Tenofovir alafenamide: An initial experience at Groote Schuur Hospital, Cape Town, South Africa.

BACKGROUND: Hepatitis B virus (HBV) remains endemic in South Africa (SA), with a concomitantly high prevalence of HIV co-infection. Chronic kidney disease in these subpopulations also has a high prevalence. Tenofovir is an important component of management, but the associated risk of nephrotoxicity makes dosing a challenge in patients with impaired kidney function. A new formulation, tenofovir alafenamide fumarate (TAF), with a more favourable renal toxicity profile, is now available. OBJECTIVES: To evaluate our initial experience of TAF use at Groote Schuur Hospital, Cape Town. METHODS: We retrospectively reviewed patients with HBV mono-infection and HIV-HBV co-infection who were initiated on TAF since 2018. We recorded all relevant demographic, serological, virological and biochemical data from patient records. Adherence was documented by pill collection at the pharmacy. RESULTS: A total of 26 patients were included in the evaluation, median (interquartile range (IQR)) age 48 (39 - 51) years, 73% (n=19) male, 27% (n=7) hepatitis B e-antigen-positive, and 46% (n=12) HIV co-infected. The median (IQR) duration of treatment with TAF was 13 (9 - 15) months. The median (IQR) baseline creatinine level was 180 (130 - 227) µmol/L, with significant improvement at 12 months, 122 (94 - 143) µmol/L; p=0.017. Reflecting this change, the estimated glomerular filtration rate improved significantly from baseline to month 12 (42 (25 - 52) and 51 (48 - 68) mL/min/1.73 m2, respectively; p=0.023). Similarly, serum alanine aminotransferase (ALT) normalised from a baseline of 33 (18 - 52) to 18 (15 - 24) U/L at month 12 (p=0.012). HBV DNA viral load also declined, from a baseline of log10 4.04 (2.5 - 7.8) IU/mL to a median of <log10 1.3 IU/mL at month 12. HIV viral load was less than the lower level of quantification at months 6 and 12. CONCLUSIONS: TAF was well tolerated, with stable and significantly improving kidney function throughout a 12-month follow-up period. Serum ALT normalised, mirrored by declining HBV viral load. HIV viral load remained undetectable at 6 and 12 months.

A natural history of efavirenz drug-induced liver injury.

BACKGROUND: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, has been a component of first-line antiretroviral therapy (ART) in the South African HIV/AIDS programme since 2004. It is extensively used in ART programmes in other low- and middle-income countries. The natural history of the previously recognised EFV drug-induced liver injury (DILI) is not known. OBJECTIVES: To define and establish a causality assessment for EFV DILI and document its natural history by detailing a patient cohort. All relevant features characterising the patterns of clinical and histological injury, the duration of clinical and biochemical recovery and the associated mortality rate were documented. Factors associated with specific histological patterns of liver injury were analysed. METHODS: Patients were prospectively included after meeting causality and inclusion criteria for EFV DILI. Clinical, demographic and liver histological features (where possible) were documented from the time of presentation and throughout follow-up. Prednisone at 0.25 - 0.5 mg/kg was initiated at the discretion of the treating hepatologist. RESULTS: Fifty patients were prospectively included in the analysis. The median age was 34 (interquartile range (IQR) 29 - 39) years, males being older than females (p=0.014). Most (92%) were female, and 86% were of black African ethnicity. The median duration of ART at presentation was 6 months, with half of the women having initiated ART during pregnancy, at a median gestation of 24 (IQR 11 - 36) weeks. The median CD4 nadir at ART treatment initiation was 517 cells/µL, with no significant difference in CD4 nadir between those who were pregnant and those who were not (p=0.6). The median RUCAM (Roussel Uclaf Causality Assessment Method) score was 7, and among the 75% of patients who had liver biopsies, three histological patterns were identified: submassive necrosis (60%), nonspecific hepatitis (35%), and mixed cholestatic hepatitis (5%). On multivariate analysis, predictors for the development of submassive necrosis included younger age (<30 years; p=0.045), ART initiation in pregnancy (p=0.02), and a baseline CD4 count >350 cells/µL (p=0.018). For the nonspecific hepatitis group, pregnancy was also an associated factor (p=0.04). The mortality rate was 14%, with a median time from admission to death of 15 days. The median (IQR) time to initial hospital discharge was a lengthy 33 (24 - 52) days. Biochemical recovery was prolonged, necessitating a follow-up period of more than a year at an outpatient specialist clinic, with 86% of patients initiating a protease inhibitor-based ART regimen successfully. CONCLUSIONS: EFV DILI is a severe drug complication of ART with appreciable mortality and significant inpatient morbidity, requiring prolonged hospitalisation and follow-up.

Why is there a paucity of clinical trials in Africa?

Disproportionately few clinical trials are undertaken on the African continent, in part due to lingering neocolonial attitudes in the Global North which keep research activity primarily in developing countries, while being skeptical of the abilities of those in the Global South to undertake organized clinical studies. In the era of the COVID-19 pandemic, applicable research and clinical trials should be undertaken in relevant populations in order to extrapolate to a population level. This is all the more important in Africa, which has a rich genetic diversity. We suggest that a lack of organized research ethics committees across the continent and a deficiency of appropriate training are responsible in part for the reluctance of clinical trial organizers in the developed countries of the Global North to engage with medical leadership in Africa. We consider ways of alleviating this problem, including suggesting a pan-continental surveillance of ethics committee agendas and of training, either through the auspices of the African Union or the World Health Organization. In addition, medical leadership in African nations must be encouraged to take ownership of their medical ethics agendas to facilitate decent international clinical trial participation for the good of the continent as a whole.

A decade of hepatitis C at the University of Cape Town/Groote Schuur Hospital Liver Clinic, South Africa, in the pre-direct-acting antivirals era.

BACKGROUND: Hepatitis C virus (HCV) in South Africa (SA) is incompletely characterised and understood. Epidemiological and clinical data will better inform our understanding and assist national policy decision-making. Against the background of more than two decades of clinical challenges in HCV management, the advent of direct-acting antivirals (DAAs) now makes HCV elimination plausible. OBJECTIVES: To better understand the base from which we come, we elected to review and characterise our HCV experience at Groote Schuur Hospital (GSH), Cape Town, SA, in the pegylated interferon (Peg-IFN) and ribavirin (RBV) management era. METHODS: Patients with chronic HCV infection attending the GSH Liver Clinic from 2002 to 2014 were included in the analysis. Relevant data were extracted from a registry and existing clinical records were accessed. Two brands of Peg-IFN were available, and patients treated with the first-generation add-on protease inhibitor telaprevir were included. RESULTS: A total of 238 patients were included in the analysis (median (interquartile range) 47 (37 - 58) years, 60.5% males). Males were significantly younger than females (43.5 (35 - 52) years v. 55 (42 - 64) years, respectively) (p<0.0001). The majority were white (55.9%) or of mixed ancestry (21.8%), 16.4% were HIV co-infected, 3.7% were hepatitis B virus (HBV) co-infected, and 1 patient (0.4%) was triple-infected with HCV, HBV and HIV. The most likely mode of HCV acquisition was blood or blood product exposure prior to 1992 (32.8%) and injecting drug use (17.6%), while 30.3% of patients had no clear risk factor identifiable. Genotypes (GTs) 1 - 5 were observed, with GT-1 (34.9%) predominating. Of patients who were biopsied (n=90), 30.0% had ≥F3 fibrosis, with 15.6% cirrhotic. With IL28B polymorphisms, the heterozygous CT (23.9%) and CC (15.5%) genotypes were most frequent. Of the patients, 32.6% accessed Peg-IFN/RBV-based therapy, 6.5% (n=5) with add-on telaprevir. GT-1 (35.1%) was most prevalent in the treatment group, followed by GT-3 (26.0%) and GT-5 (18.2%); 10.0% were HIV co-infected. The overall sustained virological response (SVR) rate was 75.3%, with 37.0% of GT-1 patients not achieving SVR. Of the patients treated, 49.4% experienced adverse events, including cytopenias (32.5%) and depression (15.6%), and 23.4% required cell support in the form of erythropoietin and/or granulocyte-macrophage colony-stimulating factor. CONCLUSIONS: HCV patients in the Peg-IFN/RBV management era typified the epidemiology of HCV. GT distribution was pangenotypic, and treatment outcomes were encouraging despite treatment challenges. Patient selection, IL28B and sensible support of cytopenias probably accounted for these favourable outcomes. However, numbers treated were limited, and the DAA era of therapy allows for rapid expansion of therapy with now growing numbers of patients and a changing local epidemiology.

Direct-acting antiviral therapy for hepatitis C: The initial experience of the University of Cape Town/Groote Schuur Hospital Liver Clinic, South Africa.

BACKGROUND: An estimated 600 000 South Africans are chronically infected with hepatitis C virus (HCV). To date, accurate prevalence data are lacking, but emerging data suggest a significant burden in key populations. Historically, pegylated interferon and ribavirin treatment was challenging, with access limited. The advent of all-oral, short-course direct-acting antiviral (DAA) therapy has revolutionised the management of HCV, being well tolerated and highly effective, although initial cost was a prohibitive factor. OBJECTIVES: To report our initial 2-year experience with DAA therapy at the University of Cape Town/Groote Schuur Hospital Liver Clinic, South Africa (SA). METHODS: Patients who were viraemic for HCV were offered access to DAA therapy. All relevant demographic, virological, serological and clinical laboratory data were captured in a registry. Liver fibrosis was assessed non-invasively with the FibroScan. DAA regimens were prescribed according to current guidance based on HCV genotype (GT), prior treatment history and degree of fibrosis. On treatment, virological response was recorded and a sustained virological response (SVR) was defined as an undetectable HCV RNA at least 12 weeks after the end of treatment. RESULTS: We report on the first 210 patients treated. Their median (interquartile range (IQR)) age was 52 (42 - 61) years and 65% were male, with men significantly younger than women at 50 (42 - 59) years v. 58 (47 - 67) years, respectively (p=0.001). All GTs were observed, with 1 and 5 most prevalent at 45% and 20%, respectively, and GTs 2, 3 and 4 frequencies of 7%, 11% and 17%, respectively. Extensive subtype diversity for GTs 2 and 4 was present. The median (IQR) HCV viral load was log10 5.9 IU/mL (5.4 - 6.5). A significant proportion of patients (39%) had advanced fibrosis or cirrhosis, with 11% F3 fibrosis and 28% F4. Of those with cirrhosis, 12% were decompensated with Childs-Pugh B or C disease. Of the patients, 19% were HIV co-infected and 2% HBV co-infected. In total, 13% were treatment experienced. The majority of patients were treated with sofosbuvir and ledipasvir (38%), daclatasvir (36%) or velpatasvir (± voxilaprevir, 9%). Less frequent combinations included partitaprevir, ritonavir, ombitasvir ± dasbuvir (11%) and sofosbuvir/ribavirin (5%). The per-protocol SVR was 96% (98% if sofosbuvir/ribavirin is excluded). The majority of treatment failures occurred with GT-4, notably subtype 4r. Mild side-effects were reported in 10% of patients, with none discontinuing therapy. CONCLUSIONS: DAA therapy for HCV in a pan-genotypic group of patients, many with advanced liver disease, was highly effective. Our outcomes correspond with existing trial and real-world data for similar treatment. DAA therapy and access need rapid upscaling in SA, especially targeting key populations at point of care.

Towards the elimination of hepatitis B and hepatocellular carcinoma.

Hepatitis B (HBV) remains a global health problem despite the availability of effective vaccines since 1982 and effective antiviral therapy. The global burden of disease is substantial, with HBV resulting in 887 220 deaths in 2015: acute hepatitis (87 076), cirrhosis (462 690) and hepatocellular carcinoma (337 454). The World Health Organization has a vision to eliminate viral hepatitis as a public health threat by 2030. Although HBV and its associated complications of cirrhosis, liver failure and hepatocellular carcinoma are entirely vaccine preventable, there is no cure for chronic hepatitis B as yet. HBV elimination strategies will need to focus on effective and implementable preventive and therapeutic strategies such as upscaling HBV birth-dose vaccination, full HBV vaccine coverage, vaccination of high-risk groups, prevention of mother-to-child transmission, and identification of HBV-infected individuals and linkage to care with sustainable access to antiviral therapy.

Hepatitis C prevalence in HIV-infected heterosexual men and men who have sex with men.

BACKGROUND: Globally 1% of individuals are infected with hepatitis C virus (HCV). In South Africa (SA) the prevalence ranges between 0.3% and 1%, with few prospective screening data available. Similarly, local data on transmission modes of HCV are limited, but probably include parenteral routes and pre-1992 blood or blood products. The risk of heterosexual transmission of HCV is low but is increased in men who have sex with men (MSM), with co-transmission risk of both HIV and HCV. OBJECTIVES: Given few local data, we sought to better understand HCV characteristics and prevalence in two groups of HIV-infected men. METHODS: HIV-positive men in the greater Cape Town metropolitan area were recruited. Sexual orientation was self-identified and demographic and other personal data were obtained via a confidential questionnaire. Participants were screened for HCV after a blood draw. Those with positive HCV tests had further HCV RNA confirmation. Risk factors associated with HCV seropositivity were determined. RESULTS: Five hundred HIV-positive men were recruited, 285 (57.0%) MSM and 215 (43.0%) non-MSM, median age 36 years (interquartile range (IQR) 20 - 64) and 37 years (IQR 21 - 56), respectively (p=NS). Overall, 3.4% (n=17) screened HCV-positive, 5.6% MSM (n=16) and 0.5% non-MSM (n=1); 82.4% were viraemic for HCV RNA. In respect of genotype distribution, 50.0% were infected with genotype 1a, 14.3% with genotype 4 and 35.7% with genotype 2. In terms of risk, MSM were more likely to have used drugs (54.4% v. 30.2%; p<0.001) and to have used all five modes of drug administration (13.0% MSM v. 0.5% non-MSM for injected drugs, 36.1% v. 2.3% for inhaled, 10.0% v. 0% for rectal, 48.1% v. 28.8% for smoked and 27.4% v. 2.3% for oral). More MSM than non-MSM (46.3% v. 16.7%) reported having sex while using recreational drugs, and similarly more MSM (21.4% v. 14%) reported having sex with a sex worker (SW). Risk factors for HCV seropositivity included drug use history (odds ratio (OR) 6.28, 95% confidence interval (CI) 1.78 - 22.12; p=0.004) and in MSM, sex with an SW (OR 5.5, 95% CI 2.06 - 14.68; p=0.001) or use of recreational drugs with sex (OR 6.88, 95% CI 2.21 - 21.44; p=0.001). CONCLUSIONS: HCV prevalence in HIV-positive MSM is higher than previously appreciated or documented in SA. Risk factors include injection drug use, use of recreational drugs with sex, and sex with SWs. Targeted interventions are required to address this emerging challenge to achieve the viral hepatitis elimination ideal by 2030.

Detection of in vivo hepatitis B virus surface antigen mutations-A comparison of four routine screening assays.

An important requirement for a state-of-the-art hepatitis B surface antigen (HBsAg) screening assay is reliable detection of mutated HBsAg. Currently, there is a striking shortage of data regarding the detection rates of in vivo HBsAg mutations for these clinically important assays. Therefore, we compared the detection rates of four commercial HBsAg screening assays using a global cohort of 1553 patients from four continents with known HBV genotypes. These samples, which represent the broadest spectrum of known and novel HBsAg major hydrophilic region (MHR) mutations to date, were analyzed for the presence of HBsAg using the Roche Elecsys® HBsAg II Qualitative, Siemens ADVIA Centaur XP HBsAg II, Abbott Architect HBsAg Qualitative II and DiaSorin Liaison® HBsAg Qualitative assays, respectively. Of the 1553 samples, 1391 samples could be sequenced; of these, 1013 (72.8%) carried at least one of the 345 currently known amino acid substitutions (distinct HBsAg mutation) in the HBsAg MHR. All 1553 patient samples were positive for HBsAg using the Elecsys® HBsAg II Qual assay, with a sensitivity (95% confidence interval) of 99.94% (99.64%-100%), followed by the Abbott Architect 99.81% (99.44%-99.96%), Siemens ADVIA 99.81% (99.44%-99.96%) and DiaSorin Liaison® 99.36% (98.82%-99.69%) assays, respectively. Our results indicate that the Elecsys® HBsAg II Qual assay exhibits the highest sensitivity among the commercial HBsAg screening assays, and demonstrate that its capacity to detect HBV infection is not compromised by HBsAg MHR mutants.

Preventing hepatitis B and hepatocellular carcinoma in South Africa: The case for a birth-dose vaccine.

Hepatitis B is a global public health issue, with some 2 billion people having current or past infection. In Africa, 65 million are chronically infected, an estimated 2.5 million of them in South Africa (SA). Hepatitis B and the associated complications of cirrhosis and hepatocellular carcinoma are entirely vaccine preventable. SA was one of the first ten countries in Africa to introduce universal hepatitis B vaccination in April 1995, but has no birth dose or catch-up programme. Although universal infant vaccination in SA has been successful in increasing population immunity to hepatitis B, improvements in terms of implementing protocols to screen all pregnant mothers for hepatitis B surface antigen (HBsAg) and ensuring full hepatitis B coverage, especially in rural areas, is justified. The World Health Organization has recommended a birth dose of hepatitis B vaccine in addition to the existing hepatitis B vaccine schedule in order to further decrease the risk of perinatal transmission. We recommend that SA implement a birth-dose vaccine into the existing schedule to attenuate the risk of perinatal transmission, prevent breakthrough infections and decrease HBsAg carriage in babies born to HIV-positive mothers.

Challenges for paediatric transplantation in Africa.

Transplantation is the accepted mode of treatment for patients with end-stage organ disease affecting the heart, lungs, kidney, pancreas, liver and intestine. Long-term outcomes have significantly improved and the aim of management is no longer only long-term survival, but also focuses on quality of life especially in children. Transplantation in Africa faces a number of challenges including wide socioeconomic disparity, lack of legislation around brain death and organ donation in many countries, shortage of skilled medical personnel and facilities, infectious disease burden and insecure access to and monitoring of immunosuppression. Whilst there is a need for transplantation, the establishment and sustainability of transplant programmes require careful planning with national government and institutional support. Legislation regarding brain death diagnosis and organ retrieval/donation; appropriate training of the transplant team; and transparent and equitable criteria for organ allocation are important to establish before embarking on a transplant programme. Establishing sustainable, self-sufficient transplant programmes in Africa with equal access to all citizens is an important step towards curtailing transplant tourism and organ trafficking and has a further beneficial effect in raising the level of medical and surgical care in these countries.

Immune tolerance and immunosuppression in solid organ transplantation.

Organ transplantation is the treatment of choice for patients with end-stage organ failure. Most of them will require lifelong immunosuppression to prevent both acute and chronic rejection. T-cell recognition of the allograft major histocompatibility complex antigens is the central event initiating cellular rejection of the allograft, and subsequent full T-cell activation requires three signals.Immunosuppressive regimens currently used in clinical practice are nonspecific and target T-cell activation, clonal expansion or differentiation into effector T cells. While these therapeutic regimens have advanced considerably and one-year graft survival figures for most solid organ transplants (SOTs) are >90%, the long-term graft survival remains fair owing to graft loss from chronic rejection. The 'holy grail' of SOT is therefore the development of a permanent specific immune tolerance against donor allogeneic antigens without the long-term use of immunosuppression.

South African guideline for the management of chronic hepatitis B: 2013.

Hepatitis B remains a significant yet preventable health issue in South Africa. The introduction of the hepatitis B vaccine into the country some 18 years ago has demonstrated benefit, but the exposure to, and prevalence of chronic HBsAg positivity remain unacceptably high. Those with chronic hepatitis B virus infection have an elevated risk of developing cirrhosis with end-stage liver disease and a markedly elevated risk of hepatocellular carcinoma, independent of the presence of cirrhosis. The challenge in South Africa remains prevention through the universal vaccination coverage of all children and the identification of those with chronic hepatitis B virus infection. Over the last decade our understanding of hepatitis B and its behaviour and natural history in those with chronic infection has significantly improved. This understanding is key to identifying those who warrant further evaluation and therapy. A number of global societies have updated their guidelines in recent years. This document draws on these guidelines and serves to contextualise, for South Africa, practice guidelines for the management of chronic hepatitis B.

Pregnancy following liver transplantation during childhood and adolescence.

More than 80% of pediatric transplant recipients will survive to reach adulthood, and many will consider having children. We report on outcomes and management of five pregnancies in four women undergoing orthotopic liver transplantation during childhood or adolescence and followed up at our Transplant Center. A retrospective clinical folder audit was performed. Mean age at transplantation was 13.3 ± 3.4 yr (range, 10-18 yr). Mean interval between transplantation and pregnancy was 15.4 ± 4.9 yr (range, 10-22 yr). Mean maternal age at conception was 28 ± 3.5 yr (range, 23-32 yr). Mean gestational age was 36.6 ± 1.7 wk. Mean birth weight was 2672 ± 249 g. Immunosuppression was cyclosporin based in three women and tacrolimus based in one woman. Pregnancy complications necessitating the induction of labor included fetal distress and rising maternal liver enzymes in two women, cholestasis of pregnancy and impaired renal graft function in one woman, fetal distress and preeclampsia in one woman. Modes of delivery were normal vaginal delivery in three women and cesarean section in one woman. No maternal or fetal deaths and no congenital malformations occurred. No episodes of rejection occurred during pregnancy. Two women experienced acute cellular rejection requiring an increase in baseline immunosuppression in the first year, following delivery. No graft losses occurred during a mean follow-up of 44 ± 17.9 months post-delivery. With careful management, pregnancy post-liver transplantation can have a successful outcome.

Effect of liver regeneration on the pharmacokinetics of immunosuppressive drugs.

In liver transplantation the graft has been known to undergo regeneration, which is associated with down-regulation of the cytochrome P450 system. The latter is involved in the metabolism of several immunosuppressive drugs. The aim of this study was to investigate the effect of liver regeneration on the pharmacokinetics (PK) of cyclosporine, rapamycin, and tacrolimus. Rats were subjected to either partial hepatectomy (PH) or sham operation (SH). Cyclosporine, rapamycin, and tacrolimus PK studies were performed at 0, 24, and 96 hours postoperatively. The areas under the curve (AUC), trough levels, and maximum concentrations (Cmax) for cyclosporine and tacrolimus were numerically higher in the animals subjected to PH. The PK studies of rapamycin were not affected by PH. These studies indicated that cyclosporine and tacrolimus metabolism may be inhibited during liver regeneration.

Overview of a paediatric renal transplant programme.

INTRODUCTION: Renal transplantation is the therapy of choice for children with end-stage renal failure. There are many challenges associated with a paediatric programme in a developing country where organs are limited. METHODS: A retrospective review was undertaken of 149 paediatric renal transplants performed between 1968 and 2006 with specific emphasis on transplants performed in the last 10 years. Survival of patients and grafts was analysed and specific problems related to drugs and infections were reviewed. RESULTS: On review of the total programme, 60% of the transplants have been performed in the last 10 years, with satisfactory overall patient and graft survival for the first 8 years post transplant. At this point, transfer to adult units with non-compliance becomes a significant problem. Rejection is less of a problem than previously but infection is now a bigger issue--specifically tuberculosis (TB), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections with related complications. A wide variety of drugs are available for tailoring immunosuppression to minimise side-effects. CONCLUSION: It is possible to have a successful paediatric transplant programme in a developing country. However, to improve long-term outcomes certain issues need to be addressed, including reduction of nephrotoxic drugs and cardiovascular risk factors and providing successful adolescent to adult unit transition.

Liver transplantation at Red Cross War Memorial Children's Hospital.

UNLABELLED: The liver transplant programme for infants and children at Red Cross War Memorial Children's Hospital is the only established paediatric service in sub-Saharan Africa. Referrals for liver transplant assessment come from most provinces within South Africa as well as neighbouring countries. PATIENTS AND METHODS: Since 1987, 81 children (range 6 months-14 years) have had 84 liver transplants with biliary atresia being the most frequent diagnosis. The indications for transplantation include biliary atresia (48), metabolic (7), fulminant hepatic failure (10), redo transplants (3) and other (16). Four combined liver/kidney transplants have been performed. Fifty-three were reduced-size transplants with donor/recipient weight ratios ranging from 2:1 to 11:1 and 32 children weighed less than 10 kg. RESULTS: Sixty patients (74%) survived 3 months-14 years post-transplant. Overall cumulative 1- and 5-year patient survival figures are 79% and 70% respectively. However, with the introduction of prophylactic intravenous ganciclovir and the exclusion of hepatitis B virus (HBV) IgG core Ab-positive donors, the 1-year patient survival is 90% and the projected 5-year paediatric survival is > 80%. Early (< 1 month) post-liver-transplant mortality was low. Causes include primary malfunction (1), inferior vena cava thrombosis (1), bleeding oesophageal ulcer (1), sepsis (1) and cerebral oedema (1). Late morbidity and mortality was mainly due to infections: de novo hepatitis B (5 patients, 2 deaths), Epstein-Barr virus (EBV)- related post-transplantation lymphoproliferative disease (12 patients, 7 deaths) and cytomegalovirus (CMV) disease (10 patients, 5 deaths). Tuberculosis (TB) treatment in 3 patients was complicated by chronic rejection (1) and TB-drug-induced subfulminant liver failure (1). CONCLUSION: Despite limited resources, a successful paediatric programme has been established with good patient and graft survival figures and excellent quality of life. Shortage of donors because of infection with HBV and human immunodeficiency virus (HIV) leads to significant waiting-list mortality and infrequent transplantation.

Restoration of liver mass after partial hepatectomy--implications for living donor liver transplantation.

In living donor liver transplantation, the recipient liver undergoes more rapid regeneration than the remnant liver in the donor. In this study we investigated the factors which may be responsible for the difference in the regenerative response between the donor and the recipient. Long Evans rats were subjected to either partial hepatectomy (PH) or sham operation (SH) and were treated with liver cytosol (C) and cyclosporine (Cy). The rats were sacrificed at 24, 48, 72 and 96 hours and 1 and 2 weeks postoperatively. The livers were removed to determine the liver weight/body weight (LW/BW) ratio and the mitotic index. The mitotic index, serum aspartate transferase (AST) and serum alanine transferase (ALT), although unchanged in the SH groups, were increased in the rats treated with PH + C + Cy, and were greater than after PH only. However LW/BW ratios increased after PH but had returned to preoperative levels by 2 weeks. The changes in LW/BW ratio were not modified by the cytosol or cyclosporine.

The effect of rapamycin on the healing of the ureteric anastomosis and wound healing.

Rapamycin is a potent immunosuppressive agent that also inhibits fibroblastic activity and therefore may affect the healing of various tissues. The aim of this study was to investigate the effect of rapamycin on wound healing and the healing of the ureteric anastomosis. Large White/Landrace pigs were subjected to a laparotomy and division and immediate anastomosis of the ureter. The animals were randomly allocated to receive either rapamycin or placebo. The animals were sacrificed on postoperative day 5, and strips of the skin and fascia closure and the ureteric anastomosis excised and used to determine the tensile strength, hydroxyproline levels, and histological changes. The tensile strength and the hydroxyproline levels in the ureter and fascia were lower in the rapamycin-treated animals. There was no difference in the tensile strength in the skin, although the hydroxyproline levels were lower. This study shows that healing of the ureteric anastomosis and fascia and skin closure may be impaired by rapamycin.