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

1. Current and Future Trends in HIV TherapyHail M. Al-AbdelyConsultant, Infectious Diseases

2. Seroconversion Asymptomatic AIDS Clinical, Virological and Immunological Course of HIV Infection 1000 CD4 Cell Count 800 600 RNA in Plasma 400 Symptoms Virus in Plasma 200 0 Infection Death Detectable VIRUS IN PLASMA Detectable > 500 cells CD4 COUNTS < 200 cells Time 0 12 Years

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

5. Latency Theory

6. 26 1 15

7. Total = 25 drug or drug combinations

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

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

13. Hospitalization Days for AIDS Patients 2,000 1,500 1,000 500 0 Hospitalization days (n) 1993/2 1994/1 1994/2 1995/1 1995/2 1996/1 1996/2 1997/1 1997/2 1998/1 1998/2 1999/1 1999/2 2000/1 2000/2 2001/1

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

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

16. 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. • Adherence & Complexity of treatment • Short and long term side effects • Resistance • Drug-drug interactions

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

18. Bad News • Incomplete response • Adherence & Complexity of treatment • Too many tablets. • Difficult schedule. • Food factor • Short and long term side effects • Resistance • Drug-drug interactions

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 • Incomplete response • Complexity of treatment • Short and long term side effects • Drug-drug interactions • Resistance

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  Mortality rates in HIV-infected patients by 50% Benefits Adapted from Grunfeld. 6th CROI; 1999; Chicago. Palella. NEJM 1998;338:853.

24. Bad News • Incomplete response • Complexity of treatment • Short and long term side effects • Drug-drug interactions • Resistance

25. Drug Category Indinavir Ritonavir* Saquinavir Nelfinavir Amprenavir Nevirapine Delavirdine Efavirenz Ca++ channel blocker (none) bepridil (none) (none) bepridil (none) (none) (none) Cardiac (none) amioderoneflecainidepropafenonequinidine (none) (none) (none) (none) (none) (none) Lipid LoweringAgents simvastatinlovastatin simvastatinlovastatin simvastatinlovastatin simvastatinlovastatin simvastatinlovastatin (none) simvastatinlovastatin (none) Anti-Mycobacterial rifampin none rifampinrifabutin rifampin rifampin (none) rifampinrifabutin (none) Antihistamine astemizoleterfenadine astemizoleterfenadine astemizoleterfenadine astemizoleterfenadine astemizoleterfenadine (none) astemizoleterfenadine astemizoleterfenadine GastrointestinalDrugs cisapride cisapride cisapride cisapride cisapride (none) cisaprideH-2 blockersProton pumpinhibitors cisapride Neuroleptic (none) clozapine pimozide (none) (none) (none) (none) (none) (none) Psychotropic midazolamtriazolam midazolamtriazolam midazolamtriazolam midazolamtriazolam midazolamtriazolam (none) midazolamtriazolam midazolamtriazolam Drugs That Should Not Be Used With Antiretrovirals

26. Bad News • Incomplete response • Complexity of treatment • Short and long term side effects • Drug-drug interactions • Resistance

27. Agent Agent Resistance mutations Resistance mutations ZDV DLV 41 103 67 69* 70 181 151 236 210 215 219 333 3TC EFV 100 103 108 69* 179 181 188 190 225 151 184 333 NV ddI 100 103 65 106 108 69* 181 74 188 190 151 184 ddC 65 69 69* 74 151 184 d4T 50 69* 75 151 178 ABC 65 69* 74 115 151 184 Resistance Genotypic Mutations Associated With Resistance to NRTI & NNRTIs

28. Agent Resistance mutations APV 10 36 46 47 48 50 54 63 71 82 84 IDV 10 20 24 32 36 46 48 54 63 71 73 82 84 90 NFV 10 30 36 46 48 71 82 84 88 90 RTV 10 20 32 33 36 46 54 63 71 82 84 90 SQV 10 20 24 30 36 46 48 54 63 71 73 82 84 90 LPV 10 32 46 47 50 84 Resistance Genotypic Mutations Associated With Resistance to PIs

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

30. Overcoming Drug Resistance Change to a drug to which virus shows greater susceptibility 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 Virologic goals Reduction in viral load to: 1) halt disease progression 2) prevent/reduce resistant variants Immunologic goals: Achieve immune reconstitution that is quantitative (CD4 to normal range) and qualitative (pathogen-specific immune response) Clinical goals Prolongation of life and improved quality of life Epidemiologic goals Reduce HIV transmission 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

33. Naïve patient Experiencedpatient Highly- experienced patient Success Failure Success Failure Success Failure Importance of Initial Therapy

34. HAART: Randomized Comparative Trials*: HIV RNA <400 Copies/mL at Week 48 (ITT) DuPont 006: IDV + AZT + 3TC CNAAB 3005: IDV + AZT + 3TC CNAAB 3005: ABC + AZT + 3TC DuPont 006: EFV + IDV Atlantic: NVP + d4T + ddI Atlantic: 3TC + d4T + ddI Agouron 542: NFV TID + d4T + 3TC Atlantic: IDV + d4T + ddI Agouron 542: NFV BID + d4T + 3TC Study 863: NFV + d4T + 3TC DuPont 006: EFV + AZT + 3TC Study 863: LPV/r + d4T + 3TC Gilead 903: TDF + 3TC + EFV 0 10 20 30 40 50 60 70 80 90 Patients (%) *All trials have ³100 patients/arm Adapted from Bartlett J et al. 7th CROI, 2000

35. Correlation Between Nonadherence and Virologic Failure 100 80 60 40 20 0 Patients with virologic failure* (%) >95 90–95 80–90 70–80 <70 Adherence (%) P<0.001, r=–0.554 *Virologic failure defined as HIV RNA >400 copies/mL at last study visit Paterson DL et al. Ann Intern Med, 2000

36. Duration of initial HAART 100 80 60 40 20 0 Patients without changein therapy (%) 0 120 240 360 480 600 720 Days 197 patients, Cologne 1997–1999 Fätkenheuer G et al. 8th ECCATH, 2001

37. Reasons for Modification of Initial HAART 35 30 25 20 15 10 5 0 Patients (%) Adverse Virologic Lost to Other events failure follow-up 197 patients, Cologne 1997–1999113/197 (57%) modified therapy Fätkenheuer G et al. 8th ECCATH, 2001

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/µLor 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 1987 AZT 1992 AZT/ddI 1995 2 NRTIs 1997 2 NRTIs + PI 1999 2 NRTI + PI/NNRTI 2002 2 NRTI + NNRTI or PI or 3d NRTI 2004 2 NRTIs + PI/r or NNRTI

45. Initial Treatment: Preferred Regimens *Avoid in pregnant women and women with pregnancy potential. NNRTI-Based # pills/day PI-Based

46. Future Trends

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

48. Entry inhibitors under development Class Target Example Compounds Attachment Inhibitors gp120, CD4 specific Mab, PRO 542 soluble CD4 and CD4-Ig Co-receptor Inhibitors CXCR-4 AMD-3100 CCR-5 SCH-C, specific Mab, Fusion Inhibitors gp41 T-1249, D-peptides

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