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

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

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

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

5. Viral dynamics u it takes 2.6 days to produce a new generation of viral particles u estimated total HIV production is 10.3 x 10 9 virions per day u at least 99% of the virus pool is produced by recently infected cells u 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. Generic NameClass Firm FDA Approval Date zidovudine, AZTNRTIGlaxo WellcomeMarch 87 didanosine, ddINRTIBristol Myers-SquibbOctober 91 zalcitabine, ddCNRTIHoffman-La RocheJune 92 stavudine, d4TNRTIBristol Myers-SquibbJune 94 lamivudine, 3TCNRTIGlaxo WellcomeNovember 95 saquinavir, SQV, hgcPIHoffman-La RocheDecember 95 ritonavir, RTVPIAbbott LaboratoriesMarch 96 indinavir, IDVPIMerck & Co., Inc.March 96 nevirapine, NVPNNRTIBoehringer IngelheimJune 96 nelfinavir, NFVPIAgouron PharmaceuticalsMarch 97 delavirdine, DLVNNRTIPharmacia & UpjohnApril 97 zidovudine and lamivudineNRTIGlaxo WellcomeSeptember 97 saquinavir, SQV, sgcPIHoffman-La RocheNovember 97 efavirenz, EFV NNRTIDuPont PharmaceuticalsSeptember 98 abacavir, ABCNRTIGlaxo WellcomeFebruary 99 amprenavirPIGlaxo WellcomeApril 99 Antiretroviral Drugs Approved by FDA for HIV

11. **Preliminary 1998 data 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.

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

13. 1.Incomplete response 2.Complexity of treatment 3.Short and long term side effects 4.Cross resistance 5.Drug-drug interactions Bad News

20. Immunotherapy

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

22. Clues to immune control of HIV? 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 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

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

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

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

26. HIV-1-specific T helper cells in individuals treated during acute infection (n=7) 1 10 100 MBJCKMNDSJDKKS 0 Months 2 Months

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