Renal transplantation in HIV-infected patients: 2010 update

Renal transplantation in HIV-infected patients:2010 updateJoan C. Trullas1, Federico Cofan2, Montse Tuset3, Marıa J. Ricart2, Mercedes Brunet4, Carlos Cervera5,Christian Manzardo5, Marıa Lopez-Dieguez5, Federico Oppenheimer2, Asuncion Moreno5,Josep M. Campistol2 and Jose M. Miro5

1Internal Medicine Service, Hospital Sant Jaume Olot (Girona), Universitat de Girona, Girona, Spain; 2Renal Transplant Unit, HospitalClinic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain; 3Pharmacy Department, Hospital Clinic-IDIBAPS, Universitat de Barcelona,Barcelona, Spain; 4Toxicology Department, Hospital Clinic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain and 5Infectious DiseasesService, Hospital Clinic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain

The prognosis of human immunodeficiency virus (HIV)

infection has improved in recent years with the introduction

of antiretroviral treatment. While the frequency of

AIDS-defining events has decreased as a cause of death,

mortality from non-AIDS-related events including end-stage

renal diseases has increased. The etiology of chronic

kidney disease is multifactorial: immune-mediated

glomerulonephritis, HIV-associated nephropathy, thrombotic

microangiopathies, and so on. HIV infection is no longer a

contraindication to transplantation and is becoming standard

therapy in most developed countries. The HIV criteria used

to select patients for renal transplantation are similar in

Europe and North America. Current criteria state that prior

opportunistic infections are not a strict exclusion criterion,

but patients must have a CD4þ count above 200 cells/mm3

and a HIV-1 RNA viral load suppressible with treatment. In

recent years, more than 200 renal transplants have been

performed in HIV-infected patients worldwide, and mid-term

patient and graft survival rates have been similar to that of

HIV-negative patients. The main issues in post-transplant

period are pharmacokinetic interactions between

antiretrovirals and immunosuppressants, a high rate of acute

rejection, the management of hepatitis C virus coinfection,

and the high cardiovascular risk after transplantation. More

studies are needed to determine the most appropriate

antiretroviral and immunosuppressive regimens and the

long-term outcome of HIV infection and kidney graft.

Kidney International (2011) 79, 825–842; doi:10.1038/ki.2010.545;

published online 19 January 2011

KEYWORDS: drug interactions; hepatitis C; HIV infection;

immunosuppression; kidney failure; kidney transplantation

A few years ago, human immunodeficiency virus (HIV)infection was an absolute contraindication for solid organtransplantation. Concerns that post-transplant immuno-suppression could result in accelerated HIV disease andincreased risk for opportunistic infections meant thatHIV-infected patients were not candidates for transplanta-tion. Since the introduction of combined antiretroviraltreatment (cART) in 1996, the natural history ofHIV-infected patients has changed dramatically. AlthoughAIDS-defining events have decreased steadily as a cause ofdeath, there has been an increase in mortality fromnon-AIDS-related infections and late-stage organ diseases.1

The first experiences for solid organ transplantation inHIV-infected patients were liver transplants in patients withhepatitis C virus (HCV) coinfection and hepatic cirrhosis.2 Inthe case of end-stage renal disease (ESRD), renal replacementtherapies (hemodialysis and peritoneal dialysis) are analternative to renal transplantation. This is one of the reasonswhy renal transplantation was not initially considered atherapeutic option for HIV-infected patients with ESRD.However, at present, renal transplantation is a valid option inadequately selected HIV-infected patients with ESRD underdialysis or pre-emptively before starting dialysis.3 We presentthe state of the art of renal transplantation in HIV-infectedpatients, focusing on clinical aspects, therapeutic strategies(immunosuppressive and antiretroviral treatments), ethicalissues, comorbidity, and challenges that have to be faced inthe coming years.

ETIOLOGY OF KIDNEY DISEASE IN HIV-INFECTED PATIENTS

Nephropathy is a common finding in patients with HIVinfection and can present as acute or chronic kidney disease.Acute renal failure can be produced by the toxic effectsof antiretroviral therapy (for example, tenofovir, indinavir)or nephrotoxic antimicrobial agents used in the treatment ofopportunistic infections (for example, aminoglycosides, ampho-tericin, foscarnet, trimethoprim-sulfamethoxazole, acyclovir).4,5

The etiology of kidney disease is multifactorial: immune-mediated glomerulonephritis, HIV-associated nephropathy

http://www.kidney-international.org r e v i e w

& 2011 International Society of Nephrology

Received 10 July 2010; revised 23 November 2010; accepted 7

December 2010; published online 19 January 2011

Correspondence: Jose M. Miro, Universitat de Barcelona, Infectious Diseases

Service, Hospital Clinic, Villarroel, 170, 08036 Barcelona, Spain.

E-mail: [email protected]

Kidney International (2011) 79, 825–842 825

http://dx.doi.org/10.1038/ki.2010.545

http://www.kidney-international.org

mailto:[email protected]

(HIVAN), drug-induced renal disease, nonreversible acuterenal failure, or thrombotic microangiopathy. Moreover,long-term survival and an increase in cART-induced meta-bolic alterations will possibly cause an increase in diabetesand hypertensive renal diseases.5

Classic HIVAN presents histologically as collapsing focalsegmental glomerulosclerosis and clinically as severe protei-nuria, renal failure, and rapid progression to ESRD. It is themost common cause of ESRD in untreated HIV-infectedblack individuals who develop renal disease. It primarilyoccurs in patients of African descent, suggesting a geneticpredisposition to the disease. Risk factors for its developmentinclude a CD4þ T-cell count o200 cells/mm3 and a highHIV-RNA viral load. Characteristic histological findingsinclude collapsing focal and segmental glomerulosclerosis,tubular epithelial atrophy with microcystic dilatation ofthe tubules, and lymphocytic interstitial infiltration. Viralinfection of renal cells seems to have an important role inthe pathogenesis of HIVAN. Without adequate treatment, theprognosis of HIVAN is poor. Although there are strongobservational data supporting a role for cART in thetreatment of HIVAN, no prospective, randomized, controlledtrials have been performed to support it. In addition,performance of a randomized trial in this disorder seemsunlikely, as it generally affects individuals with uncontrolledHIV infection who require treatment.5–7

ESRD AND RENAL REPLACEMENT THERAPY INHIV-INFECTED PATIENTS

The global incidence and prevalence of ESRD in HIV-infected patients is unknown, with only some informationavailable in selected cohorts of black individuals.8 Moststudies have focused on chronic kidney disease, althoughthere is much less information on advanced stages of kidneydisease. A recent EuroSIDA survey revealed a prevalence of0.46% (95% confidence interval, 0.38–0.54%) among theHIV-infected population with ESRD in Europe.9

Prevalence of HIV infection in dialysis units in the UnitedStates, Europe, and other regions

Prevalence of HIV infection in dialysis units varies widelybetween countries and even within the same country(Table 1). In the United States, the number of infectedpatients has increased during the past decade. In 2002, 1.5%(range 0.3–1.5%) and 0.4% (range 0.4–0.8%) of patients werereported to have HIV infection and AIDS, respectively.10

In Europe,11–17 the overall prevalence of HIV infection indialysis units was 0–5% in 1980.11 In the early 1990s, theEuropean Renal Association-Dialysis and Transplant Associa-tion created a European registry including 152,658 patientsunder dialysis; the prevalence of HIV infection was 0.12%.12

In the cART era, information on prevalence in Europeancountries is scarce, with the exception of small isolatedstudies from France14,15 and Spain.16,17

Other than three small-scale studies from the pre-cARTera, there is little information from other world regions.18–20

Survival of HIV-infected patients receiving renalreplacement therapy

Survival of HIV-infected patients receiving dialysis hasincreased in the last two decades. Early studies from the1980s reported that survival in patients with newly diagnosedAIDS and ESRD initiating hemodialysis was poor. Mostof these patients had advanced HIV disease that was oftenaccompanied by other opportunistic diseases.21 Outcomehas improved dramatically, and the mortality rate is nowapproaching that for ESRD in the general population.22

A recent study reported survival rates at 1, 3, and 5 years forHIV-infected patients on dialysis of 95.2, 71.7, and 62.7%,respectively; these were significantly lower than those of amatched HIV-negative cohort of dialysis patients.23 Differentfactors have contributed to improved survival, the mostrelevant being the introduction of cART and treatment ofopportunistic infections, as well as enhanced dialysisprocedures. Some predictors of survival have been establishedin recent studies. The risk factors for mortality in the HIV-infected dialysis population are a lower CD4þ T-cell count,a higher viral load, the absence of cART, and a history ofopportunistic infections.23–25 In addition, underexposureor inadequate dose adjustment of cART in patients whohave impaired renal function and/or are receiving dialysismay contribute to excess mortality among HIV-infectedpatients.26 Despite this overall improvement in survival inrecent years, a study including cohorts comprising blackindividuals reported poor survival in the pre-cART and in thecART era, as a consequence of inadequate HIV treatmentin those patients (nearly half of patients initiating dialysis inthe cART era were not receiving antiretroviral drugs).8

HIV-INFECTED PATIENTS ON THE RENAL TRANSPLANTWAITING LISTCriteria for including HIV-infected patients on thetransplant waiting list

Most transplant groups from Europe and North Americahave been working toward harmonizing criteria for solid

Table 1 | Prevalence of HIV infection in dialysis centers in theUnited States, Europe, and other regions

Country (reference) Year

Total numberof patientson dialysis

Prevalenceof HIV

infection (%)

United States10 1985 ND 0.32002 263,820 1.5

Europe11,12 1984–1986 44000 0–51990 152,658 0.12

Italy13 1990 21,500 0.111995 27,000 0.13

France14,15 1997 22,707 0.362002 27,577 0.67

Spain16,17 2004 4962 1.152006 14,876 0.54

Egypt18 1991 5000 1.64Japan19 1986 1314 0Brazil20 1986 132 14

Abbreviations: HIV, human immunodeficiency virus; ND, no data available.

826 Kidney International (2011) 79, 825–842

r e v i e w JC Trullas et al.: Renal transplantation and HIV

organ transplantation in HIV-infected patients.27–31 Thesecriteria are summarized in Table 2.K Clinical criteria: Ideally, no patients should have had

AIDS-defining diseases, as this may lead to a greater riskfor reactivation. However, some opportunistic infections(tuberculosis, esophageal candidiasis, and Pneumocystisjiroveci pneumonia) have been withdrawn as exclusioncriteria, because they can be treated effectively andprevented.

K Immunological criteria: All groups have agreed that theCD4þ T-cell count should be 4200 cells/mm3 for renaltransplantation, because most opportunistic infectionsappear when the CD4þ T-cell count is below this cutoff.

K Virological criteria: The ideal situation is one in whichthe patient tolerates cART before transplant with anundetectable HIV viral load in plasma by ultrasensitivetechniques (o50 copies/ml). In some cases (for example,patients who remain viremic with antiretroviral medica-tion), it is essential to carry out antiretroviral sensitivitytesting to ascertain the real therapeutic options.Some patients do not have an indication for cART, asthey are long-term non-progressors or do not fulfill theimmunological or clinical criteria to start treatment and,therefore, have viremia that is detectable in plasma.In this setting, it is unknown whether and when (pre- orpost-transplant) it would be beneficial to initiate cART,so that an undetectable viral load can be reached.

K Other criteria: The candidate must have a favorablepsychiatric evaluation. Patients who actively consumedrugs or alcohol will be excluded. In Spain, a consump-tion-free period of 2 years is recommended for heroinand cocaine and 6 months for other drugs (for example,alcohol). Patients who are on stable methadone main-tenance programs are not excluded. Finally, patients mustshow an appropriate degree of social stability to ensureadequate care in the post-transplant period.

Factors associated with failure to include HIV-infectedkidney transplant candidates on the transplant list

There is less information on the evaluation of HIV-infectedpatients for transplantation. The largest study performedto date retrospectively reviewed 309 potentially eligibleHIV-infected patients who had been evaluated for renal

transplantation. Only 20% were included on the list orunderwent transplant compared with 73% in HIV-negativepatients evaluated during the same period. The mostcommon factors associated with failure to complete trans-plant evaluation are: CD4þ T-cell count and viral load datanot provided at initial evaluation (35%), CD4þ T-cell countand viral load not meeting the eligibility criteria (21%), andother factors including black race (black HIV-infectedpatients seem less likely to complete the transplant evalua-tion, a pattern that has also been observed in the generaltransplant population32) and a history of illicit drug use.33

In Europe, recent data from the EuroSIDA cohort studyevaluated this issue among 88 HIV-infected ESRD patients.Criteria related to poor control of HIV infection (low CD4þT-cell count or detectable viral load) were reported in 30% ofcases and the remaining two-thirds of patients were excluded,usually because of cardiovascular diseases or diabetes.9

EXPERIENCE IN RENAL TRANSPLANTATION INHIV-INFECTED PATIENTSExperience in the pre-cART era (before 1996)

Between 1980 and 1990, a total of 39 HIV-infected kidneyrecipients (case reports and case series with a small numberof patients) were documented (Table 3).34–54 After a meanfollow-up of 48 months (range 8–109), 21 patients died(53.8%). This early experience was discouraging. Most casesacquired HIV infection by transplantation or by bloodtransfusion or through blood products received during orshortly after transplantation. Transplant recipients withuntreated or unrecognized HIV infection often had rapidprogression of opportunistic infections and poor outcomes.The development of a screening test for HIV antibodies in1984 and its mandatory use before blood and organ donationsince 1985 proved crucial in preventing further spread ofthe disease by medical intervention.34

Swanson et al.55 performed a retrospective study of ahistorical cohort of 63,210 cadaveric kidney recipientswith valid HIV serology entries in the USRDS (United StatesRenal Data System) from 1987 to 1997. At the time oftheir procedure, 32 patients (0.05%) were HIV infected. The5-year patient and graft survival rates were significantlyreduced in HIV-infected recipients (71 and 44%, respec-tively) in comparison with the USRDS population (78 and61%, respectively) (Table 4). In the multivariate analysis,

Table 2 | HIV criteria for renal transplantation in Spain, Italy, the United Kingdom, and the United States

Spain29 Italy31 United Kingdom30 United Statesa(ref. 28)

Opportunistic infections Someb None in theprevious year

None after cART-inducedimmunologicalreconstitution

Somec

Neoplasm No No NoCD4+ T-cell count (cells/mm3) 4200 4200 4200 4200Plasma HIV-1 RNA viral load BDL on cART Yes Yes Yes Yes

Abbreviations: BDL, below detection level; cART, combined antiretroviral treatment; HIV, human immunodeficiency virus.aCooperative Clinical Trials in Adult Transplantation criteria.bPrevious tuberculosis, Pneumocystis jiroveci pneumonia (PCP), or esophageal candidiasis are not exclusion criteria.cPCP and esophageal candidiasis are not exclusion criteria.


JC Trullas et al.: Renal transplantation and HIV r e v i e w

HIV-positive status was independently associated withpatient mortality and decreased graft survival.

Experience in the cART era (1996–2010)

In the last few years, retrospective studies, case reports, andsmall prospective studies have shown more encouragingresults, suggesting that renal transplantation is feasible inadequately selected HIV-infected patients. Patient survivaland renal allograft survival are similar to those of non-HIV-infected patients (Table 5).9,56–74

One of the largest and first experiences in renaltransplantation in HIV-infected patients was reported byKumar et al.65 and included 40 patients. The 1- and 2-yearpatient survival rates were 85 and 82%, and graft survivalrates were 75 and 71%, respectively. Plasma HIV-1 RNAremained undetectable and CD4þ T-cell counts remained4400 cells/mm3 with no evidence of AIDS for up to 2 years.Acute rejection was frequent (22%).

Roland et al.66 describe the preliminary results of aprospective cohort including 18 kidney transplants followedover 3 years. Patient survival was 94% and graft survivalwas 83%. These results were similar to those of the generaltransplant population. The CD4þ T-cell counts andHIV-RNA levels remained stable. It is important to noticethe high incidence of acute renal rejection at 1 and 3 years (52and 70%, respectively). In contrast, Gruber et al.67 recentlyreported their experience with 8 HIV-infected renaltransplant recipients; the graft and patient survival rates at1 year were 88 and 100%, respectively, and the acute rejectionrate was 13%.

The results of the largest prospective, nonrandomized trialof kidney transplantation in HIV-infected patients haverecently been published. A total of 150 HIV-infected kidneytransplant recipients were followed for up to 3 years at 19 UStransplantation centers. The patient and graft survival rates at3 years were 88.2 and 73.7%, respectively. These rates were

Table 3 | Renal transplantation in the pre-cART period (before 1996)a

Author (reference) Year Number Donor Follow-upb Fatal outcomec

Feduska et al.36 1980 2 Cadaver 44.5 2 (100%)Kumar et al.37 1982 1 LD 8 1 (100%)Imbasciati et al.38 1982 1 Cadaver 50 1 (100%)Milgrom et al.39 1982 1 Cadaver 19 1 (100%)Lang et al.40 1983 1 Cadaver 17 0Poli et al.41 1983–1985 8 Cadaver 51 3 (37.5%)Erice et al.42 1983–1984 2 Cadaver 74.5 0Prompt et al.43 1984 2 Cadaver 26.5 2 (100%)L’age-Stehr et al.44 1984 1 Cadaver 74 1 (100%)Schwartz et al.45 1983–1984 4 Cadaver 69.2 2 (50%)Margreiter et al.46 1984 1 Cadaver 69 0Briner et al.47 1984 1 Cadaver 48 1 (100%)Ahuja et al.48 1984 1 Cadaver 109 1 (100%)Simonds et al.49 1985 2 Cadaver 23 2 (100%)Bowen et al.50 1986 1 Cadaver 31 0Ward et al.51 1986 1 Cadaver 31 0Kerman et al.52 1987 2 Cadaver 27.5 1 (50%)Carbone et al.53 1988 2 1 Cadaver/1 LD 31.5 2 (100%)Tzakis et al.54 1981–1990 5 Cadaver 33 1 (20%)Global 1980–1990 39 37 Cadaver/2 LD 48 (8–109) 21 (53.8%)

Abbreviations: cART, combined antiretroviral treatment; LD, living donor.aAdapted from Schwarz et al.34 and Trullas et al.35

bMean time in months.cNumber (percentage).

Table 4 | Patient and graft survival rates in HIV-positive renal transplant recipients. Differences between pre-cART and cARTera

Pre-cART era, 1987–1997a cART era, 2003–2009b

5-year survival rates 1/3-year survival rates

USRDS (n=63,210) HIV + (n=32) P-value SRTR (age X65)c SRTR (overall)c HIV + (n=150) P-value

Patient survival 78% 71% o0.05 91.8/79.5% 96.2/90.6% 94.6/88.2% NSGraft survival 61% 44% o0.05 88.3/74.4% 92.5/82.8% 90.4/73.7% NSAcute rejection 48.4% 50% — 12.3%d 31/41% — —

Abbreviations: cART, combined antiretroviral treatment; HIV, human immunodeficiency virus; NS, non significant; SRTR, US Scientific Registry of Transplant Recipients;USRDS, United States Renal Data System.aSwanson et al.55

bStock et al.74

cSRTR survival estimates for older kidney transplant recipients (age X65 years) and for all kidney transplant recipients.dSRTR 1-year acute rejection rate (SRTR 3-year acute rejection rate not available).



generally between the reported rates in the national databasefor older kidney-transplant recipients (X65 years of age) andfor all kidney-transplant recipients (Table 4).74

European experience

In Europe, experience on renal transplantation is scarce. Thefirst report was from Toso et al.,61 who described a combinedkidney–pancreas transplant in an HIV-infected recipient inSwitzerland. This experience was later extended by Mulleret al.,68 with two kidney and five liver transplants. Ballarinet al.69 reported the first case of combined kidney–livertransplant in an HCV/HIV-coinfected patient with hemo-philia A. However, the first series of renal transplantation in aEuropean country included 10 transplants performed inSpain between 2001 and 2004.64 The same authors recentlyupdated these results comparing the outcome of 20 HIV-infected kidney recipients with 40 matched HIV-negativepatients and found similar patient survival but worse graftsurvival in the HIV-infected group.71

We reported our experience with three HIV-infectedkidney recipients who received thymoglobulin as inductiontherapy. Profound lymphocytopenia was observed in thepost-transplant period, but this was not associated withan increased risk of bacterial or opportunistic infections incomparison with a control cohort of 23 HIV-negative kidneyrecipients.70 Trullas et al.9 reported their experience with 26HIV-infected patients from the EuroSIDA cohort study whoreceived a renal transplant between 2000 and 2004; thesurvival rate was 100%. Finally, two recent publications have

reported the experience with 34 renal transplants performedin France.72,73

Acute rejection rate in the cART era

Most studies report a high rate of acute rejection incomparison with the low rate of acute rejection in non-HIV-infected renal transplant recipients. There is highvariability between studies, but in some series the rate is450%. The explanation remains unclear, although immu-nological, pharmacological, and racial factors seem to have arole; in any case, it does not seem to affect allograft survivalrates. In the National Institutes of Health trial, the onlyvariables associated with an increased risk of graft rejectionwere the use of a kidney from a deceased donor and the useof cyclosporine.74 Drug interactions resulting in alteredexposure to immunosuppressants may be associated withrejection. The use of new antiretrovirals (for example,raltegravir) with no interactions with calcineurin inhibitorsmay contribute to more stable immunosuppressive regimens,and therefore a lower risk of acute kidney rejection.75

On the other hand, experimental and clinical researchimplicates cytokines and chemokines in the process oftransplant rejection. Patients who were homozygous for CCchemokine receptor 5 (CCR5) with a 32-bp deletion(CCR5D32) show longer survival than those with othergenotypes. Antiretroviral drugs with new mechanismsof action, such as the CCR5 inhibitor maraviroc, could havean important role in avoiding acute rejection in HIV-infectedrenal transplant recipients.76,77

Table 5 | Renal transplantation in the cART period (1997–2010)

Author (reference) Year N Donor Follow-upa Acute rejectionb Graft survival Patient survival

Abbott et al.56 1996–2001 47 Cadaver 31 ND 98% 96%Qiu et al.57 1997–2004 38 ND 60 0 76% 91%Kuo et al.58 1999–2000 2 ND 6 ND ND 100%Stock et al.59 2000 6 4 Cadaver/2 LD 10 4 100% 100%Roland et al.60 2002 26 ND 10 10 (38) 88% 92%Toso et al.61 2000 1c Cadaver 84 0 100% 100%Kumar et al.62 2002 12 ND 12 4 (33) 100% 100%Stock et al.63 2003 10 6 Cadaver/4 LD 16 5 (50) 100% 100%Mazuecos et al.64 2001–2005 10 Cadaver 16 4 (40) 90% 100%Kumar et al.65 2001–2004 40 36 Cadaver/4 LD 24 9 (22) 71% 82%Roland et al.66 2000–2003 18 10 Cadaver/8 LD 36 12 (70) 83% 94%Gruber et al.67 2004–2007 8 7 Cadaver/1 LD 15 1 88% 100%Muller et al.68 ND 2 Cadaver 13 1 100% 100%Ballarin et al.69 2007 1d 1 Cadaver 12 0 100% 100%Trullas et al.70 2005–2006 3 3 Cadaver 24 2 100% 100%Mazuecos71 2001–2009 20 ND 38 8 (40) 74% 95%Trullas et al.9 2000–2004 26e 21 Cadaver/1 LD ND 8 (30) 77% 100%Billault et al.72 ND 7 Cadaver 12 0 100% 100%Touzot et al.73 2005–2009 27 25 Cadaver/2 LD 29 4 (15%) 96% 98%Stock et al.74 2003–2009 150 102 Cadaver/48 LD 20.4 41%f 73.7%g 88.2%g

Abbreviations: cART, combined antiretroviral treatment; LD, living donor; ND, no data available.aMean time in months.bNumber (percentage when NX4).cPancreas–kidney transplant.dKidney–liver transplant.eData available for 22 patients.fCumulative incidence of rejection at 3 years (49 (33%) patients had 67 acute rejection episodes).gThree-year survival rates.



SPECIAL CONSIDERATIONS FOR RENAL TRANSPLANTATIONIN HIV-INFECTED PATIENTS

Renal transplantation in HIV-infected patients is a complexscenario requiring a multidisciplinary approach. Teamsshould include nephrologists, urologists, infectious diseasesand HIV specialists, psychologist/psychiatrists, experts onalcoholism and drug abuse, and social workers. Several issuesshould be taken into account when treating HIV-infectedrenal transplant recipients.

Antiretroviral therapy in ESRD

In patients with ESRD, appropriate dose reduction iswarranted for antiretrovirals that are eliminated mainly viathe kidney, with additional doses given after hemodialysisfor those drugs that are readily removed by dialysis. There islittle clinical evidence on the dosage of antiretrovirals inESRD patients,78–93 but some general recommendations havebeen made. A summary of these recommendations isprovided in Table 6. As nucleoside and nucleotide reversetranscriptase inhibitors (NRTIs) are eliminated mainly by thekidneys, a reduced dosage is required in patients withimpaired renal function. Over- or under-prescription of thesedrugs could lead to toxicity or virological failure, respectively.Furthermore, because NRTIs are easily removed by dialysis,they should be administered after dialysis. The exception isabacavir, which has low urinary excretion, and, therefore, norequirement for dose adjustment. However, abacavir hasbeen associated with increased cardiovascular risk, and mustbe prescribed with caution in patients with previouscardiovascular events.79,81 Abacavir should only be adminis-tered in patients who are HLA-B*5701 negative. On the otherhand, non-nucleoside reverse transcriptase inhibitors(NNRTIs), protease inhibitors, and fusion inhibitors aregenerally metabolized by the liver and excreted into theurine in low amounts. Doses of NNRTIs, protease inhibitors,enfuvirtide, and raltegravir do not need to be adjusted inpatients with chronic kidney disease.78–81 For nevirapine, anadditional 200 mg dose is indicated following eachdialysis session. Atazanavir boosted with ritonavir shouldbe applied in patients under dialysis because of the loweratazanavir concentrations observed in those patients. Doseadjustment for maraviroc depends on coadministereddrugs.78–93

Based on the information presented above, the ideal cARTfor ART-naive patients undergoing dialysis is a regimencontaining abacavir (if the patient has no history ofcardiovascular risk and a plasma RNA viral load ofo100,000 copies/ml)81 or tenofovir and lamivudine/emtrici-tabine combined with a third drug that can be efavirenz, aritonavir-boosted protease inhibitor, or raltegravir. Inpatients with effective cART and NRTI side effects, the cARTregimen could be simplified to monotherapy with lopinavir/ritonavir or darunavir/ritonavir94–96 or a ritonavir-boostedprotease inhibitor with raltegravir. In patients with virologi-cal failure, rescue treatment should be based on a genotypicresistance study. When the patient is close to the renal

transplant, and in order to avoid pharmacokinetic druginteractions with immunosuppressive drugs and renaltoxicity in the graft, we would recommend, if there are nocontraindications, abacavir, lamivudine, and raltegravir asfirst choice or efavirenz as an alternative.

Donor issues

In the pre-cART era, all transplant organs for HIV-infectedpatients were from cadaveric donors. In recent years, thenumber of living donors has increased, and there is nocontraindication for the use of living donors in HIV-infectedpatients. The largest experience with 48 living donors hasrecently been reported, finding that the use of a graft from aliving donor was protective for graft loss.74 Organ transplan-tation from HIV-infected kidney donors is contraindicated atpresent, but its potential utility has recently been consid-ered.97 In South Africa, the first organ transplants involvingfour HIV-infected recipients who received kidneys fromdeceased HIV-infected donors were performed in 2008.98 At12 months after transplantation, the four recipients had goodrenal function, did not have significant graft rejection, andHIV infection remained well controlled under cART. Organtransplantation between HIV-infected patients is controver-sial, because in addition to ethical issues, recipients canacquire a different and more aggressive HIV strain (forexample, a different clade or recombinant virus or a viruswith a X4 tropism) from the donor, including HIV drug-resistant strains, leading to superinfection and HIV diseaseprogression, can acquire other viruses or subclinical infec-tions and, finally, the graft quality from the HIV donor maynot be optimal because of undetected factors at the time ofscreening and donation. In our opinion, these transplantsshould not be performed in the Western World in clinicalpractice until their efficacy and safety is evaluated inprospective long-term controlled studies. In countries witha resource-limited health system, where there is a highprevalence of HIV in the general population and HIVinfection is an absolute exclusion criterion for access todialysis or renal transplantation, the use of HIV-infecteddonors would increase the donor pool, thus providing renalallografts to patients who would otherwise die as aconsequence of ESRD. In these cases, the balance betweenjustice and equity is more difficult. Such issues shouldencourage intense scientific debate, given their ethical,nephrological, virological, and clinical implications.99

Antiretroviral therapy in renal transplant recipients

The ideal antiretroviral regimen has not been established forHIV-infected kidney transplant recipients, and generalrecommendations for treating HIV-infected patients mustbe followed.79–81 However, it is evident that the idealtherapeutic regimen must be powerful and sustainable andaim to achieve and maintain continuous viral suppressionand an increased CD4 lymphocyte count. In addition, inorder to preserve renal graft function, while avoiding thepharmacokinetic interactions with immunosuppressive drugs



Table 6 | Antiretroviral dosing recommendations in patients with renal impairmenta

Antiretroviral Renal insufficiency HD/CAPD

NRTIsAbacavir No dosing adjustment is needed No dosing adjustment is needed.

HD: minimally eliminated. Could be dosed independently of HDsession

Didanosine(enteric-coated)

X60 kgCrCl X60: 400 mg every 24 hCrCl 30–59: 200 mg every 24 hCrClo30: 125 mg every 24 h

HD/CAPD: 125 mg every 24 h. It is not necessary to administer asupplemental dose after HD

o60 kgCrCl X60: 250 mg every 24 hCrCl 10–59: 125 mg every 24 hCrCl o10: Not suitable for use in patients o60 kgwith CrCl o10 ml/min. An alternate formulation ofdidanosine should be used (Videx pediatric powderfor oral solution 75 mg every 24 h)

HD/CAPD: An alternate formulation of didanosine should beused (Videx pediatric powder for oral solution 75 mg every 24 h)

Emtricitabine CapsulesCrCl X50: 200 mg every 24 hCrCl 30–49: 200 mg every 48 hCrCl 15–29: 200 mg every 72 hCrClo15: 200 mg every 96 hOral solution 10 mg/ml. Due to a difference in thebioavailability of emtricitabine between the hardcapsule and oral solution presentations, 240 mgemtricitabine administered as the oral solution (24 ml)should provide similar plasma levels to thoseobserved after administration of one 200 mgemtricitabine hard capsule).CrCl X50: 240 mg (24 ml) every 24 hCrCl 30–49: 120 (12 ml) mg every 24 hCrCl 15–29: 80 mg (8 ml) every 24 hCrClo15: 60 mg (6 ml) every 24 h

CapsulesHD: 200 mg every 96 h, after HDCAPD: NDOral solution (10 mg/ml)HD: 60 mg (6 ml) every 24 h, after HDCAPD: ND

Lamivudineb CrCl X50: 150 mg every 12 h or 300 mg every 24 hCrCl 30–49: 150 mg every 24 hCrCl 15–29: 100 mg every 24 h (first dose 150 mg)CrCl 5–14: 50 mg every 24 h (first dose 150 mg)CrCl o5: 25 mg every 24 h (first dose 50 mg)

HD: 25 mg every 24 h (first dose 50 mg), after HD

Stavudine X60 kgCrCl X50: 40 mg every 12 hCrCl 26–49: 20 mg every 12 hCrCl 10–25: 20 mg every 24 hCrCl o10: 20 mg every 24 h

HD: 20 mg every 24 h, after HD

o60 kgCrCl X50: 30 mg every 12 hCrCl 26–49: 15 mg every 12 hCrCl 10–25: 15 mg every 24 hCrCl o10: 15 mg every 24 h

HD: 15 mg every 24 h, after HD

Zidovudine Significantly elevated GZDV (the major metabolite ofzidovudine) plasma concentrationsCrCl 10–50: 250–300 mg every 12 hCrCl o10: 250–300 mg every 24 h

300 mg every 24 h, after HDHD and CAPD appeared to have a negligible effect on theremoval of zidovudine, whereas GZDV elimination wasenhanced.

NtATenofovirdisoproxil fumarate

CrCl X50: usual doseCrCl 30–49: 300 mg every 48 hCrCl 10–29: 300 mg every 72–96 h (dosing twice aweek)No dosing recommendations can be given for non-HD patients with creatinine clearanceo10 ml/min

HD: 300 mg tenofovir disoproxil (as fumarate) may beadministered every 7 days following completion of a HD session(assuming three HD sessions per week, each of B4 h duration orafter 12 h cumulative HD)

NNRTIEfavirenz Usual dose HD: limited data suggest that there is no reason to adjust the

doseCAPD: pharmacokinetic data of only one patient suggest thatthere is no reason to adjust the dose

Nevirapine CrCl X20 ml/min. Usual dose HD: an additional 200 mg dose of nevirapine following eachdialysis treatment is recommended

Table 6 continued on following page



Table 6 | Continued

Antiretroviral Renal insufficiency HD/CAPD

Etravirine (TMC-125) Usual dose HD/CAPD: as etravirine is highly bound to plasma proteins,it is unlikely that it will be significantly removed by HD or PD

PIAmprenavir Usual dose

Because of the potential risk of toxicity from the largeamount of the excipient propylene glycol, Ageneraseoral solution is contraindicated in patients with renalfailure.

HD/CAPD: as amprenavir is highly bound to plasma proteins,it is unlikely that it will be significantly removed by HD or PD

Atazanavir Usual dose HD/CAPD: as atazanavir is highly bound to plasma proteins, it isunlikely that it will be significantly removed by HD or PDHD: consider using atazanavir boosted with ritonavir. AlthoughATV was negligibly eliminated by HD (2%), subjects on HD hadsubstantially lower ATV levels than controls (AUC 42% lower onHD days, 28% lower on non-HD days). The mechanism for thiseffect is not known (limited data). TDM is advised

Darunavir Usual dose HD/CAPD: as darunavir is highly bound to plasma proteins, it isunlikely that it will be significantly removed by HD or PD

Fosamprenavir Usual dose HD/CAPD: as amprenavir is highly bound to plasma proteins,it is unlikely that it will be significantly removed by HD or PD

Indinavir Usual dose HD: limited data showed minimal elimination of indinavir duringa dialysis session

Lopinavir/r Usual dose HD: usual dose. In 13 patients who were on HD LPV AUC valueswere similar to those obtained in patients with normal renalfunctionCAPD: ND. As lopinavir and ritonavir are highly bound to plasmaproteins, it is unlikely that it will be significantly removed byCAPD.

Nelfinavir Usual dose HD: it is unlikely that it will be significantly removed by HD.Data from one patient showed no removal of nelfinavir by a 4 hHD sessionCAPD: it is unlikely that it will be significantly removed by PD.Data from one patient showed dialysate nelfinavirconcentrations below the limit of detection

Ritonavir Usual dose HD/CAPD: as ritonavir is highly bound to plasma proteins,it is unlikely that it will be significantly removed by HD or PD

Saquinavir Usual dose HD/CAPD: as saquinavir is highly bound to plasma proteins,it is unlikely that it will be significantly removed by HD or PD

Tipranavir Usual dose HD/CAPD: as tipranavir is highly bound to plasma proteins,it is unlikely that it will be significantly removed by HD or PD

Fusion inhibitorsEnfuvirtide (T-20) No dosing adjustment is needed HD: usual dose (limited data)

CCR5 co-receptorantagonists

Maraviroc (UK-427857) No dosing adjustment is needed without potentCYP3A4 inhibitors or inducersPostural hypotension may increase the risk forcardiovascular adverse events in patients receivingmaraviroc who have severe renal impairment or ESRD(creatinine clearance o30 ml/min). Maraviroc shouldnot be prescribed for patients with severe renalimpairment who are receiving CYP3A inhibitors orinducer

HD/CAPD: ND

Integrase inhibitorsRaltegravir (MK-0518) No dosing adjustment is needed ND

Abbreviations: ATV, atazanavir; AUC, area under the plasma concentration time curve; CAPD, continuous ambulatory peritoneal dialysis; CrCl, creatinine clearance;ESRD, end-stage renal disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HD, hemodialysis; HIV, human immunodeficiency virus; LPV, lopinavir; ND, no data available;NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NtA, nucleotide reverse transcriptase inhibitor; PD, peritoneal dialysis;PI, protease inhibitor; TDM, therapeutic drug monitoring.aAdapted from Spanish GESIDA/National AIDS Plan Recommendations for antiretroviral therapy in HIV-infected adults, January 2008.79

bDose adjustment for HIV-1 and not for HBV.



and their side effects, the antiretrovirals included in theregimen should have these two additional properties:1. Low probability of inducing dyslipidemia, osteopenia/osteo-

porosis, insulin resistance, and renal toxicity (all of which areside effects of immunosuppressive drugs). Cardiovascularsafety should also be taken into consideration.

2. Avoidance of pharmacokinetic interactions with calcineurininhibitors (cyclosporine and tacrolimus) and mammaliantarget of rapamycin (m-TOR) inhibitors (sirolimus) that aremetabolized by cytochrome P450.

If there are no contraindications, we recommend abacavir(or tenofovir as an alternative) and lamivudine/emtricitabinecombined with raltegravir as the first-choice regimen orefavirenz as an alternative. Recommendations on antiretro-viral drug combinations in renal transplant recipientsare summarized in Table 7. Finally, frequent viral loadmonitoring in the early period after transplantation ishighly recommended, and resistance testing must also beconsidered.

Immunosuppression

The antiviral effects of immunosuppressive drugs have beenextensively reviewed elsewhere and are beyond the scope of thisreview.100 However, some brief recommendations can be made:1. Calcineurin inhibitors: There are no studies comparing

the effects of cyclosporine and tacrolimus on the course ofHIV infection. Cyclosporine is been the most frequentlyused drug, in the published experience, probably because

of evidence demonstrating its antiretroviral and/orimmunomodulating effects.101 However, the rate of acuterejection is higher with cyclosporine than with tacroli-mus.74 In this setting, some centers use tacrolimus asthe ‘first-line’ calcineurin inhibitor.

2. Mycophenolate mofetil: this drug has inhibitory effects onHIV replication and is synergistic with some NRTIs.102–104

The leukocyte count should be monitored regularlybecause of the myelosuppressive effect of the drug.

3. m-TOR inhibitors: Sirolimus does not seem to have anegative effect on HIV-infected patients, although experi-ence with this drug remains scarce. In experimentalstudies, sirolimus reduces CCR5 levels in CD4þ T cells,inhibits R5 HIV-1 replication, and increases the antiviralactivity of fusion inhibitors and CCR5 antagonists.105

In addition, its antiproliferative effect can prove usefulin patients with solid organ transplantation-associatedKaposi sarcoma.106 Leukocyte count monitoring is alsorecommended.

4. Basiliximab/daclizumab: These monoclonal anti-interleu-kin-2 receptor antibodies have been shown to increaseCD4 T-cell counts mainly by expanding their number andby prolonging their half-lives.107 Clinical experience hasnot shown negative effects on HIV-infected patients.

5. Antilymphocyte polyclonal antibodies: The use of thesedrugs is controversial. Carter et al.108 reported 11 HIV-infected renal transplant recipients who received thymo-globulin for acute rejection or delayed graft function.Thymoglobulin produced profound and long-lastingsuppression of the CD4þ T-cell count and was associatedwith an increased risk of infections requiring hospitaliza-tion. In contrast, in another small series (three patients),we observed that CD4þ T-cell thymoglobulin-inducedlymphocytopenia was not associated with increased risk ofinfection.70 Stock et al.74 found that patients who receivedthis therapy had about twice as many serious infectionsper follow-up year as patients who did not receive suchtherapy. In addition, the risks of death and of graft losswere marginally higher for patients who received thisinduction therapy. The authors recommend restrictingthis therapy for patients at very high immunological riskfor rejection.74

6. Monoclonal anti-CD20 antibody: There is a singleexperience with one HIV-infected renal transplant reci-pient who developed an acute humoral rejection that wassuccessfully treated with rituximab.109

In the pre-cART era, the immunosuppressive regimensmost frequently used were ‘azathioprine-corticosteroids’ and‘cyclosporine-corticosteroids.’ Schwarz et al.34 reported apositive association between cyclosporine and improvedoutcome in HIV-infected transplant recipients. Subsequentobservations have suggested that cyclosporine may attenuatethe course of HIV infection by inhibition of viral replica-tion.101 More recent series from the cART era have reporteddifferent immunosuppressive regimens (Table 8), which are

Table 7 | Antiretroviral drug regimens recommended amongHIV-infected renal transplant recipients

1. NRTIsK A combination of two NRTIs (for example tenofovir plus

emtricitabine or abacavir plus lamivudine) can be used safely inrenal transplant recipients with dose adjusted to renal function.

K Tenofovir should be used with caution and close monitoring ofrenal function.

K Abacavir should not be used in recipients receiving a kidney froman HLA-B57*01-positive donor to avoid the potential risk ofhypersensitivity reaction to abacavir.

2. NNRTIs and protease inhibitorsK Can be used safely in combination with two NRTIsK Important interactions with immunosuppressive drugs may

appear, mainly with protease inhibitors.

3. Novel classes of antiretroviralsK Must be considered in combination with NRTIsK Integrase inhibitors (raltegravir): have no interactions with

immunosuppressive agents at the CYP450 level.K Entry inhibitors (enfuvirtide (T20)): could be an alternative in

combination with NRTIs, although subcutaneous administrationis a limitation.

K CCR5 co-receptor antagonists (maraviroc): a substrate of CYP450.Its levels can be modified by inducers or inhibitors. Experimentalstudies have suggested that maraviroc could have an importantrole as an antirejection drug.

Abbreviations: CCR5, CC chemokine receptor 5; HIV, human immunodeficiency virus;NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotidereverse transcriptase inhibitor.



not significantly different from those used in HIV-negativerenal transplant recipients.9,56–74

Drug–drug interactions

Some pharmacological interactions between antiretroviralsand immunosuppressants may be clinically relevant. Druginteractions may require dosing modifications to maintainappropriate drug levels and for this reason it is veryimportant to perform close therapeutic drug monitoring.These interactions are summarized in Table 9.110–129

Mycophenolate mofetil is metabolized mainly by glucur-onidation in the liver. Atazanavir inhibits UDP-glucuronosyltransferase and, theoretically, leads to an increase in bloodmycophenolate mofetil levels, whereas ritonavir inducesglucuronidation and could reduce blood mycophenolatemofetil levels. However, clinically important drug–druginteractions between mycophenolate mofetil and theseantiretroviral agents have not been reported. Mycophenolatemofetil has inhibitory effects on HIV and is synergistic withabacavir, didanosine, and tenofovir.102–104,118

Cyclosporine, tacrolimus, and sirolimus are metabolizedin the liver by cytochrome P450 (isoenzyme 3A4). Anti-retroviral drugs can act as inhibitors or inducers of theseenzymatic systems. When they act as inhibitors (for example,protease inhibitors), they increase concentrations of theimmunosuppressive drugs, leading to toxicity; therefore,doses must be markedly reduced. Clinical experienceindicates that patients on protease inhibitors require only1–2 mg of tacrolimus per week to maintain therapeuticlevels.110–112 Stopping the protease inhibitors while taking

calcineurin inhibitors could cause an acute rejection.On the other hand, when antiretroviral drugs act as enzymeinducers (for example, NNRTIs), they reduce drug levelsand can trigger rejection. Therefore, doses of immuno-suppressive drugs must be increased.113 Stopping theNNRTI while taking calcineurin inhibitors could causetoxicity.

In one of the largest series published, Frassetto et al.114

recently described the pharmacokinetics and dosing mod-ifications in 35 patients (20 kidney recipients, 13 liverrecipients, and 2 kidney–liver transplant recipients). Patientsreceiving protease inhibitors had marked increases incyclosporine, tacrolimus, and sirolimus levels compared withthose on NNRTIs alone or with patients not on antiretroviraltreatment, and it was necessary to reduce the dose or increasethe dosing interval. Patients taking efavirenz required muchhigher doses of cyclosporine than those using any otherantiretroviral drug.

In order to avoid these interactions, some researchers havereported the use of enfuvirtide plus two NRTIs in livertransplant recipients.115 Theoretically, based on the elimina-tion pathways, a pharmacokinetic drug–drug interaction withthe new CCR5 antagonist maraviroc is unlikely. Maraviroc isa substrate of CYP3A4, but it is not an inducer or inhibitor ofCYP3A4. The HIV-1 integrase inhibitor raltegravir offersimportant advantages: it has high antiviral potency and nosignificant interactions with immunosuppressive agents,because of its lack of effect on CYP3A4 (raltegravir isprimarily metabolized by the liver via glucuronidation andnot by CYP3A4).116 Tricot et al.75 recently observed no

Table 8 | Immunosuppressive regimens in HIV-infected renal transplant recipients in the cART period

Author (reference) N CyA FK AZA SRL MMF CorticosteroidsBasiliximab/daclizumab ATG/OKT3

Abbott et al.56 47 30 (68.2) 19 (43.2) 7 (15.9%) — 38 (86.4) — —/22 (46.8%) —Qiu et al.57 38 20 (52%) 13 (34%) — 14 (36.8%) — — 10 (26.3%)/6 (15%) 4 (10%)/3 (7.9%)Kuo et al.58 2 Preferreda Preferreda — — — — — —Stock et al.59 6 Preferreda — — — Preferreda Preferreda — —Roland et al.60 26 Preferreda — — — Preferreda — — —Toso et al.61 1 — 1 (100%) — — 1 (100%) 1 (100%) 1 (100%)/— —Kumar et al.62 12 ND ND ND ND ND ND ND NDStock et al.63 10 Preferreda — — — Preferreda Preferreda — —Mazuecos et al.64 10 — 10 (100%) — — 10 (100%) 10 (100%) — 1 (10%)/—b

Kumar et al.65 40 40 (100%) — — 40 (100%) — 40 (100%) 40 (100%)/— —Roland et al.66 18 12 (66%) — — 5 (28%) 16 (89%) — 6 (34%)/1 (5.5%) —Gruber et al.67 8 8 (100%) — — — 8 (100%) 8 (100%) 8 (100%) —Muller et al.68 2 1 (50%) 1 (50%) — — 2 (100%) 2 (100%) ND NDBallarin et al.69 1 1 (100%) — — 1 (100%) — 1 (100%) 1 (100%)/— —Trullas et al.70 3 — 1 (33%) — 2 (67%) 3 (100%) 3 (300%) — 3 (100%)/—Trullas et al.9 26c 7 (32%) 15 (68%) 1 (4.5%) — 19 (86%) 19 (86%) 3 (14%)/5 (23%) 5 (23%)/—Billault et al.72 7 — 7 (100%) — — 7 (100%) 7 (100%) —/7 (100%) —Touzot et al.73 27 11 (41%) 16 (59%) — — 27 (100%) 27 (100%) 26 (97%)/— 1 (3%)/—Stock et al.74 150 33 (22%) 99 (66%) — —d 131 (87%) 150 (100%) 76 (51%) 48 (32%)/—

Abbreviations: ATG, thymoglobulin; AZA, azathioprine; Corticosteroids, prednisone; cART, combined antiretroviral treatment; CyA, cyclosporine; FK, tacrolimus; HIV, humanimmunodeficiency virus; MMF, mycophenolate mofetil; N, number of transplants; ND, no data available; OKT3, muromonab-CD3; SRL, sirolimus.aImmunosuppression regimens were based on these drugs, but the exact number of patients is not specified.bAnti CD-25 was used in 3 patients.cData available for 22 patients.dSRL was used in patients with calcineurin inhibitor-associated nephrotoxicity.



episodes of acute rejection in five raltegravir-treatedHIV-infected renal transplant recipients.

Given the speed with which new antiretroviral drugsemerge and thus generate previously unknown interactions,clinicians should regularly consult updated databases on druginteractions and product information.124–129

HCV coinfection

HCV coinfection is an important issue in settings wereintravenous drug use is the main risk factor for HIVtransmission.

HCV disease progresses more rapidly in HIV-infectedpatients and in liver and kidney transplant recipients.HCV-infected renal transplant recipients (especially thosewith active replication) have higher morbidity and mortalityrelated with infectious and hepatic complications.130 There isevidence that HCV-infected transplant recipients have asignificantly greater risk of chronic liver disease, proteinuria,and chronic allograft nephropathy. Furthermore, patientswith viral replication and chronic elevated alanine amino-transferase levels have an increased risk of death andgraft loss.131

In the absence of severe chronic liver disease, patients ondialysis with positive HCV RNA in plasma should beevaluated for anti-HCV treatment with interferon beforetransplantation. Between 30 and 50% of patients havecomplete remission, and if a reactivation occurs in thepost-transplant period, the clinical course is less severewhen patients have previously received antiviral therapy.Combination therapy with interferon and ribavirin is notrecommended in patients on dialysis because of the risk ofhemolysis.132 Options for antiviral therapy in the post-transplant period are limited. Interferon is not recom-mended, because of the risk of acute renal rejection. Thereis less experience with ribavirin in monotherapy. Ribavirinlowers alanine aminotransferase levels but has no effect onHCV viral load. The histopathological efficacy of ribavirinalone in kidney allograft recipients with hepatitis C iscontroversial. Some studies have shown ribavirin to beassociated with histological improvement,133 and otherstudies have shown no effect of ribavirin with histologicalprogression.134

Because so many HIV-infected patients with ERSD alsohave HCV infection, it is important to determine whetherrenal transplantation is effective in these patients. It isunknown if the outcome of HCV/HIV-coinfected renaltransplant recipients would be worse than for patientswithout HIV infection. In addition, there is not enoughexperience to assess the efficacy and safety of interferon and/or ribavirin treatment in HCV/HIV-coinfected transplantrecipients.

Cardiovascular diseases

As the use of cART became widespread, there has been anincrease in the incidence of non-HIV-related diseases inHIV-infected patients. These include diabetes mellitus,

hypertension, and other cardiovascular diseases, directlyrelated—in part—with antiretroviral treatment. In addition,cardiovascular diseases represent the first cause of death inrenal transplant recipients who survive in the long term.135

Therefore, blood pressure and glucose and cholesterol levelsshould be closely monitored to improve long-term survival,not only in the HIV-infected population, but especially inHIV-infected renal transplant recipients.136

Ethical issues

Organ transplantation in HIV-infected patients has raisedethical problems that have not yet been completely solved.However, with growing experience and encouraging results,most groups agree that HIV-infected patients with ESRDshould be evaluated for inclusion on the renal transplanta-tion waiting list.137

PANCREAS–KIDNEY TRANSPLANTATION IN HIV-INFECTEDPATIENTS

There is relatively little experience with simultaneouspancreas–kidney transplantation in HIV-infected patientswith diabetes mellitus. Preliminary experience suggests thatpancreas–kidney transplantations can be performed using thesame criteria as for kidney transplantation. However, there isa higher risk of procedure-related infectious complica-tions.61,138,139

THE NEXT STEP

Several issues must be clarified in the coming years, whichare as follows: (1) the most appropriate combination ofimmunosuppressive and antiretroviral drugs must be estab-lished in terms of clinical efficacy, low acute rejection rate,absence of nephrotoxicity, appropriate safety profile, minimalpharmacological interactions, and sustained virologicalsuppression; (2) knowledge of the pathogenesis of acuterejection should be expanded; (3) the most appropriatestrategy for the management of HCV/HIV-coinfectedpatients must be decided; and (4) physicians should beaware of the clinical course of HIV infection in patientsreceiving long-term immunosuppression.

CONCLUSIONS

1. Renal transplantation waiting list: All HIV-infectedpatients with ESRD should be considered candidates forrenal transplantation if they meet the HIV inclusioncriteria.

2. Patient and graft survival: There are enough data to affirmthat renal transplantation in adequately selected HIV-infected patients is a safe procedure in the short andmedium term, with patient and graft survival rates similarto those of HIV-negative renal transplant recipients.

3. Acute rejection: In comparison with the HIV-negativepopulation, HIV-infected patients have a high rate ofacute rejection. The use of antiretroviral drugs that do notreact with immunosuppressive drugs may reduce the riskof acute rejection.



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ract

ion

isu

nlik

ely

Ind

uce

rso

fC

YP

3A

4lik

eN

NR

TI

may

incr

eas

eth

em

eta

bo

lism

of

eve

rolim

us

and

de

cre

ase

blo

od

eve

rolim

us

leve

ls.

TD

Mo

fe

vero

limu

sis

reco

mm

en

de

d

Mo

de

rate

inh

ibit

ors

of

CY

P3

A4

and

P-g

psu

chas

PIs

may

incr

eas

ee

vero

limu

sb

loo

dle

vels

Wit

hTP

V/r

,co

nce

ntr

atio

ns

of

eve

rolim

us

can

no

tb

ep

red

icte

d,

du

eto

the

con

flic

tin

ge

ffe

cto

nC

YP

3A

(in

hib

itio

n)

and

P-g

p(s

ligh

tin

du

ctio

nat

ste

ady

stat

e)T

DM

of

eve

rolim

us

isre

com

me

nd

ed

Th

eore

tica

lly,

bas

ed

on

the

elim

inat

ion

pat

hw

ays,

itis

un

like

lyth

atm

arav

iro

cco

uld

mo

dif

yb

loo

de

vero

limu

sle

vels

d

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nis

un

like

ly

Me

thyl

pre

dn

iso

lon

eT

he

ore

tica

lly,

bas

ed

on

the

elim

inat

ion

pat

hw

ays,

ap

har

mac

oki

ne

tic

dru

g–d

rug

inte

ract

ion

isu

nlik

ely

Th

eo

reti

cally

,in

du

cers

of

CY

P3

A4

such

asN

NR

TIm

ayin

cre

ase

the

me

tab

olis

mo

fco

rtic

ost

ero

ids

and

de

cre

ase

blo

od

leve

ls

Th

eore

tica

lly,

inh

ibit

ors

of

CY

P3

A4

like

PIs

may

de

cre

ase

the

me

tab

olis

mo

fco

rtic

ost

ero

ids

and

incr

eas

eb

loo

dle

vels

(iat

rog

en

icC

ush

ing

’ssy

nd

rom

eh

asb

ee

nd

esc

rib

ed

asa

resu

lto

fan

inte

ract

ion

be

twe

en

rito

nav

iran

din

hal

ed

flu

tica

son

e)

Th

eore

tica

lly,

bas

ed

on

the

elim

inat

ion

pat

hw

ays,

ap

har

mac

oki

ne

tic

dru

g–d

rug

inte

ract

ion

isu

nlik

ely

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nis

un

like

ly

Tab

le9

con

tin

ue

do

nfo

llow

ing

pag

e



Ta

ble

9|C

on

tin

ue

d

An

tire

tro

vir

al

ag

en

tsb

NR

TI

(ab

aca

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FT

C,

3T

C,

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AZ

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TD

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NN

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I(N

VP

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FV,

an

de

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ine

)P

I(A

PV

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PV

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tag

on

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rav

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teg

rase

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Mu

rom

on

abC

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T3

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uro

mo

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CD

3is

anim

mu

no

glo

bu

lin;

the

refo

re,

no

me

tab

olic

dru

g–d

rug

inte

ract

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sw

ith

anti

retr

ovi

rals

are

tob

ee

xpe

cte

d.

Myc

op

he

no

late

Ab

aca

vir,

zid

ovu

din

e,an

dm

yco

ph

en

ola

tem

ofe

til

are

elim

inat

ed

mai

nly

by

glu

curo

nid

atio

n;

the

refo

re,

anin

tera

ctio

nca

nn

ot

be

rule

do

ut.

Ho

wev

er,

clin

ical

lyim

po

rtan

td

rug

–dru

gin

tera

ctio

ns

hav

en

ot

be

en

rep

ort

ed

.M

yco

ph

en

ola

teh

asin

hib

ito

rye

ffe

cts

on

HIV

and

issy

ne

rgis

tic

wit

hab

acav

ir,

did

ano

sin

e,

and

ten

ofo

vir.

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nw

ith

oth

er

NR

TIis

un

like

ly

Th

eore

tica

lly,

bas

ed

on

the

elim

inat

ion

pat

hw

ays,

ap

har

mac

oki

ne

tic

dru

g–d

rug

inte

ract

ion

isu

nlik

ely

Myc

op

he

no

late

mo

feti

lis

me

tab

oliz

ed

mai

nly

by

glu

curo

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atio

n.

ATV

inh

ibit

sU

DP

-glu

curo

no

syl

tran

sfe

rase

(UG

T)

(an

incr

eas

ein

myc

op

he

no

late

blo

od

leve

lsw

ou

ldb

ee

xpe

cte

d),

wh

ere

asR

TV(a

nd

bo

ost

ed

PI

incl

ud

ing

TPV

/r)

and

NFV

incr

eas

eg

lucu

ron

idat

ion

(ad

ecr

eas

ein

blo

od

myc

op

he

no

late

mo

feti

lle

vels

wo

uld

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exp

ect

ed

).H

ow

eve

r,cl

inic

ally

imp

ort

ant

dru

g–d

rug

inte

ract

ion

sb

etw

een

myc

op

he

no

late

mo

feti

lan

dth

ese

anti

retr

ovi

ral

age

nts

hav

en

ot

be

en

rep

ort

ed

.T

he

ore

tica

lly,

bas

ed

on

the

elim

inat

ion

pat

hw

ays,

ap

har

mac

oki

ne

tic

dru

g–d

rug

inte

ract

ion

wit

ho

the

rP

Isis

un

like

ly

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nis

un

like

ly

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nis

un

like

ly

Siro

limu

sc,d

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nis

un

like

ly

Ind

uce

rso

fC

YP

3A

4lik

eN

NR

TIm

ayin

cre

ase

the

me

tab

olis

mo

fsi

rolim

us

and

de

cre

ase

blo

od

siro

limu

sle

vels

.T

DM

of

SRL

isre

com

me

nd

ed

Ris

ko

fin

cre

ase

dd

rug

leve

ls/t

oxi

city

of

imm

un

osu

pp

ress

ive

dru

gs.

Mar

ked

lylo

we

rd

ose

so

fim

mu

no

sup

pre

ssiv

ed

rug

sm

ayb

ere

qu

ired

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Inth

est

ud

yb

yG

uar

ald

iet

al.1

17

(in

clu

din

g1

2p

atie

nts

wh

ou

nd

erw

en

tliv

er

tran

spla

nta

tio

n),

the

me

anfo

ldd

ecr

eas

ein

imm

un

osu

pp

ress

ive

dru

g(F

K,

CyA

,SR

L)d

osa

ge

that

was

ne

cess

ary

tom

ain

tain

the

rap

eu

tic

win

do

ws

was

8.7

5(r

ang

e8

–14

)af

ter

init

iati

ng

bo

ost

ed

PIs

,an

d3

(ran

ge

2–4

)af

ter

init

iati

ng

un

bo

ost

ed

PIs

.W

ith

TPV

/rth

eco

nce

ntr

atio

ns

of

siro

limu

sca

nn

ot

be

pre

dic

ted

,d

ue

toa

con

flict

ing

effe

cto

nC

YP

3A(in

hib

itio

n)

and

P-g

p(s

ligh

tin

du

ctio

nat

stea

dy

stat

e).

TD

Mo

fSR

Lis

reco

mm

en

de

d

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nis

un

like

lyd

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nis

un

like

ly

Tac

rolim

usc

,dT

he

ore

tica

lly,

bas

ed

on

the

elim

inat

ion

pat

hw

ays,

ap

har

mac

oki

ne

tic

dru

g–d

rug

inte

ract

ion

isu

nlik

ely

.A

sem

tric

ita

bin

e,la

miv

ud

ine,

and

ten

ofo

vir

are

pri

mar

ilye

xcre

ted

via

the

kid

ne

ys,

ne

ph

roto

xic

dru

gs

cou

ldim

pai

rth

eir

elim

inat

ion

Ind

uce

rso

fC

YP

3A

4su

chas

NN

RTI

may

incr

eas

eth

em

eta

bo

lism

of

tacr

olim

us

and

de

cre

ase

blo

od

tacr

olim

us

leve

ls.

TD

Mo

fFK

isre

com

me

nd

ed

.

Ris

ko

fin

cre

ase

dd

rug

leve

ls/t

oxi

city

of

imm

un

osu

pp

ress

ive

dru

gs.

Mar

ked

lylo

we

rd

ose

so

fim

mu

no

sup

pre

ssiv

ed

rug

sm

ayb

ere

qu

ired

.W

ith

LPV

/rso

me

pat

ien

tsn

ee

de

dan

init

iald

ose

of

FKo

f0

.5m

ge

very

12

h,

follo

we

db

ya

mai

nte

nan

ced

ose

of

0.5

mg

eve

ry4

8h

to1

mg

on

cew

ee

kly

or

eve

nle

ss.

Wh

en

LPV

/ris

init

iate

din

ap

atie

nt

on

FK,

the

ne

xtFK

do

sem

ayn

eed

tob

ed

ela

yed

for

be

twe

en

3an

d5

we

eks

,d

ep

en

din

go

nh

ep

atic

fun

ctio

n

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,it

isu

nlik

ely

that

mar

avir

oc

cou

ldm

od

ify

blo

od

tacr

olim

us

leve

lsd

Th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nis

un

like

ly

Tab

le9

con

tin

ue

do

nfo

llow

ing

pag

e



Ta

ble

9|C

on

tin

ue

d

An

tire

tro

vira

la

ge

nts

b

NR

TI

(ab

aca

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dI,

FT

C,

3T

C,

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I(N

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Inte

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ir)

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city

Wit

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ien

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eed

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ed

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ten

ance

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very

24

–48

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ven

less

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–70

-fo

ldd

ose

red

uct

ion

).In

the

stu

dy

by

Gu

aral

di

eta

l.11

7(i

ncl

ud

ing

12

pat

ien

tsw

ho

un

de

rwen

tliv

er

tran

spla

nta

tio

n),

the

me

anfo

ldd

ecr

eas

ein

imm

un

osu

pp

ress

ive

dru

g(F

K,

CyA

,SR

L)d

osa

ge

that

was

ne

cess

ary

tom

ain

tain

the

rap

eu

tic

win

do

ws

was

8.7

5(r

ang

e8

–14

)af

ter

init

iati

ng

bo

ost

ed

PIs

,an

d3

(ran

ge

2–4

)af

ter

init

iati

ng

un

bo

ost

ed

PIs

.TP

V/r

:co

nce

ntr

atio

ns

of

tacr

olim

us

can

no

tb

ep

red

icte

d,

du

eto

aco

nfl

icti

ng

eff

ect

on

CY

P3

A(i

nh

ibit

ion

)an

dP

-gp

(slig

ht

ind

uct

ion

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ead

yst

ate)

TD

Mo

fFK

isre

com

me

nd

ed

Th

ymo

glo

bu

linT

hym

og

lob

ulin

isan

imm

un

og

lob

ulin

;th

ere

fore

,n

om

eta

bo

licd

rug

–dru

gin

tera

ctio

ns

wit

han

tire

tro

vira

lsar

eto

be

exp

ect

ed

Ab

bre

viat

ion

s:3

TC

,lam

ivu

din

e;A

PV

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pre

nav

ir;A

TV

,ata

zan

avir

;AZ

T,z

ido

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ine

;CyA

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losp

ori

ne

A;C

YP

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och

rom

eP

45

0;d

4T

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vud

ine

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I,d

idan

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ne

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V,d

aru

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ir;

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vire

nz;

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acro

limu

s;FP

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osa

mp

ren

avir

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C,

em

tric

itab

ine

;ID

V,

ind

inav

ir;

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/r,

lop

inav

ir/r

ito

nav

ir;

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,m

yco

ph

en

ola

tem

ofe

til;

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,n

elf

inav

ir;

NN

RT

I,n

on

-nu

cle

osi

de

reve

rse

tran

scri

pta

sein

hib

ito

r;N

RT

I,n

ucl

eo

sid

ean

alo

g;

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P,

ne

vira

pin

e;

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p,

Pg

lyco

pro

tein

;P

I,p

rote

ase

inh

ibit

or;

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V,

rito

nav

ir;

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,sa

qu

inav

ir;

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siro

limu

s;T

DF,

ten

ofo

vir;

TD

M,

the

rap

eu

tic

dru

gm

on

ito

rin

g;

TP

V,

tip

ran

avir

;U

GT

,U

DP

-glu

curo

no

syl

tran

sfe

rase

.aIt

isve

ryim

po

rtan

tto

mai

nta

ing

oo

dad

he

ren

ceto

the

rap

yd

ue

tod

rug

–dru

gin

tera

ctio

ns.

Ifa

cyto

chro

me

P4

50

inh

ibit

or

issu

dd

en

lyw

ith

dra

wn

and

imm

un

osu

pp

ress

ive

do

sag

eis

no

tp

rop

erl

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cre

ase

d,a

tran

spla

nt

reje

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nm

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ccu

r.O

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rh

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acy

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rom

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45

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du

cer

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en

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ith

dra

wn

and

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osu

pp

ress

ive

do

sag

eis

no

tp

rop

erl

yd

ecr

eas

ed

,to

xici

tym

ayo

ccu

r.b

Enfu

virt

ide

:th

eo

reti

cally

,b

ase

do

nth

ee

limin

atio

np

ath

way

s,a

ph

arm

aco

kin

eti

cd

rug

–dru

gin

tera

ctio

nw

ith

imm

un

osu

pp

ress

ive

dru

gs

isu

nlik

ely

.cC

yclo

spo

rin

e,

eve

rolim

us,

tacr

olim

us,

and

siro

limu

sar

ee

xte

nsi

vely

me

tab

oliz

ed

by

cyto

chro

me

CY

P3

A.

Sub

stan

ces

that

inh

ibit

this

en

zym

e(s

uch

ascl

arit

hro

myc

in,

dilt

iaze

m,

ery

thro

myc

in,

flu

oxe

tin

e,

flu

voxa

min

e,

gra

pe

fru

itju

ice

,HIV

pro

teas

ein

hib

ito

rs,i

trac

on

azo

le,k

eto

con

azo

le,n

efa

zod

on

e,p

aro

xeti

ne

,te

lith

rom

ycin

,an

dvo

rico

naz

ole

)co

uld

de

cre

ase

me

tab

olis

man

din

cre

ase

blo

od

con

cen

trat

ion

so

fth

ese

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4. Course of HIV infection: Immunosuppressive therapydoes not have a negative impact on the course of HIVinfection, with no evidence of progression to AIDS and nofurther opportunistic infections or neoplasms. Patientsshould follow the same prophylaxis protocols as the non-HIV-infected population.

5. Immunosuppression: The best immunosuppressive regi-men in HIV-infected renal transplant recipients has notbeen completely established. Until results from larger andcontrolled studies are available, immunosuppressive therapyin the early post-transplant period should include inductiontherapy with anti-interleukin-2 receptor monoclonal anti-bodies (basiliximab) in combination with triple therapybased on calcineurin inhibitors (cyclosporine or tacroli-mus), mycophenolate mofetil, and corticosteroids. There islittle experience with sirolimus, but it does not seem to havenegative effects. The use of antilymphocyte polyclonalantibodies is not contraindicated, but produces deep andpersistent lymphocytopenia that must be closely monitored.This treatment is not recommended in patients with highviral replication or previous lymphocytopenia.

6. Antiretroviral regimens: Dose adjustment is mandatory forsome antiretroviral drugs. Physicians must be aware ofinteractions between immunosuppressive agents and anti-retroviral drugs, especially protease inhibitors and, to a lesserextent NNRTIs. For this reason, it is very important toclosely monitor immunosuppressive drugs and, whenpossible, antiretroviral drugs (NRTIs, protease inhibitors,and raltegravir). Antiretroviral regimens containing drugswith a low pharmacological interaction profile (for example,raltegravir plus two NRTIs) are recommended.

7. HCV coinfection: There is little experience in themanagement and outcome of HCV/HIV-coinfectedpatients in the pre- and post-transplant period.

8. Multidisciplinary management: Evaluation and pre- andpost-transplant management should include interdisci-plinary teams comprising nephrologists, urologists,infectious diseases and HIV specialists, psychologists,social workers, and members of alcohol and other drugdetoxification programs.

DISCLOSUREAll the authors declared no competing interests.

ACKNOWLEDGMENTSThis study was partially supported by the ‘Red Tematica Cooperativade Grupos de Investigacion en Sida of the Fondo de InvestigacionSanitaria (FIS)’ (ISCIII-RETIC RD06/006) from the Instituto de SaludCarlos III, Madrid (Spain) and the ‘Fundacion para la Investigacion yPrevencion del Sida en Espana (FIPSE grant 0858-09)’ Madrid (Spain).JMM received a Research Grant from the ‘Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS).’

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http://www.pharma.us.novartis.com/product/pi/pdf/sandimmune.pdf

Renal transplantation in HIV-infected patients: 2010 update

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