HIV complications and morbidity

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

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

cART dramatically improves life expectancy
Type of study  Decrease Mortality % 1996 Delta RCT AZT vs dual ART 1996 ACTG 175 RCT AZT vs dual ART 1997 ACTG 320 RCT Dual vs HAART 1997 SHCS OS No HAART vs HAART 1998 HOPS OS No HAART vs HAART 2003 EUROSIDA OS /97 HAART vs HAART SHCS OS No HAART vs HAART 2007 Danish Coh. OS HIV versus non HIV 30 50 86 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, 2007

Battegay et al, Antiviral Ther 2007
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

cART switch Swiss HIV Cohort Study 2000-2005
Vo et al., JID, Juni 2008

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

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

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

Time to Onset of Abacavir HSR in Clinical Trials (n=206)
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 Data on file, GlaxoSmithKline.

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).

PREDICT-1: Clinically Suspected or Skin Patch–Defined HSR with abacavir treatment
10 9 Control arm 7.8 8 Prospective HLA-B*5701 screening arm 7 6 OR: 0.03 P < .0001 Incidence (%) 5 4 3.4 Use of HLA screening reduced clinically diagnosed HSRs by more than half, but 3.4% still had clinically diagnosed HSRs. Only 2.7% of clinically diagnosed HSR in the control group had a positive SPT (all were B5701 positive retrospectively) and no one in the screening groups had a SPT positive HSR. 46% of all HLA-B5701 positive patients in the control group had an HSR. 2.7 Immunologically Confirmed HSR No Immunologically Confirmed HSR Total HLA-B*5701 Positive 23 25 48 HLA-B*5701 Negative 794 819 842 3 2 0% 1 (66/847) (27/803) (23/842) (0/802) Clinically Suspected HSR Skin Patch-Defined HSR Mallal S, et al. NEJM 2008 Specificity: 794/819 = 96.9% Sensitivity: /23 = 100% PPV: /48 = 47.9% NPV: 794/794 = 100% 13

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 HIV lipoatrophy is characterized by substantial loss of subcutaneous fat from the face (up to 50% volume loss), as well as fat loss in the peripheral limbs and buttocks1-3 Peripheral fat loss may be most immediately evident in prominent veins in the arms and legs, along with increased muscle definition1 Because lean body mass is usually not affected, the condition differs from the AIDS wasting seen before the ubiquity of HAART1 Fichtenbaum CJ, et al. IAPAC Mon. 2005;11:39-46. Grinspoon S, et al. New Engl J Med. 2005;352:48-62. Yang Y, et al. Antivir Ther. 2005;10: Grinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986.

Progression of Lipoatrophy
Clinical Assessment Progression of Lipoatrophy 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 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.

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.

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 HIV lipoatrophy is characterized by substantial loss of subcutaneous fat from the face (up to 50% volume loss), as well as fat loss in the peripheral limbs and buttocks1-3 Peripheral fat loss may be most immediately evident in prominent veins in the arms and legs, along with increased muscle definition1 Because lean body mass is usually not affected, the condition differs from the AIDS wasting seen before the ubiquity of HAART1 Fichtenbaum CJ, et al. IAPAC Mon. 2005;11:39-46. Grinspoon S, et al. New Engl J Med. 2005;352:48-62. Yang Y, et al. Antivir Ther. 2005;10:

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

Lipoatrophy Prevalence Distribution in HIV+ vs HIV– Controls
70 Men HIV Control 60 Percentage Reporting Fat Loss 50 40 P <0.001 P <0.001 P <0.001 P <0.001 30 P <0.001 P =0.025 P =0.053 20 P =0.22 P =0.004 10 P =0.058 Cheeks Face Arms Buttocks Legs Neck Chest Waist Abdominal Fat Upper Back 70 Women 60 In the FRAM Study, among both men and women, self-reported fat loss (over a preceding 5-year period) among HIV-positive patients occurred more often than self-reported fat loss in HIV-negative controls at all sites measured1,2 In men, the difference between the HIV-infected and uninfected control subjects was significant at the following sites: cheeks, face, arms, buttocks, legs, chest and waist1 In women, the difference between the HIV-infected and uninfected control subjects was significant at the following sites: cheeks, face, arms, buttocks, and legs2 Some HIV-infected men reported gain in fat. However, the prevalence of fat gain was significantly lower in HIV-infected men than controls in most central and peripheral sites.1 1. FRAM Study Group. J Acquir Immune Defic Syndr. 2005;40: 2. FRAM Study Group. J Acquir Immune Defic Syndr 2006;42: 50 Percentage Reporting Fat Loss P <0.001 40 P <0.001 P <0.001 30 P <0.001 P <0.001 P =0.055 20 P =0.090 P =0.31 10 P =0.055 P =0.47 Cheeks Face Arms Buttocks Legs Neck Chest Waist Abdominal fat Upper back FRAM Study Group. JAIDS. 2005;40: FRAM Study Group. JAIDS. 2006;42:

Lipohypertrophy Prevalence Distribution in HIV+ vs HIV– Controls
70 Men HIV Control P =0.003 60 P =0.34 50 Percentage Reporting Fat Gain 40 P <0.001 30 P =0.011 P <0.001 P =0.001 P =0.048 20 P =0.003 P =0.32 P =0.40 10 Cheeks Face Arms Buttocks Legs Neck Chest Waist Abdominal fat Upper back 70 Women P =0.13 P =0.17 60 P <0.001 P <0.001 Regarding weight gain in the FRAM Study, more control patients of both genders reported weight gain over a 5-year period than HIV-positive patients with the single exception that more HIV-positive men reported fat gain at the upper back (not significant, P =.40). The pattern of differences in reported weight gain was similar for both men and women.1,2 References 1. FRAM Study Group. J Acquir Immune Defic Syndr. 2005;40: 2. FRAM Study Group. J Acquir Immune Defic Syndr 2006;42: 50 P <0.001 Percentage Reporting Fat Gain P <0.044 40 P <0.009 P =0.039 P =0.54 30 20 P =0.43 10 Cheeks Face Arms Buttocks Legs Neck Chest Waist Abdominal fat Upper back FRAM Study Group. J AIDS. 2005;40: FRAM Study Group. J AIDS. 2006;42:

Effect of NRTIs on Limb Fat
Study 903 Study 934 *P<0.001 TDF + 3TC + EFV d4T + 3TC + EFV Mean Limb Fat (kg) 8.6* 4.5 1 2 3 4 5 6 7 8 9 10 48 96 144 5.0 7.9* 8.1 † ‡ *P=0.034 P<0.001 §P=0.001 TDF + FTC + EFV ZDV/3TC + EFV Total Limb Fat (kg) 12 6.0* 5.5 7.4* ‡P=0.01 Week Week 51 49 49 44 Gallant JE et al. JAMA. 2004;292: ; Pozniak AL et al. JAIDS. 2006;43:

Lipoatrophy at Weeks 48 and 96 (NRTI Arms Only)
P Values at Week 96 ZDV vs TDF: <0.001 d4T vs TDF: <0.001 d4T vs ZDV: 50 d4T ZDV 40 42% TDF (% with >20% loss) Lipoatrophy 30 27% 26% 20 16% N=337 (2 nuc-containing arms) Data available in the final CROI abstract 10 9% 8% 48 96 Weeks on Study d4T TDF ZDV Haubrich R et al. 14th CROI Los Angeles, CA. Abstract 38.

Lipoatrophy (>20% loss of extremity fat) at Weeks 48 and 96
P Values at Week 96 LPV/r + EFV vs LPV/r: LPV/r + EFV vs EFV: <0.001 LPV/r vs EFV: 40 EFV LPV/r 30 32% LPV/r + EFV (% with >20% loss) Lipoatrophy 20 21% 17% 10 N=510 Data available in the final CROI abstract There was a significant difference between EFV and LPV/r in change in extremity fat at 96 weeks. A significantly higher proportion of subjects met the criteria for lipoatrophy (>20% loss of extremity fat) in the EFV arm as compared to the LPV/r arm. This result was consistent regardless of NRTI chosen. There was no significant difference between EFV and LPV/r in the increase in trunk fat at 96 weeks (like what was observed in Study 613). 10% 9% 7% 48 96 Weeks on Study EFV LPV/r LPV/r + EFV Haubrich R et al. 14th CROI Los Angeles, CA. Abstract 38.

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 Results Rosiglitazone (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:

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:

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

CHD risk ractors in HIV - infected population
Gender Abdominal Obesity* Family History Inactivity, Diet Age Cigarette Smoking CHD Lipids* Risk Hyper- tension* - - Multiple factors can contribute to CVD in any patient population. These factors fall into two main categories: Non-modifiable factors, including age, gender and family history Modifiable factors that can be changed through lifestyle management, such as smoking, diet, and exercise, or through drug intervention, eg, dyslipidemia and hypertension Additionally, lifestyle changes such as smoking cessation and diet can positively impact on other modifiable factors such as abnormal lipid profiles and high blood pressure. HIV Infection Hyper- glycemia Insulin Resistance* ART Orange = Modifiable Green = Nonmodifiable Diabetes *Metabolic syndrome

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

Multiple Risk Factors: INTERHEART
Multiple Traditional Risk Factors Confer Synergistic Increase in Risk of MI in General Population 2.9 ( ) 2.4 ( ) 1.9 ( ) 3.3 ( ) 13.0 ( ) 42.3 ( ) 68.5 ( ) 182.9 ( ) 333.7 ( ) 1 2 4 8 16 32 64 128 256 512 Odds Ratio (99% CI) Check Y Axis scale Smoke (1) DM (2) ApoB/A1 (4) 1+2+3 All 4 +Obesity All Risk Factors HTN (3) Risk Factor (adjusted for all others) +Psycho- social Yusuf S et al. Lancet. 2004;364:

LDL Cholesterol (mg/dL)
Lipids and CVD Risk Increasing plasma LDL increases relative risk of CHD A 30 mg/dL ↑ in LDL is associated with ~30% ↑ CHD risk 3.7 LDL Cholesterol (mg/dL) 40 70 100 130 160 190 2.9 2.2 1.7 1.3 1.0 Relative Risk of CHD (log scale) Higher HDL reduces cardiovascular and hypertriglyceridemia is independently associated with CVD Grundy SM et al. Circulation. 2004;110:

GS 934 and GS 903: Lipid Effects of Tenofovir vs Thymidine Analogues
Prospective, randomized, double-blind studies in treatment-naive patients TDF associated with more benign lipid changes and less lipoatrophy 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) TC mmol/L 24 0.62 36 0.94 .005 30 0.79 58 1.50 .001 LDL cholesterol 10 0.26 16 0.41 NS 14 0.36 26 0.67 HDL cholesterol 13 0.34 12 0.31 9 0.23 6 0.15 .003 TG 4 0.04 .047 1 0.01 134 1.51 1. Arribas J, et al. J Acquir Immune Defic Syndr. 2008;47:74-78. 2. Gallant JE, et al. JAMA. 2004;292: 33

Mean Change From Baseline (mg/dL)
Study 934: ZDV/3TC vs TDF + FTC Mean Change Lipid Profile Triglycerides Fasting LDL TDF + FTC + EFV TDF + FTC + EFV 50 ZDV/3TC + EFV ZDV/3TC + EFV 40 30 P =0.067 Mean Change From Baseline (mg/dL) 20 10 Base line TG 149 mg/dL in TDF + FTC 141 mg/dL in ZDV/3TC P =0.12 -10 4 16 24 32 48 60 72 84 96 Study Week Pozniak AL et al. JAIDS. 2006;43:

HEAT: Lipid Effects of ABC/3TC vs TDF/FTC at Week 48
80 ABC/3TC + LPV/RTV (n = 343) TDF/FTC + LPV/RTV (n = 345) 64 60 38 40 32 Median Change From BL (%) 23 20 13 11 8 -1 TC HDL LDL TG -20 Lipid effects comparable between arms Smith K, et al. CROI Abstract 774.

A5142: LPV/r + EFV vs LPV/r + 2 NRTIs vs EFV + 2 NRTIs
Median Changes in Lipids From Baseline – Week 96 P =0.023 EFV LPV/r LPV/r + EFV * 70 * 62 57 60 P ≤0.01 * 50 46 44 NS Median Change From Baseline (mg/dL) 40 33 32 NS 30 26 * 22 19 Significantly greater increases in both HDL and non-HDL cholesterol in the NRTI-sparing (16 and 44 mg/dL) compared to the two NRTI-containing regimens (P <0.001) No difference (P >0.3) in increases in both HDL and Non-HDL cholesterol between the 2 NRTI-containing regimens +8 and +26 mg/dL in LPV/r arm, respectively +9 and +22 mg/dL in EFV arm, respectively 20 16 NS 9 8 10 TC HDL Non-HDL TG *Statistically significant difference with other 2 arms, P ≤0.01. By week 96, 10% and 12% of EFV and LPV subjects used a lipid-lowering agent. Haubrich R et al. 14th CROI Los Angeles, CA. Abstract 38.

CASTLE: Lipid Effects of ATV/RTV vs LPV/RTV at Week 48
ATV/RTV + TDF/FTC (n = 440) 60 LPV/RTV + TDF/FTC (n = 443) Median Change From BL (%) * 50 40 *P < .0001 30 * * 20 10 TC LDL HDL Non-HDL TG Difference estimates (%) -9.5 -2.9 -3.8 -11.6 -25.2 2% of ATV/RTV vs 7% of LPV/RTV subjects initiated lipid-lowering therapy during study Molina JM, et al. CROI Abstract 37. 37 37 37

Median Change From BL (%)
KLEAN: Lipid Effects of FPV/RTV vs LPV/RTV at Week 48 100 FPV/RTV 700/100 mg BID + ABC/3TC (n = 434) LPV/RTV SGC 400/100 mg BID + ABC/3TC (n = 444) 80 66 60 60 Median Change From BL (%) 41 39 39 40 33 29 For more information about this study, see the capsule summary at: 23 20 TC HDL LDL TG Lipid effects comparable between arms Eron JJ, et al. Lancet. 2006;368: 38

GEMINI: Lipids Effects of SQV/RTV vs LPV/RTV (On-Treatment Analysis)
100 SQV/RTV + TDF/FTC LPV/RTV + TDF/FTC 80 Week: 24 48 24 48 24 48 24 48 P = .0022 60 Median Change From BL to Week 24 or 48 (%) P = .0007 47 39 40 26 29 26 21 20 20 18 20 16 17 12 12 12 7 9 n = 106 109 81 100 105 108 80 99 105 108 80 99 106 109 81 99 TC LDL HDL TG 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 PS1.4.

ARTEMIS: Mean Fasting Lipid Levels Over Time for DRV/RTV vs LPV/RTV
DRV/RTV + TDF/FTC LPV/RTV + TDF/FTC TG TC:HDL Ratio ng/mL mM 250 2.9 5.0 4.5 200 2.3 Mean TG Level ( ± SE) Mean TC:HDL Ratio (± SE) 4.0 NCEP cutoff 150 1.7 DRV, darunavir; FTC, emtricitabine; HDL, high density lipoprotein; LPV, lopinavir; RTV, ritonavir; SE, standard error; TC, total cholesterol; TDF, tenofovir 3.5 100 1.1 3.0 2 4 8 12 16 24 36 48 2 4 8 12 16 24 36 48 Time (Wks) Time (Wks) DRV/RTV n = LPV/RTV n = De Jesus E, et al. ICAAC Abstract 718b.

ALERT: Lipid Effects of FPV/RTV vs ATV/RTV at Week 48
FPV/RTV 1400/100 mg QD + ABC/3TC (n = 53) ATV/RTV 300/100 mg QD + ABC/3TC (n = 53) Baseline Week 48 LDL HDL 250 TC TG 125 99 101 200 95 97 171 180 100 160 153 150 Median Lipid Levels (mg/dL) 150 131 124 75 116 Median Lipid Levels (mg/dL) 100 50 38 43 48 37 50 25 FPV/RTV ATV/RTV FPV/RTV ATV/RTV FPV/RTV ATV/RTV FPV/RTV ATV/RTV Lipid effects comparable between arms Smith K, et al. IAS Abstract WEPEB023.

Mean Change in Lipids From
2NN: Lipid Effects of EFV vs NVP at Week 48 48-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 EFV + 3TC/d4T Pooled NVP + 3TC/d4T 49 † 50 43 40 40 * 35 34 31 30 27 EFV, efavirenz; NVP, nevirapine. Mean Change in Lipids From Baseline to Week 48 (%) 20 20 10 5.9 † -4.1 -10 TC LDL HDL TG TC:HDL *P < .05 vs NVP. †P < .001 vs NVP. van Leth F, et al. PLoS Med. 2004;1:e19. 42 42

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) 43

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 76 pts had GTT Normal, IGT and DM diagnoses as per consensus guidelines fasting BSLs norm in 98% 2 hr BSLs abnormal in 23% MISTAKE (40 should be 60) Overall prevalence 22% Grinspoon S et al. N Engl J Med. 2005;352:48-62.

Impact of Various PIs on Glucose and Glucose Disposal Rate
2-Hour OGTT IDV  LPV/r  ATV/r d4T 3TC  References Noor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS. 2001;15:F11-F18. Dubé MP, Edmondson-Melançon H, Qian D, Aqeel R, Johnson DJ, Buchanan TA. Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV-infected patients. J Acquir Immune Defic Syndr. 2001;27: Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS. 1999;13:F63-F70. Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS. 1999;13: Walli RK, Michl GM, Bogner JR, Goebel FD. Improvement of HAART-associated insulin resistance and dyslipidemia after replacement of protease inhibitors with abacavir. Eur J Med Res. 2001;6: Noor MA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS. 2002;16:F1-F8. Dubé MP, Qian D, Edmondson-Melançon H, et al. Prospective, 48-week, intensive metabolic study of amprenavir-based therapy. Clin Infect Dis. 2002;35: Sension M, Thiry A, Giordano M. Absence of insulin resistance through week 24 with atazanavir once-daily and efavirenz once-daily each with fixed-dose zidovudine plus lamivudine. Antivir Ther. 2002;7:L26. Noor MA, Parker RA, O’Mara E, et al. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS. 2004;18: Lee GA, et al. Clinical Infectious Disease Sep 1;43(5): Epub 2006 Jul 26. 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:

OR (95% CI) for insulin > 15 μU/mL
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 Parameter OR (95% CI) for insulin > 15 μU/mL SQV 1.02 IDV 1.14* RTV (boosting dose) 0.95 NFV 1.10 d4T 1.22* 3TC 1.12* ZDV 0.98 ddI 0.95 0.01 1.0 2.0 *P < .05 Brown T, et al. AIDS. 2005;19: 46

Metabolic Syndrome in HIV-Infected vs HIV-Uninfected Patients
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] 26 27 .77 US; 2394 women[2] 33 22 < .001 Spain; 710 men and women[3] 17 N/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) 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: 47

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 100 80 60 51.5 Percentage of Cohort With Risk Factor at Baseline 40 33.8 22.2 20 11.4 8.5 1.4 3.5 2.5 Family History of CHD Previous History of CHD Current Smoking BMI > 30 HTN Diabetes ↑ Total Cholesterol ↑ TG Friis-Møller N, et al. AIDS. 2003;17: 48 48

D:A:D Study: Incidence of MI
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 10 8 6 Incidence of MI per 1000 PY 4 2 None < 1 1-2 2-3 3-4 4-5 5-6 6-7 >7 Exposure to ART (y) Friis-Moller N et al. N Engl J Med. 2007;356: 49

D:A:D: Traditional Risk Factors for CHD in an HIV-Infected Population
Worse Better Age per 5 yrs older RR: 1.32 ( ) Male sex RR: 2.13 ( ) Previous CVD RR: 4.64 ( ) Smoking RR: 2.92 ( ) Family history RR: 1.40 ( ) Diabetes (yes vs no) RR: 1.86 ( ) Hypertension (yes vs no) RR: 1.30 ( ) 0.1 0.5 1 5 10 Relative Rate of MI (95% CI) 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. Friis-Møller, et al. N Engl J Med. 2007;356: 50 50

Contribution of Dyslipidemia to MI Risk
HDL cholesterol (per mmol/L) Triglycerides (per log2 mmol/L higher) Total cholesterol (per mmol/L) PI exposure (per additional year) NNRTI exposure (per additional year) 1 10 0.1 Relative Rate of MI* (95% CI) *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. Friis-Moller N et al. N Engl J Med. 2007;356:

D:A:D – study results and abacavir
1st 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

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

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) Parameter HR (95% CI) Death from any cause 1.8 Risk of Complications Death from major cardiovascular, renal and hepatic events 1.7 0.1 Favors TI 1.0 Favors CT 5.0 El-Sadr W, et al. N Engl J Med. 2006;355: 54

MI Rates by Age Group in HIV-Infected and HIV-Uninfected Patients
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 6.98 120 HIV infected 90 HIV uninfected 77.68 Rates per 1000 Person-Yrs 60 43.63 36.47 33.39 30 24.47 18.74 14.78 10.13 4.65 7.56 0.88 3.34 18-34 35-44 45-54 55-64 65-74 75-84 Age Group (Yrs) Triant VA, et al. J Clin Endocrin Metab. 2007;92: 55

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) 8 7 Observed rates 6 5 Best estimate of predicted rates Rates per 1000 Person-Yrs 4 3 2 1 For more information, see the capsule summary at: None < 1 1-2 2-3 3-4 > 4 Duration of cART Exposure (Yrs) Does not include HIV-specific factors; Immune status, Increased inflammatory markers, Insulin resistance Law MG, et al. HIV Med. 2006;7: Friis-Moller N, et al. CROI Abstract 808. 56 56

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

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 100 86 87 84 81 HIV infected 80 HIV uninfected 60 Predicted 10-Year Risk of Developing CHD (%) 40 17 20 11 12 12 5 2 2 1 Low risk (< 15%) Moderate risk (15% to 25%) High risk (≥ 25%) Low risk (< 15%) Moderate risk (15% to 25%) High risk (≥ 25%) Males Females Kaplan RC, et al. Clin Infect Dis. 2007;45: 58

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:5mmol/L (~190mg/dL) (5-4mmol/L (~190- ~155mg/dL)) LDL-c cut off level:4mmol/L (~155mg/dL) (4-3mmol/L (~155- ~115mg/dL)) LDL-c cut off level:3mmol/L (~115mg/dL) (3-2mmol/L (~115- ~80mg/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

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 220 Diet Control 200 180 TC (mg/dL) 160 140 120 100 240 220 200 180 160 140 TG (mg/dL) 120 100 80 60 40 6 Lazzaretti F, et al. IAS Abstract WEAB303. 60

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

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: 62

Nicotine Replacement Therapy
Drug Action Cost Dosing OTC Gum Fast acting $56.99 110 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 $29.99 48 lozenges Patch Slow acting $52.99 2-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 $18.93 1 inhaler Wk 1–12 6–16 cart/day (max 40/day) Wk 13–24 Gradual taper Nasal spray 1 dose=2 sprays $ bottle (100 doses) Wk 1–8 1–2 doses/h (min 8/d) Wk 9–14 Nicotine Replacement Therapy (NRT) Contraindications Concomitant tobacco use Precautions Pregnancy category D – (human fetal risk); benefits must outweigh risks Cardiovascular disease - 2 wks post MI, serious arrhythmias, & worsening angina pectoris NRT is not an independent risk factor Hx of nasal airway reactions - irritation with NS form Hx of local skin irritation - may occur with patch form Available at:

Smoking Cessation: Pharmacologic Therapy
Drug Dosing Bupropion SR Days 1–3 150 mg QD Day 4–end of treatment 150 mg BID Hepatic impairment Max: Varenicline 0.5 mg QD Days 4–7 0.5 mg BID Day 8–end of treatment 1 mg BID Bupropion Mechanism of action Weak inhibitor of neuronal DA, NE, & 5-HT re-uptake Pharmacokinetics Absorption: steady state in 5-8 days Distribution: 84% protein bound, Vd = 1,950 L Metabolism: CYP2B6 Elimination: T1/2 = 21 hours Quit Date = 2 weeks after initiation Treatment duration = 7-12 weeks If no significant progress by 7 weeks  discontinue Dose titration not required If significant progress by 7-12 weeks consider ongoing therapy Chantix - In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes α4β2 neuronal nicotinic Ach receptor partial agonist Agonist activity reduces cravings & antagonist effects inhibit reward sensations High selectivity and affinity Absorption: steady state in 4 days Distribution: ≤20% protein bound Metabolism: 92% excreted unchanged in the urine Elimination: T1/2 = 24 hours Physician's Desk Reference. Available at

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 alone—most 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: 65

Lipid-Lowering Therapy Overview
Inhibit production of cholesterol Augment lipoprotein lipase (VLDL) 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 Several pharmacologic classes of lipid lowering agents (LLAs) are available, with varying effects on LDL, TG, and HDL. Side effects also vary among the classes. Niacin and bile acid sequestrants were among the first agents to become available for lowering serum lipids. However, these agents are not often used in HIV infected patients primarily due to side effects and dosing frequency. The cornerstones of modern lipid management are fibric acids and HMG CoA reductase inhibitors or statins. More recently adjunctive therapies including ezetimibe and omega 3 fatty acids derived from fish oils have been added to the statins to enhance their lipid lowering properties. Nicotinic Acid LDL  , TG , HDL  Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity Bile Acid Sequestrants LDL , TG , HDL  Side effects: GI distress/ constipation,  absorption of other drugs

Ezetimibe for Lipid Management
Open-label, 24-week study of 19 patients with LDL  130 mg/dL ( 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 250 P = .011 200 Baseline Week 24 P = .005 150 Lipid Levels (mg/dL) 100 P = .004 50 TC LDL HDL TG *Subsequent study found that ezetimibe decreased LDL levels by 12% but had no effect on HDL or TG. 1. Negredo E, et al. AIDS. 2006;20: Wohl D, et al. CROI Abstract 39.

Balancing ART and Lipid-Lowering Agents
Lipid Management With ART in HIV-Infected Patients Potential Drug–Drug Interactions With PIs Fibrates Fluvastatin Pravastatin* Ezetimibe Statin-Fibrates Atorvastatin Rosuvastatin Lovastatin Simvastatin Low Interaction Potential Use Cautiously Contraindicated With PIs *Not recommended with darunavir/ritonavir. 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; 2006.

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 350 300 250 Mean Plasma TGs (mg/dL) 200 150 100 50 3 6 9 12 Months 350 For more information about this study, see the capsule summary at: 300 250 Mean Cholesterol (mg/dL) 200 150 100 50 3 6 9 12 Months Calza L, et al. AIDS. 2005;19: 69

ATAZIP: Switch From LPV/RTV to ATV/RTV
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) 20 TG TC LDL HDL Change at Week 48 (mg/dL) -20 P < .0001 Switch to ATV -40 Continue LPV/RTV P < .0001 -60 Mallolas J, et al. IAS Abstract WEPEB117LB. 70

Strategies for Managing Hypertriglyceridemia
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 NCEP ATP III final report. Circulation. 2002;106: 71

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

A5164 Methods: Study Schema, n=282
Immediate vs. Deferred ART in the Setting of Acute AIDS-Related OIs: Final Results of a Randomized Strategy Trial ACTG A5164 OI/BI Treatment Starts Immediate Arm Start ART n=141 48 wks Deferred Arm Start ART N=141 48 wks Recommended Start window -14 2 28 42 84 224 Study day Enrollment A5164 Methods: Study Schema, n=282 Adapted from Andrew Zolopa. CROI 2008; abstract 142.

A5164: Safety outcomes over 48 weeks
Immediate Deferred CD4 (cells/mm3) Med (IQR) 31 (12 – 54) 28 (10 – 56) Multiple OI/BI < 30 32% 33% PCP n (%) 88 (62) 89 (63) Outcome P-Value Immediate Deferred IRIS Reported 10 13 IRIS Confirmed 8 (5.7%) 12 (8.5%) Outcome P-Value Immediate Deferred Lab Adverse Events Grades 2-3-4 0.77 31 – 39 – 20 36 – 45 – 21 Clinical Adverse Events 0.87 14 – 40 – 7 34 – 29 – 6 Adapted from Andrew Zolopa. CROI 2008; abstract 142.

A5164: Baseline clinical characteristics
Immediate Deferred Total 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/mm3) 31 (12 – 54) 28 (10 – 56) 29 (10 – 55) Multiple OI/BI Within 30 Days 32% 33% BI n (%) 17 (12) 34 (12) Other OI 36 (26) 35 (25) 71 (25) Crypto/Histo 20 (14) 25 (18) 45 (16) CMV 4 (3) 2 (1) 6 (2) MAC 3 (2) Toxoplasmosis 9 (6) 13 (5) PCP 88 (62) 89 (63) 177 (63) No Prior ART 131 (93) 128 (91) 259 (92) P values = ns Adapted from Andrew Zolopa. CROI 2008; abstract 142.

A5164: Time to AIDS progression or death
116 94 Probability of Surviving Without Death/New AIDS-Defining Illness HR=0.53 99%CI (0.25, 1.09) P = 0.023 Time to Death/New AIDS-Defining Illness (Weeks) Better CD4 increase, non significantly different VL results Less clinical progression Adapted from Andrew Zolopa. CROI 2008; abstract 142.

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 <100 ART after 2 weeks CD4 =100–200 ART after 8 weeks CD4 = 200–350 ART after 8 weeks* CD4 >350 ART after 8-24 weeks or after end of TB treatment* * On case by case basis in clinician’s 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

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