End-organ disease has emerged as a principal cause of morbidity and mortality in HIV infection, but organ transplantation historically was not made available to HIV-infected individuals. Initial efforts to offer transplantation to HIV-infected patients raised concerns about the potential impact of immunosuppression on accelerating HIV disease progression or reactivating AIDS-related opportunistic infections (OIs) and neoplasms. Whereas preliminary studies did not suggest that transplant-associated immunosuppression resulted in increased incidence or mortality from HIV-associated OIs, many unanswered questions about selection criteria, immunosuppressive therapy, and management of comorbidities and concurrent infections have remained. Experience with transplantation of other organs is extremely limited, and few data are available.
| Transplantation Outcomes|
Prior to 1995, treatment for HIV infection largely failed to extend life expectancy, and very few centers attempted solid-organ transplantation in HIV-infected individuals. Data from the early years of the epidemic are limited to case reports and small case series, but in general, mortality was high, particularly in those with unrecognized HIV infection at the time of transplantation, and HIV-infected patients experienced significantly higher 5-year mortality and rates of graft loss relative to HIV-uninfected individuals.(1-3) Since the advent of effective HIV therapy, transplantation outcomes have improved. Data from larger studies document acceptable patient and graft survival rates for liver transplants and survival rates for kidney transplants that approximate those seen in HIV-negative recipients (Table
1). Studies to date do not suggest that transplant-associated immunosuppression results in increased incidence of or mortality from HIV-associated OIs.
Retrospective studies and largely single-center cohorts of HIV-infected liver transplant recipients have demonstrated survival rates that generally are considered acceptable (in the range of 50-75%) but vary by site and cause of end-stage liver disease (ESLD) (Table
1). Many, but not all, studies demonstrated comparable outcomes in HIV-infected vs HIV-uninfected recipients. Coinfection with hepatitis C virus (HCV) has been associated with poorer survival in liver transplant recipients, compared with HCV-monoinfected recipients.(4-6) In contrast, 4-year survival rates of 85-100% have been reported in liver transplant patients coinfected with HIV and chronic hepatitis B, reflecting the relative success at controlling hepatitis B virus (HBV) replication posttransplant with currently available antiretroviral therapy (ART) and with hepatitis B immunoglobulin immunoprophylaxis.(7-8)
Experience in the era of suppressive ART yielded more uniform results for kidney transplantation, with most centers reporting 3-year survival rates of >90%, and graft survival of >80%, with primarily cadaveric donors (Table
1). Rates of acute rejection, however, have been high, ranging from 22% to >50%, and approximately 2-3 times those seen in HIV-uninfected recipients. A lower rate of rejection of 13%, approximating that seen in HIV-uninfected recipients, was reported in a small study of 8 kidney recipients with use of an immunosuppressive protocol consisting of an antiinterleukin-2 receptor antibody for induction, and mycophenolate mofetil (MMF), cyclosporin A, and prednisone for maintenance.(9) The authors attributed their low rate of rejection to the use of higher cyclosporin A trough-level targets and adjustment of MMF dosage according to mycophenolic acid predose trough concentrations.
A larger, U.S. multisite study (the HIVTR study) of 150 kidney and 125 liver transplants has recently been completed, with the goal of identifying optimal patient selection characteristics and posttransplant management strategies.(10-11) Median 3-year survival of kidney recipients was comparable with that in the HIV-uninfected population, at 90.6%. Acute rejection was 2- to 3-fold higher that that seen in the HIV-uninfected population, with rejection rates of 31% at 1 year and 41% at 3 years, confirming earlier reports. Kidney graft survival was 75.5 %, comparable to that achieved in the general older (>65 years) population. Initial use of thymoglobulin to induce immunosuppression, HCV coinfection, and older age decreased survival in kidney recipients. Among liver transplant recipients in the HIVTR study, 3-year survival was lower than among kidney transplant recipients at 66.4%, and graft survival was 61.5%. Receiving a dual-organ transplant, lower pretransplant body mass index (BMI), older age, and HCV coinfection were associated with decreased survival. Liver transplantation conferred a survival benefit if the pretransplantation Model for End-Stage Liver Disease (MELD) score was ≥15, but that was not associated with reduced mortality if the MELD score was <15, as has been demonstrated with HIV-uninfected recipients. Kidney transplantation, on the other hand, did not confer a survival benefit.
| Infectious Complications|
The infectious complications of posttransplantation immunosuppression overlap broadly with the array of OIs seen in advanced HIV disease. Despite this, relatively few HIV-associated OIs have been observed following transplantation in HIV-infected recipients. In the HIVTR cohort, there were only 4 cases of cutaneous Kaposi sarcoma, 2 cases of Pneumocystis jiroveci pneumonia (PCP), 1 case of cryptosporidiosis, and 6 esophageal or bronchial Candida infections, and a history of OIs was not associated with recurrence or survival differences after transplantation.(11) In contrast, nonopportunistic serious infections were common, occurring in just over half of transplant recipients; these were predominantly bacterial (64-70%) infections of the blood, respiratory, and genitourinary tracts. The remainder of infections were fungal (7-8%), viral (5-10%), or not cultured. Serious infections were more common in liver and kidney recipients with HCV coinfection, in kidney recipients who received thymoglobulin, and in liver recipients of Caucasian ethnicity. Nadir CD4 was predictive of infection risk in kidney recipients, and higher current CD4 was protective in liver recipients.
In a series of 84 HCV-coinfected liver transplant recipients in Spain, 64% experienced at least 1 infection (largely non-OIs) and 43% developed severe infections, which proved fatal in 19%.(12) Infectious etiologies were bacterial in 45%, and fungal in 19% (approximately half of which were invasive), with the remainder comprising cytomegalovirus (CMV) and herpes simplex virus (HSV) infections. Incidence of OIs was higher in this cohort than in the HIVTR cohort, at 11%, and included bacterial infections, CMV, herpes simplex, herpes zoster, tuberculosis, and fungal infections, with a 44% mortality rate. Pretransplantation MELD score >15, a history of AIDS-defining events before transplantation, and nontacrolimus-based immunosuppression were predictive of severe infection.
| Risk of Cancer after Transplantation|
Experience to date suggests that the incidence of malignancy after solid-organ transplantation in the HIV-infected population may not be significantly different than that seen in HIV-uninfected patients. In the HIVTR trial, 25 of 275 patients (9%) developed posttransplantation malignancy and 7 patients (3%) died from a cancer-related cause.(13) In the group undergoing kidney transplantation, 13 out of 150 patients (8.7%) had developed 14 malignancies at a median follow-up of 3.5 years after transplantation. This included skin cancer (n = 5), cutaneous Kaposi sarcoma (n = 3), penile squamous cell cancer (n = 1), head and neck cancer (n = 3), and renal cell cancer (n = 2). There were 3 cancer-related deaths in the kidney transplantation group. Twelve of the 125 patients undergoing liver transplantation developed 14 malignancies at a median follow-up of 2.8 years after transplantation. These comprised de novo malignancies, including skin cancer (n = 9), Kaposi sarcoma (n = 1), and lymphoma (n = 1), and 3 recurrences of pretransplantation malignancy, including 2 hepatocellular carcinomas (HCCs) and 1 cholangiocarcinoma. All de novo Kaposi sarcoma lesions in the HIVTR study were cutaneous, and all were treated successfully with the addition of rapamycin to the immunosuppressive regimen. Rapamycin has well-documented therapeutic effects on Kaposi sarcoma.(14) Investigators also evaluated the progression of human papillomavirus (HPV)-associated neoplasia. In 89 patients followed prospectively with anal cytology, there was increased risk of developing high-grade squamous intraepithelial lesions (HSILs) after transplantation, which was not influenced by the type of transplanted organ (kidney vs liver) or by the use of T-cell-depleting agents.(13)
A common indication for liver transplantation in HIV-infected patients is the occurrence of HCC. Observational cohort data suggest that HCC occurs at a younger age in HIV/HCV-coinfected patients compared with HCV-monoinfected patients, and is associated with shorter survival time.(15-16) In contrast, posttransplantation outcomes show no differences to date between HIV/HCV-coinfected patients and HCV-monoinfected patients with HCC. Similarly, Vibert et al reported on 16 HIV-infected patients undergoing liver transplantation for HCC and found no significant difference in overall survival or recurrence-free survival compared with 58 HIV-uninfected patients with HCC from the same time period.(17) In the HIVTR study, HCC was present in 45 (36%) of the 125 patients undergoing liver transplantation. HCC recurrence has been seen in 2 patients at a median follow-up of 34 months. The majority of these patients were maintained on calcineurin inhibitor-based immunosuppressive regimens; the possible significance of this is under study.(13)
| Pretransplant Evaluation and Care|
| Criteria for Transplantation|
In addition to the standard transplant criteria, most transplant centers in the United States use the HIV disease stage criteria established by the HIVTR study with the goal of offering transplantation of kidneys, liver, and certain other organs to individuals with relatively intact immune systems and controllable HIV viremia, and without an active OI (Table
2). European centers generally have adopted similar criteria.
It is recommended that CD4 cell counts should be >200 cells/µL for kidney transplant candidates. The CD4 threshold for liver transplant candidates usually is lowered to >100 cells/µL for those candidates who do not have a history of an HIV-related OI, because absolute CD4 cell counts in patients with cirrhosis may not accurately reflect their stage of HIV disease, owing to splenic sequestration of lymphocytes. For those liver transplant candidates who have had an OI, it is recommended to transplant at CD4 counts of ≥200 cells/µL. The CD4 percentage may be a better indicator of immune function than the absolute CD4 cell count in patients who are undergoing interferon-based treatment for HCV infection, as well as in those with portal hypertension.(18)
Ideally, HIV RNA should be undetectable in patients on ART. Inability to achieve complete viral suppression prior to liver transplantation has been associated with elevated mortality.(19) For liver transplant candidates who are unable to tolerate ART or have recently initiated ART and are not yet fully suppressed, an HIV clinician should be able to confidently predict full HIV suppression once ART is initiated, based on careful consideration of the patient's ART history and interpretation of genotypic and phenotypic analysis of any viral resistance patterns. In patients who maintain undetectable viral load in the absence of ART ("elite suppressors"), the safety of undertaking organ transplantation and subsequent immunosuppression in the absence of ART is not known. There is evidence from cohort studies that chronic immune activation and inflammation persists in these individuals despite undetectable viremia, and they should not be considered immunologically equivalent to persons without HIV infection, or to those who are immunosuppressed on ART.(20) The extent to which this chronically immune-activated state might contribute to increased risk of infection, increased risk of developing neoplasms, and increased rates of graft rejection is not known. At this time, the most prudent approach with these "elite suppressors" is to initiate fully suppressive ART before transplantation.
AIDS-related OIs and cancers should be treated completely prior to transplant. Patients with a history of opportunistic diseases or neoplasms for which current treatments are suboptimal (eg, progressive multifocal leukoencephalopathy, chronic cryptosporidiosis, and primary central nervous system lymphoma) usually are excluded from transplantation. Individuals with a history of resolved cutaneous Kaposi sarcoma can be offered transplantation.
| Pretransplant Vaccinations|
Prior to transplantation, all nonimmune individuals should be immunized against hepatitis A and B viruses. Pneumococcal vaccine should be administered to any individual who has not been vaccinated in the prior 5 years, and inactivated influenza vaccine should be administered as seasonally appropriate. Men and women between the ages of 15 and 26 should receive HPV vaccination, and primary varicella virus vaccine can be considered for nonimmune individuals who have a CD4 count of >200 cells/µL. Careful attention should be given to assessment of tuberculosis risk, which should include history of possible exposure (eg, imprisonment, residence in homeless shelters, institutionalization, country of origin, and travel destinations) as well as chest radiograph and either skin testing or interferon-gamma release assay. Exposed patients should be treated appropriately.
| Other Factors Affecting Listing for Transplant|
Though the utility of the MELD scoring system for assessing severity of liver disease in HIV-infected candidates has been questioned, available data support the use of MELD in these patients.(5,21-23) HIV-infected patients have been listed for transplant at lower rates than HIV-uninfected candidates; these differences have been attributed largely to severity of the patients' HIV disease. In the HIVTR study, a significantly lower proportion of candidates (34.7%) underwent liver transplantation, compared with controls (47.6%; p < .003). Another retrospective review of 309 renal transplant candidates identified factors associated with failure to be listed for transplant. Only 20% of HIV-infected candidates were listed, compared with 73% of HIV-uninfected candidates. The most common reasons for not listing the HIV-infected candidates were lack of CD4 or viral load data at evaluation, CD4 and HIV viral load levels not meeting eligibility criteria, and illicit drug use.(24) A Eurosida cohort analysis of 88 HIV-infected patients with end-stage renal disease documented a 30% rate of not meeting eligibility criteria based on CD4 and HIV viral load levels, with the remainder of exclusions related to cardiovascular disease and diabetes.(25)
| Donor Considerations|
The HIVTR study confirmed that graft survival of kidney transplants from live donors was superior to that of cadaveric organs.(26) That finding is consistent with the improved outcome demonstrated for living vs cadaveric donors in the general transplant population.
At this time, the use of organs from HIV-infected donors for HIV-infected recipients is not being considered outside resource-limited settings in which the prevalence of HIV in the general population is high enough to effectively limit the donor pool and access to organ transplantation for HIV-infected patients is restricted. Limited data suggest this approach may be successful. For example, researchers in Cape Town, South Africa, reported favorable results in 4 HIV-infected patients receiving kidneys from HIV-infected donors.(27) At 1 year posttransplant, all grafts were functioning with few episodes of rejection, and HIV suppression was maintained.
A recent analysis utilizing 2 national databases in the United States estimated that deceased HIV-infected patients constitute 500-600 potential donors per year for HIV-infected transplant candidates.(28) Currently, U.S. federal law (National Organ Transplant Act of 1984) prohibits transplant of organs from HIV-infected donors; however, restrictions may be lifted in the future, allowing for further study of this strategy. Concerns have been raised about the risk of transmission of a second strain of HIV or drug-resistant HIV from donor to recipient with this strategy, but the actual risk is unknown.(18) The implications of transplanting potential viral reservoirs and--particularly in the case of liver transplantation--introducing a second viral strain or virus with differing drug-resistant mutations are not understood. Transplantation of organs from HIV-infected donors should be carried out only in a research setting.
| Perioperative Management|
HIV infection is associated with an increased risk of venous thromboembolism that is associated with increased rates of protein C and S deficiency, the presence of anticardiolipin antibodies, low nadir CD4, CMV viremia, elevated D-dimers pre-thrombosis, and several markers of immune activation.(29,30,31) Few data on the rates and risk of arterial thrombotic complications of transplantation are available. A case-control study of 24 HIV-infected liver transplant recipients described a high rate of thrombotic complications (33%), including a significantly higher rate of hepatic artery thrombosis relative to HIV-uninfected historical controls (12% vs 3.2%; p = .016).(32) Most centers routinely administer subcutaneous heparin prophylaxis perioperatively, depending on the degree of underlying coagulopathy and thrombocytopenia related to ESLD.
| Posttransplant Management|
| Antiretroviral Therapy|
After transplant, continuous treatment with both antiretroviral and immunosuppressive medications is required to control HIV infection and to prevent graft rejection. Posttransplant management is complicated by multiple and reciprocal drug interactions between antiretroviral and immunosuppressive medications. In particular, there are substantial interactions between the certain immunosuppressive medications and HIV protease inhibitors (PIs) and nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs), owing to their effects on hepatic cytochrome P450 3A4 (CYP 450) and P-glycoprotein.(1,33) Changes in dosages and dosing intervals of immunosuppressive medications may be required, depending on the antiretroviral regimen. Changes of antiretroviral medications or interruption of ART can alter serum levels of immunosuppressants significantly and can precipitate organ rejection. For more on interactions between antiretroviral and immunosuppressive medications, see Choice of Immunosuppressive Regimen, below. Coadministration of antiretroviral and immunosuppressive agents also may cause increased or overlapping treatment toxicities. Other agents commonly used after transplantation may require adjustments in ART. Examples of special considerations are shown in Table
Raltegravir is metabolized primarily via glucuronidation, and has no effect on CYP 3A enzyme systems. Many transplant centers encourage the use of raltegravir when appropriate owing to the relative lack of drug interactions and toxicity, and preliminary experience with this agent generally has been favorable. In a retrospective study of 13 liver and kidney recipients treated with raltegravir, none had experienced rejection at 12 months.(34)
The CCR5 receptor antagonist maraviroc may have a unique role in the HIV-infected transplant recipient. Several lines of evidence suggest that CCR5 antagonism may decrease rates of graft rejection.(35-38) Another potential benefit of CCR5 antagonists in the posttransplant setting may be enhanced antiretroviral activity; in vitro antiretroviral synergy is demonstrable between sirolimus and the earlier CCR5 antagonist vicriviroc, via sirolimus-induced decreased density of CCR5.(39-40) Experience with the use rilpivirine, etravirine, and elvitegravir posttransplant remains limited.
ART should be reinitiated posttransplantation as soon as the patient can take oral medications reliably.(41) Inability to tolerate ART after liver transplant is associated with an increased risk of death.(4) With HBV-coinfected patients, antiretrovirals must suppress both HIV and HBV, and should, if possible, include tenofovir and either emtricitabine or lamivudine. The need to maintain HBV suppression must be considered if the ART regimen is changed, and failure to do so risks flare of clinical hepatitis and increased incidence of HBV immune reconstitution inflammatory syndrome (IRIS). In patients with renal insufficiency, all of the nucleoside reverse transcriptase inhibitors except abacavir require dosage adjustment and should be given postdialysis in patients on renal replacement therapy. The NNRTIs, PIs, integrase inhibitors, the entry inhibitor enfuvirtide, and the CCR5 antagonist maraviroc do not require dosage adjustment in the setting of kidney disease. Dialysis patients taking the NNRTI nevirapine should receive an additional 200 mg dose immediately following dialysis.
| Choice of Immunosuppressive Regimen|
Multiple combinations of immunosuppressive agents have been used after solid-organ transplantation in HIV-infected individuals. Experience to date has not suggested that any single agent or regimen results in superior outcomes. Cyclosporine has been the most commonly used calcineurin inhibitor, in part because of reports of antiretroviral or favorable immunomodulatory effects.(42) However, Stock et al reported a higher rate of graft rejection with cyclosporine relative to the alternative calcineurin inhibitor, tacrolimus, though this was not related to graft survival.(26) Steroids are used posttransplant at standard dosages, and target trough blood levels of calcineurin inhibitors are the same as those sought in HIV-uninfected recipients. Sirolimus is of interest in that it down-regulates CCR5 expression on CD4 cells and has in vitro antiretroviral synergy with antiretroviral agents that inhibit viral entry or CCR5 chemokine coreceptor-mediated attachment (enfuvirtide and maraviroc).(40) It also appears to ameliorate posttransplant Kaposi sarcoma.(14) Mycophenolate mofetil has synergistic antiretroviral effects with didanosine, abacavir, and tenofovir.(43,44,45) Induction with thymoglobulin (antilymphocyte polyclonal antibody) results in a marked and sustained decrease in CD4 cell counts, increases the risk of serious infections associated with hospitalization, and may increase the risk of death and graft loss.(46) The monoclonal antiinterleukin-2 receptor antibodies basiliximab and daclizumab increase CD4 cell counts, though the clinical significance of this increase is not known.(47) Experience with monoclonal anti-CD20 antibody is limited.
The immunosuppressive calcineurin inhibitors (cyclosporine and tacrolimus) and sirolimus have significant interactions with HIV PIs and NNRTIs, and dosage adjustments may be required.(1,33) In general, patients on PI-based regimens will require a decrease in dosage of immunosuppressive medications, and an increase in dosing interval, and patients on NNRTI-based regimens require an increase in dosage of immunosuppressants. When both a PI and an NNRTI are used, immunosuppressant doses are similar to those used when immunosuppressive medications are combined with PIs alone, but changes in dosing interval may be required for certain immunosuppressants. Typical initial and maintenance immunosuppressant dosing guidelines are available.(33,48) Few interactions are expected between the integrase inhibitor raltegravir, which is metabolized primarily by UGT1A1-mediated glucuronidation, and immunosuppressive medications. Raltegravir has begun to be used posttransplant by many centers, documenting that no dosage adjustment is necessary for cyclosporine and tacrolimus.(34,49-50)
| Graft Rejection|
Although considerable variability exists in reported rejection rates in the setting of HIV disease, in general, rates are reported to be 2-3 times those seen in HIV-uninfected recipients. The reason for these fairly dramatically increased rejection rates is not entirely clear, and it may be multifactorial. Drug interactions with antiretroviral agents may lead to lowered levels of immunosuppressive drugs owing to induction of metabolism (eg, NNRTIs), or indirectly through intentional dosage decreases or increased dosing intervals in an effort to avoid immunosuppressive medication toxicity from the potent inhibition of CYP 3A metabolism by the HIV PIs. In the HIVTR study, immunosuppressive medication trough levels were not associated with rejection rates; however, total drug exposure may have been decreased. The only factors related to rejection were use of a kidney from a deceased donor and use of cyclosporine.
The role of the chronic immune activation associated with HIV infection driving rejection is uncertain. T-cell activation remains chronically elevated in persons with HIV infection, even during treatment with suppressive ART.(51)
Heterologous immunity may have an important role in the higher rejection rates that have been observed following both liver and kidney transplantation in HIV-infected recipients. Cross-reactivity between the cellular response against copathogens observed in HIV infection and HLA antigen could explain the higher rate of rejection episodes observed in HIV-infected transplant recipients.(52)
| Prophylaxis against Opportunistic Infections|
In addition to standard center-specific protocols for posttransplant chemoprophylaxis, additional precautions are warranted for organ recipients with HIV disease (Table
4). Prophylaxis against PCP should be continued for life, preferably using trimethoprim-sulfamethoxazole (TMP-SMX). For patients who have sulfa allergy, desensitization may be considered. In instances whereby allergy or bone marrow suppression precludes use of TMP-SMX, dapsone is an alternative, as long as glucose-6-phosphate dehydrogenase levels are normal. Primary prophylaxis against other OIs is based on CD4 cell count. TMP-SMX will prevent toxoplasmosis reactivation disease in patients with CD4 counts of <100 cells/µL and can be used to prevent primary disease in patients who were Toxoplasma antibody negative prior to transplantation but received organs from Toxoplasma antibody-positive donors. Either dapsone with pyrimethamine or atovaquone with pyrimethamine may be used for toxoplasmosis prophylaxis in patients who cannot take TMP-SMX. Patients whose CD4 count drops to <50 cells/µL should receive weekly azithromycin to prevent Mycobacterium avium complex (MAC). Prophylaxis against histoplasmosis with itraconazole can be considered for patients with CD4 counts of ≤150 cells/µL who are at high risk because of occupational exposure or live in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years). Patients residing in Coccidioides immitis-endemic areas who have CD4 counts of <250 cells/µL may be given prophylaxis with itraconazole or fluconazole if serologic testing (IgM or IgG) results are positive.
The University of California San Francisco (UCSF) transplant center administers secondary prophylaxis to HIV-infected patients with a history of MAC, toxoplasmosis, cryptococcal infection, or histoplasmosis. Treatment generally should be continued until 3 months after the CD4 count has surpassed the recommended threshold for initiation of prophylaxis. Secondary prophylaxis also should be provided for 1 month if lymphocyte-depleting agents are used for the treatment of graft rejection, guided by CD4 cell counts.
Immunization against Streptococcus pneumoniae should be given every 3-5 years, and influenza vaccine should be given annually. This is similar to the guidelines for HIV-uninfected transplant recipients.
| Hepatitis C and HIV Coinfection|
HCV infection has been associated with poorer outcome in both liver and kidney transplant recipients.(11) In several small case series, 3-year survival in these patients has ranged between 56% and 73%.(4,53-56) Terrault et al compared the 89 HIV/HCV-coinfected liver recipients in the HIVTR study with 235 HCV-monoinfected controls.(6) Patient and graft survival was poorer in the coinfected group, with 3-year patient survival rates of 60% and graft survival rates of 53% in HCV/HIV-coinfected patients vs 79% and 74%, respectively, in HCV-monoinfected recipients (p <.001 for both). Among all HCV-infected patients, HIV infection was the only factor significantly associated with reduced patient and graft survival. Among HIV/HCV-coinfected patients, older donor age, combined kidney and liver transplant, HCV-positive donor and BMI of <21 kg/m2, were independent predictors of graft loss. In patients without these latter 3 factors, patient and graft survival rates were similar to those in HIV-uninfected liver recipients in the United States. In another study, Miro et al found HIV to be predictive of higher mortality in 84 coinfected liver recipients matched with 252 HCV-monoinfected controls, reporting 5-year survival rates of 54% in coinfected patients and 71% in the HCV-monoinfected patients.(5)
Recurrent hepatitis attributable to HCV occurs in a majority of HIV/HCV-coinfected patients after liver transplantation, and often follows an accelerated, aggressive course. The fibrosing cholestatic form of hepatitis may occur, and it portends a particularly poor prognosis.(54,56-57) In a single-center study, Duclos-Vallée et al compared 35 HIV/HCV-coinfected liver transplant recipients with 44 HCV-monoinfected recipients and noted a significantly higher progression of fibrosis in the coinfected group (p < .001).(56) Among coinfected recipients, 48% had bridging fibrosis or cirrhosis at 5 years vs 18% of the monoinfected patients. Though most patients received standard interferon and ribavirin therapy, in this and other studies, dose-limiting toxicities were common, limiting comparisons between the natural history of recurrent HCV disease in HIV-infected vs HIV-uninfected recipients. Likewise, Miro et al found that, at 5 years posttransplant, HIV-coinfected patients had a probability of remaining free from severe graft fibrosis of only 24%, compared with 49% for HCV-monoinfected recipients (p < .001).(5) In contrast, in the HIVTR study, the cumulative incidence of severe HCV disease did not differ significantly between HIV/HCV-coinfected recipients and HCV-monoinfected recipients (29% vs 23% at 3 years, respectively).(6) Of note, there also have been several reports of spontaneous clearance of HCV infection posttransplant.
Rates of response to treatment of recurrent HCV posttransplant have been disappointing, ranging from 11% to 27% with standard ribavirin and pegylated interferon regimens.(56-58) In the HIVTR study, rate of response did not differ between HIV/HCV-coinfected patients and HCV-monoinfected patients.(6) Most centers begin treating recurrent HCV at the time of proven histological change, with a majority of patients experiencing stage 0-1 fibrosis at the time of initiation, usually within the first 90 days posttransplant.(6,57-58) Because degree of liver enzyme elevation correlates poorly with histology in HCV disease, routine graft biopsy should be considered at 6 months posttransplant.(59)
The efficacy and tolerability of direct-acting antivirals for HCV in this population has yet to be determined. The first of these new agents to be approved, telaprevir and boceprevir, have substantial drug-drug interactions that complicate their use in HIV/HCV-coinfected posttransplant patients. Almost all ritonavir-boosted HIV PIs reduce plasma levels of telaprevir, and telaprevir increases levels of atazanavir and lopinavir, but decreases levels of fosamprenavir and darunavir.(60) The only HIV PI that currently may be administered with telaprevir is atazanavir, which causes only 20% reduction in telaprevir AUC.(61) Telaprevir reduces exposure to the NNRTI efavirenz, and efavirenz moderately reduces telaprevir plasma levels, requiring a dosage-adjustment of telaprevir to 1,125 mg every 8 hours from the standard dosage of 750 mg every 8 hours.(62) No significant drug interactions are expected with coadministration of telaprevir with raltegravir. Telaprevir also interacts with certain immunosuppressive medications. It increases levels of cyclosporine (therapeutic drug monitoring is required), and may increase sirolimus exposure.(63) It also increases tacrolimus levels up to 70% , and this combination is not recommended.(63)
Coadministering boceprevir with HIV PIs leads to reductions in serum levels of both boceprevir and ritonavir-boosted atazanavir, lopinavir, and darunavir.(64) At this time, coadministration of boceprevir and HIV PIs is not recommended. Efavirenz reduces boceprevir trough concentration and their coadministration is likewise currently contraindicated.(63,65) Boceprevir does not affect raltegravir levels, but clinical data for coadministration of these agents are lacking.(64) It is expected that boceprevir will increase levels of tacrolimus, sirolimus, and cyclosporine, and therapeutic drug monitoring is recommended.(63)
| Hepatitis B and HIV Coinfection|
Outcomes in HIV-infected patients undergoing transplantation for ESLD caused by chronic HBV are excellent, essentially equaling those in the HIV-uninfected population and those with nonviral etiologies of liver disease.(7-8) It is now standard of care for patients with HIV and HBV to be treated with antiretroviral regimens that include tenofovir plus either lamivudine or emtricitabine, which have excellent efficacy in suppressing HBV replication.(66) This antiviral therapy combined with immunoprophylaxis with hepatitis B immune globulin (HBIG) yields survival rates of 75-100%. Coffin et al reported results from 22 coinfected patients, 45% of whom had detectable HBV DNA pretransplant.(7) No patients had clinical evidence of HBV recurrence posttransplant, despite detection of intermittent low-level hepatitis B viremia (median 108 IU/mL; range 9-789 IU/mL) in half of them. Patient and graft survival rates were similar to those seen in matched HIV-negative controls, though a trend toward lower survival was noted in the coinfected patients (85% vs 100% in HBV monoinfected; p = .08). Thus, the current standard for HBV treatment after transplant is indefinite treatment with 2 NRTIs with anti-HBV activity (as part of a potent anti-HIV regimen) along with HBIG. In cases whereby entecavir may be required for additional antiviral activity against HBV, it is imperative to ensure that HIV replication is suppressed, as entecavir may select for HIV mutants that limit ART options, despite not having significant antiviral activity against HIV.(67)
| Multidisciplinary Team|
Pre-, peri-, and posttransplant care should be coordinated within a multidisciplinary team consisting of transplant surgeon, HIV specialist, primary care provider, hepatologist or nephrologist, transplant coordinator, social worker, pharmacist or pharmacologist, and transplant nursing specialist. All team members should participate actively in patient monitoring and management, with consistent and prompt communication. Potential drug-drug interactions and their implications for graft rejection, end-organ toxicity, and viral resistance should be reviewed by the team prior to instituting any medication changes. Owing to the substantial drug-drug interactions between antiretroviral medications and immunosuppressive medications, a change in ART may easily precipitate either acute rejection from a rapid decrease in immunosuppressive medication level or toxicity from increased exposure. A team approach should be taken in the evaluation, differential diagnosis, and treatment plan of any new symptoms or laboratory abnormalities.
In conclusion, excellent results following kidney transplantation and survival benefit in select liver transplant recipients indicate that HIV infection should not be considered a contraindication to transplantation. Although CD4 count is associated with nonopportunistic serious infections, HIV-specific factors such as nadir CD4, posttransplant CD4 count, and OI history do not affect mortality or predict OIs. Transplant selection criteria should include baseline factors that contribute to outcome, such as need for dual liver/kidney transplant, HCV-infected organ donors, and low pretransplant BMI. HCV coinfection is associated with poorer outcomes, and the impact of newer direct-acting antiviral therapies for HCV on transplant outcomes is not yet 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 posttransplant management and reduce rejection rates and improve graft survival.
|| ||Roland M, Barin B, Huprikar S , eds. HIV-related predictors and outcomes in 275 liver and/or kidney transplant recipients. American Transplant Congress; 2011; Philadelphia.|
|| ||Beatty G, Barin B, Fox L, et al. HIV-related predictors and outcomes in 275 liver and/or kidney transplant recipients. In: Program and abstracts of the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention; July 17-20, 2011; Rome. Abstract MOAB0105.|
|| ||Vennarecci G, Ettorre GM, Antonini M, et al. Liver transplantation in HIV-positive patients. Transplant Proc. 2007 Jul-Aug;39(6):1936-8.|
|| ||van Heeswijk R, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. In: Programs and absracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 3, 2011; Boston. Abstract 119.|
|| ||Dieterich D, Soriano V, Sherman K, et al. Telaprevir in combination with pegylated interferon-alfa-2a + RBV in HCV/HIV-co-infected patients: A 24-week treatment interim analysis. In: Program and abstracts of the 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle. Oral abstract 46.|
|| ||U.S. Department of Health and Human Services. Considerations for Antiretroviral Use in Special Patient Populations: HIV-Infected Adolescents and Young Adults. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/21/hiv-infected-adolescents-and-young-adults.|