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Meta-analysis of HIV-acquisition studies incomplete and unstable

Letter to the Editor

Re: Male Circumcision for the Prevention of HIV Acquisition: A Meta-Analysis

Sir,

The authors of a recent meta-analysis[1] of studies into male circumcision and HIV describe their findings as “compelling.” We disagree. They reported a remarkably high degree of inconsistency with 97% of variation across studies due to heterogeneity rather than chance (an astounding, rarely seen, level of heterogeneity). Using recently described methods[2], 28.57% of the studies would need to have been excluded to bring I2 below the 50% threshold (considered high) and 32.65% excluded to bring I2 below the 25% threshold considered acceptable (well above the expected 99th percentiles of 22% and 32%, respectively). Similarly, 65.51% and 65.93% of the total number of participants needed to be excluded to reach the 50% and 25% thresholds (above the 99th percentiles of 25% and 48%, respectively). Given this excessive between-study heterogeneity, Sharma et al. should have refrained from reporting summary estimates[3].

The authors half-heartedly attempted to explain the heterogeneity failing to recognise that both the risk profile and circumcision prevalence of the study population are significant factors[4], and also failing to acknowledge the sizeable percentage of iatrogenically transmitted HIV infections[5].

The authors excluded approximately half of the published studies that met their inclusion criteria[4]. Excluding studies that focused only on MSM, which have a distinctly different risk profile, we calculate the included studies as significantly more likely to report a greater treatment effect (random-effect summary odds ratio (circumcised versus intact) of (0.44, 95%CI=0.36-0.59) than the excluded studies (0.66, 95%CI=0.56-0.78) − (change in ln(OR)=0.35, 95%CI=0.07-0.65, t=2.44, p=0.016).

In assessing publication bias, the authors provided a funnel graph, declaring that the data plots “appear to be evenly distributed about the mean effect size, suggesting an absence of publication bias,” without applying any routine statistical tests. Four of six commonly used measures[6] exhibited significant publication bias.

The results of the randomised clinical trials (RCTs) have been noted as being “remarkably similar”[7]  − the probability of the results of these trials being so tightly clustered is only 0.03[8]. Can the 0% I2 reported in the meta-analysis of the RCTs be interpreted as indicating no appreciable variability between the studies? This certainly arouses suspicion of prior coordination: as Ioannidis noted, “At the extreme, fraud can cause perfect replication”[9].

The large sample size RCTs allowed small numerical differences to have an exaggerated impact on p-values. The Fragility Index (FI) (number of times one patient with the relevant finding is subtracted from one group and added to another group before the results are no longer significant)[10] for the three clinical trials was 4, 5, and 6, respectively, with an FI of ≥ 8 being common, and an FI of ≤ 3 being suspect.  Early discontinuance of these fragile studies with an absolute risk reduction between 0.8% and 1.9% was an artifact of being overpowered.

Given the effectiveness of condoms[11], the lack of consistent findings on national levels[12], the methodologically flawed RCTs[13], the lack of translational research, and the impressive potential uptake and effectiveness of pre-exposure prophylaxis[14], circumcision as an intervention to prevent HIV infection should be treated with greater scepticism.

Robert S. Van Howe1, MD, FAAP, and Gregory J. Boyle2, PhD, DSc, FAPS

1College of Medicine, Central Michigan University , Saginaw , MI , USA

2University of Melbourne, Parkville, VIC 3010, Australia

 

References

  1. Sharma SC, Raison N, Khan S, Shabbir M, Dasgupta P, Ahmed K. Male circumcision for the prevention of human immunodeficiency virus (HIV) acquisition: a meta-analysis. BJU Int 2018; 121:515-26. doi:10.1111/bju.14102
  2. Patsopoulos NA, Evangelou E, Ioannidis JPA. Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation. Int J Epidemiol 2008; 37: 1148-57. doi:10.1093/ije/dyn065
  3. Mueller M, D’Addario M, Egger M, et al. Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations. BMC Med Res Methodol 2018; 18: 44.
  4. Van Howe RS. Circumcision as a primary HIV preventive: extrapolating from the available data. Glob Public Health 2015; 10: 607-25.
  5. Gisselquist D, Pottarat JJ, Brody S, Vachon F. Let it be sexual: how health care transmission of AIDS in Africa was ignored. Int J STD AIDS 2003; 14: 148-61.
  6. Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta-analysis. Statist Med 2001; 20: 641-54.
  7. Sansom SL, Prabhu VS, Hutchinson AB, et al. Cost-effectiveness of newborn circumcision in reducing lifetime HIV risk among U.S. males. PLoS One 2010; 5(1): e8723.
  8. Van Howe RS. “Math is your friend: a consumer’s primer to understanding epidemiology.” Genital Autonomy 2014: Thirteenth International Symposium on Genital Autonomy and Children’s Rights. Boulder, Colorado. July 24, 2014.
  9. Ioannidis JP. Scientific inbreeding and same-team replication: type D personality as an example. J Psychosom Res 2012; 73: 408–10.
  10. Walsh M, Srinathan SK, McAuley DF, et al. The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index. J Clin Epidemiol 2014; 67: 622-8.
  11. de Vincenzi I. A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. European Study Group on Heterosexual Transmission of HIV. N Engl J Med 1994; 331: 341-6.
  12. Garenne M. Long-term population effect of male circumcision in generalised HIV epidemics in sub-Saharan Africa. Afr J AIDS Res 2008; 7: 1-8.
  13. Boyle GJ, Hill G. Sub-Saharan African randomised clinical trials into male circumcision and HIV transmission: methodological, ethical and legal concerns. J Law Med 2011; 19: 316-34.
  14. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367(5): 399-410.

 

 

Learning from The Lancet

The Lancet, established in 1823, is one of the most respected medical journals in the world. It has an impact factor of 39, and therefore attracts and publishes only the very best papers. Like most journals that have evolved with modern times, it has an active web and social media presence, particularly based around Twitter.

On a Monday morning, last autumn, the Editor of the BJUI had a meeting with the Web Editor of The Lancet at Guy’s Hospital. There was a mutual interest in surgical technology, particularly as Naomi Lee had been a urology trainee before joining The Lancet full-time. The topic of discussion was robot-assisted radical cystectomy with the emergence of randomised trials showing little difference between open and robotic surgery, despite the minimally invasive nature of the latter [1, 2]. Thereafter, The Lancet kindly invited the BJUI team to visit its offices in London. The location is rather bohemian with a mural of John Lennon on the wall across the street! Here is a summary of what we learnt that day.

Capture

1. Democracy – what gets published in The Lancet after peer review is decided at a team meeting, where editors of the main journal and its sister publications gather around a table to discuss individual articles. Most work full-time for The Lancet, unlike surgical journals that are led by working clinicians. No wonder that >80% of papers are immediately rejected and the final acceptance rate is ≈6%. Interesting case reports are still published and often highly cited because of the wider readership.

2. Quality has no boundaries – it does not matter where the article comes from as long as it has an important message. The BJUI recently published an excellent paper on circumcision in HIV-positive men from Africa [3]; the original randomised controlled trial had appeared some 7 years earlier in The Lancet [4].

3. Statisticians – the good ones are a rare breed and sometimes rather difficult to find. While we have two statistical editors at the BJUI, sometimes, it is difficult to approach the most qualified reviewer on a particular subject. The Lancet occasionally faces similar difficulties, which it almost always overcomes due to its’ team approach.

4. Meta-analysis and systematic reviews – they form a significant number of submissions to both journals. It is not always easy to judge their quality although a key starting point is to identify whether the topic is one of contemporary interest where there are significant existing data that can be analysed. Rare subjects usually fail to make the cut.

5. Paper not dead yet – this is certainly the case at The Lancet office, where its editors gather together with paper folders and hand-written notes. We are almost fully paperless at the BJUI offices, and are hoping to be completely electronic in the future. A recent live vote of our readership during the USANZ Annual Scientific Meeting in Adelaide, Australia, indicated that the majority would like us to go electronic in about 2–3 years’ time; however, ≈30% of our institutional subscribers still prefer the paper version and are reluctant to make the switch.

The BJUI and The Lancet are coming together to host a joint Social Media session at BAUS 2015, which will provide more opportunity to learn from one of the best journals ever. We hope to see many of you there.

References

 

 

2 Lee N. Robotic surgery: where are we now? Lancet 2014; 384: 1417

 

 

4 Gray RH, Kigozi G, Serwadda D et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007; 369: 65766

 


Prokar Dasgupta @prokarurol
Editor-in-Chief, BJUI 

 

Scott Millar
Managing Editor, BJUI 

 

Naomi Lee
Web Editor, The Lancet

 

Article of the Month: HIV no barrier to circumcision

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post. 

In addition to the article itself, there is an accompanying editorial written by prominent members of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

This month our lead article on HIV and circumcision comes from Uganda. The front cover of January’s issue shows the Nile at Lake Victoria in Uganda. If you only have time to read one article this week, it should be this one.

Male circumcision wound healing in human immunodeficiency virus (HIV)-negative and HIV-positive men in Rakai, Uganda

Godfrey Kigozi*, Richard Musoke*, Nehemiah Kighoma*, Stephen Watya*, David Serwadda*, Fred Nalugoda*, Noah Kiwanuka‡, James Nkale*, Fred Wabwire-Mangen, Frederick Makumbi*, Nelson K. Sewankambo§, Ronald H. Gray* and Maria J. Wawer*

*Rakai Health Sciences Program, Entebbe, Urocare, School of Public Health, Makerere University, and §College of Health Sciences, Makerere University, Kampala, Uganda, and ¶Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA

OBJECTIVE

• To assess completed wound healing after medical male circumcision (MMC) among human immunodeficiency virus (HIV)-negative and HIV-positive men with cluster of differentiation 4 (CD4) counts of <350 and ≥350 cells/mm3, as minimal data are available on the safety of MMC among HIV-positive men with low CD4 counts.

PATIENTS AND METHODS

• In all, 262 HIV-negative and 177 HIV-positive consenting males aged ≥12 years accepted MMC using the dorsal slit procedure and were enrolled in the study.

• Socio-demographic and behavioural data and blood for HIV testing and CD4 counts were collected at baseline.

• Participants were followed weekly to collect information on resumption of sex, condom use and both self-reported and clinically assessed wound healing.

• The proportions healed among HIV-positive men were compared with HIV-negative men. Time to complete wound healing was assessed by Kaplan–Meier survival analysis.

RESULTS

• There were no statistically significant differences in the proportion of men healed by HIV status.

• At 4 weeks, the proportions healed were 85.9% in HIV-negative men, 77.4% in HIV-positive men with a CD4 count of ≥350 cells/mm3and 87.1% in HIV-positive men with a CD4 count of <350 cells/mm3.

• The median time to healing was 4 weeks and did not vary by HIV or CD4 status.

• All men had certified complete wound healing at 6 weeks after MMC. In all, 1.4% of HIV-positive men with a CD4 count of <350 cells/mm3 resumed sex before healing, compared with 8.5% among HIV-positive men with a CD4 count of ≥350 cells/mm3 (P = 0.052) and 7.8% (P = 0.081) among HIV-negative men.

CONCLUSION

• Inclusion of HIV-positive men with low CD4 counts in MMC services is not deleterious to postoperative wound healing.

 

Read Previous Articles of the Week

 

Editorial: Circumcision – follow-up or not?

There is an excellent study from Uganda in this issue of the BJUI [1]. It looks at the rate of healing of men undergoing prophylactic circumcision. Some had HIV; others not. What they termed ‘complete wound healing’ was an intact scar without a scab, sutures or a sinus – effectively a ‘sealed’ wound. There are several useful data therein:

  • all men had healed by 6 weeks; the median being 4 weeks.
  • HIV status did not appear to delay wound healing, even with low CD4 counts.
  • the patient was 95% likely to judge wound healing correctly himself.
  • routine circumcision can be safely carried out by trained medical officers.
  • a complication rate of 0.5% was reported.

So what follow-up, if any, is necessary after circumcision? Based on this population it would appear that a well instructed/consented patient can be relied on to judge healing after prophylactic circumcision. They probably do not need follow-up provided their expectations are managed well, and there is ease of access to return should problems arise.

However, this may not be generalizable to men having circumcision for phimosis or other abnormality of foreskin. These patients may have delayed healing, meatal issues or a urethral stricture upstream. Histopathological examination of abnormal foreskins is sensible also as further treatment/follow-up may indicated.

I recommend a read of this superb paper.

Paul K. Hegarty
Consultant Urological Surgeon, Mater Private, Cork, Ireland

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