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Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy. International Valaciclovir HSV Study Group.

OBJECTIVE: To determine the efficacy and safety of once daily valaciclovir for the suppression of recurrent genital herpes simplex virus (HSV) infection in immunocompetent patients. METHODS: 382 otherwise healthy patients with a history of frequently recurring genital HSV infection (eight recurrences per year) were randomly allocated to receive either oral valaciclovir (500 mg once daily) or placebo (3:1 ratio) for 16 weeks or until the first genital HSV recurrence, whichever occurred first. Patients were clinically assessed at regular intervals and also if they experienced a recurrence. Safety was evaluated through adverse experience reporting and monitoring of haematology and biochemistry variables. On completion of the double blind phase, patients were eligible for follow up to a maximum of 48 weeks' treatment with open label valaciclovir (500 mg once daily) for further safety monitoring. The results from the double blind phase of the study are reported here. RESULTS: A significant difference was detected between valaciclovir and placebo in the time to first recurrence of genital HSV infection. The hazard ratio [95% confidence interval] for valaciclovir v placebo was 0.155 [0.112, 0.214], p < 0.0001. Valaciclovir prevented or delayed 85% of the recurrences that would have occurred with placebo. After 16 weeks (day 112) with treatment, 69% of patients receiving valaciclovir were recurrence free compared with only 9.5% of patients assigned to placebo. The safety profiles of valaciclovir and placebo were comparable, with adverse experiences being infrequent and generally mild. CONCLUSION: This study has demonstrated that once daily valaciclovir (500 mg), is highly effective and well tolerated for the suppression of recurrent genital HSV infection. Once daily dosing with valaciclovir provides a more convenient dosing regimen than the more frequent aciclovir regimens.

Acyclovir↗

Family planning services in developing countries: an opportunity to treat asymptomatic and unrecognised genital tract infections?

OBJECTIVE: To determine the prevalence of asymptomatic and unrecognised genital tract infections among women attending a family planning clinic in rural South Africa. METHODS: 189 consecutive women had genital samples taken to diagnose infection with Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Candida albicans, Treponema pallidum, and HIV, and to diagnose bacterial vaginosis. RESULTS: Mean age was 25 years; 155 (82%) were unmarried, 156 (83%) were currently using contraception, and 41 (22%) reported having an STD treated in the preceding 12 months. Although none volunteered abnormal urogenital symptoms, 74 (39%) had at least one elicited by direct questioning. 119 women (63%) had at least one genital infection: N gonorrhoeae (eight; 4%), C trachomatis (14; 8%), T vaginalis (26; 14%), C albicans (56; 30%), active syphilis (15; 8%), HIV (44; 24%), and bacterial vaginosis (29; 15%). 49 women (26%) had multiple infections. Most infections (71; 60%) were asymptomatic. Symptomatic women failed to recognise and report their symptoms, and routine services failed to detect the infections. CONCLUSION: Prevalence of genital tract infection is high among these women, most infections are asymptomatic, and symptomatic infections are frequently not recognised. Women attending family planning clinics in such settings should be screened for syphilis and offered testing for HIV infection. Strategies to detect and treat other genital infections need to be developed.

Adult↗

Comparison of urine, first and second endourethral swabs for PCR based detection of genital Chlamydia trachomatis infection in male patients.

OBJECTIVES: To compare endourethral swabs and urine as diagnostic specimens for the detection of genital Chlamydia trachomatis infection using the polymerase chain reaction (PCR), in male patients attending a genitourinary clinic and to assess whether the first endourethral swab used solely for diagnosing gonococcal infection could be used for C trachomatis detection as well. METHODS: Two endourethral swabs were taken from 80 male patients, in whom the likelihood of genital C trachomatis infection was high. The first swab was used for microscopy and culture for Neisseria gonorrhoeae, before being used for C trachomatis detection. First voided urine specimens were collected from 61 of these patients. All three specimens were processed for C trachomatis DNA detection using the Roche Cobas Amplicor PCR. A diagnosis of genital C trachomatis infection was made if any one of the specimens tested reproducibly positive. Samples from 13 patients showing discrepant PCR results between swabs and/or urine were retested by ligase chain reaction (LCR). RESULTS: Chlamydia trachomatis DNA was detected in 35 (43.8%) of the 80 patients. In 17 of the 35 patients (48.6%), all the genital specimens were positive. However, in 18 (51.4%) patients, one or more of the genital specimens had negative PCR results. Among the 18 patients with discrepant results, urine was found to be a more sensitive diagnostic specimen than the second urethral swab picking up 13 out of 16 positives (81.3%) as opposed to five out of 18 (27.8%). There was no significant difference between the two swabs. Retesting by LCR, of the samples from 13 of the 18 patients with discrepant PCR results confirmed them all as true positives, although as with PCR, not all specimens in the set were concordantly positive. LCR detected all the 13 positives in urine, while there was no difference in the detection rate between the first and the second urethral swabs. CONCLUSIONS: Urine appeared to be a better diagnostic specimen than the conventional second endourethral swab for C trachomatis detection by PCR in this cohort of male patients. There was no difference between the first swab, intended primarily for N gonorrhoeae testing and the second swab intended for C trachomatis detection. This raises questions over the need for the conventional second swab for detecting C trachomatis.

Adolescent↗

Acyclovir suppression to prevent clinical recurrences at delivery after first episode genital herpes in pregnancy: an open-label trial.

OBJECTIVE: To continue evaluation of the use of acyclovir suppression in late pregnancy after first episode genital herpes simplex virus (HSV) infection, using an open-label study design. METHODS: Ninety-six women diagnosed with genital herpes for the first time in the index pregnancy were prescribed suppressive acyclovir 400 mg orally three times daily from 36 weeks until delivery in an open-label fashion. Herpes cultures were obtained when patients presented for delivery. Vaginal delivery was permitted if no clinical recurrence was present; otherwise a Cesarean delivery was performed. Neonatal HSV cultures were obtained and infants were followed clinically. Rates of clinical and asymptomatic genital herpes recurrences and Cesarean delivery for genital herpes were measured, and 95% confidence intervals were calculated. RESULTS: In 82 patients (85%) compliant with therapy, only 1% had clinical HSV recurrences at delivery. In an intent to treat analysis of the entire cohort, 4% had clinical recurrences (compared with 18-37% in historical controls). Asymptomatic shedding occurred in 1% of women without lesions at delivery. Two of the four clinical recurrences were HSV-culture positive. No significant maternal or fetal side-effects were observed. CONCLUSIONS: In clinical practice the majority of patients are compliant with acyclovir suppression at term. The therapy appears to be effective at reducing clinical recurrences after a first episode of genital herpes complicating a pregnancy.

Acyclovir↗

Case-control study of vulvar vestibulitis risk associated with genital infections.

OBJECTIVE: To evaluate the risk of vulvar vestibulitis syndrome (VVS) associated with genital infections in a case-control study. METHODS: Diagnosed cases with VVS (n = 69) and age-frequency-matched healthy controls (n = 65) were enrolled from gynecology clinics in a university medical hospital during 1999. They were compared for potential risk factors and symptoms of disease. RESULTS: VVS cases had a significantly higher risk of physician-reported bacterial vaginosis (BV) (odds ratio, OR = 9.4), Candida albicans (OR = 5.7), pelvic inflammatory disease (PID) (OR = 11.2), trichomoniasis (OR = 20.6), and vulvar dysplasia (OR = l5.7) but no risk associated with human papillomavirus (HPV), ASCUS, cervical dysplasia, genital warts, chlamydia, genital herpes or gonorrhea. Genital symptoms reported significantly more often with VVS included vulvar burning (91 vs. 12%), dyspareunia (81 vs. 15%), vulvar itching (68 vs. 23%) and dysuria (54 vs. 19%) (p < 0.0001). CONCLUSION: A history of genital infections is associated with an increased risk of VVS. Long-term follow-up case-control studies are needed to elucidate etiologic mechanisms, methods for prevention and effective treatment.

Adult↗

Epithelial-mesenchymal interactions in development of the mouse fetal genital tubercle.

Epithelial-mesenchymal interactions play a central role in the development of urogenital organs. We hypothesized that normal development of the external genitalia depends upon proper mesenchymal-epithelial signaling. The mesenchyme of the adult mouse penis consists of a corpus cavernosum and proximal and distal bones. The differentiation of penile mesenchyme into bone and cartilage begins after birth and can be accelerated by androgens. After determining the sex, genital tubercles of fetal mice at gestational day 15 were removed. The genital tubercles were trypsinized and microdissected to remove the epidermis and urethra from the mesenchyme. Recombinant specimens were created by combining genital tubercle mesenchyme with genital tubercle epithelium, bladder epithelium or tail epidermis. Tissues were grafted under the renal capsule of male athymic mice. After 3 weeks of growth, grafts were removed from the kidney, weighed and stained with hematoxylin and eosin, Alcian blue and peanut agglutinin. Male and female grafts showed no difference in growth or differentiation. Intact grafts and recombinant grafts, irrespective of the epithelial source, grew significantly more than grafts of the mesenchyme only. Recombinant grafts demonstrated a significantly higher prevalence of cartilage formation and mesenchymal differentiation compared to grafts of the mesenchyme without epithelium. Since heterologous epithelium is able to induce equivalent growth and differentiation of phallic mesenchyme, epithelium carries a permissive, but critical, role in genital mesenchyme development.

Animals↗

Genital herpes simplex virus type 1 infection: new fields for an old acquaintance?

Herpes simplex virus (HSV)-2 is the principal agent of chronic remittent genital herpes. Worldwide, only 10-20% of genital isolates are HSV-1. Studies from the British Isles and Scandinavia indicate, however, that HSV-1 is responsible for a significant proportion or even the majority of first clinical episodes of genital herpes in young women. Actual data show that a trend towards genital HSV-1 infections may also hold true for Germany. This article summarizes possible reasons for and consequences of the observed changes in the epidemiology of genital HSV infections.

Adult↗

Recurrent genital herpes simplex virus infection in guinea pigs.

After recovery from initial genital herpes simplex virus (HSV) infections, female guinea pigs developed spontaneous recurrent infections characterized by discrete erythematous or vesicular herpetic lesions on the external genital skin. HSV type 2 (HSV2) caused significantly more recurrent infections in guinea pigs than did HSV type 1 (HSV1). HSV2-infected animals demonstrated a significant decline in frequency of recurrences over time. The viral nature of the recurrent lesions was confirmed by recovery of infectious HSV, detection of HSV antigen, and histologic examination. Latent HSV2 could be demonstrated in dorsal root ganglia and external genital skin after recovery from the primary infection. Recurrent genital HSV infection in the guinea pig shares many features with recurrent genital herpes in humans and provides a model for studying the relationship between latency and recurrences and for exploring methods for control of recurrent disease.

Animals↗

Herpes simplex types 1 and 2: latency in the genital tract of guinea pigs.

Guinea pigs were infected with herpes simplex virus (HSV) intravaginally and then sacrificed during latent infection. Virus was recovered from the ganglia, spinal cord and genital tissues by co-cultivation after 1-6 weeks in culture. The virus could not be recovered from the genital tract during the first week of co-cultivation, nor from homogenized genital tissue. Cultivation of genital tissues with acyclovir did not reduce the recovery of HSV. Thus, HSV appeared to establish a truly latent infection in the genital tract and not a persistent infection as previously described.

Acyclovir↗

Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment.

Reactivation of herpes simplex virus type 2 (HSV-2) occurs intermittently as perceived clinically and by viral culture. We performed a series of studies to evaluate the frequency and pattern of HSV-2 reactivation using both viral isolation and HSV PCR assay. Daily samples of genital secretions were obtained from 27 HSV-2 seropositive women; a subset of subjects obtained samples while receiving oral acyclovir 400 mg PO twice a day. HSV DNA was detected in genital swab specimens on 28% of 1,410 d compared with 8.1% of days by viral isolation. 11 of 20 women had HSV DNA detected on > 20% of days, 4 on > 50%, and 2 on > 75% of days; in contrast, none of the women shed on > 21% of days by viral isolation. The daily administration of oral acyclovir promptly reduced the frequency of HSV DNA detection by a median of 80%. Within 3-4 d of discontinuing daily acyclovir, HSV DNA again appeared in the genital area. HSV-2 shedding in the genital mucosa occurs much more frequently than previously appreciated. This frequent reactivation likely plays a role in the epidemic spread of genital herpes worldwide.

Acyclovir↗

Significance of Bacteroides ureolyticus in the lower genital tract.

In a study to determine the significance of Bacteroides ureolyticus in the lower urogenital tract using a new selective and differential medium, this organism was isolated from 30.1% of asymptomatic men, 37.8% of men with genital warts, and 26.3% of men with non-gonococcal urethritis. Using the same selective medium B. ureolyticus was isolated from 49% of women attending the same genitourinary clinic with symptoms of vaginal discharge and/or pruritus vulvae, 44.1% of asymptomatic women, and 50% of asymptomatic women attending a local family planning clinic. Furthermore, this organism was isolated from 27.1% of women whose vaginal specimens isolated commensal organisms only, 43.2% with C. albicans, 59.4% with U. urealyticum, 74.4% with M. hominis, and 76.8% with G. vaginalis. On testing with the API ATB 32A test strips, 86% of the positive isolates of B. ureolyticus from the female genital tract were indistinguishable from those isolated from the male genital tract indicating that this organism is common to the lower genital tract of both sexes. These results indicate that B. ureolyticus is a commensal in the lower genital tract.

Adult↗

Reducing the risk of transmitting genital herpes: advances in understanding and therapy.

BACKGROUND: This review considers the epidemiology and impact of genital herpes, discusses how herpes simplex virus-2 (HSV-2) is transmitted, and reviews data on methods of reducing the risk of HSV transmission. SCOPE: Information for the paper was identified through multiple PubMed searches. Information in the section on interventions was identified through PubMed searches using several pairs of key words (herpes and transmission, herpes and treatment, herpes and antiviral, herpes and valacyclovir, herpes and famciclovir, herpes and acyclovir, herpes and condom, herpes and clinical trial). The searches, conducted in January 2005, did not have date limits. Papers were selected for inclusion based on the author's judgment of their relevance to the topic of the review. FINDINGS: An estimated 45 million persons in the United States have genital herpes infection, and new infections occur at a rate of approximately one million per year. Approximately 85% to 90% of infections are unrecognized and therefore undiagnosed. Individuals with genital HSV-2 infection shed virus during asymptomatic periods as well as symptomatic periods. In fact, transmission frequently occurs during periods of asymptomatic viral shedding. Asymptomatic viral shedding (1) occurs in the majority of patients with genital HSV-2 infection; (2) accounts for approximately one third of the days of viral shedding; (3) occurs regardless of duration of infection but is most frequent during the first year after infection; (4) occurs more than 7 days before or after a symptomatic recurrence 50% of the time; and (5) does not differ significantly when comparing patients with 1 to 12 annual recurrences to those with no recurrences. A recently published study of discordant couples counseled on safe sex practices found that once daily suppressive therapy with valacyclovir reduced the risk of transmission of HSV-2 in heterosexual immunocompetent adult couples discordant for HSV-2 infection. In an 8-month study, daily valacyclovir compared with placebo reduced the risk of acquisition of symptomatic genital HSV-2 infection by 75% (2.2% placebo vs. 0.5% valacyclovir; hazard ratio = 0.25; p = 0.008). The overall risk of acquisition of HSV-2 infection (defined via laboratory-confirmed symptoms or seroconversion) was reduced by 48% (3.6% placebo vs. 1.9% valacyclovir hazard ratio = 0.52; p = 0.04). The most common adverse events in the study were headache, nasopharyngitis, and upper respiratory infection. CONCLUSION: Daily suppressive therapy is recommended as a therapeutic option for HSV-2 seropositive individuals at risk of transmitting HSV-2. Because no intervention completely protects against transmission of HSV, infected individuals and their partners should be counseled to use safer sex practices, including the use of condoms.

Acyclovir↗

The role of prostaglandins in masculine differentiation: modulation of prostaglandin levels in the differentiating genital tract of the fetal mouse.

The present study was designed to test the hypothesis that the stimulation of arachidonic acid prostaglandins (PG) mediates the masculinizing effects of testosterone in the fetal mouse. We examined a number of situations in which masculine organization was either induced or inhibited by external agents and determined whether PG levels in the fetal genital tracts were altered in a manner coincident with those situations. We show here that both PGE2 and 6-keto-PGF1 alpha levels in the male fetal genital tracts increased with the advancement of masculine differentiation. PG levels in males (1.2 +/- 0.3 pg PGE2 and 0.1 +/- 0.03 pg 6-keto-PGF1 alpha on day 14 of gestation) increased to 2.1 +/- 0.3 pg PGE2 and 1.2 +/- 0.3 PG 6-keto-PGF1 alpha on day 18 of gestation. The PG levels in the male genital tract were significantly higher than the PG levels in the female genital tract throughout the period of sexual differentiation. Before this period, however, such as on day 14 of gestation (when male and female fetuses have identical genital tracts) we found no difference in their PG levels. Moreover, administration of testosterone (40 mg/kg) during the critical period of masculine differentiation (days 13-17 of gestation) significantly increased PG levels (approximately 2-fold) of female fetuses. Furthermore, we found that cyproterone acetate (20 mg/kg), an inhibitor of masculine differentiation, on days 13-17 of gestation deceased PG levels in male fetuses. In addition, administration of PG synthesis inhibitors, namely indomethacin (1 mg/kg) and aspirin (100 mg/kg), inhibited both resting and androgen-inducible PG levels in male and female fetuses. Considering these results together, it may be concluded that PGs have a critical role in the masculinizing action of fetal testosterone.

6-Ketoprostaglandin F1 alpha↗

A case control study of active genital Chlamydia trachomatis infection among patients with tubal infertility in northern Nigeria.

A case-controlled study of the prevalence of genital Chlamydia trachomatis infection in 120 patients with tubal infertility (study group) and 120 clients of the family planning clinic (control group) attending the Ahmadu Bello University Teaching Hospital, Zaria in northern Nigeria is reported. The prevalence was 38.3%, 95% confidence interval (CI) (29.6-47.6%) in the study group and 13.3%, 95% CI (7.8-20.7%) in the control group. There was a fourfold risk of having genital Chlamydial infection among the cases compared to the controls (odds ratio [OR] = 4.04, 95% CI (2.04 < OR < 8.09). Tubal infertility was found to be significantly associated with genital C. trachomatis infection (P < 0.001). Out of the 58 cases of primary infertility, 22(37.9%) tested positive for genital C. trachomatis compared with 24 of the 62 (38.7%) that had secondary infertility. The infection was not found to be significantly associated with a particular type of infertility (primary or secondary), number of sexual partners or previous sexually transmitted disease (P < 0.05). There is need for provision of facilities to enable screening for genital C. trachomatis infection in view of its high prevalence in the study population.

Adult↗

Incidence of concurrent sexually transmitted infections in patients with genital warts.

A case-note audit of patients presenting to a genitourinary (GU) medicine clinic with external genital warts during a six-month period was conducted. Approximately 40% of patients were referred by a general practitioner or other primary care agency, and >50% were suitable for home-based treatment. Overall incidence of co-existing sexually transmitted infections (STIs) in the study population was 14.0%. Multivariate logistic regression analysis found that age<25 years and presence of other genital symptoms were risk factors for co-existing STIs. All patients with a non-chlamydial STI had genital symptoms. We recommend that patients with uncomplicated genital warts and no additional genital symptoms can be treated in primary care, with chlamydia-screening offered to those aged<25 years.

Adult↗

Association between HSV-2 and HIV-1 viral load in semen, cervico-vaginal secretions and genital ulcers of Thai men and women.

We studied the association between herpes simplex virus type-2 (HSV-2) and HIV-1 viralload in plasma, semen, cervico-vaginal secretions and genital ulcers. Forty-seven (68%) men and 57 (80%) women were HSV-2 antibody positive, of whom 12 (26%, 95% confidence interval [CI] 20, 32) and five (8%, 95% CI 4, 12), respectively, had HSV-2 genital shedding detected by polymerase chain reaction. The mean HIV-1 seminal and cervico-vaginal viral loads did not differ significantly according to the presence of HSV-2 shedding. Eleven men and 15 women presented with genital ulcers; all ulcers were due to HSV-2. Ten men and nine women were followed up over six days: the mean (95% CI) HIV-1 log viral load copies/mL in the genital ulcers at baseline and final visits were 2.5 (2.3, 2.7) and 3.1 (2.0, 4.2) for men and 3.0 (2.6, 3.4) and 2.7 (2.3, 3.1) for women. These findings do not support the hypothesis that HSV-2 increases the HIV-1 viral load in genital secretions.

Adult↗

Survey of the management of genital herpes in general practice.

In a questionnaire survey of the management and treatment of genital herpes in the community by general practitioners (GPs) in 16 UK cities considered to have good access to genitourinary services, the mean number of cases seen per GP in the previous 12 months was 1.37 for first episodes and 0.96 cases for recurrent episode genital herpes. First episode genital herpes was regularly managed solely in the community by 21% of responding GPs, while 45% of those referring directly to the genitourinary medicine clinic initiated treatment prior to referral; the vast majority prescribing acyclovir. Overall, three-quarters of GPs prescribed oral acyclovir for first episode genital herpes. Recurrent genital herpes was regularly treated solely in the community by 47% of responding GPs, while 53% of those referring directly to the genitourinary medicine clinic initiated treatment prior to referral. There was almost equal usage between acyclovir cream and tablets in the treatment of recurrent infections.

Acyclovir↗

Genital surgery among females with congenital adrenal hyperplasia: changes over the past five decades.

The treatment of intersex patients, including any patient born with genital ambiguity, is being reassessed. The re-evaluation is primarily focused upon the indications for and age of genital surgery, the impact of prenatal androgen levels upon gender development, and the potential for maximum sexual responsiveness as an adult. As a background to document changes in genital surgery for females with 21-hydroxylase congenital adrenal hyperplasia, this report is a review of surgical treatment of this most common form of genital ambiguity. Results document changes in the 1960s from clitorectomy to clitoroplasty using more refined techniques, but more interestingly a choice by parents against any surgery during childhood. This shift preceded the current impetus from intersex support groups. It appears to result from an appreciation by parents of variation in female genital configurations plus a realization that the clitoris will regress with the withdrawal of excessive androgens with relative size diminishing as growth proceeds. The primary impetus for this shift apparently has not been to preserve the vascular and neural supply to enhance sexual responsiveness, since parents in the past assumed that such could be preserved with appropriate surgical techniques.

Adrenal Hyperplasia, Congenital↗