Chronic complications of HIV infection. An update Pablo Tebas, MD

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1 Activity Code TM809

2 Chronic complications of HIV infection. An update 2014 Pablo Tebas, MD

3 Learning Objectives Upon completion of this presentation, learners should be better able to: Identify and update their knowledge about recent data on the long-term complications of HIV infection Describe the data on available interventions to delay and/or prevent long-term complications of HIV infection. Implement interventions for the prevention and management of the long-term complications of HIV infection

4 I serve in an adjudication panel in a VZV vaccine study (Glaxo) I serve in a DSMB for IL-7 studies (Cytheris) I consult for Merck, Astra Zeneca, Gilead and Jansen My research is supported indirectly (through Penn) by all the manufacturers of HIV drugs I do not give non CME talks

5 Traditional complications Lipodystrophy Lipids and cardiovascular disease Insulin resistance Osteopenia/osteoporosis Renal issues New complications Accelerated aging Persistent inflammation and associated badness

6 THE PATIENT Individual and social factors Higher rate of traditional risk factors: smoking, dyslipidemia, HTN, diabetes Obesity Renal disease THE VIRUS HIV infection itself Ongoing inflammation despite HAART Metabolic Complications THE TREATMENT Antiretroviral therapy and toxicity

7 Grinspoon, S. et al. N Engl J Med 2005;352:48-62

8 A. Martin et al. AIDS 2004;18:

9 Bozzette S et al. N Engl J Med 2003;348:

10 The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group,. N Engl J Med 2003;349:

11 CVD risk Rapid decrease after starting ART Moderate increase overtime driven by Traditional risk factors Persistent inflammation Drugs? Time after starting antiretroviral therapy

12 Avoid (if possible) regimens that exacerbate known co-morbidities Aggressive management of traditional risk factors Guidelines for the general population are usually adequate Switches occasionally useful but limited benefit Beware of pharmacological interactions

13 EACS Guidelines, October 2011

14 Approach to bone problems in HIV patients CID 2010; 51(8):

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16 Are these curves the same? If they are not the same, why? This is HIV and its treatment This part is population specific

17 HIV + versus HIVpeople 1.61 ( ) HIV + on treatment vs HIV ( ) Islam et al. HIV Medicine 2012; 13:

18 THE PATIENT Individual and social factors Higher rate of traditional risk factors: smoking, dyslipidemia, HTN, diabetes Obesity Renal disease THE VIRUS HIV infection itself Ongoing inflammation despite HAART CVD THE TREATMENT Antiretroviral therapy and toxicity

19 Calvo M. et al. HIV Medicine. 2013; 14: 40 48

20 Patients (%) Update of analysis of ABC and risk of acute MI in pts with low, medium, and high CVD risk After initial D:A:D report in March 2008, decline in ABC initiations in pts with higher CVD risk Framingham Risk Group Before March 2008 ABC Use as Proportion of All ART Initiations, % Low/unknown CVD risk 13.6 Moderate/high CVD risk 17.1 After March 2008 Low/unknown CVD risk 7.6 Moderate/high CVD risk Patients on ABC by CVD Risk Low CVD risk Moderate CVD risk High CVD risk CVD risk unknown Total cohort Sabin C, et al. CROI Abstract 747LB.

21 Current ABC use remained associated with increased risk of acute MI Similar RR in post-3/08 group vs pre- 3/08 group, despite decrease in ABC use in pts with high CVD risk Absolute risk in the post 2008 small: 6 cases /2000 PY vs 3 cases/2000 PY or absolute risk 0.15% Overall cohort: 941 MI events during 367,599 PYs 0.47/100 PYs (95% CI: ) with current ABC 0.21 (95% CI: ) with no current ABC No Current ABC Events/PYs 600/295, /169, /126,225 Rate/100 PYs Adjusted Relative Rate of MI in Pts Currently Receiving ABC Overall Pre-3/08 Post-3/ ( ) ( ) ( ) 0.20 ( ) 0.25 ( ) 0.14 ( ) Current ABC Events/PYs 341/ / /31084 Rate/100 PYs 0.47 ( ) 0.61 ( ) 0.30 ( ) Sabin C, et al. CROI Abstract 747LB.

22 MIs per 100,000 PY Retrospective analysis of Kaiser cohort EMRs during for inpatient MI diagnosis HIV-/HIV+ pts matched 10:1 MI rates in HIV+ and HIVconverged over time 40% increased risk of MI in HIV+ pts overall, but difference no longer observed in most recent yrs Framingham Risk Score Components, Mean Framingham score, 10-yr risk of MI, % HIV+ HIV- P Value <.001 Male, % Mean age, yrs <.001 TC > 200 mg/dl, % <.001 HDL-C < 40 mg/dl, % <.001 Hx of hypertension, % <.001 Hx of smoking, % <.001 HIV+ HIV- Klein D, et al. CROI Abstract 737. Reproduced with permission.

23 Treat the lipids and other traditional risk factors Switch or not to switch?

24 Mean Total Cholesterol (mg/dl) EFV NVP Pravastatin Bezafibrate -10% -27% -38% -46% Months Mean Total Cholesterol (mmol/l) Calza L, et al. AIDS. 2005;19:

25 SPIRIT Study Design VL <50 copies/ml Stable PI + RTV + 2 NRTIs 6 months On 1st or 2nd regimen without prior NNRTI use No known resistance to study agents (N=476) n=317 2:1 n=159 FTC/RPV/TDF STR PI + RTV +2 NRTIs FTC/RPV/TDF STR FTC/RPV/TDF STR 24 weeks 48 weeks Primary Endpoint Secondary Endpoint Primary Endpoint: Non-inferiority to PI+RTV+2 NRTIs HIV-1 RNA <50 copies/ml at 24 weeks Secondary Endpoints: Change in CD4 cell count at 24 and 48 weeks Safety and tolerability at 24 and 48 weeks Change in fasting lipid parameters at 24 and 48 weeks Palela et al. AIDS Jan 28;28(3):335-44

26 FTC/RPV/TDF n=317 Total Cholesterol PI+RTV+2NRTIs n=159 <200 mg/dl 200 to <240 mg/dl 240 mg/dl Desirable Borderline High High % of Subjects % of Subjects At baseline, no difference in distribution across Total Cholesterol NCEP categories comparing FTC/RPV/TDF and PI+RTV+2NRTIs (p=0.93) At Week 24, statistically significant difference in distribution across Total Cholesterol NCEP categories comparing FTC/RPV/TDF and PI+RTV+2NRTIs (p<0.001) Tebas et al. Lipodystrophy meeting 2012

27 HIV patients have higher CVD than the non infected population The cause is a combination of individual, viral and treatment factors Management approach includes aggressive management of traditional risk factors Ongoing inflammation may be a future therapeutic target

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29 * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.63) A5224s

30 Philip Grant et al. Clin Infect Dis Nov;57(10):1483-8

31 % BMD change from baseline at Week 48 % BMD change from baseline at Week week treatment-naive study, n=80 Treatments: RAL + DRV/r vs DRV/r + TDF/FTC Results Changes in CTx and P1NP predicted BMD changes at Week 48. Patients in the TDF-containing arm had higher BTMs and more bone loss and similar body composition changes. Changes in Bone Turnover Markers at Week 16 predict BMD at Week % P1NP change from baseline at Week 16 R= (overall) RAL + DRV/r DRV/r + TDF/FTC P1NP: procollagen type 1 N-terminal propeptide (range: mg/l) Bedimo et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WEPE % CTx change from baseline at Week 16 R= (overall) RAL + DRV/r DRV/r + TDF/FTC CTx: C-terminal telopeptide of type 1 collagen (range: ng/ml) Tebas et al. ICAAC 2013; Denver, CO. Abstract H-1461.

32 Phase 2 Study Design GS-US Randomized, placebo-controlled, double-blind study Treatment Arm 1 (n=100) 17% VL> , 13% CD Treatment-naive subjects (n=150) E/C/F/TAF QD E/C/F/TDF (STB) Placebo QD Randomized 2:1 Stratification by HIV RNA >/ 100,000 Treatment Arm 2 (n=50) E/C/F/TDF (STB) QD E/C/F/TAF Placebo QD 28% VL> , 19% CD Week 48 TAF 10mg in E/C/F/TAF has PK comparable to TAF 25mg alone; COBI TAF levels ~2.2-fold. Primary endpoint --Proportion with HIV-1 RNA < 50 at Week 24 (Snapshot) A Zolopa, et al., CROI 2013; Paper # 99LB

33 A Zolopa, et al., CROI 2013; Paper # 99LB

34 Change in BMD (%) Randomized, double-blind trial in pts initiating TDF/FTC/EFV with baseline vitamin D ng/ml Vitamin D IU/day plus Calcium carbonate 1000 IU/day Significant, 50% reduction in loss of hip BMD at Wk 48 in treated pts Smaller nonsignificant difference in spine BMD in treated pts Smaller increase in markers of bone turnover in treated pts Decline in BMD From Baseline to Wk 48 Vitamin D/calcium Placebo P <.001 P = Total Hip Lumbar Spine Lower and upper edges of box indicate 25th and 75th percentiles; lines inside box indicate median. Overton ET, et al. CROI Abstract 133.

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36 Estimated Number of Persons Living with HIV/AIDS Patients with HIV are getting older (BTW you and me too ) Age Distribution (in years) of HIV Positive Individuals Living in the United States 110, ,000 90,000 80, ,000 60,000 50,000 40,000 30,000 20,000 10,000 0 < >65 Age Group (Years) Adapted from CDC Surveillance Report 2006

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38 Aging is the accumulation of changes in a person over time Accelerated aging implies a global process, not a selective one.

39 Incidence an HIV patient of 50 looks like somebody of 70 This must be accelerated aging Or is this increased risk? HIV+ HIV

40 AMI: Clinically comfirmed. ESRD: Dialysis or transpl. Cancer: Registry validated. Period: Oct 2003-Sep 2008 Matched 1:2 for: Age, Race, Clinical site. K Althoff. 20 TH CROI #59.

41 K Althoff. 20 TH CROI #59.

42 K Althoff. 20 TH CROI #59.

43 Liver and Lung classified as AIDS-defining (!) HIV+ individuals had a greater rate of MI, ESRD, and HIV associated cancers. No difference in the rate of other cancers. No difference in mean age at MI, ESRD or non-aids cancer diagnosis. K Althoff. 20 TH CROI #59.

44 The term is catchy, and drives attention to co-morbidities associated with HIV, but I think it is misleading By definition patients with HIV are aging, but I do not think at a faster rate than any of us They are at an increased risk of comorbidities and we need to deal with those

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46 Hunt P W et al. J Infect Dis. 2008;197:

47 Hunt et al. AIDS November 13; 25(17):

48 Hunt et al. AIDS November 13; 25(17):

49 Tien et al. JAIDS, 2010

50 Direct proof of aortic inflammation in patients with well controlled HIV replication S Subramanian, et al. JAMA 2012; 308: Arterial Inflammation in patients with HIV

51 1. Finding a cure for HIV-infected individuals 2. Developing therapeutic strategies for preventing and treating tuberculosis (TB) and hepatitis C 3. Addressing the long-term consequences of treatment of HIV infection and ongoing inflammation. Future Priorities for NIAID s HIV Research Carl W. Dieffenbach, Ph.D., Director of NIAID's Division of AIDS

52 Why? IL-7 Ganciclovir Intensification Sevelamer Rifaximin Chloroquine Metrotexate

53 Effect of Statin on Immune Activation and Inflammation in HIV+ Subjects on ART: A Randomized Placebo Controlled Trial McComsey G, et al. 20th CROI; Atlanta, GA; March 3-6, Abst. 186LB.

54 Raltegravir switch decreases same markers of inflammation and lipids (mainly TG) Martinez et al. AIDS 2012;

55 HIV patients on treatment have persistent inflammation That inflammation is probably not good for many reasons We still do not know much about why this is happening, how clinically relevant it is (probably it is) or what to do about it.

56 Activity Code TM809