- Email: [email protected]
Syphilis, still a major cause of infant mortality
Comment
the deleterious immune activation associated with the disease.2,4,6 A recent study by Murray and colleagues6 showed that chloroquine significantly decreased expression of CD38 (a marker of treatment failure and progression to AIDS, which is associated with immune activation induced by viral replication) on CD8 T cells10 and induced downmodulation of Ki67 (a marker associated with immune-activation-induced lymphocyte mitosis) on memory T cells;11 in-vitro and in-vivo anti-inflammatory effects were in good agreement. One reason behind this agreement is suggested by a recent study of hydroxychloroquine,12 which showed that the drug accumulates at high concentrations in lymphoid tissues of patients infected with HIV. These reproducible in-vivo effects of quionoline antimalarials could be used as, or added to, new strategies for restricting the HIV reservoir, which are aimed at counteracting the residual immune activation during antiretroviral therapy (favouring sustained viral replication in anatomic sanctuaries), and targeting activation or proliferation of central and transitional memory T cells harbouring silent copies of the HIV proviral DNA (contributing to maintenance of the virus’s genome during treatment).11 Notwithstanding the poor efficacy of chloroquine for influenza prevention, the results reported by Paton and colleagues1 will help to address the process of drug repositioning for treatment of infectious diseases.
Andrea Savarino Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy [email protected] I declare that I have no conflicts of interest. 1
2
3
4
5
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8 9
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Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011; published online May 6. DOI:10.1016/S1473-3099(11)70065-2. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis 2003; 3: 722–27. Keyaerts E, Li S, Vijgen L, et al. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 2009; 53: 3416–21. Sperber K, Louie M, Kraus T, et al. Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1. Clin Ther 1995; 17: 622–36. Sperber K, Chiang G, Chen H, et al. Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with human immunodeficiency virus type 1. Clin Ther 1997; 19: 913–23. Murray SM, Down CM, Boulware DR, et al. Reduction of immune activation with chloroquine therapy during chronic HIV infection. J Virol 2010; 84: 12082–86. Di Trani L, Savarino A, Campitelli L, et al. Different pH requirements are associated with divergent inhibitory effects of chloroquine on human and avian influenza A viruses. Virol J 2007; 4: 39. Vezmar M, Georges E. Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs. Biochem Pharmacol 2000; 59: 1245–52. Saladino R, Barontini M, Crucianelli M, Nencioni L, Sgarbanti R, Palamara AT. Current advances in anti-influenza therapy. Curr Med Chem 2010; 17: 2101–40. Savarino A, Bottarel F, Malavasi F, Dianzani U. Role of CD38 in HIV-1 infection: an epiphenomenon of T-cell activation or an active player in virus/host interactions? AIDS 2000; 14: 1079–89. Chomont N, DaFonseca S, Vandergeeten C, Ancuta P, Sékaly RP. Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. Curr Opin HIV AIDS 2011; 6: 30–36. Aguirre-Cruz L, Torres KJ, Jung-Cook H, et al. Preferential concentration of hydroxychloroquine in adenoid tissue of HIV-infected subjects. AIDS Res Hum Retroviruses 2010; 26: 339–42.
Syphilis, still a major cause of infant mortality Published Online June 16, 2011 DOI:10.1016/S14733099(11)70150-5 See Online/Articles DOI:10.1016/S14733099(11)70104-9
654
In The Lancet Infectious Diseases today, Sarah Hawkes and colleagues1 review the effect of interventions to increase the coverage of screening and treatment for syphilis in pregnancy on the uptake of testing and treatment, and on adverse pregnancy outcomes averted. This study is a timely reminder that syphilis has not disappeared, and remains a major, although entirely preventable, cause of death in newborn babies. Syphilis is estimated to be responsible for almost 500 000 perinatal deaths per year in sub-Saharan Africa alone.2 Many of these are stillbirths, which have been largely ignored by the global-health community. They are rarely counted, are not included in national statistics, or in estimates of the global burden of disease, and are not mentioned in the Millennium Development Goals
(MDGs). The Lancet’s Stillbirths Series is a welcome attempt to redress the balance. Lawn and colleagues3 estimated that 2·65 million stillbirths occur annually, 98% of them in developing countries. In northern Tanzania, 51% of stillbirths in women who had not been screened for syphilis during pregnancy could be attributed to syphilis after adjustment for other possible causes.4 In live born infants, most deaths from syphilis occur in the first weeks of life. As many countries make progress towards achieving MDG 4—to reduce mortality by two thirds in children younger than 5 years—neonatal mortality (in the first 4 weeks of life) remains high, now accounting for some 40% of the total mortality. Early neonatal mortality (in the first week of life) has been a www.thelancet.com/infection Vol 11 September 2011
Comment
particularly intractable issue5 and could be improved by screening and treatment of all pregnant women. If all pregnant women were screened, and those who tested positive were treated with one dose of benzathine penicillin before 28 weeks’ gestation, no stillbirths or neonatal deaths would be due to syphilis. This is one of the most cost-effective health interventions. In Tanzania, the cost was $1·44 per woman screened, $20 per woman treated, and $10·56 per disabilityadjusted life year (DALY) saved, if the stillbirths averted were included in the calculation.6,7 Screening of pregnant women for syphilis is recommended in nearly all countries, but is not widely implemented. In Tanzania, less than half of women attending antenatal clinics are screened for syphilis, and less than two thirds of those testing positive receive treatment.8 These figures are not unusual in sub-Saharan Africa, where access to laboratory testing is often poor, especially in rural areas.9 The rapid-plasma-reagin serological test is cheap, and can give a result in 10 min; but it requires electricity. Many rural health facilities can’t offer this test. In facilities where it is available, samples are usually tested in batches, and many women do not come back for their results. Several of the studies reviewed by Hawkes and colleagues1 showed that offering a decentralised, sameday testing and treatment service increased the coverage of screening and treatment. Simple, affordable pointof-care tests for syphilis have recently become available. These tests do not need laboratory equipment or refrigeration, and give a reliable result in 15 min, greatly facilitating the provision of a same-day testing and treatment strategy in even the most remote rural health facilities.10 These tests can be done on the same drop of blood as an HIV rapid test, offering an opportunity to integrate prenatal screening for these two infections and hence to reduce costs and to avoid the tragedy of babies avoiding HIV infection only to die of syphilis.11 The perception among many public health experts, programme managers, and policy makers that syphilis has disappeared has probably been the greatest barrier to prevent syphilis deaths in babies. If you don’t test for it, you don’t find it, which reinforces the impression that it is no longer an issue. Conclusions from systematic reviews12,13 using the rigid criteria laid down by the Cochrane and Child Epidemiology Research Group (CHERG) guidelines were that no good evidence that the treatment of syphilis in pregnant women improved pregnancy outcome existed, www.thelancet.com/infection Vol 11 September 2011
since no randomised trials showed it to be beneficial. This is hardly surprising, since it would not be ethical to do such trials when the evidence of benefit from observational studies is so overwhelmingly strong; but the real danger is that these reviews could convince policy makers and programme managers that ignoring syphilis is justified. This systematic review1 will remind policy makers that syphilis continues to kill many babies, and will show them how this needless burden of disease can be reduced. David Mabey and Rosanna W Peeling Clinical Research Department, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK (DM, RWP) [email protected] We declare that we have no conflicts of interest 1
2 3
4
5 6
7
8
9 10
11 12 13
Hawkes S, Matin N, Broutet N, Low N. Effectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis. Lancet Infect Dis 2011; published online June 16. DOI:10.1016/S1473-3099(11)70104-9. Schmid G. Economic and programmatic aspects of congenital syphilis prevention. Bull World Health Organ 2004; 82: 402–09. Lawn JE, Blencowe H, Pattinson R, et al, Lancet’s Stillbirths Series steering committee. Stillbirths: Where? When? Why? How to make the data count? Lancet 2011; 377: 1448–63. Watson-Jones D, Changalucha J, Gumodoka B, et al. Syphilis in pregnancy in Tanzania. I. Impact of maternal syphilis on outcome of pregnancy. J Infect Dis 2002; 186: 940–47. Lawn JE, Cousens S, Zupan J, for the Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: When? Where? Why? Lancet 2005; 365: 891–900 Watson-Jones D, Gumodoka B, et al. Syphilis in pregnancy in Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J Infect Dis 2002; 186: 948–57. Terris-Prestholt F, Watson-Jones D, Mugeye K, et al. Is antenatal syphilis screening still cost effective in sub-Saharan Africa. Sex Transm Infect 2003; 79: 375–81. Watson-Jones D, Oliff M, Terris-Prestholt F, et al. Antenatal syphilis screening in sub-Saharan Africa: lessons learned from Tanzania. Trop Med Int Health 2005; 10: 934–43. Gloyd S, Chai S, Mercer MA. Antenatal syphilis in sub-Saharan Africa: missed opportunities for mortality reduction. Health Policy Plan 2001; 16: 29–34. Mabey D, Peeling RW, Ballard R, et al. Prospective, multi-centre clinic-based evaluation of four rapid diagnostic tests for syphilis. Sex Transm Infect 2006; 82 (suppl 5): v13–16. Peeling RW, Mabey D, Fitzgerald DW, Watson-Jones D. Avoiding HIV and dying of syphilis. Lancet 2004; 364: 1561–66. Walker GJ. Antibiotics for syphilis diagnosed during pregnancy. Cochrane Database Syst Rev 2001; 3: CD001143. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives saved tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health 2011; 11 (suppl 3): S9.
Erratum Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011; published online May 6. DOI:10.1016/S1473-3099(11)70065-2—In this Article, a hyphen was missing from an author’s surname. Her correct name is Annelies Wilder-Smith. This correction has been made to the online version as of Aug 22, 2011, and to the printed Article.
655
the deleterious immune activation associated with the disease.2,4,6 A recent study by Murray and colleagues6 showed that chloroquine significantly decreased expression of CD38 (a marker of treatment failure and progression to AIDS, which is associated with immune activation induced by viral replication) on CD8 T cells10 and induced downmodulation of Ki67 (a marker associated with immune-activation-induced lymphocyte mitosis) on memory T cells;11 in-vitro and in-vivo anti-inflammatory effects were in good agreement. One reason behind this agreement is suggested by a recent study of hydroxychloroquine,12 which showed that the drug accumulates at high concentrations in lymphoid tissues of patients infected with HIV. These reproducible in-vivo effects of quionoline antimalarials could be used as, or added to, new strategies for restricting the HIV reservoir, which are aimed at counteracting the residual immune activation during antiretroviral therapy (favouring sustained viral replication in anatomic sanctuaries), and targeting activation or proliferation of central and transitional memory T cells harbouring silent copies of the HIV proviral DNA (contributing to maintenance of the virus’s genome during treatment).11 Notwithstanding the poor efficacy of chloroquine for influenza prevention, the results reported by Paton and colleagues1 will help to address the process of drug repositioning for treatment of infectious diseases.
Andrea Savarino Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy [email protected] I declare that I have no conflicts of interest. 1
2
3
4
5
6
7
8 9
10
11
12
Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011; published online May 6. DOI:10.1016/S1473-3099(11)70065-2. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis 2003; 3: 722–27. Keyaerts E, Li S, Vijgen L, et al. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 2009; 53: 3416–21. Sperber K, Louie M, Kraus T, et al. Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1. Clin Ther 1995; 17: 622–36. Sperber K, Chiang G, Chen H, et al. Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with human immunodeficiency virus type 1. Clin Ther 1997; 19: 913–23. Murray SM, Down CM, Boulware DR, et al. Reduction of immune activation with chloroquine therapy during chronic HIV infection. J Virol 2010; 84: 12082–86. Di Trani L, Savarino A, Campitelli L, et al. Different pH requirements are associated with divergent inhibitory effects of chloroquine on human and avian influenza A viruses. Virol J 2007; 4: 39. Vezmar M, Georges E. Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs. Biochem Pharmacol 2000; 59: 1245–52. Saladino R, Barontini M, Crucianelli M, Nencioni L, Sgarbanti R, Palamara AT. Current advances in anti-influenza therapy. Curr Med Chem 2010; 17: 2101–40. Savarino A, Bottarel F, Malavasi F, Dianzani U. Role of CD38 in HIV-1 infection: an epiphenomenon of T-cell activation or an active player in virus/host interactions? AIDS 2000; 14: 1079–89. Chomont N, DaFonseca S, Vandergeeten C, Ancuta P, Sékaly RP. Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. Curr Opin HIV AIDS 2011; 6: 30–36. Aguirre-Cruz L, Torres KJ, Jung-Cook H, et al. Preferential concentration of hydroxychloroquine in adenoid tissue of HIV-infected subjects. AIDS Res Hum Retroviruses 2010; 26: 339–42.
Syphilis, still a major cause of infant mortality Published Online June 16, 2011 DOI:10.1016/S14733099(11)70150-5 See Online/Articles DOI:10.1016/S14733099(11)70104-9
654
In The Lancet Infectious Diseases today, Sarah Hawkes and colleagues1 review the effect of interventions to increase the coverage of screening and treatment for syphilis in pregnancy on the uptake of testing and treatment, and on adverse pregnancy outcomes averted. This study is a timely reminder that syphilis has not disappeared, and remains a major, although entirely preventable, cause of death in newborn babies. Syphilis is estimated to be responsible for almost 500 000 perinatal deaths per year in sub-Saharan Africa alone.2 Many of these are stillbirths, which have been largely ignored by the global-health community. They are rarely counted, are not included in national statistics, or in estimates of the global burden of disease, and are not mentioned in the Millennium Development Goals
(MDGs). The Lancet’s Stillbirths Series is a welcome attempt to redress the balance. Lawn and colleagues3 estimated that 2·65 million stillbirths occur annually, 98% of them in developing countries. In northern Tanzania, 51% of stillbirths in women who had not been screened for syphilis during pregnancy could be attributed to syphilis after adjustment for other possible causes.4 In live born infants, most deaths from syphilis occur in the first weeks of life. As many countries make progress towards achieving MDG 4—to reduce mortality by two thirds in children younger than 5 years—neonatal mortality (in the first 4 weeks of life) remains high, now accounting for some 40% of the total mortality. Early neonatal mortality (in the first week of life) has been a www.thelancet.com/infection Vol 11 September 2011
Comment
particularly intractable issue5 and could be improved by screening and treatment of all pregnant women. If all pregnant women were screened, and those who tested positive were treated with one dose of benzathine penicillin before 28 weeks’ gestation, no stillbirths or neonatal deaths would be due to syphilis. This is one of the most cost-effective health interventions. In Tanzania, the cost was $1·44 per woman screened, $20 per woman treated, and $10·56 per disabilityadjusted life year (DALY) saved, if the stillbirths averted were included in the calculation.6,7 Screening of pregnant women for syphilis is recommended in nearly all countries, but is not widely implemented. In Tanzania, less than half of women attending antenatal clinics are screened for syphilis, and less than two thirds of those testing positive receive treatment.8 These figures are not unusual in sub-Saharan Africa, where access to laboratory testing is often poor, especially in rural areas.9 The rapid-plasma-reagin serological test is cheap, and can give a result in 10 min; but it requires electricity. Many rural health facilities can’t offer this test. In facilities where it is available, samples are usually tested in batches, and many women do not come back for their results. Several of the studies reviewed by Hawkes and colleagues1 showed that offering a decentralised, sameday testing and treatment service increased the coverage of screening and treatment. Simple, affordable pointof-care tests for syphilis have recently become available. These tests do not need laboratory equipment or refrigeration, and give a reliable result in 15 min, greatly facilitating the provision of a same-day testing and treatment strategy in even the most remote rural health facilities.10 These tests can be done on the same drop of blood as an HIV rapid test, offering an opportunity to integrate prenatal screening for these two infections and hence to reduce costs and to avoid the tragedy of babies avoiding HIV infection only to die of syphilis.11 The perception among many public health experts, programme managers, and policy makers that syphilis has disappeared has probably been the greatest barrier to prevent syphilis deaths in babies. If you don’t test for it, you don’t find it, which reinforces the impression that it is no longer an issue. Conclusions from systematic reviews12,13 using the rigid criteria laid down by the Cochrane and Child Epidemiology Research Group (CHERG) guidelines were that no good evidence that the treatment of syphilis in pregnant women improved pregnancy outcome existed, www.thelancet.com/infection Vol 11 September 2011
since no randomised trials showed it to be beneficial. This is hardly surprising, since it would not be ethical to do such trials when the evidence of benefit from observational studies is so overwhelmingly strong; but the real danger is that these reviews could convince policy makers and programme managers that ignoring syphilis is justified. This systematic review1 will remind policy makers that syphilis continues to kill many babies, and will show them how this needless burden of disease can be reduced. David Mabey and Rosanna W Peeling Clinical Research Department, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK (DM, RWP) [email protected] We declare that we have no conflicts of interest 1
2 3
4
5 6
7
8
9 10
11 12 13
Hawkes S, Matin N, Broutet N, Low N. Effectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis. Lancet Infect Dis 2011; published online June 16. DOI:10.1016/S1473-3099(11)70104-9. Schmid G. Economic and programmatic aspects of congenital syphilis prevention. Bull World Health Organ 2004; 82: 402–09. Lawn JE, Blencowe H, Pattinson R, et al, Lancet’s Stillbirths Series steering committee. Stillbirths: Where? When? Why? How to make the data count? Lancet 2011; 377: 1448–63. Watson-Jones D, Changalucha J, Gumodoka B, et al. Syphilis in pregnancy in Tanzania. I. Impact of maternal syphilis on outcome of pregnancy. J Infect Dis 2002; 186: 940–47. Lawn JE, Cousens S, Zupan J, for the Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: When? Where? Why? Lancet 2005; 365: 891–900 Watson-Jones D, Gumodoka B, et al. Syphilis in pregnancy in Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J Infect Dis 2002; 186: 948–57. Terris-Prestholt F, Watson-Jones D, Mugeye K, et al. Is antenatal syphilis screening still cost effective in sub-Saharan Africa. Sex Transm Infect 2003; 79: 375–81. Watson-Jones D, Oliff M, Terris-Prestholt F, et al. Antenatal syphilis screening in sub-Saharan Africa: lessons learned from Tanzania. Trop Med Int Health 2005; 10: 934–43. Gloyd S, Chai S, Mercer MA. Antenatal syphilis in sub-Saharan Africa: missed opportunities for mortality reduction. Health Policy Plan 2001; 16: 29–34. Mabey D, Peeling RW, Ballard R, et al. Prospective, multi-centre clinic-based evaluation of four rapid diagnostic tests for syphilis. Sex Transm Infect 2006; 82 (suppl 5): v13–16. Peeling RW, Mabey D, Fitzgerald DW, Watson-Jones D. Avoiding HIV and dying of syphilis. Lancet 2004; 364: 1561–66. Walker GJ. Antibiotics for syphilis diagnosed during pregnancy. Cochrane Database Syst Rev 2001; 3: CD001143. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives saved tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health 2011; 11 (suppl 3): S9.
Erratum Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011; published online May 6. DOI:10.1016/S1473-3099(11)70065-2—In this Article, a hyphen was missing from an author’s surname. Her correct name is Annelies Wilder-Smith. This correction has been made to the online version as of Aug 22, 2011, and to the printed Article.
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