Infections in solid organ transplant HIV-infected patients
J. M. Miro1, F. Ag€uero1*, J.-C. Duclos-Vallee2,3,4,5, N. J. Mueller6, P. Grossi7and A. Moreno1on behalf of the ESCMID Study Group of Infection in Compromised Hosts (ESGICH)
1) Infectious Diseases Service, Hospital Clınic-IDIBAPS, University of Barcelona, Barcelona, Spain, 2) AP-HP H^opital Paul Brousse, Centre Hepato-Biliaire, 3) Inserm, Unite 785, 4) Univ Paris-Sud, UMR-S 785, 5) DHU Hepatinov, 6) Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland and 7) Infectious Diseases Section, Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
Solid organ transplantation (SOT) is an appropriate therapeutic option for HIV-infected patients with end-stage organ disease. Recent experience in North America and Europe indicates that 3- to 5-year survival in HIV/HCV-coinfected liver recipients is lower than that of HCV-monoinfected recipients. Conversely, 3- to 5-year survival of non-HCV-coinfected transplant patients (liver, kidney and heart) was similar to that of non-HIV-infected patients. Preliminary experience with lung transplantation and combined kidney and pancreas transplantation is also satisfactory. Infections in HIV-infected recipients during the post-transplant period are similar to those seen in non-HIV-infected patients, although the incidence rates of tuberculosis and fungal infections seem to be higher. HIV-infected patients who are being evaluated for SOT should follow the same recommendations as those used for non-HIV-infected patients in order to prevent infections during the pre-transplant period. After transplantation, HIV-infected SOT recipients must follow recommendations on post-SOT and anti-HIV immunization and on antimicrobial prophylaxis. The recommended antiretroviral regimen is one based on raltegravir or dolutegravir plus two nucleos(t)ide reverse transcriptase inhibitors (tenofovir+ emtricitabine or abacavir + lamivudine), because it can prevent pharmacokinetic interactions between antiretroviral drugs, immunosuppressive drugs and some of the antimicrobial agents used to treat or prevent post-transplant infections. In this manuscript, we review current recommendations for preventing infections both before and after transplantation. We also analyse the incidence, aetiology and clinical characteristics of opportunistic and non-opportunistic bacterial, mycobacterial, fungal and viral infections in HIV-infected SOT recipients during the post-transplant period.
Keywords: End-stage organ disease, highly active antiretroviral therapy, hepatitis B virus, hepatitis C virus, HIV/AIDS, infections, prophylaxis of opportunistic infections, solid organ transplantation
Article published online: 9 July 2014 Clin Microbiol Infect 2014; 20 (Suppl. 7): 119–130
Corresponding author: J. M. Miro, Infectious Diseases Service, Hospital Clınic. Helios Building, Desk no. 26. Villarroel, 170. Zip Code 08036 Barcelona, Spain.
*JMM and FA contributed equally to this work.
Infection by human immunodeﬁciency virus (HIV) is not a contraindication for transplant in appropriate candidates with end-stage organ disease (AII).
Efforts should be made to identify the HIV serostatus of both the donor and the recipient before solid organ transplant (SOT) in order to prevent transmission of HIV
and to enable appropriate pre-transplant evaluation of patients.
Most HIV-infected patients with end-stage organ disease who are being evaluated for SOT should follow the general recommendations for non-HIV-infected persons. Liver transplant candidates are an exception, as they can be placed on a waiting list with a CD4+ T-cell count <200/mm3 and must therefore take antimicrobial
All patients undergoing SOT must follow recommended preventive measures (e.g. antimicrobial prophylaxis and post-SOT and anti-HIV immunization) in the post-transplant period (BII).
Although recommendations for prevention of post-trans-plant infections were not speciﬁcally thought to be useful in the HIV-infected SOT recipient, they have been validated in several observational studies (BII).
The combination of two nucleos(t)ide reverse transcriptase inhibitors (tenofovir + emtricitabine or abacavir + lamivu-dine) + raltegravir or dolutegravir seems to be the antiret-roviral regimen of choice in HIV-infected SOT recipients (BII).
Infections are a major source of morbidity and mortality in the post-transplant period (BII). HIV-related immunosuppression and exogenous immunosuppression due to the immunosup-pressive drugs used for maintenance therapy and to treat rejection play a key role in increased morbidity and mortality.
Further research is needed in the HIV/AIDS setting to optimize current antimicrobial prophylaxis (i.e. duration of prophylaxis against Pneumocystis jiroveci pneumonia (PCP)) and to evaluate the safety and effectiveness of using HIV-infected donors (e.g. kidney transplantation). It is also important to know the impact of new antiretroviral drugs (e.g. dolutegravir) and new molecules for HCV infection (e.g. protease inhibitors and polymerase inhibitors), both of which are thought to have a safe pharmacokinetic proﬁle and/or optimal clinical effectiveness that could facilitate management of this complex clinical scenario.
Basic research is necessary to improve our knowledge of the cumulative effect of factors, both HIV related and drug related, involved in immunosuppression and the individual role of each factor.
With the advent of highly active antiretroviral therapy (HAART) in 1996, patients infected with HIV are living longer and dying from illnesses other than AIDS . Liver disease due to chronic hepatitis C is now a leading cause of mortality among patients coinfected with HIV and hepatitis C virus (HCV) in the developed world [2,3]. The prevalence of end-stage renal disease (ESRD) is also increasing among HIV-infected patients , for whom solid organ transplant (SOT) is the only therapeutic option and HIV infection is not a contraindication . Recent experience in North America and Europe indicates that 3- to 5-year survival in HCV/HIV-coin-fected liver recipients is lower than that of HCV-monoinHCV/HIV-coin-fected recipients [6–8]. Conversely, 3- to 5-year survival of non-HCV-coinfected liver recipients and kidney recipients is
similar to that of non-HIV-infected patients [9,10]. Experience with heart , pancreas  and lung  transplantation in HIV-infected patients is very limited. The post-transplant period is complicated by the risk of infection and becomes even more problematic as a result of factors such as pharmacokinetic and pharmacodynamic interactions between drugs (antiretrovirals, immunosuppressors and antimicrobial agents), the increased rate of acute rejection, and HCV re-infection in HIV-infected liver recipients, which is the main cause of mortality. In this context, team learning curves could improve the prognosis of these patients .
In the present manuscript, we review infections in HIV-infected SOT recipients, because transplantation in patients with HIV/AIDS has become more common in Western countries in the last decade. Hospitals wishing to carry out transplants in HIV-infected patients must have a multidisciplinary team that can regularly evaluate patients both before and after transplantation. In order to design appropri-ate preventive strappropri-ategies, ensure early diagnosis and select appropriate therapy for potentially life-threatening infections, the team should include staff from the transplant unit itself (medical, surgical, social work and psychological/psychiatric), experts on alcoholism and drug abuse, HIV/infectious disease specialists and tropical medicine specialists.
Magnitude of the Problem in Europe
End-stage liver disease
According to current estimates, there are around 540 000 HIV-infected patients in Western Europe . The preva-lence of coinfection by HCV and HBV in this population is 33%  and 9% , respectively. Therefore, the estimated number of HCV- and HBV-coinfected patients is around 180 000 and 49 000, respectively [15,16]. In a cross-sec-tional study performed in Spain , 8% of coinfected patients had clinical or histological criteria for liver cirrhosis, and 17% met the Spanish criteria for inclusion on an orthotopic liver transplantation (OLT) waiting list. Therefore, there could be approximately 3100 potential candidates for OLT in Europe.
Other end-stage organ diseases
The prevalence of HIV infection in dialysis units varies widely between countries, and even within the same country. Information on prevalence in Europe during the HAART era is scarce. A EuroSIDA survey revealed a prevalence of 0.46% among HIV-infected persons with ESRD in Europe .
The prevalence of other end-stage organ diseases in HIV-infected patients in Europe is unknown, although
end--stage ischaemic cardiovascular disease and, therefore, heart transplantation, is likely to become increasingly prevalent.
Criteria for SOT in HIV-Infected Persons
HIV-infected patients are included on the SOT waiting list according to the speciﬁc organ disease, HIV infection criteria and other criteria [3,5].
The disease criteria are the same as for non-HIV-infected transplant patients [3,5].
HIV infection criteria
Most transplant groups from Europe and North America use similar HIV criteria. These are summarized in Table 1 [5,6,19– 22].
Clinical criteria: Ideally, no patients should have had AIDS-deﬁning diseases, as these increase the risk of reactivation . However, some opportunistic infections (OIs) have been withdrawn as exclusion criteria in most countries, as they can be treated effectively and prevented. In fact, the inclusion criteria for OI were updated in a study sponsored by the National Institutes of Health (NIH), and only untreatable diseases are still exclusion criteria for SOT.
Immunological criteria: For OLT, most groups [5,6,19–21] agree that the CD4+ lymphocyte count should be >100 cells/mm3. This ﬁgure is lower than that recom-mended for other SOT recipients (>200 cells/mm3), because patients with cirrhosis often have lymphopenia due to hypersplenism, which leads to a lower absolute CD4+ count despite high CD4+percentages and good virological control of HIV . On the other hand, in Spain, Italy and the
USA, the CD4+ T-cell count must be >200 cells/mm3 in patients with a previous OI [5, 19, 20]. In the UK , the CD4+cut-off is 200 cells/mm3, unless patients have decom-pensated cirrhosis or portal hypertension, which is the same CD4+ cell threshold as used in Spain and the USA (>100 cells/mm3). In France, patients with <100 CD4+ cells/mm3are evaluated on an individual basis.
Virological criteria: Ideally, the patient should tolerate HAART before transplantation and have an undetectable HIV viral load in plasma using ultra-sensitive techniques (<50 copies/mL) [5,6,21,23]. In some cases (e.g. patients who remain viraemic on HAART), it is essential to carry out antiretroviral sensitivity testing to ascertain real therapeutic options.
HAART regimens should be tailored according to the grade of end-stage organ disease (dose adjustment of ARVs for patients with impaired hepatic function) , drug interactions and HIV genotyping results. Some patients do not have an indication for HAART, as they are long-term non-progressors or do not fulﬁl the immunological or clinical criteria to start treatment and, therefore, have a detectable plasma viral load. In this setting, it is unknown whether and when (before or after transplant) it would be beneﬁcial to initiate HAART so as to reach an undetectable viral load. However, in most centres, HAART is initiated before or after transplantation in order to prevent progression of end-stage organ disease and HIV infection, because the effects of HIV on these organs (e.g. inﬂammation) contribute to HIV-related morbidity and mor-tality. In addition, HAART-associated sustained viral suppres-sion and higher CD4+ count can delay, prevent or reverse some non-AIDS-deﬁning complications .
The candidate must have a favourable psychiatric evaluation . Patients who actively consume drugs or alcohol are
TABLE 1. HIV criteria for SOT in Europe and the USA
Spain  Italy  UK  USA  France [6,22]
Previous C events 
Opportunistic infections None except PCP, TB, OC
None except PCP, TB, OC
None after HAART-induced immune reconstitution
All except untreatable
diseasesa None except PCP, TB, OC
Malignant neoplasms No No No Not deﬁned
Liver transplantation >100b >100b >200 or >100 if portal
Other SOT >200 >200 >200 >200 Not deﬁned
Plasma HIV RNA viral load
BDL on HAARTd Yes Yes Yes Yes Yes
SOT, solid organ transplantation; BDL, below detection limit (<50 copies/mL); TB, tuberculosis; PCP, Pneumocystis jiroveci pneumonia; OC, esophageal candidiasis.
aOnly untreatable diseases are exclusion criteria for SOT (e.g. progressive multifocal leukoencephalopathy, chronic cryptosporidiosis, multidrug-resistant systemic fungal
infections, primary CNS lymphoma and visceral Kaposi sarcoma).
bPatients with previous opportunistic infections should have>200 CD4 cells/mm3.
cNo exclusion criteria are available for patients with<100 CD4/mm3; cases should be evaluated on an individual basis. dIf plasma HIV RNA viral load is detectable, post-transplant suppression with HAART should be provided for all liver recipients.
excluded . A consumption-free period of 2 years is recommended for heroin and cocaine and 6 months for alcohol . Patients who are on stable methadone mainte-nance programmes are not excluded. Finally, patients must show an appropriate degree of social stability to ensure adequate care in the post-transplant period.
Antiretroviral Therapy in SOT Recipients
The optimal HAART regimen in the post-transplant period is currently unknown (Table 2). One of the most challenging treatment issues has been that of managing the numerous drug interactions associated with antiretrovirals, immunosuppres-sive agents and medications such as the anti-HCV direct antiviral agents (DAAs) (Table 3). Some drugs should not be co-administered (i.e. efavirenz and voriconazole at standard doses or rifampin and rilpivirine). In addition, patients receiving regimens based on a ritonavir-boosted protease inhibitor (PI) or cobicistat-boosted elvitegravir require rapid and signiﬁcant dose adjustments of both calcineurin inhibitors and mTOR inhibitors [6,25–27]. Ritonavir and cobicistat are potent inhibitors of CYP3A4 enzymes [26,27].
Drug interactions also exist with non-nucleoside reverse transcriptase inhibitors (NNRTIs) because of their ability to induce clearance of drugs metabolized by CYP3A4; however,
these drugs seem to be associated with less marked dose adjustments than ritonavir and cobicistat . In any case, levels of immunosuppressive drugs should be closely moni-tored. Interestingly, there is a growing body of knowledge on the appropriateness of HAART regimens, including raltegravir (the ﬁrst integrase inhibitor) plus two nucleos(t)ide reverse transcriptase inhibitors (NRTI; tenofovir + emtricitabine or abacavir+ lamivudine), which are not a substrate of CYP450 and can therefore be safely used in HIV-1 SOT recipients [24,28–31].
The same pharmacokinetic safety proﬁle is probably obtained with dolutegravir-based HAART, although no pub-lished data are available .
Given that raltegravir and, probably, dolutegravir lack signiﬁcant interactions with calcineurin inhibitors and the new HCV DAAs [28,33,34], management of immunosuppres-sive and HCV treatments is simpliﬁed (Table 3). In addition, the results of two clinical studies (liver, kidney and heart recipients treated with raltegravir-based HAART) revealed excellent tolerability without events related to outcome (acute rejection) or to HIV infection [29,31]. Therefore, the combi-nation of two NRTIs (tenofovir/emtricitabine or abacavir/ lamivudine) with a non-boosted integrase inhibitor (raltegravir and, probably, dolutegravir) is the antiretroviral regimen of choice in HIV-infected SOT recipients. The second option could be the combination of two NRTIs plus efavirenz (an NNRTI), because the pharmacokinetic proﬁle of efavirenz is safer than that of ritonavir-boosted PIs.
Finally, given the speed with which new antiretrovirals and DAAs to treat HCV are becoming available, new interactions may emerge; therefore, physicians should consult updated databases on drug interactions [33,35,36].
Most HIV-infected patients with end-stage organ disease who are being evaluated for SOT do not need to follow a speciﬁc antimicrobial prophylactic regimen to prevent OI, because the immunological threshold for waiting list acceptance is a CD4+ T-cell count >200 cells/mm3. The only HIV-infected SOT candidates who can be placed on a waiting list with a CD4+T-cell count of 100–200 cells/mm3are OLT recipients. The 2013 updated guidelines for prevention of OI and primary PCP prophylaxis must be followed (Table 4) . Recurrence of PCP (secondary prophylaxis) must also be prevented . Primary PCP prophylaxis (A1) and secondary PCP prophylaxis (B2) can be stopped in patients with a CD4+ T-cell count>200 cells/mm3for more than 3 months and an
TABLE 2. Recommendations for HAART in HIV-infected
solid organ recipients
1. HAART should be designed on an individual basis, taking into account factors such as grade of end-stage organ disease, drug interactions and, when possible, antiretroviral sensitivity testing 2. The optimal HAART regimen in the post-transplant period is
3. Pharmacokinetic interactions between antiretrovirals, immunosuppressive agents and other drugs used during the post-transplant period play a major role in this complex clinical s cenario (BII)
4. PIs and cobicistat act as CYP3A4 inhibitors and require rapid and considerable dose adjustment of immunosuppressive agents (BII) 5. NNRTIs (mainly efavirenz and nevirapine) are inducers of CYP3A4
and lead to more rapid elimination of calcineurin inhibitors, thus necessitating higher doses of these drugs (BII)
6. The integrase inhibitor raltegravir is not a substrate of cytochrome P450, thus making it safe and effective in this setting (BII). The second-generation integrase inhibitor dolutegravir could prove to be a useful therapeutic option, although data are lacking
7. The combination of two nucleos(t)ide reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) with a non-boosted integrase inhibitor (raltegravir and, probably, dolutegravir) is the antiretroviral regimen of choice in HIV-infected liver recipients (BII)
undetectable plasma HIV RNA viral load while on HAART . A previous report showed that discontinuation of primary PCP prophylaxis may be safe in patients with CD4 T-cell counts of 101–200 cells/mm3if the HIV-1 viral load is suppressed .
Screening and treatment of latent tuberculosis (TB) infection is a cornerstone of the prevention of OI, owing to the difﬁculties involved in diagnosis and the impact of the disease on the management of HIV-infected patients (Table 4) [39,40]. SOT candidates with a tuberculin skin test (TST) induration ≥5 mm, a history of untreated tuberculosis or a history of contact with a patient with active tuberculin should be treated with isoniazid (300 mg/day) supplemented with vitamin B6 for 9 months . Ideally, patients should receive this treatment before transplantation, except in the case of OLT, where, if treatment cannot be completed before the procedure, it should be completed after the procedure .
Additionally, susceptible HIV-infected patients should receive the vaccines included in the immunization schedules for SOT candidates before transplant (Tables 4 and 5) [33,37,39,42]. In patients with a CD4+ T-cell count <200 cells/mm3
, varicella vaccine and measles, mumps and rubella vaccine are contraindicated [33,37,39,42]. On the other hand, killed and recombinant vaccines (e.g. inﬂuenza, diphtheria, tetanus, rabies, HAV, HBV, Japanese encephali-tis and meningococcal) should be administered to HIV-infected persons as they would be to non-HIV-infected persons.
Finally, in order to prevent surgery-related infectious complications, the recommended antimicrobial agents for surgical prophylaxis are the same as for non-HIV-infected patients . Previous case-control studies [44,45] revealed that the rate of surgery-related infections after cardiac  and orthopaedic surgery  in HIV-infected patients were similar to those reported in non-HIV-infected patients.
HIV-infected patients who undergo SOT are thought to have an increased risk of developing OI resulting from conventional exogenous immunosuppression, which may cause an initial and long-lasting decline in the CD4+ T-cell count, particularly in patients receiving thymoglobulin . Moreover, these patients frequently receive additional doses of immunosuppressive drugs to treat rejection, which is more frequent than in non-HIV-infected patients [7–9,46]. Prophylaxis for prevention of OI is essential and should be administered to HIV-infected transplant recipients (BII) [6,7,37,47] (Tables 4 and 5).
Despite the lack of speciﬁc guidelines on prophylaxis regimens for the prevention of OI in HIV-infected transplant recipients, both recommendations on prevention in HIV-in-fected patients [37,48] and general recommendations for SOT recipients [39,40] are being used. These recommendations are summarized brieﬂy in Tables 4 and 5.
TABLE 3. Antiretroviral drug options for patients taking HCV direct-acting antivirals
HCV NS34 PIs HCV NS5A replication
complex inhibitor HCV NS5B polymerase inhibitor Boceprevir 800 mg tid Telaprevir
750 mg tida Simeprevir150 mg qd Faldaprevir240 mg qd Daclatasvir 60 mg qd Sofosbuvir 400 mg qd
Lopinavir/ritonavir Not recommended Not recommended Not recommended No data No data Recommended
Darunavir/ritonavir Not recommended Not recommended Not recommended Recommended at
120 mg qd
No data Recommended
Atazanavir/ritonavir Consider on an individual basis
Recommended Not recommended Recommended at
120 mg qd
Recommended at 30 mg qd
Recommended HIV NNRTIs
Efavirenz Not recommended Recommended at
1125 mg tid
Not recommended Recommended at 240 mg qd
Recommended at 90 mg qd
Rilpivirine Recommended Caution because of
Recommended No data No data Recommended
Etravirine Consider on an
Recommended No data No data No data No data
Dolutegravir Recommended Recommended No data No data No data No data
Raltegravir Recommended Recommended Recommended Recommended No data Recommended
Elvitegravir/cobicistat No data Recommended Not recommended No data No data No data
Tenofovir Recommended Recommended Recommended Recommended Recommended Recommended
Maraviroc Reduce maraviroc to
150 mg bid
Reduce maraviroc to 150 mg bid
No data No data No data No data
HIV, human immunodeﬁciency virus; HCV, hepatitis C virus; PIs, protease inhibitors; NNRTIs, non-nucleoside reverse-transcriptase inhibitors; InSTIs, integrase strand transfer inhibitors; ARV, antiretroviral; tid, three times a day; bid, twice daily; qd, once daily.
Modiﬁed from Karageorgopoulos et al. and Antiretroviral Treatment Options for Patients on DAAs - Summary available at http://www.hcvdruginfo.ca (accessed 5 January 2014).
Post-transplant vaccination has not been fully evaluated in non-HIV-infected patients. However, most centres restart vaccination at approximately 3–6 months after transplantation, once baseline immunosuppression levels are attained . Immunization schedules are indicated in HIV-infected trans-plant recipients, although they must take the CD4+ T-cell count into consideration .
The most widely used antimicrobial prophylaxis regimens include antifungal prophylaxis and valganciclovir to prevent cytomegalovirus infection in high-risk recipients [6,49–52]. However, there are differences in the duration of prophylaxis against PCP (life-long in the USA , at least 1 year in Spain , 6 months in Italy  and 3 months in the UK ). This issue remains controversial in non-HIV-infected patients , and recommendations can vary between transplant centres.
Observational studies [6,49–53,55] have shown that HIV-infected patients do not have a signiﬁcantly greater risk of OI than non-HIV-infected patients thanks to currently available prophylaxis, monitoring and treatment. The studies cited conﬁrm the appropriateness of these measures (AII).
Prevention of Donor-Transmitted Infections
Pre-transplant screening of infections in organ donors is the same in both HIV-infected and non-HIV-infected patients; HIV-infected donors are ruled out . Of note, in recent years, the use of kidneys from HIV-infected donors for non-HIV-infected kidney recipients with ESRD has been the subject of debate in South Africa [57–60]. The preliminary results for 26 HIV-infected patients who received a kidney from an HIV-infected donor were satisfactory . In 2013, 24 (92%) patients were alive, and most continued to have undetectable HIV viral loads . Moreover, in the USA, the recently passed HIV Organ Policy Equity Act (HOPE)  allows transplantation of organs from deceased HIV-infected donors to HIV-infected recipients. This law is expected to expand the number of donor organs available for transplantation in patients living with HIV and to facilitate research into this ﬁeld. However, we believe that further studies are needed to establish the effectiveness and safety of this type of transplantation . Unfortunately, the results from a similar experience (HIV/HCV-coinfected transplant recipients receiving grafts from an anti-HCV-po-sitive donor) were discouraging, and the procedure is no longer recommended owing to severe and faster HCV recurrence .
Post-Transplant Infections in HIV-Infected
Nowadays, the vast majority of HIV-infected transplant recipients know their HIV serostatus before transplant. The efforts of transplant professionals and the release of guide-lines for reducing transmission of blood-borne viruses (mainly HIV, HBV and HCV) through organ transplantation have facilitated this knowledge. Conversely, when systematic screening of donors had not yet been fully established, the proportion of transplant patients with HIV seroconversion after transplantation in the pre-HAART era was around 60% (14/25) .
Post-transplant infections are a major cause of morbidity and mortality in transplant recipients with HIV infection [53,65,66], and severe infection was generally more frequent in HIV/HCV-coinfected SOT recipients [9,53]. Post-transplant infections can be classiﬁed into three types: healthcare-related infections and post-surgical infections (e.g. biliary tract, urinary tract); infections caused by immunosuppressive drug therapy; and infections related to complications of end-stage graft disease (e.g. liver cirrhosis and dialysis).
TABLE 4. Recommendations for prevention of infectious diseases in HIV-infected solid organ transplant (SOT) recip-ients
1. Most HIV-infected SOT candidates must follow the same recommendations as non-HIV-infected candidates (BII) 2. OLT candidates with a CD4 T-cell count between 100 and
200 cells/mm3must take primary PCP prophylaxis (AI) 3. In OLT candidates, primary PCP prophylaxis (AI) and secondary
PCP prophylaxis (BII) should be discontinued for patients who have responded to HAART with an increase in CD4+T-cell counts to >200 cells/mm3for >3 months
4. Live-virus vaccines are not generally recommended in HIV-infected persons (see Table 5) (AIII)
5. Screening for latent tuberculosis should be performed and treatment administered to patients on waiting lists (AII) 6. Recommended antimicrobial agents should be used for surgical
1. HIV-infected transplant recipients must receive the same prophylaxis for OIs as non-HIV-infected SOT recipients (BII)
2. Antiviral prophylaxis or pre-emptive therapy should be used for the prevention of CMV replication and disease after SOT (BII) 3. Antifungal and PCP prophylaxis should be used (BII), although the
duration of prophylaxis against PCP remains unclear 4. Immunization regimens should be used as in the pre-transplant
It is generally accepted that the incidence and aetiology of infections in HIV-infected patients during the early post-trans-plant period are similar to those reported in non-HIV-infected patients [67,68]. Moreover, the occurrence of HIV/AIDS-re-lated infections is uncommon when appropriate antimicrobial prophylaxis is administered [6–8,49–51,55]. However, most published results on HIV-infected transplant recipients do not provide details of non-AIDS-related infections after transplan-tation. Furthermore, OI rates are generally not adequately
reported in either HIV-infected cohorts or non-HIV-infected cohorts.
HIV-infected recipients generally receive the same immu-nosuppressive regimens as non-HIV-infected recipients. In order to suppress plasma HIV RNA viral load, HAART is usually administered until the day of surgery and resumed once the patient is stable and oral intake can be reintroduced, as recommended in national guidelines [69,70].
It is difﬁcult to separate the complications of a speciﬁc HIV-associated OI from the complications associated with the immunosuppression required for transplantation. Cellular immunity is affected in both cases. In patients on HAART with suppressed viral replication, CD4+ T-cell counts are stable or increased and the frequency of OI decreases . Because all HIV transplant programmes require full control of HIV viral replication and a speciﬁc CD4+ T-cell threshold [5,20,21,72,73], it is more likely that OI will be related to a post-transplant immunosuppressive state than to HIV infec-tion. Table 6 summarizes the OIs diagnosed in the major studies on liver and kidney transplantation in HIV-infected patients [9,46,53,74,75].
Infections in HIV-Infected Liver Recipients
The most signiﬁcant comorbid condition associated with OLT in HIV/HCV-coinfected patients is post-transplant recurrence of HCV infection. In addition, HCV infection is more severe in this group than in non-HIV-infected patients, and ﬁbrosing cholestatic hepatitis is more frequent [7,8,67,76,77]. Con-versely, recurrence of HBV infection is easily prevented in the post-transplant period .
TABLE 6. Post-transplant opportunistic infections in HIV-infected liver and kidney recipients
Liver recipients Kidney recipients
Country (reference) Spain  France  USA  Spain  USA [9,74]
No. of patients 84 105 125 20 150
Follow-up (months) 24 36 32 40 28
No. of cases with at least one opportunistic infection 9 (11%) 5 (5%) 6 (5%) ND 7 (5%)
Tuberculosis 2 1 0 0 0
PCP 1 0 1 0 1
Oesophageal candidiasis 2 2 3 0 2
Other invasive fungal infections 3a 0 0 1 0
CMV disease 2 1 0 1 0
Other opportunistic infections 0 1b 1c 2d 1e
Kaposi sarcoma 0 ND 1 0 3
Non-Hodgkin lymphoma 0 ND 0 1 0
ND, no data; PCP, Pneumocystis jiroveci pneumonia; CMV, cytomegalovirus.
aTwo mucormycosis and one aspergillosis. bNon-tuberculous mycobacteria. cBronchial candidiasis. dOther viruses. e
TABLE 5. Guidelines for the vaccination of solid organ transplant candidates and recipients
transplant After transplant
Inﬂuenza (I) Yes Yes (every year)
Hepatitis B Yes Yes
Hepatitis A Yes Yes (if HAV-seronegative)
Tetanus Yes Yes (if no booster in the
last 10 years)
Pertussis Yes Yes (especially in patients
who have contact with infants)
Polio (I) Yes Yes
Diphtheria Yes Yes
Streptococcus pneumoniae (P)
Yes Yes (once after 3–5 years)
Varicella (LA) Yesa No
HPV Yes Yes
Rotavirus, measles, mumps, rubella
Yesa(in children or
Vibrio choleraeb Yes Yes
Yellow feverb Yesa No
Salmonella typhi (I)b Yes Yes
Japanese encephalitisb (JE-MB is an inactivated mouse-brain-derived vaccine)
Yes Yes (this vaccine should
only be given to persons traveling to endemic areas for longer periods of time) I, inactivated vaccine; LA, live-attenuated vaccine; P, polysaccharide vaccine; HPV, human papilloma virus.
aSusceptible patients with CD4 counts≥200 cells/lL. b
In a Spanish cohort of HIV/HCV-coinfected liver recipients , severe infections increased mortality almost two-fold (HR, 2.9). Independently associated factors for severe infection included pre-transplant MELD score >15 (HR, 3.50), non-ta-crolimus-induced immunosuppression (HR, 2.5), and a history of OI prior to transplantation (HR, 2.5). The last of these three groups warrants special attention, because patients are at high risk of dying from severe infection. An AIDS-deﬁning OI before transplantation is not an exclusion criterion if the infection can be prevented or treated [5,20,21,72,73]; however, if this ﬁnding is conﬁrmed in larger studies, a pre-transplant AIDS-deﬁning OI could become an exclusion criterion. Effec-tive antiretroviral treatment has been found to have a protective effect .
In Spain, Moreno et al.  evaluated 84 consecutive HIV/ HCV-coinfected liver recipients and found that bacteria were the principal aetiological agent of post-transplant infections. Forty-six per cent of patients developed a bacterial infection during follow-up, and 9.5% had bacteraemia. The incidence of surgical site infection was 2.3% (similar to that observed in non-HIV-infected patients), although the incidence of intra-abdominal infections was slightly higher in HIV-infected recipients (8% vs. 4%) . Most cases of early bacterial infection were related to surgery and invasive procedures. Data from a recent US study  reported that 70 of 125 liver recipients (56%) had 243 serious infections, of which 71% were bacterial. The most common sites of infection were the respiratory tract (17%), blood (17%) and the genitourinary tract (12%) . These results are similar to those reported for infections in non-HIV-infected transplant recipients. Nev-ertheless, signiﬁcantly higher mortality due to infectious complications has been reported in a small case series of HIV-infected recipients (four out of 15) .
Opportunistic infections (AIDS-related and non-AIDS-related)
In the study by Moreno et al. , approximately 11% of HIV/ HCV-coinfected liver recipients developed an OI (e.g. CMV disease, disseminated herpes simplex virus, invasive fungal infection and tuberculosis). In 44% of cases they were late infections (>6 months post-transplant). In another large Span-ish cohort study  of non-HIV-infected SOT recipients, the incidence of OI was only 6%, whereas in that of Moreno et al. the incidence of OI was 40%; at the time of the OI, the CD4+ T-cell count was<200 cells/mm3and plasma HIV-1 RNA viral load was undetectable. This higher proportion is similar to that reported in SOT recipients treated with alemtuzumab (humanized monoclonal anti-CD52 antibody) . Invasive
fungal infections occurred in 7% of patients . The authors report two episodes of zygomycosis (rhinocerebral and surgical site). Another single case of zygomycosis has been published .
Ragni et al.  found the incidence of invasive fungal infection in the late post-transplant period to be 8% (two of 24 HIV-infected liver recipients). The incidence of invasive fungal infection is slightly higher in HIV-infected transplant recipients and should be prevented . The percentage of patients who developed tuberculosis was 2.4%, and the incidence rate was 3140 cases per 100 000 transplants per year (i.e. four- to ﬁve-fold higher than in non-HIV-infected transplant recipients) . The incidence of OI was higher, with a combined HIV-infected sample size of 39 patients (20.5%), than reported in other liver transplant studies [83,84]. Overall, the incidence of post-transplant OI was low when plasma HIV RNA viral replication was controlled and CD4+T-cell count was higher than a speciﬁc threshold.
Beatty et al.  reported fungal, viral and protozoal infections in 7%, 5% and 1% of cases, respectively; however, culture was negative or not performed in 17% of cases.
Infections in HIV-Infected Kidney Recipients
In the largest prospective, non-randomized trial on kidney transplantation (150 HIV-infected patients), Stock et al.  reported that 140 infections in 57 cases (38%) required hospital admission. Of these, 69% were bacterial. The three most common sites of infection were the genitourinary tract (26%), respiratory tract (20%) and blood (19%). Sixty per cent of severe infections occurred within the ﬁrst 6 months after transplantation . Similar results were reported in a French study (27 cases)  and a Spanish study (20 cases) .
Opportunistic infections (AIDS-related and non-AIDS-related)
A recent international 12-study meta-analysis of 254 patients reported infection in 29% of recipients, although only three were AIDS-deﬁning infections .
In the study by Stock et al. , no evidence of accelerated HIV disease progression was found, despite an initial decline in the CD4+ T-cell count. HIV replication remained under control on HAART despite challenging interactions between antiretroviral and immunosuppressive drugs. The authors reported two cases of newly diagnosed cutaneous Kaposi sarcoma and one case each of oesophageal candidiasis, presumptive PCP and cryptosporidiosis. The two patients with newly diagnosed Kaposi sarcoma were successfully
treated with sirolimus, which has been reported to control human herpesvirus-8 infection . A trend toward reduced rates of survival detected among patients with HCV coinfec-tion may be related to an increased risk of other serious infections. Treatment with antithymocyte globulin enabled profound and long-lasting suppression of CD4+T-cell counts, which was associated with an increased risk of infections requiring hospitalization [9,87,88].
Beatty et al.  recently reported data on OI in 275 HIV-infected transplant recipients from the USA (150 kidney recipients (from the study by Stock et al. ) and 125 liver recipients) . The authors detected only 13 cases of OI: four cutaneous Kaposi sarcoma, two PCP, one cryptosporidiosis and six Candida infections (mostly oesoph-ageal). This low incidence was similar to that previously described [6,89]. Importantly, there were no recurrences of OIs and no differences in survival based upon these infections.
Finally, data from the largest reported cohort of HIV-in-fected kidney recipients reveal that fungal, viral and protozoan infections accounted for 9%, 6% and 1% of OIs, respectively . Polyomavirus (BK virus) nephropathy was reported in ﬁve patients .
Infections in HIV-Infected Heart, Pancreas
and Lung Recipients
The largest US heart transplantation study  describes the medium-term outcome of only ﬁve HIV-infected recipients. Postoperative treatment was similar to that of non-HIV-in-fected heart recipients. No surgical wound infection was observed. At least three similar cases have been reported in Europe . Miro et al.  reviewed cases of simultaneous pancreas-kidney transplantation in HIV-infected patients. In one case, the pancreas graft failed at 2 weeks, and the patient died at 9 months because of a relapsing multidrug-resistant Pseudomonas aeruginosa infection. A further three patients survived, despite the failure of both the pancreas and kidney grafts in one patient. Grossi et al.  recently reported four simultaneous pancreas-kidney transplants in HIV-infected recipients. In this series, the most common infections were urinary tract infection and bacteraemia. Infectious processes occurred in three patients (subdiaphragmatic abscess, pelvic abscess subsequent to complicated cholecystitis, and infected psoas hematoma). The same author  reported a case of double lung transplant in an HIV/HBV-coinfected patient with cystic ﬁbrosis and end-stage respiratory failure. The operation was successful, and the patient recovered rapidly after surgery. After 2 years of follow-up, major infectious complications and
rejection have been avoided thanks to careful management of infection and immunosuppression.
Challenges for the Future
Further data are needed to conﬁrm current ﬁndings on SOT in patients with HIV infection. Results from the largest cohorts of HIV-infected transplant recipients will provide more robust evidence in the near future and could help to ﬁll knowledge gaps in this speciﬁc clinical setting.
Further studies should try to identify the risk factors for mycobacterial and fungal infections in HIV-infected SOT recipients in order to prevent these life-threatening diseases.
Transplantation of organs from deceased HIV-infected donors to HIV-infected recipients is controversial, although it is expected to expand the number of donor organs available for transplantation in HIV-infected patients and will facilitate research in this ﬁeld. The effectiveness and safety of this approach must be demonstrated, and recommendations should be evidence based.
Basic research based on the immunological ﬁndings under-lying transplantation in the setting of HIV/AIDS should be also a priority area. The optimal immunosuppressive regi-men and the impact of factors affecting immune status (mainly HIV and immunosuppressive drugs) have yet to be elucidated. Research will help us to better manage these patients.
More work is necessary on speciﬁc research lines. It is essential to determine the effect on patient management of new antiretroviral drugs such as dolutegravir and new DAAs for treatment of HCV. These drugs have safer pharmaco-kinetic proﬁles and, therefore, fewer interactions and are more efﬁcacious. They are expected to facilitate rapid immunosuppression and increase the cure rate in HCV infection. Both factors should simplify the management of HCV and its impact on the development of post-transplant infectious complications and prognosis.
Finally, we propose that international consensus guidelines for preventing infection in transplant recipients should include a special section on HIV-infected patients.
We are grateful for the assistance of Mr R. Rogers, Dr M. Roland and Dr P. Stock for providing the data on OIs in HIV-infected liver and kidney transplant recipients from the US NIH-funded cohort study and to Dr Elina Teicher (France) for her suggestions.
This review was supported in part by grants from the Spanish Foundation for AIDS Research and Prevention (FIPSE, Madrid, Spain) (TOH-VIH/05, TOH-VIH/08, TOH-VIH/12 and 24-0858-09) and the Spanish Ministry of Health (Madrid, Spain) (‘Investigacion Clınica Independiente’ grant EC11-150). Dr Fernando Ag€uero held a Rio Hortega Research Grant (CM12/ 00195) from the ‘Instituto de Salud Carlos III’ and the ‘Ministerio de Economia and Competitividad’ Madrid (Spain) in 2013-2015.
The authors declare that they have no conﬂict of interests.
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