How Pharmacists Can Help HIV-Positive Candidates for Solid Organ Transplant

Since the advent of highly active antiretroviral therapy (HAART) in the 1990s, there’s been a shift: patients with HIV who might have died from opportunistic infections are living much longer with HIV and developing other long-term disease states like end-stage renal disease and cirrhosis.

Patients living with HIV are at high risk for HIV-associated nephropathy, drug-related nephrotoxicity, and IgA nephropathy, and they commonly contract hepatitis B or C coinfections that lead to cirrhosis. For these reasons, renal and liver transplants are the most commonly needed transplants for HIV patients.

When an HIV patient is being considered for transplantation, most of the factors and criteria considered are organ- and institution-specific. In general, a high CD4 count and undetectable viral load on HAART is required.

Many institutions are cautious with patients who have hepatitis B or C coinfections, due to the risk of poor outcomes. Therefore, if cirrhosis is already present, a kidney transplant may be out of the question. Most importantly, patients must be compliant with their HAART regimen and willing to take lifelong prophylactic medications to prevent opportunistic infections when indicated.

The risk of a transplant for an HIV-positive recipient isn’t the same as with other recipients. In fact, the rejection rate is 2 to 3 times higher than in otherwise healthy individuals of the same age, although it’s lower than in elderly, HIV-negative transplant recipients.

The reason for this increased risk is multifactorial and not exactly clear. It’s hypothesized there’s an innate immunity dysregulation occurring in these patients, or there’s actually HIV infection of the graft. Finally, there’s the very real possibility that due to drug—drug interactions with HAART, there’s inadequate immunosuppressant exposure. Increased rejection rates in HIV-positive kidney recipients are associated with increased donor age, higher cold ischemia time, delayed graft function, and hepatitis C coinfection. Increased risk of rejection for liver patients is associated with a higher Model for End-Stage Liver Disease score and hepatitis C coinfection.

Pharmacists’ biggest concern should be immunosuppression and the drug—drug interactions that can occur between HAART and immunosuppressants. Again, these patients are at high risk of rejection and therefore need a high, sustained level of immunosuppression.

There are a few clinical pearls to consider when choosing an immunosuppression regimen. Early data showed cyclosporine to be the calcineurin inhibitor of choice, but more recent studies have shown that high doses of tacrolimus has decreased rates of rejection. Mycophenolate, when combined with nucleoside reverse transcriptase inhibitors (NRTIs), may have some intrinsic antiviral activity of its own. Sirolimus has been shown in vitro to enhance the antiviral activity of certain HAART regimens, including those containing enfurvutide, efavirenz, and CCR5 inhibitors. For induction, thymoglobulin isn’t recommended because it depletes lymphocytes and puts patients at higher risk of opportunistic infections. Conversely, basiliximab has a positive effect on CD4 count and is the induction agent of choice in these patients.

There are many drug—drug interactions to consider when an HIV patient is preparing to have a solid organ transplant. The ideal approach is to establish patients on an effective HAART regimen prior to transplant that has a minimal amount of drug interactions with their planned immunosuppressive agents, and plan to continue that regimen post-transplant.

Some HAART drug-class interactions should be considered when dosing immunosuppressants. First, calcineurin inhibitors, either cyclosporine or tacrolimus, are the backbone of immunosuppressive therapy in most cases, and both are cytochrome P450 3A4 (CYP3A4) and p-glycoprotein substrates. Protease inhibitors (PI) should be avoided because they’re generally dosed with ritonavir or cobicistat as a booster. For example, when tacrolimus is dosed in combination with a boosted PI regimen, doses of only 0.375 mg to 0.5 mg weekly are required, versus usual doses of 2 mg twice daily (starting dose). Non-NNRTIs, like neviripine, efavirenz, and etravirine, are known CYP3A4 inducers and should be avoided, as well. Overall, integrase inhibitor-based regimens are the HAART regimen of choice for patients receiving transplants due to low risk of drug interactions.

The last medication consideration pharmacists should be vigilant about is prophylaxis for opportunistic infections. Because HIV-positive patients who receive an organ transplant are further immune-suppressed, the indications for prophylaxis of opportunistic infections are different. The drugs used for prophylaxis are the same, but the CD4 counts are stricter in transplant patients. The indications are outlined below. The most important difference is transplant patients with HIV need prophylaxis for life, regardless of their CD4 count.

Opportunistic Infection (OI) Prophylaxis

OI

HIV

HIV + Transplant

PCP

CD4 < 200 or CD4% <14%

Oropharyngeal candidiasis

Prophylaxis for life

Toxoplasmosis

IgG+ and CD4 <100

IgG+ and CD4 <200

Or recipient of donor seropositive with toxoplasmosis

MAC

CD4 <50

CD4 <75

OI = opportunistic infection; PCP = Pneumocystic jiroveci Pneuomonia; MAC = Mycobacterium Avium Complex

As you can see, there’s a great deal of opportunity in the transplant world for pharmacist intervention because the medications can get so complicated. For HIV patients in particular, there are many considerations for therapy and drug interactions that may require pharmacists’ expertise.