Trends in AIDS and Mortality in HIV-Infected Subjects With Hemophilia From 1985 to 2003: The Competing Risks for Death Between AIDS and Liver Disease

Objective: To study trends in progression to AIDS, all-cause mortality, and cause-specific mortality (AIDS-related, liver disease, and hemorrhagic complications) over calendar periods with different exposure to highly active antiretroviral therapy (HAART) in a cohort of hemophiliacs in Spain, taking into account the competing risks of the causes of death. Methods: Multicenter cohort of HIV-infected hemophiliacs. HIV seroconversion was estimated using mathematic techniques for interval-censored data from 1979 through 1985. Rates of AIDS and cause-specific death were calculated by Poisson regression, allowing for late entry, for the periods 1985 through 1992, 1993 through 1996, 1997 through 2000 (early HAART), and 2001 through 2003 (late HAART), also allowing for competing risks. Results: Of 585 subjects, 44% were younger than 15 years of age, 82% had severe hemophilia, 86% had type A hemophilia, and the median seroconversion date was October 1982. Calendar period and age at HIV seroconversion strongly influenced AIDS and death rates. Compared with 1993 through 1996, decreases of 75% (relative risk [RR] = 0.25, 95% confidence interval [CI]: 0.14 to 0.43) and 72% (RR = 0.28, 95% CI: 0.12 to 0.63) in the RR of AIDS were observed in early and late HAART. For all-cause mortality, 72% (RR = 0.28, 95% CI: 0.18 to 0.42) and 83% (RR = 0.17, 95% CI: 0.09 to 0.33) decreases were observed by 1997 through 2000 and 2001 through 2003. For liver-related deaths, increases were observed in the late-HAART period (RR = 2.80, 95% CI: 0.94 to 8.36) compared with 1993 through 1996, but using competing risks, this RR was substantially reduced (RR = 1.70, 95% CI: 0.57 to 5.04). Discussion: Major reductions in AIDS and death rates were observed from 1997 to 2003 in hemophiliacs. These survival improvements are largely attributable to decreases in AIDS-related deaths and have been accompanied by increases in liver disease death rates, which are overestimated if competing risks are not taken into account.

[1]  Roel A. Coutinho,et al.  Time from HIV-1 seroconversion to Aids and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis: collaborative Group on Aids incubation and HIV survival including the CASCADE EU concerted action , 2000 .

[2]  Anne M Johnson,et al.  Changes over calendar time in the risk of specific first AIDS-defining events following HIV seroconversion, adjusting for competing risks. , 2002, International journal of epidemiology.

[3]  Hiv Survival,et al.  Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis , 2000, The Lancet.

[4]  I. Hernández-Aguado.  El período de incubación del sida en España antes de la terapia antirretroviral de alta eficacia , 2000 .

[5]  J. Julian,et al.  Causes of death in Canadians with haemophilia 1980–1995 , 1998, Haemophilia : the official journal of the World Federation of Hemophilia.

[6]  J. M. Cisneros,et al.  Imputación del instante de seroconversión al VIH en cohortes de hemofílicos , 2003 .

[7]  G. Dusheiko,et al.  The natural history and antiviral treatment of hepatitis C in haemophilia , 2002, Haemophilia : the official journal of the World Federation of Hemophilia.

[8]  S. Darby,et al.  The impact of HIV on mortality rates in the complete UK haemophilia population , 2004, AIDS.

[9]  G. Lüchters,et al.  Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection , 2003, The Lancet.

[10]  C. Sabin,et al.  Pre-AIDS mortality and its association with HIV disease progression in haemophilic men, injecting drug users and homosexual men , 2000, AIDS.

[11]  J. Goedert,et al.  Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. , 1993, Journal of acquired immune deficiency syndromes.

[12]  J. Goedert,et al.  End-stage liver disease in persons with hemophilia and transfusion-associated infections. , 2002, Blood.

[13]  James J. Goedert,et al.  Effect of age at seroconversion on the natural AIDS incubation distribution , 1994, AIDS.

[14]  S. Darby,et al.  Mortality before and after HIV infection in the complete UK population of haemophiliacs , 1995, Nature.

[15]  R. Holman,et al.  Effects of HIV infection on age and cause of death for persons with hemophilia A in the United States , 2001, American journal of hematology.

[16]  M. T. Paixão,et al.  Expanded European AIDS case definition , 1993, The Lancet.

[17]  S. Pérez-Hoyos,et al.  Progression of HIV infection and mortality by hepatitis C infection in patients with haemophilia over 20 years , 2003, Haemophilia : the official journal of the World Federation of Hemophilia.

[18]  P. Morlat,et al.  Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. , 2005, Journal of hepatology.

[19]  V. Soriano,et al.  Impact of chronic liver disease due to hepatitis viruses as cause of hospital admission and death in HIV-infected drug users , 2004, European Journal of Epidemiology.

[20]  S. Belle,et al.  Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C virus infection. , 2001, The Journal of infectious diseases.

[21]  J. Goedert,et al.  Natural history of human immunodeficiency virus infections in hemophiliacs: effects of T-cell subsets, platelet counts, and age. , 1987, Annals of internal medicine.

[22]  A. Hatzakis,et al.  Determinants of progression of HIV infection in a Greek hemophilia cohort followed for up to 16 years after seroconversion. , 1998, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[23]  A. Phillips,et al.  Progression of HIV disease in a haemophilic cohort followed for 11 years and the effect of treatment. , 1991, BMJ.

[24]  S. Darby,et al.  Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C , 1997, The Lancet.

[25]  C. Sabin,et al.  Two decades of HIV infection in a cohort of haemophilic individuals: clinical outcomes and response to highly active antiretroviral therapy , 2000, AIDS.

[26]  J. Vandenbroucke,et al.  Mortality and causes of death in Dutch haemophiliacs, 1973–86 , 1989, British journal of haematology.

[27]  M. Colombo,et al.  Hepatitis C in haemophilia: lights and shadows , 2004, Haemophilia : the official journal of the World Federation of Hemophilia.

[28]  J. Goedert,et al.  Factors predictive of death among HIV‐uninfected persons with haemophilia and other congenital coagulation disorders , 2002, Haemophilia : the official journal of the World Federation of Hemophilia.

[29]  C. Rizza,et al.  Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population , 1996, The Lancet.

[30]  A. Phillips,et al.  The practical significance of potential biases in estimates of the AIDS incubation period distribution in the UK register of HIV seroconverters. , 1999, AIDS.

[31]  S. Suissa,et al.  The impact of hepatitis C virus coinfection on HIV progression before and after highly active antiretroviral therapy. , 2003, Journal of acquired immune deficiency syndromes.