- Email: [email protected]
Incubation period of human prion disease – Author's reply
Correspondence
Finally, since the other transmissible spongiform encephalopathies have very different routes of transmission and hence different infectious loads, no extrapolations about their incubation periods can be made from data on kuru. I declare that I have no conflict of interest.
Daniele Focosi [email protected] Division of Hematology, University of Pisa, 56100 Pisa, Italy 1
2
Collinge J, Whitfield J, McKintosh E, et al. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. Lancet 2006; 367: 2068–74. Gajduzek DC, Zigas V. Degenerative disease of the central nervous system in New guinea: the endemic occurrence of “kuru” in the native population. N Engl J Med 1957; 257: 974–78.
John Collinge and collaborators describe 11 kuru patients with very long incubation periods of at least 34 years, and probably more than 40 years. With 2700 kuru cases altogether, this observation shows that 0·4% of kuru cases incubated for more than 40 years. A comprehensive statistical analysis had earlier reported that the mean incubation period was between 10·3 and 13·2 years, but the tail of the distribution was long.2 Using these estimates, we calculated that the upper 0·4% quantile was 40 years, and even larger for those infected young (>50 years), very much in line with these new observations. So far, all clinical vCJD patients have been methionine homozygous at PRNP codon 129. Current prediction models only apply to those with the same characteristic (roughly 40% of the UK population). Since 2001, there remains very good agreement between observed and predicted cases.3 But the current absence of clinical cases with other genotypes at PRNP codon 129 might simply mean that these patients have longer incubation periods. This raises the possibility of a second wave of vCJD patients, infected at the same time as the homozygous patients but incubating the disease for longer. We reported that the absence 1
914
of such cases by the end of 2004 meant a mean incubation period of longer than 25 years,4 which would lead to an additional 250 clinical cases in the 60% non-methioninehomozygous population. However, if 95% of the population had an incubation period longer than 25 years owing to yet unknown genetic effects, this could amount to 400 more cases. The biggest threat today is from potential asymptomatic infectious carriers of the vCJD agent. Careful surveillance of patients undergoing surgery, transplantation, or blood transfusion is probably the only way to get a direct answer. We declare that we have no conflict of interest.
*Pierre-Yves Boelle, AlainJacques Valleron [email protected] INSERM, Epidemiologie, Systemes d’information, Modelisation, Paris, France (PYB, AJV); Université Pierre et Marie Curie, UMR S-707, Paris, France (PYB, AJV); and Assistance Publique, Hôpitaux de Paris, Paris, France (PYB, AJV). 1
2
3
4
Collinge J, Whitfield J, McKintosh E, et al. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. Lancet 2006; 367: 2068–74. Huillard d’Aignaux JN, Cousens SN, Maccario J, et al. The incubation period of kuru. Epidemiology 2002; 13: 402–08. Valleron AJ, Boelle PY, Will R, Cesbron JY. Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. Science 2001; 294: 1726–28. Valleron AJ, Boëlle PY, Chatignoux E, Cesbron J. Can a second wave of new variant CJD be discarded in absence of observation of clinical non Met-Met cases? Revue d’épidémiologie et de Santé Publique 2006; 54: 111–15.
Author’s reply The epidemiological study of kuru is unusual in that it does not involve sampling but examines the total number of cases.1 We reported cases ascertained between July, 1996, and June, 2004. The incubation periods were established not through statistical modelling but deterministic arguments based on epidemiological, historical, and human behavioural data. Since in the past individuals were exposed many times to infection at mortuary feasts, the incubation period
cannot generally be determined. A measure of the extent of the incubation periods has been possible only since transmission stopped. Those with short incubation periods (especially children) all died before prions were discovered. Thus contemporary comparisons could only be made with healthy controls. However, analysis of previously collected samples enabled Lee and colleagues2 to show that younger patients, with shorter incubation periods, were more likely to be PRNP codon 129 methionine homozygotes. We have also previously reported an excess of codon 129 heterozygosity among elderly survivors with multiple exposures at mortuary feasts.3 The earlier work of Robert Klitzman and colleagues4 was important in establishing that kuru had, in some cases, long incubation periods. Although it might have been suspected, it could not have been determined then that the incubation period occasionally extends beyond 50 years. This has required the evidence obtained from our study. Transmission by parenteral routes through skin or mucosa might well have occurred in a small number of cases of kuru, but the high frequency of subsequent kuru in those who took part in the ritual eating of the body4 and the wide spread of incubation periods suggest that most transmissions occurred through the oral route.5 Furthermore, the oral route is not always inefficient and, in particular, the BSE prion strain is much more efficiently transmitted (including to other species) by the oral route than would have been predicted from study of rodent-adapted scrapie strains used in laboratory studies. The discontinuation of endocannibalism was not arbitrarily assumed, as Daniele Focosi suggests. It was carefully established, based on local knowledge by participant observers, from within and outside the Fore communities. One of us has continued to be a member of such a community for the past 45 years. Nevertheless, we www.thelancet.com Vol 368 September 9, 2006
Correspondence
We declare that we have no conflict of interest.
John Collinge, Michael P Alpers, on behalf of all authors [email protected] MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, UK 1
2
3
4
5
Alpers MP, Kuru Surveillance Team. The epidemiology of kuru in the period 1987 to 1995. Commun Dis Intell 2005; 29: 391–99. Lee HS, Brown P, Cervenáková L, et al. Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype. J Infect Dis 2001; 183: 192–96. Mead S, Stumpf MP, Whitfield J, et al. Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science 2003; 300: 640–43. Klitzman RL, Alpers MP, Gajdusek DC. The natural incubation period of kuru and the episodes of transmission in three clusters of patients. Neuroepidemiology 1984; 3: 3–20. Prusiner SB, Cochran SP, Alpers MP. Transmission of scrapie in hamsters. J Infect Dis 1985; 152: 971–78.
The Trivacan study
*Franco Maggiolo, Diego Ripamonti, Fredy Suter
Christine Danel and colleagues’ Trivacan study (June 17, p 1981)1 raises the question of the meaning of structured treatment interruptions. The word “structured” means that the interruption of treatment is organised within the management strategy of chronic HIV infection and maintains the same goals of active treatment—ie, prevention of disease progression and death. Patients whose immunological status indicates a low risk of disease progression can either continue therapy or interrupt it until their CD4 counts approach a more risky threshold. As is well known and was highlighted by the US Department of Health and Human Services guidelines for HIV therapy2 before the Trivacan study started, the Multicenter AIDS Cohort study3 showed that the 3-year risk of progression to AIDS was 38·5% among patients with CD4 counts of 201–350 cells per μL. Thus to maintain patients’ CD4 counts at between 250 and 350 cells per μL in such a high-risk area as Abidjan can hardly be considered a part of a structured therapeutic design. Other studies of structured treatment interruption have shown that resumption of therapy at higher CD4 thresholds is invariably related to a better outcome.4,5 We therefore think that a treatment interruption strategy with limits of 250–350 CD4 per μL should be discouraged not just in Abidjan or in developing countries, but in the western world as well. We further wonder whether structured treatment interruptions, even with more conservative CD4 limits, are manageable in developing countries. Such strategies are not simple, and require constant and frequent monitoring to be safe. Clinicians with expertise in the management of HIV infection in subSaharan Africa know how difficult it is to do laboratory tests for CD4 and HIVRNA regularly.
[email protected]
We declare that we have no conflict of interest.
www.thelancet.com Vol 368 September 9, 2006
Division of Infectious Diseases, Ospedali Riuniti, 24128 Bergamo, Italy 1
2
3
4
5
Danel C, Moh R, Minga A, et al. CD4guided structured antiretroviral treatment interruption strategy in HIV-infected adults in West Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 2006; 367: 1981–89. Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. http://www.hivatis.org/Guidelines/ GuidelineDetail.aspx?MenuItem=Guidelines&Se arch=Off&GuidelineID=7&ClassID=1 (accessed Aug 21, 2006). Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126: 983–85. International Study Group on CD4-monitored treatment interruptions. CD4 cell-monitored treatment interruptions in patients with a CD4 cell count >500 x 106 cells/L. AIDS 2005; 19: 287–94. Maggiolo F, Ripamonti D, Gregis G, Quinzan G, Callegaro A, Suter F. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. AIDS 2004; 18: 439–46.
We do not have the rights to reproduce this image on the web. Panos Pictures
specifically revisited and re-examined all possible routes of continued exposure and found no evidence that exposure continued after the dates we cite. Had endocannibalism continued undetected, patients born after 1960 would have developed kuru: no such patients have been identified. We do not know how many of the 2700 cases of kuru had long incubation periods, except that it will certainly be more than 11 and will include most of the men in the past and some of the women. The figure we presented of 11 cases of long incubation periods cannot therefore be applied to the whole epidemic as Pierre-Yves Boelle and Alain-Jacques Valleron suggest. We agree that mathematical models need to take into account successive waves of the epidemic and that there are important implications with respect to asymptomatic carriers of vCJD prions who pose a risk of secondary transmission to others. The very long incubation periods predicted by kuru would augment the number of person years of such carriers in the population, who present a risk of secondary transmission even if their own incubation periods exceed their lifespan.
Christine Danel and colleagues1 describe the results of a CD4-guided structured antiretroviral treatment interruption trial in west Africa. A main finding was that severe bacterial infections including bacteraemia were significantly more frequent in the interruption group than the continuous treatment group. Most strains were resistant to the cotrimoxazole given as prophylaxis. Danel and colleagues attribute this finding to the lower CD4 count in the interruption group. One important issue, however, could be the antimicrobial effect of zidovudine, which was part of the nucleoside backbone in this trial. Several studies describe potent bactericidal activity of zidovudine against many Enterobacteriaceae, including strains of Escherichia coli, Salmonella typhimurium, and Shigella spp.2–5 The greater exposure to zidovudine in the continuous treatment group probably reduced the incidence of bacteraemia in these patients2 and contributed to the better outcome of the continuous treatment group. 915
Finally, since the other transmissible spongiform encephalopathies have very different routes of transmission and hence different infectious loads, no extrapolations about their incubation periods can be made from data on kuru. I declare that I have no conflict of interest.
Daniele Focosi [email protected] Division of Hematology, University of Pisa, 56100 Pisa, Italy 1
2
Collinge J, Whitfield J, McKintosh E, et al. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. Lancet 2006; 367: 2068–74. Gajduzek DC, Zigas V. Degenerative disease of the central nervous system in New guinea: the endemic occurrence of “kuru” in the native population. N Engl J Med 1957; 257: 974–78.
John Collinge and collaborators describe 11 kuru patients with very long incubation periods of at least 34 years, and probably more than 40 years. With 2700 kuru cases altogether, this observation shows that 0·4% of kuru cases incubated for more than 40 years. A comprehensive statistical analysis had earlier reported that the mean incubation period was between 10·3 and 13·2 years, but the tail of the distribution was long.2 Using these estimates, we calculated that the upper 0·4% quantile was 40 years, and even larger for those infected young (>50 years), very much in line with these new observations. So far, all clinical vCJD patients have been methionine homozygous at PRNP codon 129. Current prediction models only apply to those with the same characteristic (roughly 40% of the UK population). Since 2001, there remains very good agreement between observed and predicted cases.3 But the current absence of clinical cases with other genotypes at PRNP codon 129 might simply mean that these patients have longer incubation periods. This raises the possibility of a second wave of vCJD patients, infected at the same time as the homozygous patients but incubating the disease for longer. We reported that the absence 1
914
of such cases by the end of 2004 meant a mean incubation period of longer than 25 years,4 which would lead to an additional 250 clinical cases in the 60% non-methioninehomozygous population. However, if 95% of the population had an incubation period longer than 25 years owing to yet unknown genetic effects, this could amount to 400 more cases. The biggest threat today is from potential asymptomatic infectious carriers of the vCJD agent. Careful surveillance of patients undergoing surgery, transplantation, or blood transfusion is probably the only way to get a direct answer. We declare that we have no conflict of interest.
*Pierre-Yves Boelle, AlainJacques Valleron [email protected] INSERM, Epidemiologie, Systemes d’information, Modelisation, Paris, France (PYB, AJV); Université Pierre et Marie Curie, UMR S-707, Paris, France (PYB, AJV); and Assistance Publique, Hôpitaux de Paris, Paris, France (PYB, AJV). 1
2
3
4
Collinge J, Whitfield J, McKintosh E, et al. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. Lancet 2006; 367: 2068–74. Huillard d’Aignaux JN, Cousens SN, Maccario J, et al. The incubation period of kuru. Epidemiology 2002; 13: 402–08. Valleron AJ, Boelle PY, Will R, Cesbron JY. Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. Science 2001; 294: 1726–28. Valleron AJ, Boëlle PY, Chatignoux E, Cesbron J. Can a second wave of new variant CJD be discarded in absence of observation of clinical non Met-Met cases? Revue d’épidémiologie et de Santé Publique 2006; 54: 111–15.
Author’s reply The epidemiological study of kuru is unusual in that it does not involve sampling but examines the total number of cases.1 We reported cases ascertained between July, 1996, and June, 2004. The incubation periods were established not through statistical modelling but deterministic arguments based on epidemiological, historical, and human behavioural data. Since in the past individuals were exposed many times to infection at mortuary feasts, the incubation period
cannot generally be determined. A measure of the extent of the incubation periods has been possible only since transmission stopped. Those with short incubation periods (especially children) all died before prions were discovered. Thus contemporary comparisons could only be made with healthy controls. However, analysis of previously collected samples enabled Lee and colleagues2 to show that younger patients, with shorter incubation periods, were more likely to be PRNP codon 129 methionine homozygotes. We have also previously reported an excess of codon 129 heterozygosity among elderly survivors with multiple exposures at mortuary feasts.3 The earlier work of Robert Klitzman and colleagues4 was important in establishing that kuru had, in some cases, long incubation periods. Although it might have been suspected, it could not have been determined then that the incubation period occasionally extends beyond 50 years. This has required the evidence obtained from our study. Transmission by parenteral routes through skin or mucosa might well have occurred in a small number of cases of kuru, but the high frequency of subsequent kuru in those who took part in the ritual eating of the body4 and the wide spread of incubation periods suggest that most transmissions occurred through the oral route.5 Furthermore, the oral route is not always inefficient and, in particular, the BSE prion strain is much more efficiently transmitted (including to other species) by the oral route than would have been predicted from study of rodent-adapted scrapie strains used in laboratory studies. The discontinuation of endocannibalism was not arbitrarily assumed, as Daniele Focosi suggests. It was carefully established, based on local knowledge by participant observers, from within and outside the Fore communities. One of us has continued to be a member of such a community for the past 45 years. Nevertheless, we www.thelancet.com Vol 368 September 9, 2006
Correspondence
We declare that we have no conflict of interest.
John Collinge, Michael P Alpers, on behalf of all authors [email protected] MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, UK 1
2
3
4
5
Alpers MP, Kuru Surveillance Team. The epidemiology of kuru in the period 1987 to 1995. Commun Dis Intell 2005; 29: 391–99. Lee HS, Brown P, Cervenáková L, et al. Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype. J Infect Dis 2001; 183: 192–96. Mead S, Stumpf MP, Whitfield J, et al. Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science 2003; 300: 640–43. Klitzman RL, Alpers MP, Gajdusek DC. The natural incubation period of kuru and the episodes of transmission in three clusters of patients. Neuroepidemiology 1984; 3: 3–20. Prusiner SB, Cochran SP, Alpers MP. Transmission of scrapie in hamsters. J Infect Dis 1985; 152: 971–78.
The Trivacan study
*Franco Maggiolo, Diego Ripamonti, Fredy Suter
Christine Danel and colleagues’ Trivacan study (June 17, p 1981)1 raises the question of the meaning of structured treatment interruptions. The word “structured” means that the interruption of treatment is organised within the management strategy of chronic HIV infection and maintains the same goals of active treatment—ie, prevention of disease progression and death. Patients whose immunological status indicates a low risk of disease progression can either continue therapy or interrupt it until their CD4 counts approach a more risky threshold. As is well known and was highlighted by the US Department of Health and Human Services guidelines for HIV therapy2 before the Trivacan study started, the Multicenter AIDS Cohort study3 showed that the 3-year risk of progression to AIDS was 38·5% among patients with CD4 counts of 201–350 cells per μL. Thus to maintain patients’ CD4 counts at between 250 and 350 cells per μL in such a high-risk area as Abidjan can hardly be considered a part of a structured therapeutic design. Other studies of structured treatment interruption have shown that resumption of therapy at higher CD4 thresholds is invariably related to a better outcome.4,5 We therefore think that a treatment interruption strategy with limits of 250–350 CD4 per μL should be discouraged not just in Abidjan or in developing countries, but in the western world as well. We further wonder whether structured treatment interruptions, even with more conservative CD4 limits, are manageable in developing countries. Such strategies are not simple, and require constant and frequent monitoring to be safe. Clinicians with expertise in the management of HIV infection in subSaharan Africa know how difficult it is to do laboratory tests for CD4 and HIVRNA regularly.
[email protected]
We declare that we have no conflict of interest.
www.thelancet.com Vol 368 September 9, 2006
Division of Infectious Diseases, Ospedali Riuniti, 24128 Bergamo, Italy 1
2
3
4
5
Danel C, Moh R, Minga A, et al. CD4guided structured antiretroviral treatment interruption strategy in HIV-infected adults in West Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 2006; 367: 1981–89. Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. http://www.hivatis.org/Guidelines/ GuidelineDetail.aspx?MenuItem=Guidelines&Se arch=Off&GuidelineID=7&ClassID=1 (accessed Aug 21, 2006). Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126: 983–85. International Study Group on CD4-monitored treatment interruptions. CD4 cell-monitored treatment interruptions in patients with a CD4 cell count >500 x 106 cells/L. AIDS 2005; 19: 287–94. Maggiolo F, Ripamonti D, Gregis G, Quinzan G, Callegaro A, Suter F. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. AIDS 2004; 18: 439–46.
We do not have the rights to reproduce this image on the web. Panos Pictures
specifically revisited and re-examined all possible routes of continued exposure and found no evidence that exposure continued after the dates we cite. Had endocannibalism continued undetected, patients born after 1960 would have developed kuru: no such patients have been identified. We do not know how many of the 2700 cases of kuru had long incubation periods, except that it will certainly be more than 11 and will include most of the men in the past and some of the women. The figure we presented of 11 cases of long incubation periods cannot therefore be applied to the whole epidemic as Pierre-Yves Boelle and Alain-Jacques Valleron suggest. We agree that mathematical models need to take into account successive waves of the epidemic and that there are important implications with respect to asymptomatic carriers of vCJD prions who pose a risk of secondary transmission to others. The very long incubation periods predicted by kuru would augment the number of person years of such carriers in the population, who present a risk of secondary transmission even if their own incubation periods exceed their lifespan.
Christine Danel and colleagues1 describe the results of a CD4-guided structured antiretroviral treatment interruption trial in west Africa. A main finding was that severe bacterial infections including bacteraemia were significantly more frequent in the interruption group than the continuous treatment group. Most strains were resistant to the cotrimoxazole given as prophylaxis. Danel and colleagues attribute this finding to the lower CD4 count in the interruption group. One important issue, however, could be the antimicrobial effect of zidovudine, which was part of the nucleoside backbone in this trial. Several studies describe potent bactericidal activity of zidovudine against many Enterobacteriaceae, including strains of Escherichia coli, Salmonella typhimurium, and Shigella spp.2–5 The greater exposure to zidovudine in the continuous treatment group probably reduced the incidence of bacteraemia in these patients2 and contributed to the better outcome of the continuous treatment group. 915