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The efficacy of Gardasil nonavalent HPV vaccine

21 Sep, 17 | by Leslie Goode, Blogmaster

The best choice of HPV vaccine – Gardasil 4vHPV, Cervatrix 2vHPV or Gardasil 9vHPV – will no doubt vary from one country to another. But decisions regarding the relative cost-effectiveness and affordability of a particular vaccine depend upon estimates of its efficacy. As regards the most recent vaccine, Gardasil 9vHPV, Huh & Luxembourg (H&L) have just published the final results of a phase III randomized trial involving nearly 12,000 16-26 year old women in 18 countries over a trial period of 54 months. Because cancer prevention benefits emerge only over the long-term, researchers must rely on various proxies. Previous ecological studies have already attempted to evaluate the impact of vaccination on the basis of declines in infection due to cancer-causing HPV strains (Chow & Fairley/STI; Garland & Jayasinghe/STI), genital warts (Chow & Fairley 2/STI; Ali & Donovan/STI; Wilson & Baker/STI), or HPV specific neoplasia or cytological abnormalities (Paavonen/STI). This randomized, double-blind trial takes account of evidence of all female genital disease, cytological abnormalities and clinical procedures associated with nonavalent HPV types – cervical, vulvar or vaginal. Ethical considerations required the use of Gardasil 4vHPV as a comparator rather than a placebo.

For 9vHPV types not covered by the quadrivalent vaccine (31, 33, 45, 52, 58), H&L report efficacy, as compared with 4vHPV, of: 97.4% for any high-grade disease; 96% for 6-month persistent HPV infection; 100% for cervical neoplasia grade 3; >90% for any grade of cervical or external genital disease, cervical cytological abnormalities or cervical therapy. For 9vHPV types covered by the quadrivalent vaccine, the 9vHPV vaccine showed efficacy in all respects not inferior to the 4vHPV vaccine.

The 9vHPV vaccine is at present licensed in over 60 countries. On the basis of an earlier report from this trial, Durham & Galvani conclude that, for the US, switching entirely to 9vHPV would be cost-effective at all levels of vaccine coverage, and that it would achieve an overall benefit equivalent to an 11% increase in coverage. It should be noted, however, that the trial reported by H&L concerns only the impact of 9vHPV vaccination on female genital disease. It does not investigate the impact of a switch from 4qHPV to 9qHPV either on male (including MSM) anogenital or oropharyngeal disease (Field & Lechner/STI; King & Sonnenberg/STI; Poynten & Grulich/STI), nor, for that matter, its impact on female anal cancers (Sand & Kjaer).

Modelling the scale-down of HIV services in sub-Saharan Africa

19 Sep, 17 | by Leslie Goode, Blogmaster

Search BMJ STI archive, and you will find frequent references to ‘scaling up’, and few – if any – to ‘scaling back’ or ‘scaling down’ (other than Parker/STI).  Who knows if all this may not be about to change, if the US government goes ahead with threats to cut current foreign aid budget ear-marked for HIV by $6.7 billion? How would this affect local HIV programmes?

Walensky & Paltiel  (W&P) model alternative strategies and combinations of strategies for the Republic of South Africa (RSA) and Cote d’Ivoire (CI) to determine which would offer the maximum budgetary return for each year of life lost. Strategies include ‘no new ART’, ‘reduced HIV testing and linking to care’, ‘ART eligibility at a lower CD4 count’, etc.; but all presuppose that commitments to those currently in ART care will be maintained. If scale-back is unavoidable, then it matters how those cuts are implemented; certain combinations of strategies, the authors claim, achieve synergies between strategies such that their combination produces budgetary savings that are greater, per year of life lost, than the total of the two strategies considered separately – for example, ‘late presentation’ and ‘reduced retention’ in RSA. However, ‘no new ART’ turns out to be the strategy that delivers the greatest budgetary savings in an ‘efficient’ manner.

It is hard to gauge the tone of these recommendations – which sound more like a ‘wake-up call’ to the US government than a sober proposal for scale-backs in sub-Saharan countries. Certainly this is not an argument for the long-term cost-effectiveness of any policy for scale-backs, since any short-term savings, they claim, will soon be overtaken by the downstream economic costs of increased HIV transmissions. And even the maximum of savings achievable by these strategies turns out not to exceed 30% of present expenditure. The most efficient alternatives for achieving cuts of 10%-20% will achieve c.$900 and c.$600-900 per every year of life lost in RSA and CI respectively.

In practice, however, it is hard to imagine the necessary cut-backs being achieved in so transparent and rational a manner. At all events, the effect of US cuts to HIV programmes will be presumably be more keenly felt – and will harder to make up for from other (e.g. local) resources – where the proportion of the national HIV budget funded by the US is higher. So, in CI, for example, where 90% of HIV spending comes from international sources, a 10% cut in PEPFAR (President’s Emergency Plan for AIDS Relief) funding would result in a 9% reduction in HIV spending, whereas, in RSA, where most of the funding is self-financed, it would represent a reduction of only 2%. It remains the case, however, that, in absolute terms, that 2% of spending in the RSA is worth $40 million, or double the $20 million saved by the 9% of savings in the CI.

Boys’ BV?

4 Sep, 17 | by Leslie Goode, Blogmaster

Recent studies in STIs have drawn attention to the impact of the state of the microbiome of the female genital tract (FGT) and susceptibility to STIs – and, in particular, the protective effect of the hydrogen peroxide-releasing microbe Lactobacillus crispatus (L.c.) (Antonio & Hillier/STIs) (A&H). Such STIs include, not only BV (53% less likely with L.c., according to A&H), but apparently also HIV, gonorrhea and HSV-2, which show, according to a Uganda based study (Francis & Grosskurth/STIs) an association of BV estimated at RR 2.35, 1.3, 1.69, respectively. A recent study of 236 young women participating in the S. African FRESH cohort found that, of the 24 of these having a FGT microbiome dominated by L.c., none figured among the 31 HIV seroconversions (STI blogs: Susceptibility of sub-Saharan women to HIV). Haggerty & Ness/STIs (, in the PID Evaluation and Clinical Health Study, find a strong (RR 4.7) association of certain FGT microbiotic bacteria with PID. Finally, a mouse based study by Gilbert & Lewis (STI/blogs: Bacterial vaginosis associated bacterium) seems to confirm the hypothesis, proposed in 2001 by Shahmanesh/STIs (, that Gardnerella may indirectly cause NGU (non-gonococcal urethritis) by triggering the emergence of covert Escheridia coli.

But if the importance now seems established of the composition of the woman’s FGT microbiome for the susceptibility to a whole range of STI (BV, HIV, Ng, HSV-2, PID, NGU), what are we to think of the finding of a recent paper in mBio (the journal of the American Society for Microbiology) that bacteria in the penile microbiome play a comparable role in the case of men – at least, in respect to HIV?

Liu & Price;8/4/e00996-17) uses data from 182 uncircumcised men from Rakai, Uganda, 46 of whom go on, over a two-year period, to develop HIV. In the case of five genera of bacteria suspected of playing a role in the association between male circumcision and reduced HIV risk, a strong association was discovered between their baseline prevalence in the penile microbiome and the risk of infection with HIV. With each 10-fold increase in the abundance of Prevotella, and Diliaster, for example, an increased risk was noted (AOR: 1.63 and 1.57, respectively). Other genera associated with increased risk were Peptoniphilus, Finegoldia, Porphyromonas, Mobiluncus, Peptostreptococcus, and Murdochiella. HIV risk was also found to be associated with inflammatory markers – especially interleukin-8. Presence of the latter increased significantly with densities of anaerobic bacteria. The greatest risk was observed where three are more cytokines were detected. These findings lead the researchers to conclude that the response of the immune system to shifts in the penile microbiome facilitate infection by HIV.

Of course, this is precisely the mechanism that may account for the increased susceptibility to STI (including HIV) in women with FGT deficient in L.c.. However, the problem can be largely resolved in the case of men by means of circumcision.

The authors also make the interesting point that the bacterial dysbiosis that they observe in the male microbiome may be passed on to women through sexual activity – so that the genital microbiome is, to some extent, ‘shared’ between them. Presumably, this could also mean that voluntary male medical circumcision reduces this risk of HIV transmission for women as well as men to the extent that women are at less risk of infection with bacteria that render them susceptible to HIV.

Achieving UNAIDS 90-90-90: More haste less speed?

31 Aug, 17 | by Leslie Goode, Blogmaster

UNAIDS (2014) has set targets for HIV management that seem ambitious, if not unrealistically so  (UNAIDS: 90-90-90): 90% of those living with HIV to know their status; 90% of known HIV+ individuals to undergo ART initiation; 90% of ART+ initiated to achieve viral suppression. A one-year-in report from a large cluster-randomized study of home-based testing and treatment in four Zambian communities, HPTN-071 (Hayes & Fidler (H&F)), recently discussed in this blog (Mountainous challenge of 90-90-90/STI/blogs), suggests that engagement with care may constitute a significant challenge. It gives rates of engagement after six months and one year of care of 42% and 53% respectively. It also confirms what earlier studies (Schwartz & Baral/STIs)  ( say about the difficulty of attaining this second target. Estimates as of 2015 for engagement with care in southern and eastern Africa range from 17% to 78% (Wringe & Skovdal/STIs).

Against this somewhat gloomy backdrop, the 2016-17 results from the Swaziland HIV Incidence Measurement Survey (SHIMS2)( from a house-hold based national survey strike a surprisingly hopeful note. 84% of people living with HIV (PLHIV) aged 15 or over report knowing their HIV status; 87.4% of PLHIV knowing their status self-report current use of ART; 91.9% of PLHIV on ART are virally suppressed. Furthermore, rates of response to the survey, at 84.5% (=6,417 eligible households) are impressive. However, PLHIV who are diagnosed but not engaged in care and PLHIV who have become disengaged from care are notoriously difficult to reach (Wringe & Skovdal (STIs)), and likely to be among the non-respondents.

So maybe there is some hope that the UNAIDS targets can be realized by the deadline of 2020 …..

Yet amidst all the anxiety to achieve these targets, a series of qualitative studies reported in the recent supplementary issue of STIs sound a note of caution (STIs: July 2017: 93-3: Understanding the Bottlenecks). This work emphasizes the importance of clients’ personal experiences of health care as a factor in determining likely success in terms of retention in care over time. Among factors likely to have an impact are the painful or disagreeable side-effects from treatment (Renju & Wringe (STIs), or the coercive nature of testing itself (Wringe & Renju (STIs). They also include the attitudes of health-care workers, who are often ‘expert patients’, as well as inappropriate or pressurizing assumptions that test social and moral expectations regarding women’s relationship with men and invoke their moral duty as mothers (Kielmann & Cataldo (STIs). In short, achievement of the benefits of viral suppression requires cooperation of individuals over the longer-term. This in turn depends on trust and good will that are easily forfeited where the pressure to achieve quick results leads health systems to overlook the dimension of personal experience.

Why STI-induced infertility can also be a male problem.

2 Aug, 17 | by Leslie Goode, Blogmaster

Among long-term sequelae of STI that are asymptomatic and may consequently remain untreated are a number that affect men.  The condition of Chronic Pelvic Pain Syndrome (CPPS) has recently been discussed by Kenyon & Horner (STI), along with the feasibility of its treatment in the STI clinic (Crofts & Horner (STIs); Crofts & Horner (II) (STIs)).  But another important, and much dreaded, consequence of untreated STI in heterosexual men is infertility or sub-fertility.  It should not be forgotten that this is potentially a male problem – not just in the sense that it affects men, but because, in many cases, it is STI-induced damage to the genital tract of the male rather than the female partner that gives rise to the condition.

This male aspect of STI-induced infertility constitutes the topic of a recent review paper by Schuppe & Weidner (S&W).  A key finding cited (Schuppe & Hardt), apparently originating from work by same team of authors, is that a remarkable 25% of testicular biopsies obtained from infertile men reveal focal inflammatory reactions.  Of these, only 2% reported any previous episode of orchitis.  Yet, when it comes to determining the pathogens responsible for male infertility (which could be uropathogens as well as STI), current evidence allows us to draw few conclusions.  The same is true regarding the mechanisms by which these pathogens have an impact on male fertility.  Finally, it is not possible to  establish with any certainty the proportion of total cases of male infertility for which STI are responsible. Of course, where acute epididymitis is involved, there is evidence for azoospermia (c.10%) or oligospermia (c.30%).  Here the authors are reassuring as to the non-persistence of these effects (Pilatz & Linn). But where cases of STI are asymptomatic, they do not, of course, figure in information for ‘accessory gland infection’ as defined by WHO criteria.

Regarding the pathogens implicated, the investigations of the role of Mycoplasma genitalium (see Idahl & Fredland (STI)) and HPV viruses have produced conflicting results; Trichomas vaginalis has no significant effect.  As regards the mechanism, S&W consider evidence relating to reduced sperm motility, oxidative damage and immune-mediated infertility, but reach no very firm conclusions. As for the proportion of male infertility attributable to STI, the authors point to the variation in rates of infertility (between 9% in Germany and 30% in countries with less adequate healthcare) as offering some indicator.

Despite the inconclusiveness of these findings, the review has the merit of drawing attention to an aspect of STI that seems to receive relatively infrequent attention in these pages.  The authors recommend ‘systematic diagnostic evaluation and appropriate treatment’ where there is any suspicion of infectious disease.  However, they look forward to the day when the elucidation of mechanisms and the identification of biomarkers may enable more ‘conservative’ strategies of management.

Vertical HIV transmission may be influenced by complex synergies with other STI – such as Cytomegalovirus

26 Jul, 17 | by Leslie Goode, Blogmaster

The apparently greater susceptibility of sub-Saharan African women to HIV infection has led researchers to consider the various potential synergies between HIV and other genital infections (White & Glynn (STIs); Lurie & Matthews (STIs)) or conditions of the vaginal microbiome (The susceptibility of heterosexual sub-Saharan women (STI/blog)).  A recent study, Adachi & Nielson-Saines, brings this wider perspective to bear on mother-to-child transmission, casting some fresh light on the complex interrelation between the ‘vertical’ transmission of HIV and active and Cytomegalovirus (CMV) viruria.

The study is a late spin-off from HPTN-040 (reported in a 2012 paper by Nielson-Saines & Mofenson IN&M).  This compared the efficacy of different post-partum ART regimes for HIV infected children.  The original participants were c. 1,700, largely S. American women who presented in late pregnancy with HIV.  Matched urine specimens were available for 264 mother-child pairs.  Researchers returned to these specimens after the closure of the main trial in order to investigate through PCR testing the impact of CMV viral shedding on vertical transmission of Cytomegalovirus (CMV) and its concomitants.

The results were as follows.  Out of the 264 maternal urine samples 24 (9.2%) showed evidence of CMV shedding. Matching these maternal samples with infant samples revealed vertical CMV transmission in 10/264 cases.  Five of these were from among the 24 with maternal shedding (20.8%); five were from among the 240 without shedding (2.1%).  When the ratio of transmissions with shedding to transmissions without shedding was adjusted for mode of delivery, maternal gonorrhoea and maternal HIV viral load, it came out at 29.7%.   Women with CMV viral shedding also showed significantly higher odds of HIV transmission to their infants (aOR = 5.6%).

These findings are striking; but what is their relevance?  Maternal CMV shedding may indeed be a very good marker of vertical CMV and HIV transmission.  Presumably, however, health workers would give appropriate anti-retroviral therapy to 100% of infants at risk of HIV infection in any case – and anti-retroviral therapy has been shown to deal successfully with the CMV, without the need to give additional, and potentially toxic, drugs specifically for the CMV (Anfumborn & Tejiokern). So N&M’s research have little implications for management of these infections.

However, their importance may lie in showing how the problem of HIV – including vertically transmitted HIV – cannot be isolated from the wider problem of STI and sexual health in general. Maternal HIV may, for example, increase the likelihood of CMV transmission, and CMV infection of the infant may, in turn, lead to a more rapid progression of HIV.  Complex synergies with vertical HIV transmission may operate in the case of other STI as well – such as HSV-2 (Sivarajah & Tan (STIs)).  So the messages to take away may include not just ‘the necessity of controlling maternal HIV infection during pregnancy through cART’, but also the importance of STI control – above all through the promotion of practices of safe sex.


The challenges and achievements of conducting a multi-country qualitative study to explore the Bottlenecks to HIV care and treatment in sub-Saharan Africa

24 Jul, 17 | by lfountain

Blog post by Joyce Wamoyi1, Dominic Bukenya2, Robert Ssekubugu3, Alison Wringe4 and Jenny Renju4

  1. National Institute for Medical Research, Tanzania
  2. Medical Research Council, Uganda
  3. Rakai health Sciences Programme, Uganda
  4. London School of Hygiene and Tropical Medicine, UK

A newly published supplement to Sexually Transmitted Infections on the HIV Bottlenecks study presents the multiple tensions that exist between HIV programmes and the complex social realities that characterize the lives of PLHIV in seven health and demographic surveillance sites (HDSS) across sub Saharan Africa.


To tweet or not to tweet?

4 Jul, 17 | by Leslie Goode, Blogmaster

Blog post by Katy Turner (@katymeturner)

Who is responsible for tweet etiquette at conferences? Organisers? Presenters? Tweeters?

Conference organisers can certainly set the tone for an event with pronouncements like this one:

Tweet from Trish Groves (@trished)

Clear guide #ICTMC2017 on seeking permission to blog, tweet, take pics (I should’ve read this sooner)


This feels rather heavy handed and puts all the responsibility onto tweeters to “get permission” which rules out real time tweeting and could limit or even censor open discussion of ideas including the community outside conference attendees. I am going venture that the above was written by someone (or a committee of someones) who doesn’t “tweet”.

In our connected 21st century world, most conferences actively encourage tweeting. There are some excellent guidelines e.g. Ten Simple Rules of Live Tweeting at Scientific Conferences
( These are aimed at conference organisers e.g. choose a short hashtag (and check for unexpected clashes), publicise hashtag, encourage tweeting, use twitter to enable questions from outside and tweeters (mechanics of what to tween and how to tweet responsibly).

What about the presenters themselves? Conferences are exciting because they are a place to share new ideas with the other 3 people in the world similarly passionate about modelling sexually transmitted infections (or whatever floats your boat). Tweeting can widen and broaden the conversation and include people inside and beyond the conference. How can we continue to extend and diversify the conversation, whilst also protecting unpublished research and intellectual property?

Here are my top tips for presenters

1) Visual cues on all slides as tweetable or not

Presenters can indicate how much tweeting of their talk is acceptable. This doesn’t need to be onerous. I used the following stickers on all my slides when I had early unpublished results in a couple of slides that I didn’t want tweeted (FIgure 1). Simple to explain and use.

Figure 1 To tweet or not to tweet


2) Accurate informative reference information on all slides which include published data large enough to actually read

Ideally, references will be open access so tweeters can then help publicise the research by locating references and linking during the talk (I find this really useful as a twitter consumer) as well as linking to other relevant material the tweeter may be aware of.

3) Make slides tweet- (and audience-) friendly

Large, bold graphics and clear visual message make better tweets (and slides) than a table of numbers or list of bullet points.

If you have any other ideas for making tweeting work better for you during conference season we would like to hear from you.

Does it ever make sense to target HPV screening at HIV-infected individuals?

4 Jul, 17 | by Leslie Goode, Blogmaster

A number of recent studies have considered the case for HPV-related cancer prevention interventions that are targeted at specific populations. In the developed world, interventions of cervical screening and teenage vaccination aim to cover the female, or male and female, population (at a certain age) in order to prevent cervical cancer.  The question of more targeted interventions generally arises in relation to MSM – and especially HIV+ MSM – on account of their heightened risk of HPV-induced anal cancers.  There has been a marked rise in these cancers since the 1980s.  Unlike cervical cancers in heterosexual women (which decline with age), anal cancers are prevalent in MSM of all ages (Poynton & Grulich (STI)) – possibly reflecting higher rates of exposure through new partners.  Particularly high rates of anal cancer in older MSM living with HIV may be attributable to long-term immunologic defects in this population (van der Laar & Richel (STI)).  Elevated HPV rates have also been shown in sexual minority women (Reiter & McRee (STI)).  Of course, the problem of anal cancers in MSM could be resolved through vaccination of adolescent boys.  However, a recent UK study has investigated the feasibility of delivering a targeted HPV vaccination programme to adult MSM through STI clinics (Bayley & Soldan (STI)).

In developing countries, there could also be a case for targeting HPV screening – but for the prevention of cervical cancer in heterosexual women, rather anal cancer amongst MSM.  In most parts of sub-Saharan African, and other limited resource settings, neither cervical screening nor widespread adolescent vaccination have proved feasible, and rates of cervical cancer are relatively high (WJCO: Cervical Screening in Limited Resource Settings).  Here, Whitham & Kulasingam (W&K) have argued in a recent analysis of the evidence from six longitudinal studies undertaken in Senegal from 1994-2010, that some targeting of the available resources towards women who are HIV+ is justified given their considerably elevated levels of risk.  Like the HIV+ MSM in the studies mentioned above, HIV+ heterosexual women, according to W&K, have much higher rates of progression from HPV to high-grade squamous intraepithelial lesions (HSIL) (HR 2.55 times), as well as higher levels of progression from normal to HPV, and from normal to HSIL (respectively, HR 1.53 and 1.58). These rates corroborate the results of earlier studies (e.g. Mayaud & Lacey (STI)) that suggest high-risk HPV types and a tendency to HSIL in HIV+ in the older female population.

These findings prompt W&K to recommend, in the sub-Saharan setting, the policy of targeting of HPV vaccination to the HIV+ population recently proposed in the developed world for HIV+ MSM.  Unfortunately, various problems make such an intervention considerably less feasible in the case of sub-Saharan HIV+ women.  First, the sheer prevalence of HPV amongst the target population make HPV testing inefficient as a stand-alone screening strategy and tends to reduce its positive predictive value.  Second, the tests current in the West (cytology and Hybrid Capture 2) require laboratory equipment and technician expertise not likely to be available in Africa.  On the latter point, however, W&K note that the recently developed careHPV test may offer a more effective alternative to Visual Inspection with Acetic acid (VIA).

Can laboratory-guided treatment of gonorrhoea with ciprofloxacin help to stem the emergence of resistance to ceftiaxone?

28 Jun, 17 | by Leslie Goode, Blogmaster

With antimicrobial-resistant gonorrhoea now an urgent health threat, requiring improved antibiotic stewardship, one option frequently proposed is laboratory-guided recycling of older antibiotics (Lewis (STI); Ison & Unemo (STI); A new kind of treatment for gonorrhoea? (STI/blogs)).  Lewis (STI) alludes to the potential use of floroquinolone therapy – specifically in respect to the oropharyngx, which is the site at which treatment failure is most likely to occur.  Epidemiological typing to detect markers associated with antibiotic resistance makes this kind of intervention a real possibility (Graham & Jennison (STI).

Lao-tzu & Klausner (L&K) have recently reported a trial that claims to demonstrate the feasibility of just the kind of therapy envisaged by Lewis.  The researchers at University of California Los Angeles (UCLA) Health Clinical Microbiology Laboratory developed and implemented a molecular assay for the prediction of gonorrhoea (Ng) ciprofloxacin susceptibility.  Over the period from November 2015 to July 2016 all Ng positive specimens were subjected to the assay, and treatment recommendations issued on that basis.  In the final two months (June-July 2016) electronic reminder notifications were introduced – and it was only at that point that the intervention had any substantial impact on the treatment of patients.

Of the 176 infections detected, 121 (69%) were successfully genotyped.  Of the latter, 72 (60%) showed wild-type gyrA (the gene associated with antimicrobial resistance, 49 (40%) were mutant.  In the final successful two-month phase of assay implementation, this enabled 9 out of 11 (82%) of Ng infections to be treated with ciprofloxacin. The authors claim this shows the potential for laboratory-guided treatment of floroquinolones to limit recourse to ceftriaxone – and thereby slow the emergence of antibiotic resistant Ng.  Clearly, the trial needs to be run again, but this time using electronic reminder notifications from the start.

When it comes to the more specific issue of antimicrobial resistance to Ng at the oropharyngeal site, the results of the study are less promising. The proportion of gyrA mutant Ng infections did not vary significantly by site (pharyngeal 33%; rectal 45.7%; vaginal/cervical 57%; urine 39%); but of the 62 pharyngeal infections, most (40) could not be genotyped.  So laboratory-guided ciprofloxacin treatment would be of limited usefulness in key populations – such as MSM.




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