We declare that we have no conﬂicts of interest.
*Aaron A R Tobian, Thomas C Quinn, Ronald H Gray [email protected]
Department of Pathology (AART), Department of Epidemiology (AART, RHG), and Department of Medicine (TCQ), Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; and Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA (TCQ) 1
Monsonego J. Genital infection with HPV in men: research into practice. Lancet 2011; 377: 881–83. Giuliano AR, Lee JH, Fulp W, et al. Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study. Lancet 2011; 377: 932–40. Tobian AA, Gray RH, Quinn TC. Male circumcision for the prevention of acquisition and transmission of sexually transmitted infections: the case for neonatal circumcision. Arch Pediatr Adolesc Med 2010; 164: 78–84. Wawer MJ, Tobian AA, Kigozi G, et al. Eﬀect of circumcision of HIV-negative men on transmission of human papillomavirus to HIVnegative women: a randomised trial in Rakai, Uganda. Lancet 2011; 277: 209–18. Giuliano AR, Lazcano E, Villa LL, et al. Circumcision and sexual behavior: factors independently associated with human papillomavirus detection among men in the HIM study. Int J Cancer 2009; 124: 1251–57.
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Giuliano AR, Palefsky JM, Goldstone S, et al. Eﬃcacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 2011; 364: 401–11.
Author’s reply Aaron Tobian and colleagues raise several points concerning my Comment on Giuliano and colleagues’ paper. It is indeed true that on the one hand, some observational studies show that female partners of circumcised men have a signiﬁcantly reduced risk of cervical cancer. However, on the other hand, not all observational studies have provided evidence to support a reduced risk of cervical cancer or human papillomavirus (HPV) infection in female partners of circumcised men. This question has recently been addressed in further analyses of four studies: three randomised trials in Uganda,1 Kenya,2 and South Africa,3 which showed a decreased risk of HIV acquisition after adult male circumcision, and the Ugandan Rakai trial,4 which showed a decreased risk of HPV infection after circumcision. Two randomised trials by Tobian and colleagues (their reference 3)5 suggest ﬁrst that there is a reduced HPV prevalence and incidence in female partners of men randomised to adult circumcision at 1 and 2 years after surgery. Assessments 3 and 4 years after surgery are ongoing. Second, male circumcision was eﬀective in reducing HPV incidence in female partners, with the best results seen in younger women who had fewer sexual partners. The eﬀect of circumcision was greatest when done before the man’s ﬁrst sexual contact. Additionally, eﬃcacy was lower in older men and in those who were more sexually active, this being diﬃcult to verify owing to the inability to distinguish HPV reactivation from initial HPV acquisition. Although the relative eﬀect of male circumcision on the incidence of their female partners developing HPV is signiﬁcant, the risk in women with circumcised partners is still high. Other interventions, such as
HPV vaccination, are likely to have a greater eﬀect on HPV-associated disease prevention in high prevalence regions. I declare that i have no conﬂicts of interest.
Joseph Monsonego [email protected]
Département de Colposcopie, Institute of the Cervix, 75017 Paris, France 1
Gray RH, Kigozi G, Serwadda D, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007; 369: 657–66. Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet 2007; 369: 643–56. Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2005; 2: e298. Tobian AA, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009; 360: 1298–309. Tobian AA, Kong X, Wawer MJ, et al. Circumcision of HIV-infected men and transmission of human papillomavirus to female partners: analyses of data from a randomised trial in Rakai, Uganda. Lancet Infect Dis 2011; published online April 11. DOI:10.1016/S14733099(11)70038-X.
Human papillomavirus vaccination in Africa In an Editorial (May 7, p 1544),1 you comment on the ﬁrst national prevention programme for cervical cancer in Africa. Other African countries are expected to follow. The programme in Rwanda is made possible through donations by Merck and Qiagen, the manufacturers of a human papillomavirus (HPV) vaccine and an HPV screening test, respectively. After the ﬁrst 3 years, the country would have to bear the costs. These costs are kept a secret; however, GAVI will most likely have to shoulder the bulk of it. We have serious doubts that this arrangement is in the best interest of the people. First, although the burden of cervical cancer in lowincome and middle-income countries
Additionally, observational studies and one randomised trial showed that male circumcision reduces high-risk HPV prevalence in female partners.3,4 In both men and their female partners, male circumcision reduces high-risk HPV prevalence by reducing acquisition and increasing clearance of the virus.4 Giuliano and colleagues5 have previously shown that male circumcision reduces penile high-risk HPV prevalence. Unfortunately, few data are presented in their more recent study2 on the eﬀect of male circumcision on high-risk HPV acquisition or clearance. Currently there are no fully protective measures for high-risk HPV prevention in men. The quadrivalent HPV vaccine only reduces external genital lesions in men by 60·2% and persistent infection with any HPV genotype by 27·1%.6 Therefore, several interventions might be required to signiﬁcantly reduce high-risk HPV infection in men and women, and the potential, albeit incomplete, protection aﬀorded by male circumcision cannot be ignored.
is substantial (3·8 million disabilityadjusted life-years [DALYs]), it ranks well behind that of other vaccinepreventable diseases such as tetanus (8·3 million DALYs) and measles (23 million DALYs).2 Second, the eﬀectiveness of the HPV vaccine against cervical cancer is still unknown.3 This uncertainty concerns African populations in particular, with their high HIV prevalence.4 Third, to remain cost-eﬀective in GAVI-eligible countries, the costs for a vaccinated individual should not exceed US$10 for the three doses.5 This cost contrasts unfavourably with the arguably lowest price negotiated so far—$16·95 per dose.1 When the donations are drained oﬀ, GAVI will be in a diﬃcult position: terminating this highly publicised programme will be unpopular. Representatives of vaccine manufacturers and the Rwandan Minister of Health are on the GAVI Board—an obvious conﬂict of interest. It would be a tragedy if funds were shifted from proven, cost-eﬀective vaccines and the strengthening of health systems to new but costly vaccines of unknown eﬀectiveness. We declare that we have no conﬂicts of interest.
Nobila Ouedraogo, *Olaf Müller, Albrecht Jahn, Ansgar Gerhardus [email protected]
Ruprecht-Karls-University, Institute of Public Health, INF 324, 69120 Heidelberg, Germany (NO, OM, AJ); and University of Bremen, Department for Health Services Research, Bremen, Germany (AG) 1 2
The Lancet. Financing HPV vaccines in developing countries. Lancet 2011; 377: 1544. Lopez AD, Mathers CD, Ezzati M, Jamisson DT, Murray CJL, eds. Global burden of disease and risk factors. Washington, DC, and New York: World Bank and Oxford University Press, 2006. Gerhardus A, Razum O. A long story made too short: surrogate variables and the communication of HPV vaccine trial results. J Epidemiol Community Health 2010; 64: 377–78. Cutts FT, Franceschi S, Goldie S, et al. Human papillomavirus and HPV vaccines: a review. Bull World Health Organ 2007; 85: 9. Goldie SJ, O’Shea M, Campos NG, Diaz M, Sweet S, Kim SY. Health and economic outcomes of HPV 16,18 vaccination in 72 GAVI-eligible countries. Vaccine 2008; 26: 4080–93.
Blocking out the real diagnosis Antonio Gambardella and colleagues (Feb 19, p 690)1 report a case of paroxysmal atrioventricular block misdiagnosed as epilepsy. Of note, they report that the patient’s symptoms worsened with carbamazepine. Various bradycardias have been reported with carbamazepine.2–5 In patients with epilepsy who deteriorate on carbamazepine, a cardiac cause should be considered. I declare that I have no conﬂicts of interest.
Kathryn Hewetson [email protected]
We declare that we have no conﬂicts of interest.
*Antonio Gambardella, Angelo Labate, Laura Mumoli, Aldo Quattrone [email protected]
Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, Italy (AG, AL, AQ); and *Division of Neurology, University Magna Graecia Catanzaro, 88100 Catanzaro, Italy (AG, AL, LM, AQ) 1
Kasarskis EJ, Kuo CS, Berger R, Nelson KR. Carbamazepine-induced cardiac dysfunction: characterization of two distinct clinical syndromes. Arch Intern Med 1992; 152: 186–91. Prasad AN, Stefanelli M, Nagarajan L. Seizure exacerbation and developmental regression with carbamazepine. Can J Neurol Sci 1998; 25: 287–94. Snead OC 3rd, Hosey LC. Exacerbation of seizures in children by carbamazepine. N Engl J Med 1985; 313: 916–21.
40 Berberry Close, Birmingham B30 1TB, UK 1
Gambardella A, Curcio A, Labate A, Mumoli L, Indolﬁ C, Quattrone A. Blocking out the real diagnosis. Lancet 2011; 377: 690. Beerman B, Edhag O, Vallin H. Advanced heart block aggravated by carbamazepine. Br Heart J 1975; 37: 668. Boesen F, Andersen EB, Jensen EK, Ladeforged SD. Cardiac conduction disturbances during carbamazepine therapy. Acta Neurol Scand 1983; 68: 49. Herzberg L. Carbamazepine and bradycardia. Lancet 1978; 1: 1097. Hewetson KA, Ritch AES, Watson RDS. Sick sinus syndrome aggravated by carbamazepine therapy for epilepsy. Postgrad Med J 1986; 62: 497–98.
Authors’ reply We agree with the recommendation by Kathryn Hewetson to consider a cardiac cause in patients with epilepsy who deteriorate on carbamazepine. This is especially true for older women who can develop potentially lifethreatening bradyarrhythmias or atrioventricular conduction delay during the course of routine treatment with therapeutic doses of carbamazepine.1 In our patient, carbamazepine is therefore likely to have worsened her episodes because it aggravated the paroxysmal complete heart block. However, carbamazepine can also precipitate or exacerbate absence, atonic, or myoclonic epileptic seizures in patients with generalised epilepsies,2 or in children with mixed epilepsy disorder and generalised bilaterally synchronous discharges on the electroencephalogram.3
Brazilian health-service organisation: problems at a glance The Lancet’s Series on Brazil1 covers almost all important health ﬁelds: health politics, violence, infectious diseases, chronic non-communicable diseases, and maternal and child health. But overall it gives a biased view of a poor country with a vertical health system based on programmes. The Series is missing at least a paper on the theory of primary care and how it is working in Brazil and a paper on health service organisation in general. Such papers might cover the uneven geographical distribution of physicians (eg, one per 574 inhabitants in the Amazonas state capital, Manaus, compared with one per 9000 in the rest of Amazonas),2 or the poor accessibility of health centres forcing patients to visit walk-in clinics with no continuity of care. Questions that remain unanswered are: does Brazilian society want a universal public health system?; do members of Brazil’s upper and middle classes know the importance of a strong public health system?; are Brazilian politicians promoting a public health system for the poor and a private one for the rest of the population? www.thelancet.com Vol 378 July 23, 2011