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10.1111/1469-0691.12754
Infections in solid organ transplant HIV-infected patients
J. M. Miro1, F. Ag€
uero1*, J.-C. Duclos-Vall
ee2,3,4,5, N. J. Mueller6, P. Grossi7and A. Moreno1 on 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
Abstract
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.
E-mail: [email protected]
*JMM and FA contributed equally to this work.
Hot Topics
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 prophylaxis (BII).
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Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases
120
Clinical Microbiology and Infection, Volume 20 Supplement 7, September 2014
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-transplant 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 + lamivudine) + raltegravir or dolutegravir seems to be the antiretroviral 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 immunosuppressive 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.
Introduction
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 [1]. 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 [4], for whom solid organ transplant
(SOT) is the only therapeutic option and HIV infection is not a
contraindication [5]. Recent experience in North America and
Europe indicates that 3- to 5-year survival in HCV/HIV-coinfected liver recipients is lower than that of HCV-monoinfected
recipients [6–8]. Conversely, 3- to 5-year survival of
non-HCV-coinfected liver recipients and kidney recipients is
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similar to that of non-HIV-infected patients [9,10]. Experience
with heart [11], pancreas [12] and lung [13] 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 [7].
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 appropriate preventive strategies, 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 [14]. The prevalence of coinfection by HCV and HBV in this population is
33% [15] and 9% [16], respectively. Therefore, the estimated
number of HCV- and HBV-coinfected patients is around
180 000 and 49 000, respectively [15,16]. In a cross-sectional study performed in Spain [17], 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 [18].
The prevalence of other end-stage organ diseases in
HIV-infected patients in Europe is unknown, although end--
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Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 7), 119–130
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Miro et al.
stage ischaemic cardiovascular disease and, therefore, heart
transplantation, is likely to become increasingly prevalent.
USA, the CD4+ T-cell count must be >200 cells/mm3 in
patients with a previous OI [5, 19, 20]. In the UK [21], the
CD4+ cut-off is 200 cells/mm3, unless patients have decompensated 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/mm3 are 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.
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].
Organ disease
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 [6]. 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)[20],
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 recommended 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 [5]. On the other hand, in Spain, Italy and the
Infections in SOT HIV-infected patients
121
HAART regimens should be tailored according to the grade
of end-stage organ disease (dose adjustment of ARVs for
patients with impaired hepatic function) [24], 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 mortality. In addition, HAART-associated sustained viral suppression and higher CD4+ count can delay, prevent or reverse
some non-AIDS-defining complications [24].
Other criteria
The candidate must have a favourable psychiatric evaluation
[5]. Patients who actively consume drugs or alcohol are
TABLE 1. HIV criteria for SOT in Europe and the USA
Spain [5]
Previous C events [92]
Opportunistic infections
Malignant neoplasms
CD4+ T-cells/mm3
Liver transplantation
Other SOT
Plasma HIV RNA viral load
BDL on HAARTd
Italy [19]
UK [21]
USA [20]
France [6,22]
None except
PCP, TB, OC
No
None except
PCP, TB, OC
No
None after HAART-induced
immune reconstitution
All except untreatable
diseasesa
No
None except PCP, TB, OC
>100b
>100b
>100b
>100c
>200
>200
>200 or >100 if portal
hypertension
>200
>200
Not defined
Yes
Yes
Yes
Yes
Yes
Not defined
SOT, solid organ transplantation; BDL, below detection limit (<50 copies/mL); TB, tuberculosis; PCP, Pneumocystis jiroveci pneumonia; OC, esophageal candidiasis.
Only 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).
b
Patients with previous opportunistic infections should have >200 CD4 cells/mm3.
c
No exclusion criteria are available for patients with <100 CD4/mm3; cases should be evaluated on an individual basis.
d
If plasma HIV RNA viral load is detectable, post-transplant suppression with HAART should be provided for all liver recipients.
a
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Clinical Microbiology and Infection, Volume 20 Supplement 7, September 2014
excluded [5]. A consumption-free period of 2 years is
recommended for heroin and cocaine and 6 months for
alcohol [5]. Patients who are on stable methadone maintenance 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, immunosuppressive 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,
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
unknown
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)
these drugs seem to be associated with less marked dose
adjustments than ritonavir and cobicistat [25]. In any case,
levels of immunosuppressive drugs should be closely monitored. 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 published data are available [32].
Given that raltegravir and, probably, dolutegravir lack
significant interactions with calcineurin inhibitors and the
new HCV DAAs [28,33,34], management of immunosuppressive 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 combination 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].
General Preventive
Pre-transplant Period
Measures
in
the
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/mm3 are OLT recipients.
The 2013 updated guidelines for prevention of OI and
primary PCP prophylaxis must be followed (Table 4) [37].
Recurrence of PCP (secondary prophylaxis) must also be
prevented [37]. Primary PCP prophylaxis (A1) and secondary
PCP prophylaxis (B2) can be stopped in patients with a CD4+
T-cell count >200 cells/mm3 for more than 3 months and an
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Miro et al.
Infections in SOT HIV-infected patients
123
TABLE 3. Antiretroviral drug options for patients taking HCV direct-acting antivirals
HCV NS34 PIs
Boceprevir
800 mg tid
HIV PIs
Lopinavir/ritonavir
Darunavir/ritonavir
Atazanavir/ritonavir
HIV NNRTIs
Efavirenz
Simeprevir
150 mg qd
Faldaprevir
240 mg qd
Not recommended
Not recommended
Not recommended
Not recommended
Not recommended
Not recommended
Consider on an
individual basis
Recommended
Not recommended
Not recommended
Recommended at
1125 mg tid
Caution because of
QT prolongation
Recommended
Not recommended
Recommended
Recommended
No data
HCV NS5B
polymerase inhibitor
Daclatasvir 60 mg qd
Sofosbuvir 400 mg qd
No data
Recommended at
120 mg qd
Recommended at
120 mg qd
No data
No data
Recommended
Recommended
Recommended at
30 mg qd
Recommended
Recommended at
90 mg qd
No data
Recommended
Recommended
Recommended at
240 mg qd
No data
No data
No data
No data
No data
Recommended
Recommended
Recommended
No data
Recommended
Not recommended
No data
Recommended
No data
No data
No data
No data
No data
Recommended
No data
Recommended
Recommended
Recommended
Recommended
Recommended
Recommended
Reduce maraviroc to
150 mg bid
Reduce maraviroc to
150 mg bid
No data
No data
No data
No data
Rilpivirine
Recommended
Etravirine
Consider on an
individual basis
HIV InSTIs
Dolutegravir
Raltegravir
Elvitegravir/cobicistat
HIV NtRTI
Tenofovir
CCR5 inhibitor
Maraviroc
Telaprevir
750 mg tida
HCV NS5A replication
complex inhibitor
Recommended
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).
a
Telaprevir is equally efficacious at a dose of 1125 mg tid in monoinfected patients. However, most drug interaction studies are based on tid dosing.
undetectable plasma HIV RNA viral load while on HAART
[37]. A previous report showed that discontinuation of
primary PCP prophylaxis may be safe in patients with CD4
T-cell counts of 101–200 cells/mm3 if the HIV-1 viral load is
suppressed [38].
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 [41]. 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 [40].
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 encephalitis 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 [43]. Previous case-control studies [44,45] revealed
that the rate of surgery-related infections after cardiac [45]
and orthopaedic surgery [44] in HIV-infected patients were
similar to those reported in non-HIV-infected patients.
General Preventive Measures
Post-transplant Period
in
the
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 [9]. 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-infected patients [37,48] and general recommendations for SOT
recipients [39,40] are being used. These recommendations are
summarized briefly in Tables 4 and 5.
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TABLE 4. Recommendations for prevention of infectious
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Prevention of Donor-Transmitted Infections
diseases in HIV-infected solid organ transplant (SOT) recipients
Pre-transplant period
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/mm3 must 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/mm3 for >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
prophylaxis (AII)
Post-transplant period
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
period (see Table 5) (BII)
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 [39].
Immunization schedules are indicated in HIV-infected transplant recipients, although they must take the CD4+ T-cell
count into consideration [37].
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 [50], at least 1 year in Spain
[53], 6 months in Italy [51] and 3 months in the UK [52]).
This issue remains controversial in non-HIV-infected patients
[54], 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).
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 [56]. 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 [61]. In 2013,
24 (92%) patients were alive, and most continued to have
undetectable HIV viral loads [62]. Moreover, in the USA,
the recently passed HIV Organ Policy Equity Act (HOPE)
[63] 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 [58]. Unfortunately, the
results from a similar experience (HIV/HCV-coinfected
transplant recipients receiving grafts from an anti-HCV-positive donor) were discouraging, and the procedure is no
longer recommended owing to severe and faster HCV
recurrence [8].
Post-Transplant Infections in HIV-Infected
SOT Recipients
Nowadays, the vast majority of HIV-infected transplant
recipients know their HIV serostatus before transplant. The
efforts of transplant professionals and the release of guidelines 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) [64].
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).
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TABLE 5. Guidelines for the vaccination of solid organ
reported in either HIV-infected cohorts or non-HIV-infected
cohorts.
HIV-infected recipients generally receive the same immunosuppressive 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 [71].
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 infection. Table 6 summarizes the OIs diagnosed in the major
studies on liver and kidney transplantation in HIV-infected
patients [9,46,53,74,75].
transplant candidates and recipients
Vaccine
Before
transplant
Influenza (I)
Hepatitis B
Hepatitis A
Tetanus
Yes
Yes
Yes
Yes
Pertussis
Yes
Polio (I)
Diphtheria
Streptococcus
pneumoniae (P)
Varicella (LA)
HPV
Rotavirus, measles,
mumps, rubella
Yes
Yes
Yes
Vibrio choleraeb
Yellow feverb
Salmonella typhi (I)b
Japanese encephalitisb
(JE-MB is an inactivated
mouse-brain-derived
vaccine)
After transplant
Yes (every year)
Yes
Yes (if HAV-seronegative)
Yes (if no booster in the
last 10 years)
Yes (especially in patients
who have contact with
infants)
Yes
Yes
Yes (once after 3–5 years)
Yesa
Yes
Yesa (in children or
non-vaccinated
adults)
Yes
Yesa
Yes
Yes
No
Yes
No
Yes
No
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.
Susceptible patients with CD4 counts ≥200 cells/lL.
b
Travel vaccine.
Adapted from Gavalda et al. 2012.
a
It is generally accepted that the incidence and aetiology of
infections in HIV-infected patients during the early post-transplant period are similar to those reported in non-HIV-infected
patients [67,68]. Moreover, the occurrence of HIV/AIDS-related 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 transplantation. Furthermore, OI rates are generally not adequately
Infections in SOT HIV-infected patients
125
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]. Conversely, recurrence of HBV infection is easily prevented in the
post-transplant period [10].
TABLE 6. Post-transplant opportunistic infections in HIV-infected liver and kidney recipients
Liver recipients
Country (reference)
No. of patients
Follow-up (months)
No. of cases with at least one opportunistic infection
Opportunistic infections
Tuberculosis
PCP
Oesophageal candidiasis
Other invasive fungal infections
CMV disease
Other opportunistic infections
Neoplasm
Kaposi sarcoma
Non-Hodgkin lymphoma
Kidney recipients
Spain [53]
France [75]
USA [74]
Spain [46]
USA [9,74]
84
24
9 (11%)
105
36
5 (5%)
125
32
6 (5%)
20
40
ND
150
28
7 (5%)
2
1
2
3a
2
0
1
0
2
0
1
1b
0
1
3
0
0
1c
0
0
0
1
1
2d
0
1
2
0
0
1e
0
0
ND
ND
1
0
0
1
3
0
ND, no data; PCP, Pneumocystis jiroveci pneumonia; CMV, cytomegalovirus.
a
Two mucormycosis and one aspergillosis.
b
Non-tuberculous mycobacteria.
c
Bronchial candidiasis.
d
Other viruses.
e
Chronic cryptosporidiosis.
ª2014 The Authors
Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 7), 119–130
126
Clinical Microbiology and Infection, Volume 20 Supplement 7, September 2014
In a Spanish cohort of HIV/HCV-coinfected liver recipients
[53], 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-tacrolimus-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. Effective antiretroviral treatment has been found to have a
protective effect [53].
Bacterial infections
In Spain, Moreno et al. [53] 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%) [78]. Most cases of early bacterial
infection were related to surgery and invasive procedures.
Data from a recent US study [74] 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%) [74]. These results are similar to those reported
for infections in non-HIV-infected transplant recipients. Nevertheless, significantly higher mortality due to infectious
complications has been reported in a small case series of
HIV-infected recipients (four out of 15) [66].
CMI
fungal infections occurred in 7% of patients [53]. The authors
report two episodes of zygomycosis (rhinocerebral and
surgical site). Another single case of zygomycosis has been
published [81].
Ragni et al. [82] 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 [53]. 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)
[53]. 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. [74] 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
Bacterial infections
In the largest prospective, non-randomized trial on kidney
transplantation (150 HIV-infected patients), Stock et al. [9]
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 [9]. Similar results were reported in a French
study (27 cases) [85] and a Spanish study (20 cases) [46].
Opportunistic infections (AIDS-related and
Opportunistic infections (AIDS-related and
non-AIDS-related)
non-AIDS-related)
In the study by Moreno et al. [53], 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 Spanish cohort study [79] 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/mm3 and 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) [80]. Invasive
A recent international 12-study meta-analysis of 254 patients
reported infection in 29% of recipients, although only three
were AIDS-defining infections [55].
In the study by Stock et al. [9], 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
ª2014 The Authors
Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 7), 119–130
CMI
Miro et al.
treated with sirolimus, which has been reported to control
human herpesvirus-8 infection [86]. A trend toward reduced
rates of survival detected among patients with HCV coinfection 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. [75] recently reported data on OI in 275
HIV-infected transplant recipients from the USA (150 kidney
recipients (from the study by Stock et al. [9]) and 125 liver
recipients) [74]. The authors detected only 13 cases of OI:
four cutaneous Kaposi sarcoma, two PCP, one
cryptosporidiosis and six Candida infections (mostly oesophageal). 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-infected kidney recipients reveal that fungal, viral and protozoan
infections accounted for 9%, 6% and 1% of OIs, respectively
[9]. Polyomavirus (BK virus) nephropathy was reported in five
patients [9].
rejection have been avoided thanks to careful management of
infection and immunosuppression.
127
Challenges for the Future
Further data are needed to confirm current findings on SOT
Infections in HIV-Infected Heart, Pancreas
and Lung Recipients
The largest US heart transplantation study [90] describes the
medium-term outcome of only five HIV-infected recipients.
Postoperative treatment was similar to that of non-HIV-infected heart recipients. No surgical wound infection was
observed. At least three similar cases have been reported in
Europe [11]. Miro et al. [91] 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. [12] 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 [13] 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
Infections in SOT HIV-infected patients
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 underlying transplantation in the setting of HIV/AIDS should be
also a priority area. The optimal immunosuppressive regimen 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 pharmacokinetic 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.
Acknowledgements
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.
ª2014 The Authors
Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 7), 119–130
128
Clinical Microbiology and Infection, Volume 20 Supplement 7, September 2014
Funding
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)
(‘Investigaci
on 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.
Transparency Declaration
The authors declare that they have no conflict of interests.
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