Adults and Children Newly Infected With HIV in 2008

1. Adults and Children Newly Infected With HIV in 2008 Eastern Europe and Central Asia 110,000 Total: 1.5 million North America and Western/Central Europe 81,000 Total: 2.0 million North Africa and Middle East 40,000 Total: 380,000 Asia 380,000 Total: 4.2 million Caribbean 20,000 Total: 230,000 Sub-Saharan Africa 1.9 million Total: 22 million Latin America 140,000 Total: 1.7 million Oceania 13,000 Total: 74,000 UNAIDS, 2008. http://www.unaids.org.

2. Human Immunodeficiency Viruses • HIV-2 • HIV-2 is less virulent and less transmissible • HIV-2 is closely related to SIVsm, found in Sooty Mangebey monkeys • HIV-2 is epidemic in Western Africa, India • HIV-1 • HIV-1 is more virulent and more transmissible • HIV-1 is closely related to SIVcpz, found in Chimpanzees • HIV-1 is pandemic • HIV-1 strains are divided into three groups (M - main, N, O - outlier) • HIV-1 group M is divided into several subtypes (Clades A through J)

3. Global HIV Estimates • Cumulative HIV-1 infections = 80 million • Persons living with HIV-1 • Adults 40 million • Children 2.7 million • New HIV-1 infections yearly • Adults 5 million • Children 0.9 million • AIDS Orphans • 14 million • 20 million by 2010

4. Global Burden of HIV-1 Infection in Women • Half of all new infections occur in women • Half of the 40 million individuals living with HIV are women • Sub-Saharan Africa: 60% (75% ages 15-24) • Caribbean: 50% • Latin America: 35% • South/SE Asia: 30% Quinn and Overbaugh, Science 308: 1582, 2005

5. Where do we find HIV? • Blood • Seminal fluid • Vaginal fluid • Breast milk • Saliva • Tears • Urine/feces

6. How is it transmitted (cont) • Use of unclean needles for drug use including steroids, piercing • From HIV+ mother to unborn child • Contaminated blood products • Needlesticks

7. Who is at risk for HIV? • Men who have unprotected sex with men • Men who have unprotected sex with men and women • Men/women who use unclean needles • Women who have unprotected sex with women who are menstruating • Women who have unprotected sex with men

8. What age groups are vulnerable? • Women have represented approximately 50% of cases of HIV in Africa all along • In the US, women were only 5% in the 1980’s now approaching 50% • Fastest growing numbers of new cases in ages 13-24 and over 50 • Men who have sex with men have begun to represent an upward spiral of new cases

9. The hidden life of HIV

10. Cellular CD4 receptor CD4 ( T Helper) Cell Human DNA chromosome

11. Reverse transcriptase Integrase Protease gp120 gp41 HIV HIV RNA chromosome CD4 ( T Helper) Cell Cellular CD4 receptor Human DNA chromosome

12. 4. Fusion of cell and virus 2. Gp120-CD4 interaction 3. Conformational change in gp120, exposing hydrophobic fusion protein (harpoon) of gp41 1. HIV approaches CD4 cell

13. CD4 ( T Helper) Cell Reverse transcriptase Cellular CD4 receptor Integrase Protease gp120 gp41 HIV RNA chromosome Human DNA chromosome

14. CD4 ( T Helper) Cell Reverse transcriptase Cellular CD4 receptor Integrase Protease gp120 gp41 RNA nucleotides HIV RNA chromosome Human DNA chromosome

15. CD4 ( T Helper) Cell Reverse transcriptase Cellular CD4 receptor Integrase Protease gp120 gp41 RNA nucleotides DNA nucleotides HIV RNA chromosome Human DNA chromosome

16. CD4 ( T Helper) Cell Reverse transcriptase Cellular CD4 receptor Integrase Protease gp120 gp41 HIV RNA chromosome HIV DNA provirus Human DNA chromosome

17. CD4 ( T Helper) Cell Reverse transcriptase Cellular CD4 receptor Integrase Protease gp120 gp41 Reverse Transcriptase Inhibitors:Nucleoside and Non-Nucleosides HIV RNA chromosome Human DNA chromosome

18. CD4 ( T Helper) Cell Reverse transcriptase Cellular CD4 receptor Integrase Protease gp120 gp41 HIV RNA chromosome HIV DNA provirus Human DNA chromosome

19. CD4 ( T Helper) Cell Reverse transcriptase Cellular CD4 receptor Integrase Protease gp120 gp41 Cellular Activation HIV RNA chromosome HIV DNA provirus Human DNA chromosome

20. HIV Protease gp120 gp41 Functional proteins Protease Inhibitors Non-functionalgp160 precursor

21. HIV CD4 ( T Helper) Cell Reverse transcriptase Cellular CD4 receptor Integrase Protease gp120 gp41 HIV RNA chromosome HIV DNA provirus Human DNA chromosome

22. CD4 Cell Count and Viral Load • CD4 cell count • The number of T helper cells, or CD4 cells, in your blood. The count is measured as the number of cells per cubic millimeter (cells/mm3). Higher CD4 cells counts are a sign of a healthier immune system. Levels below 1000 indicate that the immune system is impaired. Blood tests measuring CD4 cells can help to determine if HAART is working. • Viral Load • The number of viruses circulating in your blood. Measured as counts per milliliter (c/mL or counts/mL). 1 milliliter = a cubic centimeter. Counts of 50 and below are termed “undetectable”. Blood Test: Viral Load also used to indicate whether HAART is Working/resistance is developing

23. 90,000 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 Number of AIDS cases and number of deaths from AIDS in the USA 1981-2001 400,000 300,000 Number of deathsfrom AIDS/year Number of new AIDS cases/year Total number of AIDS cases 200,000 100,000 0 81 85 90 95 00 01 Year 10th CROI, Boston 2003, #4; Incidence and deaths data from the CDC

25. 1996 2004 1987 When to Start Therapy? CD4 lymphocytes HIV RNA load Treatmentinitiation in: 6–24 weeks 0.5–15 (?) years 2–3 years Infection with HIV Clinical AIDS Original slide courtesy of Dr Sven A. Danner.

26. Updated IAS-USA Guidelines: When to Start *Non-AIDS risk factors include HIV-associated nephropathy, hepatitis C, hepatitis B Hammer SM, et al. JAMA. 2008;300:555-570.

27. High A partially effective regimen Resistance A highly effective regimen Low Low High Adherence Start on the most potent drug to keep the virus down • 100% adherence to a partially effective regimen will still result in virologic failure due to resistance • With a highly effective regimen, resistance is highest when adherence is intermediate • To avoid resistance: • Pr0viders should use a potent medication that will achieve maximum suppression of the virus and that the patient can strictly stick to • The patient should adhere to the regimen Adapted from Bangsberg DR, et al. XI International HIV Drug Resistance Workshop. Seville, 2002. #160

28. Overview of Available Antiretroviral Sites of Action

29. News on metabolic side effects News in brief • Triglycerides • In 23 patients (of ~1300 patients) who had received HAART from 1997-2003 and who had developed high trigs: • Severe high trigs were more likely in patients receiving high dose ritonavir (more than 300 mg per day) • High trigs above 1000 mg/dL is associated with pancreatitis • There were no cases of pancreatitis associated with high trigs in this study • Abnormal fat distribution • A diet rich in polyunsaturated fats may help to reduce cell death which has been correlated with abnormal fat distribution as a side effect of HIV meds – the implications are unknown as this study was done in the laboratory and not in patients • Avascular necrosis • Smoking is a risk factor for avascular necrosis in HIV-infected patients • Cardiovascular • Smoking was the most frequent indicator of CV risk for patients on HAART. Other considerations included : lower CD4 nadir, male gender, protease inhibitor use. 43rd ICAAC, Chicago 2003, #H-1947, #H-1948, #H-1956, #H-1958

31. Risk Factors: Lipodystrophy • Age > 40 years • Hx of AIDS > 3 years • CD4+ nadir < 100 or CD4+% nadir < 15% • Body mass index (BMI) loss of ≥ 1 kg/m2 • BMI change of ≥ 2 kg/m2 • White race • Duration of Rx with indinavir or stavudine associated with increased risk of lipodystrophy Lichtenstein KA, et al. J Acquir Immune Defic Syndr. 2003;32:48-56.

32. Lipoatrophy Risk: Dual NRTI + PI vs Dual NRTI Risk of lipoatrophy with 2 NRTI + PI greater than with 2 NRTI alone 1.0 0.8 2 NRTIs 0.6 probability of remaining free of subcutaneous lipoatrophy 2 NRTIs + PI 0.4 0.2 0.0 0 200 400 600 800 1000 time (days) from start of dual therapyto lipoatrophy Mallal SA. AIDS 2000;14:1309

33. +30 +15 0 -15 -30 Median % change from BL 0 24 48 72 96 120 144 Week central abdominal fat limb fat lean mass Evolution of body fat over time,following initiation of ART • Australian lipodystrophy cohort starting HAART • measurements by DEXA: • initial increase in central and peripheral fat • limb fat declines from baseline after ~1yr • central abdominal fat remains increased from baseline Mallon PWG, et al. AIDS 2002;

34. GS 903 Study:Patients (%) with Lipodystrophy+ TDF+3TC+EFV d4T+3TC+EFV * * % Patients with Selected Toxicities * * Week 48 Week 96 Week 144 +Investigator-defined * p value < 0.001

35. Metabolic Syndrome • Many different definitions of the metabolic syndrome • Prevalence and association with HIV infection may be dependent on choice of definition • WIHS: found higher prevalence of metabolic syndrome in HIV-infected women, but factors significantly associated with metabolic syndrome were traditional risk factors (age, race, higher BMI, smoking), not HIV related[1] • MACS: HIV-infected men who are treated have larger waists as they age; reversal of previous decrease in waist size with NRTI treatment[2] 1. Sobieszczyk ME, et al. IAC 2006. Abstract WEPE0147. 2. Brown T, et al. IAC 2006. Abstract WEPE0136.

36. Australian Prevalence Study; buffalo hump was found in 2% of HIV+ Buffalo hump (BH) and associated metabolic abnormalities • Buffalo hump is commonly found in overweight people and is associated with metabolic changes seen in overweight individuals - insulin resistance and larger body mass index • Presence of BH is not associated with high blood lipids, e.g. triglycerides, cholesterol 1. Miller M, HIV Med 2003; 4:293-301; Mallon PWG, et al.2nd IAS, Paris 2003, #715

37. Adherence

38. Treatment Plan- Individualized • Pill burden • Number of doses per day • Lifestyle issues • Side effects • Effectiveness (potency and durability) • Preserving future options(sequencing) • Provide adherence support

39. Advances in current treatment and care: Summary • Once-daily combinations • No required water or food • Many can be stored in cool areas but no need for refrigeration • Side effects less gastrointestinal but more metabolic

40. How Much Adherence is Needed? (number of pills taken / number of pills prescribed) Ann Intern Med 2000;133:21

41. What is treatment failure? • When antiretroviral medications stop controlling HIV,viral load goes up and CD4 counts go down • Immune damage continues • Risk of an opportunistic infection increases • Drug resistance is a major cause of treatment failure.

42. Nurses and HIV • Leaders • Educators • Counselors /Testers • Treatment managers • Adherence coaches • Symptom managers • Prevention counselors