Vaccines for Hiv Technology Assessment

Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH VACCINES FOR HIV TECHNOLOGY ASSESSMENT

NO. 68 JANUARY 2006 Generic (Trade Name): ALVAC vCP1521 (ALVAC-HIV); AIDSVAX B/E (AIDSVAX®)

Manufacturer: ALVAC-HIV (sanofi pasteur); AIDSVAX® (VaxGen, Inc.)

Indication: These vaccines are designed to prevent human immunodeficiency virus (HIV) infection (prophylactic vaccine), or if infection has occurred, to control the spread of the virus to other cells (therapeutic vaccine), delaying progression to acquired immunodeficiency syndrome (AIDS).1

Current Regulatory The combination of ALVAC-HIV vCP1521 and AIDSVAX® B/E vaccines (“prime-boost” Status: vaccine combination) is being evaluated in a phase III trial (RV144) in Thailand.1,2

Description: ALVAC-HIV is one of a group of HIV vaccines that use genetically modified canarypox viruses (CPVs) to carry HIV genes. CPV is non-replicative in human cells. Once administered, the recombinant CPV express the foreign HIV molecules, triggering an HIV- specific immune response. The ALVAC-HIV construct, vCP1521, carries three genes, env, gag, and a portion of pol, from the HIV subtype found predominately in Thailand (CRF01_AE, formerly clade E).3

HIV gp120 proteins are normally expressed on the outer surface of the virus. They bind to human cells during infection, playing an essential role in virus infectivity and patho- genesis. The AIDSVAX® vaccine contains gp120 surface proteins from two HIV strains.4 AIDSVAX® B/E is made with genetically engineered gp120 proteins from the viral strain that predominates in Thailand. The goal of AIDSVAX® immunotherapy is to train the immune system to recognize gp120, create antibodies to coat gp120, and so prevent HIV from entering human cells.4

The aim of the prime-boost combination is to stimulate both arms of the immune system. The canarypox vector (ALVAC-HIV) is designed to stimulate HIV-specific T cells, while AIDSVAX® is intended to stimulate antibodies that neutralize HIV.5

Current Treatment: The goal of therapy is to keep the level of HIV in the body as low as possible, for as long as possible, delaying the progression to AIDS.6 Combination antiretroviral therapy is the standard of care for patients who are infected with HIV.6,7 There are two classes of antiretroviral medications—reverse transcriptase inhibitors (RTIs) and protease inhibitors (e.g., saquinavir, indinavir, ritonavir). There are nucleoside RTIs (e.g., zidovudine, didanosine, zalcitabine), non-nucleoside RTIs (e.g., nevirapine, efavirenz), and nucleotide RTIs (e.g., tenofovir). In general, treatment includes the use of a combination of at least three antiretroviral medications from different classes, an approach that is commonly referred to as highly active antiretroviral therapy (HAART).8,9 The choice of drugs for combination therapy is individualized. It depends on factors such as anticipated viral load

The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is funded by Canadian federal, provincial and territorial governments. (www.ccohta.ca) Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH VACCINES FOR HIV TECHNOLOGY ASSESSMENT

reduction, side effects, drug interactions, patients’ tolerance, and dosing schedules.6 Preventive strategies for HIV infection remain abstinence and condom use. Topical microbicides are being developed as a possible preventive approach.10

Cost: There is no cost information on HIV vaccines, because they are not marketed in any country.

Evidence: The combination of ALVAC-HIV and AIDSVAX® B/E has been evaluated in a phase II trial of 133 HIV-negative Thai adults.5 Participants were randomized to receive ALVAC- HIV [106.5 TCID50 (50% tissue culture infectious doses)], administered at zero, one, three, and six months, combined with 200 μg or 600 μg AIDSVAX® (a “boost”) at three and six months. In each group, one participant received placebo for every three who received active vaccine. The vaccines and placebo were administered intramuscularly.5 Results showed that the vaccine combination was safe and well tolerated, and that it induced cellular and humoral immune responses. In the trial, the lymphoproliferative response, a measure of T-cell mediated immune response to gp120 E, was induced in 63% of vaccine recipients compared with 7% of placebo recipients. HIV-specific immune responses were detected in 24% of vaccine recipients. The trial also demonstrated that the higher dose of “boosting” vaccine induced stronger immune responses. Immune responses were not detected in patients who received ALVAC-HIV alone or placebo.5

Based on the safety and immunogenicity data from the phase II study, the US and Royal Thai governments jointly initiated a phase III study (RV144) on September 29, 2003. The primary objective of the trial is to determine if the combination vaccine prevents HIV infection. Its secondary objective is to determine whether the vaccine controls infection among patients who acquire HIV. The trial is set to recruit an estimated 16,000 HIV-negative Thai adults who are 20 to 30 years old. Completion of enrolment was projected to be in the fourth quarter of 2005. Patients will be monitored for three and a half years.1

Adverse Effects: ALVAC-HIV and AIDSVAX® have well documented safety profiles. Evaluated in over 2,000 recipients, including HIV-infected and uninfected adults, children, and newborns, ALVAC-HIV has been found to be safe and well tolerated, with no serious adverse events reported.11 AIDSVAX® was found to be safe and well tolerated in more than 2,500 Thai adults.1 The combination of ALVAC-HIV and AIDSVAX® has been evaluated in approxi- mately 200 Thai adults, and found to be well tolerated, with no serious vaccine-related adverse events or concurrent HIV infections reported.5

Commentary: Significant controversy has surrounded study RV144.

Many researchers argue that the combination of ALVAC-HIV and AIDSVAX® gp120 will not provide protection against HIV, based on earlier trials of the individual compo- nents.12,13 They claim that prior studies showed poor immunogenicity and no protective efficacy against HIV when the vaccines were given separately,14-16 and that the phase II results of the combination therapy were inadequate to justify a large trial. For these reasons, a similar phase III trial to be conducted in the US was cancelled by the HIV Vaccine Trials Network (HVTN).17

Proponents of study RV144 argue that the combination of ALVAC-HIV and AIDSVAX® induced better cellular and humoral responses than either component alone, warranting further investigation.12 Based on the complexity of HIV and the pace of progress, it is plausible that the prime-boost combination may not provide immune protection against HIV. It is agreed that regardless of the study outcome, the information gained will advance HIV vaccine development.18 A limitation of any HIV vaccine trial is the potential length of time required to declare that the vaccine is effective (i.e., prevents AIDS).

References: 1. U.S. Army Medical Materiel Development Activity, U.S. Army Medical Research and Materiel Command, Detrick F. Read ahead for FDA/VRBPAC meeting 23 September 2004. Rockville (MD): U.S. Food and Drug Administration; 2004. Available: http://www.fda.gov/ohrms/dockets/ac/04/brief- ing/4072B2_2.pdf (accessed 2005 Nov 21). 2. Cohen J. Public health. AIDS vaccine still alive as booster after second failure in Thailand. Science 2003;302(5649):1309-10. 3. Marovich MA. ALVAC-HIV vaccines: clinical trial experience focusing on progress in vaccine development. Expert Rev Vaccines 2004;3(4 Suppl):S99-104. 4. Billich A. AIDSVAX VaxGen. Curr Opin Investig Drugs 2004;5(2):214-21. 5. Nitayaphan S, Pitisuttithum P, Karnasuta C, Eamsila C, de Souza M, Morgan P, et al. Safety and immunogenicity of an HIV subtype B and E prime-boost vaccine combination in HIV-negative Thai adults. J Infect Dis 2004;190(4):702-6. Available: http://www.journals.uchicago.edu/JID/journal/contents/v190n4.html (accessed 2005 Nov 2). 6. Rachlis AR, Zarowny DP. Guidelines for antiretroviral therapy for HIV infection. Canadian HIV Trials Network Antiretroviral Working Group. CMAJ 1998;158(4):496-505. 7. Yeni PG, Hammer SM, Hirsch MS, Saag MS, Schechter M, Carpenter CC, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. JAMA 2004;292(2):251-65. 8. Anti-HIV agents. [TreatmentUpdate 151, no 5]. Toronto: Canadian Aids Treatment Information Exchange (CATIE); 2005. Available: http://www.catie.ca/pdf/tu/tu151 (accessed 2005 Nov 21). 9. Anti-HIV medications (anti-retroviral therapy). [Plain and simple fact sheets]. Toronto: Canadian Aids Treatment Information Exchange (CATIE); 2003. Available: http://www.catie.ca/ACASfs_e.nsf/dfac88ab9edb2ab485256cc2006448f6/68bd4cb953b6d46b85256cf60 06ea3b9?OpenDocument (accessed 2005 Nov 21). 10. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ 2005;172(4):461-4.

11. de Bruyn G, Rossini AJ, Chiu YL, Holman D, Elizaga ML, Frey SE, et al. Safety profile of recombinant canarypox HIVvaccines. Vaccine 2004;22(5-6):704-13. 12. Burton DR, Desrosiers RC, Doms RW, Feinberg MB, Gallo RC, Hahn B, et al. Public health: a sound rationale needed for phase III HIV-1 vaccine trials. Science 2004;303(5656):316. 13. Lahey TP. Controversy over vaccine trial. AIDS Clin Care 2004;16(3):1. Available: http://aids-clinical- care.jwatch.org/issue_pdf/AC0403.PDF (accessed 2005 Nov 15). 14. Gilbert PB, Ackers ML, Berman PW, Francis DP, Popovic V, Hu DJ, et al. HIV-1 virologic and immunologic progression and initiation of antiretroviral therapy among HIV-1-infected subjects in a trial of the efficacy of recombinant glycoprotein 120 vaccine. J Infect Dis 2005;192(6):974-83. 15. Gilbert PB, Peterson ML, Follmann D, Hudgens MG, Francis DP, Gurwith M, et al. Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. J Infect Dis 2005;191(5):666-77. Available: http://www.journals.uchicago.edu/JID/journal/contents/v191n5.html (accessed 2005 Nov 2). 16. McCarthy M. AIDS vaccine fails in Thai trial. Lancet 2003;362(9397):1728. 17. N IAID Phase III HIV vaccine trial to determine correlates of protection will not proceed [news release]. Bethesda (MD): National Institute of Allergy and Infectious Diseases (NIAID); 2003. Available: http://www3.niaid.nih.gov/news/newsreleases/2002/phase3hiv.htm (accessed 2005 Nov 21). 18. Belshe R, Franchini G, Girard MP, Gotch F, Kaleebu P, Marthas ML, et al. Support for the RV144 HIV vaccine trial. Science 2004;305(5681):177-80.

This series highlights medical technologies that are not yet in widespread use in Canada and that may have a significant impact on health care. The contents are based on information from early experience with the technology; however, further evidence may become available in the future. These summaries are not intended to replace professional medical advice. They are compiled as an information service for those involved in planning and providing health care in Canada.

These summaries have not been externally peer reviewed.

Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Ontario, Prince Edward Island, Québec, Saskatchewan, and Yukon. The Canadian Coordinating Office for Health Technology Assessment takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada or any provincial or territorial government.

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The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is funded by Canadian federal, provincial and territorial governments. (www.ccohta.ca)