Darrell H. S. Tan

Awareness of, usage of and willingness to use HIV pre-exposure prophylaxis among men in downtown Toronto, Canada:

Pre-exposure prophylaxis (PrEP) is a promising strategy whereby HIV-uninfected people could take antiretroviral (ARV) medications to reduce their risk of HIV acquisition. Reports suggest that unsupervised PrEP use has been occurring in gay communities of USA cities before human safety and efficacy data became available. We administered a 20-item questionnaire to men undergoing HIV testing at Hassle Free Clinic, a sexual health clinic in the gay village of Toronto. Questionnaire items enquired about demographics, sexual partners, substance use and awareness of, usage of and willingness to use PrEP. Logistic regression was used to identify characteristics associated with PrEP-related outcomes. Of 256 participants, 11.7% were aware of PrEP, with more men who have sex with men (MSM) aware (14.1%) than non-MSM (4.9%). No participants reported PrEP usage. Willingness to consider PrEP use was high and associated with high-risk activities, suggesting opportunities for PrEP use in the future.

Disseminated fungal infection in a renal transplant recipient involving Macrophomina phaseolina and Scytalidium dimidiatum: case report and review of taxonomic changes among medically important members of the Botryosphaeriaceae

We report the first case of human infection with the fungal plant pathogen Macrophomina phaseolina in a Sri Lankan-born Canadian man following a renal transplant in India. The patient subsequently succumbed to invasive infection with Scytalidium dimidiatum. Molecular sequence analysis confirmed the identification of both fungi and revealed that they are related species within the ascomycete family Botryosphaeriaceae. We review the rationale for the recent reclassification of S. dimidiatum as Neoscytalidium dimidiatum and of Nattrassia mangiferae (formerly considered a synanamorph of S. dimidiatum) as Neofusicoccum mangiferae. This and other recent cases illustrate the potential for plant pathogenic fungi to cause invasive human diseases which are refractory to antifungal therapy.

Multidrug-Resistant HIV-1 Infection despite Preexposure Prophylaxis

This letter indicates that infection with HIV type 1 can occur despite preexposure prophylaxis with combination antiretroviral therapy.

No impact of oral tenofovir disoproxil fumarate on herpes simplex virus shedding in HIV-infected adults

Objective:To determine the impact of oral tenofovir as part of combination antiretroviral therapy on asymptomatic herpes simplex virus (HSV) shedding. Design:Observational study of a cohort of HSV, HIV-1 co-infected adults. Methods:HSV infection was diagnosed using type-specific serology (HerpeSelect ELISA, Focus Technologies). Asymptomatic HSV, HIV-1 co-infected individuals achieving HIV viral load below 50 copies/ml on antiretroviral therapy self-collected oral, genital and anal swabs daily for 28 days. Refrigerated specimens were dropped off weekly for HSV-1 and HSV-2 testing by polymerase chain reaction (PCR). Shedding rate was calculated as the proportion of days on which HSV PCR was positive. Results:Forty co-infected patients were enrolled, of whom 30 were HSV-2 seropositive. Tenofovir was part of the antiretroviral regimen in 22 of 40 (55%) participants overall and 17 of 30 (57%) of HSV-2 infected participants. The median (interquartile range) HSV-2 shedding rate among HSV-2 seropositive participants was low, at 7.1% (0, 14.3) of specimen collection days, and did not differ between tenofovir users and nonusers (P = 0.36). There was no difference in the number of HSV-2 shedders in the tenofovir and nontenofovir groups (59 vs. 46%; P = 0.49). Rates of shedding for HSV-1 alone (P = 0.59), and for either HSV-1 or HSV-2 (P = 0.38), were also similar between tenofovir users and nonusers. Conclusion:Although topical tenofovir 1% gel was associated with a significant decrease in HSV-2 acquisition among high-risk women in the recent CAPRISA 004 trial, in these preliminary data we did not observe an impact of oral tenofovir on HSV-2 or HSV-1 shedding rates among HIV, HSV co-infected asymptomatic adults.

Patterns of syphilis testing in a large cohort of HIV patients in Ontario, Canada, 2000–2009

BackgroundSince 2000, reported syphilis cases increased ten-fold in Canada, particularly among men who have sex with men (MSM) co-infected with HIV. We characterized temporal patterns of of syphilis testing in a large cohort of HIV patients in Ontario, Canada.MethodsWe analyzed data from a multi-site cohort of people in HIV care from 2000 to 2009. Data were obtained from medical charts, interviews and record linkage with the syphilis test database at the Public Health Ontario Laboratories. We estimated the proportion that had syphilis testing at least once per year and the period and annual prevalence of reactive tests.ResultsAmong 4232 participants, the annual proportion tested rose from 2.7% (95%CI 1.9, 3.5) in 2000 to 54.6% (95%CI 52.9, 56.3) in 2009. Testing was most common for participants who were men who have sex with men (MSM), aged <30, recently diagnosed with HIV, were antiretroviral treatment naive, had routine HIV lab testing at least twice in that year, or tested for syphilis in the preceding year. The proportion with at least one reactive test in 2000–09 was 21.0% (95%CI 19.4, 22.7) for MSM, 5.3% (95%CI 3.3, 7.4) for non-MSM males, and 2.6% (95%CI 1.2, 4.0) for women. Among MSM, the annual prevalence of reactive syphilis tests with high RPR titre (≥1:16) peaked at 3.8% in 2009.ConclusionsThe burden of syphilis co-infection rose considerably among HIV-positive MSM, such that by 2009, at least 1 in 5 men had laboratory evidence of current or past infection. Interventions may be needed to boost syphilis testing to achieve goals set by guidelines even in settings with universal health care.

Gemcitabine-Related "Pseudocellulitis": Report of 2 Cases and Review of the Literature

Gemcitabine is a chemotherapeutic agent whose cutaneous toxicities are easily mistaken for infections. We describe 2 patients, 1 with gemcitabine-induced radiation recall dermatitis and 1 with gemcitabine-related erysipeloid reaction, who received misdiagnoses of infectious cellulitis and were given empirical antibiotics. Recognition of these syndromes is important to avoid unnecessary antibiotic use.

A Randomized Controlled Pilot Trial of Valacyclovir for Attenuating Inflammation and Immune Activation in HIV/Herpes Simplex Virus 2–Coinfected Adults on Suppressive Antiretroviral Therapy

BACKGROUND Human immunodeficiency virus (HIV) is associated with increased systemic inflammation and immune activation that persist despite suppressive antiretroviral therapy (ART). Herpes simplex virus type 2 (HSV-2) is a common coinfection that may contribute to this inflammation. METHODS Sixty HIV type 1 (HIV-1)/HSV-2-coinfected adults on suppressive ART were randomized 1:1:1 to 12 weeks of placebo, low-dose valacyclovir (500 mg twice daily), or high-dose valacyclovir (1 g twice daily) in this 18-week trial. Co-primary outcome measures were the percentage of activated (CD38(+)HLA-DR(+)) CD8 T cells in blood, and highly sensitive C-reactive protein, interleukin 6, and soluble intercellular adhesion molecule 1 in plasma. Secondary outcomes included additional immune, inflammatory cytokine, and endothelial activation markers. The impact of valacyclovir (both groups combined) on each outcome was estimated using treatment × time interaction terms in generalized estimating equation regression models. RESULTS Participants were mostly white (75%) men who have sex with men (80%). Median age was 51 (interquartile range [IQR], 47-56) years, median duration of HIV infection was 15 (IQR, 8-21) years, median CD4 count at enrollment was 520 (IQR, 392-719) cells/µL, and median nadir CD4 count was 142 (IQR, 42-240) cells/µL. Valacyclovir was not associated with significant changes in any primary or secondary immunological outcomes in bivariate or multivariable models. Medication adherence was 97% by self-report, 96% by pill count, and 84% by urine monitoring. Eight patients had adverse events deemed possibly related to the study drug (5 placebo, 1 low-dose, 2 high-dose), and 6 patients reported at least 1 HSV outbreak (3 placebo, 3 low-dose, 0 high-dose). CONCLUSIONS Valacyclovir did not decrease systemic immune activation or inflammatory biomarkers in HIV-1/HSV-2-coinfected adults on suppressive ART. CLINICAL TRIALS REGISTRATION NCT01176409.

Pre-exposure prophylaxis for sexually-acquired HIV risk management: a review

Despite significant efforts, the rate of new HIV infections worldwide remains unacceptably high, highlighting the need for new HIV prevention strategies. HIV pre-exposure prophylaxis (PrEP) is a new approach that involves the ongoing use of antiretroviral medications by HIV-negative individuals to reduce the risk of HIV infection. The use of daily tenofovir/emtricitabine as oral PrEP was found to be effective in multiple placebo-controlled clinical trials and approved by the United States Food and Drug Administration. In addition, the Centers for Disease Control and Prevention in the United States and the World Health Organization have both released guidelines recommending the offer of oral PrEP to high-risk populations. The scale-up of PrEP is underway, but several implementation questions remain unanswered. Demonstration projects and open-label extensions of placebo-controlled trials are ongoing and hope to contribute to our understanding of PrEP use and delivery outside the randomized controlled trial setting. Evidence is beginning to emerge from these open-label studies and will be critical for guiding PrEP scale-up. Outside of such studies, PrEP uptake has been slow and several client- and provider-related barriers are limiting uptake. Maximizing the public health impact of PrEP will require rollout to be combined with interventions to promote uptake, support adherence, and prevent increases in risk behavior. Additional PrEP strategies are currently under investigation in placebo-controlled clinical trials and may be available in the future.

Left out but not forgotten: Should closer attention be paid to coinfection with herpes simplex virus type 1 and HIV?

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are among the most common coinfections seen in individuals infected with HIV-1. Most research on HSV-HIV coinfection has focused on HSV-2, and in particular, on its impact on HIV transmission. HSV-2 is associated with micro- and macroulcerations in genital mucosal surfaces, increased numbers of HIV target cells in genital mucosal tissue and increases in plasma HIV viral load of up to 0.5 log(10) copies/mL, such that HSV-2 infection increases the risk of both HIV acquisition and transmission. Because plasma HIV RNA levels are a major determinant of rates of CD4 cell decline, HSV-2 coinfection may also adversely affect the progression of HIV disease. Anti-HSV medications have in fact been associated with reciprocal decreases in HIV viral load in short-term studies. These findings have led to the development of several clinical trials of HSV-2 suppression as strategies for preventing HIV transmission and slowing the rate of HIV disease progression. HSV-1 coinfection has largely been ignored from this growing body of research, yet there are several reasons that this coinfection remains an important issue for study. First, the seroprevalence of HSV-1 is consistently higher than that of HSV-2 among both HIV-infected and HIV-uninfected populations, underscoring the relevance of HSV-1 coinfection to the majority of HIV-infected persons. Second, pre-existing HSV-1 antibodies in individuals may modulate the course of subsequently acquired HSV-2 infection; the implications of such changes on HSV-HIV coinfection remain unexplored. Third, HSV-1 and HSV-2 are closely related viruses that share 83% genetic homology. Their virological and pathobiological similarities suggest that their implications on HIV pathogenesis may be similar as well. Finally, HSV-1 is becoming increasingly relevant because the incidence of genital HSV-1 has risen. Although genital herpes is traditionally associated with HSV-2, recent studies have shown that the majority of serologically confirmed primary genital herpes in some settings is attributable to HSV-1. Because the genital tract is an important site of biological interaction between HSV and HIV, this epidemiological change may be clinically important.

Antiretroviral therapy is not associated with reduced herpes simplex virus shedding in HIV coinfected adults: an observational cohort study

Objectives Herpes simplex virus types 1 and 2 (HSV-1/2) may have adverse consequences on HIV type 1 infection. We quantified the frequency of HSV reactivations in highly active antiretroviral therapy (HAART)-treated adults with HIV, and compared it with that in HAART-naïve patients. Setting 2 academic hospital sites in Toronto, Canada. Participants Asymptomatic HAART-naive (n=44) or treated (with HIV RNA <50 copies/mL, n=41) adults with HSV-1 and/or 2, HIV coinfection. Outcome measures HSV-1 and HSV-2 shedding as measured by PCR on oral, genital and anal swabs self-collected daily for 28 days. Results Of the 85 participants, 88%, 67% and 53% were coinfected with HSV-1, HSV-2 and both HSV types, respectively. Median (IQR) CD4 count was 516 (382, 655) cells/mm3. HSV (type 1 and/or 2) shedding occurred on a median (IQR) of 7.1% (0, 17.9%) of days in HAART users and 3.6% (0, 10.7%) of days in non-HAART users. No significant relationship was observed between HAART and HSV-1/2 shedding in univariable (OR=1.55, 95% CI 0.83 to 2.87) or multivariable negative binomial models adjusted for sex, baseline CD4 count, recent immigrant status and time since HIV diagnosis (adjusted OR, aOR=1.05, 95% CI 0.43 to 2.58). Similar null results were observed for HSV-2 shedding in HSV-2 seropositive participants (aOR=1.16, 95% CI 0.40 to 3.36) and HSV-1 shedding in HSV-1 seropositive participants (aOR=0.70, 95% CI 0.14 to 3.47). Conclusions HSV reactivations persist despite suppressive HAART among adults coinfected with HSV and HIV. Clinical trials of suppressive anti-HSV therapy are warranted in this population.