UK-CAB 7 – Introduction to statistics 1

21 November 2003

Notes for the meeting

Reading for November CAB
Note on programme:
Programme
Report from the meeting

Programme

PowerPoint slides from the meeting
Dr Caroline Sabin Royal Free Hospital
Colour slide collection PDF File [628k]
Black and white slide collection PDF File [448k]

Geraldine Reilly, Gilead

FTC PowerPoint Slides [5.6MB]
FTC Slides as PDF File [2.7MB]
Tenofovir Powerpoint Slides [2.2MB]

Reading for November 03 CAB

Please find links below to three articles about understanding the jargon and terms used in clinical trials. If you can read one or two of these before Friday, this would be very helpful. I included links to the other articles in case you have more time.

Each article is written in non-technical language, and although it is not exactly the same as Caroline Sabin’s statistics talk, many of the same terms are discussed.

Each article is about 6 pages long.

‘How to read a scientific paper’ by  Carlton Hogan

Part One:

http://www.thebody.com/content/art13659.html

Part Two:

http://www.thebody.com/content/art13389.html

Part Three:

www.thebody.com/content/art13457.htm

For the afternoon meeting with Gilead it would be helpful to know about the recent interactions reported with tenofovir: – Interactions with tenofovir and atazanavir (where atazanavir levels are reduced and tenofovir levels increased, and requires atazanavir dose to be reduced and boosted by ritonavir

http://www.i-base.info/pub/htb/v4/htb4-8/TREATMENT.html

– Interaction with abacavir/3TC in the triple nucleoside combination

http://www.i-base.info/pub/htb/v4/htb4-7/TREATMENT.html

– Interaction with ddI/3TC in triple nucleoside combination

http://www.i-base.info/pub/htb/v4/htb4-9/TREATMENT.html

All three interactions have led to Safety letters being issued by regualtory agencies directly to doctors and the above web addresses link directly to the articles in HIV treatment bulletin.

A separate article is posted below.

Tenofovir drug-drug interactions
Paul E. Sax, M.D. TheBody.com

http://www.i-base.info/pub/htb/v4/htb4-9/Tenofovir.html

Tenofovir (TDF, Viread) is generally a well tolerated medication with a low pill burden and demonstrates potent antiretroviral activity. These characteristics have led to its widespread use in clinical practice. Unlike other NRTIs, however, tenofovir use is associated with several drug interactions, most notably the reduction in levels of atazanavir (ATV, Reyataz) and an increase in levels of ddI (didanosine, Videx).

The pharmacokinetic studies presented here explore further potential drug interactions related to tenofovir, specifically related to lopinavir/ritonavir (LPV/r, Kaletra), abacavir (ABC, Ziagen) and oral contraceptives.

In the lopinavir/ritonavir study, 27 HIV-negative controls received an initial seven days of tenofovir alone at standard doses; they were then randomized to receive lopinavir/ritonavir both with and without tenofovir. At the end of 14 additional days, they were crossed over to the other treatment arm. Careful pharmacokinetic analyses were performed, and showed no change in lopinavir or ritonavir levels regardless of whether tenofovir was co-administered. In contrast, tenofovir exposure was increased by 32% when administered with lopinavir/ritonavir compared with tenofovir alone.

To explore whether this increase in tenofovir levels was clinically significant, the investigators reviewed renal and other safety data on 271 patients in the tenofovir expanded access programme who also received lopinavir/ritonavir. Five (1.8%) patients experienced serum creatinine changes leading to tenofovir discontinuation, with one developing Fanconi’s syndrome with hypophosphatemia; this individual had a similar complication from high-dose adefovir (Hepsera) in the past.

While the data presented provide reassurance that tenofovir does not lead to a clinically significant reduction in lopinavir levels, the issue of lopinavir/ritonavir increasing tenofovir exposure (and possible toxicity) remains unsettled. This will require further analyses in larger populations of patients treated with this combination, controlling for other potential causes of renal dysfunction. In the meantime, patients receiving these two drugs in combination should have their renal function regularly monitored as part of their routine safety laboratories. Furthermore, the combination should be used with caution – and appropriate tenofovir dose reduction – in those with pre-existing renal disease.

The triple-NRTI combination of tenofovir, abacavir and 3TC (lamivudine, Epivir) has shown surprisingly poor antiviral activity in two prospective studies: a single-arm study presented previously at this year’s IAS meeting in Paris, and a comparative study presented at ICAAC. Potential (but still unproven) explanations for this include: 1) a tenofovir-abacavir pharmacokinetic drug interaction; 2) intracellular interaction, such as competition for a critical intracellular enzyme; or 3) low barrier to resistance via the K65R mutation. This pharmacokinetic study explored the first of these potential explanations.

Eight non-HIV-infected volunteers received a single 300-mg dose of abacavir while receiving either no other treatment or tenofovir 300-mg daily. Tenofovir and abacavir concentrations in plasma were measured, with calculated Cmax, Cmin, and area under the curve. The results showed that abacavir plasma levels were not affected by tenofovir, and that similarly, tenofovir levels did not differ from historical controls.

The results of this small pilot study suggest it is unlikely that a tenofovir-abacavir drug interaction is the cause of the suboptimal antiviral responses seen in abacavir-tenofovir-3TC treated patients, and that other explanations should be pursued. Furthermore, it enables clinicians to use abacavir and tenofovir together as part of a more comprehensive salvage regimen using other active drugs.

Hormonal contraception is an important and commonly-used medication in women with HIV infection. While tenofovir would not be expected to lead to suboptimal drug concentrations and lower contraceptive efficacy, this study explored this potential drug interaction.

Twenty-four HIV-negative women receiving norgestimate/ethinyl estradiol (Ortho Tri-Cyclen, OTC) were enrolled, with 20 ultimately eligible for pharmacokinetic analyses. OTC drug levels were assessed on study day one, with tenofovir 300 mg started on day 23. On day 29, both OTC and tenofovir pharmacokinetic measurements were repeated. The results showed that time curves for OTC levels with and without tenofovir were virtually superimposable, showing no significant drug interaction. Similarly, tenofovir levels were similar to those observed in prior studies.

The above three studies provide important data on use of tenofovir with three commonly used drugs. The precise mechanism of action accounting for the various tenofovir drug interactions remains under investigation, as does the explanation for the suboptimal response to the abacavir-tenofovir-3TC regimen.
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Note on programme:

We’ve tried to keep the programme very simple for this meeting and not to cram too much difficult information in to one day.

The morning training will be on basic statistics, but this is not nearly as dry or scary as it first sounds. It is central to understanding how trials and results are presented – and it will make it much easier to follow and understand other training in the future.

Caroline Sabin will start form very basic principles. so that at the end you will end up understanding a lot of new terms and why they are relevant. Caroline recently gave a similar presentation to the European CAB and it was very successful – the talk is in non-technical language with liberal references to childrens television, the Clangers, gambling and many other real life situations.

In the afternoon, we will start with a short internal meeting where we can discuss some recent treatment news. We we then have a short meeting with Gilead until 4.00pm.

We’ve taken on board some of the previous comments about meetings with companies. This will be a shorter meeting and will include fewer slides etc. Geraldine Reilly trained as nurse and now works with Gilead.

The session could start with a list of questions that we’d like covered, but the main focus will be on drug interactions (with atazanavir, ritonavir and in triple nucleoside combinations), and then include a discussion about side effects.
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Financial support

The UK-CAB receives unrestricted funding from some pharmaceutical companies towards the direct costs of holding four meetings each year. This funding supports the travel and accommodation costs for members to attend from outside London, plus the cost of catering.

The content, programme and agenda for meetings is decided by the UK-CAB steering group in consultation with the wider membership. Funding is unconnected to meeting content.

We believe that manufacturers who currently develop and market medicines have a responsibility to actively engage with advocacy organisations and that HIV positive people and their advocates should be able to directly question manufacturers about the safety and efficacy of their products and proposals for future research.

For a list of companies that support the UK-CAB please see the “about us” page.

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