- Email: [email protected]
HCV coinfection
CORRESPONDENCE
Authors’ reply Sir—Julia del Amo and colleagues and Philippe Guardiola address potential sources of bias that could have affected our analysis of liver-related mortality in HIV-infected patients. del Amo and colleagues are correct that our haemophiliac patients had become infected between 1982 and 1985, so that our cohort was enriched with long-term non-progressors during the 1990–2002 observation period of our study. However, long-term nonprogressors were not preferentially allocated to the HAART-treated group and could not have therefore contributed to the lower liver-related and overall mortality seen in this group. This fact can be illustrated by analysis of survival in the subgroup of patients who had actually been alive at the beginning of the HAART era (figure). At entry into the HAART era, patients receiving HAART had significantly lower CD4 counts than those who did not receive HAART during their further follow-up (median 190 cells per L vs 385 cells per L, p<0·01), indicating an increased a-priori mortality risk for patients in the HAART group. Thus, the type of bias addressed by del Amo and colleagues seems to have acted against any beneficial effects of HAART in our study. We agree with Guardiola that our study reflects a competing-risk situation, for which alternative statistical approaches have been developed. However, the difference between
Kaplan-Meier analysis and competingrisk approaches is greatest when deaths from competing causes are particularly prevalent.1 For our analysis, however, there exists circumstantial evidence to suggest that the risk of dying from causes other than liver disease is greatly diminished in HAART-treated patients.2–5 Thus, the a-priori risk of dying from liver disease increases in HAART-treated patients, potentially counteracting beneficial effects of HAART on liver-related survival. In this situation we judged the conservative approach with Kaplan-Meier analysis and Cox’s regression modelling to be appropriate, since we assumed it would underestimate rather than overestimate the effects of HAART on liver-related mortality. However, it might be worthwhile reanalysing our observational data with a competing-risk approach as outlined by Guardiola to learn more about the actual differences in statistical estimates between Kaplan-Meier analysis and competing-risk models when such models are applied to a situation in which competing risks are more decreased by treatment than the risk of interest. *Nazifa Qurishi, Tilman Sauerbruch, Jürgen Rockstroh, Ulrich Spengler Medizinische Klinik und Poliklinik I, 53105 Bonn, Germany (e-mail: [email protected]) 1
Alberti C, Métivier F, Landais P, Therver E, Legendre C, Chevret S. Improving estimates of event incidence over time in populations exposed to other events: application to three large databases. J Clin Epidemiol 2003; 56: 536–45.
1·1
Cumulative survival
p=0·045
1·0 HAART
No HAART
0·9
0·8 1000
0
2000
3000
Observation time in the HAART era (days) Number of patients under observation HAART No HAART
94 102
93
93
92
97
96
94
Liver-related mortality for HIV/HCV-infected patients who had survived until beginning of HAART era (Jan 1, 1996) Vertical bars indicate number of patients censored—ie, those who were lost to follow-up or those who died from other causes.
2
3
4
5
Puoti M, Spinetti A, Donato F, et al. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr 2000; 24: 211–17. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32: 492–97. Cacoub P, Geffray L, Rosenthal E, Peronne C, Veyssier P, Raguin G. Mortality among human immunodeficiency virusinfected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French Departments of Internal Medicine/Infectious Diseases, in 1995 and 1997. Clin Infect Dis 2001; 32: 1207–14. Martin-Carbonero L, Soriano V, Valencia E, Garcia-Samaniego J, López M, González-Lahoz J. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res Hum Retroviruses 2001; 17: 1467–71.
Availability of SARS information in Japan Sir—In their Correspondence letter (Dec 13, p 2026),1 Akira Ehara and Tatsuhito Tono-oka criticise the Japanese Ministry of Health, Labour, and Welfare (MHLW) for providing insufficient information during the outbreak of severe acute respiratory syndrome (SARS), and suggest that such actions hindered local-level SARS prevention. However, their arguments seem to be based on inaccurate assumptions about the MHLW’s measures for SARS. Although the MHLW established the original definition for confirmed SARS cases as stated in Ehara and Tono-oka’s letter, probable cases and suspected cases based on the WHO definition were also reported to the MHLW. Information on all cases, totalling 16 probable cases and 52 suspected cases, was made available to the public through our website and the mass media within a working day of being received. Furthermore, the MHLW’s specialist committee on SARS examined all reported cases to judge the possibility of SARS, and the conclusions were also announced promptly with the relevant explanation. The MHLW released only partial information, such as number of cases and their conditions, because of privacy issues. However, we think that our cautious attitude could not have affected local-level activities to prevent SARS because responsible health centres appropriately coped with the reported cases, gathering enough information from physicians in charge, patients, and other related people. Additionally, the MHLW made all
THE LANCET • Vol 363 • February 14, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
571
Authors’ reply Sir—Julia del Amo and colleagues and Philippe Guardiola address potential sources of bias that could have affected our analysis of liver-related mortality in HIV-infected patients. del Amo and colleagues are correct that our haemophiliac patients had become infected between 1982 and 1985, so that our cohort was enriched with long-term non-progressors during the 1990–2002 observation period of our study. However, long-term nonprogressors were not preferentially allocated to the HAART-treated group and could not have therefore contributed to the lower liver-related and overall mortality seen in this group. This fact can be illustrated by analysis of survival in the subgroup of patients who had actually been alive at the beginning of the HAART era (figure). At entry into the HAART era, patients receiving HAART had significantly lower CD4 counts than those who did not receive HAART during their further follow-up (median 190 cells per L vs 385 cells per L, p<0·01), indicating an increased a-priori mortality risk for patients in the HAART group. Thus, the type of bias addressed by del Amo and colleagues seems to have acted against any beneficial effects of HAART in our study. We agree with Guardiola that our study reflects a competing-risk situation, for which alternative statistical approaches have been developed. However, the difference between
Kaplan-Meier analysis and competingrisk approaches is greatest when deaths from competing causes are particularly prevalent.1 For our analysis, however, there exists circumstantial evidence to suggest that the risk of dying from causes other than liver disease is greatly diminished in HAART-treated patients.2–5 Thus, the a-priori risk of dying from liver disease increases in HAART-treated patients, potentially counteracting beneficial effects of HAART on liver-related survival. In this situation we judged the conservative approach with Kaplan-Meier analysis and Cox’s regression modelling to be appropriate, since we assumed it would underestimate rather than overestimate the effects of HAART on liver-related mortality. However, it might be worthwhile reanalysing our observational data with a competing-risk approach as outlined by Guardiola to learn more about the actual differences in statistical estimates between Kaplan-Meier analysis and competing-risk models when such models are applied to a situation in which competing risks are more decreased by treatment than the risk of interest. *Nazifa Qurishi, Tilman Sauerbruch, Jürgen Rockstroh, Ulrich Spengler Medizinische Klinik und Poliklinik I, 53105 Bonn, Germany (e-mail: [email protected]) 1
Alberti C, Métivier F, Landais P, Therver E, Legendre C, Chevret S. Improving estimates of event incidence over time in populations exposed to other events: application to three large databases. J Clin Epidemiol 2003; 56: 536–45.
1·1
Cumulative survival
p=0·045
1·0 HAART
No HAART
0·9
0·8 1000
0
2000
3000
Observation time in the HAART era (days) Number of patients under observation HAART No HAART
94 102
93
93
92
97
96
94
Liver-related mortality for HIV/HCV-infected patients who had survived until beginning of HAART era (Jan 1, 1996) Vertical bars indicate number of patients censored—ie, those who were lost to follow-up or those who died from other causes.
2
3
4
5
Puoti M, Spinetti A, Donato F, et al. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr 2000; 24: 211–17. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32: 492–97. Cacoub P, Geffray L, Rosenthal E, Peronne C, Veyssier P, Raguin G. Mortality among human immunodeficiency virusinfected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French Departments of Internal Medicine/Infectious Diseases, in 1995 and 1997. Clin Infect Dis 2001; 32: 1207–14. Martin-Carbonero L, Soriano V, Valencia E, Garcia-Samaniego J, López M, González-Lahoz J. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res Hum Retroviruses 2001; 17: 1467–71.
Availability of SARS information in Japan Sir—In their Correspondence letter (Dec 13, p 2026),1 Akira Ehara and Tatsuhito Tono-oka criticise the Japanese Ministry of Health, Labour, and Welfare (MHLW) for providing insufficient information during the outbreak of severe acute respiratory syndrome (SARS), and suggest that such actions hindered local-level SARS prevention. However, their arguments seem to be based on inaccurate assumptions about the MHLW’s measures for SARS. Although the MHLW established the original definition for confirmed SARS cases as stated in Ehara and Tono-oka’s letter, probable cases and suspected cases based on the WHO definition were also reported to the MHLW. Information on all cases, totalling 16 probable cases and 52 suspected cases, was made available to the public through our website and the mass media within a working day of being received. Furthermore, the MHLW’s specialist committee on SARS examined all reported cases to judge the possibility of SARS, and the conclusions were also announced promptly with the relevant explanation. The MHLW released only partial information, such as number of cases and their conditions, because of privacy issues. However, we think that our cautious attitude could not have affected local-level activities to prevent SARS because responsible health centres appropriately coped with the reported cases, gathering enough information from physicians in charge, patients, and other related people. Additionally, the MHLW made all
THE LANCET • Vol 363 • February 14, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
571