UK-CAB 2 – Meeting Report

Report on Second Meeting, Friday 2 Aug 2002

Contents

Members and attendees

Introduction
Genetics, resistance and HIV: Prof Clive Loveday
Approaches to salvage therapy: Dr Mike Youle
BMS: Dr Andrew Clarke

  • Atazanavir
  • DuPont acquisition
  • D4T

Feedback
UK-CAB email list
Next meeting
Appendices:

Members and attendees

Willys Akoko Africa Advocacy Project
Kenneth Amoateng Abibimman Foundation
Joyce Attaro Positively Women
William Babumba African HIV Policy Network (AHPN)
Agnes Baziwe Africa Advocacy Project
Polly Clayden HIV i-Base
Simon Collins HIV i-Base
Richard Day Yorkshire Mesmec
Jenni Fredriksson Information Officer AVERT
Paul Hindley Rainbow Project
Robert James Hat Trick Group/Haemophilia Society
Jim Jewers The Globe Center
Rupert Jones Barnardos Castle Project & THT Yorkshire
Mohamade Jowata Brent PCT
Edith Kaggwa Positively Women
Monica Kizairwe Blackliners
Andrew Lumsden HIV i-Base
Esther Moshinghi Positively Women
Simon Mwendapole Ugandan AIDS Advocacy Foundation (UAAF)
Jo Robinson THT. London
Brian West Solas
Apologies:
Haydn Forde THT Living Well. London
Badru Male Blackliners
Henry Mumbi HIV/AIDS Association of Zambia
Flavia Namutebi Uganda Community Relief Association (UCRA)
Mary Okoth MOAT Consultancy
Ruth Webb UK Coalition
Minutes and reports: Andrew Lumsden and Simon Collins

1. Introduction

Simon Collins and Polly Clayden of HIV i-Base welcomed those attending the second meeting of UK-CAB and Treatment Advocates Network and everyone introduced themselves.

The first UK-CAB meeting (in May) focused on clinical trials – in which HIV-positive people are either asked to take part in as patients, or whose results are likely to affect their treatment. Professor Tim Peto of John Radcliffe Hospital, Oxford, and Douglas Newberry of the Medical Research Council described how to evaluate the value of different studies and Tamm Norbert discussed trials form a patient perspective and gave an overview of current studies at St Marys Hospital.

The second UK-CAB meeting’s morning session turned to the needs of the long-term PWA. Professor Clive Loveday, who was the UK’s first professor of HIV and AIDS (at the Royal Free) – and who has more recently founded the non-profit making International Clinical Virology Centre (ICVC) in Buckinghamshire, gave a presentation on resistance and resistance testing and was followed by Dr Mike Youle on salvage therapy.

2. HIV drug resistance and resistance testing – Professor Clive Loveday

Drug resistance testing has supported therapy for a variety of infectious diseases for many years. Professor Loveday began with the underlying genetics. [See appendix for the slides that accompanied this talk, and for the full transcription]. He stressed that though by June 2000 scientists understood the rough chemical sequence of the human genome or genetic code, carrying all information about the individual in every cell nucleus, “all we have done is made a list. We don’t understand yet the different sections are responsible for.”

The 30-80,000 genes in human carrying all the genetic information represent only about 10% of the total DNA in cells. The other 90% contains non-coding, archived or other DNA. Professor Loveday told the meeting that fragments of retrovirus have been found in this ‘junk DNA’, indicating that the human beings have experienced and overcome HIV-type infections in the past.

Warning that the virus may at any time evolve away from existing assay techniques, requiring fresh starts, he turned to the brief modern history of HIV viral load testing:

  • 1981: first reported cases of AIDS
  • 1986: first antiretroviral drug (AZT) offered to patients
  • 1987: heterosexual spread identified
  • 1989: individual resistance to antiretroviral drugs (AZT) first described
  • 1990: ‘viral load test’ developed (using PCR technology)
  • 1991: ‘resistance test’ first used in clinical care
  • 1993-94: commercial viral load testing available

Professor Loveday recalled a government body (the Medical Research Council) objecting to resistance assays in 1991 on the grounds that “it would be individualising patient care.”

Ques. Why were patients kept on AZT monotherapy for so long, when these first viral load tests showed that it only worked for six months or so?

Resp. We were very clear about our results, but not everyone wanted to listen. Also, the situation then was to either be on AZT or nothing, and people often preferred to be taking something. It took till early 1995 to get assay results published in The Lancet.

Ques. Why was dosing so haphazard, and why so high?

Resp. Dosing of any new drug always is. The early trial of AZT was a drip form in orange juice. Also, it was our longest-surviving patients who got first treatment. This was ethically the right thing to do but it meant that the sickest patients got the very high early doses, and also showed the highest rate of side effects.

Ques. Is there a difference of replication between HIV- I and HIV-2?

Resp. No, although the structure of each virus is very different and many drugs that work against HIV-1 do not work against HIV-2.

Ques. Now that it’s known there can be variations in the virus within each HIV-positive person, how is it possible for resistance tests to pick the majority virus?

Resp. Even with all the different variations, there is less than 1% difference in their genetic structure. The virus is being produced at different rates in different parts of the body and assaying is done by ‘consensus sequencing’, and this ensures we are testing the majority virus.

Professor Loveday then described the different resistance tests: genotype tests look at the structure of the virus and phenotype tests try to grow a sample of the virus in the presence of different quantities of each drug. The slides and transcription of this talk explain this in more detail, and also explain the different was that the results are given to doctors (and patient) and the importance of expert interpretation in understanding the results.

Importantly, if a resistance test shows that you are sensitive to a drug now, this doesn’t mean that you don’t have resistance! Interpreting resistance involves knowing your whole treatment history – which drugs you have taken, for how long, the viral load responses, and the original virus that you were infected with. Each patient should develop a treatment history, with either results form resistance tests, or blood sample being stored for testing later, from every treatment change.

Use of resistance tests in treatment guidelines were reviewed. Controversially, Prof Loveday has always recommended a resistance test before starting treatment for all patients ‘on the basis that this is what I would want for myself… why risk your first treatment failing fo something as simple as this that could be detected right at the start’. He also said that guidelines were generally coming round to this approach.

3. Approaches to salvage therapy – Dr Mike Youle

The second session of the morning, on salvage therapy, was led by Dr Mike Youle, who is Director of HIV Research at the Royal Free Centre for HIV Medicine. He started with a motto:

“There are lots of bad doctors, bad nurses, bad drugs and bad documentation.”

The major determinant of whether you’re successful with your therapy, he said, is how far you reverse these four factors. In many respects, this is the reason that people out of London have the most trouble getting the right treatment.

Patient-support, the sharing of new experiences, is under-utilised in his opinion. He described how the Royal Free has made a video of patients talking to each other about injecting twice-daily with the new T20.

Warning of the trends away from safer sex and dangers of barebacking amongst gay men, Dr Youle emphasised the risks of other sexually transmitted infections – including hepatitis C and syphilis, and that becoming infection with drug-resistant HIV puts you in the same position as people infected in 1986 – as there will be no treatment that will work for you. He speculated that T-20 may be an interesting drug to look at as monotherapy during seroconversion: “Have a shot in your fridge for next time your condom breaks.”

Humorously cautioning “everything I tell you will be wrong in two years!” he emphasised the successes of combination therapy: “we have very few sick patients at the Royal Free now” and almost no-one with KS. Mega ART, or combination antiretroviral therapy with five or more drugs, is “throwing the kitchen sink at the virus”.

Quality of life, too, is being assisted by new drugs coming through that are involving decreasing numbers of pills. (At the first UK-CAB meeting on 31 May the American pharma company Gilead predicted that within five years there won’t be many drugs left that are more than once-daily).

And there is quite a lot of evidence, said Dr Youle, that some drugs may induce replication-deficient viruses which people can live with.

For the assistance of patients with long clinical treatment records “we should be moving towards a historic collection of information on what h as been tried with the individual patient, like a report card, which the patient can keep. Especially why a patient stopped using a particular therapy and whether they could use it again.”

On the progress so far of the Optima trial, the salvage therapy study started in 2001 by the Medical Research Council, in collaboration with American and Canadian research institutes, to monitor treatment strategies in people whose existing regimes have failed, Dr Youle was however disappointingly despondent: ‘It’s spectacularly unsuccessful so far,” he said, “because we don’t have enough patients yet taking part.”

4. Meeting with Bristol Myers Squib

The afternoon presentation was by Dr Andrew Clarke, Medical Director of HIV Products at Bristol Myers Squib, who described BMS’s new drug atazanavir. Prior to joining BMS he worked for many years as an HIV clinician in South Africa.

Still to be submitted for approval, and so not yet marketed, atazanavir is similar to other protease inhibitors (PI) but has a different molecule basis. With a half-life of eight hours, against four hours for most PIs, it is the first PI that can be given once a day without being boosted by ritonavir.

Atazanavir should be taken with a light meal. In more than 70 studies so far, over 3000 patients have been exposed to atazanavir globally in trials.

Dr Clarke also emphasised that safety is as important than efficacy in marketing a drug.

Jaundice (yellowish skin-colouring from an increase in bile in the blood) occurred in about 5% of patients in trials. Patients with Gilbert’s syndrome would have their dose reduced.

No appreciable effects on lipids have been detected, and this may make atazanavir applicable for people on currently available PIs who have raised lipids and/or lipodystrophy. Current studies have not shown reduced lipodystrophy, although there has only been relatively short term follow up so far.

Potential benefits

  • two pills a day (gelatine capsules)
  • favourable lipid and glucose profile
  • potential for use in naive, experienced and highly experienced treatment profiles
  • recommended use with a light meal, eg toast and butter, but not essential
  • no gender difference
  • almost entirely gut-excreted

Ques. Any prospect of taking drugs once a month?

Resp. No – we are nowhere near that at the moment, and very unlikely to ever be at that stage for any drug.

Atazanavir access timetable

  • Development of atazanavir started in 1998.
  • An expanded access programme started in May 2002 in the USA and at about the same time in France. The UK should see an expanded access programme from September 2002, but this may be later depending on how quickly the necessary
  • Epanded access include people who are intolerant to, or who have lipid abnormalities with current PIs

Ques. What will atazanavir cost?

Resp. Can’t say – but it is a protease inhibitor, and is likely to be priced accordingly.

Ques. What size are the tablets?

Resp. 20 millimetres by seven millimetres: approximately the size of a chewing gum.

Ques. And haemophiliacs? Only 400 positive haemophiliacs are left in Britain. What would be the effect on bleeding?

Resp. No-one seems to know. Haemophiliacs were actively excluded from the earlier trials but they will be in the extended trials and expanded access. We would advise caution. Usually the effects on haemophiliacs are looked at after approval.

Ques. What becomes of those in developing countries who take part in tria ls, but for whom there would be no money to fund continued treatment after the trial is over?

Resp: People who have taken part in trials, eg in Thailand and South Africa, will continue to receive treatment for life. BMS supplies at cost and sometimes below cost in eg Brazil and some southern African states.

Dr Clarke said: “Advocacy groups should make sure western governments continue to fund the purchase of drugs from pharma companies at prices that allow us to supply at or about cost in some of the worst-afflicted poorer nations.”

DuPont drugs

Bristol Myers Squib recently took over DuPont Pharmaceuticals and Dr Clarke informed the meeting that the whole of that companies HIV drug portfolio is being appraised now. This included several ‘pipeline’ drugs including an new NNRTI and PI, the future of which is now uncertain.

Efavirenz (Sustiva) is now marketed by BMS in the countries where this was previously marketed by DuPont (MSD, who originally co-developed the drug, still has marketing rights for efavirenz in some countries). A new formulation of efavirenz (one capsule once-daily instead of three capsules once-daily) is now available in the US and will be available in Europe shortly.

d4T (stavudine):

The Zerit Prolonged Release Capsule, to be taken once-daily instead of t wice dialy, is being prepared for the market.

A lively debate on the prospects for prevention of, or secure reversal of, lipodystrophy drew this comment from Dr Clarke: “No link to a single culprit drug has been established. We have no clue what leg-fat metabolism is or what fat distribution should be in various parts of the population. It is very complex, and maybe even if the viral-load is undetectable it still has an effect on fat-cells. Some people have seen lipodystrophy (fat loss) improve with no change in their therapy.”

5. Feedback

In a brief feedback meeting, people agreed on the value of the newly-established UK-CAB. Occasional difficulty with clinical terms was noted, and a glossary will be developed for future meetings.

A steering group for CAB meetings would help with programme planning. An invitation/request will be sent to the new UK-CAB list.

Please could each member produce a short description of your organisation and the work that you do. This can be included as information to new members and can also go on the UK-CAB website.

6. UK-CAB email list

Mailing list: most admin (meeting announcements, distribution of reports etc) will be though the new UK-CAB email list. Emails sent to this list will go to the 70 or so treatment advocates that have registered for this group. Your patience is appreciated during any teething difficulties – but have this list working should be very useful in the future.

Only one email can go to any single address – so where organisations use one generic address (ie info@…. Or admin@….) this will not be highlighted as mail for individual members.

It would help if every CAB member could get an individual email account for this work.

7. Next meeting

Provisionally last week in October. Further details to follow.

8 . Appendices

Slides from presentations are all available to download as pdf files from the website for this meeting.

Transcriptions from the two training sessions from the August 2002 are now on-line.

PDF files of the slides for these sessions are on the same webpage.

Direct links for each talk are :

Resistance and Resistance Tests

Approaches to Salvage Therapy

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Published: August 2, 2002
Last edited: January 17, 2011