 Above 55,000 Above 30,000 85.5 64.4 42.9 32.6 32.6

** indicates lack of data.

**Guidelines debate continues

Differing approaches to treatment were discussed at the TAT forum last month, with presentations from Dr Gabriel Torres from St Vincent's Hospital in New York, who was a member of the panel that drew up the US guidelines, and Professor Brian Gazzard, chair of the British HIV Association (BHIVA).

Dr Torres noted that the new draft had been modified to include a fuller discussion of the pros and cons of aggressive therapy. He pointed out that the new viral load predictions suggest that even among individuals with normal CD4 counts (above 750), almost 10% are likely to develop AIDS within three years if their viral load is between 20,000 and 55,000, and nearly a third of those whose viral load is greater than 55,000. "Some would say this risk is enough to warrant therapy despite the high CD4 count".

However, he acknowledged that starting treatment also involves risks, including a reduction in quality of life because of side-effects or the inconvenience of treatment regimens, and encouraging the evolution of drug-resistant HIV strains.

He also noted that there remains huge uncertainties about effective `salvage' treatment options for people whose initial therapy fails. "The weakest point of the guidelines is the advice on salvage therapy for people who are failing on a PI-containing regimen", said Dr Torres. "There are many possible options, but none has been adequately addressed in clinical trials".

Professor Gazzard suggested that treatment guidelines have "very limited usefulness; we mustn't believe that we know any more than we did before, just because a group of like-minded people have drawn up a document". He stressed that people with HIV should always discuss their personal treatment strategies with their doctor, "rather than going by someone else's off-the-shelf recipe".

He argued that it is just as reasonable to base treatment decisions on your CD4 count, rather than putting the emphasis on viral load: "People die because their immune system is destroyed - the immune system is the crucial thing". That might mean delaying treatment if your CD4 count is still relatively high, "and not taking too much notice of viral load". He argued that the benefits of early anti-HIV therapy remain "largely theoretical. The evidence that you'll suffer irreversible immune damage if you don't treat early is absolutely not there."

Professor Gazzard accepted that when people do decide to start treatment, "dual therapy is no longer a popular first-line option and can rarely be recommended". However, he argues that it may be wiser to start treatment with two NRTIs plus an NNRTI such as nevirapine, rather than using a protease inhibitor as the third drug. "If you start with an NNRTI you still have very powerful drugs to use later, but if you start on indinavir and develop resistance, there's nothing left that's proven effective".

**References

The latest draft of the guidelines can be read on the Internet at http://www.healthcg.com/hiv/nihreport/guide/

A summary of the major changes is available at http://www.miningco.com/library/weekly/aa111697.htm

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