José Moreira

Sexual Transmission of Zika Virus: Implications for Clinical Care and Public Health Policy

TO THE EDITOR—Zika virus (ZIKV), a flavivirus transmitted primarily by Aedes mosquitos (predominantly Aedes aegypti in urban and periurban cycles), has been spreading rapidly for the first time across theWestern Hemisphere, where >30 countries have reported autochthonous transmission [1]. Due to its probable causal relationship with microcephaly and other neurologic syndromes, the World Health Organization declared that the current ZIKV outbreak in Americas represents a Public Health Emergency of International Concern [1]. Nonvector transmission routes, especially sexual contact, have been described, but their impact during an epidemic and in nonepidemic settings remains largely unknown. Here we discuss ZIKV sexual-borne transmission and its impact on clinical practice and public health policies. To date, ZIKV transmission through sexual contact was documented in 9 cases [2–5]. All of them were acquired from symptomatic males (median age, 30 years) who had traveled to regions where ZIKV was circulating. Infectious semen ZIKV particles were recovered in cell culture in 2 instances [6, 7]. The longest that the virus was detected by polymerase chain reaction (PCR) in semen was 62 days after the onset of symptoms [8], demonstrating that a much larger infectiousness period possible through this route exists, compared with the viremia duration, which usually does not surpass 7 days. Detection was possible in convalescent-phase semen samples long after clearance of acute viremia. Two of 9 cases reported hematospermia [3, 7]. The presumed mode of transmission involved unprotected vaginal intercourse with the patients’ female partners, some of them pregnant. All women developed acute ZIKV illness shortly after sexual contact with posterior confirmation of infection through serum PCR or plaque neutralization serology. Transmission of ZIKV through sexual contact has resulted in locally acquired cases in 3 countries where vector transmission is extremely unlikely to occur (United States, France, and Italy) [1]. The spread of ZIKV through sexual contact has several implications. First, detection of ZIKV RNA in semen at high concentrations and later in the disease course may be of interest for diagnostic and transmission control interventions. Viremia is short lived (approximately 7 days after disease onset) and of low level, different from the long-lived, high-level presence of viable virus in semen [8, 9]. Second, it adds complexity to the traditional prevention paradigm of the vector-based model by the addition of a sexually transmitted infection model (ie, abstinence, condoms, sexual education). However, we do recognize that in the ongoing ZIKV epidemic in the Americas, transmission is primarily driven by Aedes species, but sexual contact could, at least, explain transmission from travelers who had been in areas of active ZIKV epidemic and returned to their countries. This makes it very difficult to measure the contribution of alternative transmission routes in places where vector transmission is intense. Third, the persistence of ZIKV in semen may pose a risk of transmission for healthcare providers involved in the management of severe ZIKV cases, especially when performing urogenital manipulations. Finally, ZIKV genital shedding may trigger a change in protocols for gamete preservation and conservation in semen banks. We understand that more research is clearly needed to better define the prevalence and duration of genital shedding. Furthermore, it is unknown if infected females also transmit through sexual contact to their partners. Until more data emerge, we suggest that ZIKV be perceived as a potentially sexually transmitted infection with wider implications for clinical care and public health. A more consistent evidence will probably need integrating

Dolutegravir monotherapy as a simplified strategy in virologically suppressed HIV-1-infected patients

Sir, I have read with interest the articles by Rokx et al. and Gubavu et al. describing the efficacy of a simplified dolutegravir regimen as a maintenance strategy in virologically suppressed HIV-1infected patients. However, there is insufficient evidence regarding whether simplification to dolutegravir monotherapy in virologically suppressed HIV-1-infected patients is effective and safe. Thus, the clinical evidence was evaluated and a meta-analysis of observational studies was performed to assess the efficacy and safety of switching to dolutegravir monotherapy (50 mg once daily) in patients with long-term virological suppression. Studies were considered eligible if they provided data with respect to efficacy and safety of dolutegravir monotherapy in virologically suppressed HIV-1-infected adult patients. Systematic searches of PubMed and conference proceedings were conducted with the following keywords: ‘dolutegravir’, ‘monotherapy’, ‘dolutegravirbased monotherapy’ and ‘HIV’. The primary outcome was the proportion of patients maintaining HIV-1 RNA levels ,50 copies/mL. In addition, the proportion of subjects that developed treatment failure was calculated. Secondary outcomes included the proportion of subjects developing treatment adverse events and primary dolutegravir resistance mutations. Treatment failure was defined as discontinuation, switching of the regimen or virological failure (i.e. two consecutive viral loads .50 copies/mL). Outcomes were assessed over a 24 week period, with the exception of two studies that were assessed at 32 and 48 weeks. Meta-analysis of observational studies in epidemiology was performed. The proportion rate and 95% CIs were estimated using random-effects models and heterogeneity was assessed using the I statistic. Comprehensive Meta-Analysis, version 3.0, was used for the analyses. Four studies met the inclusion criteria and included a total of 87 patients, with the median age ranging from 48 to 63 years. Forty-eight patients (55%) were males, with the median time since HIV diagnosis ranging from 11 to 20 years. The HIV viral load was undetectable from 5.9 to 8 years. Antiretroviral strategies used at baseline in the 87 patients before switching to dolutegravir monotherapy were triple ART (47%), dual ART (22%) and mono ART (31%). Twenty-three patients (26.4%) had prior integrase inhibitor (INI) use. The reasons for switching included comorbidities (n1⁄437), drug–drug interactions (n1⁄428), ART-related adverse effects (n1⁄429) and archived resistance compromising ART efficacy (n1⁄416). The proportion of patients maintaining virological suppression after switching to dolutegravir monotherapy was 91.9% (95% CI 82.4–96.5; Z1⁄45.34; I1⁄412.5%) (Table 1). Furthermore, the proportion of treatment failures was 8.1% (95% CI 3.5 –17.6; Z1⁄45.34; I1⁄412.5%). No patient experienced serious adverse effects or discontinued dolutegravir monotherapy. Four out of five patients that had virological failure had prior INI exposure, but without viral failure at baseline. Four developed major INI resistance-associated mutations that compromised dolutegravir activity (i.e. 118R, 138K, 148R, 74I and 155H). Evidence from observational studies suggests that heavily treatment-experienced and virologically suppressed HIV-infected patients have a higher chance to maintain viral suppression when switching to dolutegravir monotherapy. Several properties make dolutegravir attractive for use as a simplified regimen. Dolutegravir has a high genetic barrier comparable to a boosted PI. Those that failed on an initial dolutegravir-based regimen did not develop dolutegravir-associated mutations, in contrast to other agents of the same class (i.e. elvitegravir and raltegravir). Further, dolutegravir has been shown to have superior antiviral potency compared with efavirenz, darunavir and raltegravir, especially in patients with a higher viral load (i.e. HIV viral load .100 000 copies/mL). Even in treatmentexperienced patients, irrespective of previous INI failure, dolutegravir was superior to raltegravir in achieving virological suppression. Lastly, registration studies of dolutegravir showed an excellent safety profile, with severe reactions (grade III or IV) in 1%. Moreover, a large amount of the drug is not metabolized by the cytochrome P450 metabolic pathway, averting potential drug– drug interactions commonly seen with other antiretroviral agents. I believe that switching to dolutegravir monotherapy in specific HIV-infected patients is beneficial.

Cutaneous mucormycosis in advanced HIV disease

Angionvasive mucormycosis is an emerging fungal disease known to affect mainly diabetics or subjects with profound neutropenia. Infection usually occurs through the inhalation route, but cutaneous inoculation may occur after trauma or burns. However, mucormycosis remains unusual in HIV infection. We report a fatal case of cutaneous mucormycosis due to Rhizopus arrhizus involving the scalp following herpes zoster infection. The patient was a 42-year-old man with advanced AIDS failing on salvage antiretroviral therapy. The fungus was diagnosed on the basis of histopathology and culture. Our case emphasizes the need to consider mucormycosis in the differential diagnosis of necrotic cutaneous lesions in patients with late-stage HIV disease.

Fungemia associated with Schizophyllum commune in Brazil

Manoel Marques Evangelista Oliveira*, Alberto Santos Lemos, Marcelo Luiz Carvalho Gonçalves, Rodrigo Almeida-Paes, Vitor Ribeiro Gomes de Almeida Valviesse, José Alfredo Moreira, Marco Antônio Sales Dantas Lima, Eleonora Carregal, Maria Clara Gutierrez Galhardo, Cristiane da Cruz Lamas, Rosely Maria Zancopé Oliveira 1 Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil, 2 Programa de Residência Médica em Infectologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil, 3 Centro de Clı́nicas, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil, 4 Laboratório de Pesquisa Clı́nica em Neuroinfecções, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil, 5 Serviço de Imagem, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil, 6 Laboratório de Pesquisa Clı́nica em Dermatologia Infecciosa, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil

Hyperglycemia during tuberculosis treatment increases morbidity and mortality in a contemporary cohort of HIV-infected patients in Rio de Janeiro, Brazil

BACKGROUND Hyperglycemia occurs in tuberculosis (TB), but the long-term impact is unknown. We estimated the prevalence of hyperglycemia and compared the TB treatment outcomes and 1-year mortality rate according to the glycemic status noted during TB treatment. METHODS We conducted a retrospective cohort analysis of adult patients who had TB and HIV coinfection and started receiving TB treatment at the Instituto Nacional de Infectologia Evandro Chagas, Brazil, between 2010-2015. Diabetes Mellitus (DM) and hyperglycemia were defined according to the American Diabetes Association. After excluding for known DM at baseline, the proportion of participants who developed new-onset DM after TB treatment was assessed. TB outcome was classified as successful or adverse (i.e., treatment failure, abandonment, and death). Kaplan-Meier survival curves were compared by the log-rank test based on the glycemic status of patients. Multivariate Cox regression models were used to assess the association between hyperglycemia and 1-year mortality. Two-sided p values <0.05 were considered statistically significant. RESULTS We identified 414 euglycemic patients (87.5%), 49 hyperglycemic patients (10.3%), and 10 patients with known DM (2.1%). Diabetic patients were older compared to the euglycemic and hyperglycemic patients (47.9 vs. 37 vs. 39.7 years, respectively, p=0.001). Diabetic patients frequently had cavitation on chest image compared to hyperglycemic and euglycemic patients (50% vs. 23.4% vs. 15.3%, p=0.007, respectively). Hyperglycemic patients had more new-onset DM at follow-up compared to euglycemic (22 vs. 1; p<0001). Hyperglycemia was associated with adverse outcomes (71.4% vs. 24.6%, p<0.0001) compared to euglycemia. Crude 1-year mortality was significantly higher in patients with hyperglycemia compared with euglycemia (48.9% vs. 7.9%; unadjusted HR: 5.79 (3.74-8.96)). In the adjusted Cox models, hyperglycemia remained a significant factor for increased 1-year mortality (adjusted HR: 3.72 (2.17-6.38)]. CONCLUSIONS Hyperglycemia frequently occurs in HIV-infected patients who commence TB treatment, and it increases the risks of adverse TB outcomes and 1-year mortality. Glucose testing during TB treatment detects patients at risk of adverse outcomes.

Co-trimoxazole in people on antiretroviral therapy for HIV

I read with great interest the metaanalysis of data on the initiation, discontinuation, and dosing of cotrimoxazole prophylaxis in adults with HIV by study of Suthar and colleagues. Their fi ndings reinforce recent WHO recommendations for long-term cotrimoxazole prophylaxis in adults with HIV who are receiving antiretroviral therapy irrespective of CD4 cell count or WHO clinical stage, especially in resource-constrained settings with high prevalences of invasive bacterial diseases and malaria. On the basis of preliminary evidence, continuous co-trimoxazole prophylaxis after antiretroviral-induced immune recovery might provide benefits in resource-rich settings as well. Patients with HIV are at risk of residual immune dysregulation syndrome even with proper viral suppression. This syndrome is characterised by deregulated immunecoagulation pathways and increased morbidity and mortality caused by non-AIDS events. In this context, the use of co-trimoxazole has been postulated as adjunct therapy, attenuating both T-cell activation and the microbial translocation across impaired gut epithelial barrier common seen in treated HIV individuals. For instance, a substudy of the ARROW trial showed that in patients with HIV on long-term antiretroviral therapy continuous co-trimoxazole prophylaxis was associated with substantial ly lower concentrations of plasma proinflammatory biomarkers (ie, c-reactive protein, sCD14, interleukin 6) than was interrupted prophylaxis. A randomised, placebo-controlled trial to assess the effi cacy of co-trimoxazole in reducing the relapse of Wegener’s granulomatosis showed a lower risk of relapses in the interventional arm, emphasising the emergent role of co-trimoxazole as a potent immunomodulatory drug with antiinflammatory proprieties. Further investigations are urgently required to assess the true eff ect of co-trimoxazole on the persistent inflammatory state associated with chronic HIV. Whether short-term or long-term prophylaxis will be needed to reduce immune activation in people receiving antiretroviral therapy is unknown; and concerns about drug interactions between and tolerability might arise. Data from the Swiss HIV Cohort Study have shown that cumulative and current co-trimoxazole prophylaxis reduce all-cause mortality and incident tuberculosis rate in ART-naive and ART-experienced patients. These fi ndings suggest that the protection attributed to co-trimoxazole prophylaxis might be of use in diverse settings including regions with lowburden of infectious diseases in more developed countries.

At the crossroads between early or delayed antiretroviral therapy initiation during tuberculosis/human immunodeficiency virus coinfection.

Saraceni et al.1 report the results of the THRio observational cohort, which showed an 89% increased risk of mortality when antiretroviral therapy (ART) was delayed (more than 60 days and less 365 days after tuberculosis (TB) treatment) during HIV-associated TB. However, the median CD4 count at TB diagnosis in this cohort was 150 cells/ L, a fact that may compromise the generalization and interpretation of the study results. On the other hand, the investigators provide further support to WHO guidelines, which recommend that all HIVinfected individuals with active TB (regardless of CD4 cell count) should receive ART as soon as possible, generally within 2–8 weeks.2 Recently, Mfinanga et al.3 showed that delaying ART prescription for at least six months (TB treatment) was not inferior in terms of TB treatment outcome and overall survival, when compared to early ART within two weeks of starting TB treatment in patients with CD4 cell counts more than 220 cells/ L. Additionally, the early ART arm was associated with a non-significant increase in TB recurrences. The treatment of HIV-associated TB remains a daunting and challenging task; challenges include excessive pill burden, patient compliance, drug interactions, overlapping treatment toxicities, and emergence of immune reconstitution disease.4 Moreover, it is estimated that severe drug adverse events occurred more often among HIV-infected TB patients compared with uninfected subjects.5 Conversely, obviating the concomitant TB/HIV therapy, especially in individuals with preserved immune function, might simplify TB management cases, increasing adherence as well as maintaining the same overall survival outcome, as seen in early