Brenda Hoagland

Disseminated sporotrichosis as a manifestation of immune reconstitution inflammatory syndrome

We describe two cases of disseminated sporotrichosis as a manifestation of immune reconstitution inflammatory syndrome. After the initiation of highly active anti‐retroviral therapy, one patient presented disseminated lesions, whereas the other patient’s preexisting lesions worsened and became more extensive. Simultaneously, their CD4 T cell counts increased and HIV viral loads decreased.

Daily oral emtricitabine/tenofovir preexposure prophylaxis and herpes simplex virus type 2 among men who have sex with men

Background In addition to protecting against HIV acquisition, antiretroviral preexposure prophylaxis (PrEP) using topical 1% tenofovir gel reduced Herpes simplex virus type 2 (HSV-2) acquisition by 51% among women in the CAPRISA 004 study. We examined the effect of daily oral emtricitabine/tenofovir (FTC/TDF) PrEP on HSV-2 seroincidence and ulcer occurrence among men who have sex with men (MSM) in the iPrEx trial. Methods HSV-2 serum testing was performed at screening and every six months. Among HSV-2-seronegative individuals, we used Cox regression models to estimate hazard ratios (HRs) of HSV-2 seroincidence associated with randomization to FTC/TDF. We used multiple imputation and Cox regression to estimate HRs for HSV-2 seroincidence accounting for drug exposure. We assessed ulcer occurrence among participants with prevalent or incident HSV-2 infection. Results Of the 2,499 participants, 1383 (55.3%) tested HSV-2-seronegative at baseline, 892 (35.7%) tested positive, 223 (8.9%) had indeterminate tests, and one test was not done. Of the 1,347 HSV-2-seronegative participants with follow-up, 125 (9.3%) had incident HSV-2 infection (5.9 per 100 person-years). Compared with participants receiving placebo, there was no difference in HSV-2 seroincidence among participants receiving FTC/TDF (HR 1.1, 95% CI: 0.8–1.5; P = 0.64) or among participants receiving FTC/TDF with a concentration of tenofovir diphosphate >16 per million viable cells (HR 1.0, 95% CI: 0.3–3.5; P = 0.95). Among participants with HSV-2 infection, the proportion with ≥1 moderate or severe ulcer adverse event was twice as high in the placebo vs. active arm (5.9% vs. 2.9%, P = 0.02), but there were no differences in the proportions with ≥1 clinical examination during which perianal or groin ulcers were identified. Conclusions Tenofovir in daily oral FTC/TDF PrEP may reduce the occurrence of ulcers in individuals with HSV-2 infection but does not protect against HSV-2 incidence among MSM.

Unprotected sex among men who have sex with men living with HIV in Brazil: a cross-sectional study in Rio de Janeiro

BackgroundMany countries are facing concentrated HIV epidemics among vulnerable populations, including men who have sex with men (MSM). Unprotected anal intercourse (UAI) is the main HIV transmission route among them and its understanding in the different cultures and how it relates to HIV transmission, re-infection and development of HIV antiretroviral resistance has important public health implications. Data on UAI among Brazilian MSM are scarce. This study aims to evaluate the prevalence and associated factors of UAI among HIV-infected MSM who had sex with seronegative or male partners with an unknown serostatus.MethodA cross-sectional study nested in a cohort was conducted in Rio de Janeiro, Brazil. The one hundred and fifty five MSM included in the study answered an ACASI interview and provided biological samples. Generalized linear models were used to identify variables associated with UAI.ResultsOverall, UAI with an HIV-negative or unknown serostatus male partner was reported by 40.6% (63/155) of MSM. Lifetime sexual abuse or domestic violence was reported by 35.9%, being more frequent among MSM who reported UAI compared to those who did not (P = 0.001). Use of stimulants before sex was reported by 20% of the MSM, being slightly higher among those who reported UAI (27.0% vs. 15.2%; P = 0.072). Commercial sex was frequent among all MSM (48.4%). After multivariate modeling, the report of sexual abuse or domestic violence (OR = 2.70; 95% CI: 1.08-7.01), commercial sex (OR = 2.28; 95% CI: 1.04- 5.10), the number of male sexual partners (p = 0.039) and exclusively receptive anal intercourse (OR = 0.21; 95% CI: 0.06-0.75) remained associated with UAI. CD4 levels, HIV viral load and antiretroviral therapy were not associated with UAI.ConclusionThe UAI prevalence found with negative or unknown HIV status partners points out that other interventions are needed as additional prevention tools to vulnerable MSM. The main factors associated with UAI were a lifetime history of violence, commercial sex and the number of male sexual partners. This clustering of different behavioral, health and social problems in this population reinforce the need of a comprehensive approach on treating and preventing HIV among MSM.

Retention, engagement, and adherence to pre-exposure prophylaxis for men who have sex with men and transgender women in PrEP Brasil: 48 week results of a demonstration study

BACKGROUND PrEP Brasil was a demonstration study to assess feasibility of daily oral tenofovir diphosphate disoproxil fumarate plus emtricitabine provided at no cost to men who have sex with men (MSM) and transgender women at high risk for HIV within the Brazilian public health system. We report week 48 pre-exposure prophylaxis (PrEP) retention, engagement, and adherence, trends in sexual behaviour, and incidence of HIV and sexually transmitted infections in this study cohort. METHODS PrEP Brasil was a 48 week, open-label, demonstration study that assessed PrEP delivery at three referral centres for HIV prevention and care in Rio de Janeiro, Brazil (Fundação Oswaldo Cruz), and São Paulo, Brazil (Universidade de São Paulo and Centro de Referência e Treinamento em DST e AIDS). Eligible participants were MSM and transgender women who were HIV negative, aged at least 18 years, resident in Rio de Janeiro or São Paulo, and reported one or more sexual risk criteria in the previous 12 months (eg, condomless anal sex with two or more partners, two or more episodes of anal sex with an HIV-infected partner, or history of sexually transmitted infection [STI] diagnosis). Participants were seen at weeks 4, 12, 24, 36, and 48 for PrEP provision, clinical and laboratory evaluation, and HIV testing. Computer-assisted self-interviews were also done at study visits 12, 24, 36, and 48, and assessed sexual behaviour and drug use. PrEP retention was defined by attendance at the week 48 visit, PrEP engagement was an ordinal five-level variable combining presence at the study visit and drug concentrations, and PrEP adherence was evaluated by measuring tenofovir diphosphate concentrations in dried blood spots. Logistic regression models were used to quantify the association of variables with high adherence (≥4 doses per week). The study is registered with ClinicalTrials.gov, number NCT01989611. FINDINGS Between April 1, 2014, and July 8, 2016, 450 participants initiated PrEP, 375 (83%) of whom were retained until week 48. At week 48, 277 (74%) of 375 participants had protective drug concentrations consistent with at least four doses per week: 183 (82%) of 222 participants from São Paulo compared with 94 (63%) of 150 participants from Rio de Janeiro (adjusted odds ratio 1·88, 95% CI 1·06-3·34); 119 (80%) of 148 participants who reported sex with HIV-infected partners compared with 158 (70%) of 227 participants who did not (1·78, 1·03-3·08); 67 (87%) of 77 participants who used stimulants compared with 210 (71%) of 298 participants who did not (2·23, 1·02-4·92); and 232 (80%) of 289 participants who had protective concentrations of tenofovir disphosphate at week 4 compared with 42 (54%) of 78 participants who did not (3·28, 1·85-5·80). Overall, receptive anal sex with the last three partners increased from 45% at enrolment to 49% at week 48 (p=0·17), and the mean number of sexual partners in the previous 3 months decreased from 11·4 (SD 28·94) at enrolment to 8·3 (19·55) at week 48 (p<0·0013). Two individuals seroconverted during follow-up (HIV incidence 0·51 per 100 person-years, 95% CI 0·13-2·06); both of these patients had undetectable tenofovir concentrations at seroconversion. INTERPRETATION Our results support the effectiveness and feasibility of PrEP in a real-world setting. Offering PrEP at public health-care clinics in a middle-income setting can retain high numbers of participants and achieve high levels of adherence without risk compensation in the investigated populations. FUNDING Brazilian Ministry of Health, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Secretaria de Vigilancia em Saúde, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, and Fundação de Amparo à Pesquisa do Estado de São Paulo.

Next-generation sequencing analyses of the emergence and maintenance of mutations in CTL epitopes in HIV controllers with differential viremia control

BackgroundDespite the low level of viral replication in HIV controllers (HICs), studies have reported viral mutations related to escape from cytotoxic T-lymphocyte (CTL) response in HIV-1 plasma sequences. Thus, evaluating the dynamics of the emergence of CTL-escape mutants in HICs reservoirs is important for understanding viremia control. To analyze the HIV-1 mutational profile and dynamics of CTL-escape mutants in HICs, we selected 11 long-term non-progressor individuals and divided them into the following groups: (1) viremic controllers (VCs; n = 5) and (2) elite controllers (ECs; n = 6). For each individual, we used HIV-1 proviral DNA from PBMCs related to earliest (VE) and latest (VL) visits to obtain gag and nef sequences using the Illumina HiSeq system. The consensus of each mapped gene was used to assess viral divergence, and next-generation sequencing data were employed to identify SNPs and variations within and flanking CTL epitopes.ResultsDivergence analysis showed higher values for nef compared to gag among the HICs. EC and VC groups showed similar divergence rates for both genes. Analysis of the number of SNPs showed that VCs present more variability in both genes. Synonymous/non-synonymous mutation ratios were < 1 for gag among ECs and for nef among ECs and VCs, exhibiting a predominance of non-synonymous mutations. Such mutations were observed in regions encoding CTL-restricted epitopes in all individuals. All ECs presented non-synonymous mutations in CTL epitopes but generally at low frequency (< 1%); all VCs showed a high number of mutations, with significant frequency changes between VE and VL visits. A higher frequency of internal mutations was observed for gag epitopes, with significant changes across visits compared to Nef epitopes, indicating a pattern associated with differential genetic pressure.ConclusionsThe high genetic conservation of HIV-1 gag and nef among ECs indicates that the higher level of viremia control restricts the evolution of both genes. Although viral replication levels in HICs are low or undetectable, all individuals exhibited CTL epitope mutations in proviral gag and nef variants, indicating that potential CTL escape mutants are present in HIC reservoirs and that situations leading to a disequilibrium of the host-virus relationship can result in the spread of CTL-escape variants.

Plasmatic Levels of IL-18, IP-10, and Activated CD8+ T Cells Are Potential Biomarkers to Identify HIV-1 Elite Controllers With a True Functional Cure Profile

Elite controllers (ECs) are rare individuals able to naturally control HIV-1 replication below the detection limit of viral load (VL) commercial assays. It is unclear, however, whether ECs might be considered a natural model of a functional cure because some studies have noted CD4+ T cell depletion and disease progression associated with abnormally high levels of immune activation and/or inflammation in this group. Here, we propose the use of immunological parameters to identify HIV-1 ECs that could represent the best model of a functional cure. We compared plasma levels of six inflammatory biomarkers (IP-10, IL-18, sCD163, sCD14, CRP, and IL-6) and percentages of activated CD8+ T cells (CD38+HLA-DR+) between 15 ECs [8 with persistent undetectable viremia (persistent elite controllers) and 7 with occasional viral blips (ebbing elite controllers)], 13 viremic controllers (VCs—plasma VL between 51 and 2,000 RNA copies/mL), and 18 HIV-1 infected patients in combined antiretroviral therapy, with suppressed viremia, and 18 HIV-uninfected controls (HIV-neg). The two groups of ECs presented inflammation and activation profiles similar to HIV-neg individuals, and there was no evidence of CD4+ T cell decline over time. VCs, by contrast, had higher levels of IL-18, IP-10, and CRP and a lower CD4/CD8 ratio than that of HIV-neg (P < 0.05). Plasma levels of IL-18 and IP-10 correlated positively with CD8+ T cell activation and negatively with both CD4/CD8 and CD4% in HIV-1 controllers. These results suggest that most ECs, defined using stringent criteria in relation to the cutoff level of viremia (≤50 copies/mL) and a minimum follow-up time of >5 years, show no evidence of persistent inflammation or immune activation. This study further suggests that plasmatic levels of IL-18/IP-10 combined with the frequency of CD8+CD38+HLA-DR+ T cells can be important biomarkers to identify models of a functional cure among HIV-1 ECs.

Syndemics among individuals enrolled in the PrEP Brasil Study

BACKGROUND Concurrent psychosocial problems may synergistically increase the risk of HIV infection (syndemics), representing a challenge for prevention. We aimed to evaluate the prevalence and associated factors of syndemics among men who have sex with men (MSM) and transgender women (TGW) enrolled in the Brazilian pre-exposure prophylaxis demonstration study (PrEP Brasil Study). METHODS Secondary cross-sectional analysis of the PrEP Brasil Study was performed. Of 450 HIV-seronegative MSM/TGW enrolled in the PrEP Brasil Study- conducted at Rio de Janeiro and São Paulo, Brazil- 421 participants with complete data were included in the present analysis. Syndemics was defined as occurrence of ≥2 of the following conditions: polysubstance (≥2) use, binge drinking, positive depression screen, compulsive sexual behavior, and intimate partner violence (IPV). RESULTS The prevalence of recent polysubstance use was 22.8%, binge drinking 51.1%, positive depression screening 5.2%, compulsive sexual behavior 7.1%, and IPV 7.3%. Syndemics prevalence was 24.2%, and associated factors were younger age (adjusted Odds Ratio (aOR) 0.95, 95% Confidence Interval (95% CI) 0.92-0.98 per year increase), TGW vs. MSM (aOR 3.09, 95% CI: 1.2-8.0), some college education or more vs. less than college (aOR 2.49, 95% CI: 1.31-4.75), and multiple male sexual partners in prior 3 months (aOR 1.69, 95% CI: 0.92-3.14). CONCLUSION Given the high prevalence of syndemics, particularly of polysubstance use and binge drinking, PrEP delivery offers an opportunity to diagnose and intervene in mental and social well-being.

Asymptomatic anorectal Chlamydia trachomatis and Neisseria gonorrhoeae infections are associated with systemic CD8+ T-cell activation

Background: Oral preexposure prophylaxis (PrEP) has been established as a pivotal strategy in HIV prevention. However, bacterial sexually transmitted infections (STIs), such as Chlamydia trachomatis and Neisseria gonorrhoeae, are also highly prevalent. Although the presence of STI-related mucosal lesions is a known risk factor for HIV acquisition, the potential increase in risk associated with asymptomatic STIs is not completely understood. Recent data demonstrated higher T-cell activation is a risk factor for sexually acquired HIV-1 infection. We examined the effect of asymptomatic C. trachomatis and N. gonorrhoeae anorectal infection on systemic immune activation, potentially increasing the risk of HIV acquisition. Methods: We analyzed samples from participants of PrEP Brasil, a demonstration study of daily oral emtricitabine/tenofovir disoproxil fumarate HIV PrEP among healthy MSM, for T-cell activation by flow cytometry. We included 34 asymptomatic participants with anorectal swab for C. trachomatis and/or N. gonorrhoeae infection, whereas negative for other STIs, and 35 controls. Results: We found a higher frequency of human leukocyte antigen DR+CD38+ CD8+ T cells (1.5 vs. 0.9%, P < 0.005) and with memory phenotype in the group with asymptomatic C. trachomatis and/or N. gonorrhoeae infection. Exhaustion and senescence markers were also significant higher in this group. No difference was observed in the soluble CD14 levels. Conclusion: Our findings suggest asymptomatic anorectal C. trachomatis and/or N. gonorrhoeae increase systemic immune activation, potentially increasing the risk of HIV acquisition. Regular screening and treatment of asymptomatic STIs should be explored as adjuvant tools for HIV prevention.