Recent Advances in Antiretroviral Therapy

1. Recent Advances in Antiretroviral Therapy Hail M. Al-Abdely, MD Consultant, Infectious Diseases

2. Rationale for Drug Combinations CD4 + cell NRTIs Work here NNRTIs Work here PIs Work here

3. Development of AIDS is like an impending train wreck Viral Load = Speed of the train CD4 count = Distance from cliff HIV infection J. Coffin, XI International Conf. on AIDS, Vancouver, 1996

4. Viral Dynamics of HIV-1 Infection Latently infected CD4 lymphocytes Productively infected CD4 lymphocytes <1% T 1/2 ~1.6d 99% Uninfected CD4 lymphocytes 2.6 days per generation T1/2 ~5.7 hrs HIV CD4 lymphocytes infected with defective virus <1% Uninfected activated CD4 lymphocytes Long-lived cell populations Perelson et.al. Science 271:1582 (1996)

5. Viral dynamics • it takes 2.6 days to produce a new generation of viral particles • estimated total HIV production is 10.3 x 109 virions per day • at least 99% of the virus pool is produced by recently infected cells • retroviral therapy should be able to reduce viral load within a few days

6. GOALS OF THERAPY • Clinical goals:Prolongation of life and improved quality of life • Virologic goals: Reduction in viral load as much as possible for as long as possible to: 1) halt disease progression, and 2) prevent/reduce resistant variants • Immunologic goals:Achieve immune reconstitution that is quantitative (CD4 to normal range) and qualitative (pathogen-specific immune response) • Therapeutic goals:Rational sequencing of drugs in a fashion that achieves virologic goals, but also: 1) maintains therapeutic options; 2) is relatively free of side effects; and 3) is realistic in terms of probability of adherence • Epidemiologic goals:Reduce HIV transmission

9. Antiretroviral Drugs Approved by FDA for HIV Generic Name Class Firm FDA Approval Date zidovudine, AZT NRTI Glaxo Wellcome March 87 didanosine, ddI NRTI Bristol Myers-Squibb October 91 zalcitabine, ddC NRTI Hoffman-La Roche June 92 stavudine, d4T NRTI Bristol Myers-Squibb June 94 lamivudine, 3TC NRTI Glaxo Wellcome November 95 saquinavir, SQV, hgc PI Hoffman-La Roche December 95 ritonavir, RTV PI Abbott Laboratories March 96 indinavir, IDV PI Merck & Co., Inc. March 96 nevirapine, NVP NNRTI Boehringer Ingelheim June 96 nelfinavir, NFV PI Agouron Pharmaceuticals March 97 delavirdine, DLV NNRTI Pharmacia & Upjohn April 97 zidovudine and lamivudine NRTI Glaxo Wellcome September 97 saquinavir, SQV, sgc PI Hoffman-La Roche November 97 efavirenz, EFV NNRTI DuPont Pharmaceuticals September 98 abacavir, ABC NRTI Glaxo Wellcome February 99 amprenavir PI Glaxo Wellcome April 99

11. Trends in Age-Adjusted* Rates of Death due to HIV Infection, USA, 1982-1998 *Using the age distribution of the projected year 2000 US population as the standard. **Preliminary 1998 data

12. Good News Highly active antiretroviral therapy has Changed our view toward HIV from inevitably fatal to a manageable disease over several decades

13. Bad News • Incomplete response • Complexity of treatment • Short and long term side effects • Cross resistance • Drug-drug interactions

14. Bad News • Incomplete response • Complexity of treatment • Short and long term side effects • Cross resistance • Drug-drug interactions

15. Bad News • Incomplete response • Complexity of treatment • Short and long term side effects • Cross resistance • Drug-drug interactions

16. Bad News • Incomplete response • Complexity of treatment • Short and long term side effects • Cross resistance • Drug-drug interactions

17. Bad News • Incomplete response • Complexity of treatment • Short and long term side effects • Cross resistance • Drug-drug interactions

18. Bad News • Incomplete response • Complete RNA suppression and sustained CD4 increase happens only in 60-80%. • Effectiveness is even lower in patients with high replication rates and extensive antiretroviral experience. • Complexity of treatment • Short and long term side effects • Cross resistance • Drug-drug interactions

20. Immunotherapy

21. Immunotherapy • Directions • Augmentation of specific immune response to control viral replication. • Preventive Vaccines.

22. Clues to immune control of HIV? Subject JP: Sx: Fever, Rash, Headache Dx: HIV ELISA Neg. HIV RNA >700,000 F/U: Extensive Rx AIDS at 11 mo. Rapid CD4 cell decline Viral Load >750,000 Subject 161J: Sx: Fever, Rash, Headache Dx: HIV ELISA Neg. HIV ELISA Pos. F/U: No Rx Well at 19 yrs. CD4 1000 Viral Load < 500

23. Acute HIV-1 infection Stimulation of HIV-1-specific immune CD4 cells (Helper cells) Generation of HIV-1-specific killer cells (CTL) Infection of activated helper cells Loss of CTL function due to inadequate HIV-1-specific helper cells Loss of HIV-1-specific helper cells Progression

24. T helper cells are the central orchestrator of the immune system CTL Function NK Cell Function T helper cell B Cell Function APC Function Antibody Production Cytokine production

25. Acute HIV-1 infection Stimulation of HIV-1-specific immune CD4 cells (Helper cells) Antiviral Rx Generation of HIV-1-specific killer cells (CTL) Protection of activated helper cells Maintenance of CTL function due to adequate HIV-1-specific helper cells Maintenance of HIV-1-specific helper cells Nonprogression

26. 0 Months 2 Months HIV-1-specific T helper cells in individuals treated during acute infection (n=7) 1 0 0 1 0 1 M B J C K M N D S J D K K S

27. Barriers to the Development of an Effective AIDS Vaccine • Sequence variation • Protective immunity in natural infection not clearly established • Desire to achieve sterilizing immunity • Lack of adequate animal model to study vaccine protection with HIV • Latency and integration of HIV into host genome • Transmission by cell-associated virus • Limited knowledge about mucosal transmission and immune responses • Financial disincentives • Ethical issues