AIDS TREATMENT UPDATE, Issue 37, January 1996
Edward King

The two liposome-encapsulated chemotherapy drugs used to treat Kaposi's sarcoma are gaining international approval.

Liposomal doxorubicin (Doxil or DOX-SL) was licensed in the USA in late November for the treatment of people with KS that has progressed despite prior combination chemotherapy, or who cannot tolerate the side-effects of standard treatment. However, its manufacturer is expected to apply for it also to be approved for initial treatment of advanced KS, after the results of an American trial reported in early December found that it was at least as effective as standard combination chemotherapy regimes.

At present, doctors in the UK can obtain liposomal doxorubicin on a named patient basis. European drug regulators are due to consider approving it in February 1996.

Liposomal daunorubicin (DaunoXome) was approved in the UK in late October 1995 to be used as the initial treatment of advanced KS. An American trial found that it was as effective as standard treatment with a combination of chemotherapy drugs, but caused significantly fewer side-effects. The options for treating mild-to-moderate KS (such as isolated lesions on the skin) remain as described in AIDS Treatment Update issue 34, such as radiotherapy, cryotherapy or intra-lesional chemotherapy.

NeXtar, makers of liposomal daunorubicin, say that they are developing a liposomal form of the anti-CMV drug foscarnet.

* Nevirapine trial

A new trial is planned to test the clinical effects of combination therapy using nevirapine with 3TC among people already taking nucleoside analogue anti-HIV therapy.

Participants must have CD4 counts below 200 and already be taking nucleoside therapy, although they must not be taking protease inhibitors. They will be divided into two groups. One group will receive nevirapine plus 3TC in addition to their nucleoside therapy. The other will take placebo plus 3TC in addition to their nucleoside therapy.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has shown good anti-HIV effects, despite the fact that resistance can occur quickly. Trial participants must not have taken this or another NNRTI before.

Participants will receive treatment for 18 months. The trial is designed to be able to detect a difference in the effect of the treatment regimes on disease progression and survival. The following UK clinics plan to take part, and recruitment is expected to begin in February:

- Claude Nichol Centre, Brighton Dr Fiona Clarke (01273 664721)

- King's College Hospital, London Dr Anton Pozniak (0171-346 3453)

- Kobler Centre, London Dr Mike Youle (0181-746 5594)

- Mortimer Market Centre, London Dr Ian Williams (0171-380 9660)

- Royal Free Hospital, London Deborah Farmer (0171-794 0500)

- St Bartholomew's Hospital, London Dr Lynn Riddell (0171-601 7738)

- St Mary's Hospital, London Jo Kepple (0171-725 6738)

* Saquinavir licensed

Saquinavir has become the first protease inhibitor to be approved anywhere in the world, after the US Food and Drug Administration granted it a licence in early December. It will be marketed under the tradename Invirase for use in combination with nucleoside analogue anti-HIV drugs such as AZT. The decision follows the recommendation of the FDA's Anti-viral Drugs Advisory Committee (see AIDS Treatment Update issue 36).

In the European Union, a decision on licensing the drug is not expected before late summer 1996 at the earliest. In the meantime, a clinical trial testing combination therapy regimes containing saquinavir is still recruiting at several clinics around the country. To be eligible, you must have a CD4 count between 50 and 350 and have taken little or no prior anti-HIV treatment.

The drug's manufacturer, Roche, is also running an expanded access scheme to provide saquinavir to people who have exhausted currently licensed treatments. For details, see AIDS Treatment Update issue 35.

* Ritonavir results

The results of a placebo-controlled trial of the protease inhibitor ritonavir, made by Abbott, were formally published in the New England Journal of Medicine. The findings had previously been reported at conferences, and in AIDS Treatment Update issue 24/25. The trial found that for the first four weeks of treatment, people with CD4 counts above 50 who took one of four doses of ritonavir had similar increases in CD4 count and falls in viral load. However, sustained anti-HIV effects lasting over 4 months were seen only in the group receiving the highest dose of 1200 mg/day. After 32 weeks of treatment, these seven participants had an average CD4 count increase of 230 and an average reduction in viral load of 0.81 log. Side-effects included nausea, numbness or tingling around the mouth and liver abnormalities.

Subsequent trials, already reported at conferences, have reported greater and more prolonged effects when ritonavir is taken as part of combination therapy regimes, rather than as monotherapy.

On 21st December, Abbott announced that it has formally applied for ritonavir to be licensed for prescription in the USA.

* New protease trial

The Kobler Centre and St Mary's Hospital in London are to run one of the first trials of a new protease inhibitor called KNI-272. The drug, made by Japan Energy Corporation, has shown anti-HIV effects against a range of virus strains in test-tube studies.

Pilot studies among people with HIV found that they developed liver abnormalities when started on the dose of the drug needed for it to be effective in the body. This trial is using a new formulation of the drug, and will test whether this side-effect is avoided if people start on a lower dose and gradually increase the dose over time. People who experience a substantial fall in viral load without serious side-effects after 12 weeks of treatment will be able to remain on the drug.

30 participants will be recruited. For more information contact the trial centres.

* PENTA changes

Researchers involved in the PENTA paediatric anti-HIV drug trials have reviewed the studies in the light of the results of Delta.

PENTA 1 has enrolled almost 200 children, testing the effects of AZT monotherapy taken early or only after symptoms develop. Since Delta showed that two drug combinations are better than Azt alone, all children in the study will be told whether they were receiving Azt or placebo, and offered the opportunity to change their treatment regime. Last October, the Data and Safety Monitoring Committee reviewed the data from the study and found no clear difference in benefit for children treated early as opposed to late.

PENTA 3 has enrolled 33 children who have just started anti-HIV treatment, and is studying the safety of the combination of AZT plus ddC, compared with that of AZT. All children will now be offered the combination.

PENTA 4 is the latest trial, for children who have already been taking AZT, ddI or both drugs for at least 3 months and are stable on their therapy. It is examining whether children who are also given 3TC as well as their current treatment suffer more side-effects than those who do not take 3TC. Recruitment began in November.

9601
ATU3704

Copyright © 1996 - AIDS Treatment Update. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used. Subscription lists are kept confidential. NAM Publications 16a Clapham Common Southside, London, England SW4 7AB; TEL: 01-71-627-3200 (from outside the UK: +44-171-627-3200); FAX: 01-71-627-3101 (from outside the UK: +44=171-627-3101)  info@nam.org.uk  http://www.nam.org.uk