Brandon May

, men who have sex with men who seek out sexual partners on smartphone apps are more likely to have sexually-transmitted infections—including syphilis, gonorrhea, and chlamydia&mdash;than those who do not use these apps. Mobile platforms dedicated to HIV prevention may help reduce this likelihood, the study’s investigators suggest.

“The prevalence of men who have sex with men-related HIV infection is increasing worldwide. Advances in communication technology now offer men who have sex with men different opportunities to meet sexual partners,” the investigators, led by Haidong Wang, MD, of the North China University of Science and Technology, wrote. “With the proliferation of apps, increased use of these apps may facilitate finding casual sexual partners, resulting in unsafe sexual practices. Prior work has shown that men who have sex with men who use these apps (app-users) tend to have more sexual encounters, more frequent anal intercourse, more unprotected sex, and a larger number of sexual partners known to have HIV and other sexually-transmitted infections …[yet] some studies suggested that app-users may be more likely to practice safer sex with these partners than are non-users.”

Investigators from China reviewed relevant studies related to mobile dating and/or sex apps specifically targeting men who have sex with men, selecting articles that focused on app users and non-app users as well as those that reported data for sexual behaviors or sexual health in this population. Data extracted from the 25 selected studies included the date of sexually-transmitted infections (ie, HIV, syphilis, gonorrhea and chlamydia) and sexual behaviors (eg, the number of partners met via apps, HIV testing, unprotected anal/oral sex).

In the pooled analysis of the studies, the self-reported prevalence of an HIV diagnosis prior to app use was between 2.2% and 37.7% (pooled prevalence, 6%; 95% confidence interval [CI], 4%—11%). The lifetime range rates of HIV testing among app users and non-app users was roughly similar (49.1%-96.7% vs 50.1%-97.1%, respectively). Users of apps were more likely to report chlamydia (odds ratio [OR] = 2.22; 95% CI, 1.92–2.56) and gonorrhea (OR = 2.36; 95% CI, 2.07–2.70) in studies that compared these users with non-users. Both app users and non-app users had similar rates of HIV (OR = 0.89, 95% CI, 0.68–1.16) and syphilis (OR = 1.92; 95% CI, 0.91–4.03) diagnoses. Following the omission of 1 study with noticeable heterogeneity, the OR for contract syphilis among app users rose to 3.00 (95% CI, 1.84–4.91).

“Our study was not exceptional for finding that risky sexual behaviors (eg, greater number of sexual partners, unprotected sex) were common among app-users,” the authors wrote. “Apps potentially foster risky behavior because users could carry their smartphones with them at all times.”

A limitation of the meta-analysis was the inclusion of mostly studies that were descriptive and without a suitable comparable group, such as non-app users. Additionally, the study’s investigators indicate that the associations observed between app use and sexual risk behaviors and/or sexually-transmitted infections prevalence can merely be interpreted as correlational rather than causational.

“Taken together, the advancements in apps and the increase in men who have sex with men using these apps may produce more adverse effects on sexual health,” the investigators concluded. “The data demonstrate the need for increased app-based prevention interventions among men who have sex with men. In addition, more studies, especially longitudinal studies, are needed to confirm the relative risk between app-user and non-users.”

Wang H, Zhang L, Zhou Y, et al. The use of geosocial networking smartphone applications and the risk of sexually transmitted infections among men who have sex with men: a systematic review and meta-analysis. 

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Men who have sex with men who seek out sexual partners online are more likely to report sexually transmitted infections, including syphilis, gonorrhea, and chlamydia.

MSM Who Use Mobile Apps for Sex More Likely to Have STIs

The proliferation of malaria-specific cord blood CD4

 T cells is associated with protection from childhood malaria, particularly in the first 2 years of life, according to a study by Margaret E. Feeney, MD, and colleagues, published in a new edition of 

“We have identified a population of fetal malaria-responsive T cells in infants born to mothers with active placental malaria that have phenotypic features of effector memory cells and a variety of inflammatory effector functions,” the study authors wrote. “Here, we add to our current understanding of how the fetus is capable of responding to pathogens by demonstrating effector memory differentiation, inflammatory cytokine production, and robust antigen-specific T cell proliferation after in utero exposure to malaria.”

Additionally, the investigators added that the “transplacental exposure of the fetus, as occurs with placental malaria, similarly results in limited exposure to blood-stage antigens and may, therefore, lead to priming of protective memory CD4

 T cells that can respond vigorously after re-exposure to malaria during infancy.”

In their study, investigators from California and Uganda sought to assess the impact of in utero exposure to malaria on fetal T cell immunity. To accomplish this, the investigators evaluated the frequency, phenotype, and function of central memory (T

T cells in cord blood of infants (n = 182) who were born to women with placental malaria and without placental malaria in a malaria-endemic area of Uganda. Mothers were enrolled in a study regarding prenatal and early childhood malaria intermittent preventative treatment (IPT) and were assessed each month for malaria from baseline to delivery.

cells were observed in infants who were born to women with active placental malaria vs without active placental malaria (

=.0001). Histopathology also visualized significantly higher frequencies of CD4

cells among infants with parasite-containing placentas vs infants with placentas without parasites (

=.018). In an additional analysis which sought to determine the activation profile, differentiation status, and TH subset distribution of fetal non-nai&#776;ve CD4

cells demonstrated the proapoptotic marker CD95/Fas, the high-affinity interleukin-2 (IL-2) receptor CD25, and the inhibitory receptor programmed cell death-1 (PD-1) compared with naïve T cells (T

In addition, Dr. Feeney and colleagues observed that fetal CD4

proliferation to malaria antigens if they were found among infants who were exposed to malaria while in the womb. High proliferation was associated with a greater than 70% lower malaria incidence within the first 2 years of life vs low proliferation (incidence rate ratio [IRR], 0.28; 

 T cell proliferation of malaria was also associated with a reduced time to malaria following birth compared with low proliferation (intermediate group: hazard ratio [HR], 0.40; 

 =.01). These findings, according to the investigators, suggest that malaria-specific CD4

 T cell proliferation exerts a potentially protective effect against childhood malaria.

A limitation of the analysis was the inclusion of only women who had received “the standard-of-care 3-dose IPT for 

, providing some protection from malaria during pregnancy.”

Additionally, the investigators of the study noted that misdiagnoses were possible in this cohort, and the relatively small number of included infants, as well as the inclusion of only women from Uganda, may result in the reduced generalizability of the findings across the population.

“It is possible that malaria antigenemia from breakthrough infections may drive the differentiation of protective CD4

 T cell responses into regulatory IL-10—producing T

 T cell phenotype observed in highly exposed children,” the authors wrote. “Nonetheless, our findings raise the intriguing possibility that vaccination during pregnancy could benefit infants through the induction of fetal effector memory T cell responses.”

Odorizzi PM, Jagannathan P, McIntyre TI, et al. In utero priming of highly functional effector T cell responses to human malaria. 

The proliferation of malaria-specific cord blood CD4+ T cells is associated with protection from childhood malaria.

Malaria-Specific CD4+ T Cell Proliferation May Protect Against Childhood Malaria

According to a review of a lifetime of research literature, the herpes simplex virus type 1 is associated with an increased risk of Alzheimer’s disease. Despite this increased risk, new data show that antiviral drug regimens to treat the infection may substantially reduce the risk of senile dementia in patients with severe herpes infections. Findings from this review were published in 

“The most important finding is that anti-herpes antivirals are protective against the development of Alzheimer’s disease,” Ruth F. Itzhaki, MSc, PhD, of the University of Manchester, told 

when asked about the clinical implications of her findings. “[Therefore,] a clinical trial is warranted to find out if anti-herpes antivirals are effective in preventing further deterioration in patients with mild Alzheimer’s disease.”

According to the data presented by Dr. Itzhaki, the majority of the population is infected with herpes simplex virus type 1 by the time they reach 70 years of age. In middle age, the virus travels to the brain where it remains latent, followed by intermittent reactivation and major inflammation in brain tissue. Carriers of the Apolipoprotein-E (APOE)-ε4 protein may be at particular risk for expedited Alzheimer’s disease development in the presence of herpes infection, because of the protein’s known associated risk with dementia. 

The literature consistently demonstrate that viral DNA are frequently located within Alzheimer’s disease plaques, and beta-amyloid (Aβ), the main plaque component, “accumulates in herpes simplex virus type 1-infected cell cultures.” Additionally, the tau (P-tau) protein in neurofibrillary tangles also accumulate in herpes simplex virus type 1-infected cell cultures, lending to the theory of an association between herpes and Alzheimer’s disease genesis.

Other studies demonstrate that there may exist a role of human herpes virus type 6 and 7 in Alzheimer’s disease development and/or progression. In a recently published study, the risk of senile dementia was 2.56-fold greater in patients with herpes simplex virus type 1 and herpes simplex virus type 2 patients compared with healthy controls during a 10-year period. An approximate 10-fold reduction in senile dementia risk was found in another study of patients who were treated with several different anti-herpes agents compared with untreated patients.

Treatment of herpes simplex virus type 1 typically relies on the routine use of several antivirals, either as monotherapy or combination therapy. Acyclovir (ACV), for instance, inhibits viral DNA replication and is frequently used intravenously against herpes simplex virus type 1. According to the literature compiled by Dr. Itzhaki, the formation of P-tau depends on the replication of viral DNA, suggesting that antivirals may indeed reduce the risk of Alzheimer’s disease. “Clearly, the types of antiviral which might be used for treating Alzheimer’s disease should be carefully chosen, especially if combined with an anti-inflammatory agent, as well as the duration of treatment and stage at which their usage would most effective,” Dr. Itzhaki explained in her paper. “Even if the effects were merely a delay in onset of the disease, this would still be enormously beneficial for patients, careers and the economy.”

Reduction of inflammatory components involved in herpes may be partly attributed to the reduced risk of Alzheimer’s disease in patients treated with antiviral regimens; however, Dr. Itzhaki mentions that the exact mechanisms associated with the reduced risk are currently unknown. The currently available data do, however, suggest that antivirals, as well as anti-inflammatory medications, may be important combination therapy strategies in herpes-infected patients, particularly those who have an increased risk for Alzheimer’s disease.

“The detailed mechanisms of the action of herpes simplex virus type 1 in leading to Alzheimer’s disease are still unclear,” Dr. Itzhaki added. “Another point is that the Taiwan epidemiological studies were restricted to subjects with severe herpes simplex virus type 1 symptoms. They do very probably apply also to those with mild symptoms, and to asymptomatic people, but no investigations have yet been done on such subjects.”

Itzhaki RF. Corroboration of a major role for herpes simplex virus type 1 in Alzheimer's disease [published online October 18, 2018]. 

Herpes simplex virus type 1 is associated with a higher risk of Alzheimer’s disease, yet the antivirals prescribed to treat the infection may reduce the risk of dementia.

Antivirals to Treat Herpes Infection May Decrease Risk of Dementia

The currently recommended therapy for gonorrhea is still effective; however, work is still needed that is mindful of mutations in antimicrobial genes that could ultimately result in resistance in strains identified in the future, according to a study presented at US Centers for Disease Control and Prevention’s (CDC) 2018 STD Prevention Conference, held August 27-30, 2018, in Washington, DC.

“The current CDC recommended therapy for the treatment of uncomplicated gonorrhea remains the dual combination therapy of 250 mg ceftriaxone delivered intramuscularly and 1 g of azithromycin taken oral,” lead author Jesse C. Thomas IV, PhD, MS, told 

in an interview. “Although the findings from our study identified several isolates with elevated minimum inhibitory concentrations (MICs) [to azithromycin and a cephalosporin], none of them were linked to verified treatment failures.”

For the study, which characterized genomics of 

 strains with potential elevated MICS to azithromycin and extended-spectrum cephalosporins, the investigators selected isolates from the US Gonococcal Isolate Surveillance Project (GISP) that featured elevated MICs to azithromycin between 1993-2005 (MIC ≥1 μg/ml) and 2006-2016 (MIC ≥2 μg/ml). Additionally, isolates with either an elevated MIC to cefixime (MIC ≥0.25 μg/ml) or ceftriaxone (MIC ≥0.125 μg/ml) were selected. Characterization of the identified GISP isolates and 11 international isolates featuring comparable susceptibility patterns was performed using core genome phylogeny, multi-locus sequence typing (MLST), and mutational analysis.

“The GISP monitors antimicrobial resistance trends over time using data collected from routine antimicrobial susceptibility testing of specimens collected from patients diagnosed with urethral gonorrhea,” Dr. Thomas explained. “The program tests specimens against a variety of antibiotics (eg, fluoroquinolones, azithromycin, cephalosporins, etc). And so, the largest benefit, in my opinion, is in knowing the prevalence and incidence of antimicrobial resistance within the US population. These data aid in informing CDC’s treatment guidelines.”

Of 164,900 isolates identified in the GISP between 1993-2016, a total of 20 isolates featured elevated MICs to both azithromycin and a cephalosporin. Only 12 of these isolates are currently sequenced. Birmingham-2000 was the oldest isolate identified, and this isolate featured a unique MLST (ST10316) sequence type (ST). Baltimore isolates between 2001-2012 and Phoenix isolates in 2011 clustered together phylogenetically, yet showed different sequence types. A total of 7 isolates in each the GISP and international databases formed a single clade. Adenine deletion in mosaic penA, ponA L421P, and porB (A121K and A121N) mutations, as well as mtrR promotor, which the investigators cited, was a marker of elevated azithromycin MIC, were carried by all isolates with the exception of the Birmingham-2000.

According to Dr. Thomas, point-of-care testing may “be widely available that are able to assist physicians in determining what the 

 strain infecting their patient is resistant or susceptible to [the strain].” He added that an individualized therapeutic approach “could help physicians in prescribing the best treatment therapy for their patient, but we first need to understand antimicrobial resistance trends in circulating gonococcal strains. From that aspect, I think the kind of monitoring GISP does could help inform the development of POC tests.”

“The current study, as it was designed, does what it was intended to do, which was to characterize the genetics of GISP isolates between 1993 and 2016 on the basis of their antimicrobial resistance mutations, particularly to azithromycin and the cephalosporins, and to investigate relatedness with similar international strains,” Dr. Thomas concluded. “I do think it opens the door for larger retrospective studies. GISP has a large number of un-sequenced isolates, so it would interesting to look at the prevalence of antimicrobial resistance mutations over time. I think that is a logical next step, to have that historical genetic background, and to see how strains are evolving and developing resistance.”

Additionally, the investigators added that their findings highlight the overall need for continual international monitoring and collaboration of 

 isolates. “Mitigating the emergence and spread of resistant 

 supports the need for robust surveillance systems with the capacity to rapidly identify known resistant strains and novel resistance mechanisms as they arise,” they reported.

Jesse Thomas IV, Sandra Seby, Audrey Abrams, Matthew Schmerer, Cau Pham, Samera Sharpe, Kevin Pettus, Sancta St. Cyr, Elizabeth Torrone, Ellen Kersh, Kim Gernert. Genomic Characterization of Neisseria Gonorrhoeae Strains Displaying Elevated Minimum Inhibitor Concentrations (MICS) to Azithromycin and Extended-Spectrum Cephalosporins — United States, 1993—2016.

The current CDC recommended therapy for the treatment of uncomplicated gonorrhea remains the dual combination therapy of 250 mg ceftriaxone delivered intramuscularly and 1 g of azithromycin taken orally.

Current Recommended Treatment for Gonorrhea Still Effective, According to New Study

Severe hospitalized cases of varicella occur primarily in unvaccinated children, yet these cases are still reported in children in a 1-dose vaccination program, according to a study in the 

. Additionally, the investigators found that viral genotyping was important for monitoring disease caused by the Oka-vaccine strain in complex hospitalized cases.

“In an era of 1-dose varicella programs in Australia, continued strain surveillance is important: virus genotyping should especially be considered in children with VZV disease who have previously been vaccinated with varicella vaccine or who are immunocompromised,” the investigators, led by Helen Marshall, MD, wrote.

“Our results show varicella breakthrough disease due to waning immunity or primary vaccine failure was responsible for over a quarter of hospitalized cases, although over half of these cases were in immunocompromised children,” they added. “Although we found an association between being immunocompromised and reduced likelihood of complications, this may have been attributed to differences in admitting practices and management, whereby immunocompetent children are less likely to be hospitalized following varicella infection unless a complication is present and less frequently receive antiviral treatment.”

The investigators enrolled 327 children who were hospitalized with varicella (n = 238) or herpes zoster (n = 89) at 5 different tertiary pediatric hospitals in 5 Australia states. Cases of varicella and herpes zoster were defined as any child between the ages of 1 month and 15 years of age hospitalized with laboratory- or clinical-confirmed varicella as well as any child who was hospitalized with a vesicular rash and a dermatomal distribution with or without laboratory confirmation, respectively.

A length of hospital stay >7 days and/or admission to the intensive care unit (ICU) represented severe cases of hospitalized varicella. The investigators swabbed lesions for genotyping. Single nucleotide polymorphism (SNP) detection was used to differentiate between wild-type and vaccine strains using an analysis of Orf1, 21, 37, 60, and 62 gene targets as well as a DNA sequence analysis of ORF22.

Approximately 18% of immunocompetent children had clinical evidence of prior vaccination against varicella or herpes zoster. Children were more likely to be immunocompromised if they were vaccinated vs unvaccinated (48.2% vs 26.9%, respectively; P =.007). Children aged >18 months who were vaccinated were significantly less likely to present with severe disease when compared with unvaccinated children (9% vs 21%, respectively; 

Breakthrough disease was associated with fewer varicella lesions compared with unvaccinated patients (33% vs 75% of having ≥50 lesions, respectively; 

 =.002). The Oka/vaccine strain was associated with varicella (n=2) or zoster (n=2) in patients who had virus genotyping data available for analysis. Clades of European origin were significantly associated with more severe disease in the overall cohort (odds ratio 3.2; 95% CI 1.1-9.5); 

Clinical diagnosis, rather than standardized laboratory confirmation, was used to define varicella in this study, which may have led to misdiagnoses or misclassifications. Additionally, the findings from this analysis may lack wide scale generalizability, considering only patients from 5 states in Australia were enrolled in the 

“Although disease in vaccinated children is considerably attenuated, it has the potential for serious health-related outcomes. A second dose of varicella vaccine could provide increased protection against varicella and further reduce VZV-related disease and hospitalizations, albeit at an increased cost,” the investigators concluded. “Although targeted strategies are often less successful than population programs, a second dose could be considered if children at risk of complications or severe disease could be identified. Our study indicates this would be difficult to implement with no obvious associations with severity apart from genotype and country of birth.”

Investigators find that severe hospitalization cases of varicella still occur in vaccinated children, yet not vaccinating against the virus confers the greatest threat.

Severe Varicella-Related Hospitalizations Occur in Vaccinated, But Mostly Unvaccinated Children

According to study findings published in 

, treatment with the anti-inflammatory steroid dexamethasone is associated with slowed clearance of fungal infections in HIV-associated cryptococcal meningitis. Additionally, the use of dexamethasone in these patients may accelerate the decline rate of TNF-α concentrations, resulting in worsened clinical outcomes. The study was led by Justin Beardsley, PhD, of the Oxford University Clinical Research Unit in Vietnam.

“HIV-associated cryptococcal meningitis (CM) affects approximately 230,000 people annually, mostly in low and low-middle income countries [1]. Even with optimal anti-fungal treatment, outcomes are poor, with ten-week mortality rates of around 30%,” the researchers wrote. “Our data…extended the understanding of the mycological benefits of high baseline concentrations of pro-inflammatory cytokines, by showing that even once established on effective anti-fungal therapy, persistently higher concentrations can be advantageous.”

Individuals from Vietnam, Thailand, and Uganda who carried and HIV-positive diagnosis and presented with a syndrome consistent with cryptococcal meningitis were enrolled. Additional inclusion criteria stipulated that patients had to have had ≥1 of positive CSF India ink stain, positive CSF or blood culture for Cryptococcus, or positive CSF cryptococcal antigen (IMMY CrAg LFA).

All participants had undergone prior randomization to either intravenously administered dexamethasone (n = 133) or placebo (n = 138). Treatment was administered for 2 weeks at 0.3mg/kg/day for the first week then 0.2mg/kg/day for the second week. Additionally, treatment was then given orally at week 3 (0.1mg/kg/day), week 4 (3mg/day), week 5 (2mg/day), and week 6 (1mg/day).

Researchers measured the concentrations of IFN-γ, TNF-α, GM-CSF, IL-6, IL-12p70, IL-8, MCP-1, MIP-1α, IL-4, IL-10, and IL- 17 in cerebrospinal fluid (CSF) from day 1 of treatment to day 7. The main outcome of interest included the change rates of IFN-γ, TNF-α, IL-4, IL-10 and IFN-γ/IL-4 and TNF-α/IL-10 CSF concentration ratios over the 7-day treatment period.

By 10 weeks, patients with good (34%) or intermediate (38%) outcomes were more likely to have IFN-γ concentrations of >30pg/ml compared with those with severe disability (13%) or death (22%) (

=0.02). Over the first 7-day treatment period, patients randomized to dexamethasone demonstrated faster decline rates of TNF-α concentrations vs those randomized to placebo (difference in slope -0.13; 95% CI -0.22 to - 0.06; 

In addition, treatment with dexamethasone was significantly associated with greater rapid CSF TNF-α:IL-10 ratio declines compared with placebo (95% CI -0.14 [-0.21 to -0.06]; 

<0.001). The faster rate in TNF-α decline was also associated with slower fungal clearance (correlation -0.62; -0.83 to -0.26). The investigators also observed a deleterious effect of dexamethasone on 10-week mortality between 21 and 70 days of treatment for patients with the CC (hazard ratio [HR] 3.24; 95% CI 1.31-8.04) and CT genotypes (HR 3.41; 95% CI 1.07-10.90).

Limitations of the analysis included the unbalanced genotype cohorts as well as the enrollment of patients from Vietnam, Thailand, and Uganda, which limit the generalizability of the findings.

“The body of evidence suggests that, in contrast to TBM and bacterial meningitis, pro- inflammatory immune responses are beneficial in HIV-associated cryptococcal meningitis,” the investigators concluded. “Our data support this conclusion and show that a pro-inflammatory response remains important for fungal clearance even once established on effective anti-fungal therapy.”

Beardsley J, Hoang NLT, Kibengo FM, et al. Do intra-cerebral cytokine responses explain the harmful effects of dexamethasone in HIV-associated cryptococcal meningitis? [published August 30, 2018] 

Study results suggest that treatment with the anti-inflammatory steroid dexamethasone is associated with slowed clearance of fungal infections in HIV-associated cryptococcal meningitis.

Brandon May

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