Transplantation of HIV+ organs: from ban to HOPE

Organ donation from HIV positive patients has been prohibited in the USA since 1988. Pre-transplant screening for HIV is mandatory using nuclear amplification test (NAT), though false negative results during “window period” are a potential concern in donor selection.

Elmi Muller spoke at our Transplant Grand Rounds yesterday and told us about the challenge she faces in South Africa, where HIV infection affects more than 15% of the population, HIV patients frequently develop HIV-associated nephropathy (HIVAN) and progress to ESRD. Moreover, the availability of renal replacement therapy (hemodialysis) is limited.

In the early 90's, there were a number of uncertainties related to transplanting HIV positive patients including the worrisome concern about introducing a donor-derived virus that could lead to out of control HIV infection (resistant strain?); the effect on the immune system of HIV infection in combination with immunosuppression (worse immunodeficiency?); and the financial burden of expanding the services of transplantation to HIV+ patients in a country with limited health budget.

Against all the odds, Elmi performed four cases of HIV positive kidney donors to HIV positive recipients in South Africa in 2008. No IRB approval... Elmi reported having some intuition that it would work and she was in touch with other physicians around the world who shared her view. In her side, HIV resistance rate is very low in South Africa.

After performing those transplant, her colleagues and the hospital prosecuted her and banned her from performing surgery for more than 1 year. This past week, the HIV Organ Policy Equity (HOPE) Act was approved by the US Congress, permitting donation from HIV-positive organs to HIV-positive recipients. It took time but she is now recognized as a pioneer in the field and her courage to perform those surgeries were remarkable. The law that passed will help expand the availability of organ donors to HIV positive patients and will help with organ shortage.

Some challenges though still remain. HIV resistance is much higher in the States (~19%) and HIV+ transplant recipients experience a higher rate of rejection and significant difficulties with drug-drug interactions (P450 inhibitors). Details about a recent trial can be reviewed on this prior blog. In contrary to the idea of over-immunosuppression, recent paper suggests that ATG may be a better induction therapy choice for these patients. Closely monitoring of these patients will be essential as we learn more about HIV and transplantation. By bending rules, Elmi changed a transplant policy and made history.

Naoka Murakami
Leo Riella

Management of CMV after transplantation

Pre-transplant:

All the donors and recipients of kidney transplants (both living and deceased) should be tested for status of CMV by CMV IgG in the blood. If there is history of recent transfusion, pre-transfusion status should be regarded as the true status of CMV. The status of both donor and recipient for a given pair. should be documented in the record post-transplant

Post-transplant:

Prophylaxis:

• CMV related illness is common in the KTRs and the risk is highest in D+/R- group and the least in D-/R-. 
• We do prophylaxis KTRs with Valganciclovir (Valcyte) 900 mg daily (adjusted for renal function) for 6 months in D+/R- group, and 450 mg daily for 3 months for R+ group regardless of the donor status. No CMV prophylaxis is required for the D-/R- group (this group receives acyclovir for prophylaxis of other opportunistic viruses like HSV and HZV).
• Leukopenia is a side effect of Valcyte and the anti-metabolites. If leukopenia is encountered, valcyte dose or dose of the anti-metabolite (eg MPA derivative, azathioprine, or TOR inhibitor) or both be adjusted based on the physician’s discretion (consider checking for CMV pcr). Consider use of G-CSF if the absolute neutrophil count is less than 500. If Valcyte dose must reduced or discontinued for more than one week, weekly monitoring of CMV Quantitative (blood PCR) could be considered for a total of 3-4 months from the time of transplant.
• Routine CMV PCR testing is NOT recommended in patients receiving full doses of prophylactic therapy unless there is some other clinical suspicion for breakthrough CMV infection.

Treatment - CMV related illness is divided into:

1. CMV infection:

Active viral replication (based on blood PCR) without any symptoms attributable to CMV. It is recommended to start treatment even at a low level of viral load. It should be noted that a change of viral load less than or greater than three times the previous value (0.5 times log 10) does not mean a true change in the viral load. 

Valcyte at treatment dose (900 mg BID), adjusted for renal function) is recommended for treatment. Weekly Quantitative PCR in plasma is recommended while on treatment and duration of treatment to continue at least for two consecutive negative Quantitative PCRs, and not less than a total of 2 weeks. Secondary prophylaxis at the end of treatment (at prophylaxis dose of Valcyte) for a month or two after finishing treatment can be considered if suspicion for relapse is high.

2. CMV disease:

Active viral replication plus symptoms: Either 1) a flu-like illness with fever and general malaise,  often associated with leukopenia or 2) tissue invasive disease (commonly GI but also including hepatitis, pulmonary and rarely uveitis and encephalitis).

Treatment either with Valcyte at treatment dose or IV Ganciclovir at treatment dose (for life threatening illness and GI disease). IV Ganciclovir can be switched to corresponding dose of Valcyte at any time during the therapy if considered appropriate. Monitoring for response and duration of treatment are similar to CMV infection treatment. Please note that tissue invasive disease can rarely occur with negative quantitative PCR in blood (especially when disease is limited to the GI tract). In that situation, duration of therapy should consist of at least two weeks of the antiviral or longer as guided by clinical response. Secondary prophylaxis at the end of treatment with Valcyte for a month or two (at prophylaxis dose of valcyte) can be considered if suspicion for relapse is high. 

Lowering of immunosuppression should be considered starting with the anti-metabolite (definitely for life threatening illness) at the discretion of physician. If leukopenia is encountered, it is recommended to lower anti-metabolite rather than lowering valcyte dose to avoid failure of therapy and resistance of CMV to valcyte.

CMV resistance, although rare, should be suspected if no response to therapy even after a total duration of 5 weeks with Valcyte. If CMV resistance is confirmed, consider foscarnet for treatment, the dose of which should be also adjusted based on renal function

CrCl (ml/min)	Maintenance/Prophylaxis	Treatment
Valcyte
>60	900 mg q day	900 mg bid
40-59	450 mg q day	450 mg bid
25-39	450 mg q 2 days	450 mg q day
10-24	450 mg twice weekly	450 mg q 2 days
<10	100 mg 3 times a week, after HD	200 mg 3 times a week, after HD
IV Ganciclovir
>70		5 mg/kg q 12 hr
50-69		2.5 mg/kg q 12 hr
25-49		2.5 mg/kg q 24 hr
10-24		1.25 mg/kg q 24 hr
<10		1.25 mg/kg 3 times a week after HD

 

Posted by Raj Sabaru