Cathy Logan, MD, of the UC San Diego AntiViral Research Center, presents "Solid Organ Transplantation and HIV" at AIDS Clinical Rounds on August 29, 2014

1. The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
AIDS CLINICAL ROUNDS

2. Cathy Logan, MD
August 29, 2014

3. Transplantation in HIV

Organ transplantation is the treatment of choice for advanced organ failure

Previously HIV was considered an absolute contraindication for transplantation

Exclusion has based on the following concerns

Immunosuppression medications accelerating progression to AIDS --- Increased morbidity and death

Transplantation in HIV was felt to have increased mortality and was a “waste” of viable organs

4. Pre-HAART Era Experience

Bouscarat at al 1994: 11 liver recipients infected with HIV 1985-1987. Seven- year survival rate was 36%, compared with approximately 70% in HIV- negative patients

Gordon et al: Poor outcomes in HIV-positive hemophiliac patients with liver transplant in the United States, Canada, and Europe between 1982 to 1996. One and three year survival of HIV positive recipients (67% and 23%) was significantly poorer (p = 0.0003) than that of HIV negative recipients (90% and 83%).

Lang et al. 22 HIV-infected renal transplant recipients in France revealed a five- and seven-year death rate of 50 and 70 percent.

Univ of Pittsburgh: 25 HIV-positive individuals transplanted between 1981 and 1988. The survival after a mean period of 2.75 years (0.7 to 6.6 years):

46 percent (7 of 15) for liver recipients

40 percent (2 of 5) for heart recipients

80 percent (4 of 5) for kidney recipients.

AIDS was the leading cause of death

5. Pre-HAART Experience

Prior to reliable diagnostics, some individuals with HIV received transplants and others undergoing transplant were infected peri-operatively.

Many had much worse outcomes compared to HIV negative recipients

Numbers are small

Duration of infection not consistent

Immunosuppression regimens varied

6. Advances in HIV Therapy

Survival in the HAART era is now similar to other chronic diseases

With increased survival of HIV+ patients, many now experience advanced stages of other illnesses

End-stage renal disease requiring dialysis**

End-stage liver disease**

Advanced heart failure

Advanced lung disease from various etiologies

7. Comorbidities in HIV

HAART has decreased HIV-related mortality

Liver Disease

Common exposures increase rates of hepatitis co-infection

HIV accelerates HCV and HBV infection

ESLD now significant cause of mortality in HIV patients (HCV, HBV, EtOH abuse, toxic medications)

Renal Disease: increased demand for kidney transplantation due to renal failure from complications associated with HIV infection:

HIVAN

IgA nephropathy

Glomerulonephritis from co-infection with hepatitis

8. Distribution of causes of death among CCC participants, 2003-2013.
Canadian Coinfection Cohort

9. Changing Attitudes

Improving prognosis in HIV suggested that transplantation should be reconsidered as an option for some HIV-infected patients with ESRD.

A few HIV-infected individuals had reportedly done well

Spital et al. 248 US renal transplant centers surveyed in 1997

148 responding centers said they require HIV testing of prospective kidney recipients

84% of these centers would not transplant an individual who refuses HIV testing.

The vast majority of responding centers would not transplant a kidney from a cadaveric (88%) or a living donor (91%) into an asymptomatic HIV-infected patient who is otherwise a good candidate for transplantation.

In 2002 Halpern made ethical arguments comparing transplantation in HIV+ with transplantation in patients with other chronic illnesses.

Data more robust over time

According to UNOS the number of centers that said they performed an organ transplant for an HIV-positive patient increased from 25 of the nation's 242 transplant centers in 2005 to 48 centers in 2011.

10. Outcomes

11. Positive Evidence in the HAART era

Stock et al. 2003: 14 patients (10 kidney; four liver transplants; f/u over 1 year).

All kidney recipients (100%) alive with functioning grafts, three liver patients (75%) alive with functioning grafts. 1 death due to rapid HCV recurrence.

Rejection occurred in 5 of 10 kidney recipients but 0/4 liver recipients.

HIV viral loads have remained undetectable

CD4 counts have remained stable
Kumar 2005 Drexel. Prospective study. 40 HIV-positive patients received kidney transplantation 2001-2004.
One- and 2-year patient survival was 85% and 82%
graft survival was 75% and 71%, respectively.
Plasma HIV-1 RNA remained undetectable
CD4 counts remained in excess of 400 cells with no evidence of AIDS for up to 2 years.
CONCLUSION: One- and 2-year graft survival is comparable to other high-risk populations and survival is higher than HIV patients maintained on dialysis. Immunosuppression does not adversely affect HIV recipients maintained on HAART in the short term.

12. Positive Evidence in the HAART era

Roland et al 2008: Eleven liver and 18 kidney recipients (median 3.4 years)

One- and 3-year liver recipient survival was 91% and 64%

One- and 3-year liver graft survival was 82% and 64%, respectively

Kidney recipient survival was 94% (similar to the general transplant population)

Kidney graft survival was 83% (similar to the general transplant population)

CD4+ T-cell counts and HIV RNA levels were stable

2 opportunistic infections (OI)

The 1- and 3-year incidence of rejection episodes for kidney recipients was 52% and 70%

CONCLUSION: Good outcomes in kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV-infected patients

13. Stock et al. New Engl J Med 2010;363(21):2004-14

14. Stock et al. New Engl J Med 2010;363(21):2004-14

15. Stock et al. New Engl J Med 2010;363(21):2004-14

16. Positive Evidence in the HAART era

Stock et al. 2010: 150 patients underwent kidney transplantation 2003-2009 (f/u 1.7yrs)

Patient survival at 1 year and 3 years were 94.6% and 88.2%

Graft-survival rates 90.4% and 73.7% (somewhere between older recipients (≥65 years) and all kidney-transplant recipients.

Risk of graft loss was increased in those treated for rejection (HR 2.8) and those receiving thymoglobulin induction therapy (HR 2.5)

Living-donor transplants were protective (HR 0.2)

Higher-than-expected rejection rate: 1 and 3 year @ 31% and 41%

HIV infection remained well controlled, with stable CD4+ T-cell counts and few HIV-associated complications.
CONCLUSIONS:

Both patient- and graft-survival rates were high at 1 and 3 years, with no increases in complications associated with HIV infection.

The unexpectedly high rejection rates are of serious concern and indicate the need for better immunotherapy.

17. Other Findings

Use of a kidney from a deceased donor and cyclosporine use were independently associated with an increased risk of graft rejection

Several studies report significant decreases in CD4 counts with use of thymoglobulin, but these were transient and no evidence for accelerated HIV

Numbers of heart transplants in HIV are VERY small, but also encouraging

18. Mr. E: 50yom with HIV-HBV with compensated cirrhosis. Doing well at routine visit.

PMH:

Steroid-induced DM

Herpes Zoster

Anogenital HSV

h/o thrush 2002

PCP 2002

Ocular KS 2002

Cryptococcal Meningitis 2002 (off flucon since 2008)

Hypogonadism

Nephrolithiasis-recurrent

CKD grade II

Anal Dysplasia 2002

Depression

Notable Meds:

Etravirine 200mg bid

DRV/r 600/100mg bid

Lamivudine 300mg daily

Raltegravir 400mg bid

Entecavir**

Statin, valtrex, propranolol
Regimen simplified in May:

Complera (TDF/FTC/Rilpivirine)

Dolutegravir

DRV/r 800/100 daily
Social: no drugs/tobacco/ etoh, never had anal sex, uses condoms 100% with wife

19. Mr. E: Presented July with fatigue, malaise, 10lb wt loss, increased abd girth, poor concentration. Admitted with labs below. Further decompensated with ESRD requiring CRRT, AMS leading to intubation.

Labs/Studies in 5/2014

CBC: 5/9>15/44<118

Chem BUN 18/Cr 1.1

LFTs 36/68/92/0.7

HIV VL undetectable since 2005

CD4 326 (300-500) and >200 since 2008

HBV PCR 170,000,000 (previously undetectable)

Labs 7/2014

422/602/178/16 Alb 2.7

Cr 1.74

CK 7000, lipase 138

Crypto Ag 1:10 (1:2-1:8)
Is Mr. E a candidate for liver transplantation?

20. Criteria For Transplantation

21. New Questions

Who should be transplanted?

Comorbidities

Stable HIV

How should they be managed?

Organ selection

Medication interactions

Prophylaxis

Co-infection treatment

22. Transplantation Evaluation and Selection

Selection Team

Transplant Surgeons

Organ Specialist (Nephrology, Hepatology, Cardiology, Pulmonology)

Psychiatrist

Social Worker

Nutritionist

Nurses

Transplant Coordinators

Other healthcare professionals: Infectious Diseases, Cardiology

Tests: Rule out barriers to transplantation including cancer, significant cardiovascular disease, ongoing substance abuse

Social: Patient must prove they can understand and follow complex medication regimens, attend multiple appointments without difficulty, prove social support for the post-transplant period.

Financial: meet with financial counselors about insurance and other ways to cover the costs of the transplant and follow-up care

23. Criteria for Transplantation in HIV
Stock et al. Curr HIV/AIDS Rep (2013) 10:217–225

24. Mr. E: Received liver transplant 8/2014 for decompensated ESLD with MELD 44.

HAART:

Truvada, one tablet per day (also important for his HBV infection treatment)

Dolutegravir (Tivicay), 50mg once per day

Darunavir (Prezista), 800mg once per day

Ritonavir (Norvir), 100mg once per day.

Etravirine (Intelence), 200mg twice a day

Entecavir 1mg daily

HBIG given at time of transplant

Prophy: Valcyte, Septra, Fluconazole**

Immunosuppression: Tacrolimus, MMF, Prednisone taper

25. Pharmacology of Transplantation in HIV

26. Pharmacology of Transplantation

No clear evidence that any particular immunosuppressive regimen is more effective

Many centers avoid thymoglobulin due to profound effects on CD4+ T-cells

Higher rejection rates prompted most centers to use IL-2 receptor inhibitors (Basiliximab) for induction in kidney transplant

27. Choice of Immunosuppression

Most centers: steroids + calcineurin inhibitor tacrolimus or cyclosporin) + mycophenolate mofetil (MMF)

Both MMF and cyclosporine have antiretroviral qualities

Cyclosporine often preferred due to decreased glucose intolerance (particularly with PIs)

mTOR inhibitor sirolimus

may be used over CNIs due to less nephrotoxicity

is anti-proliferate agent against Kaposi’s Sarcoma

May enhance ART by downregulating expression of CCR5 receptors and acting synergistically with entry inhibitors

28. HAART

Goals:

provide suppression of HIV

ensure adequate therapeutic levels of immunosuppression

and minimize drug interactions/toxicities

Protease inhibitors inhibit cytochrome P450 3A4 system  increases levels of CNIs and sirolimus

Efavirenz is a potent inducer of P450

Several antibiotics and antifungals used for prophylaxis and treatment can inhibit P450

29. Medication Interactions
Port J Nephrol Hypert vol.26 no.2 Lisboa abr. 2012

31. Management

32. Prophylaxis
Stock et al. Curr HIV/AIDS Rep (2013) 10:217–225

33. HBV and HIV Co-infection

Excellent outcomes in HIV-HBV co-infected transplant recipients has been documented

Coffin et al.2010: Prospective cohort of 22 patients 2001- 2007 compared to 20 HBV mono-infected patients.

Patient and graft survival was similar: 100% vs. 85% in mono- vs co-infected patients

All patients received anti-HBV therapy and HBIG

All remained HBsAg negative with no clinical evidence of recurrence (median f/u 3.5 yrs)

Low level HBV viremia seen in half, but without transaminase elevation

34. Liver Transplantation in HCV-HIV Co-infection

Outcomes are more variable

Spanish study compared 84 HCV-HIV to 252 matched HCV mono

5-yr survival rates of 54% and 71%

Risk Factors for increased mortality: HCV genotype 1, donor risk index, positive plasma HCV RNA

US prospective, multicenter study of 89 HCV-HIV compared to 235 HCV mono and all recipients >65 yrs old:

3-yr patient and graft survival HCV-HIV: 60% and 53%

3-yr patient and graft survival HCV mono:79% and 74%

HIV only risk factor for decreased pt or graft survival

Rejection occurred significantly more in co-infected

Older donor age, kidney-liver, anti-HCV–positive donor and BMI<21 were predictors of graft loss

Without these risk factors patient and graft survival rates were similar to HCV mono-infected liver recipients

35. % of patients with sustained virological response (SVR)
IFN
24 W
70
50
30
20
10
60
40
IFN
48 W
IFN
+RBV
24 W
IFN
+RBV
48 W
PEG-IFN
+RBV
48 W
0
80
90
2002
2011
1999
2014
PEG-IFN
+RBV
+new PI
Telaprevir
Or Boceprevir
INF-free regimens
12 weeks
? 95-100% SVR 34
16
New HCV Therapies could level the playing field in HIV-HCV Outcomes
K. Lacombe1, M. Lemoine2, G. Raguin3, A. Fontanet4, F. Zoulim5—HCV in HIV Patients, Cure and Beyond. IAS 2013.

36. Transplant Hope HIV Organ Policy Equity Act

U.S. federal law (National Organ Transplant Act of 1984) prohibited transplant of organs from HIV-infected donors

HOPE Act November 21, 2013: Organs infected with HIV may be transplanted into individuals who are: (1) infected with such virus before receiving such an organ; and (2) participating in clinical research approved by and IRB, or if participation in research is no longer warranted, receiving a transplant under such standards and regulations

Uninfected may be transplanted faster because HIV-infected patient will be able to draw from a unique supply

Infected patients may be transplanted faster

More HIV patients will be referred for transplant

37. Conclusion

Outcomes data indicate that HIV infection should not be considered a contraindication to transplantation.

Selection criteria should address HIV viral suppression, active/prior OIs, CD4 count, and include factors that contribute to outcomes, such as need for dual liver/kidney transplant, HCV-infected organ donors, and low BMI.

HCV co-infection is associated with poorer outcomes, but impact of newer DAA therapies for HCV on transplant outcomes is not known.

Careful attention to drug interactions between immunosuppressive medications and antiretroviral medications is required.

The use of newer antiretroviral medications such as integrase inhibitors or CCR5 antagonists may simplify post-transplant management and reduce rejection rates and improve graft survival.

38. www.cafepress.com

39. References

Roland et al. Am J Transplantation 2008; 8: 355-65

Stock et al. New Engl J Med 2010;363(21):2004-14

Stock et al. Transplant Proc. 2001;33(7-8):3646.

Stock et al. Transplantation. 2003;76(2):370.

Stock et al. Curr HIV/AIDS Rep (2013) 10:217–225

Abbot et al. J Am Soc Nephrol. 2004;15(6):1633.

Gathogo, et al. Int J STD AIDS. 2014 Jan;25(1):57-66

Feduska NJ. Human immunodeficiency virus, AIDS, and organ transplantation. Transplant Rev 1990; 4: 93

Tzakis AG, Cooper MH, Dummer JS, Ragni M, Ward JW, Starzl TE. Transplantation in HIV+ patients. Transplantation 1990; 49: 354.

Kumar et al. Kidney Int. 2005;67(4):1622.

Qiu et al. Transplantation. 2006;81(12):1658.

Bouscarat et al. Clin Infect Dis. 1994;19(5):854.

Gordon et al. Gut. 1998;42(5):744.

Lang et al. Transplant Proc. 1991;23(1 Pt 2):1352.

Poli et al. Transplantation. 1989;47(4):724.

Dummer et al. Transplantation. 1989;47(1):134.

Bontempo et al. Blood. 1987;69(6):1721.

Ragni et al. N Engl J Med. 1990;322(26):1886.

Spital et al. Transplantation. 1998;65(9):1187.

Halpern et al. N Engl J Med. 2002;347(4):284.

Coffin et al. Am J Transplant. 2010;10:1268–75

www.uptodate.com