Antiviral therapy for the sexually transmitted viruses: recent updates on vaccine development.

INTRODUCTION: The sexually transmitted infections (STIs) caused by viruses including human T cell leukemia virus type-1 (HTLV-1), human immunodeficiency virus-1 (HIV-1), human simplex virus-2 (HSV-2), hepatitis C virus (HCV), hepatitis B virus (HBV), and human papillomavirus (HPV) are major public health issues. These infections can cause cancer or result in long-term health problems. Due to high prevalence of STIs, a safe and effective vaccine is required to overcome these fatal viruses. AREAS COVERED: This review includes a comprehensive overview of the literatures relevant to vaccine development against the sexually transmitted viruses (STVs) using PubMed and Sciencedirect electronic search engines. Herein, we discuss the efforts directed toward development of effective vaccines using different laboratory animal models including mice, guinea pig or non-human primates in preclinical trials, and human in clinical trials with different phases. EXPERT OPINION: There is no effective FDA approved vaccine against the sexually transmitted viruses (STVs) except for HBV and HPV as prophylactic vaccines. Many attempts are underway to develop vaccines against these viruses. There are several approaches for improving prophylactic or therapeutic vaccines such as heterologous prime/boost immunization, delivery system, administration route, adjuvants, etc. In this line, further studies can be helpful for understanding the immunobiology of STVs in human. Moreover, development of more relevant animal models is a worthy goal to induce effective immune responses in humans.

Mathematical modeling of HIV-1 transmission risk from condomless anal intercourse in HIV-infected MSM by the type of initial ART.

BACKGROUND: Initiation of antiretroviral therapy (ART) for HIV infection using regimens that include integrase strand transfer inhibitors (INSTIs) is associated with a faster decline in HIV-1 RNA than what is observed with regimens that are anchored by other ART drug classes. We compared the impact of ART regimens that include dolutegravir (DTG), raltegravir (RAL), efavirenz (EFV), or darunavir/ritonavir (DRV/r), in treatment naïve men who have sex with men (MSM) on the probability of HIV-1 sexual transmission events (HIV-TE). SETTING: Mathematical model. METHODS: We used discrete event simulation modeling to estimate HIV-TE during the first 8 weeks after initiation of ART. HIV-1 RNA decay in men was modeled from the databases of three clinical trials: Single (DTG vs. EFV), Spring-2 (DTG vs. RAL) and Flamingo (DTG vs. DRV/r). RESULTS: All regimens substantially reduced the number of HIV-TE compared to no treatment. DTG led to fewer HIV-TE than its comparator in each of the three trials: 22.72% fewer transmissions than EFV; 0.52% fewer transmissions than RAL; and 38.67% fewer transmissions than DRV/r. The number of patients needed to treat with DTG to prevent one transmission event instead of comparator was 48 vs EFV, 2,194 vs RAL, and 31 vs DRV/r. CONCLUSION: Unsurprisingly, this mathematical model showed that all regimens reduced HIV-TE compared to no treatment. The results also suggest that that initial use of INSTIs, by virtue of their superior viral decay kinetics, have the potential to reduce HIV-1 horizontal transmission following initiation of ART in naïve MSM. TRIAL REGISTRATION: ClinicalTrials.gov NCT03183154.

In Silico Studies against Viral Sexually Transmitted Diseases.

Sexually Transmitted Diseases (STDs) refer to a variety of clinical syndromes and infections caused by pathogens that can be acquired and transmitted through sexual activity. Among STDs widely reported in the literature, viral sexual diseases have been increasing in a number of cases globally. This emphasizes the need for prevention and treatment. Among the methods widely used in drug planning are Computer-Aided Drug Design (CADD) studies and molecular docking which have the objective of investigating molecular interactions between two molecules to better understand the three -dimensional structural characteristics of the compounds. This review will discuss molecular docking studies applied to viral STDs, such as Ebola virus, Herpes virus and HIV, and reveal promising new drug candidates with high levels of specificity to their respective targets.

Evaluation of the reproductive toxicity of antiretroviral drug loaded lactoferrin nanoparticles.

Multiple prevention therapy has gained importance for the prevention and treatment of sexually transmitted diseases, especially HIV/AIDS. Antiretroviral drugs encapsulated in nanoparticles have been developed for efficient delivery of the drugs to the vaginal surface. Lactoferrin nanoparticles (LFNPs) encapsulating anticancer or antiretroviral drugs are found to be promising agents to specifically deliver drugs at the target sites. Recent studies indicate that the bioavailability is higher for antiretroviral drugs delivered by LFNPs than when the drugs are administered alone. Although LFNP-mediated drug delivery via the oral or vaginal route for the treatment of HIV/AIDS is promising, the effect of such administrations is not well studied. Drug-loaded LFNPs when administered to rats by the vaginal route did not show any effect on the reproductive performance, fertility, and postnatal development. Oral administration of drug-loaded LFNPs caused a significant decrease in litter size, whereas the reproductive performance and postnatal development remained normal. In our model system, the results indicate that vaginal administration of drug-loaded LFNPs appears safer and can be projected for the delivery of antiretroviral agents via the vaginal route. Abbreviations: LFNPs: lactoferrin nanoparticles; STIs: sexually transmitted diseases infections; NPs: nanoparticles; LF: lactoferrin; DL-LFNPs: drug loaded lactoferrin nanoparticles; MPT: multiple prevention techniques.

Antiviral effect of the nucleoside analogue cidofovir in the context of sexual transmission of a gammaherpesvirus in mice.

Objectives: To investigate the efficacy of cidofovir to block gammaherpesvirus replication in the context of sexual transmission. Methods: A luciferase-expressing strain of murid herpesvirus 4 (MuHV-4) was used to monitor genital virus excretion from infected female BALB/c mice and sexual transmission to naive males. The efficiency of cidofovir to block genital excretion from infected females or replication and host colonization of naive males after sexual contact was tested by treating infected females (either once daily or at a single timepoint), naive males before exposure (either once daily or at a single timepoint) or males 24 h post-exposure. Results: We showed that daily treatment of infected females can reduce MuHV-4 genital shedding by 75%. Similarly, daily preventive treatment of naive males was sufficient to block viral replication and latency establishment in males. In contrast, a single administration of cidofovir to infected females at day 14 post-infection or to naive males 2 to 6 days before contact with MuHV-4-excreting females was not sufficient to significantly reduce viral shedding from females or infection of males, respectively. Interestingly, a single administration of cidofovir to males 24 h after contact with MuHV-4-infected females excreting the virus in the genital tract significantly reduced virus replication in males and seroconversion. Conclusions: Altogether, our results show that cidofovir can significantly reduce gammaherpesvirus replication, excretion and colonization of the naive partner in the context of sexual transmission. Such treatments could therefore be recommended in some specific conditions where gammaherpesvirus infections could be deleterious.

Ebselen alleviates testicular pathology in mice with Zika virus infection and prevents its sexual transmission.

Despite the low case fatality, Zika virus (ZIKV) infection has been associated with microcephaly in infants and Guillain-Barré syndrome. Antiviral and vaccine developments against ZIKV are still ongoing; therefore, in the meantime, preventing the disease transmission is critical. Primarily transmitted by Aedes species mosquitoes, ZIKV also can be sexually transmitted. We used AG129 mice lacking interferon-α/ß and -γ receptors to study the testicular pathogenesis and sexual transmission of ZIKV. Infection of ZIKV progressively damaged mouse testes, increased testicular oxidative stress as indicated by the levels of reactive oxygen species, nitric oxide, glutathione peroxidase 4, spermatogenesis-associated-18 homolog in sperm and pro-inflammatory cytokines including IL-1ß, IL-6, and G-CSF. We then evaluated the potential role of the antioxidant ebselen (EBS) in alleviating the testicular pathology with ZIKV infection. EBS treatment significantly reduced ZIKV-induced testicular oxidative stress, leucocyte infiltration and production of pro-inflammatory response. Furthermore, it improved testicular pathology and prevented the sexual transmission of ZIKV in a male-to-female mouse sperm transfer model. EBS is currently in clinical trials for various diseases. ZIKV infection could be on the list for potential use of EBS, for alleviating the testicular pathogenesis with ZIKV infection and preventing its sexual transmission.

Prevalence and treatment of sexually transmitted diseases in gynecological practices in Germany: A retrospective study with more than 1,000,000 patients
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BACKGROUND: The aim of this study was to analyze the prevalence and treatment of sexually transmitted diseases (STDs) in gynecological practices in Germany. MATERIALS AND METHODS: This study included women who were followed in gynecological practices in Germany between 2013 and 2015. The first outcome was the prevalence of women diagnosed with STDs during this time period. Eight different types of STD infections were included in the analysis: chlamydial infection, gonococcal infection, anogenital warts, anogenital herpes infection, trichomoniasis, ulcus molle, phthiriasis, and syphilis. The second outcome was the prevalence of women with STDs who received appropriate medication within 90 days of STD diagnosis. RESULTS: There were 1,030,968 patients available for analysis. The most frequent infection was chlamydia (0.59%), and the least frequent one was syphilis (0.01%). The prevalence of STDs was found to be the highest in women aged 21 - 25 years (3.42%). Mean age at diagnosis ranged from 27.3 years (chlamydia infection) to 40.6 years (syphilis). Finally, the share of women receiving medication therapy was the highest for syphilis (83.3%) and the lowest for anogenital warts (52.7%). CONCLUSIONS: The prevalence of STDs ranged from 0.01 to 0.59% in women followed in gynecological practices in Germany between 2013 and 2015.
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HIV-1 viral load and resistance in genital secretions in patients taking protease-inhibitor-based second-line therapy in Africa.

BACKGROUND: HIV is transmitted primarily through sexual intercourse, and the objective of this study was therefore to assess whether there is occult viral replication and resistance in genital secretions in patients on protease inhibitor (PI)-based second-line therapy. METHODS: HIV-infected adults taking ritonavir-boosted lopinavir with either two nucleoside reverse transcriptase inhibitors (NRTIs), raltegravir or as monotherapy for 96 weeks, were enrolled at seven clinical sites in Uganda. Viral load (VL) was measured in cervico-vaginal secretions or semen and in a corresponding plasma sample. Genotypic resistance was assessed in genital secretion samples and plasma samples. Results were compared between compartments and with the plasma resistance profile at first-line failure. RESULTS: Of the 111 participants enrolled (91 female, 20 male), 16 (14%) and 30 (27%) had VL >1,000 and >40 copies/ml, respectively, in plasma; 3 (3%) and 23 (21%) had VL >1,000 copies/ml and >40 copies/ml, respectively, in genital secretions. There was 74% agreement between plasma and genital secretion VL classification above/below 40 copies/ml threshold (kappa-statistic =0.29; P=0.001). RT mutations (both NRTI and non-nucleoside reverse transcriptase inhibitor) were detected in genital secretions in four patients (similar profile to corresponding plasma sample at first-line failure) and PI mutations were detected in two (one polymorphism with no impact on resistance; one with high-level PI resistance). CONCLUSIONS: High level (>1,000 copies/ml) viral replication and development of new RT or PI resistance in the genital compartment were rare. The risks of transmission arising from resistance evolution in the genital compartment are likely to be low on PI-based second-line therapy.

A tale of two countries: all-cause mortality among people living with HIV and receiving combination antiretroviral therapy in the UK and Canada.

OBJECTIVES: We sought to compare all-cause mortality of people living with HIV and accessing care in Canada and the UK. METHODS: Individuals from the Canadian Observational Cohort (CANOC) collaboration and UK Collaborative HIV Cohort (UK CHIC) study who were aged ≥ 18 years, had initiated antiretroviral therapy (ART) for the first time between 2000 and 2012 and who had acquired HIV through sexual transmission were included in the analysis. Cox regression was used to investigate the difference in mortality risk between the two cohort collaborations, accounting for loss to follow-up as a competing risk. RESULTS: A total of 19 960 participants were included in the analysis (CANOC, 4137; UK CHIC, 15 823). CANOC participants were more likely to be older [median age 39 years (interquartile range (IQR): 33, 46 years) vs. 36 years (IQR: 31, 43 years) for UK CHIC participants], to be male (86 vs. 73%, respectively), and to report men who have sex with men (MSM) sexual transmission risk (72 vs. 56%, respectively) (all P < 0.001). Overall, 762 deaths occurred during 98 798 person-years (PY) of follow-up, giving a crude mortality rate of 7.7 per 1000 PY [95% confidence interval (CI): 7.1, 8.3 per 1000 PY]. The crude mortality rates were 8.6 (95% CI: 7.4, 10.0) and 7.5 (95% CI: 6.9, 8.1) per 1000 PY among CANOC and UK CHIC study participants, respectively. No statistically significant difference in mortality risk was observed between the cohort collaborations in Cox regression accounting for loss to follow-up as a competing risk (adjusted hazard ratio 0.86; 95% CI: 0.72-1.03). CONCLUSIONS: Despite differences in national HIV care provision and treatment guidelines, mortality risk did not differ between CANOC and UK CHIC study participants who acquired HIV through sexual transmission.

Occurrence of equine coital exanthema (ECE) in stallions in Japan and effectiveness of treatment with valacyclovir for ECE.

Equine coital exanthema (ECE) has been reported in many countries, but equine herpesvirus 3 (EHV-3) has been isolated only once in Japan. In 2015, symptoms of ECE were found, and EHV-3 was isolated in two stallions. Valacyclovir, an anti-herpesvirus agent, was administered orally. The stallions rested from mating for more than two weeks, causing enormous financial losses because of their high fees. This is the first study in which valacyclovir was administered for ECE. Though valacyclovir treatment did not shorten the duration of healing, the affected area did not expand after administration of valacyclovir. Valacyclovir therefore seems to be effective for suppression of EHV-3 infection. Further investigation about the administration protocol might be required.

Emerging viral STIs among HIV-positive men who have sex with men: the era of hepatitis C virus and human papillomavirus.

The number of infectious disease outbreaks and the number of unique pathogens responsible have significantly increased since the 1980s. HIV-positive men who have sex with men (MSM) are a vulnerable population with regards to the introduction, spread and clinical consequences of (newly introduced) STIs. After the introduction of combination antiretroviral treatment (cART), the incidence of sexually acquired hepatitis C virus (HCV) infection and human papillomavirus (HPV)-induced anal cancers have significantly increased among HIV-positive MSM. The introduction and expansion of HCV is the result of increased sexual risk behaviour and sexually acquired mucosal trauma within large interconnected networks of HIV-positive MSM in particular. With the availability of cART, postexposure and pre-exposure prophylaxis (PEP and PrEP) and direct-acting antivirals (DAAs) for HCV, less concern for HIV and HCV might require a new approach to develop effective behavioural intervention strategies among MSM. The marked rise in HPV-induced anal cancers can be ascribed to the long-term immunologic defects in an ageing population affected by HIV. More evidence with regards to effective treatment options for anal dysplastic lesions and the usefulness of anal malignancy screening programmes is urgently needed. Most anal cancers in the future generation of HIV-positive MSM could be prevented with the inclusion of boys in addition to girls in current HPV vaccination programmes.

Sexually-transmitted seronegative HCV infection in an HIV-positive post-liver transplant recipient. Case report and review of the literature.

We report an HIV-positive patient post liver transplant for non-alcoholic steatohepatitis. Posttransplant liver enzymes became persistently elevated, however HCV antibody was repeatedly negative. Nucleic acid testing subsequently revealed ongoing HCV viremia. Exposure to HCV was on the basis of sexual transmission. The patient was subsequently successfully treated with sofosbuvir/ledipasvir.

[Interferon in combined therapy of human papillomavirus infections associated with sexually transmitted infections. linical observation].

To investigate the effectiveness of Ingaron (interferon-) in the treatment of HPV infection associated with sexually transmitted infections, the authors analyzed the scientific literature on the association of human papillomavirus infection with other viral and microbial pathogens. A clinical case of the association of human papillomavirus infection, urogenital infections (urogenital chlamydia and genital herpes) and localized scleroderma penis is described. The results of integrated therapy of diseases with the help of Interferon-gamma have been presented. According to the literature, up to 70-80% of HPV infections are associated with microbial (opportunistic, obligate pathogens) and viral infectious agents. Chronic inflammation caused by bacterial and viral associations destroys the immune system and it leads to the ineffectiveness of the therapy. Pathogenic therapy of sexually transmitted infections in combination with interferon-gamma (Ingaron) contributes to the eradication of bacterial pathogens, prevention of viral STI recurrence and elimination of high oncogenic risk types of HPV. Thus, we can reasonably infer that Ingaron (interferon-) alleviates the initial immune disturbances, improves the effectiveness of the treatment and may be recommended for treating HPV infection associated with sexually transmitted infections.

Clinical picture and overall status of newly diagnosed HIV patients at Turku University Hospital in 2013.

Our patient material consists of the 12 patients diagnosed during one year. In all cases, sex was the likely mode of transmission, the number of partners having been high for some patients. Some of the cases were originally detected as a result of contact tracing. In two patients the disease had already at the time of diagnosis progressed to the AIDS stage, naturally complicating the initial phase of treatment. In a quarter of our patients the disease could have been discovered earlier from the symptoms of the primary infection, provided that testing had been done. Adherence to treatment in a HIV patient and treatment outcome are usually excellent.

Acute HCV in HIV-infected MSM: modes of acquisition, liver fibrosis, and treatment.

Hepatitis C virus (HCV) is not considered to be efficiently transmitted sexually, but since the early 2000s, HCV infection of HIV-infected men who have sex with men has emerged as an epidemic worldwide. In this review, we discuss the epidemiology of sexually transmitted acute HCV, the growing body of literature regarding risk factors for acquisition, and possible mechanisms of transmission. We also discuss the progression of liver disease in these men and the advances in therapy of acute HCV with interferon-free regimens and put forth our current approach of evaluating and treating these men in New York City.

Severe acute pharyngotonsillitis due to herpes simplex virus type 2 in a young woman.

Whereas herpes simplex virus type 1 (HSV-1) is a recognized cause of acute oropharyngeal infection in young adults, HSV-2 infections are mostly associated with genital symptoms. We report a case of acute and prolonged febrile ulcerative pharyngotonsillitis with inflammatory syndrome which persisted despite antibiotic therapy for 8 days and required hospitalization in an 18-year old immune competent and sexually active female patient. HSV-2 was evidenced in tonsillar samples and blood by real time PCR, and HSV type-specific serology showed HSV-2 primary infection. Despite delayed diagnosis, acyclovir treatment led to rapid clinical improvement. This case highlights HSV-2 as an unusual cause of pharyngotonsillitis that should be reminded in sexually active patients.

Co-delivery of antiviral and antifungal therapeutics for the treatment of sexually transmitted infections using a moldable, supramolecular hydrogel.

In this investigation, a therapeutic co-delivery hydrogel system is developed to provide effective HIV prophylaxis, alongside the prevention and/or treatment of candidiasis. Two components-a HIV reverse transcriptase inhibitor, tenofovir, and a cationic macromolecular antifungal agent derived from a vitamin D-functionalized polycarbonate (VD/BnCl (1:30))-are formulated into biodegradable vitamin D-functionalized polycarbonate/PEG-based supramolecular hydrogels. The hydrogels exhibit thixotropic properties and can be easily spread across surfaces for efficient drug absorption. Sustained release of tenofovir from the hydrogel is observed, where approximately 85% tenofovir is released within 3 h. VD/BnCl (1:30) does not impede drug diffusion from the hydrogel as the drug release profiles are similar with and without the polycation. Antimicrobial efficacy studies indicate that the hydrogels kill C. albicans efficiently with a minimum bactericidal concentration (MBC) of 0.25-0.5 g L(-1) . These hydrogels also eradicate C. albicans biofilm effectively at 4× MBC. When human dermal fibroblasts (as model mammalian cells) are treated with these hydrogels, cell viability remains high at above 80%, demonstrating excellent biocompatibility. When applied topically, this dual-functional hydrogel can potentially prevent HIV transmission and eliminate microbes that cause infections in the vulvovagina region.

Protein and oligonucleotide delivery systems for vaginal microbicides against viral STIs.

Intravaginal delivery offers an effective option for localized, targeted, and potent microbicide delivery. However, an understanding of the physiological factors that impact intravaginal delivery must be considered to develop the next generation of microbicides. In this review, a comprehensive discussion of the opportunities and challenges of intravaginal delivery are highlighted, in the context of the intravaginal environment and currently utilized dosage forms. After a subsequent discussion of the stages of microbicide development, the intravaginal delivery of proteins and oligonucleotides is addressed, with specific application to HSV and HIV. Future directions may include the integration of more targeted delivery modalities to virus and host cells, in addition to the use of biological agents to affect specific genes and proteins involved in infection. More versatile and multipurpose solutions are envisioned that integrate new biologicals and materials into potentially synergistic combinations to achieve these goals.

Prevalence of sexually transmitted infections among healthy Korean women: implications of multiplex PCR pathogen detection on antibiotic therapy.

In this study, we investigated the prevalence of sexually transmitted infections (STIs) using multiplex real-time PCR assay in healthy Korean women. We also evaluated the risk factors of STIs, and compared the various factors between the STI-positive and the STI-negative groups. A total of 799 endocervical swab samples from healthy Korean women who visited our hospital for general medical check-ups during January 2012 to October 2012 were included. Eight STIs including Human papillomavirus (HPV), Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), Mycoplasma hominis (MH), Ureaplasma urealyticum (UU), Ureaplasma parvum (UP), and Trichomonas vaginalis (TV) were detected using Anyplex II STI-7 Detection assay Detection (Seegene, Seoul, Korea) and Hybrid Capture 2 High-Risk HPV DNA test (Digene Corporation, Gaithersburg, MD, USA) according manufacture's protocols. Ninety-seven (12.1%) subjects were positive for HPV. Of 393 (49.2%) subjects were infected with at least one microorganism and a total of 499 STIs were identified. Among the 393 STI-positive subjects, the proportion of single, double and triple infection was 76.3%, 20.4% and 3.3%, respectively. The median age of the STI-positive group (47 years, range 42-52) was younger than the STI-negative group (49 years, range 43-56; P < 0.001). The infection rate of HPV was significantly higher in the STI-positive group (15.8%, 62/393) than the STI-negative group (8.6%, 35/406) (P = 0.002).