HIV Therapy in 2009: Where We Are, What are the Current Questions?

1. HIV Therapy in 2009: Where We Are, What are the Current Questions? Paul Volberding, MD

2. Fine Tuning and Unfinished Business • Remember how far we’ve come

6. HIV/AIDS Care Has Saved 3 Million Life Years in the US Substantially more life years saved than other accepted therapies of chronic illneses 91% of AIDS cases in 2000-2002 survived to next “treatment era” ARV averted 2900 HIV infected infants PMID 16741877

7. Antiretroviral Therapy Has a Striking Effect Compared to Other Health Care Interventions PMID 16741877

8. Fine Tuning and Unfinished Business • Remember how far we’ve come • Without forgetting those left behind

10. 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 Estimated Number of AIDS Cases, Deaths, and Persons Living with AIDS,1985-2004, United States 450 90 AIDS 1993 definition implementation 400 Deaths 80 Prevalence 350 70 300 60 No. of cases and deaths (in thousands) 250 50 Prevalence (in thousands) 200 40 150 30 20 100 10 50 0 0 Year of diagnosis or death Note. Data adjusted for reporting delays.

11. HIV Therapy • Treat the virus: Antiretroviral therapy. Often called HAART for Highly Active Antiretroviral Therapy. • Treat infections and cancers arising from immune deficiency • Treat complications of HIV therapy • Treat conditions associated with patient demographics (STDs, HCV, infections from IDU etc) • Treat conditions which seem unrelated to HIV

12. Issues in Medical Care • Treatment works • Survival prolonged (30+ years?) • Decreased in-patient burden • Increased out-patient load (which is especially poorly compensated) • Care focused on antiretrovirals • Adherence, toxicity, drug resistance central concerns • In the developing economies, testing and drug rollout and task shifting

13. Who Provides Care? • In the US, fewer than 900 physicians write 85% of antiretroviral prescriptions • Care is increasingly delivered in large care systems • By specialty a combination of Internal Medicine, ID, Family Medicine but also nursing, pharmacy, social work, dentistry involved in larger comprehensive clinics • No specific fully recognized specialty training and credentialing programs

14. Typical Course of HIV Infection 1100 Primary Infection Death 1100 • Possible acute HIV syndrome • Wide dissemination of virus • Seeding of lymphoid organs 1000 1:512 Opportunistic disease 900 1:256 Clinical Latency 800 1:128 700 1:64 CD4 T Cells/mm3 Plasma Viremia Titer 600 1:32 Constitutional symptoms 500 1:16 400 1:8 300 1:4 200 1:2 100 0 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 Weeks Years Pantaleo et al, NEJM, 1993

15. Likelihood of Developing AIDS in 3 Years CD4+ cells/µL Percent progressing >30,000 10,000- 3,000- 501- <500 30,000 10,000 3,000 Plasma HIV RNA (copies/mL) Adapted from: Mellors J et al. Ann Intern Med. 1997.

16. What are the Goals of HIV Therapy? • Begin therapy at the optimal point for each patient • Choose best drug regimen that: • Is potent enough to achieve maximal suppression of replication • Is well tolerated both in short and long term use • Considers potential need for salvage (without compromising potency)

17. Virus from latent reservoir The Goal of Ideal First Line HIV Therapy: Viral Decay and “Complete” Virus Suppression 1000000 100000 1st phase 10000 2nd phase 1000 100 10 Plasma HIV RNA (copies/ml) 1 0.1 0.01 0.001 0.0001 0 5 10 15 20 Time on HAART (months)

18. Steps Prior to Therapy • Understand in as much depth as possible the patient’s social network and resources • Identify goals of therapy, plan for monitoring of therapy and plan for incomplete or transient response • Stage disease • Directed history and physical exam,CD4 count, viral load (ideally test twice close to time of initiating to confirm indication and establish baseline for later comparison) • Identify and treat non-HIV related diseases (STDs etc) • Support behavior of low HIV-transmission risk

19. Issues in the Timing of HIV TherapyThe “Old” Paradigm • Start before immune deficiency fixed, before HIV becomes more virulent • Start as late as possible to avoid • Toxicity of unnecessarily long term drug exposure • Eventual selection of drug resistant mutations • Cost • Treatment burnout

20. Issues in the Timing of HIV TherapyThe “New” Paradigm • Start before immune deficiency fixed, before HIV becomes more virulent • Start to decrease chance of viral replication causing serious “non-AIDS” problems (heart disease, cancer, kidney failure) • Start to decrease chance of HIV transmission • Look for any reason not to treat instead of looking for a reason to treat!

21. Immune Recovery With Potent Antiretroviral Therapy “Normal” Immune Competence “Safe” ? “Dangerous”

22. Suboptimal CD4 T Cell Gains are Common Among Patients who Initiate HAART Late (ATHENA) Baseline CD4(cells/mm3) 1000 900 >500 (n=389) 800 350 – 500 (n=694) 700 200 – 350 (n=1,513) 600 50 – 200 (n=1,773) CD4 Cell Count (cells/mm3) 500 <50 (n=930) 400 300 ~50% of those with CD4 nadir <200 fail to reach 500 after 7 years VL suppression. 200 100 0 0 48 96 144 192 240 288 366 Week Gras L, et al. JAIDS. 2007;45:183–192.

23. When to Start Therapy: Balance Tipping in Favor of Earlier Initiation • Potency, durability, simplicity • and safety of current regimens • Improved formulations and PK • Enhanced adherence • Diminished emergence of resistance • More treatment options • Recognition of deleterious effect • of uncontrolled viremia at all CD4 levels • Drug toxicity • Preservation of limited Rx options IAS USA 2008

25. HIV Drugs • Three main enzymatic targets: reverse transcriptase, protease, integrase • Five drug classes • Reverse Transcriptase Inhibitors (RTIs) • Nucleoside analogs (and nucleotide analogs) often termed nRTIs • Non-nucleoside analogs often termed nnRTIs • Protease Inhibitors often termed PIs • Integrase Inhibitors • Attachment inhibitors • Fusion inhibitors

26. Current ARV Medications

27. HIV Drug Regimens • Always combine multiple agents • Usually 2 nRTIs along with: • A PI enhanced with a low dose of a second PI, RTV • An nnRTI • An integrase inhibitor • An attachment inhibitor

28. Is There A Single Best Initial Regimen? • Potency comparable in various regimens • Achieving non-detectability in naïve patient almost routine • Regimen choice individualized • Convenience [pill number and size, frequency, food restrictions etc.] • Tolerability [short term side effects, metabolic side effects] • Durability of benefit [probability of breakthrough if non-compliant] • “Strategic considerations” [does first regimen limit salvage options?]

29. Adherence in HIV Care • Best virologic and immunologic outcome if viral load in blood below limits of detection • This requires nearly perfect and continuous adherence • If virus remains detectable on therapy, degree of adherence correlates with degree of drug resistance • One factor in increasing prevalence of drug resistance in population

30. HIV Drug Toxicity • All drugs have side effects (toxicities) • HIV drugs have side effects that are either drug or drug class specific (but distinguishing them from effects of prolonged infection are challenging) • Toxicities can be severe, life-threatening, and essentially irreversible • Toxicities may make subsequent use of that drug or related drugs impossible • Our understanding of the actual cause of a toxicity and ability to predict it is limited but improving

31. HIV Drug Resistance • HIV mutates readily • If virus replicates in presence of drug, mutations that allow faster replication (drug resistance) will be selected with all antiretroviral drugs • Selection of drug resistance mutations will allow higher levels of viremia and progression of immunologic disease unless drugs changed and replication again controlled • Drug resistance can be transmitted

32. Basic Pharmacology Principles Drug Level Cmax Area Under the Curve (AUC) Cmin IC90 Area of Potential Replication IC50 Dosing Interval Time

33. Issues Beyond Antiretroviral Therapy • Finding undiagnosed infections • Bringing people into care • Treatment as a means of preventing transmission • Education and behavioral means of HIV prevention • Prevention through male circumcision • Our responsibility for the global epidemic

34. NormalAging HAART Toxicity Lifestyle Persistent Immune Dysfunction Non-AIDS events are more common in HIV disease, even after attempts are made to adjust for age, HAART exposure and traditional risk factors Premature Aging

35. Awareness of HIV Status among Persons with HIV, United States Number HIV infected 1,039,000 – 1,185,000 Number unaware of their HIV infection 252,000 - 312,000 (24%-27%) Estimated new infections 40,000 annually Glynn M, Rhodes P. 2005 HIV Prevention Conference

36. HIV Testing Should Become Routine in Health Care Setting Voluntary Opt-Out Without Written Consent Arguably most important paper of 2006 Will increase diagnosis, adding to burden on facilities and providers Will allow earlier treatment and may decrease transmission PMID 16988643

37. Women are more vulnerable to HIV than men: • Biologically • E.g: larger mucosal surface, more virus in semen • Economically • E.g: financial dependence on men, compensated sex • Socio-culturally • E.g: double standard

38. A relief on the tomb of Ankh-Mahor History of Male Circumcision • Circumcision may be oldest and most common surgery performed on humans. 20-25% of men circumcised. • Simple procedure that confers many benefits. • As a surgical procedure also entails risks. • Benefits must be weighed against risks. • Cultural considerations.

39. MALE CIRCUMCISION AND POPULATION BASED HIV PREVALENCE IN AFRICA High (>80%) male circumcision Low (<20%) male circumcision Sources: ORC/MACRO, 2005, USAID, 2002

41. HIV Acquisition among Male Partners of HIV + Female Partners By Circumcision Status In Rakai Female viral load 40/137 uncircumcised men (16.7/100 py)vs. 0/50 of circumcised men became infected after two+ years (p = 0.004). Quinn et al NEJM 2000

42. Circumcision Status and HIV Transmission to Women Male Viral load Of 47 couples in which circumcised male partner was HIV+ AND whose viral load was <50,000 particles, 0 of female partners were infected after two years, vs. 26 of 143 female partners of uncircumcised HIV+ men (9.6/100 py) (p = 0.02). Quinn et al NEJM 2000

43. HIV in 2009Why Should You Care? • No matter what you do in healthcare, wherever you plan to live and work, you will encounter this epidemic (and the next one) • The response to HIV n the past and now is perhaps the best example of medical professionalism and should make us proud of our career choices • Working with HIV involves us in confronting the challenges of healthcare in the US and globally

44. Thanks!