The first report of the deliberate transplantation of a liver from an HCV-viremic donor to a nonviremic recipient was published in August 2017. The recipient was a 57-year old woman with a history of Child-Turcotte-Pugh class A HCV cirrhosis, who had been on the liver transplant waiting list for 3 years. She had HCV genotype 1A, which had previously been treated with 12 weeks of sofosbuvir/simeprevir combination therapy as part of an industry-sponsored clinical trial, and a sustained virological response had been achieved. However, 6 months later the patient developed hepatopulmonary syndrome and was granted 22 MELD exception points. The patient agreed to accept an HCV-positive liver, understanding that she would have to be retreated with DAAs. The donor was an 18-year-old man who had died from an IV heroin overdose: the donors' HCV genotype was not known at the time of transplantation, but 3 days after transplantation, the recipient's HCV genotype was reported as 1A. Treatment with ledipasvir/sofosbuvir was commenced on posttransplant day 25, and HCV RNA was undetectable by week 8 posttransplant. Two years postliver transplant, the patient remained HCV-RNA-negative, with excellent graft function.
One of the areas, where more evidence is currently required, is with regard to the safe use of DAAs for HCV in patients with impaired kidney function. In most of the trials of DAA-based therapies, patients with severe renal impairment were excluded; in addition, the nucleotide polymerase inhibitor sofosbuvir is eliminated through the kidney and is, therefore, not appropriate for patients with estimated glomerular filtration rate less than 30 mL/min per 1.73 m2. The HCV protease inhibitor asunaprevir and the Ns5A inhibitor daclatasvir are mainly eliminated through the liver, and combination therapy with daclatasivir and asunaprevir has been demonstrated to be highly effective and safe in genotype 1 HCV-infected patients with estimated glomerular filtration rate less than 45 mL/min per 1.73 m2. Other drug protocols, including ombitasvir/paritaprevir/ritonavir without ribavirin, or elbasvir and grazoprevir combination therapy, have also been shown to be safe and effective in genotype 1 HCV-infected patients with chronic kidney disease stages 4 and 5, including hemodialysis patients. Effective DAA therapies for genotype 2 HCV-infected patients with impaired kidney function are lacking, however. A Japanese study of the outcomes of sofosbuvir and ribavirin combination therapy in genotype 2 HCV-infected patients with chronic kidney disease stages 1 to 3 found that patients with stage 3 chronic kidney disease were significantly more likely to not experience a sustained virological response, but that otherwise the regimen was safe for patients with kidney impairment. Other studies have reported serious adverse events of sofosbuvir therapy in patients with kidney impairment.
Current TSANZ guidelines allow for transplantation of organs from HCV-positive donors to HCV-negative recipients in exceptional circumstances only; however, this is likely to evolve in the light of successful trials of DAAs in D+/R- pairs. At the present time, if there is a patient who is highly likely to die on the transplant waiting list before receiving another organ offer, transplantation with an HCV-NAT-positive organ may go ahead after discussion with an infectious disease or hepatology specialist. The recipient would be then monitored frequently (eg, twice weekly) by plasma HCV RNA, with initiation of DAA therapy as soon as RNA became positive (personal communication P Boan). Factors affecting the choice of DAA regimen would include HCV genotype, renal function, interaction with immunosuppressant medications (eg, protease inhibitors with calcineurin inhibitors), and any organ-specific protocols. HCV infection itself affects dosing requirements of calcineurin inhibitors, and thus the eradication of HCV requires a corresponding close monitoring of immunosuppression trough levels. Treatment protocols are still being refined at the time of writing:when to introduce DAAs, the optimal duration of treatment, and the full extent of drug interactions are questions that are rapidly being addressed.
More data and longer term follow up of clinical trial participants are now required to establish whether HCV-negative recipients transplanted with organs from HCV-positive donors experience any survival detriment. In the case of liver transplantation, chronic HCV infection in the donor may have caused fibrosis of the donated liver, which could still affect graft and patient survival even if HCV is successfully cleared in the recipient posttransplant. Also, little is currently known about the risk of treatment failure, which has implications for the informed consent of D+/R- transplants. In addition, there is a need for data on the cost effectiveness of HCV-positive transplantation that inform the appropriate usage of DAAs in organ transplantation:from expanding the donor pool, to reducing the liver transplant waiting list, to preventing and treating donor-derived HCV transmission.
The Human T-cell lymphocytic virus-1 (HTLV-1) is an oncogenic retrovirus that preferentially infects CD4+ T-cells. Transmission may occur as a result of breast feeding, IV drug use, sexual intercourse or blood transfusion. Although infection is usually asymptomatic in most individuals, approximately 2% to 5% of infected individuals will subsequently develop acute T-cell leukemia/lymphoma (ATL) around 20 to 30 years after infection. A smaller proportion (0.25-4%) will develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) soon after the initial infection. The majority of HTLV-1-infected individuals will not develop clinical manifestations of ATL or HAM/TSP in their lifetime. However, infection with HTLV-1 suppresses immune surveillance and increases susceptibility to other infections including parasitic infection with Strongyloides stercoralis and scabies, bacterial infections including Mycobacterium tuberculosis, Mycobacterium leprae, and infectious dermatitis, and viral infections including HIV, HCV, and HBV. Breaches in the skin or intestinal mucosa as a consequence of HTLV-1-associated infections (especially scabies and S. stercoralis) may lead to bloodstream infections with S. aureus, Escherichia coli, Streptococcus pyogenes, or other organisms. In addition, HTLV-1 infection is associated with pulmonary disease, including bronchiectasis. Therefore, in affected individuals, HTLV-1 infection is likely to be associated with an increased risk of morbidity and indirectly with increased mortality risk.
HTLV-1 is not a ubiquitous virus, rather, it is present throughout the world in clusters of high endemicity. The main foci of HTLV-1 are southwestern Japan (Kyushu Island and the Okinawa archipelago), sub-Saharan Africa (Guinea-Bissau, Ghana, Nigeria, Zaire), the Caribbean (Martinique, Jamaica, Haiti), parts of South America (French Guyana, Peru), and parts of the Middle East and Australo-Melanesia. It is hypothesized that this highly specific geographical distribution originates from a founder effect in certain population groups with the persistence of a high viral transmission rate. On the other hand, large global regions have not been investigated for HTLV-1 infection and population-based studies to estimate HTLV-1 prevalence at the country level are rare, thus the prevalence remains unknown in many areas of the world. What is clear from the areas that have been studied is that HTLV-1 distribution is not homogenous. In Australia, HTLV-1 is endemic among ATSI populations in Central Australia, where infection with the Australo-Melanesian HTLV-1 subtype C predominates; by contrast, studies conducted among mostly non-Indigenous blood donors living in Australian cities found a very low prevalence of HTLV-1, ranging from 0.001% to 0.032%. A retrospective assessment of serology requests made to the Northern Territory Government Pathology Service between 2008 and 2011 found a gradient of HTLV-1 prevalence from Central Australia (highest) to Northern Australia (lowest), ranging from a regional high of 51.7% in the Anangu Pitjantjatjara Lands in northern South Australia, 50% in Ngaanyatjarraku Shire in Western Australia, and 25.3% in the MacDonnell Shire of the Northern Territory, to less than 1% in the greater Darwin region, East and West Arnhem Shire, Roper Gulf Shire, and Tiwi Islands. In terms of the wider Australo-Melanesian region, estimates of the population prevalence of HTLV-1 in the Solomon Islands range from 1.2% to 3%, and a population-based study in the Vanuatu archipelago reported HTLV-1 prevalence of 0.62%. Studies in Fiji and New Caledonia did not detect HTLV-1 in these populations.
Risk factors for HTLV-1 among Indigenous Australians living in Central Australia include older age, male sex, previous STI, and residence in the south or west of Central Australia. Each of the major recognized complications of HTLV-1:ATL, HAM/TSP, infective dermatitis, strongyloidiasis, HTLV-1-associated pulmonary disease, crusted scabies:has been described in the Indigenous residents of this region.
Although immunosuppression might theoretically affect the rate of onset of HTLV-1-associated disease, reports regarding outcomes among HTLV-1-infected solid organ recipients have been mixed. Retrospective studies of HTLV-1-infected kidney transplant recipients in Japan found no HTLV-1-associated disease in 2 case series of 10 and 16 recipients followed up for an average of 13 and 8 years, respectively. In contrast, a third case series Japan observed 3 cases of ATL at 6, 9, and 25 months after living donor liver transplantation from 8 HTLV-1-infected recipients. There has also been 1 report of an HTLV-positive recipient developing HAM/TSP after a living donor kidney transplant, and 1 report in which 3 recipients from a single deceased donor rapidly developed HAM/TSP posttransplant.
Standard testing for HTLV-1 is performed using a combined serological test for HTLV-1 and HTLV-2. An important issue with serological tests for HTLV-1/2 is the extremely high rate of false-positive results in low HTLV prevalence settings. False-positive rates of up to 100% have been reported for potential organ donors in nonendemic settings. A second issue with serological tests is that, at the current time, available assays are unable to distinguish between HTLV-1 and HTLV-2, which is a relevant limitation as HTLV-2 has not been found to be associated with any human disease and should not preclude transplantation. HTLV-1 and HTLV-2 can be distinguished by confirmatory NAT testing, or by virus-specific Western blot or line immunoassay.
Given the high false-positive rate, testing is generally not performed in countries where seroprevalence of HTLV-1 is low, or alternatively it is restricted to donors coming from high-risk subpopulations or endemic areas. OPTN has removed the requirement for pretransplant screening for HLTV-1, and it is left to individual organ procurement agencies to decide whether to perform targeted screening on donors thought to be at increased risk of HTLV-1 infection. OPTN recommends that positive HTLV-1/2 screening test results be confirmed using Genelabs HTLV 2.4 (Western blot) or inn genetics HTLV-1/2 Line Immunoassay.
European guidelines recommend screening in endemic areas and for donors coming from endemic populations only, and also stipulate that any initial reactive test must be confirmed as a true-positive for HTLV-1 before decisions are made about organ utilization. France and Portugal currently screen for HTLV-1/2, and Spain recommends HTLV-1/2 screening for donors at higher risk of HTLV-1 including immigrants or sexual partners of immigrants from endemic areas and children at risk of vertical transmission.
In the Australian context, HTLV serology should be considered for donors from endemic regions (the Caribbean, South America, Africa, Asia, Iran, Romania) and for ATSI people living in the Northern Territory, Queensland, Kimberley, and northern South Australia.
Between 1994 and 2001, the UNOS reported 12 HTLV-positive deceased donors, from whom 5 organs were transplanted. As of 2003, 4 of 5 recipients were alive and without malignancy, and a heart transplant recipient of an HTLV-positive organ had died 1 month posttransplant from multiorgan failure although there was no indication that this was related to HTLV-1 infection. A retrospective analysis of outcomes among liver transplant recipients in the United States who received their transplants before August 2007 found no statistically significant difference in graft or patient survival according to the HTLV status of the donor. However, the authors note that their analysis was limited by the short recipient follow-up period (mean, 1.2 years) and the high false-positive rate for HTLV testing.
The first European cases of donor-derived HTLV-1 transmission were reported in Spain in 2001. Three recipients of organs from the same donor (a liver and 2 kidney recipients) presented 2 years posttransplant with clinical manifestations of subacute myelopathy. The donor was retrospectively found to be seropositive for HTLV-1 and, despite having no apparent risk factors for HTLV-1, it was found on further investigation that his mother was originally from Venezuela, where HTLV-1 is endemic. Genetic analysis of the transmitted strain of HTLV-1 in this case showed multiple substitutions in the tax gene characteristic of the taxA subgroup, which is associated with greater risk of HAM/TSP development. The investigators hypothesize that the presence of taxA may at least in part account for the rapid onset of neurological disease in these organ recipients.
This cluster of HTLV-1 cases in Spain prompted a survey of HTLV-1 seroprevalence among potential organ donors to inform an appropriate national approach to donor screening. This survey, conducted from January 2002 to December 2003 screened for HTLV-1 antibodies in 1298 organ donors. Not a single seropositive donor was identified. Simultaneously, HTLV screening was conducted in a sample of 1079 immigrants, finding a prevalence of asymptomatic carriers of 0.5% (with carriers predominantly originating from South America or Africa). These findings supported the existing policy in Spain of testing for anti-HTLV antibodies only among organ donors from HTLV-1 endemic areas or among native Spaniards with a high suspicion of HTLV-1 infection.
There are currently no treatments for HTLV-1 infection. OPTN guidelines state that if the donor is confirmed to be HTLV-1-positive, the recipient(s) should be screened by HTLV-1-specific NAT and serology at 1, 3, and 12 months posttransplant, and should receive ongoing clinical monitoring for the appearance of unexplained neurological disease and/or T-cell leukemia/lymphoma. Counseling to avoid secondary transmission to sexual partners or breast-fed infants of recipients may also be required.
The effect of immunosuppression on the outcomes of HTLV-1 infection is not well characterized. Immunosuppression may promote a rapid increased in HTLV-1 proviral load due to a lack of cytotoxic T lymphocyte response to infection, thus leading to a more rapid onset of neurological disease. However, the immunosuppressed status of the organ recipient is only one of several factors that will potentially affect the outcomes of HLTV-1 infection. Certain HTLV-1 subtypes are more likely to result in HTLV-1-related disease than others (eg, Cosmopolitan A viruses carrying the taxA gene are linked to greater risk of TSP/HAM development), and the proviral load is typically higher in patients with TSP/HAM versus asymptomatic carriers. Host factors, including HLA haplotype, may influence the outcome of infection, with the class I allele HLA-A*02 appearing to confer protection against TSP/HAM. Lastly, the route of transmission is also likely to have a role in patient outcomes: HTLV-1 transmission by organ transplantation or blood transfusion exposes the patient to a much larger viral inoculum than by other transmission routes, and it is hypothesized that this results in a shorter latency period and greater risk of TSP/HAM. These factors are likely to account for the variation in outcomes of HTLV-1 infection in solid organ transplant recipients reported in the published literature: although there have been several cases of ATL and TSP/HAM in HTLV-1-positive organ recipients after transplantation, there have also been multiple studies demonstrating an absence of HTLV-1-related diseases in HTLV-1-infected recipients and recipients of HTLV-positive donor organs over long-term follow-up.
Data on the epidemiology of HSV types 1 and 2 (HSV-1 and HSV-2) in Australia come from the baseline AusDiab survey, a population-representative survey of adults 25 years and older conducted between 1999 and 2000. Serum analysis of a stratified random sample of 4000 individuals from the original cohort of 11 000 found a seroprevalence of HSV-1 in the Australian population of 76% and a seroprevalence of HSV-2 of 12%. Seroprevalence of HSV-1 peaked in the 65- to 74-year age groups at 85% compared with a seroprevalence of 67% in the 25- to 34-year age groups. Seroprevalence of HSV-2 peaked in the 35- to 44-year age groups at 16% compared with the lowest seroprevalence of 8% in the 65- to 74-year age groups. Seroprevalence of both HSV-1 and HSV-2 were higher in women than in men (80% vs 71% and 16% vs 8%, respectively). Seroprevalence of HSV-2 was higher in capital cities (14%) and metropolitan areas (13%) compared with rural and remote areas (9%). Estimated seroprevalence of both HSV-1 and HSV-2 was higher in Aboriginal and Torres Straight Islander people than non-Indigenous Australians (100% vs 75% and 18% vs 12%, respectively). Although not analyzed as part of the AusDiab survey, international studies have reported HSV-2 seroprevalence among MSM of 24% to 87%.
Since its identification in 1994, Kaposi sarcoma herpes virus (KSHV) has been demonstrated to be associated with all forms of Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's disease, and is the most common malignancy of HIV-1-infected persons. KSHV is homologous with, but distinct from, the gamma herpes viridae, EBV, and herpes virus saimiri, and:unlike most herpes viruses:human infection with KSHV is not ubiquitous but has a wide geographic variation. Seroprevalence is estimated to be less than 10% in North America and northern Europe, and between 20% and 80% in the Mediterranean and parts of Africa. Modes of KSHV transmission vary in different parts of the world: in nonendemic regions, sexual transmission is likely the main route of transmission; in endemic regions, primary KSHV infection also commonly occurs in childhood (probably via salivary transmission), and cases of vertical transmission have also been reported.
Multiple cases of KSHV transmission from organ donors to recipients have been reported in the literature. Primary infection with KSHV in immunocompromised persons is characterized by fever, splenomegaly, lymphoid hyperplasia, pancytopenia, and in some cases, rapid onset Kaposi sarcoma. In immunosuppressed transplant recipients, KSHV is more commonly associated with neoplastic disease.
International guidelines do not require any specific donor screening for HSV-1 or HSV-2, and no contraindication exists to organ donation from donors with latent herpes family viral infections due to high rates of donor and recipient exposure and routine effective antiviral prophylaxis (acyclovir, valaciclovir, ganciclovir, valganciclovir. Nonetheless, it is important to note the potential for fatal de novo infections in naive recipients from organs recovered from latently infected donors (see Transmission), as well as the potential for reactivation in latently infected recipients. Active infection in the potential donor should also not be disregarded. Some transplant centers perform retrospective additional donor tests for latent HSV in cases of seronegative recipients (usually in the case of pediatric recipients) to decide on specific antiviral prophylaxis or treatments and follow-up, although there is minimal evidence to support this approach. European guidelines state that organs can be accepted from donors with latent herpes family viral infections, except in the case of acute herpes viremia in the donor without effective antiviral treatment.
Kaposi sarcoma herpes virus DNA is not detectable in all infected individuals; therefore, KSHV must be detected by serological assay. Given that donor-derived primary KSHV infection can be associated with severe disease, European guidelines recommend screening donors for KSHV antilytic antilatent antibodies in areas of high KSHV prevalence (eg, Mediterranean region). As KSHV serology is generally unavailable before deceased donor organ transplantation, screening for KSHV antibodies may be performed retrospectively in the days immediately after transplantation. In the case of a transplant from a positive donor to negative recipient, European guidelines recommend close monitoring of KSHV DNA in the blood to detect infection early.
A case of donor-derived HSV-2 infection affecting 6 solid organ recipients occurred in Victoria in 2014. Lungs, kidneys, pancreas, and liver were retrieved from the original donor and transplanted into 4 recipients. The recipient of the kidney-pancreas had an acute myocardial infarction and cardiac arrest 2 days posttransplant and subsequently deteriorated, with brain death declared on day 9. Serological testing on day 9 was negative for HSV-2 IgG, but subsequent HSV-2 NAT later performed on stored samples was positive. This recipient then became a donor, with his lungs and the recently transplanted kidney from the original donor going to new recipients. The original donor had died of hypoxic brain injury; no clinical evidence of HSV-2 infection was seen and no history of recurrent HSV-2 infection was reported. On retrospective laboratory testing, HSV DNA was not detected; however, the donor's serology was positive for HSV-2 IgG (but not for HSV IgM). Biopsy of the kidney originally transplanted into the kidney-pancreas recipient (biopsy performed before retransplantation) showed histiocytes with enlarged nuclei containing possible viral inclusions, and HSV-2-specific staining confirmed the diagnosis of disseminated HSV-2 infection.
Of the other recipients of organs from the original donor, only the recipient of the liver developed HSV viremia and clinical symptoms. Evidence of hepatitis was observed on day 13 posttransplant, and HSV-2 viremia was detected. Valaciclovir treatment was increased to 1 g 8 hourly, but on day 19 a disseminated rash developed suspected to be cutaneous HSV. The patient was admitted and IV acyclovir 600 mg was administered 8 hourly, and eventually, the hepatitis and rash resolved and the patient remained symptom free at 12 months posttransplant.
None of the other recipients in this case became symptomatic. The recipient of the lungs from the original donor had received CMV prophylaxis with IV ganciclovir and CMV hyperimmune globulin due to CMV-status mismatch, and there was no evidence of viremia or HSV disease up to 12 months posttransplant. The recipient of the second kidney from the original donor also received anti-CMV prophylaxis (valganciclovir 450 mg 12 hourly) and did not develop viremia or any symptoms of HSV disease.
The recipient of the retransplanted kidney was seropositive for HSV-1 IgG and HSV-2 IgG at the time of transplantation but negative for HSV IgM and was commenced on valaciclovir 1 g daily on day 1 posttransplant. HSV-2 viremia was noted on day 5 and treatment switched to IV acyclovir 400 mg; viremia resolved and the patient was asymptomatic at 12 months posttransplant.
Finally, the recipient of the bilateral lung transplant from the kidney-pancreas recipient was similarly HSV-1 IgG and HSV-2 IgG-positive at the time of transplantation but negative for HSV IgM and was treated with IV ganciclovir 5 mg/kg on day 1 posttransplant. HSV-2 viremia was detected on day 2 posttransplant, and the patient switched to valaciclovir 1 g every 8 hours. Viremia resolved, and the patient was asymptomatic at 12 months posttransplant.
These 2 clusters of cases demonstrate that HSV-2 may be transmitted by HSV DNA-negative donors; however, the impact on the recipient depends on whether they have preexisting immunity and on the prophylaxis regimen used. Symptomatic HSV disease only occurred in the recipients who were serologically negative and did not receive prophylactic antiviral therapy.
Studies of the seroprevalence of human herpes virus-8 (HHV-8) in organ donors and recipients pretransplantation and posttransplantation have reported rates of seroconversion in D+/R- pairs of between 12 and 29%. The risk of KSHV seroconversion appears to be higher for liver transplant recipients than for kidney transplant recipients. Although relatively rare, the development of KS or other lethal nonmalignant illnesses after donor-derived transmission of HHV-8 has been reported on multiple occasions. It has also been demonstrated that Kaposi sarcoma progenitor cells may be transmitted through solid organ transplantation, with individual HHV-8-infected neoplastic cells able to seed tumors in the recipient. Table 21 summarizes published cases of donor-derived KSHV transmission and their outcomes.