1292
LETTERS to the EDITOR
Antibiotic
prophylaxis and infective endocarditis
SiR,—The Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy last updated its recommendations for the antibiotic prophylaxis of infective endocarditis in January, 1990.1 We have now revised them again. Most are unchanged and the amendments are given below. In its first report,2 the working-party pointed out that the introduction of antibiotic prophylaxis in Britain had not been followed by a decline in infective endocarditis and that there was no firm evidence for the protective effect of antibiotics for dental procedures. Nevertheless, the working-party felt that the circumstantial evidence of benefit was strong enough to warrant its recommendations. Dr van der Meer and colleagues (Jan 18, p 135) have attempted to assess the value of antibiotic prophylaxis for dental patients with a nationwide case-control study in the Netherlands. They found that the protective efficacy of prophylaxis against first episodes of native valve endocarditis was 49%, but because fewer than 15% of cases follow dental treatment the potential for prophylaxis to reduce the rate of endocarditis in the population at risk is very small. Imperiale and Horwitz,3 in a smaller study, found the protective efficacy of prophylactic antibiotics against first-time native valve endocarditis to be 91% and they concluded that this justified the use of prophylaxis in patients with high-risk cardiac lesions. Both studies demonstrate the efficacy of prophylaxis for the individual, albeit at a different level, but its value and cost-effectiveness for the population at risk remain difficult to assess. Your editorial (Feb 29, p 525) suggests that a large European study might resolve the issues. We are discussing with colleagues in Europe the value and feasibility of such an investigation. However, at present we firmly believe that our recommendations should stand.
Changes to recommendations In 1990 we proposed oral clindamycin 600 mg as one dose 1 h before a dental procedure as an alternative to the original erythromycin regimen for adults at risk from endocarditis who are allergic to penicillin and who are not to have a general anaesthetic. We have received no reports of side-effects with the clindamycin regimen and have decided that it should replace erythromycin. We also recommended that the dose of oral clindamycin for children should be 6 mg/kg, but we have been advised that this is equivalent lower dose than the one we recommended for adults. We now recommend that for children 5-10 years of age the dose should be half the adult dose (300 mg) and for children under 5 a quarter the adult dose (150 mg). Until now, for adults who are allergic to penicillins or who have had penicillin more than once in the previous month, we have recommended vancomycin 1 g by slow intravenous (iv) infusion over 60 min followed by gentamicin iv just before induction or 15 min before the surgical procedure. There are practical difficulties to a
with this regimen. Vancomycin may produce serious side-effects, and it has recently been recommended that the duration of its administration should be increased to at least 100 min.4 We have therefore continued to look for alternatives. Teicoplanin is now available in the UK. It reduces the prevalence of bacteraemia after dental extractionis easier to give than vancomycin, and has fewer side-effects. We have therefore decided to recommend teicoplanin 400 mg iv and gentamicin 120 mg iv as our first alternative to the infusion of vancomycin and gentamicin. Children under 14 years should receive teicoplanin 6 mg/kg iv plus gentamicin 2 mg/kg iv. The American Heart Association has recommended that penicillin-allergic patients unable to take oral medications should be given iv clindamycin 300 mg before the dental procedure and an iv or oral administration of 150 mg 6 h later.6 As far as we can determine, in more than 20 years there has been only one reported case of pseudomembranous colitis after a single injection of clindamycin. We have therefore decided to recommend iv clindamycin as a second alternative to the vancomycin and gentamicin regimen before dental procedures or operations on the upper respiratory tract, but not for patients undergoing
genitourinary surgery or instrumentation, obstetric, gynaecological, or gastrointestinal procedures. In some patients receiving large amounts of clindamycin by rapid iv injection, blood pressure has fallen precipitately, with nausea, vomiting, and arrhythmias. The 300 mg iv dose should therefore be given in 50 ml of diluent over 10 min and the 150 mg dose, similarly diluted, over 10 min. When clindamycin is used, periodontal or other multistage procedures should be repeated only after an interval of at least 2 weeks. Children 5-10 years of age should receive half the adult dose and children under 5 a quarter the adult dose. Iv teicoplanin or clindamycin should be given at the time of induction of anaesthesia or 15 min before the dental procedure. We have previously recommended that patients having a general anaesthetic, not allergic to the penicillins and not given a penicillin more than once in the previous month, should be given intramuscular amoxycillin. Correspondents have suggested that in some circumstances it would be better to give the drug by the iv route particularly to children, and we accept the suggestion. Intraligamentary injection of local analgesic solutions is sometimes used. With this technique the solution is injected into the periodontal ligament and forced under high pressure to the apex of the tooth. This may carry a risk of severe bacteraemia and is best avoided in patients susceptible to endocarditis. We emphasise, as we did in our first report, the need for regular dental attendance for the maintenance of dental health in patients susceptible to infective endocarditis. Such care should reduce the frequency and severity ofbacteraemias of dental origin and the need for extractions. Application of an antiseptic such as chlorhexidine gel (1 %) to the dry gingival margin or the use of a chlorhexidine mouthwash (02%) 5 min before dental procedures should reduce
1293
the severity of bacteraemia and may be used antibiotic prophylaxis.
to
supplement
women
A warning card giving our recommendations, including the amendments in full, will shortly be available from the British Heart Foundation, 14 Fitzhardinge Street, London W1H 4DH.
N. A. SIMMONS, Chairman, Working Party of the
Department of Clinical Bacteriology, Guy’s Hospital, London SE1 9RT, UK Cameron
British
Society for Antimicrobial Chemotherapy A. P. BALL
Hospital, Fife
Guy’s Hospital, London
R. A. CAWSON
St Thomas’ Hospital, London
S. J. EYKYN
University of Birmingham
W. A. LITTLER
University of Glasgow
D. A. McGOWAN
Royal Postgraduate Medical School,
Londorn
C. M. OAKLEY D. C. SHANSON
1. Working
Party of the British Society for Antimicrobial Chemotherapy. Antibiotic prophylaxis of infective endocarditis. Lancet 1990; 335: 88-89. 2. Working Party of the British Society for Antimicrobial Chemotherapy. The antibiotic prophylaxis of infective endocarditis. Lancet 1982; ii: 1323-26. 3. Imperiale TF, Horwitz RI. Does prophylaxis prevent postdental infective endocarditis? A controlled evaluation of protective efficacy. Am J Med 1990; 88: 131-36. 4 British National
Formulary
no
23. London: British Medical
Association/Royal
Pharmaceutical Society of Great Britain (in press). 5. Shanson DC, Shehata A, Tadayon M, Harris M. Comparison of intravenous teicoplanin with intramuscular amoxycillin for the prophylaxis of streptococcal bacteraemia in dental patients. J Antimicrob Chemother 1987; 20: 85-93. 6. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association.
JAMA 1990; 264: 2919-22.
SIR,-Dr Kirby and colleagues (April 4, p 828) show that women with mild or moderate dyskaryosis have a 10-20-fold greater risk of cervical intraepithelial neoplasia (CIN) III over 10 years than do women with a normal smear. Although the actual figures are not provided, from figure 3 and table i the actual 10-year cumulative incidence of CIN III seems to range from 65% to 25%. When the women with CIN II are added to these, the overall rate is likely to be well over 50%. There were also 5 women with invasive cancer in the group with mildly abnormal smears. Although the number of women-years of follow-up is not provided, the cumulative annual incidence of invasive cancer in this group is likely to be about 200 per 100 000 women-years. This may be compared with the incidence of 13-6 per 100 000 for the region in 1989 that Kirby et al cite. The report accords with previous studies that showed a very high prevalence of CIN II and III and, more worrying still, of invasive cancer in women with mild cytological abnormalities.1,2 Is it really right to continue to ignore these very high risks of CIN and invasive disease and to rely upon cytological surveillance rather than referring these women for colposcopic assessment? Colposcopy is not synonymous with biopsy and cone biopsy. Women who do not have cervical disease can be reassured and returned to routine screening while those who do can be treated promptly. With appropriate explanationmany women would find this less stressful than having repeated smears. (Who now can say to these women that the mild abnormality in their smear is unlikely to reflect serious pathology?) Early referral to colposcopy might even be more cost-effective than doing the extra smears needed for intensive cytological follow-up. Institute of Obstetrics and Gynaecology, Royal Postgraduate Medical School, Hammersmith Hospital,
W. P. SOUTTER
1. Robertson JH, Woodend BE, Crozier EH, Hutchinson J. Risk of cervical associated with mild
dyskaryosis. Br Med J 1988; 297:
biopsy.
An audit of prompt colposcopy at the Royal Northern Hospital has shown a striking increase in the proportion of high grade CIN (II or III) seen at referral colposcopy, as the grade of referral smear changes from borderline to severe. Nearly 70% of all cases of CIN II or III were associated with a moderately or severely first dyskaryotic smear. A third of all patients attending with a first moderately dyskaryotic smear proved to have CIN II or III. Kirby et al have shown the potential pitfalls of keeping patients with middle-grade smear abnormalities under review by describing the development of a stage IB carcinoma in a woman with moderate-to-severe dyskaryosis who was not promptly referred for
colposcopy. Finally, their study, which judges the prevalence of disease by a last smear result, is potentially flawed because of the well recognised significant false-negative rate for cytology. Only 198 of 500 of the patient group had had a smear within 4 years. Without the use of colposcopical biopsy to diagnose end-point disease, there is a risk of underestimating disease prevalence. This is clearly important when attempting to formulate management policy, in view of a well documented increase in the incidence of abnormal past 10 years.3
Conservative treatment of mild/moderate cervical dyskaryosis
London W12 0NN, UK
with
SIR,-We welcome Dr Kirby and colleagues’ report addressing the debate about management of women with lesser grades of cytological abnormality. However, is there really much controversy about moderately dyskaryotic smears? According to National Health Service cervical screening guidelines1 "moderate dyskaryosis should usually be referred for colposcopy when first encountered". It certainly seems logical that higher grades of smear abnormalities are more likely to be associated with high-grade CIN on
Charing Cross and Westminster Medical School, London
N, Grubb C, Chamberlain J. Four and a half years follow up of dyskaryotic cervical smears. Br Med J 1990; 301: 641-44. 3. Wilkinson C, Jones JM, McBride J. Anxiety caused by abnormal result of cervical smear test: a controlled trial. Br Med J 1990; 300: 440.
2. Fletcher A, Metaxas
18-21.
cancer
Department of Colposcopy, Royal Northern Hospital, London N7, UK;
smears
in the
and Queens Medical Centre,
M. H. JONES D. JENKINS
Nottingham
A. SINGER
ID, ed. Guidelines for clinical practice and programme management: NHS cervical screening programme. Dundee: University of Dundee, 1992. 2. Giles JA, Crow J, Walker P, Hudson E, Williams D. Colposcopic assessment of the accuracy of cervical cytology screening. Br Med J 1988; 296: 1099-102. 3. Cancer Research Campaign. Factsheet 12.2.1990. London: Imperial Cancer Research Fund, 1990. 1. Duncan
SIR,-Dr Cuzick and co-workers’ (April 18, p 959) conclusions based on the association between moderate or high levels of human papillomavirus 16 (HPV 16) DNA and CIN3. In the women in whom the highest incidence ofHPV16might have been expected (ie, those presenting with severe dyskaryosis) only 50% were positive for HPV16 DNA-but 78% of women with cytological abnormalities consistent with mild or moderate dyskaryosis but biopsy proven CIN3 were positive. This difference between the two groups might not be significant because of the small sample size. Cuzick et al raise several possibilities to explain the absence of are
HPV-DNA with CIN3. Other HPV types have been associated with cervical neoplasia, particularly HPV18, which is present in about 10% of cancers. However, other HPV types (eg, HPV31, 33, 35) have not been recorded in the UK and at most are associated with 2% of invasive cancers. Transient infection of the normal cervix with HPV has been described, but in women with CIN, who have been followed prospectively, persistent HPV infection is usual.1.2 Integration of HPV 16 DNA occurs in CIN but at a lower rate than with invasive cancers.3 Integration of HPV16 DNA results in the disruption of the E1-E2 open reading frames with the upstream regulatory region E6-E7 remaining intact.4,5Therefore the region of HPV 16 Cuzick et al use for PCR amplification would most probably be uninterrupted as a result of integration so could not explain the low incidence of HPV16 DNA. There is increasing evidence that not all cervical cancers are associated with HPV and that mutations in tumour suppressor genes might be important in such cases.6 Clinical studies suggest that HPV-negative tumours are associated with a poor prognosis.’
LETTERS to the EDITOR
Antibiotic
prophylaxis and infective endocarditis
SiR,—The Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy last updated its recommendations for the antibiotic prophylaxis of infective endocarditis in January, 1990.1 We have now revised them again. Most are unchanged and the amendments are given below. In its first report,2 the working-party pointed out that the introduction of antibiotic prophylaxis in Britain had not been followed by a decline in infective endocarditis and that there was no firm evidence for the protective effect of antibiotics for dental procedures. Nevertheless, the working-party felt that the circumstantial evidence of benefit was strong enough to warrant its recommendations. Dr van der Meer and colleagues (Jan 18, p 135) have attempted to assess the value of antibiotic prophylaxis for dental patients with a nationwide case-control study in the Netherlands. They found that the protective efficacy of prophylaxis against first episodes of native valve endocarditis was 49%, but because fewer than 15% of cases follow dental treatment the potential for prophylaxis to reduce the rate of endocarditis in the population at risk is very small. Imperiale and Horwitz,3 in a smaller study, found the protective efficacy of prophylactic antibiotics against first-time native valve endocarditis to be 91% and they concluded that this justified the use of prophylaxis in patients with high-risk cardiac lesions. Both studies demonstrate the efficacy of prophylaxis for the individual, albeit at a different level, but its value and cost-effectiveness for the population at risk remain difficult to assess. Your editorial (Feb 29, p 525) suggests that a large European study might resolve the issues. We are discussing with colleagues in Europe the value and feasibility of such an investigation. However, at present we firmly believe that our recommendations should stand.
Changes to recommendations In 1990 we proposed oral clindamycin 600 mg as one dose 1 h before a dental procedure as an alternative to the original erythromycin regimen for adults at risk from endocarditis who are allergic to penicillin and who are not to have a general anaesthetic. We have received no reports of side-effects with the clindamycin regimen and have decided that it should replace erythromycin. We also recommended that the dose of oral clindamycin for children should be 6 mg/kg, but we have been advised that this is equivalent lower dose than the one we recommended for adults. We now recommend that for children 5-10 years of age the dose should be half the adult dose (300 mg) and for children under 5 a quarter the adult dose (150 mg). Until now, for adults who are allergic to penicillins or who have had penicillin more than once in the previous month, we have recommended vancomycin 1 g by slow intravenous (iv) infusion over 60 min followed by gentamicin iv just before induction or 15 min before the surgical procedure. There are practical difficulties to a
with this regimen. Vancomycin may produce serious side-effects, and it has recently been recommended that the duration of its administration should be increased to at least 100 min.4 We have therefore continued to look for alternatives. Teicoplanin is now available in the UK. It reduces the prevalence of bacteraemia after dental extractionis easier to give than vancomycin, and has fewer side-effects. We have therefore decided to recommend teicoplanin 400 mg iv and gentamicin 120 mg iv as our first alternative to the infusion of vancomycin and gentamicin. Children under 14 years should receive teicoplanin 6 mg/kg iv plus gentamicin 2 mg/kg iv. The American Heart Association has recommended that penicillin-allergic patients unable to take oral medications should be given iv clindamycin 300 mg before the dental procedure and an iv or oral administration of 150 mg 6 h later.6 As far as we can determine, in more than 20 years there has been only one reported case of pseudomembranous colitis after a single injection of clindamycin. We have therefore decided to recommend iv clindamycin as a second alternative to the vancomycin and gentamicin regimen before dental procedures or operations on the upper respiratory tract, but not for patients undergoing
genitourinary surgery or instrumentation, obstetric, gynaecological, or gastrointestinal procedures. In some patients receiving large amounts of clindamycin by rapid iv injection, blood pressure has fallen precipitately, with nausea, vomiting, and arrhythmias. The 300 mg iv dose should therefore be given in 50 ml of diluent over 10 min and the 150 mg dose, similarly diluted, over 10 min. When clindamycin is used, periodontal or other multistage procedures should be repeated only after an interval of at least 2 weeks. Children 5-10 years of age should receive half the adult dose and children under 5 a quarter the adult dose. Iv teicoplanin or clindamycin should be given at the time of induction of anaesthesia or 15 min before the dental procedure. We have previously recommended that patients having a general anaesthetic, not allergic to the penicillins and not given a penicillin more than once in the previous month, should be given intramuscular amoxycillin. Correspondents have suggested that in some circumstances it would be better to give the drug by the iv route particularly to children, and we accept the suggestion. Intraligamentary injection of local analgesic solutions is sometimes used. With this technique the solution is injected into the periodontal ligament and forced under high pressure to the apex of the tooth. This may carry a risk of severe bacteraemia and is best avoided in patients susceptible to endocarditis. We emphasise, as we did in our first report, the need for regular dental attendance for the maintenance of dental health in patients susceptible to infective endocarditis. Such care should reduce the frequency and severity ofbacteraemias of dental origin and the need for extractions. Application of an antiseptic such as chlorhexidine gel (1 %) to the dry gingival margin or the use of a chlorhexidine mouthwash (02%) 5 min before dental procedures should reduce
1293
the severity of bacteraemia and may be used antibiotic prophylaxis.
to
supplement
women
A warning card giving our recommendations, including the amendments in full, will shortly be available from the British Heart Foundation, 14 Fitzhardinge Street, London W1H 4DH.
N. A. SIMMONS, Chairman, Working Party of the
Department of Clinical Bacteriology, Guy’s Hospital, London SE1 9RT, UK Cameron
British
Society for Antimicrobial Chemotherapy A. P. BALL
Hospital, Fife
Guy’s Hospital, London
R. A. CAWSON
St Thomas’ Hospital, London
S. J. EYKYN
University of Birmingham
W. A. LITTLER
University of Glasgow
D. A. McGOWAN
Royal Postgraduate Medical School,
Londorn
C. M. OAKLEY D. C. SHANSON
1. Working
Party of the British Society for Antimicrobial Chemotherapy. Antibiotic prophylaxis of infective endocarditis. Lancet 1990; 335: 88-89. 2. Working Party of the British Society for Antimicrobial Chemotherapy. The antibiotic prophylaxis of infective endocarditis. Lancet 1982; ii: 1323-26. 3. Imperiale TF, Horwitz RI. Does prophylaxis prevent postdental infective endocarditis? A controlled evaluation of protective efficacy. Am J Med 1990; 88: 131-36. 4 British National
Formulary
no
23. London: British Medical
Association/Royal
Pharmaceutical Society of Great Britain (in press). 5. Shanson DC, Shehata A, Tadayon M, Harris M. Comparison of intravenous teicoplanin with intramuscular amoxycillin for the prophylaxis of streptococcal bacteraemia in dental patients. J Antimicrob Chemother 1987; 20: 85-93. 6. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association.
JAMA 1990; 264: 2919-22.
SIR,-Dr Kirby and colleagues (April 4, p 828) show that women with mild or moderate dyskaryosis have a 10-20-fold greater risk of cervical intraepithelial neoplasia (CIN) III over 10 years than do women with a normal smear. Although the actual figures are not provided, from figure 3 and table i the actual 10-year cumulative incidence of CIN III seems to range from 65% to 25%. When the women with CIN II are added to these, the overall rate is likely to be well over 50%. There were also 5 women with invasive cancer in the group with mildly abnormal smears. Although the number of women-years of follow-up is not provided, the cumulative annual incidence of invasive cancer in this group is likely to be about 200 per 100 000 women-years. This may be compared with the incidence of 13-6 per 100 000 for the region in 1989 that Kirby et al cite. The report accords with previous studies that showed a very high prevalence of CIN II and III and, more worrying still, of invasive cancer in women with mild cytological abnormalities.1,2 Is it really right to continue to ignore these very high risks of CIN and invasive disease and to rely upon cytological surveillance rather than referring these women for colposcopic assessment? Colposcopy is not synonymous with biopsy and cone biopsy. Women who do not have cervical disease can be reassured and returned to routine screening while those who do can be treated promptly. With appropriate explanationmany women would find this less stressful than having repeated smears. (Who now can say to these women that the mild abnormality in their smear is unlikely to reflect serious pathology?) Early referral to colposcopy might even be more cost-effective than doing the extra smears needed for intensive cytological follow-up. Institute of Obstetrics and Gynaecology, Royal Postgraduate Medical School, Hammersmith Hospital,
W. P. SOUTTER
1. Robertson JH, Woodend BE, Crozier EH, Hutchinson J. Risk of cervical associated with mild
dyskaryosis. Br Med J 1988; 297:
biopsy.
An audit of prompt colposcopy at the Royal Northern Hospital has shown a striking increase in the proportion of high grade CIN (II or III) seen at referral colposcopy, as the grade of referral smear changes from borderline to severe. Nearly 70% of all cases of CIN II or III were associated with a moderately or severely first dyskaryotic smear. A third of all patients attending with a first moderately dyskaryotic smear proved to have CIN II or III. Kirby et al have shown the potential pitfalls of keeping patients with middle-grade smear abnormalities under review by describing the development of a stage IB carcinoma in a woman with moderate-to-severe dyskaryosis who was not promptly referred for
colposcopy. Finally, their study, which judges the prevalence of disease by a last smear result, is potentially flawed because of the well recognised significant false-negative rate for cytology. Only 198 of 500 of the patient group had had a smear within 4 years. Without the use of colposcopical biopsy to diagnose end-point disease, there is a risk of underestimating disease prevalence. This is clearly important when attempting to formulate management policy, in view of a well documented increase in the incidence of abnormal past 10 years.3
Conservative treatment of mild/moderate cervical dyskaryosis
London W12 0NN, UK
with
SIR,-We welcome Dr Kirby and colleagues’ report addressing the debate about management of women with lesser grades of cytological abnormality. However, is there really much controversy about moderately dyskaryotic smears? According to National Health Service cervical screening guidelines1 "moderate dyskaryosis should usually be referred for colposcopy when first encountered". It certainly seems logical that higher grades of smear abnormalities are more likely to be associated with high-grade CIN on
Charing Cross and Westminster Medical School, London
N, Grubb C, Chamberlain J. Four and a half years follow up of dyskaryotic cervical smears. Br Med J 1990; 301: 641-44. 3. Wilkinson C, Jones JM, McBride J. Anxiety caused by abnormal result of cervical smear test: a controlled trial. Br Med J 1990; 300: 440.
2. Fletcher A, Metaxas
18-21.
cancer
Department of Colposcopy, Royal Northern Hospital, London N7, UK;
smears
in the
and Queens Medical Centre,
M. H. JONES D. JENKINS
Nottingham
A. SINGER
ID, ed. Guidelines for clinical practice and programme management: NHS cervical screening programme. Dundee: University of Dundee, 1992. 2. Giles JA, Crow J, Walker P, Hudson E, Williams D. Colposcopic assessment of the accuracy of cervical cytology screening. Br Med J 1988; 296: 1099-102. 3. Cancer Research Campaign. Factsheet 12.2.1990. London: Imperial Cancer Research Fund, 1990. 1. Duncan
SIR,-Dr Cuzick and co-workers’ (April 18, p 959) conclusions based on the association between moderate or high levels of human papillomavirus 16 (HPV 16) DNA and CIN3. In the women in whom the highest incidence ofHPV16might have been expected (ie, those presenting with severe dyskaryosis) only 50% were positive for HPV16 DNA-but 78% of women with cytological abnormalities consistent with mild or moderate dyskaryosis but biopsy proven CIN3 were positive. This difference between the two groups might not be significant because of the small sample size. Cuzick et al raise several possibilities to explain the absence of are
HPV-DNA with CIN3. Other HPV types have been associated with cervical neoplasia, particularly HPV18, which is present in about 10% of cancers. However, other HPV types (eg, HPV31, 33, 35) have not been recorded in the UK and at most are associated with 2% of invasive cancers. Transient infection of the normal cervix with HPV has been described, but in women with CIN, who have been followed prospectively, persistent HPV infection is usual.1.2 Integration of HPV 16 DNA occurs in CIN but at a lower rate than with invasive cancers.3 Integration of HPV16 DNA results in the disruption of the E1-E2 open reading frames with the upstream regulatory region E6-E7 remaining intact.4,5Therefore the region of HPV 16 Cuzick et al use for PCR amplification would most probably be uninterrupted as a result of integration so could not explain the low incidence of HPV16 DNA. There is increasing evidence that not all cervical cancers are associated with HPV and that mutations in tumour suppressor genes might be important in such cases.6 Clinical studies suggest that HPV-negative tumours are associated with a poor prognosis.’
