UK-CAB 8 – Introduction to statistics 2

27 February 2004

Reading for February 2004 CAB
Programme

Black and white PDF of PowerPoint slides for 8th meeting (464 Kb)

Agenda

Reading for February 2004 CAB

Pre meeting reading should include the November CAB report for the basics statistics training from that meeting. Any other material will follow by email.

Slides for the 8th meeting:

Black and white slide set (PDF) (464 Kb)

Managing hepatitis C coinfection

The following is a useful easy to read interview with Vincent Soriano who is one of the authors of a recent set of coinfection guidelines:

Managing Viral Hepatitis Coinfection: An Expert Interview With Vicente Soriano, MD. Medscape HIV/AIDS 10(1), 2004. © 2004 Medscape. Posted 23 February 2004.
www.medscape.com/viewarticle/469674_print .

Full text available of the new guidelines are online at NATAP or Medscape.
www.natap.org/2004/jan/012604_04.htm
www.medscape.com/viewarticle/467365

Two retrovirus studies

This first study shows the wide variation in the ways that different people absorb and process drugs. In this case the found a strong link to gender and race – ie African women absorbed significantlt higher levels of efavirenz and it took much longer for it to leave their bodies.

This has real practical importance for how to stop treatment safely without getting resistance.

The two presentations after this study at the Retrovirus conference linked these differences to genetic differences. I will show the slides from this study at the CAB

The second study is the largest HIV/HCV coinfection study – APRICOT – using Roche PEG-interferon + ribavirin – and follows up the training on HCV we had last year.

This has been given a lot of coverage. People did better than previous coinfection studies (see comment section for discussion) but worse than mono-infection and the 29% genotype-1 response may mean that only genotype 2-3 can easily get treatment in the UK.

Abstract 131 – Stop Study: After Discontinuation of Efavirenz, Plasma Concentrations May Persist for 2 Weeks or Longer

S Taylor*1, S Allen2, S Fidler3, D White1, S Gibbons4, J Fox3, J Clarke3, J Weber3, P Cane5, A Wade2, E Smit5, and D Back4

1Birmingham Heartlands Hosp. and Univ. of Birmingham, UK; 2Coventry and Warwickshire Hosp., UK; 3Imperial Coll. London & St. Marys Hosp., UK; 4Univ. of Liverpool, UK; and 5HPA, Birmingham Heartlands Hosp., UK

Background: Current antiretroviral drugs differ in their relative plasma elimination half-lives. The reported t1/2 of EFV is 40 to 55 hours; therefore EFV concentrations may persist at therapeutic levels for longer than 1 week following discontinuation. If drugs with a shorter half-life are stopped at the same time as EFV, patients will effectively be receiving monotherapy for a significant period. This may be important if there is ongoing viral replication, as nNRTI-resistant variants may be selected.

Methods: For 8 HIV-1+ patients who took part in an extended pharmacokinetics study, blood was drawn at baseline (day 0) and at days 4, 7, 14, and 21 after stopping EFV. Plasma samples were analyzed for EFV concentrations by HPLC and the half-life determined by regression analysis. Viral RNA+- resistance testing was performed at each time point. A further 25 patients who stopped EFV after short-course antiretroviral therapy following seroconversion were assessed to obtain virological data on patients stopping EFV 5 to 7 days prior to other agents in the regimen. These patients had resistance testing before commencement of treatment and an average of 4 weeks after stopping EFV.

Results: In the pharmacokinetics study the reasons for stopping EFV were virologic failure (n = 4), toxicity (n = 1), stopping 1 of 2 NNRTI (n = 2), and post seroconversion (n = 1). The median EFV concentration at day 0 (n = 8) was 3004 ng/mL (range 894 to 8216); at day 7 was 310 ng/mL (<40 to 4478); at day 14 was 149 ng/mL (<40 to 1845), and at day 21 was 62 ng/mL (<40 to 637). The calculated half-life ranged from 36 to 100 hours. Of the 25 patients in the virologic study only 1 exhibited resistance 4 weeks after stopping treatment. However this was also present prior to EFV therapy. Using a protein-corrected EC95 value of 93 ng/mL for wild type virus, 4/7 patients had EFV concentrations above this at day 7, 3/7 at day 14, and 2/7 at day 21.

Conclusions: Based on virologic data it would appear reasonable to stop EFV 7 days prior to stopping other shorter-acting drugs in the regimen. It may also be possible to consider exchanging EFV for a drug with a shorter half-life before stopping all drugs. However, based on this extended pharmacokinetics data, it may be more prudent to increase the stop window to 2 weeks to minimize the potential for selecting for nNRTI resistance. These findings will have implications for conserving future therapeutic options and also stopping other agents with long plasma or intracellular half-lives.

Abstract 112 – Final Results of APRICOT: A Randomized, Partially Blinded, International Trial Evaluating Peginterferon-alfa-2a + Ribavirin vs Interferon-alfa-2a + Ribavirin in the Treatment of HCV in HIV/HCV Co-infection

Background: The AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT) was designed to evaluate the safety and efficacy of HCV therapies approved for patients with HCV mono-infection in patients with HIV/HCV co-infection.

Methods: We randomized 868 HIV/HCV co-infected subjects in 19 countries to 48 weeks of treatment with interferon-a-2a (IFN) 3-MIU 3 times a week plus 800 mg/day ribavirin (RBV), peginterferon-a-2a (40 kD) 180 mg weekly (PEGASYS) plus placebo, or PEGASYS 180 mg weekly plus 800 mg/day RBV. Eligible subjects were HCV RNA and HCV antibody positive, had compensated liver disease, a CD4+ count ‰¥100 cells/mL, and stable HIV disease, with or without antiretroviral therapy (ART). The primary endpoint, sustained virological response, was defined as HCV RNA <50 IU/mL at the end of 24 weeks of treatment-free follow-up (week 72), determined by the COBAS AMPLICOR HCV Test v 2.0. Sustained virological response rates were compared by Cochran-Mantel-Haenszel test stratified by geographical region, genotype and CD4+ count using a closed testing procedure.

Results: A total of 860 subjects received study drugs. Final week-72 results are presented in the table:

Conclusions: The combination of PEGASYS + RBV produced significantly higher sustained virological response rates than conventional IFN + RBV in HCV/HIV co-infection (40% vs 12%, p <0.0001).

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.

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