AIDS TREATMENT UPDATE, Issue 39, March 1996
Edward King

CLINICAL BENEFITS

The most striking study focused on ritonavir, the protease inhibitor made by Abbott under the new trade-name Norvir. The international trial enrolled 1090 people with CD4 counts below 100 who had taken other anti-HIV drugs for at least nine months. They were allowed to continue taking whatever anti-HIV regimen they were currently taking, if any; 18% were not taking any anti-HIV drugs. They were then randomly allocated to add either ritonavir (600 mg twice daily) or an inactive placebo for one year. However, people who had been in the trial for four months and developed an AIDS-defining event were allowed to receive ritonavir on an open basis.

After participants had received an average of only six months of treatment, the trial was stopped when a pre-planned analysis showed that ritonavir approximately halved the risk of disease progression or death. The death-rate among treated people was 4.8%, compared with 8.4% among placebo recipients. The combined risk of developing a new AIDS condition or dying was 15.7% in the ritonavir group, and 33.1% in the placebo group.

17% of people assigned to ritonavir stopped taking it because of side-effects; the commonest were nausea, vomiting and diarrhoea. 6% of the placebo arm dropped out because of perceived side-effects. It is also important to note that ritonavir can have extremely serious interactions with other drugs commonly used by people with HIV.

A distinctive factor about this trial was the low average CD4 count of participants, which was about 20. People with CD4 counts below 50 are often excluded from clinical trials; this study clearly establishes that they may benefit substantially from anti-HIV treatment.

This is the first trial to show clinical benefits from a protease inhibitor; all previous studies have used surrogate markers such as increases in recipients' CD4 counts and decreases in their viral load. The results are expected to secure US approval for ritonavir at the end of February. The European Medicines Evaluation Agency (EMEA) has told French activists that it expects to receive Abbott's formal application for approval in Europe at the end of February, and that this is likely to be agreed within 60 to 90 days.

Several UK clinics originally planned to enrol patients in ritonavir trials. However, the Medicines Control Agency (MCA) did not allow the trials to proceed; it wanted more information on the drug's effects in animals than was required by any other country, leading Abbott to drop the UK centres. An expanded access scheme to provide ritonavir to 80 people with advanced HIV infection in the UK has been designed for months, but is also on hold pending MCA approval.

TRIPLE COMBINATIONS

Two research teams reported promising short-term results from small trials using three drug combination regimens. One study based on Merck's protease inhibitor indinavir (also known as Crixivan) enrolled nearly 100 people with CD4 counts between 50 and 400 and relatively high viral load (over 20,000 copies/ml) who had received AZT for at least 6 months. They were treated with either: - indinavir alone, or - AZT and 3TC, or - AZT, 3TC and indinavir

The greatest decreases in viral load were seen in the triple combination arm. The interim results showed that after 12 weeks of treatment, HIV levels had fallen so low as to be undetectable (by the test used) in 8% of the AZT/3TC arm, 41% of the indinavir monotherapy arm, and 88% of the triple combination arm. At the time of reporting, only a small proportion of trial participants had received 24 weeks of treatment; however, among them none of the AZT/3TC group but 44% of the indinavir monotherapy group and 86% of the triple combination group still had unmeasurable viral load. For a discussion of the meaning of 'undetectable' viral load, see the front-page article in this issue.

Another trial enrolled 78 people with CD4 counts below 500, viral load above 20,000 copies/ml and no prior use of AZT. The treatment arms were the same as above, except that ddI was given in place of 3TC. The preliminary results showed that after 24 weeks of treatment, 59% of the triple combination arm had undetectable viral load levels, compared with only 15 to 20% of the other two arms. In this study 10 of the 52 people assigned to receive ddI stopped taking it because of side-effects.

A third triple combination study tested Abbott's ritonavir with AZT and ddC. Only 29 previously untreated people with advanced HIV infection were given the combination. After 6 months of treatment their average CD4 count had increased from 156 to 303, and their viral load had decreased about 2 logs, or 99%.

CONCERNS

The indinavir trial results are thought likely to lead to the drug's accelerated approval in the USA in late February. In Europe, Merck may be required to produce more clear-cut evidence of the drug's benefits, such as information on its effects on symptoms or survival, before it is made available for prescription. A 30-person expanded access scheme is now fully enrolled at three British clinics.

While these results are promising, some activists and researchers have serious concerns about these triple combination regimens. First, the trials have all involved small numbers of people, which limits their reliability. Secondly, the results to date have been very short-term, reflecting the period when the regimens are likely to to be most effective.

Thirdly, no-one yet knows whether the development of drug-resistant HIV strains will block the effectiveness of the drugs. With other combination therapy regimens, multi-drug resistant strains of HIV have emerged over time. The problem of cross-resistance means that people who become resistant to one drug may find themselves unable to benefit from a number of related drugs that they have not yet taken, limiting their future treatment options. If people taking AZT, ddC and indinavir do develop HIV that is simultaneously resistant to all three drugs, that virus may well be cross-resistant to stavudine (d4T), ddC, ddI, ritonavir, saquinavir and AG1343.

However, Merck scientists point out that HIV has to develop at least four different mutations before it is significantly resistant to indinavir. They argue that if viral load can be reduced quickly and substantially by starting treatment with a multi-drug combination, the pool of HIV that remains in the blood will be relatively small, making it less likely that the resistance mutations can emerge.

TRIAL OPTIONS

Two London clinics are planning to participate in an international trial testing Agouron's protease inhibitor AG1343 (now renamed nelfinavir or Viracept) in combination with AZT and 3TC. The one-year study is the third phase of the AVANTI trial, described in AIDS Treatment Update issue 33. To be eligible you must have a CD4 count between 150 and 500 and not have taken anti-HIV drugs before.

In Washington, Agouron told community groups that Phase II trials of nelfinavir had produced promising anti-HIV effects at the higher doses tested. A small pilot study of the combination of stavudine (d4T) and nelfinavir also produced marked reductions in viral load.

REFERENCES

The abstract numbers for these studies are: LB 6 (ritonavir ); LB7 (AZT, 3TC & indinavir ); 200 (AZT, ddI & indinavir); 285 (AZT, ddC & ritonavir)

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