Presentation is loading. Please wait.

Presentation is loading. Please wait.

Manuel Battegay Div. Infectious Diseases & Hospital Epidemiology HIV complications and morbidity.

Similar presentations


Presentation on theme: "Manuel Battegay Div. Infectious Diseases & Hospital Epidemiology HIV complications and morbidity."— Presentation transcript:

1 Manuel Battegay Div. Infectious Diseases & Hospital Epidemiology HIV complications and morbidity

2 Content Introduction Selected specific adverse events ART and body shape changes ART, HIV and metabolism –Cardiovascular risk general remarks –ART and Lipids –ART, Insulin resistance and diabetes –HIV and cardiovascular risk –Therapeutic approaches, Guidelines Immune reconstitution inflammatary syndrome

3 cART dramatically improves life expectancy Type of study Decrease Mortality % 1996DeltaRCT AZT vs dual ART 1996ACTG 175RCT AZT vs dual ART 1997ACTG 320RCT Dual vs HAART 1997SHCSOS No HAART vs HAART 1998HOPSOS No HAART vs HAART 2003 EUROSIDA OS 96/97 HAART vs HAART 2005 SHCSOS No HAART vs HAART 2007Danish Coh. OS HIV versus non HIV year old: another 43 years years life prolongation with cART Normal life expectancy (?), The ART-Cohort Collaboration, The Lancet 2008 Hammer et al NEJM 1996; NEJM 1997; Gulick et al, NEJM 1998, Lancet 1996; Lancet 1997, Egger & Battegay et al, The SHCS, BMJ 1997; Palella et al, NEJM 1998; Jaggy et al, Lancet 2003; Mocroft et al, EuroSIDA, Lancet 2003; Sterne et al, The SHCS, Lancet, 2005, Lohse N et al, Ann Med,

4 HIV Complications 1. HIV diarrhea, dementia, wasting 2. Defined HIV related complication opportunistic diseases 3. Drug - related complication ART OI treatment Interaction 4. IRIS 5. Concurrent unrelated complication Catheter related infection Urinary tract infection 6. Unrelated diseases Tumors Cardiovascular Battegay et al, Antiviral Ther 2007

5 cART switch Swiss HIV Cohort Study Vo et al., JID, Juni 2008

6 Reasons for switch Vo et al., JID, Juni 2008

7 Trends for specific side effects Vo et al., JID, Juni 2008

8 Content Introduction Selected specific adverse events ART and body shape changes ART, HIV and metabolism –Cardiovascular risk general remarks –ART and Lipids –ART, Insulin resistance and diabetes –HIV and cardiovascular risk –Therapeutic approaches, Guidelines Immune reconstitution inflammatary syndrome

9 Hammer, S. M. et al. IAS Guidelines JAMA 2008;300: Recommended Components of Initial Antiretroviral Therapy and Considerations for Choosing a Regimen

10 Hammer, S. M. et al. IAS Guidelines JAMA 2008;300: Recommended Components of Initial Antiretroviral Therapy and Considerations for Choosing a Regimen

11 Time to Onset of Abacavir HSR in Clinical Trials (n=206) Data on file, GlaxoSmithKline. Median time to onset 9 days 89% of cases occurred within 6 weeks of ABC initiation Serious and sometimes fatal hypersensitivity Symptoms worsen during continued therapy with abacavir and usually resolve upon discontinuation

12 Hypersensitivity to Abacavir multi organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: fever rash gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain) constitutional (including generalized malaise, fatigue, or achiness) respiratory (including dyspnea, cough, or pharyngitis).

13 OR: 0.40 P <.0001 (0/802) OR: 0.03 P <.0001 PREDICT-1: Clinically Suspected or Skin Patch–Defined HSR with abacavir treatment Mallal S, et al. NEJM % Clinically Suspected HSRSkin Patch-Defined HSR Incidence (%) Control arm Prospective HLA-B*5701 screening arm 10 (66/847)(27/803)(23/842)

14 Content Introduction Selected specific adverse events ART and body shape changes ART, HIV and metabolism –Cardiovascular risk general remarks –ART and Lipids –ART, Insulin resistance and diabetes –HIV and cardiovascular risk –Therapeutic approaches, Guidelines Immune reconstitution inflammatary syndrome

15 Lipoatrophy vs Wasting Syndrome Lipoatrophy: loss of subcutaneous fat in face, buttocks, abdomen, and limbs Lean tissue: (muscle) not lost Wasting syndrome: both fat, lean tissue, and weight diminish Grinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986.

16 Clinical Assessment Facial lipoatrophy grading Grade 1: Mild/localized. Appearance almost normal Grade 2: Deeper, longer central cheek atrophy. Facial muscles (especially zygomaticus major) beginning to show through Grade 3: Deeper, wider atrophic area. Muscles clearly showing Grade 4: Widespread atrophy. Facial skin lies directly on muscles over wide area, extending toward orbital region Grinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986. Progression of Lipoatrophy

17 Lipoatrophy: Risk Factors Almost certainly interrelated –Antiretroviral therapy Thymidine analogue exposure (d4T >ZDV) Combinations of ART (eg, EFV + NRTIs, NFV + NRTIs) –Host factors Age –HIV disease factors Duration of illness Severity of illness: AIDS, low CD4 + cell count Grinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986.

18 Lipohypertrophy increase in fat depots typically visceral, dorsocervical, and breast tissue fat Subcutaneous fat (pinch an inch fat) does not increase Difficult to distinguish from general lipohypertrophy associated with modern living

19 HIV+ patient with obesity. Subcutaneous fat is thick and fat in the abdomen is scant. HIV+ patient with visceral adiposity. Subcutaneous fat is scant and fat in the abdomen is thick. CT Scans of Two HIV+ Patients Subcutaneous Fat (pinch an inch fat) Visceral Fat (dark shaded areas) Images courtesy of D.A. Wohl.

20 P <0.001 Upper back Abdominal fat WaistChestNeckLegsButtocksArmsFaceCheeks 0 P <0.001 P =0.055 P =0.090 P =0.055 P =0.31 P =0.47 Lipoatrophy Prevalence Distribution in HIV+ vs HIV– Controls FRAM Study Group. JAIDS. 2005;40: FRAM Study Group. JAIDS. 2006;42: P <0.001 P =0.058 P =0.22 P =0.004 P =0.025 P =0.053 Upper Back Abdominal Fat Waist ChestNeckLegsButtocksArmsFaceCheeks 0 Men Women HIV Control Percentage Reporting Fat Loss

21 Upper back Abdominal fat WaistChestNeckLegsButtocksArmsFaceCheeks P =0.039 P <0.044 P <0.001 P <0.009 P =0.43 P =0.13 P =0.17 P =0.54 FRAM Study Group. J AIDS. 2005;40: FRAM Study Group. J AIDS. 2006;42: P =0.011 P <0.001 P =0.003 P <0.001 P =0.32 P =0.001 P =0.048 P =0.003 P =0.40 Upper back Abdominal fat WaistChestNeckLegsButtocksArmsFace Cheeks P =0.34 Men Women HIV Control Percentage Reporting Fat Gain Lipohypertrophy Prevalence Distribution in HIV+ vs HIV– Controls Percentage Reporting Fat Gain

22 Effect of NRTIs on Limb Fat Gallant JE et al. JAMA. 2004;292: ; Pozniak AL et al. JAIDS. 2006;43: Week Study 903 Week Study *P<0.001 TDF + 3TC + EFV d4T + 3TC + EFV Mean Limb Fat (kg) 8.6* * *P=0.034 P<0.001 § P= TDF + FTC + EFV ZDV/3TC + EFV Total Limb Fat (kg) * § * P=0.01

23 Weeks on Study d4T ZDV TDF Lipoatrophy at Weeks 48 and 96 (NRTI Arms Only) 16% 8% 26% 27% 9% 42% P Values at Week 96 ZDV vs TDF: <0.001 d4T vs TDF: <0.001 d4T vs ZDV: d4T TDF ZDV Lipoatrophy (% with >20% loss) Haubrich R et al. 14th CROI Los Angeles, CA. Abstract 38.

24 Lipoatrophy (>20% loss of extremity fat) at Weeks 48 and Weeks on Study Lipoatrophy (% with >20% loss) EFV LPV/r LPV/r + EFV P Values at Week 96 LPV/r + EFV vs LPV/r: LPV/r + EFV vs EFV: <0.001 LPV/r vs EFV: % 17% 32% 7% 10% 21% EFV LPV/r LPV/r + EFV Haubrich R et al. 14th CROI Los Angeles, CA. Abstract 38.

25 Rosiglitazone vs Metformin in HIV-Infected Patients 39 HIV-infected men with lipodystrophy randomized to rosiglitazone 8 mg/day or metformin 2 g/day for 26 weeks –Both drugs increased insulin sensitivity –Metformin associated with fat loss, rosiglitazone with SAT gain Week 26 ResultsRosiglitazone (n = 19)Metformin (n = 20) Insulin resistance SAT VAT TG TC Adiponectin Flow mediated vasodilatation van Wijk JP, et al. ICAAC Abstract H-339. van Wijk JP, et al. Ann Intern Med. 2005;143:

26 Psychosocial Impact of body shape changes Self-evaluated quality of relationships with friends, family, sexual partner is inversely associated with self-perception of peripheral fat loss in HIV/AIDS outpatients (N=457) 1 A survey of HIV/AIDS patients with body fat changes (N=33) 2 –Social withdrawal –Adversely affected sexual relationships –Forced disclosure of HIV status due to facial lipoatrophy –Depression –Poor body image –ART noncompliance –Economic impact of surgical interventions –more challenging than living with HIV Santos CP et al. AIDS. 2005;19(suppl 4):S14-S21. Collins E et al. AIDS Reader. 2000;10:

27 Conclusions Body shape changes are multifactorial Lipoatrophy and lipohypertrophy do not commonly occur together Newer NRTI have low- or non-existing potential for body shape changes (abacavir, tenofovir) Body shape changes are partly reversible Abdominal fat increases are common to all ART regimens studied so far The psychosocial impact is strong

28 Content Introduction Selected specific adverse events ART and body shape changes ART, HIV and metabolism –Cardiovascular risk general remarks –ART and Lipids –ART, Insulin resistance and diabetes –HIV and cardiovascular risk –Therapeutic approaches, Guidelines Immune reconstitution inflammatary syndrome

29 CHD risk ractors in HIV - infected population HIV Infection ART CHD Risk - - Diabetes *Metabolic syndrome Lipids* Family History Abdominal Obesity* Hyper- tension* Cigarette Smoking Hyper- glycemia Insulin Resistance* Inactivity, Diet AgeGender Orange = Modifiable Green = Nonmodifiable

30 Variation despite risk factors Huge geographical variation, not explained by risk factors (French paradox) Increase in Eastern Europe, Asia, Africa Increase with age, lag of about 10 years in women, no independent effect of menopause Multifactorial aetiology, diabetes more important in women, role of triglycerides controversial Tunstall-Pedoe et al, Lancet 1998

31 Multiple Risk Factors: INTERHEART Odds Ratio (99% CI) 2.9 ( ) 2.4 ( ) 1.9 ( ) 3.3 ( ) 13.0 ( ) 42.3 ( ) 68.5 ( ) ( ) ( ) Smoke (1) DM (2) ApoB/A1 (4) 1+2+3All 4+Obesity All Risk Factors HTN (3) Risk Factor (adjusted for all others) +Psycho- social Yusuf S et al. Lancet. 2004;364: Multiple Traditional Risk Factors Confer Synergistic Increase in Risk of MI in General Population

32 Lipids and CVD Risk Increasing plasma LDL increases relative risk of CHD A 30 mg/dL in LDL is associated with ~30% CHD risk Relative Risk of CHD (log scale) 3.7 LDL Cholesterol (mg/dL) Grundy SM et al. Circulation. 2004;110: Higher HDL reduces cardiovascular and hypertriglyceridemia is independently associated with CVD

33 GS 934 and GS 903: Lipid Effects of Tenofovir vs Thymidine Analogues Mean Δ From BL to Week 144, mg/dL GS 934 [1] GS 903 [2] TDF + FTC + EFV (n = 255) ZDV/3TC + EFV (n = 254) P Value TDF + 3TC + EFV (n = 299) d4T + 3TC + EFV (n = 303) P Value TC mmol/L LDL cholesterol mmol/L NS HDL cholesterol mmol/L NS TG mmol/L Arribas J, et al. J Acquir Immune Defic Syndr. 2008;47: Gallant JE, et al. JAMA. 2004;292: Prospective, randomized, double-blind studies in treatment-naive patients TDF associated with more benign lipid changes and less lipoatrophy

34 Study 934: ZDV/3TC vs TDF + FTC Pozniak AL et al. JAIDS. 2006;43: Mean Change From Baseline (mg/dL) Study Week TDF + FTC + EFV ZDV/3TC + EFV Triglycerides Fasting LDL P =0.12 TDF + FTC + EFV ZDV/3TC + EFV P =0.067 Mean Change Lipid Profile

35 HEAT: Lipid Effects of ABC/3TC vs TDF/FTC at Week TC HDL LDLTG ABC/3TC + LPV/RTV (n = 343) TDF/FTC + LPV/RTV (n = 345) Median Change From BL (%) Smith K, et al. CROI Abstract 774. Lipid effects comparable between arms

36 A5142: LPV/r + EFV vs LPV/r + 2 NRTIs vs EFV + 2 NRTIs * * * * *Statistically significant difference with other 2 arms, P P =0.023 P 0.01 NS By week 96, 10% and 12% of EFV and LPV subjects used a lipid-lowering agent. Median Change From Baseline (mg/dL) Haubrich R et al. 14th CROI Los Angeles, CA. Abstract TCHDLNon-HDLTG EFVLPV/rLPV/r + EFV Median Changes in Lipids From Baseline – Week 96

37 CASTLE: Lipid Effects of ATV/RTV vs LPV/RTV at Week 48 2% of ATV/RTV vs 7% of LPV/RTV subjects initiated lipid-lowering therapy during study TC LDL HDLNon-HDL TG Median Change From BL (%) *P <.0001 ATV/RTV + TDF/FTC (n = 440) LPV/RTV + TDF/FTC (n = 443) Difference estimates (%) * * * Molina JM, et al. CROI Abstract 37.

38 Eron JJ, et al. Lancet. 2006;368: KLEAN: Lipid Effects of FPV/RTV vs LPV/RTV at Week TCHDLLDLTG FPV/RTV 700/100 mg BID + ABC/3TC (n = 434) LPV/RTV SGC 400/100 mg BID + ABC/3TC (n = 444) Median Change From BL (%) Lipid effects comparable between arms

39 GEMINI: Lipids Effects of SQV/RTV vs LPV/RTV (On-Treatment Analysis) More patients in the LPV/RTV group exceeded the NCEP threshold (39%) for total cholesterol vs the SQV/RTV arm (31%) Significant difference in fasting TC:HDL ratio between arms at Week 24 lost at Week 48 Walmsley SL, et al. EACS Abstract PS Median Change From BL to Week 24 or 48 (%) 0 TCLDLHDLTG P =.0022 LPV/RTV + TDF/FTCSQV/RTV + TDF/FTC n = P =.0007 Week:

40 ARTEMIS: Mean Fasting Lipid Levels Over Time for DRV/RTV vs LPV/RTV De Jesus E, et al. ICAAC Abstract 718b Mean TG Level ( ± SE) Time (Wks) DRV/RTV n = LPV/RTV n = LPV/RTV + TDF/FTC Mean TC:HDL Ratio (± SE) NCEP cutoff mM ng/mL DRV/RTV + TDF/FTC Time (Wks) TG TC:HDL Ratio

41 ALERT: Lipid Effects of FPV/RTV vs ATV/RTV at Week 48 Smith K, et al. IAS Abstract WEPEB023. FPV/RTV 1400/100 mg QD + ABC/3TC (n = 53) ATV/RTV 300/100 mg QD + ABC/3TC (n = 53) LDL HDL FPV/RTVATV/RTVFPV/RTV ATV/RTV TCTG FPV/RTVATV/RTVFPV/RTV ATV/RTV BaselineWeek 48 Lipid effects comparable between arms Median Lipid Levels (mg/dL)

42 van Leth F, et al. PLoS Med. 2004;1:e19. 2NN: Lipid Effects of EFV vs NVP at Week week, multicenter, open- label, randomized trial in treatment-naive patients (N = 1216) –NVP 400 mg QD (n = 220) –NVP 200 mg BID (n = 387) –EFV 600 mg QD (n = 400) –NVP 400 mg + EFV 800 mg QD (n = 209) –All plus d4T + 3TC Similar efficacy with NVP BID and EFV but NVP did not meet equivalence criteria Greater lipid changes with EFV *P <.05 vs NVP. P <.001 vs NVP. Mean Change in Lipids From Baseline to Week 48 (%) * TCLDLHDLTGTC:HDL EFV + 3TC/d4TPooled NVP + 3TC/d4T

43 43 Insulin Resistance Failure of target organs to respond normally to the action of insulin Ability of insulin to store exogenous glucose (muscle/fat) Ability of insulin to suppress endogenous glucose production (liver)

44 Diabetes and Insulin Resistance in HIV Infection Type 2 diabetes secondary to insulin resistance Usually asymptomatic Prevalence of type 2 diabetes –Random glucose 1%–2% –OGTT 6%–10% Impaired glucose tolerance extra 15%–30% Associations –Lipoatrophy and fat accumulation – Age Grinspoon S et al. N Engl J Med. 2005;352:48-62.

45 Impact of Various PIs on Glucose and Glucose Disposal Rate PI 2-Hour OGTT IDV LPV/r ATV/r d4T 3TC 1. Noor MA et al. AIDS. 2001;15:F11-F18; 2. Dubé MP et al. JAIDS. 2001;27: ; 3. Behrens G et al. AIDS. 1999;13:F63-F70; 4. Martinez E et al. AIDS. 1999;13: ; 5. Walli RK et al. Eur J Med Res. 2001;6: ; 6. Noor MA et al. AIDS. 2002;16:F1-F8; 7. Dubé MP et al. Clin Infect Dis. 2002;35: ; 8. Sension M et al. Antivir Ther. 2002;7:L26; 9. Noor MA et al. AIDS. 2004;18: ; 10. Lee GA et al. Clin Infect Dis. 2006;43:

46 Insulin Resistance in HIV-Infected Pts According to Specific Antiretrovirals 533 HIV-infected and 755 HIV-uninfected men in MACS prospectively evaluated at 6-month intervals between 1999 and 2003 Cumulative exposure to NRTIs, but not PIs or NNRTIs, associated with significant increases in insulin resistance –Based on markers for insulin resistance and hyperinsulinemia Brown T, et al. AIDS. 2005;19: OR (95% CI) for insulin > 15 μU/mL NFV Parameter SQV IDV RTV (boosting dose) d4T 3TC ddI ZDV 1.14* * 1.12* *P <.05

47 Metabolic Syndrome in HIV-Infected vs HIV-Uninfected Patients 1. Mondy K, et al. Clin Infect Dis. 2007;44: Sobieszczyk ME, et al. IAS Abstract WEPE Jerico C, et al. Diabetes Care. 2005;28: Conflicting data on whether metabolic syndrome more prevalent in HIV-infected patients and whether associated with antiretroviral therapy May also reflect background regional variations in risk Study, % Prevalence of Metabolic Syndrome P Value HIV-Infected Patients HIV-Uninfected Controls US; 471 men and women [1] US; 2394 women [2] 3322<.001 Spain; 710 men and women [3] 17N/A-- NCEP ATP III, 3 of the following: Abdominal obesity (waist circumference > 102 cm for men; >88 cm for women), TG 150 mg/dL ( 1.70 mmol/L), HDL < 40 mg/dL (< 1.04 mmol/L) for men, < 50 mg/dL (< 1.30 mmol/L) for women, Blood pressure 130/ 85 mm Hg, Fasting glucose 110 mg/dL ( 5.55 mmol/L)

48 Friis-Møller N, et al. AIDS. 2003;17: Prevalence of Traditional Cardiac Risk Factors at Baseline in the D:A:D Study Large cohort of HIV-infected patients on HAART followed longitudinally (N = 23,468) 18,962 (80.8%) with previous ART exposure; 4506 (19.2%) antiretroviral naive Family History of CHD Previous History of CHD Current Smoking BMI > 30 HTNDiabetes Total Cholesterol TG Percentage of Cohort With Risk Factor at Baseline

49 D:A:D Study: Incidence of MI Friis-Moller N et al. N Engl J Med. 2007;356: A Small Increase in Incident CVD Is Associated With Duration of Combination Antiretroviral Therapy RR per Year of ART Overall 1.16 Men 1.13 Women 1.36 Exposure to ART (y) Incidence of MI per 1000 PY None 10 < >7

50 D:A:D: Traditional Risk Factors for CHD in an HIV-Infected Population Multivariable Poisson model adjusted for age, sex, BMI, HIV risk, cohort, calendar year, race, family history of CVD, smoking, previous CVD event, TC, HDL, hypertension, diabetes. Relative Rate of MI (95% CI) WorseBetter RR: 1.86 ( ) Diabetes (yes vs no) RR: 1.30 ( ) Hypertension (yes vs no) Family history Previous CVD Male sex Age per 5 yrs older Smoking RR: 1.40 ( ) RR: 2.92 ( ) RR: 2.13 ( ) RR: 4.64 ( ) RR: 1.32 ( ) Friis-Møller, et al. N Engl J Med. 2007;356:

51 Contribution of Dyslipidemia to MI Risk *Adjusted for conventional risk factors (sex, cohort, HIV transmission group, ethnicity, age, BMI, family history of CVD, smoking, previous CVD events, lipids, diabetes, and hypertension). Unadjusted model. Relative Rate of MI* (95% CI) 0.72 (0.52–0.99); P=0.05* 1.58 (1.43–1.75); P< (1.19–1.35); P<0.001* 1.10 (1.01–1.18); P=0.002 * 1.00 (0.93–1.09); P=0.92* Total cholesterol (per mmol/L) Triglycerides (per log 2 mmol/L higher) HDL cholesterol (per mmol/L) PI exposure (per additional year) NNRTI exposure (per additional year) Friis-Moller N et al. N Engl J Med. 2007;356:

52 D:A:D – study results and abacavir 1 st Feb 2007, 33,347 patients, 157,912 person-years. 517 MI (event rate 3.3 [95% CI ] per 1,000 person- years) Abacavir and ddI associated with increased relative risk of MI of 1.9 # and 1.49 respectively Associated with recent abacavir and ddI use (<6mths), not cumulative exposure. Reversible on cessation of drug therapy Association remained after adjustment for HIV-RNA levels, CD4 count, dyslipidaemia, blood pressure, diabetes, fat loss/gain or latest glucose, Most pronounced in patients with a high underlying cardiovascular risk Insufficient data to assess TDF and FTC D:A:D Study Group, The Lancet, 26 April, 2008

53 D:A:D – study results and abacavir Analysis of 54 clinical trials involving 9,639 subjects exposed to ABC (7845 pyrs) and 5,044 subjects treated with non-ABC-containing regimens (4653 pyrs) Incidence of myocardial ischaemic events and MI similar regardless of therapy. no increased risk of coronary or myocardial events in any of the ABC-treated groups. Analysis of spontaneous reports submitted to GSK and the FDA found no signal of an increased risk of MI associated with use of ABC. 1 million patient years of abacavir experience Cutrell A et al, The Lancet, 26 April, 2008

54 Parameter HR (95% CI) Death from any cause Death from major cardiovascular, renal and hepatic events Favors TIFavors CT Risk of Complications SMART: Treatment Interruption Associated With Increased CV Risk 2 HIV treatment strategies assessed for overall clinical benefit: CT or CD4-guided TI TI associated with significantly greater disease progression or death, compared with CT: RR: 2.5 (95% CI: ; P <.001) El-Sadr W, et al. N Engl J Med. 2006;355:

55 MI Rates by Age Group in HIV- Infected and HIV-Uninfected Patients Triant VA, et al. J Clin Endocrin Metab. 2007;92: Acute MI rates determined in 3851 HIV-infected and 1,044,589 HIV- uninfected patients from –Overall rates per 1000 person-years higher in HIV-infected vs HIV-uninfected patients: vs Age Group (Yrs) Rates per 1000 Person-Yrs HIV infected HIV uninfected

56 Law MG, et al. HIV Med. 2006;7: Friis-Moller N, et al. CROI Abstract 808. Framingham Underpredicts MI Risk in HIV Age, Sex, TC, HDL, Smoking, SBP, Medication for HBP Observed and Predicted MI Rates According to ART Exposure (D:A:D Study) Duration of cART Exposure (Yrs) Rates per 1000 Person-Yrs < > 4 Observed rates Best estimate of predicte d rates None Does not include HIV-specific factors; Immune status, Increased inflammatory markers, Insulin resistance

57 Conclusions Strong correlation between LDL-C and CVD risk HDL-C independent predictor of CVD cART associated with increased risk of CVD, but uncontrolled HIV infection also risk for CV events Other traditional risks for CVD prevalent, including those that can be modified (smoking) NRTIs, NNRTIs, and PIs have varying effects on lipids, insulin resistance, and fat distribution changes Boosted PIs associated with increased prevalence of dyslipidemia, although evidence suggests that RTV contributes substantially to lipid effects

58 Prevalence of Elevated Cardiovascular Risk in HIV-Infected Patients 17% and 12% of HIV-infected men and women, respectively, had high predicted 10-year CHD risk according to Framingham equation Kaplan RC, et al. Clin Infect Dis. 2007;45: Males Low risk (< 15%) Moderate risk (15% to 25%) High risk ( 25%) Predicted 10-Year Risk of Developing CHD (%) Females HIV infected HIV uninfected Low risk (< 15%) Moderate risk (15% to 25%) High risk ( 25%)

59 Prevention of cardiovascular disease EACS guidelines 2007 Estimate risk of IHD (Ischaemic Heart Disease) in next 10 yrs IHD risk <10% IHD risk 10-20% IHD risk >20%, prior CVD, type II diabetes, type I diabetes with microalbuminuria Encourage lifestyle changes (diet, exercise, cessation of smoking), reduce visceral fat, reduce insulin resistance and treat hypertension LDL-c cut off level:3mmol/L (~115mg/dL) (3-2mmol/L (~115- ~ 80mg/dL)) LDL-c cut off level:4mmol/L (~155mg/dL) (4-3mmol/L (~155- ~ 115mg/dL)) LDL-c cut off level:5mmol/L (~190mg/dL) (5-4mmol/L (~190- ~ 155mg/dL)) Consider modifying ART if: LDL-c is above cut off, i ART thought to contribute to LDL-c level, if possible without compromising HIV suppression Consider modifying ART if: LDL-c is above cut off, i ART thought to contribute to LDL-c level, if possible without compromising HIV suppression Consider modifying ART if: LDL-c is above cut off, i ART thought to contribute to LDL-c level, if possible without compromising HIV suppression If lifestyle changes, with or without modification of ART, do not result in sufficient lowering of LDL-c to below target level, use of lipid-lowering medication should be considered Accessed from

60 Dietary Prevention of Dyslipidemia Randomized trial of NCEP diet in adults initiating ART (N = 90) –95% on ZDV/3TC –75% on EFV 15- to 30-minute session with a dietician every 3 months Other outcomes –Reduced fat, calorie intake –Reduced BMI –Increased dietary fiber intake Lazzaretti F, et al. IAS Abstract WEAB303. Diet Control TC (mg/dL) TG (mg/dL)

61 Smoking Cessation: Nonpharmacologic Therapy Interventions –Identify reasons for quitting –Discuss options –Set a quit date, chosen by the patient –Set up a support system –Identify rationalizations –Identify alternatives for cravings –Provide reliable sources of information –Refer to local smoking cessation programs

62 Effective Smoking Cessation Strategies DHHS guidelines: pharmacotherapy for all patients attempting to quit smoking except those with medical contraindications –Approved pharmacotherapies: sustained-release bupropion, varenicline, nicotine gum, inhaler, nasal spray, and patch More intensive intervention strategies significantly more effective than less intensive ones –Counseling sessions lasting > 3 minutes and > 10 minutes were 1.3-fold and 2.3-fold, respectively, more likely to result in abstinence vs < 3 minutes –8 sessions were 2.3-fold more likely to result in abstinence vs 0-1 sessions –Treatment by various clinician types, individualized counseling, and multiple intervention strategies associated with successful outcomes Elzi L et al, Antiviral Therapy 2006, Fiore MC. Respir Care. 2000;45:

63 Nicotine Replacement Therapy DrugActionCostDosing OTC Gum Fast acting $ Wk 1–6 1 q 1–2 h Wk 7–9 1 q 2–4 h Wk 10–12 1 q 4–8 h Lozenge Fast acting $ lozenges Wk 1–6 1 q 1–2 h Wk 7–9 1 q 2–4 h Wk 10–12 1 q 4–8 h Patch Slow acting $ wk kit Step 1 21 mg X 6 wk Step 2 14 mg X 2 wk Step 3 7 mg X 2 wk Prescription Inhaler 10 mg cartridge Fast acting $ inhaler Wk 1–12 6–16 cart/day (max 40/day) Wk 13–24 Gradual taper Nasal spray 1 dose=2 sprays Fast acting $ bottle (100 doses) Wk 1–8 1–2 doses/h (min 8/d) Wk 9–14 Gradual taper Available at:

64 Smoking Cessation: Pharmacologic Therapy Drug Dosing Bupropion SR Days 1 – mg QD Day 4 – end of treatment 150 mg BID Hepatic impairment Max: 150 mg QD Varenicline Days 1 – mg QD Days 4 – mg BID Day 8 – end of treatment 1 mg BID Physician's Desk Reference. Available at

65 Interactions Between Antiretrovirals and Smoking Cessation Drugs Varenicline –No reported drug interactions with antiretroviral agents –minimal metabolism, 92% excreted unchanged in the urine Bupropion –Metabolized in liver by various CYP450 enzymes, predominantly CYP2B6 –LPV/RTV and bupropion coadministration resulted in significantly decreased concentrations of bupropion and hydroxybupropion [1] –Administration of ritonavir alonemost potent CYP3A4 inhibitor may slow buproprion metabolism [2] –Patients receiving boosted PIs should be monitored carefully for bupropion lack of efficacy and adverse effects 1. Hogeland GW, et al. Clin Pharmacol Ther. 2007;81: Hesse LM, et al. Drug Metab Dispos. 2001;29:

66 Lipid-Lowering Therapy Overview Nicotinic Acid LDL, TG, HDL Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity Statins LDL, TG, HDL Side effects: myopathy, liver enzymes Fibric Acids LDL, TG, HDL Side effects: dyspepsia, gallstones, myopathy Ezetimibe LDL, TG, HDL Side effects: liver enzymes, diarrhea Omega-3 Fatty Acids LDL, TG, HDL Side effects: GI, taste Bile Acid Sequestrants LDL, TG, HDL Side effects: GI distress/ constipation, absorption of other drugs Inhibit production of cholesterol Augment lipoprotein lipase ( VLDL)

67 Ezetimibe for Lipid Management Open-label, 24-week study of 19 patients with LDL 130 mg/dL ( 3.37 mmol/L) receiving ezetimibe 10 mg/day, pravastatin 20 mg/day, and current antiretrovirals [1] Significant in TC and LDL and significant in HDL at Week 24* No adverse events noted 1. Negredo E, et al. AIDS. 2006;20: Wohl D, et al. CROI Abstract 39. Baseline P =.011 P =.005 P = Lipid Levels (mg/dL) TCLDLHDLTG *Subsequent study found that ezetimibe decreased LDL levels by 12% but had no effect on HDL or TG. Week 24

68 Balancing ART and Lipid-Lowering Agents Fibrates Fluvastatin Pravastatin* Ezetimibe Low Interaction Potential Statin-Fibrates Atorvastatin Rosuvastatin Lovastatin Simvastatin Use Cautiously Contraindicated With PIs Lipid Management With ART in HIV-Infected Patients Potential Drug–Drug Interactions With PIs Dubé M et al. Clin Infect Dis. 2003;37: ; Van Der Lee M et al. 13th CROI Denver, CO. Abstract 588; Prezista [package insert]. Raritan, NJ: Tibotec Therapeutics; *Not recommended with darunavir/ritonavir.

69 Lipid-Lowering Therapy vs Switching PI 12-month, open-label study of 130 patients; 60% male; mean age: 39 years Stable on first HAART regimen randomized to –PI EFV (n = 34) –PI NVP (n = 29) –Add bezafibrate (n = 31) –Add pravastatin (n = 36) Pravastatin or bezafibrate significantly more effective in management of hyperlipidemia than switching ART to an NNRTI Calza L, et al. AIDS. 2005;19: Months Months Mean Plasma TGs (mg/dL) Mean Cholesterol (mg/dL)

70 Mallolas J, et al. IAS Abstract WEPEB117LB. ATAZIP: Switch From LPV/RTV to ATV/RTV TGLDLHDLTC P <.0001 Change at Week 48 (mg/dL) P <.0001 Continue LPV/RTV Switch to ATV Randomized trial of patients on LPV/RTV > 6 months randomized to continue LPV/RTV 400/100 mg BID (n = 127) or switch to ATV/RTV 300/100 mg QD (n = 121)

71 Strategies for Managing Hypertriglyceridemia NCEP ATP III final report. Circulation. 2002;106: Initial intervention: dietary modifications Consider antiretroviral switch options If TG > mg/mL (> mmol/L) and antiretroviral switch not possible, consider fibrates –Gemfibrozil 600 mg BID or fenofibrate 200 mg QD associated with 20% to 50% decrease in TG in general population If hypertriglyceridemia remains uncontrolled –Fish oil (up to 6 g/day) or niacin (0.5 to 2g twice-dialy) can be added –Niacin associated with flushing and increased insulin resistance

72 Content Introduction Selected specific adverse events ART and body shape changes ART, HIV and metabolism –Cardiovascular risk general remarks –ART and Lipids –ART, Insulin resistance and diabetes –HIV and cardiovascular risk –Therapeutic approaches, Guidelines Immune reconstitution inflammatary syndrome

73 IRIS = Inflammatory Immune Reconstitution Syndrome Incidence 3-25% CD4 very low CD4 function and increase +++ Pathogen +++ Before ART Advanced disease High pathogen endemicity Battegay et al, JAC, 2008, Hirsch et al, CID 2004, French et al, AIDS 2004; Shelbourne et al, Med 2002 Threshold clinical disease Pathogen (+) After ART initiation ART early initiation VL decrease, CD4 increase Inflammation Pathogen specific immunity inflammation

74 A5164 Methods: Study Schema, n=282 Study day Enrollment OI/BI Treatment Starts Immediate Arm Start ART n=141 Deferred Arm Start ART N=141 Recommended Start window 48 wks 48 wks Immediate vs. Deferred ART in the Setting of Acute AIDS- Related OIs: Final Results of a Randomized Strategy Trial ACTG A5164 Adapted from Andrew Zolopa. CROI 2008; abstract 142.

75 A5164: Safety outcomes over 48 weeks OutcomeP-ValueImmediateDeferred IRIS Reported1013 IRIS Confirmed8 (5.7%)12 (8.5%) OutcomeP-ValueImmediateDeferred Lab Adverse Events Grades – 39 – 2036 – 45 – 21 Clinical Adverse Events Grades – 40 – 734 – 29 – 6 Adapted from Andrew Zolopa. CROI 2008; abstract 142. ImmediateDeferred CD4 (cells/mm 3 )Med (IQR)31 (12 – 54)28 (10 – 56) Multiple OI/BI< 3032%33% PCPn (%)88 (62)89 (63)

76 A5164: Baseline clinical characteristics CharacteristicImmediateDeferredTotal HIV RNA (log10)Median (IQR)5.07 (4.74 – 5.59)5.08 (4.64 – 5.64)5.07 (4.71 – 5.63 ) CD4 (cells/mm 3 )Median (IQR)31 (12 – 54)28 (10 – 56)29 (10 – 55) Multiple OI/BIWithin 30 Days32%33% BIn (%)17 (12) 34 (12) Other OIn (%)36 (26)35 (25)71 (25) Crypto/Histon (%)20 (14)25 (18)45 (16) CMVn (%)4 (3)2 (1)6 (2) MACn (%)3 (2) 6 (2) Toxoplasmosisn (%)9 (6)4 (3)13 (5) PCPn (%)88 (62)89 (63)177 (63) No Prior ARTn (%)131 (93)128 (91)259 (92) P values = ns Adapted from Andrew Zolopa. CROI 2008; abstract 142.

77 A5164: Time to AIDS progression or death Probability of Surviving Without Death/New AIDS-Defining Illness Time to Death/New AIDS-Defining Illness (Weeks) Adapted from Andrew Zolopa. CROI 2008; abstract 142. HR= %CI (0.25, 1.09) P = Better CD4 increase, non significantly different VL results Less clinical progression

78 NEW NIH DHHS Guidelines Some experts base the timing of initiation of antiretroviral therapy in treatment-naive patients with active TB disease on CD4 cell counts at the start of treatment, as shown below CD4 <100ART after 2 weeks CD4 =100–200ART after 8 weeks CD4 = 200–350ART after 8 weeks* CD4 >350ART after 8-24 weeks or after end of TB treatment* * On case by case basis in clinicians judgment. A rifamycin should be included for pts receiving ART (dose adjustment) (AII). Rifabutin is the preferred rifamycin in HIV- infected pts with active TB disease due to its lower risk of substantial interactions with ART (AII). Compiled from Benson et al at 2008


Download ppt "Manuel Battegay Div. Infectious Diseases & Hospital Epidemiology HIV complications and morbidity."

Similar presentations


Ads by Google