Category: Research

New sensitive DNA assay for PCP infection

Pneumocystis jirovecii pneumonia (PCP) is a leading cause of morbidity and mortality in HIV and other immunocompromised patients. Currently the commonly used PCR for diagnosing P. jirovecii will miss some organisms by staining methods. The authors of a study published in Clinical Microbiology and Infection  developed a new assay using the same targeted genes.

This assay was compared with the currently used PCR and other conventional assays (Giemsa staining and immunofluorescence assay).   Brochoalveolar lavage (BAL) sample collected from human immunodeficiency virus (HIV)-infected (n = 66) and non-HIV (n = 36) immunocompromised patients presenting with fever, dyspnoea, cough and pulmonary infiltrates was tested by all the assays. Pneumocystis jirovecii was diagnosed with Giemsa-stained smear, immunofluorescence assay, conventional single-round and nested PCR, and the new PCR in 46 (45.1%), 53 (52.0%), 69 (67.6%), 74 (72.6%), 87 (85.3%) and 91 (89.2%) patients, respectively.

The new PCR could detectP. jirovecii DNA in BAL fluids two to three orders of magnitude more dilute than conventional PCR.  Although both conventional and new PCR assays were highly specific for diagnosing P. jirovecii, the new PCR yielded more positive results than conventional PCR among BAL samples that were negative by both Giemsa stain and immunofluorescence assay. Hence, the new PCR offered a more sensitive detection of P. jirovecii infection and colonization than conventional PCR.

Current vaccines cover only a minority of human papillomavirus (HPV) subtypes associated with cancer and genital warts

Effective vaccination exists for two sexually transmittable viruses, human papilloma virus (HPV) and hepatitis B virus (HBV). Other viruses have proved more problematic. A recent study in the New England Journal of Medicine showed, yet again, that a vaccine for herpes virus remains elusive. The same is true for hepatitis C and even more for HIV.

Thus identifying at risk groups for HPV and HBV is essential for targeting vaccination strategies. Particularly as persistent infection with high-risk sexually transmitted HPVs (HR-HPV) can lead to development of cervical and other cancers, while low-risk types (low-risk HPV) may cause genital warts. In a recent publication by Ann Johnson and colleagues at University College London they explored the epidemiology of different HPV types in men and women in the UK and their association with demographic and behavioural variables.

Data collected for the British National Survey of Sexual Attitudes and Lifestyles, a cross-sectional survey undertaken in 1999–2001 were analysed. Half of all sexually experienced male and female respondents aged 18–44 years were invited to provide a urine sample. They tested 3123 stored urine samples for HPV DNA.

HPV infection, was prevalent in this population, detected in 29% of samples from women and 17% from men. Significantly 13 high risk HPV subtypes were detected in 16% of women and 10% of men. HPV subtypes, HPV types 16/18, which for part of the two available vaccines in the market, were found in only 5% of women and 3% of men. Types 6/11 which are responsible for most cases of genital warts were isolated in in 5% of women and 2%  of men. In multivariate analysis, HR-HPV was associated with new partner numbers, in women with younger age, single status and partner concurrency, and in men with number of partners without using condom(s) and age at first intercourse.

They concluded that HPV DNA was detectable in urine of a high proportion of the sexually active British population. In both genders, HR-HPV was strongly associated with risky sexual behaviour. The minority of HPV infections were of vaccine types that are currently used in the two available vaccines. These cover HPV 16/18 and 6/11 only.

The authors pointed out t is important to monitor HPV prevalence and type distribution following the introduction of vaccination as vaccination itself may alter the prvalence of the difefrent sun

Sexual behaviour as well as HPV types 6 and 11 are associated with genital warts

A recent study by GM Anic et al from  the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., have found that human papillomavirus types 6 and 11, as well as recent sexual behavior, are strongly associated with the incidence of genital condyloma (wart) infection.

The strongest associations were found for infections with HPV types 6 and 11. The risk for condyloma also increased with an increasing number of female sexual partners but decreased with age. Sexual behaviors in the previous 3 months were also associated with a high risk for condyloma: a high number of male anal sex partners, more frequent vaginal intercourse and infrequent condom use. Also influencing the incidence of condyloma was ever having a sexually transmitted infection and ever having a partner with condyloma.

Since subclinical infection with HPV is more common than condylomas, this latter finding suggests that patients with visible genital warts are more likely to transmit condylomata to their sexual partner. This finding confirms an old study by the veteran British venerologist JD Oriel in 1971.

Factors strongly associated with condyloma were incident infection with human papillomavirus (HPV) types 6 and 11 (hazard ratio [HR], 12.42 [95% confidence interval {CI}, 3.78–40.77]), age (HR, 0.43 [95% CI, .26–.77]; 45–70 vs 18–30 years), high lifetime number of female partners (HR, 5.69 [95% CI, 1.80–17.97]; ≥21 vs 0 partners), and number of male partners (HR, 4.53 [95% CI, 1.68–12.20]; ≥3 vs 0 partners). The results suggest that HPV types 6 and 11 and recent sexual behavior are strongly associated with incident condyloma.

“The strong association between recent sexual history and incident condyloma after accounting for HPV infection suggests that prevention efforts targeting behavioral modification may be effective at reducing condyloma incidence among men who have not received the HPV vaccine,” the researchers wrote.

New ways of getting treatment to sexual partners of patients infected with chamydia or gonorrhoea

Treating a sexually transmitted infection in a person is incomplete without treating te sexual partner and thus closing the loop. Current forms of partner notification (PN) are not particularly successful with less than one half of sexual partners attending sexual health (genitourinary medicine) clinics.

A recent study by Claudia Escourt and her colleagues has looked at the feasibility of two different approaches to PN. One was to set up a hotine for the partner to phone a health care worker in the sexual health clinic and after appropriate consultation to collect their treatments either at the sexual health clinic and the secone was for the partner go to a a designated pharmacy and obtain treatment from a trained pharmacist. The partners were also asked to provide urine for chlamydia testing and to attend the sexual health clinic at a time of their own convenience for syphilis and HIV testing.

The preliminary results were encouraging and showed that both systems were acceptable to clients and increased uptake of treatment from 36% to 59% in the case of the clinic hotline and 66% in case of pharmacy.

The only drawback of either strategy was that almost none of the partners accessed HIV or syphilis testing at a later date.

Oral human papillomavirus infection more common in US males

Almost 7 percent of American men and women are infected orally with the human papillomavirus (HPV), new research reveals, with men showing significantly higher infection rates than women. Indeed among those between the ages of 14 and 69, men seem to face a nearly threefold greater risk than women for oral HPV infection.

The study was part of the ongoing National Health and Nutrition Examination Survey (NHANES). To better understand that connection, Gillison’s team sifted through data on nearly 5,600 men and women collected between 2009 and 2011 NHANES. All NHANES participants had been examined in person, during which all were tested for HPV.

In a study published in the Journal of the American Medical Association (JAMA) on Janury 26, 2012 Dr. Maura Gillison, chair of cancer research in the department of viral oncology at Ohio State University’s Comprehensive Cancer Center in Columbus reported  an overall oral HPV infection rate of 6.9 percent, with HPV-16 being the most common type.

Oral HPV incidence varied with age, however, with peak rates occurring among those between the ages of 30 and 34 (at 7.3 percent) as well as among men and women between 60 and 64 (11.4 percent). Overall, oral HPV infection hit the 10 percent mark among men. Among women it was just shy of 4 percent.

While those with a history of smoking, heavy drinking, and/or marijuana use appeared to face a higher risk for infection, sexual behavior also plays a key role in upping a person’s risk. For example, while those who had never had sex faced less than a 1 percent risk for oral HPV infection, prevalence hit 7.5 percent among those who were sexually active. And the greater the number of sexual partners, the higher the risk.

HIV highly homogeneous in early infection

Current findings suggest that the mucosal barrier is the major site of viral selection in sexual transmission of human immunodeficiency virus type 1 (HIV-1), transforming the complex inoculum to a small, homogeneous founder virus population. In a recent study from Zurich the authors analyzed HIV-1 viral seqiuences in the C2-V3-C3 region in 145 patients with characteristics  primary HIV-1 infection. They found that  the meedian viral diversity within env was 0.39% (range 0.04%–3.23%). Viral diversity did not correlate with viral load, but it was slightly correlated with the duration of infection.

They also found that  neither transmission mode, gender, nor STI predicted transmission of more heterogeneous founder virus populations. Only 2 patients (1.4%) were infected with CXCR4-tropic HIV-1 with a duakl-tropic R5/X4-tropic–mixed population. The other patients were infecetd by the CCR5-trophic virus which targets the macrophage series.

The authors concluded that transmission of multiple HIV-1 variants might be a complex process that is not dependent on mucosal factors alone. CXCR4-tropic viruses can be sexually transmitted in rare instances, but their clinical relevance remains to be determined. These results have imprtant implications for vaccine development.

An alternative explanation for these results, not discussed by the authors, is that the individuals were infected by a small number or even a single CCR5-trophic virus which subseqeuntly mutates to the complex virus soup that is seen in long-term infected subjects.

Vitamin D deficiency and cardiovascular disease: more information needed

Vitamin D deficiency is common in the general population. It has been linked with hypertension, myocardial infarction, and stroke, as well as other cardiovascular-related diseases, such as diabetes, congestive heart failure, peripheral vascular disease, atherosclerosis, and endothelial dysfunction.

Yet a recent publication in The Annals of Internal Medicine  has highlighted the conflicting nature of the information available, as it relates to increased cardiovascular disease, and has called for proper prospective randomised studies.

Vitamin D deficiency, along with cardiovascular disease, diabetes and some malignancies are more commonly seen in HIV infected patients compared to age-matched controls. While the mechanism for the vitamin D deficiency in HIV infection is still unclear, this deficiency has been shown to be associated with an increased prevalence of type 2 diabetes mellitus.

In a cross sectional study of their HIV cohort in Pennsylvania, USA, Guaraldi and colleagues showed an almost doubling (OR 1.85 CI 1.03-3.3) of diabetes mellitus in those with vitamin D levels below 20 ng/ml compared to those with normal levels. The authors controlled for vitamin D supplementation, sex, age, body mass index (BMI), and hepatitis C, all of which are known to effect glucose metabolism.

We urgently need prospective studies to confirm these findings and to answer the question if vitamin D supplementation will prevent these putative complications of vitamin D deficiency.

Antiretroviral prophylaxis: a defining moment in HIV control

According to an editorial by Salim Abdool Karim in the Lancet  a defining moment in the global AIDS response has been reached. The discourse is no longer about HIV prevention or HIV treatment; it is now about HIV control through the implementation of antiretroviral treatments as key components of combination interventions.

Barely a year ago, visions of HIV control would have been considered far-fetched. The impetus for this change in mindset, which has been building since the XVIII International AIDS Conference in Vienna last year, emanates from the compelling evidence that antiretroviral drugs prevent HIV infection in the general heterosexual population, which is released this week and presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome by the Partners PrEP and Botswana TDF2 trials.

The Partners PrEP trial, involving 4758 HIV discordant couples from Kenya and Uganda, found that daily oral tenofovir disoproxil fumarate (TDF) and TDF-emtricitabine reduced HIV transmission by 62% and 73%, respectively. The Bostwana TDF2 trial, in 1200 heterosexual men and women from the general population, found that daily oral TDF-emtricitabine reduced HIV transmission by 63%.

Both these are of a similar order of magnitude to that seen with male circumcision and is probably caused by a significant reduction of HIV in the genital tract.

see fig 1 for comparison between different prevension strategies

Several issues were raised by the authors that need further research. There is now no doubt that antiretroviral drugs prevent HIV infection. However, important scientific questions remain. Does the inclusion of emtricitabine in pre-exposure prophylaxis (PrEP) formulations provide sufficient additional benefit to warrant the additional costs and side-effects? Are levels of effectiveness and safety similar for daily use and use-with-sex of PrEP? Do the safety, effectiveness, cost, and acceptability profiles of oral and topical PrEP merit implementation of both formulations? Does PrEP lead to masking of HIV acquisition that is then revealed once PrEP is withdrawn?

Ghost authorship of scientific articles is very common

According to recent study by Wislar and colleagues appearing in the BMJ 21% of scientific papers published in reputable ‘high impact’ biomedical journals are either written by an unnamed ‘ghost’ author and then attributed to someone as honorary author (8%) or has had the names of authors that had nothing to do with the study (18%), or both. There was however a significant decline from a survey carried out in 1996 using an identical questionnaire which showed a prevalence of ghost or honorary authorship of 29%.

Over the last twelve years honorary authorship had not significantly changed overall, although it was significantly higher for research articles as opposed to review articles or editorials. Ghost authorship showed a small but significant fall over the two periods under study.

The journals that were investigated by the present study were all English language with high impact factors in 2008: Annals of Internal Medicine, JAMA, Lancet, Nature Medicine, New England Journal of Medicine, and PLoS Medicine. 

As the authors state ‘inappropriate authorship remains a problem, although the more serious ghost authorship may be declining’.

UK NHS finally accepts to use quadrivalent HPV vaccine in girls

From next September girls in the United Kingdom being vaccinated against human papillomavirus (HPV) will receive Gardasil, the vaccine that protects against genital warts as well as cervical cancer.

The Joint Committee on Vaccination and Immunisation recommended that the HPV vaccine should be offered routinely to girls aged 12 to 13 years and in a catch-up programme to those up to 18 years of age. Since then, 1.5 million young women and girls have been protected.

GlaxoSmithKline, which has been providing the Cervarix vaccine to the UK’s HPV vaccination programme since it launched in September 2008, said in a statement that it did not take part in the latest tendering exercise to provide a vaccine for the programme because the government made it clear that it wanted to protect girls against the types of HPV that caused cervical cancer and those that caused genital warts.

Gardasil, which is supplied by Sanofi Pasteur MSD, protects against HPV types 16 and 18, which cause 70% of cervical cancers, and HPV 6 and 11, which are responsible for nine in 10 cases of genital warts. Cervarix protects against HPV types 16 and 18.

When the UK programme launched, health campaigners criticised the choice of Cervarix as being short sighted and a missed opportunity (BMJ 2008;336:a451, doi:10.1136/bmj.a451)

Worldwide Gardasil has been the vaccine of choice. It has been selected by health authorities in the United States, Australia, New Zealand, Canada, Switzerland, Italy, Spain, and Sweden for regional or national vaccination programmes against cervical cancer.

Research from Australia has shown that cases of genital warts have nearly disappeared since 2007 when the national vaccination programme against cervical cancer using Gardasil was introduced (Sexually Transmitted Infectionsdoi:10.1136/sextrans-2011-050234). The study found that new diagnoses of genital warts among women under 21 years attending a sexual health centre in Melbourne fell from 18.6% in 2007-8 to 1.9% in 2010-11 and in heterosexual men aged under 21 from 22.9% to 2.9%. During the period before the introduction of the vaccination programme, new cases of genital warts rose by 1.8%.