1. Current and Future Trends in HIV Therapy Hail M. Al-Abdely Consultant, Infectious Diseases

2. CD4 Cell Count Virus in Plasma Symptoms Detectable VIRUS IN PLASMA Detectable > 500 cells CD4 COUNTS < 200 cells SeroconversionAsymptomaticAIDS Time 012 Years InfectionDeath Clinical, Virological and Immunological Course of HIV Infection 0 200 400 600 800 1000 RNA in Plasma

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

5. Latency Theory

6. 26 1 15

7. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Abacavir (Ziagen) Abacavir + Lamivudine (Epzicom) Abacavir+Lamivudine+Zidovudine (Trizivir) Didanosine (Videx, ddI) Emtricitabine (Emtriva, FTC) Emtricitabine + Tenofovir DF (Truvada) Lamivudine (Epivir, 3TC) Lamivudine+Zidovudine (Combivir) Stavudine (Zerit, d4T) Tenofovir DF (Viread) Zalcitabine (Hivid, ddC) Zidovudine (Retrovir, AZT, ZDV) Nonnucleoside Reverse Transcriptase Inhibitors(NNRTIs) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Delavirdine (Rescriptor) Efavirenz (Sustiva) Nevirapine (Viramune) Protease Inhibitors (PIs) Amprenavir (Agenerase) Atazanavir (Reyataz) Fosamprenavir (Lexiva, 908) Indinavir (Crixivan) Lopinavir+Ritonavir (Kaletra) Nelfinavir (Viracept) Ritonavir (Norvir) Saquinavir (Fortovase, Invirase) Tipranavir Fusion Inhibitors Fusion Inhibitors Enfuvirtide (Fuzeon, T-20) Total = 25 drug or drug combinations

8. RT Provirus Proteins RNA RT Viral protease Reverse transcriptase RNA DNA Current antiretroviral targets ZDV, ddI, ddC, d4T, 3TC, ABC, DLV, NVP, EFV SQV RTV IDV NFV APV LPV

9. Monotherapy Dual therapy Triple therapy Viral Suppression with Monotherapy versus Multiple Drugs

13. Hospitalization Days for AIDS Patients Hospitalization days (n) 2,000 1,500 1,000 500 0 1993/21994/11994/21995/11995/21996/11996/21997/11997/21998/11998/21999/11999/22000/12000/22001/1

14. Highly active antiretroviral therapy has Changed our view toward HIV from inevitably fatal (Cancer) to a manageable disease (Diabetes, HTN) Good News

15. 1.Incomplete response 2.Adherence & Complexity of treatment 3.Short and long term side effects 4.Resistance 5.Drug-drug interactions Bad News

17. Monotherapy Dual therapy Triple therapy Viral Suppression with Monotherapy versus Multiple Drugs

18. Bad News

19. Predictors of Inadequate Adherence Regimen complexity and pill burden Poor clinician-patient relationship Active drug use or alcoholism Unstable housing Mental illness (especially depression) Lack of patient education Medication adverse effects Fear of medication adverse effects

20. Bad News

21. Metabolic Complications of PIs Hyperbilirubinemia Hyperlipidemia –Coronary artery disease Insulin resistance Abnormal fat distribution. Lipodystrophy

22. From NEJM

23. Risk: Benefit Analysis of Coronary Heart Disease and HAART Average calculated increase in CHD events = 0.14% per year Risks Benefits  Mortality rates in HIV- infected patients by 50% Adapted from Grunfeld. 6th CROI; 1999; Chicago. Palella. NEJM 1998;338:853.

24. Bad News

25. Drug CategoryIndinavirRitonavir**SaquinavirNelfinavirAmprenavirNevirapineDelavirdineEfavirenz Ca++ channel blocker (none)bepridil(none) bepridil(none) Cardiac(none)amioderone flecainide propafenone quinidine (none) Lipid Lowering Agents simvastatin lovastatin (none)simvastatin lovastatin (none) Anti- Mycobacterial rifampinnonerifampin rifabutin rifampin (none)rifampin rifabutin (none) Antihistamineastemizole terfenadine (none)astemizole terfenadine Gastrointestinal Drugs cisapride (none)cisapride H-2 blockers Proton pump inhibitors cisapride Neuroleptic(none)clozapine pimozide (none) Psychotropicmidazolam triazolam (none)midazolam triazolam Drugs That Should Not Be Used With Antiretrovirals

26. Bad News

27. Resistance AgentResistance mutations ZDV416769*70151210215219333 3TC69*151184333 ddI6569*74151184 ddC656969*74151184 d4T5069*75151178 ABC6569*74115151184 AgentResistance mutations DLV103181236 EFV100103108179181188190225 NV100103106108181188190 Genotypic Mutations Associated With Resistance to NRTI & NNRTIs

28. Resistance Genotypic Mutations Associated With Resistance to PIs AgentResistance mutations APV1036464748505463718284 IDV1020243236464854637173828490 NFV10303646487182848890 RTV102032333646546371828490 SQV1020243036464854637173828490 LPV103246475084

29. Overcoming Drug Resistance Change to a drug to which virus shows greater susceptibility Increase exposure to drug RESISTANCE Drug

30. Change to a drug to which virus shows greater susceptibility Overcoming Drug Resistance Guided by Genotypic resistance testing

31. Goals of Antiretroviral Therapy (ART) Eradication of HIV? Not possible with currently available antiretroviral medications.

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

33. Importance of Initial Therapy SuccessFailureSuccessFailureSuccessFailure Naïve patient Experienced patient Highly- experienced patient

34. HAART: Randomized Comparative Trials*: HIV RNA <400 Copies/mL at Week 48 (ITT) *All trials have  100 patients/arm Study 863: LPV/r + d4T + 3TC DuPont 006: EFV + AZT + 3TC Study 863: NFV + d4T + 3TC Agouron 542: NFV BID + d4T + 3TC Atlantic: IDV + d4T + ddI Agouron 542: NFV TID + d4T + 3TC Atlantic: 3TC + d4T + ddI Atlantic: NVP + d4T + ddI DuPont 006: EFV + IDV Patients (%) DuPont 006: IDV + AZT + 3TC CNAAB 3005: IDV + AZT + 3TC CNAAB 3005: ABC + AZT + 3TC 0102030405060708090 Gilead 903: TDF + 3TC + EFV Adapted from Bartlett J et al. 7th CROI, 2000

35. Correlation Between Nonadherence and Virologic Failure Paterson DL et al. Ann Intern Med, 2000 Patients with virologic failure* (%) Adherence (%) 100 80 60 40 20 0 >9590–9580–9070–80<70 P<0.001, r=–0.554 *Virologic failure defined as HIV RNA >400 copies/mL at last study visit

36. Duration of initial HAART 100 80 60 40 20 0 Patients without change in therapy (%) 0120240360480600720 Days 197 patients, Cologne 1997–1999 Fätkenheuer G et al. 8th ECCATH, 2001

37. Reasons for Modification of Initial HAART 197 patients, Cologne 1997–1999 113/197 (57%) modified therapy 35 30 25 20 15 10 5 0 AdverseVirologicLost toOther eventsfailurefollow-up Fätkenheuer G et al. 8th ECCATH, 2001 Patients (%)

38. Considerations in Initiating ART: Asymptomatic HIV Willingness of patient to begin and the likelihood of adherence Degree of immunodeficiency (CD4+ T cell count) Plasma HIV RNA Risk of disease progression Potential benefits and risks of therapy

39. Considerations in Initiating ART: Chronically HIV-Infected Patient, Asymptomatic Strong evidence of decreased mortality and morbidity with ART if CD4 <200 cells/µL or symptomatic Theoretical benefit of treatment at higher CD4 Few data establish clinical benefit for treatment if CD4 >200 cells/µL; optimal point to initiate ART is unknown Individualize treatment decisions

40. Indications for ART in the Chronically HIV-Infected Patient Treat all (regardless of viral load): Symptomatic (AIDS, severe symptoms) Asymptomatic, CD4 count <200 cells/µL

41. Indications for ART in the Chronically HIV-Infected Patient Offer treatment, after discussion of pros and cons: Asymptomatic, CD4 count 200-350 cells/µL

42. Indications for ART in the Chronically HIV-Infected Patient Defer Treatment: Asymptomatic, CD4 count >350 cells/µL –If HIV RNA >100,000 copies/mL, may consider treatment

43. Initial Treatment for Previously Untreated Patients: Choosing Regimens Three categories: –1 NNRTI + 2 NRTIs –1 PI + 2 NRTIs –3 NRTIs Few clinical endpoints to guide choices Advantages and disadvantages to each type of regimen Individualize regimen choice

44. GUIDELINES 1987AZT 1992AZT/ddI 19952 NRTIs 19972 NRTIs + PI 19992 NRTI + PI/NNRTI 20022 NRTI + NNRTI or PI or 3 d NRTI 20042 NRTIs + PI/r or NNRTI

45. Initial Treatment: Preferred Regimens * Avoid in pregnant women and women with pregnancy potential. Efavirenz* + (lamivudine or emtricitabine) + (zidovudine or tenofovir) 2-5 # pills/day Lopinavir/ritonavir (Kaletra) + (lamivudine or emtricitabine) + zidovudine 8-10 NNRTI-Based PI-Based

46. Future Trends

47. New agents in the pipeline New agents should: 1.Exhibit high potency. 2.Adequate drug levels. 3.Activity against resistant isolates. 4.Penetration into all cellular and bodily compartments (eg, central nervous system, genital tract). 5.Favorable drug interaction profile. 6.Minimal side effects. 7.Convenient to take, with no food restrictions and minimal dosing requirements; preferably once daily.

48. ClassTargetExample Compounds Attachment Inhibitors gp120, CD4specific Mab, PRO 542 soluble CD4 and CD4-Ig Co-receptor Inhibitors CXCR-4AMD-3100 CCR-5SCH-C, specific Mab, Fusion Inhibitors gp41T-1249, D-peptides Entry inhibitors under development

49. Barriers to the Development of an Effective AIDS Vaccine Sequence variation Protective immunity in natural infection not clearly established 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

50. Conclusion HIV/AIDS is no longer a “death sentence” for infected individuals Cure is beyond reach at this stage, but patients can survive years to decades longer. Better understanding of the HIV has allowed better treatment modalities. More drugs and drug problems are on the horizon. Control of HIV replication by the host immune system may be the best outlook for future research. Intense vaccine research is ongoing and ultimately will be the major preventive measure against HIV infection