Janaki Amin

Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study

BACKGROUND Hepatitis B and hepatitis C virus infections are common causes of death related to liver disease. In this large study, we aimed to investigate all cause mortality of the viruses in a community-based setting. METHODS In the study population, 39,109 people had hepatitis B, 75,834 had hepatitis C, and 2604 had hepatitis B and hepatitis C co-infection, notified to the New South Wales state health department, Australia, between 1990 and 2002. Their data were probabilistically linked to the National Death Index. Standardised mortality ratios for all causes of death were calculated and adjusted for age, sex, and calendar year. RESULTS The number of deaths identified by the linkage were 1233 (3.2%) for hepatitis B, 4008 (5.3)% for hepatitis C, and 186 (7.1)% for hepatitis B and C co-infection. Raised risk of liver-related death (standardised mortality ratios 12.2, 95% CI 10.7-13.9; 16.8, 15.4-18.3, and 32.9, 23.1-46.7, for hepatitis B, hepatitis C, and hepatitis B and C co-infected patients, respectively) and drug-induced death (1.4, 1.0-2.0; 19.3, 18.1-20.5; and 24.7, 18.2-33.5, respectively) were detected. In people with hepatitis C, raised risk of dying from drug-related causes was significantly greater than from liver-related causes (p=0.012), with the greatest excess risk in women aged 15-24 years (56.9, 39.2-79.9). INTERPRETATION All groups had increased risk of liver-related death compared with the standard population, with the greatest excess in people diagnosed with hepatitis B and hepatitis C co-infection. Our data highlight that young people with hepatitis C and with co-infection face a higher mortality risk from continued drug use than from their infection, whereas the main cause of hepatitis B death was liver related.

Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population

Background:Due to the success of antiretroviral therapy (ART), it is relevant to ask whether death rates in optimally treated HIV are higher than the general population. The objective was to compare mortality rates in well controlled HIV-infected adults in the SMART and ESPRIT clinical trials with the general population. Methods:Non-IDUs aged 20–70 years from the continuous ART control arms of ESPRIT and SMART were included if the person had both low HIV plasma viral loads (⩽400 copies/ml SMART, ⩽500 copies/ml ESPRIT) and high CD4+ T-cell counts (≥350 cells/&mgr;l) at any time in the past 6 months. Standardized mortality ratios (SMRs) were calculated by comparing death rates with the Human Mortality Database. Results:Three thousand, two hundred and eighty individuals [665 (20%) women], median age 43 years, contributed 12 357 person-years of follow-up. Sixty-two deaths occurred during follow up. Commonest cause of death was cardiovascular disease (CVD) or sudden death (19, 31%), followed by non-AIDS malignancy (12, 19%). Only two deaths (3%) were AIDS-related. Mortality rate was increased compared with the general population with a CD4+ cell count between 350 and 499 cells/&mgr;l [SMR 1.77, 95% confidence interval (CI) 1.17–2.55]. No evidence for increased mortality was seen with CD4+ cell counts greater than 500 cells/&mgr;l (SMR 1.00, 95% CI 0.69–1.40). Conclusion:In HIV-infected individuals on ART, with a recent undetectable viral load, who maintained or had recovery of CD4+ cell counts to at least 500 cells/&mgr;l, we identified no evidence for a raised risk of death compared with the general population.

The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection.

Although 20%‐40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin‐28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 7% had human immunodeficiency virus (HIV) coinfection. Twenty‐eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow‐up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non‐genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males. Conclusions: Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex‐based differences in HCV control. (Hepatology 2014;58:109–120)

Simplification of Antiretroviral Therapy with Tenofovir-Emtricitabine or Abacavir-Lamivudine: A Randomized, 96-Week Trial

BACKGROUND There are 2 once-daily, fixed-dose-combination, dual-nucleoside analogue tablets: tenofovir 300 mg-emtricitabine 200 mg (TDF-FTC) and abacavir 600 mg-lamivudine 300 mg (ABC-3TC). Which fixed-dose-combination tablet is more effective and safe is uncertain. METHODS We compared TDF-FTC and ABC-3TC in a randomized, open-label, 96-week trial in which either fixed-dose-combination was substituted for current nucleoside treatments in human leukocyte antigen-B*5701-negative adults with human immunodeficiency virus loads <50 copies/mL. The primary end point was virological failure (consecutive viral load measurements >400 copies/mL, by intention-to-treat). Secondary end points included death, AIDS, adverse events, serious non-AIDS events, metabolic parameters, and body composition. We used exact statistics for differences in proportions, T tests to compare means, and Cox regression for hazard ratios. RESULTS Of 441 patients who were screened, 357 were treated; 98% were men, the mean age was 45 years, 30% were receiving TDF, 20% were receiving ABC, and 24% were receiving a protease inhibitor. Virological failure was uncommon (5.6% for ABC-3TC and 3.9% for TDF-FTC; difference, 1.7%; 95% confidence interval [CI], -2.8% to 6.1%; P = .62). No participant developed AIDS, whereas 18 (5%) participants developed a serious non-AIDS event (rate, 2.79 events per 100 person-years; 95% CI, 1.76-4.43), of which 4 were fatal. TDF-FTC was associated with significantly fewer serious non-AIDS events than ABC-3TC (1.2 vs 4.8 events per 100 patient-years; hazard ratio [HR], 0.24; 95% CI, 0.08-0.73; P = .012), influenced mostly by a lower rate of cardiovascular events (0.3 vs 2.2 events per 100 patient-years; HR, 0.12; 95% CI, 0.02-0.98; P = .048). TDF-FTC resulted in significantly lower bone mineral density (mean difference in hip t score, 0.16; 95% CI, 0.08-0.23; P < .001) but not in more fractures. CONCLUSIONS In this population, TDF-FTC and ABC-3TC had similar virological efficacy, but ABC-3TC was associated with more serious non-AIDS events, particularly cardiovascular events. Clinical trials registration. NCT00192634 .

HIV and hepatitis C coinfection within the CAESAR study

The declining incidence of AIDS‐related opportunistic diseases among people with HIV infection has shifted the focus of clinical management to prevention and treatment of comorbidities such as chronic liver disease. The increased risk of hepatitis C virus (HCV)‐related advanced liver disease in people with HIV infection makes early HCV diagnosis a priority. To assess HCV prevalence and predictors of HIV/HCV coinfection, we have conducted a retrospective analysis of people enrolled in the CAESAR (Canada, Australia, Europe, South Africa) study, a multinational randomized placebo‐controlled study of the addition of lamivudine to background antiretroviral therapy. The impact of HCV on HIV disease progression was also examined. Anti‐HCV antibody testing on 1649 CAESAR study participants demonstrated a HIV/HCV coinfection prevalence of 16.1%, which varied from 1.9% in South Africa to 48.6% in Italy. The strongest predictor of HIV/HCV coinfection was HIV exposure category (P<0.0001), with odds ratios (ORs) compared to homosexual as follows: injecting drug use (IDU), 365 [95% confidence interval (CI): 179–742]; transfusion or blood products, 32.2 (95% CI: 15.2–67.6); homosexual and IDU, 22.9 (95% CI: 8.5–62.1). The prevalence of HIV/HCV was low (3.7%) among homosexual men without reported IDU. Other predictors of HIV/HCV coinfection were alanine aminotransferase (ALT), country of residence, ethnicity and stage of HIV disease. A history of IDU or ALT ≥40 U/L at baseline had a positive predictive value (PPV) of 35%, negative predictive value (NPV) of 96%, sensitivity of 82% and specificity of 71% for HIV/HCV coinfection. HIV disease progression was similar in HIV monoinfected and HIV/HCV coinfected patients. People with HIV and a history of IDU or elevated liver function tests should be targeted for HCV testing. The low prevalence of HIV/HCV coinfection among homosexual men without a history of IDU suggests low efficiency of sexual HCV transmission.

The pattern of excess cancer in dialysis and transplantation

BACKGROUND After transplantation, cancer risk varies from no increase for several common cancers to a many-fold increase for a number of, chiefly virus-associated, cancers. The smaller excess of cancer in dialysis has been less well described, but two studies suggested that impaired immunity might be responsible. METHODS In a population-based cohort study of 28 855 patients who received renal replacement therapy (RRT), we categorized incident cancers as end-stage kidney disease (ESKD) related, immune deficiency related, not related to immune deficiency, or of uncertain status, according to whether they were, or were not, increased in published reports of cancer in ESKD prior to starting RRT, organ transplantation or human immunodeficiency virus infection. Standardized incidence ratios for, and excess burdens of, cancer were calculated for all persons normally resident in Australia starting treatment by dialysis or renal transplantation from 1982 to 2003. RESULTS The risk for ESKD-related cancers was increased 4-fold in dialysis and during transplant function. For immune deficiency-related cancers, the increase was 1.5 (95% CI 1.3-1.6) times in dialysis, and 5-fold after transplantation. ESKD- or immune deficiency-related cancers contributed to approximately 90% of the excess burden of cancer, 48% and 36%, respectively, in dialysis, and 10% and 78% after transplantation. The remaining excess malignancy was contributed by cancers whose relationship with ESKD and immune deficiency is not yet certain. CONCLUSIONS In RRT, the increase in cancer is restricted, largely if not wholly, to cancers with origins in ESKD or related to immune deficiency. For the former, the cancer risk is similar in dialysis and transplantation, but for immune deficiency-related cancers, the relative risk is much greater after transplantation.

A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naïve individuals in Thailand

Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is associated with considerable liver disease morbidity and mortality. Emerging HIV epidemics in areas of high HBV endemicity such as Asia are expanding the population with HIV/HBV coinfection. Limited randomized trial data exist to support current guidelines for HBV combination therapy in HIV/HBV coinfection. The objective of this prospective randomized clinical trial was to compare the strategy of HBV monotherapy with lamivudine (LAM) or tenofovir disoproxil fumarate (TDF) versus HBV combination therapy with LAM/TDF in antiretroviral‐naïve HIV/HBV‐coinfected subjects in Thailand. Thirty‐six HIV/HBV‐coinfected subjects initiating highly active antiretroviral therapy (HAART) were randomized to either LAM (arm 1), TDF (arm 2), or LAM/TDF (arm 3) as HBV‐active drugs within HAART. At week 48, time‐weighted area under the curve analysis revealed that the median HBV DNA reduction from baseline was 4.07 log10 c/mL in arm 1, 4.57 log10 c/mL in arm 2, and 4.73 log10 c/mL in arm 3 (P = 0.70). HBV DNA suppressed to <3 log10 c/mL in 46% in arm 1, 92% in arm 2, and 91% in arm 3 (P = 0.013, intent‐to‐treat analysis). HBV‐resistant changes were detected in two subjects, both in arm 1. Hepatitis B e antigen (HBeAg) loss was observed in 33% of HBeAg‐positive subjects, and 8% experienced hepatitis B surface antigen loss. Hepatic flare was observed in 25% of subjects. Conclusion: LAM monotherapy resulted in a greater proportion of subjects with HBV DNA >3 log10 c/mL at week 48 and in early resistance development. This study confirms current treatment guidelines that recommend a TDF‐based regimen as the treatment of choice for HIV/HBV coinfection, but does not demonstrate any advantage of HBV combination therapy in this short‐term setting. (HEPATOLOGY 2008.)

A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor-associated hypertriglyceridaemia.

Background: Hypertriglyceridaemia is common in patients with HIV, especially those taking protease inhibitors or with lipodystrophy, frequently observed at levels associated with accelerated cardiac disease. This study aimed to explore the efficacy and safety of gemfibrozil for hypertriglyceridemia in patients with HIV infection. Methods: A 16-week, randomized, double-blind, comparative study of low saturated fat diet versus low saturated fat diet with gemfibrozil 600 mg twice daily in patients with triglycerides ⩾ 3mmol/l receiving protease inhibitor therapy. Following a 4-week period of dietary intervention alone, patients were randomized to gemfibrozil or matching placebo. The primary outcome was the difference in mean change in fasting triglycerides at week 16 between the two groups. Results: 37 men were randomized (17 gemfibrozil, 20 placebo) with median fasting triglycerides 5.6 mmol/l. Mean changes in triglycerides from week 4 to week 16 were –1.22 mmol/l and +0.35 mmol/l for the gemfibrozil and placebo groups respectively (between-group mean difference of 1.57 mmol/l; 95% confidence interval, –6.7 to 3.5; P = 0.08). Only one patient treated had triglycerides return to a desirable range (⩽ 2.00 mmol/l). No significant changes in the other metabolic parameters were observed. Gemfibrozil was well tolerated, did not appear to induce additional protease inhibitor toxicity, and did not induce changes in CD4 lymphocyte counts or HIV RNA load. Conclusions: Gemfibrozil is safe and demonstrated at most, modest efficacy for hypertriglyceridemia in HIV-infected patients receiving protease inhibitors. Given the level of response, however, it is unclear whether these reductions will confer clinical benefit, at least in the presence of continued protease inhibitor use.

High incidence of hepatitis C virus reinfection within a cohort of injecting drug users.

Summary.  A retrospective cohort study was established of injecting drug users (IDUs) to assess evidence for hepatitis C virus (HCV) protective immunity through a comparison of incidence of initial HCV infection and HCV reinfection. Incidence of initial HCV infection was determined among HCV seronegative IDUs, and HCV reinfection determined among IDUs with newly acquired HCV infection, HCV viraemia and subsequent HCV RNA clearance. Serum was available for HCV RNA analysis from stored samples taken at the time of prior blood‐borne virus screening. Potential HCV reinfection was defined as a positive HCV RNA following at least one negative HCV RNA. Incidence of initial HCV infection was 17/100 person‐years (95% CI, 14–20/100 person‐years). The incidence of potential HCV reinfection was 42/100 person‐years (95% CI, 25–61/100 person‐years), and after excluding cases without a change in HCV genotype and less than three consecutive HCV RNA negative assessment, incidence of reinfection was 31/100 person‐years (95% CI, 17–62/100 person‐years). Following adjustment for HCV risk behaviour variables the incidence rate ratio of HCV reinfection to initial infection was 1.11 (P = 0.8). Several cases of HCV reinfection appear to have developed persistent infection.

Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study.

Objective To compare cancer incidence in kidney transplant recipients during periods of transplant function (and immunosuppression) and after transplant failure (when immunosuppression is ceased or reduced). Design, setting, and participants Nationwide, population based retrospective cohort study of 8173 Australian kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry who first received a transplant during 1982-2003. Incident cancers were ascertained using linkage with national cancer registry records. Main outcome measures Cancer-specific standardised incidence ratios for periods of transplant function and for dialysis after transplant failure. Incidence was compared between periods using multivariate incidence rate ratios adjusted for current age, sex, and duration of transplantation. Results All cases of Kaposi’s sarcoma occurred during transplant function. Standardised incidence ratios were significantly elevated during transplant function, but not during dialysis after transplant failure, for non-Hodgkin’s lymphoma, lip cancer, and melanoma. For each of these cancers, incidence was significantly lower during dialysis after transplant failure in multivariate analysis (incidence rate ratios 0.20 (95% CI 0.06 to 0.65) for non-Hodgkin’s lymphoma, 0.04 (0.01 to 0.31) for lip cancer, and 0.16 (0.04 to 0.64) for melanoma). In contrast, standardised incidence ratios during dialysis after transplant failure remained significantly elevated for leukaemia and lung cancer, and cancers related to end stage kidney disease (kidney, urinary tract, and thyroid cancers), with thyroid cancer incidence significantly higher during dialysis after transplant failure (incidence rate ratio 6.77 (2.64 to 17.39)). There was no significant difference in incidence by transplant function for other cancers. Conclusions The effect of immunosuppression on cancer risk is rapidly reversible for some, but not all, cancer types. Risk reversal was mainly observed for cancers with a confirmed infectious cause. Risk of other cancers, especially those related to end stage kidney disease, remained significantly increased after reduction of immunosuppression.