Kit Fairley (http://sti.bmj.com/content/87/Suppl_2/ii25.full)  in this journal offers an overview of the many ways in which information technology can be used in the area of STIs.  This is most obviously through the role of electronic medical records (EMR); but also through the possibility these offer for clinical decision support systems that can be used to generate prompts and reminders.  Information Technology (IT) has also opened up possibilities such as computer assisted self-interviewing (http://sti.bmj.com/content/86/4/310.abstract?sid=07f1ed96-1c3f-4a99-9da5-58f02157ea9e), provision of wider access to counselling services, facilitation of partner notification.  If Gaydos et al.  are on the right track (http://www.iwantthekit.org), IT may one day “completely change the way services are provided”.  A number of papers published by STIs have focussed on trialling short message system reminders for re-testing/re-screening.  These have been show to have some effectiveness in the area of Chlamydia screening (http://sti.bmj.com/content/89/1/11.abstract?sid=07f1ed96-1c3f-4a99-9da5-58f02157ea9e; http://sti.bmj.com/content/89/1/16.abstract?sid=07f1ed96-1c3f-4a99-9da5-58f02157ea9e; http://sti.bmj.com/content/87/Suppl_1/A258.3.abstract?sid=07f1ed96-1c3f-4a99-9da5-58f02157ea9e) and in the area of MSM HIV retesting achieved a fourfold increase in uptake (http://sti.bmj.com/content/87/3/229.abstract?sid=07f1ed96-1c3f-4a99-9da5-58f02157ea9e).

A recent randomized control (RCT) study from a USAID-funded paediatric referral clinic in Kenya (Were & Vreeman), however, points to one impressively fruitful application of IT to STIs which seems to have failed to attract the attention it deserves (http://pediatrics.aappublications.org/content/131/3/e789.abstract?sid=f4698a8a-9724-4227-8896-3a9f57f92729).  In limited resource settings the complex process of pediatric HIV follow-up seems particularly apt to benefit from EMRs that can generate prompts to clinicians – especially where such staff are less than adequately trained, or are subject to high rates of turn-over, or overwhelmed by patient demand.  The reminders generated through this clinical decision support system (CDSS) include PCR tests, CD4 tests, ARV reminders, as well as baseline chemistry & hematology studies, chest X-rays and malnutrition reminders.  The RCT study claims a nearly fourfold improvement in adherence to protocols overall – admittedly with some procedures (e.g. chest x-rays, laboratory tests other than ELISA) benefiting enormously more than others (e.g. initiation of ART ).  Of course, the effectiveness of such reminders, as the authors emphasize, ultimately depends on the quality of the input data informing the “summaries” from which reminders are generated.

The effectiveness of CDSS in this area seems less remarkable than the apparent absence of studies like that of Were & Vreeman.  The authors cite studies of the use of computer-based alerts and reminders for HIV care in the US, and a comparative study between 2 clinics of a system of computer-generated reminders for CD4 testing of adults.  But, “rigorously controlled trials of CDSS effectiveness in resource-limited settings could not be found”.  The authors conclude that pediatric HIV care in limited resource settings is one area where the application of technology has the potential dramatically to improve compliance with protocols.  Such a claim seems to warrant further investigation.

Quadrivalent HPV vaccination (qHPV) for adolescent girls is recommended and publicly financed in a number of countries.  This intervention promises to prevent up to 70% of HPV generated cancers in those vaccinated, as well as vastly reducing the burden of genital warts (GW).  In relation to prevention of HPV generated cancer and cancerous lesions, its effective contribution will need to be evaluated in relation to cervical screening, and as part of an overall cancer prevention strategy: the question of the right mix of interventions, including vaccination and its relation to the method and interval of screening, are questions of ongoing debate.  Regarding HPV generated GW, however, it may already be possible to score up certain gains.

A recent Swedish national cohort study of 2.2 million women aged 10-44 years offers evidence of the effectiveness of qHPV in relation to genital warts (GW) that complements the findings of clinical trials regarding its therapeutic efficacity (http://jnci.oxfordjournals.org/content/105/7/469.abstract?sid=e0d178cd-8985-42e4-b934-201c858ca42e). The results of efficacity trials follow pre-specified inclusion criteria and are consequently not generalizable.  Now, however, thanks to the rigorous registration of patients and treatment in Sweden, these researchers have been able, so they claim, to gain an insight into the effectiveness of the vaccine – better than would been possible in many other countries.  Results are stratified by age: vaccine effectiveness was 93% against GW where administered at under 14 years;  80% for girls aged 14-16 years; 71% for those aged 17-19; 48% for those aged 20-22 years; and effectively zero for those above 22 years.  This study confirms at the level of national surveillance the general picture offered, at the level of the STI clinic, by Read & Fairley’s account of the “near disappearance” of heterosexually transmitted GW from  vaccinated <21 years, four years after the introduction of a qHPV program in Melbourne, Australia (vaccination restricted for three years to girls ≤26 years and thereafter to 12-13 years) (http://sti.bmj.com/content/87/7/544.abstract?sid=58e7950b-ccdf-4899-b67b-c7ad3b00081d).

Given the steep decline in effectiveness of qHPV for girls aged >13 years as indicated by these studies, it is disquieting to discover in a recent study of US parents expressing their non-intention to have their teens vaccinated with qHPV that as many as 11% of them gave as the reason that their children were “not yet sexually active”.  The study (Darden & Jacobson) was initiated on the basis of data from the National Immunization Survey, and involved asking parents of children who were “not-up-to-date” with qHPV (along with Tdap and MCV4) and who further indicated their non-intention to vaccinate, the reasons for their decision (http://pediatrics.aappublications.org/content/131/4/645.abstract?sid=082b138f-5a8d-47c5-bf41-5c45d343b129).  The percentage of US girls in the immunization cohort taking up the full three doses of qHPV has increased over the three years 2008-2010 from 17.9% to 32%, but remains substantially below that for Tdap and MCV4 (81.2% & 62.7% for 2010 as against 32%); there is a rising percentage giving as reason for non-vaccination “safety concerns/side effects” – rising over the three years from 4.5% to 16.4%.

The long term implications of incorporating qHPV into the STI toolkit are very unclear, though the reduction of GW is, of course, very welcome.  Aside from the much discussed question of how the choice of cervical screening method should complement vaccination in a post qHPV era (http://sti.bmj.com/content/87/Suppl_1/A14.3.abstract?sid=190a5031-ecc8-4f7f-a4bc-1411d34798f1) there is the question of how a woman’s knowledge that she has been vaccinated is likely to impact on her behaviour in relation to cervical screening (http://jms.rsmjournals.com/content/18/1/41.full.pdf+html?sid=9162f5ac-9762-43c5-bcd8-5e09044c2368;

http://ruizscience.webs.com/HPVvaccineCervicalCancerScreening.pdf).  If we suppose a moderate level of HPV cover combined with a partial collapse in cervical screening compliance what will be effect on the incidence of cervical cancer? Given many health systems are already embarked on the route of qHPV vaccination, it is imperative to maximize the vaccination uptake.  The study of Darden and Jacobson may indicate the challenge posed, with the integration of qHPV into the toolkit, by the urgent need to ensure we communicate the right public health messages.

Congenital syphilis (syphilis transmitted from mother to child (MTCT)) remains a scourge in many low- and middle- income countries (LMIC) causing stillbirth and neonatal death.  This is despite the existence of inexpensive, cost-effective and feasible testing and treatment – and despite the fact that a majority of pregnant women, even in LMIC, attend antenatal clinics (ANC), where such testing and treatment could, in principal, be offered.  A recent multi-country study, for example, found levels of testing of 1.7% and 17.8% respectively in rural ANCs in Uganda, and 51 health facilities in Tanzania (http://blogs.bmj.com/sti/2012/06/25/sustained-health-systems-strengthening-holds-the-key-to-prevention-of-mother-to-child-transmission-of-syphilis/).  The year 2007 saw the launch of a WHO initiative for the Global Elimination of Congenital Syphilis, with the goal that by 2015 ≥90% of pregnant of women should be tested.

One complicating factor of any public health policy where syphilis is concerned is the difficulty of establishing definitive diagnosis.  This complicates the task of quantifying MTCT and assessing progress in eliminating it. It also makes it difficult to evaluate screening tools, such as the relatively recent point-of-care tests (POCT) that promise to extend effective diagnosis to countries without a robust laboratory infrastructure.   In both cases – the assessment of the scale of MTCT, and evaluating screening tools – researchers have had to find a way round the absence of a good reference standard.  Two recently-published papers have addressed themselves to these problems.  One is an analysis of global surveillance data (Newman & Broutet) using modelling to estimate total global adverse outcomes from syphilis, and the impact on these outcomes, of testing in ANCs for the year following launch of the WHO initiative (2008) (http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001396).  The other (Jafari and Pai) addresses itself to evaluating the diagnostic accuracy of POCT, employing the technique of Bayesian analysis to get round the problem of an inadequate reference standard for syphilis (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054695).

Newman & Broutet estimate global adverse events for 2008 at 521,000, including 212,000 stillbirths and 92.000 neonatal deaths.  This provides a baseline for evaluating subsequent progress.  Of the adverse events, 66% are estimated to involve women who attended ANCs – which indicates the potential improvements that might be achievable through ANCs.  As things were in 2008, testing and treatment by ANCs was reckoned to have averted a quarter of the adverse events that might otherwise have been expected;  the model predicts that achievement in 2008 of the 2015 WHO target for testing in ANCs would have eliminated over half of these events.

So much then for the potential for improvement.  Such future developments will be dependent on the success of POCTs, which promise both an inexpensive form of screening without the need for laboratory infrastructure, and the possibility of same day treatment for ANC attendees.  There remains the question of their effectiveness compared with traditional methods of diagnosis.  Here again the difficulty of establishing definitive diagnosis has been a problem.  The absence of a reference standard has, according to Jafari & Pai, impeded the comparative evaluation of POCTs.  A recent meta-analysis of electronic databases using a Bayesian hierarchical latent class model has attempted to put a figure on sensitivity and specificity of four globally used POCTs with both serum and whole blood samples. These estimates are comparable of those for lab-based testing: with serum (sensitivity/specificity) Determine 90.04/94.15; SD Bioline 87.06/95.85; VisiTect 85.13/96.45; Syphicheck 74.48/99.14; with whole blood Determine 86.32/95.85; SD Bioline 84.5/97.95; VisiTect 74.26/99.43; Syphicheck 74.47/99.58. As it turns out, these estimates are close to those of Mabey, Zheng et al., using treponemum pallidum haemagglutination assay or fluorescent treponemal antibody absorbed as a reference standard (http://sti.bmj.com/content/82/suppl_5/v13.full.pdf+html).

POCTs have also been shown to be cost effective (http://sti.bmj.com/content/82/suppl_5/v38.abstract?sid=82a53292-0a5a-46d1-a01d-9cf6bbade9ae).  So a substantial reduction of syphilis related adverse events seems achievable even in LMICs – if they can meet the training and organizational challenges to deployment of POCTs in ANCs.   According a recent paper of Mabey & Peeling, it is this latter area of health service organization that we find the greatest obstacle to delivering the promise of POCTs  (http://blogs.bmj.com/sti/2012/06/25/sustained-health-systems-strengthening-holds-the-key-to-prevention-of-mother-to-child-transmission-of-syphilis/).

It is a criminal offence in the UK (as in some other countries) to transmit HIV “intentionally” or “recklessly”.  Community advocates claim there have been over 200 investigations in the UK regarding HIV transmission on grounds of recklessness, leading to 20 prosecutions (http://www.hivandthelaw.com/information/fast-facts).  (Canada & the US lead the world for HIV criminalization with a combined total over 300 convictions).  How does the threat of prosecution impact on sexual health services and the relations between sexual health providers and users?

A report of the qualitative research study Keeping Confidence (Dodds, Weatherburn et al.) considers how the criminalization of HIV transmission in the UK is perceived by clinical and voluntary service workers on the basis of evidence provided by seven focus groups (http://sigmaresearch.org.uk/projects/policy/project55/).  Sections of the report deal with: how well staff understand the UK law (1); in what circumstances the topic of criminalization arises in their dealings with service users (2); how they perceive the responsibilities both of service users and of themselves in respect to “criminal” HIV transmission (3); what access they have to information and guidance (4).

Not surprisingly, participants see their primary function as meeting the needs of their patients, rather than those of their patients’ partners (2).   The issue that elicited the liveliest debate among participants concerned whether they saw themselves as having, in addition, some measure of responsibility for protecting third parties – i.e. patients’ partners or the health of the public more generally (3).  Participants sometimes spoke in general terms of using the threat of the law to alter behaviour – which would suggest the recognition of some such wider responsibility.  But this may seem hard to reconcile with the widespread negative perception of the impact of criminalization on health care, with no positive benefit being anticipated from prosecutions, either for the individuals concerned or for public health generally.  The authors comment on the disagreement between those clear about where they placed responsibility, and those who were more inclined to problematize situations – or, in the rather unsympathetic terms of the authors (and maybe of those taking the former position?) “having unresolved personal dilemmas”.  Interestingly, the latter position tended to be occupied by those in junior and non-managerial roles.

The least satisfactory section of this report is the first.  It seems doubtful whether it is possible to conclude that participants “get the law wrong” or “elide their own subjective understanding …. with the technical legal definition of recklessness”, as the authors claim, on the basis of the kind of statements cited in the report.  So we remain largely in the dark, therefore, about the true state of the participants understanding of the law.  Why not assess participants’ knowledge by an individual written test, using multiple choice questions?  Surely this would work better than seeking indications of knowledge in the statements that were clearly meant to communicate a perception or express a view in the context of a lively discussion with fellow participants?

STI readers and (potential) contributors may be interested to hear that STI will be publishing a Special Issue on HIV criminalization, guest-edited by David Gurnham, later in the year, in collaboration with two other BMJ specialist journals – The Journal of Medical Humanities and The Journal of Medical Ethics.

Earlier blogs have featured the disquieting propensity of neisseria gonorrhoea to evolve resistance to every known line of treatment (http://blogs.bmj.com/sti/category/gonorrhoea/).  Surveillance data indicate the prevalence of the infection in core populations, and the importance of focussing treatment on them ( http://sti.bmj.com/content/85/5/317.abstract?sid=c28b9898-65c9-4548-a10e-9f6ebade86f9); at the same time this is precisely the strategy most likely to disseminate resistance (http://sti.bmj.com/content/88/3/200.abstract?sid=c28b9898-65c9-4548-a10e-9f6ebade86f9).  The quandary that this represents for public health is all the more serious, now that resistance seems to be emerging in cephalosporins, which are our last line of defence – with no new anti-biotic therapies in the pipeline (http://sti.bmj.com/content/86/6/415.abstract?sid=c28b9898-65c9-4548-a10e-9f6ebade86f9).

This brings an urgency to the question dealt with in a recent paper by Allen and Low (http://www.ncbi.nlm.nih.gov/pubmed/23299608): namely, what the state of the clinical evidence actually is on cephalosporin resistance in gonorrhoea leading to treatment failure.  Since the late 90s, pharmacokinetic analyses across the world have identified gonorrhoea isolates showing increasing levels of resistance to cefixime – with minimum inhibitory concentrations (MIC) rising to ≥0.12 μg/mL.  There have also been reports from Japan, UK, Norway France and Austria of cefixime treatment failure due to isolates with cefixime MIC at ≥0.12 μg/mL.  Currently lacking, however, are studies that demonstrate and evaluate the relationship between cefixime resistance and treatment failure in clinical settings – no doubt on account of the de-normalization of testing for cure and of culture-based methods of detection.   Allen & Low seeks to fill this gap for North America by means of a longitudinal cohort study in the context of a Toronto clinic where both testing for cure and culture-based detection remain routine practice.

Of the 133 (out of 291) participants returning for repeat-testing, 13 appeared to have treatment failure, of whom 9 provided explicit denial of sexual re-exposure.  Assuming an equivalent level of treatment failure for non-returners as for returners, the study demonstrates clinical treatment failure of 6.77% – which exceeds the 5% threshold established by CDC and WHO for an acceptable treatment.  As regards the relationship of cefixime resistance to treatment failure, the study finds  a treatment failure rate of 25% for gonorrhoea with a cefixime MIC of ≥0.12 μg/mL, and a failure rate of 1.9% for gonorrhoea with cefixime MIC <0.12 μg/mL.  This is worrying when seen against the background of the trend indicated by pharmokinetic data for the years 2000-2010 from the US CDC which shows the proportion of gonorrhoea with cefixime MIC of ≥0.25 μg/mL rising from 0.2% to 1.4%, and data for the same years from Canadian Surveillance Program showing the modal cefixime MICs rising from 0.016 to 0.12 μg/mL.  The US CDC now recommends as sole preferred treatment ceftriaxone, 250g,  intramuscularly combined with either azithromycin, 1g orally, or doxycyline 100mg, orally twice a day for 7 days as sole preferred treatment regimen.  But resistance in ceftriaxone is following the same trend as in cefixime: pharmokinetic data for the years 2000-2010 from US CDC show the proportion of gonorrhoea with ceftriaxone MIC  ≥0.12 μg/mL rising from 0.1% to 0.3%, data from the Canadian Surveillance Program show modal ceftriaxone MICs rising from 0.016 to 0.063 μg/mL.  The elimination of ceftriaxone would leave the world of bereft of any known effective defence against the onset of gonorrhoea.

Reports of modest success from two trials (2010) of tenofovir as pre-exposure prophylaxis against HIV (PrEP)– CAPRISA 004 (1) (topical gel/women) relative risk reduction (RRR) 39%; iPrEX (2) (oral tablet/MSM) RRR 44% – have inspired recent contributions to STI journal.  In particular, there have been attempts to model the possible impact on the epidemic of incorporating PrEP in the toolbox of interventions (STI 2011; 87: suppl. 1, see especially: http://sti.bmj.com/content/87/Suppl_1/A36.1.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9; http://sti.bmj.com/content/87/Suppl_1/A350.2.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9): also studies evaluating the potential acceptability of PrEP in various settings (see: http://sti.bmj.com/content/early/2012/09/25/sextrans-2012-050648.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9; http://sti.bmj.com/content/88/4/258.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9).

Further tenofovir PrEP trials have produced results that are puzzlingly varied, and, given the hopes placed in PrEP as a preventative tool, somewhat disappointing:  CDC TDF2 (3) (oral tablet/heterosexual partners of men/women of indeterminate HIV status) RRR 62%; Partner’s PrEP (4) (oral tablet/heterosexual partners of HIV+ men/women) RRR 75%;  FEM-PrEP (5) (oral tablet/women) discontinued for futility; VOICE (topical gel/women) discontinued for futility. This has prompted some reflection on the efficacy of large RCT of the kind, with the discussion focussing on the difficulties around adherence (http://sti.bmj.com/content/87/Suppl_1/A196.3.abstract?sid=778e710d-42a6-4de3-a7e3-b9cd3f22a57e).  Crucially, Hendrix discusses the problem of disentangling the drug-related factors from issues of adherence (http://sti.bmj.com/content/87/Suppl_1/A1.4.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9).

One complicating factor in assessing tenofovir PrEP trial results is the use of two “routes” – oral tablet and topical gel – likely to produce concentrations of the drug at different anatomical sites.  This issue has now been taken up in an important recent paper (Hendrix & Bumpus) reporting the results of Microbicide Trials Network (MTN) study 001 (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055013).  In discussing pharmacokinetic issues, this paper also deals with the role of adherence as an explanatory variable in a way that casts an altogether fresh light on the issues Hendrix tackles in the above-cited paper (http://sti.bmj.com/content/87/Suppl_1/A1.4.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9).

MTN-001 is a crossover study in which all participants were assigned to a randomized sequence of daily tenofovir orally vaginally, or both orally and vaginally in three 6-week periods.  The key finding is that the concentration of the drug in its active form tenofovir disphosphate in vaginal mucosa achieved by the gel is 130-173 times greater than that achieved by the tablet; whereas the concentration in the serum and peripheral blood mononuclear cells (PMBC) achieved by the gel is respectively 58 and 56 times less.

It has generally been assumed that it is vaginal tissue concentration of the drug which gives protection.  One possible conclusion we might draw from these findings is that vaginal tissue is not, in fact, the critical site of ARV action.  The problem is that CAPRISA 004 (1) demonstrates that vaginal gel is having some effect through the vaginal compartment; yet that effect – given that it exists – is not at the level that might have been anticipated given 1. the increased HIV protection, and, especially, 2. increased toleration of missed doses, that we would expect from such a concentration. The second point is particularly important given the weight attached in this discussion to adherence as an explanatory variable.  With the half-life of elimination of tenofir diphosphate an estimated 90 hours, women having dosed once with gel could stop all dosing for more than 2 weeks before their vaginal tissue concentration fell to the vaginal concentrations achieved in oral dosing!  Hence, non-adherence appears not to be a plausible as a sole explanatory variable.  Something else must be going on.  But what?  The authors suggest, first, the possibility of tissue toxicity either from the tenofovir or the gel vehicle; second, some other factor that we are as yet unable to determine.

The authors conclude, naturally, that identification of the unknown variable is essential to improving future PrEP development…

The year 1939 saw total US syphilis deaths at 15 per 100,000 and syphilis deaths of black males at 72.5 per 100,000: this is a death rate comparable to that for HIV/AIDS at the height of the epidemic in 1995 when total deaths and deaths of black males stood, respectively, at 16.2 and 80.2 per 100,000.  Subsequently, in the late 40s and early 50s, incidence and mortality from syphilis were to fall precipitously – thanks to penicillin.  A recent paper in the Archives for Sexual Behavior by an economist, Andrew Francis, argues for the importance of this collapse in the “cost” of syphilis in spurring the sexual revolution (http://link.springer.com/article/10.1007%2Fs10508-012-0018-4). His exploration of this hypothesis prompts general reflection on the link between the “cost” of disease (which he equates with absence of an effective treatment) and sexual behaviour.

The paper correlates data across US states on syphilis incidence and mortality with measures of “risky non-traditional sex” – which, in the context of the poverty of relevant data for the period, is evaluated on the basis of gonorrhoea rate, illegitimate birth ratio and teen birth share.  Coefficients are given from regressions of measures of sexual behaviour on indicators for the number of years since syphilis collapse (which varies by state).  As regards illegitimate birth ratio and teen birth share, a positive correlation emerges which goes back as early as three years or less from syphilis collapse; gonorrhoea, however, continues to decline from its WW2 peak, as we might expect.

Ultimately, however, Francis’s argument rests also on the claim that his own explanation of sexual revolution fits the facts better than the alternative explanations, of which the most familiar is that “anti-conception technology”, especially the pill, played a decisive role.  Francis admits that, from the late sixties, conception technologies and measures of risky behaviour increase simultaneously.  Yet measures of risky sexual behaviour, he claims, had already been rising sharply for a decade before anti-conception technology began to make its impact.  His own data show that the two changes do not coincide.   Nor do measures of permissive values or religious observance show any discontinuous change that would coincide with the increase in risky behaviour.  So if Francis’ hypothesis is wrong, then the precise timing of the sexually revolution remains mysterious.  Francis gestures vaguely towards the possibility of the change in sexual behaviour being triggered by still less definable “economic, social and cultural changes”.

The obvious recent parallel to the syphilis collapse in our own times would be impact of the introduction of HAART on HIV/AIDS mortality.  The concern that an effective therapy might lead to disinhibition has been widely discussed in STI journal and elsewhere.  An increase in risk-taking behaviour among MSM during the late 1990s has been established:  http://sti.bmj.com/content/77/3/184.abstract?sid=5d909365-4627-4232-8ef4-a93445f5baed (Stolte & Coutinho: Amsterdam);  http://sti.bmj.com/content/80/6/451.abstract?sid=5d909365-4627-4232-8ef4-a93445f5baed (Elford & Hart: London); http://sti.bmj.com/content/80/6/518.abstract?sid=5d909365-4627-4232-8ef4-a93445f5baed(Cox & Allard: Montreal); http://sti.bmj.com/content/79/1/7.abstract?sid=5d909365-4627-4232-8ef4-a93445f5baed (Stephensen & Williams: London).  But opinions on the contribution of HAART to changing sexual behaviour seem divided, with Stolte & Coutinho supporting the hypothesis, and the others inclined to attribute it to other factors.  The probable future emergence of multi-resistant gonorrhoea (http://sti.bmj.com/content/87/Suppl_2/ii39) represents the inverse case (loss of a therapy leading to potential inhibition).  If the diminished “cost” of an STI (syphilis) can spur an increase in risky sexual behaviour, should we not expect an increased cost to have the opposite result?  Time will tell.

Older women who have had ≥5 lifetime sexual partners could turn out to be a relatively high-risk group for Human Papilloma Virus (HPV) and associated cervical lesions – regardless of declining sexual activity.  If – that is – Gravitt, Viscidi et al. (http://jid.oxfordjournals.org/content/207/2/272.full.pdf+html?sid=4bc8141c-9b7c-4a13-8a43-451d6fa85fcf; http://jid.oxfordjournals.org/content/207/2/211.full.pdf+html?sid=4bc8141c-9b7c-4a13-8a43-451d6fa85fcf) are correct to see the results of their cohort study of Baltimore women attending obstetric-gynaecology clinic as supportive of the hypothesis that the HPV experienced by these older high-risk women is a reactivated form of the infection.  The virus, they suggest, may remain undetectable in the body for years in order to emerge in later years with immune-senescence – like the varicella zoster virus that reactivates as shingles.  This would explain the double peak in age-specific HPV prevalence (debut and menopause) in some cultures; while the absence of this pattern in the US and N. Europe, they hypothesize, may be an effect of the more restrictive sexual mores of the pre-sixties generation.

What is the evidence?  When the results are stratified according to number of lifetime sexual partners, it is discovered that the Population Attributable Risk (PAR) of high-risk (HR) variants of HPV (i.e. those causing cancerous lesions) due to ≥5 lifetime partners is 87% among the older study participants, and 28% among the younger ones; while the PAR of HR-HPV due to a new sex partner is 7.7% among the older group and 28% among the younger.  This, as the authors argue, is consistent with reactivation of the virus in later life, though they admit reactivation is difficult to prove.

If this hypothesis is supported by further research, it will certainly impact on a number of issues that have been a concern for our readers and contributors.  First, the question of women’s perceived risk of cervical cancer – important because it has been shown to predict cancer screening attendance and has been associated with HPV vaccination uptake (http://sti.bmj.com/content/88/6/400.abstract?sid=2f5a46a3-43d9-4648-a3f6-9f1a46384f61, pp.1-2).  If Gravitt et al. are right, then currently less sexually active older women, who are nevertheless in the higher-risk group on account of past sexual activity, are in serious danger of underestimating their risk; furthermore, that risk could, in reality, be greater that we imagined owing to the behavioural impact of the sexual revolution.  Second, the question of stigmatization, especially in relation to HPV testing at routine “smear” tests (http://sti.bmj.com/content/82/2/169.abstract?sid=2f5a46a3-43d9-4648-a3f6-9f1a46384f61).  If HPV is often present, but undetected, and, when detected, may turn out to have no relation to current sexual activity, then the stigmatizing link between HPV status and current sexual behaviour is, at least, weakened – which ought to have a de-stigmatizing effect.  Third, HPV vaccination, and the concern of certain parents that it might lead to sexual disinhibition (http://sti.bmj.com/content/87/4/349.abstract?sid=44f0f0a6-c872-4cb1-9ca1-afa0aa8db872).  Here, again, the idea that sexually inactive, or less active, people can be at serious risk runs counter to the public perception of a direct link between current sexual behaviour and cervical cancer risk – which ought to make HPV vaccination easier to justify to a public concerned about sexual disinhibition.

Papers explored in earlier STI blogs have traced the distribution through the world of the different HIV subtypes (http://blogs.bmj.com/sti/2013/01/04/reading-the-history-of-the-progress-of-the-hiv-epidemic-through-the-evidence-of-hiv-subtype-distribution/?q=w_sti_blog_sidetab; http://sti.bmj.com/content/87/2/101.full?sid=2b7658a8-4f84-4d8a-b2bc-d5104c523180), and have used this information to track the origins of HIV-AIDS in central/western Africa probably at the beginning of the last century (http://journals.lww.com/aidsonline/pages/results.aspx?k=Tatem%20AND%20Salemi&Scope=AllIssues&txtKeywords=Tatem%20AND%20Salemi).  Now a research article published in Evolutionary Biology – Zhao, Roca et al. – has attempted to take back the story a further stage to the crossing of the species barrier and before (http://www.biomedcentral.com/1471-2148/12/237/abstract). Certainty in these matters is impossible; but Zhao, Roca et al. develop an interesting hypothesis based on genetic evidence – which is as follows.

Their point of departure is that transmission of the virus from the common chimpanzee to humans must have taken place at least four times, since the four principal HIV-1 strains present in humans (M, N, O, P) are closer in genetic sequence to strains of SIV, the chimpanzee form of HIV, than they are to the various HIV-1 sub-groups (A,B,C etc.) that derive from  strain M. On this basis, the authors hypothesize that, given the existence of SIV strains for 20,000 years, if the virus crossed the species barrier four times (between 1884 and 1924), in all probability it crossed it repeatedly over the centuries, but failed to generate persistent outbreaks in humans before the appearance of large cities.  If this hypothesis is correct, then genomic “signatures” in the chromosomes of the descendants of the affected populations ought to reflect the generation of selection pressure in these populations for resistance to SIV/HIV.

Among the diverse populations intensively genotyped as part of the human genome diversity panel are the Biaka Western Pygmies of the Central African Republic who have always resided within range of the SIV infected common chimpanzee.  The researchers seek genetic evidence for selection among the Biaka, by running pairwise genomic comparisons between the Biaka and four other central African peoples (including the Mbuti Eastern Pygmies, who are genetically close to the Biaka, but have always lived out of range of SIV infected chimpanzees).  They look for regions of the genome that: 1. signal strong selection pressure, and 2. have been associated with HIV-1 by various kinds of studies.

What they find is that of the ten possible pairwise comparisons between the five peoples, five comparisons detect regions with strong selection associated with HIV.  These involved CUL5, TRIM5, PARD3B and TSG101 which are detected as under strong selection eight times across the pairwise comparisons.  Seven out of the eight involve the Biaka.  The probability that randomly drawn genes would overlap seven or more signals of selection in a single population is reckoned by the authors at 0.05.  For the purposes of this analysis the researchers exclude from consideration host-genes associated with HIV that are below a genome-wise significance p<5×10⁸.  Where this restriction is lifted a total of eight genomic regions are specified as showing protective variants.

On the basis of this evidence the authors consider their hypothesis that SIV/HIV has shaped the genomes of some west central African populations as worthy of further investigation.

The impact of human mobility on the spread of HIV is often recognized in the medical literature (http://sti.bmj.com/content/78/suppl_1/i91.abstract?sid=2b7658a8-4f84-4d8a-b2bc-d5104c523180). Does it follow that the existence and development of transport infrastructure may have had its part in the history of the epidemic?  Can we go further, and read the whole history of an epidemic like HIV in terms of “spatial accessibility”?

Tatem & Salemi (AIDS journal) adopt a geographically-based approach, setting out to demonstrate that “the HIV/AIDS pandemic worldwide is a travel story whose episodes can be traced by molecular tools and epidemiology” (http://journals.lww.com/aidsonline/Fulltext/2012/11280/Spatial_accessibility_and_the_spread_of_HIV_1.10.aspx).  The evidence on the basis of which this story is reconstructed – the medium in which we find it written – consists in the data of HIV-1 subtypes and recombinants.  “The distribution of HIV-1 subtypes in a population”, state Mumtaz & Raddad in a study of the HIV pandemic in the Middle East, “tracks the spread and evolution of the epidemic” (http://sti.bmj.com/content/87/2/101.full?sid=2b7658a8-4f84-4d8a-b2bc-d5104c523180). Tatem & Salemi go a step further than this, interpreting the story of HIV-1 subtype distribution, as represented by 72 locations across sub-Saharan Africa (SSA), in reference to a sophisticated measure of spatial accessibility (“surface friction”) that takes into account surface cover, transport network, gradient etc., in order to reflect the ease of human travel across a landscape.

The results are presented graphically in the map on p.2353.  The 72 locations clearly fall, by and large, into four or so regions (broadly: west Africa, N. Ethiopia, east African, southern Africa), each of which is characterized by a relative homogeneity in the distribution of subtypes within it, and by a relative heterogeneity in relation to the distribution of subtypes characteristic of other regions.  These “regions” also show up on the map as continuous areas of high connectivity separated from each other by areas of low, or lower, accessibility.  Interestingly, there are four or five locations in central Africa (characterized by relatively low accessibility) which fail to show the pattern of strong dominance by one or two subtypes that we find in each of the regions of high accessibility.

There appears, therefore, to be a pattern of subtype dominance within continuous areas of high accessibility.  How does this accord with what we know about the epidemiology of HIV/AIDS?  The relative subtype homogeneity across accessible regions seems to reflect the swift diffusion of the infection across those regions.  Conversely, the greater diversity of subtypes attested in low-accessibility areas is evidence of slow spread.  The story, therefore, has two phases.  The first, during the earlier part of the twentieth century, takes place in central African subsequent to the infection crossing the species barrier.  During this period there is little diffusion, owing to poor connectivity, and the diversification of HIV-1 into its many subtypes.  The second phase, during the latter part of the century, sees the seeding of particular subtypes in different religions of high accessibility and their explosive growth thanks to good connectivity within those regions.  Subtypes A and D arrive in eastern Africa in the 1950s and 1960s respectively, whereas it is subtype C which starts the epidemic in southern Africa around 1970s, and travels to Ethiopia around 1982.

Apparently, recent analyses of the distribution of Malaria resistance markers show a similar spatial pattern to the one we see here.  The authors conclude that a comprehensive understanding of accessibility, travel and mobility in resource-poor settings could provide a valuable resource for the strategic planning of disease control.  Certainly, their study demonstrates the value of a multi-disciplinary approach to public health issues.