HIV in Kidney Transplantation

Wisit Cheungpasitporn

May 22, 2015

Disclosure• None

Adults Living with a Diagnosis of HIV Year-End 2008—United States

Classic pathologic features of HIVAN

Wyatt CM et al. Annu Rev Med. 2012;63:147-59.

Naicker S et al. Clin Nephrol. 2015;83(7 Suppl 1):32-8.

Age- and sex-standardized incidence of ESRD among HIV-infected adults

Abraham AG et al. Clin Infect Dis. 2015;60(6):941-9.

Trullas JC et al. Kidney Int. 2011 Apr;79(8):825-42

HIV and ESRD

• Nearly 90% of U.S. patients living with ESRD attributed to HIVAN are African-American.

• Nearly 900 patients with a presumptive diagnosis of HIVAN progress to ESRD each year.

• With improved survival of HIV-infected dialysis patients and increasing prevalence of HIV related ESRD.

United States Renal Data System 2010

HIV+ on dialysis vs. HIV- on dialysis

87%

54%

79%

41% HIV+

HIV-

Ahuja TS et al. J Am Soc Nephrol. 2002;13(7):1889-93.

USRDS data

Probability for kidney transplant

HIV-

HIV+

-National, multicenter, retrospective cohort study of HIV infectedpatients starting dialysis in Spain (1999–2006).

-66 HIV+ and 66 HIV- patients on dialysis

-Matching for dialysis center, year of startingdialysis, age, sex, and race.

Trullàs JC et al. J Acquir Immune Defic Syndr. 2011;57(4):276-83.

Factors Associated with Failure to List HIV+ Kidney Transplant Candidates

Sawinski D et al. Am J Transplant. 2009;9(6):1467-71.

Outcomes: HIV-Infected Recipients

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

150 patientsCD4+ >200Undetectable HIV RNA levelsTreated with a stable ARV regimen

Outcomes: HIV-Infected Recipients

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

31%

41%

12.3%

• SRTR; 2002–2011

• 510 adult kidney transplant recipients with HIV (median follow-up, 3.8 years) matched 1:10 to HIV-negative controls

Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]

The number of kidney transplants

Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]

Graft survival

Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]

HR 1.06; 95% CI, 0.85-1.33; P=0.61

HIV-/HCV-

HIV+/HCV-

Graft survival

Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]

HR 1.38; 95% CI, 1.08-1.77; P=0.01

HIV-/HCV+

HIV+/HCV+

Patient survival

Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]

HIV-/HCV-

HIV+/HCV-

Patient survival

Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]

HIV-/HCV+

HIV+/HCV+

Wyatt CM et al. AIDS 2008, 22:1799–1807

Non-transplant HIV+ pts

Gonzalez VD et al. J Virol. 2009;83(21):11407-11.

T-cell activation in co-infected individuals

• CD38 is expressed selectively during the activation of a subset of mature T cells

Wyatt CM et al. AIDS 2008, 22:1799–1807

HIV-Positive–to–HIV-Positive Kidney Transplantation?

• November 2013: Organs infected with HIV may be transplanted only into individuals who are: (1) infected with such virus before receiving such an organ; and (2) participating in clinical research approved by an institutional review board.

HIV Organ Policy Equity (HOPE) Act approved by US Congress. 2013

HOPE

HIV-Infected Donor Eligibility and Selection in the USA

Richterman A et al. Curr Infect Dis Rep (2015) 17: 17

Moreno CN et al. Rev Assoc Med Bras. 2011;57(1):100-6

• Nationally, approximate 356 potential HIV+ deceased donors yielding 192 kidneys and 247 livers annually.

Richterman A et al. Am J Transplant. 2015 May 14. [Epub ahead of print]

Muller E et al. N Engl J Med. 2010;362(24):2336-7.

-In South Africa

-HIV+ recipients to HIV+ donors

-September to November 2008

-None had access to dialysis

-4 transplants from 2 deceased donors •not received ART•no opportunistic infection or cancer•had normal renal biopsies •without evidence of proteinuria

-ATG as induction therapy Maintenance: prednisone, mycophenolate mofetil, and tacrolimus.

7.7 6.6 19.4 8.2

1.3 1.3 2.01.2

1.11.0 1.2 1.0

-A patient receiving tacrolimus had calcineurin toxicity and was switched to sirolimus.

-At 12 months after transplantation, all patients had good renal function, did not have clinically significant graft rejection.

N Engl J Med. 2015 Feb 12;372(7):613-20.

Method

• Prospective nonrandomized study

• Groote Schuur Hospital, Cape town, South Africa• 50-70 KTx/year• Donor: living (30%) vs deceased (70%)

• All HIV-positive patients with stage 5 CKD who underwent KTx from HIV-positive donors

• September 2008 – February 2014

Donor selectionInclusion

• HIV-infected deceased donors

• Not on ART or received first-line treatment

• Undetectable plasma HIV RNA viral load (<50 copies/mL)

Exclusion

• Severe sepsis

• Active tuberculosis

• WHO stage 4 HIV disease (AIDS)

• Abnormal renal function

• Proteinuria on urine dipstick

• Alb:Cr ratio ≥ 300 µg/g

RecipientInclusion

• HIV-infected

• Receiving ART for ≥ 3 Mo

• CD4 T-cell ≥ 200 /mm3

• Undetectable plasma HIV RNA viral load

Exclusion

• History of opportunistic infection (AIDS)

Immunosuppression

• Induction: rabbit antithymocyte globulin• Thymoglobuline (1.5 mg/kg/d for 5-7 days) or

• ATG (2 mg/kg/d for 5 – 7 days)

• Maintenance: start on day 0• Prednisone (30 5 mg/d over the first 3 Mo after KTx)

• MMF (1 g q 12 hr)

• Tacrolimus (0.2 mg/kg adjusted for trough level 6-8 ng/mL)

Antiretroviral therapy

• Initially, NNRTI-based ART were switched to a boosted PI-based regimen at the time of KTx

• To increase the suppression of donor-virus replication • To lower the costs of immunosuppressive Tx by the inhibitory

effect of ritonavir on calcineurin-inhibitor metabolism

• Due to concern regarding calcineurin-inhibitor toxicity, recipients continued to receive their pre-KTx regimen

• Prophylaxis for opportunistic infection• TMP 80 mg and SMX 400 mg daily for PCP• Isoniazid 300 mg/d for TB • Valganciclovir 900 mg/d for the first 3 Mo for CMV

Clinical protocol

• Follow-up: weekly for 1st month and monthly thereafter

• Lab• Monthly: Urea .Cr• Every 6 Mo: CD4 T-cell count, plasma HIV RNA viral load

• Allograft biopsy• Performed yearly • When clinical suspicion of acute rejection

• Acute rejection: biopsy proven using Banff classification

Statistical analysis

• Kaplan Meier method was used to estimate patient survival, graft survival and allograft rejection

• Data regarding graft survival were censored at the time of patient’s death

Result - Donor

• 15 eligible donors

• Median age 30 (IQR 23-36) years

• Cause of death• 13 trauma• 1 overdose• 1 subarachnoid hemorrhage

• ART therapy before death• 1 NNRTI-based first-line therapy• 14 no ART

Result - Recipient

• 27 recipients

• Survivors were followed for a median of 2.4 yr

RESULTS – Patient and graft survival

• 2 had delayed graft function and required dialysis during the 1st week after KTx

• 1 graft failure due to venous thrombosis on day 1• 1 acute severe Ab-mediated rejection , refractory to

plamapheresis, which necessitated graft removal after 2 weeks

• 25 well-functioning graft at the end of 1st year

• Median Cr at 1 year 1.3 (1.2-1.3 mg/dL)

RESULTS – Patient survival

Time (Yr)

HIV +ve HIV -ve

1 84 91

3 84 -

5 74 85

RESULTS – Patient survival

• 5 patients died after KTx• 1 Sepsis (E.coli and pseudomonas) and acute pancreatitis• 1 MI• 1 recurrent klebsiella pneumoniae septicemia due to UTI• 1 rapidly progressive, invasive pulmonary aspergillosis • 1 pulmonary squamous cell carcinoma

1 month

6 months1st year

1st year

5 years

RESULTS – Graft survival

Time (Yr)

HIV +ve HIV -ve

1 93 88

3 84 -

5 84 75

RESULTS – Allograft rejection

• 8 episodes of biopsy-confirmed acute rejection• 6 were successfully reversed using steroid, ATG, or

plasmapheresis• 2 graft failure

• 1st week: acute severe Ab-mediated rejection• 2 years: chronic scarring and fibrosis

• Rejection rate; 8% at 1 year and 22% at 3 years

RESULTS – Pharmacologic interactions

• Type of ART regimen had a consierable effect of the tacrolimus dosing

• The median tacrolimus dose was 0.5 mg q 7 – 10 days in PI-based regimen vs 8.5 mg q 12 hours in NNRTI-based regimen

• Side effect of tacrolimus were more pronounced in PI-based regimen

• 5 renal biopsy of calcineurin-inhibitor toxicity

RESULTS – Progression of HIV disease

• CD4 T-cell count• Median was 179 (IQR 141-310) in 1st year and 386 (IQR 307-

484) at 3 years

• Viral load• All had undetectable viral load (<50 copies/mL) during F/U

• Histologic finding• 3 routine renal biopsy revealed typical change of early HIV-

associated nephropathy; none had clinically significant renal impairment, proteinuria or required dialysis

Discussion

• Outcomes in HIV+ patient who received kidneys from HIV+ donors were comparable with those who received from HIV- donor

• Concerns• The risk of transmission of a new and possibly

resistant strain of HIV from donor to recipient• The appearance in the postoperative biopsy

specimens of early changes related to HIV-associated nephropathy that were not present in the baseline biopsy specimens

• Interaction between medications

Discussion

• The patients in this study did not have any increase in plasma viral load, and viral levels remained undetectable after transplantation.

• All the donors in this study had not received ART previously or had received first-line treatment with no known virologic evidence that would suggest resistance, although genotyping was not performed.

• Protocol renal transplant biopsies performed at 3 months from 19 recipients with HIV-1

• Undetectable levels of plasma HIV-1 RNA at transplantation

• HIV-1 infected the kidney allograft in 68% of these patients

• Podocyte infection associated with a faster decline in allograft function compared with tubular cell infection.

Canaud G et al. J Am Soc Nephrol 2014;25:407-19

in situ hybridization of HIV-1 RNA

Discussion

• The interaction between ART and immunosuppressants• Ritonavir and TAC

• Decreases the metabolism of TAC, resulting in a decrease of more than 80% in the clearance of TAC

• Required minimal doses of TAC every 7 to 10 days to maintain adequate levels.

• A higher incidence of CNI nephrotoxicity

• The NNRTIs and TAC• Induce the cytochrome P450 enzyme system• Increases the metabolism of tacrolimus, necessitating

higher doses (median, 8.5 mg twice daily) to maintain adequate levels.

Discussion

• Rejection rates among HIV-positive recipients have been reported to be approximately 3 times as high as those among HIV-negative recipients: unclear reasons

• Immune dysregulation• Challenge of managing the drug interactions

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

Conclusions

• Kidney transplantation from an HIV-positive donor appears to be an additional treatment option for HIV-infected patients requiring renal-replacement therapy.

Questions & Discussion

Apply to the United States?

• Lack of access to dialysis severely limits options for HIV-infected individuals with ESRD in South Africa, altering the risk–benefit dynamic.

• South African donors have been untreated for HIV; given the homogeneity of HIV infection in South Africa, it is unlikely that there will be resistance issues complicating management of the recipients.

Apply to the United States?

• The population of HIV-infected individuals in U.S.- higher rates of antiretroviral exposure and resistance:

• making it less likely that a single empiric choice of antiretrovirals will be sufficient to treat both donor and recipient.

Ethics of HIV-Infected Donation

• Attitudes of HIV-Infected Patients on waiting list- No data available

• Beneficence- strive to expand access to transplant in novel ways because of the discrepancy between the need for transplant and organ shortage.

• Non-maleficence-requires a cautious process forward because of limited outcomes data from HIV-infected donors.

• Informed consent