You don't need to be signed in to read BMJ Blogs, but you can register here to receive updates about other BMJ products and services via our site.


Harms of HSV-2 may include association of latent infection with autism as well as transfer of active infection to the neonate

11 Apr, 17 | by Leslie Goode, Blogmaster

Mahic & Lipkin (M&L) draw attention to a wholly new health concern in relation to Herpes Simplex Virus 2.

The condition is highly contagious, and the symptoms may be very unpleasant especially during the ‘primary outbreak’, the virus is not, in itself, a major public health concern.  Indeed, up until the 1980s, it was rarely mentioned in this journal – perhaps because it was less common before the 1970s, or maybe because the condition was insufficiently severe to warrant much discussion.

HSV-2 owes its status as a serious health problem to two issues that are independent of its impact on the everyday sufferers.  The first concerns the potentially devastating consequences of transmission of HSV-2 to the neonate (generally in the course of birth rather than in utero) (Preventing neonatal herpes (STIs)).  These are so severe as to have led to a considerable debate on the cost-effectiveness of screening in various parts of the world (Mindel & Cunningham (STIs) (Australia);  Barnabas & Garnett (STIs) (US); Sudfeld & Mensch (STIs) (Malawi)).  The second concerns the links between HSV infection and HIV transmission.  This is an issue discussed primary in the sub-Saharan African context, where HSV is particularly prevalent and its treatment could potentially impact the HIV epidemic (White and Glynn (STIs); Lurie & Matthews (STI)) – though also in the Indian context (Foss & Watts (STI)).

To these two serious concerns Mahic & Lipkin, in a paper recently appearing in the microbiology journal mSphere, have added a third of as yet uncertain importance – the possibility of an association with male autism.  Basing their investigation on data from the Norwegian Autism Birth Cohort (comprising mothers, fathers and infants recruited over the period 1999-2008), the researchers compared maternal immunoglobulin (IgG) antibodies to HSV-2 (amongst other viruses), which had been measured in 442 mothers of male offspring with ASD mid-term, against a frequency-matched control of 464 mothers of ASD unaffected offspring.  An increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was found to be associated with a doubling (RR=2.07) in the odds of ASD.  This was not replicated in the case of antibodies to other viruses that were tested for.

The authors suggest that it is the ‘impact of immune activation and inflammation on a vulnerable developing nervous system’ which is likely to be the mechanism here rather than ‘the specific pathogen per se’ – maybe the transfer of maternally produced antibodies and cytokines across the placenta, or the exposure of the fetus to inflammatory molecules produced by the placenta and deciduas in relation to viral shedding.

The question posed by this outcome – should it be confirmed by subsequent research – is whether this third potential harm, when added to the well-established harm of neo-natal infection, might contribute to tipping the balance in favour serological monitoring and suppressive therapy during pregnancy – at least in certain contexts (cf. Barnabas & Garnett (STIs) (US)).


Global patterns in ante-natal syphilis prevalence: Why is sub-Saharan Africa different?

18 Jul, 16 | by Leslie Goode, Blogmaster

‘Can a meaningful pattern be discerned in the large variations in syphilis rates over the last century?’ This is the question addressed by a recent systematic review – Kenyon & Tsoumanis (K&T) – based on published data on ante-natal syphilis prevalence (ASP) from those countries for which that data is available since at least 1951.   This cutoff reduces the number of countries that qualify for inclusion, but allows more recent trends in the late twentieth, and early twenty-first, centuries, to be set against the background of the impact of the introduction of penicillin in the 1950s. A pattern emerges from the data, which K&T then to seek to explain by investigating its association with various potential variables through multivariate analysis: per capita GDP; circumcision practice; health expenditure; efficacy of diagnosis/treatment; geographical region.

The pattern itself is: in most parts of the world, a more or less steep decline following the introduction of penicillin – ultimately, by the 1990s, to below 1%, and by the 2000s, to below (massively below, in many cases) 0.5%; in sub-Saharan Africa alone, a decline plateauing out at around 6% up until the end of the twentieth century, when there is a further decline to just above 1.5%.  A limitation of the study is its concentration on eleven countries for which ASP data is available from before the days of penicillin, with only two of those countries being in sub-Saharan Africa (South Africa and Zimbabwe).  So far as concerns more recent evidence for ASP prevalence, the kind of rates that the authors give for SA and Zimbabwe seem, broadly, to be replicated in other countries of sub-Saharan Africa (Otieno-Nyunya & Kaiser/STIs (Kenya); Makasa & Sandoy/STIs (Zambia); Kirakoya-Samadoulougou & Nagot/STIs (Burkina-Faso);  Ardu-Sarkodie & Peeling/STIs (Ghana), and their rates for the other regions to be replicated in other non-sub-Saharan African settings (Cheng & Cai/STIs (China); Galdava & Domeika/STIs (Georgia) Thirumoorthy & Lim/STIs (Singapore)).

As for the explanation of this pattern, the authors find no association on multivariate analysis with any of their potential variables, save with residence in sub-Saharan Africa.  This is itself an interesting negative finding, and prompts the authors to consider other population-level correlations also included in the evidence reviewed – notably, with prevalence of HIV and HSV-2; ‘the populations that in the 1990s had high prevalences of syphilis and HSV-2 went on to have high HIV prevalences’.  The correlation with prevalence of HSV-2 is of particular interest because it is unlikely that the prevalence of the one infection could have influenced that of the other (see also: Hochberg & Dandona/STIs).  To K&T, it suggests the likely importance of ‘more connected sexual networks’ and ‘greater partner concurrency’ in explaining traditionally – and currently – high relative ASP levels in sub-Saharan Africa.  However, they refer to studies that contest this hypothesis, and emphasize the need for further research to elucidate the factors underpinning difference in syphilis rates – especially given the possibility that the successful use of ART in those countries may be accompanied by the re-establishment of former sexual networks.

HIV epidemic among heterosexual non-intravenous drug-users: could HSV-2 co-infection be the driver?

24 Jul, 14 | by Leslie Goode, Blogmaster

Why such high HIV prevalence reported for non-injecting drug users who are predominantly heterosexual?  This reaches 37% in Porto Alegre, Brazil; 43% in China; 13% in Canada; 20% in Florida; 19% in New York City; 24% in Portugal; 29% in Russia?  Possible factors include impaired decision making under the influence of drugs or the exchange of sex for drugs.  Studies published in STI Journal also propose high prevalence of, amonst other STI infections,  HSV-2 as a particular risk for HIV amongst non-injecting drug users (STIs/Plitt & Taha), and comparable groups, e.g. Tanzanian female bar-workers (STIs/Riedner & Hayes).  HSV increases susceptibility to HIV through disruption of the epithelial surface, as well as increasing transmissibility from persons co-infected with HSV and HIV through raising levels of plasma HIV-1 RNA.

A recent study of non-injecting drug users (NIDU)  (Jarlais & Cooper) attending a New York drug detoxification centre and a methadone maintenance programme – 785 over the period 1995-1999 and 1,764 over the period 2005-2011 – claims that HSV-2 co-infection is the principal driver of HIV transmission, especially amongst female NIDUs.  Over both periods that latter group shows: very high levels of HSV-2 mono-infection (78% and 86% respectively), high levels of HIV/HSV-2 co-infection (10% and 21%, and negligible HIV mono-infection.  The pattern is similar though less pronounced in the case of males.  As between the two periods (1995-1999 & 2005-2011) there is a doubling in the prevalence of HIV (from 7% to 13% overall) which is represented more or less uniformly across all ethic and behavioural groups.  Though the specific quantitative contribution of HSV-2 to the HIV infection cannot be determined by this type of study, these results suggest that the rise in HIV among NIDUs should be considered an epidemic of HSV-2/HIV co-infection, and that HSV-2 is likely to be the driver of the increased HIV incidence.

So what should be done to minimize HIV transmission among non-injecting drug users?  The obvious response would be suppressive HSV-2 therapy.  Unfortunately, however, trials have not as yet shown this to be effective in reducing HIV transmission (STIs/Mujugira & Wald; Barnabas & Celum).  The authors recommend further research into the effectiveness of higher dosages of HSV-2 suppressive therapy: also of HSV-2 suppressive therapy prior to ART or in combination with ART – since a recent study found evidence of HIV in the semen of men who had reached viral suppression on ART (Politch & Anderson).  At all events, HIV/HSV-2 co-infected NIDUs would appear to be a priority for ART as prevention, and the authors recommend providing ART to this group at all CD4 cell counts.  (New York introduced in 2011 a new policy of offering ART to all HIV sero-positive persons in the city regardless of CD4 count).

Who wants to know their HSV-2 serology status, anyway?

15 May, 11 | by Leslie Goode, Blogmaster

Though 75% to 90% of HSV-2 infected persons may be unaware of their condition, they may still be capable of transmitting the infection. A recent study investigates the patterns of viral shedding and presumed infectivity in “asymptomatic” HSV-2 (i.e. HSV-2 in persons unaware of their condition prs to diagnosis) as against “symptomatic” infection. The occasion seems to have been offered by a group of 88 asymptomatic persons whose status emerged during a previous trial. These, along with a group of 410 symptomatic persons, were instructed to inspect the genital region for lesions daily and obtain swabs.
What do we learn? Overall, viral shedding in the asymptomatic participants took place in 10.2% of days, as opposed to 20.1% (risk ratio for asymptomatic group on adjusted multivariate model = 0.57). Shedding occurred sub-clinically both in asymptomatic and in symptomatic, though less than in asymptomatic participants (8.5% vv. 12.9%, RR = 0.66); and it also occurred in the presence of lesions in asymptomatic as well as symptomatic (3.8% vv. 13.8%, RR = 0.28), since lesions were detected by 19 of the 88 asymptomatic participants in the course of the follow-up. Presence of lesions impacted on infectivity through increased duration of episodes of viral shedding. Asymptomatic differed from symptomatic infection in the frequency of these episodes of greater duration. For those in the asymptomatic group who reported lesions, shedding rate was 18.7 % as against 7.6% for those in the asymptomatic group who reported no lesions.
What are the implications of this study? The authors claim to be addressing a management problem posed by the situation of “asymptomatic patients with an HSV-2 seropositive test result”. Given the mildness of the condition, we might ask whether this “management problem” is created by the HSV-2 infection or the seropositive test result! So it is disconcerting to find a Swedish health researcher on Herpes using findings from this study (and her own) in order to urge us not to “wait for sores to appear or other visual symptoms” but to “go get checked out” ( Is this really a sensible reaction to the findings of this trial?

Elizabeth Tronstein et al., “Genital Shedding of Herpes Simplex Virus Among Symptomatic and Asymptomatic Persons With HSV-2 Infection”, Journal of the American Medical Association 2011;305(14)

Is African HSV-2 different ?

15 May, 11 | by Leslie Goode, Blogmaster

Still on the topic of HSV-2 … A clinically effective vaccine has yet to be achieved, though efforts are being made to develop one. A replication-defective HSV-2 mutant virus – the US strain HSV-2 dl5-29 – has been shown to induce immunity against the US strains HSV-2 G and 333 in mice and guinea pigs. The potential benefits of an effective vaccine could be enormous in sub-Saharan Africa, where epidemiological studies have shown that genital herpes leads to a multi-fold increase in the risk of HIV transmission.
In line with these ambitions, a recent study has sought to improve our knowledge of the genetic and epitope diversity of HSV-2, and its effect on vaccine efficacy, by testing HSV-2 vaccine candidates against HSV-2 strains derived from African, as well as, US isolates. A first stage involved the testing of HSV-2 dl5-29 against both a panel of three US strains (G, 89-390, 186) and a panel of African strains (SD15, SD66, SD90). HSV-2 dl5-29 proved effective against both US and African strains, though in the latter case equivalent protection required higher doses. A second stage involved assessment of the ability of two replication-defective mutant viruses to protect against the same panels of US and African derived viruses – 5BlacZ, deriving from a US strain, and SD90-8LacZ, deriving from an African one. The US derived 5BlacZ tended to be more protective against US strains, and the African derived SD90-LacZ against African strains; at the same time, neither vaccine was as protective against the African strains as 5BlacZ was against the US ones, despite levels of humoral and cellular immune response that were equivalent in the US and African case.
The authors draw two conclusions: first, that immune protection appears to be partially specific for the viruses from the US versus Africa; second, that the African HSV-2 viruses seem more virulent. They call for further research in this area on account of its potential impact on the reduction of HIV transmission risk.

Timothy E. Dudek, “Evidence for Differences in Immunologic and Pathogenesis Properties of Herpes Simplex Virus 2 Strains From the United States and South Africa”, Journal of Infectious Diseases 2011:203 (15th May)

Sexually Transmitted Infections blog

Sexually Transmitted Infections

Discussion and suggestion space for readers of STIs.
Visit site

Creative Comms logo

Latest from Sexually Transmitted Infections

Latest from Sexually Transmitted Infections