AIDS TREATMENT UPDATE, December 1995
Raffi Babakhanian

The FDA's decisions only affect the USA. In Europe, these drugs remain available only through clinical trials or expanded access schemes. Experts predict that 3TC may be licensed in April 1996, and saquinavir in September 1996.

* 3TC

3TC, made by Glaxo-Wellcome, was approved for use in combination with AZT for adults and children, both those with advanced HIV disease and as first-line therapy for all HIV-positive people who are starting treatment. It will be marketed under the tradename Epivir. However activists, doctors and statisticians all expressed serious concerns about the lack of clear information on how and when to use this combination.

The results of paediatric clinical trials presented at the meeting showed that around 15% of the children developed pancreatitis while on 3TC. In adults with similarly advanced HIV disease, pancreatitis was not a major problem. This relatively high risk was not matched by any clear benefit of taking 3TC. The average CD4 count increase was only 4 for children who had not taken anti-HIV drugs before, and there was an actual decrease in CD4 count for the drug-experienced children.

There were also concerns expressed about the risk of cross-resistance between 3TC and ddI or ddC. Most people who take 3TC quickly develop two mutations against 3TC in their HIV. In test-tube studies one of these re-sensitises the virus to AZT, but the other is thought to cause cross-resistance to ddI and ddC. That could mean that once one takes 3TC, subsequent use of ddI or ddC may be of little benefit. For this reason Dr Douglas Mayers of the Walter Reed Hospital in Maryland raised concerns about licensing AZT and 3TC as first-line therapy against HIV, suggesting that it might be better for people to try the combination of AZT plus ddI or ddC first, and only switch to AZT plus 3TC when those therapies failed.

In order for an anti-HIV drug to receive accelerated approval in the USA, studies must show that it has a clear benefit over existing therapies on what are called surrogate markers (the level of virus, known as viral load, and the number of CD4 cells in the circulating blood). A drug company must also show that it has a larger trial under way to test whether the drug also shows any clinical benefits i.e. whether people develop fewer opportunistic infection or whether they live longer by taking the drug. These are called confirmatory trials. The committee's statistician, Dr Laurence Freedman, expressed concern that in the case of 3TC there is no confirmatory trial for HIV-positive people with CD4 counts above 250, although the drug has been recommended for approval for all HIV-positive people who are starting anti-HIV therapy. Without such a trial, no-one will ever know people with CD4 counts above 250 derive clinical benefits from taking AZT plus 3TC.

* Saquinavir

Saquinavir, the first protease inhibitor to seek approval anywhere, was recommended for approval in combination with AZT for people who had advanced HIV disease. It was not recommended for use as monotherapy for people who had failed all other therapies.

The hearings on saquinavir revealed two main concerns: the choice of dose, and the development of HIV strains that are resistant to saquinavir. The FDA revealed that Roche had carried out their initial dose-ranging studies of saquinavir in an unusual way. Normally when a drug is first approved for experimental use in humans, a study is done to determine the highest dose that is non-toxic. In the case of saquinavir, Roche decided to use the lowest dose that showed signs of efficacy - namely 1800 mg/day. The FDA recommended that Roche do more research to determine whether higher doses were non-toxic and had greater anti-HIV effects, but the company decided not to carry out those studies, citing difficulties with making adequate supplies of the drug for clinical trials.

More recent research has focused on a dose of 7200 mg/day - four times the current dose. There were problems with this higher dose; it translates into 36 capsules per day which must always be taken on a full stomach, and it caused mild diarrhoea. But it had two main advantages over the 1800 mg/day dose: viral load dropped much more and resistance to saquinavir took longer to emerge, meaning that the drug was effective for a longer period of time. Taking saquinavir in combination with AZT and/or ddC also reduces the chance that HIV strains that are resistant to saquinavir will emerge.

Roche acknowledges that higher doses are more effective and is developing a new higher-dose form of saquinavir, but this may not be approved for another two years. People who take the current, lower dose of saquinavir may experience a smaller benefit for a shorter period of time than someone taking the higher doses. Switching later to a higher dose may be of no benefit.

Another worrying possibility is that people who develop resistance to saquinavir may be less able to benefit from the next two protease inhibitors, Abbott's ritonavir and Merck's indinavir. Research suggests that these drugs are the most powerful anti-HIV treatments seen so far, with relatively few side-effects. Roche has presented data suggesting that HIV that is resistant to saquinavir remains susceptible to other protease inhibitors, but other researchers, including scientists at Merck, remain concerned that cross-resistance could occur. Some speakers at the FDA hearings recommended that saquinavir should not be approved until further studies of cross-resistance had been completed. These studies could be done relatively quickly, but would require inter-company co-operation which has so far not occurred.

Many activists (including this writer) expressed concerns about licensing the sub-optimal dose, and several suggested that the drug's label should carry strong warnings about the possibility of cross-resistance to other protease inhibitors. But because the drug causes few side-effects and shows some benefit, and because many people in the USA have already exhausted the usefulness of other approved drugs, most activists strongly recommended the approval of saquinavir. However, European drug approval agencies have traditionally been more cautious in approving anti-HIV drugs, and it is uncertain whether they will approve the current dose. These concerns about using saquinavir at its current dose should make people with HIV think carefully before taking it. If they have no other treatment options left, the possible benefits from taking saquinavir probably outweigh the risks. But the risks of more rapid development of resistance and cross-resistance to future protease inhibitors, and the fact that people who have already taken saquinavir are likely to be excluded from many future trials of other protease inhibitors, need to be carefully considered before people with relatively high or stable CD4 counts decide to take saquinavir.

* Saquinavir UK extended access scheme

A scheme is now under way to provide saquinavir to selected people in the UK who are no longer benefitting from or can no longer tolerate approved anti-HIV treatments. Over 60 clinics have asked Roche for details of how to join the program. People who are currently receiving 3TC through Glaxo-Wellcome's expanded access scheme are likely to be eligible to add saquinavir to their existing regimen.

Although in principle people at any CD4 count are eligible for the scheme, Roche has advised doctors to prioritise people with CD4 counts below 100, since they are in the greatent need of new treatment options. People with higher CD4 counts may be better advised to wait until higher doses of saquinavir or trials of saquinavir in combination with other drugs become available.

* Stavudine

The committee also recommended that stavudine, a drug which has been available through accelerated approval in the USA since June 1994, be given full approval for people who have been on AZT for two years or more. Stavudine, also known as d4T, is made by Bristol-Myers Squibb under the tradename Zerit.

Stavudine initially received accelerated approval in the USA after the preliminary results of a trial showed that AZT-experienced people had increases in their CD4 count if they switched to stavudine. Earlier this year, Bristol-Myers released the full results of this trial, showing that switching to stavudine provided a three-month delay in the risk of developing a new AIDS-defining disease or dying. But at the meeting the FDA presented a re-analysis of the trial results in which they found that the margin of error was larger than had previously been reported. This meant that the apparent benefits of stavudine in reducing the risk of disease progression and survival were not statistically significant i.e. they could have been due to chance.

Some clear information did emerge. Stavudine was much better tolerated by the study participants than AZT. People taking stavudine were able to continue on the drug for an average of 79 weeks, whereas people taking AZT were only able to continue for an average of 53 weeks. There was also some evidence that people who had already been diagnosed with AIDS when they entered the study seemed to progress slightly slower on stavudine than on AZT.

The committee was unable to consider approving stavudine for any other group of HIV-positive people because no other trial results are available. Many activists and doctors in the USA feel that stavudine may be useful as first-line therapy in combination with other drugs such as 3TC, and several doctors reported that they were already using it in that way.

Stavudine is not yet approved in any European country, and it is unlikely that it will gain approval based on the data that was presented to the FDA. However the drug is widely available in Europe through an expanded access scheme. The company outlined its plans for the future development of the drug, which include combination therapy trials and studies at different stages of HIV infection. There is hope that the results of these trials (which are still either in their early stages or are yet to start) will provide a clearer picture of how stavudine can best be used against HIV.

[Raffi Babkhanian was sponsored to attend the FDA Advisory Committee hearings on behalf of the European AIDS Treatment Group by Glaxo-Wellcome and Roche.]

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