Chlamydia retesting remains low among young women in Australia: an observational study using sentinel surveillance data, 2018-2022.

BACKGROUND: Chlamydia remains the most notified bacterial sexually transmissible infection in Australia with guidelines recommending testing for re-infection at 3months post treatment. This paper aimed to determine chlamydia retesting and repeat positivity rates within 2-4months among young women in Australia, and to evaluate what factors increase or decrease the likelihood of retesting. METHODS: Chlamydia retesting rates among 16-29-year-old women were analysed from Australian Collaboration for Coordinated Enhanced Sentinel Surveillance of sexually transmissible infection and bloodborne virus (ACCESS) sentinel surveillance data (n =62 sites). Among women with at least one positive test between 1 January 2018 and 31 August 2022, retesting counts and proportions within 2-4months were calculated. Logistic regression was performed to assess factors associated with retesting within 2-4months. RESULTS: Among 8758 women who were positive before 31 August 2022 to allow time for follow up, 1423 (16.2%) were retested within 2-4months, of whom 179 (12.6%) tested positive. The odds of retesting within 2-4months were 25% lower if tested in a coronavirus disease 2019 (COVID-9) pandemic year (2020-2022) (aOR=0.75; 95% CI 0.59-0.95). Among 9140 women with a positive test before 30 November 2022, 397 (4.3%) were retested too early (within 7days to 1month) and 81 (20.4%) of those were positive. CONCLUSIONS: Chlamydia retesting rates remain low with around a sixth of women retested within 2-4months in line with guidelines. Re-infection is common with around one in eight retesting positive. An increase in retesting is required to reduce the risk of reproductive complications and onward transmission.

Moving Towards Hepatitis C Microelimination Among People Living With Human Immunodeficiency Virus in Australia: The CEASE Study.

BACKGROUND: Microelimination of hepatitis C virus (HCV) among people living with human immunodeficiency virus (HIV) may be feasible in Australia, given unrestricted access to direct-acting antiviral (DAA) therapy from 2016. Our aim was to evaluate progress towards elimination goals within HIV/HCV-coinfected adults in Australia following universal DAA access. METHODS: The CEASE prospective cohort study enrolled adults with HIV/HCV, irrespective of viremic status, from 14 primary and tertiary clinics in Australia. Annual and cumulative HCV treatment uptake, outcome, and HCV RNA prevalence were evaluated, with follow-up through May 2018 (median follow-up, 2.63 years). Factors associated with DAA uptake were analyzed. RESULTS: Between July 2014 and March 2017, 402 participants who were HIV/HCV antibody positive were enrolled (95% male [80% gay and bisexual men,], 13% cirrhosis, 80% history of injecting drug use [39% currently injecting]). Following universal DAA access, annual HCV treatment uptake in those eligible increased from 7% and 11% per year in 2014 and 2015, respectively, to 80% in 2016. By 2018, cumulative HCV treatment uptake in those ever eligible for treatment was 91% (336/371). HCV viremic prevalence declined from 82% (95% CI, 78-86%) in 2014 to 8% (95% CI, 6-12%) in 2018. Reinfection was reported in only 5 participants for a reinfection incidence of 0.81 per 100 person-years (95% CI, 0.34-1.94). CONCLUSIONS: High uptake and effectiveness of unrestricted DAA therapy in Australia have permitted rapid treatment scale-up, with a dramatic reduction in HCV infection burden and low reinfection rate among people living with HIV, suggesting that microelimination is feasible. CLINICAL TRIALS REGISTRATION: NCT02102451.

The rise of targeted HIV oral rapid testing in Australia.

OBJECTIVE: To assess the performance and acceptability of the OraQuick Advance Rapid HIV-1/2 Antibody Test (ORT) in Australia. DESIGN, PARTICIPANTS AND SETTING: Cross-sectional study of 1074 men who have sex with men (MSM) and individuals aged 18 years or older at high risk of acquiring HIV infection who attended five public HIV or sexual health services, two general practices and one community clinic in Sydney from 1 January to 31 December 2013. INTERVENTION: One ORT confirmed by fourth-generation HIV enzyme immunoassay (EIA). MAIN OUTCOME MEASURES: ORT sensitivity and specificity compared with EIA; acceptabiity of the ORT to participants. RESULTS: 83.5% of participants were MSM, 90.3% were aged under 50 years, and 9% had never been tested for HIV. There were 11 true-positive ORT results, two false-negative (non-reactive) results (both were early infections), and one false-positive (reactive) result (due to reader error). Sensitivity and specificity were 84.6% and 99.8%, respectively (compared with a sensitivity of 99.3% and specificity of 99.8% listed by the manufacturer). Three quarters of participants (74.0%; 730/987) found the ORT less stressful than venous sampling. Those who usually had tests at intervals of greater than 3 months deemed the ORT less stressful than those who had quarterly tests (77.5% v 64.8%; P<0.001). Nearly all participants (99.2%; 998/1006) would have an ORT again and 99.4% (994/1000) would recommend it to peers. Most participants (69.1%; 720/1042) felt ORT approval by Australia's Therapeutic Goods Administration (TGA) would encourage testing. CONCLUSION: ORT sensitivity is reduced in early HIV infection. The test is highly acceptable and less stressful than venous sampling. Participants are keen to be tested with the ORT in future, would recommend it to peers and would have tests more frequently if the ORT were licensed. TGA approval of this test might slow increasing HIV infection rates among MSM and others by facilitating diagnosis and treatment.

Recording the sexual orientation of male patients attending general practice.

BACKGROUND: Determination of a patient's sexual orientation is important to guide appropriate health care. We assessed how frequently sexual orientation is included in the health records of men attending general practice and factors associated with its recording. METHODS: Routine consultation data were extracted from seven Australian general practices in a 2-year period (2011-12) as part of a sexual health testing intervention for gay and bisexual men. We calculated the proportion of male patients with sexual orientation recorded and used logistic regression to determine patient, provider, clinic and community factors associated with recording. RESULTS: There were 12475 men who attended the clinics in the study period and sexual orientation was recorded for 42%, of whom 67% were identified as homosexual, 3% bisexual and 30% heterosexual. Recording ranged from 3% to 81% between clinics. Patient factors independently associated with recording of sexual orientation were: being HIV-positive [adjusted odds ratio (AOR) = 1.2, 95% CI: 1.1-1.4], previous sexually transmissible infection/HIV testing at the clinic (AOR = 1.8, 95% CI: 1.6-2.0), and ≥6 previous clinic visits (AOR =1 .1, 95% CI: 1.0-1.1). Provider, clinic and community factors independently associated with sexual orientation recording were: regularly attending a female GP (AOR = 1.3, 95% CI: 1.1-1.4), ≥4 previous consults with a particular GP (AOR = 1.4, 95% CI: 1.2-1.7), attending a clinic with a high caseload of gay/bisexual patients (AOR = 8.8, 95% CI: 1.6-48.1), and the patient residing in a community with ≥10% same-sex partner households (AOR = 1.2, 95% CI: 1.0-1.3). CONCLUSIONS: Sexual orientation was incomplete for more than half of male patients. Initiatives targeting both the patients and providers need to be considered to improve recording.

The microRNA-9/B-lymphocyte-induced maturation protein-1/IL-2 axis is differentially regulated in progressive HIV infection.

The fine control of T-cell differentiation and its impact on HIV disease states is poorly understood. In this study, we demonstrate that B-lymphocyte-induced maturation protein-1 (Blimp-1/Prdm1) is highly expressed in CD4(+) T cells from chronically HIV-infected (CHI) patients compared to cells from long-term nonprogressors or healthy controls. Stimulation through the T-cell receptor in the presence of IL-2 induces Blimp-1 protein expression. We show here that Blimp-1 levels are translationally regulated by microRNA-9 (miR-9). Overexpression of miR-9 induces Blimp-1 repression, restoring IL-2 secretion in CD4(+) T cells via reduction in the binding of Blimp-1 to the il-2 promoter. In CHI patients where IL-2 expression is reduced and there is generalized T-cell dysfunction, we show differential expression of both miR-9 and Blimp-1 in CD4(+) cells compared with levels in long-term nonprogressors. These data identify a novel miR-9/Blimp-1/IL-2 axis that is dysregulated in progressive HIV infection.

NKT cell depletion in humans during early HIV infection.

Natural killer T (NKT) cells bridge across innate and adaptive immune responses and have an important role in chronic viral infections such as human immunodeficiency virus (HIV). NKT cells are depleted during chronic HIV infection, but the timing, drivers and implications of this NKT cell depletion are poorly understood. We studied human peripheral blood NKT cell levels, phenotype and function in 31 HIV-infected subjects not on antiretroviral treatment from a mean of 4 months to 2 years after HIV infection. We found that peripheral CD4(+) NKT cells were substantially depleted and dysfunctional by 4 months after HIV infection. The depletion of CD4(+) NKT cells was more marked than the depletion of total CD4(+) T cells. Further, the early depletion of NKT cells correlated with CD4(+) T-cell decline, but not HIV viral levels. Levels of activated CD4(+) T cells correlated with the loss of NKT cells. Our studies suggest that the early loss of NKT cells is associated with subsequent immune destruction during HIV infection.

Availability of substance use screening and treatment within HIV clinical sites across seven geographic regions within the IeDEA consortium.

BACKGROUND: Overwhelming evidence highlights the negative impact of substance use on HIV care and treatment outcomes. Yet, the extent to which alcohol use disorder (AUD) and other substance use disorders (SUD) services have been integrated within HIV clinical settings is limited. We describe AUD/SUD screening and treatment availability in HIV clinical sites participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS: In 2020, 223 IeDEA HIV clinical sites from 41 countries across seven geographic regions completed a survey on capacity and practices related to management of AUD/ SUD. Sites provided information on AUD and other SUD screening and treatment practices. RESULTS: Sites were from low-income countries (23%), lower-middle-income countries (38%), upper-middle income countries (17%) and high-income counties (23%). AUD and SUD screening using validated instruments were reported at 32% (n=71 located in 12 countries) and 12% (n=27 located in 6 countries) of the 223 sites from 41 countries, respectively. The North American region had the highest proportion of clinics that reported AUD screening (76%), followed by East Africa (46%); none of the sites in West or Central Africa reported AUD screening. 31% (n=69) reported both AUD screening and counseling, brief intervention, psychotherapy, or Screening, Brief Intervention, and Referral to Treatment; 8% (n=18) reported AUD screening and detox hospitalization; and 10% (n=24) reported both AUD screening and medication. While the proportion of clinics providing treatment for SUD was lower than those treating AUD, the prevalence estimates of treatment availability were similar. CONCLUSIONS: Availability of screening and treatment for AUD/SUD in HIV care settings is limited, leaving a substantial gap for integration into ongoing HIV care. A critical understanding is needed of the multilevel implementation factors or feasible implementation strategies for integrating screening and treatment of AUD/SUD into HIV care settings, particularly for resource-constrained regions.

Patterns and causes of suboptimal response to tenofovir-based therapy in individuals coinfected with HIV and hepatitis B virus.

BACKGROUND: Tenofovir (TDF) is effective for treatment of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) infection; however, some individuals have ongoing HBV viremia, the reasons for which are unclear. We determined the patterns and factors associated with detectable HBV DNA in HIV-HBV-coinfected subjects on highly active antiretroviral therapy (HAART). METHODS: One hundred sixty-five HIV-HBV-coinfected individuals from the United States, Australia, and Thailand, the majority of whom were on HAART at study entry, were prospectively followed semiannually for a median of 2.8 years. Logistic regression was used to determine factors associated with detectable HBV DNA. RESULTS: Anti-HBV regimens were TDF/emtricitabine (57%), lamivudine or emtricitabine (19%), or TDF monotherapy (13%). During follow-up, HBV DNA was detected at 21% of study visits and was independently associated with hepatitis B e antigen (HBeAg), HAART <2 years, CD4 <200 cells/mm(3), detectable HIV RNA, reporting <95% adherence, and anti-HBV regimen. TDF/emtricitabine was less likely to be associated with detectable HBV than other regimens, including TDF monotherapy (odds ratio, 2.79; P = .02). In subjects on optimal anti-HBV therapy (TDF/emtricitabine) and with undetectable HIV RNA, HBeAg, CD4 <200 mm(3), and reporting <95% adherence remained associated with detectable HBV DNA. Three main patterns of HBV viremia were observed: persistent HBV viremia, viral rebound (>1 log from nadir), and viral blips. No TDF resistance was identified. CONCLUSIONS: Tenofovir/emtricitabine was superior to other anti-HBV regimens in long-term HBV suppression. HBV viremia on therapy was identified in 1 of 3 main patterns. Suboptimal adherence was associated with detectable HBV DNA during therapy, even when HIV was undetectable.

HIV immune escape at an immunodominant epitope in HLA-B*27-positive individuals predicts viral load outcome.

The CTL response in HLA-B*27(+) HIV-infected individuals is characterized by an immunodominant response to a conserved epitope in gag p24 (aa 263-272, KRWIILGLNK; KK10). Mutations resulting in substitution of the arginine (R264) at position 2 of this epitope have been identified as escape mutations. Nineteen HLA-B*27(+) long-term nonprogressors were identified from an Australian cohort with an average follow-up of 16 y following infection. Viral and host genetic factors impacting on disease progression were determined at multiple time points. Twelve of 19 had wild-type sequences at codon 264 at all time points; 7 of 19 carried CTL escape variants. Median viral load and CD4(+) T cell counts were not significantly different between these groups at enrollment. Viral load, as judged by levels at their last visit (1,700 and 21,000 RNA copies/ml, respectively; p = 0.01) or by time-weighted area under the curve was higher in the escape group (p = 0.02). Escape mutants at other HLA-B*27-restricted epitopes were uncommon. Moreover, host polymorphisms, such as CCR5Δ32, CCR2-64I, and SDF1-3'A, or breadth of TCR repertoire responding to KK10 did not segregate to wild-type or escape groups. Host and viral factors were examined for a relationship to viral load. The only factor to affect viral load was the presence of the R264 escape mutations at the immunodominant epitope. CTL escape at R264 in the KK10 epitope is a major determinant of subsequent viral load in these HLA-B*27(+) individuals.

A longitudinal evaluation of Treponema pallidum PCR testing in early syphilis.

BACKGROUND: Syphilis is a growing public health problem among men who have sex with men (MSM) globally. Rapid and accurate detection of syphilis is vital to ensure patients and their contacts receive timely treatment and reduce ongoing transmission. METHODS: We evaluated a PCR assay for the diagnosis of Treponema pallidum using swabs of suspected early syphilis lesions in longitudinally assessed MSM. RESULTS: We tested 260 MSM for T pallidum by PCR on 288 occasions: 77 (26.7%) had early syphilis that was serologically confirmed at baseline or within six weeks, and 211 (73.3%) remained seronegative for syphilis. Of 55 men with primary syphilis, 49 were PCR positive, giving a sensitivity of 89.1% (95% CI: 77.8%-95.9%) and a specificity of 99.1% (95% CI: 96.5%-99.9%). Of 22 men with secondary syphilis, 11 were PCR positive, giving a sensitivity of 50% (95% CI: 28.2%-71.8%) and a specificity of 100% (95% CI: 66.4%-71.8%). Of the 77 syphilis cases, 43 (56%) were HIV positive and the sensitivity and specificity of the PCR test did not vary by HIV status. The PCR test was able to detect up to five (10%) primary infections that were initially seronegative, including one HIV positive man with delayed seroconversion to syphilis (72 to 140 days) and one HIV positive man who did not seroconvert to syphilis over 14 months follow-up. Both men had been treated for syphilis within a week of the PCR test. CONCLUSIONS: T pallidum PCR is a potentially powerful tool for the early diagnosis of primary syphilis, particularly where a serological response has yet to develop.

Patterns and correlates of hepatitis C virus phylogenetic clustering among people living with HIV in Australia in the direct-acting antiviral era: A molecular epidemiology study among participants in the CEASE cohort.

Background and Aims: In moving towards the elimination of hepatitis C virus (HCV) infection among people living with HIV, understanding HCV transmission patterns may provide insights to guide and evaluate interventions. In this study, we evaluated patterns of, and factors associated with HCV phylogenetic clustering among people living with HIV/HCV co-infection in Australia in the direct-acting antiviral era. Methods: HCV RNA was extracted from dried blood spot (DBS) samples collected between 2014 and 2018 in the CEASE cohort study. The HCV Core-E2 region was amplified by a polymerase chain reaction and Sanger sequenced. Maximum likelihood phylogenetic trees (1000 bootstrap replicates) were used to identify patterns of clustering (3% genetic distance threshold). Mixed-effects logistic regression was used to determine correlates of phylogenetic clustering. Factors assessed were sexual risk behavior, education, injecting drug use, housing, employment, HIV viral load, age, sex, and sexuality. Results: Phylogenetic trees were reconstructed for HCV subtype 1a (n = 139) and 3a (n = 63) sequences, with 29% (58/202) in a pair or cluster. Overall (n = 202), phylogenetic clustering was positively associated with younger age (under 40; adjusted odds ratio [aOR] 2.52, 95% confidence interval [CI] 1.20-5.29), and among gay and bisexual men (n = 168), was positively associated with younger age (aOR 2.61, 95% CI 1.10-6.19), higher education (aOR 2.58, 95% CI 1.09-6.13), and reporting high-risk sexual behavior (aOR 3.94, 95% CI 1.31-11.84). During follow-up, five reinfections were observed, but none were in phylogenetic clusters. Conclusion: This study found a high proportion of phylogenetic relatedness, predominantly among younger people and gay and bisexual men reporting high-risk sexual behavior. Despite this, few reinfections were observed, and reinfections demonstrated little relationship with known clusters. These findings highlight the importance of rapid HCV treatment initiation, together with monitoring of the phylogeny.

Real-world trends in incidence of bacterial sexually transmissible infections among gay and bisexual men using HIV pre-exposure prophylaxis (PrEP) in Australia following nationwide PrEP implementation: an analysis of sentinel surveillance data.

BACKGROUND: Although data from large implementation trials suggest that sexually transmissible infection (STI) risk increases among gay and bisexual men who initiate HIV pre-exposure prophylaxis (PrEP), there are few data on the trends in population-level STI incidence in the years following widespread PrEP implementation. We aimed to describe trends in bacterial STI incidence among gay and bisexual men using PrEP across Australia in the context of broad PrEP availability through Australia's subsidised medicines scheme. METHODS: We analysed linked clinical data from HIV-negative gay and bisexual men aged 16 years or older who had been prescribed PrEP across a sentinel surveillance clinical network, including 37 clinics in Australia, between Jan 1, 2016, and Dec 31, 2019. Patients were included if they had STI testing at least twice during the observation period. Repeat testing methods were used to calculate chlamydia, gonorrhoea, syphilis, and any STI incidence rates during individuals' periods of PrEP use. Incidence rate ratios (IRRs) for estimated change in incidence per half calendar year (6-month) period were calculated using negative binomial regression. Secondary analyses compared STI incidence rates across individuals initiating PrEP in each year from 2016 to 2019, as well as by length of time using PrEP (per each additional 6 months of PrEP use). FINDINGS: 22 730 men were included in the analyses. During the observation period, 11 351 chlamydia infections were diagnosed in 6630 (30·1%) of 22 034 men over 25 991·2 person-years of PrEP use (incidence rate 43·7 cases [95% CI 42·9-44·5] per 100 person-years). Chlamydia incidence decreased from 48·7 cases per 100 person-years in July-December, 2016, to 42·0 cases per 100 person-years in July-December, 2019 (IRR for estimated change per 6-month period 0·98 [95% CI 0·97-0·99]; p=0·0031). 9391 gonorrhoea infections were diagnosed in 5885 (26·9%) of 21 845 men over 24 858·7 person-years of PrEP use (incidence rate 37·8 cases [95% CI 37·0-38·5] per 100 person-years). Gonorrhoea incidence decreased from 45·5 cases per 100 person-years in July-December, 2016, to 37·2 cases per 100 person-years in July-December, 2019 (IRR 0·97 [95% CI 0·96-0·98]; p<0·0001). Declines in chlamydia and gonorrhoea incidence were most prominent in the first 18 months of observation and incidence was stable thereafter. 2062 syphilis infections were diagnosed in 1488 (7·7%) of 19 262 men over 21 978·9 person-years of PrEP use (incidence rate 9·4 cases [95% CI 9·0-9·8] per 100 person-years). Syphilis incidence increased from 6·2 cases per 100 person-years in July-December, 2016, to 9·8 cases per 100 person-years in July-December, 2019 (IRR 1·08 [95% CI 1·05-1·10]; p<0·0001). INTERPRETATION: Chlamydia and gonorrhoea incidence among gay and bisexual men using PrEP were highest in the early months of PrEP implementation in Australia and stabilised at slightly lower rates thereafter following wider PrEP uptake. Lower prospective STI risk among people initiating PrEP in later years contributed to the observed trends in STI incidence. Widespread PrEP implementation can contribute to increased STI screening and detection. FUNDING: Australian Department of Health, National Health and Medical Research Council.

Farmer social networks: The role of advice ties and organizational leadership in agroforestry adoption.

With the decline in public budgets for agricultural extension support, ties between members of farmer groups are becoming more important to facilitate information transfer about agroforestry. This paper examines the role of social network ties in predicting organizational leadership in an agroforestry-based farmer group. Using social network data derived from interviews with members of farming groups based in the Ayeyarwady Delta of Myanmar, we established a positive relationship between advice-seeking ties and organizational leadership. In other words, farmers who were highly sought for agroforestry advice were more likely to be elected as leaders of the farmer group. Results show the frequency of interactions through advice-seeking ties also had a positive influence on the probability of farmers holding leadership positions. We found a core-periphery structure for the advice networks, whereby farmer leaders were overrepresented at the network core. Interestingly, general members of the farmer group were also in the core of the core-periphery structure, suggesting that engaging with farmers without leadership roles can also effectively disseminate agroforestry information to peripheral farmers. We conclude that farmer groups are valuable in agroforestry adoption and persistence and further analyses of formal leadership structures are needed to support more transparent and accountable governance.

Long-term protection from HIV infection with oral HIV pre-exposure prophylaxis in gay and bisexual men: findings from the expanded and extended EPIC-NSW prospective implementation study.

BACKGROUND: Daily pre-exposure prophylaxis (PrEP) is effective in preventing HIV, but few long-term data are available on effectiveness and adherence in real-world settings. Here, we report trends in HIV incidence over 3 years in individuals at high risk who were prescribed PrEP in New South Wales (NSW), as well as adherence before the transition to subsidised PrEP. METHODS: Expanded PrEP Implementation in Communities-New South Wales (EPIC-NSW) was a pragmatic, prospective, single-arm, implementation study of daily, oral PrEP in 31 sites (sexual health clinics, general practices, and a hospital) in NSW, Australia. Eligible participants were HIV-negative adults (aged ≥18 years) who were at high risk of HIV infection as defined in local PrEP guidelines. Participants were prescribed coformulated (once-daily, oral tablet) tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) as HIV PrEP and were followed up with HIV testing, sexually transmitted infection testing, and PrEP dispensing. Originally planned for 3700 participants followed for 1 year, the study was expanded so that all eligible participants in the state could obtain PrEP and extended until publicly subsidised PrEP became available in Australia. The primary outcome was new HIV infection among all participants who were dispensed PrEP at least once and had at least one follow-up HIV test result. Adherence was estimated by medication possession ratio (MPR), defined as the proportion of PrEP pills dispensed in 90 days, assuming daily dosing. This study is registered with ClinicalTrials.gov, NCT02870790. FINDINGS: Between March 1, 2016, and April 30, 2018, we enrolled 9709 participants. 9596 participants were dispensed PrEP, of whom 9448 (98·3%) were gay or bisexual men. Participants were followed up until March 31, 2019, with at least one follow-up HIV test available in 9520 (99·2%) participants. Mean MPR declined from 0·93 to 0·64 from the first to the ninth quarter. There were 30 HIV seroconversions over 18 628 person-years, an incidence of 1·61 per 1000 person-years (95% CI 1·13-2·30). Being younger, living in a postcode with fewer gay men, reporting more risk behaviours at baseline, and having an MPR of less than 0·6 were each univariately associated with increased HIV incidence. In the final year of follow-up, when PrEP was mostly purchased rather than provided free by the study, HIV incidence remained low at 2·24 per 1000 person-years (1·46-3·44). INTERPRETATION: HIV incidence remained low over up to 3 years of follow-up, including during a transition from study-provided to publicly subsidised PrEP. In a setting of affordable PrEP and associated health-care services, very low HIV incidence of 1 to 2 per 1000 person-years can be maintained in gay and bisexual men who were previously at high risk. FUNDING: New South Wales Ministry of Health, Australian Capital Territory Health Directorate, Gilead Sciences.

Immunodominant epitopes in herpes simplex virus type 2 glycoprotein D are recognized by CD4 lymphocytes from both HSV-1 and HSV-2 seropositive subjects.

In human recurrent cutaneous herpes simplex, there is a sequential infiltrate of CD4 and then CD8 lymphocytes into lesions. CD4 lymphocytes are the major producers of the key cytokine IFN-gamma in lesions. They recognize mainly structural proteins and especially glycoproteins D and B (gD and gB) when restimulated in vitro. Recent human vaccine trials using recombinant gD showed partial protection of HSV seronegative women against genital herpes disease and also, in placebo recipients, showed protection by prior HSV1 infection. In this study, we have defined immunodominant peptide epitopes recognized by 8 HSV1(+) and/or 16 HSV2(+) patients using (51)Cr-release cytotoxicity and IFN-gamma ELISPOT assays. Using a set of 39 overlapping 20-mer peptides, more than six immunodominant epitopes were defined in gD2 (two to six peptide epitopes were recognized for each subject). Further fine mapping of these responses for 4 of the 20-mers, using a panel of 9 internal 12-mers for each 20-mers, combined with MHC II typing and also direct in vitro binding assay of these peptides to individual DR molecules, showed more than one epitope per 20-mers and promiscuous binding of individual 20-mers and 12-mers to multiple DR types. All four 20-mer peptides were cross-recognized by both HSV1(+)/HSV2(-) and HSV1(-)/HSV2(+) subjects, but the sites of recognition differed within the 20-mers where their sequences were divergent. This work provides a basis for CD4 lymphocyte cross-recognition of gD2 and possibly cross-protection observed in previous clinical studies and in vaccine trials.

Low hepatitis C virus reinfection rate despite ongoing risk following universal access to direct-acting antiviral therapy among people living with HIV.

OBJECTIVE(S): To evaluate changes in injecting and sexual risk behaviours, and hepatitis C virus (HCV) reinfection incidence among people with HIV/HCV coinfection following unrestricted access to direct-acting antiviral therapy in Australia. DESIGN: Prospective observational cohort study (2014-2018). METHODS: Among people enrolled in the Control and Elimination of HCV from HIV-infected individuals within Australia study, changes in injecting and sexual behaviour were evaluated, including injecting drug use (IDU) in the last 6 months and last month, frequency of IDU and equipment sharing, condom-less anal intercourse with casual male partner(s), and group sex. HCV reinfection incidence was evaluated with follow-up through May 2018. RESULTS: Overall, 272 HIV/HCV antibody-positive participants [median age; 50 years, 96% male, 83% identified as gay and bisexual men (GBM)] had behavioural data at enrolment and follow-up (median 2.91 years) available for analysis. The proportion reporting IDU in the last 6 months remained stable from enrolment (35%) to follow-up (39%). Among GBM, the proportion reporting condom-less anal intercourse with casual partner(s) at enrolment (48%) and follow-up (46%) was also similar. Reinfection was detected in five individuals (all GBM) during total follow-up of 474 person-years for an overall incidence of 1.05 per 100 person-years (95% confidence interval, 0.44-2.53). CONCLUSION: No change was observed in levels of injecting or sexual risk behaviour for HCV infection following unrestricted access to direct-acting antiviral therapy in an Australian HIV/HCV cohort. Incidence of HCV reinfection was low potentially reflecting high levels of treatment coverage within this population. Continued screening and rapid retreatment of reinfection will be required to maintain progress towards elimination.

HIV-1 DNA Is Maintained in Antigen-Specific CD4+ T Cell Subsets in Patients on Long-Term Antiretroviral Therapy Regardless of Recurrent Antigen Exposure.

Memory CD4+ T cells (mCD4s) containing integrated HIV DNA are considered the main barrier to a cure for HIV infection. Here, we analyzed HIV DNA reservoirs in antigen-specific subsets of mCDs to delineate the mechanisms by which HIV reservoirs persist during antiretroviral therapy (ART). HIV Gag, cytomegalovirus (CMV), and tetanus toxoid (TT)-specific mCD4s were isolated from peripheral blood samples obtained from 11 individual subjects, 2-11 years after commencing ART. Antigen-specific mCD4s were identified by the sensitive OX40 assay and purified by cell sorting. Total HIV DNA levels were quantified by real-time PCR, and clonal viral sequences generated from mCD4 subsets and pre-ART plasma samples. Quantitative results and sequence analysis were restricted to five and three study participants, respectively, which was likely due to the low frequency of the antigen-specific mCD4s and relatively low HIV DNA proviral loads. Median HIV Gag-, CMV-, and TT-specific mCD4s were 0.61%, 2.46%, and 0.78% of total mCD4s, and they contained a median of 2.50, 2.38, and 2.55 log10 copies of HIV DNA per 106 cells, respectively. HIV DNA sequences were derived from antigen-specific mCD4s clustered with sequences derived from pre-ART plasma samples. There was a trend toward increased viral diversity in clonal viral sequences derived from CMV-specific mCD4s relative to TT-specific mCD4s. Despite limitations, this study provides direct evidence that HIV reservoirs persist in memory CD4+ T cell subsets maintained by homeostatic proliferation (TT) and adds to growing evidence against viral evolution during ART. Similar future studies require techniques that sample diverse HIV reservoirs and with improved sensitivity.

A retrospective clinical audit of general practices in Australia to determine the motivation for switch to dolutegravir/abacavir/lamivudine and clinical outcomes.

The most common reasons for switching HIV-1 therapy in patients with virologic suppression are treatment regimen simplification and resolving tolerability issues. Single-pill regimens that include an integrase inhibitor are recommended options. A retrospective clinical audit was performed to determine the motivations for switching to dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC) at high HIV-caseload general practice clinics in Australia. The most common reasons for switching from a prior suppressive therapy to DTG/ABC/3TC were simplification of regimen, resolving toxicity/intolerance and patient preference (73%, 13% and 12%, respectively). Kaplan-Meier analysis showed that the probability of patients remaining on DTG/ABC/3TC therapy at 12 months was 95.1%. Switching to DTG/ABC/3TC from a range of other regimens was associated with a discontinuation rate of 3.2%, with 2.5% of patients discontinuing due to adverse events and no patients discontinuing due to virologic failure. Switching to DTG/ABC/3TC was a viable treatment strategy in this cohort of Australian patients.

Funding antiretroviral treatment for HIV-positive temporary residents in Australia prevents transmission and is inexpensive.

Background The aim of this study is to estimate the reduction in new HIV infections and resultant cost outcomes of providing antiretroviral treatment (ART) through Australia's 'universal access' health scheme to all temporary residents with HIV infection living legally in Australia, but currently deemed ineligible to access subsidised ART via this scheme. METHODS: A mathematical model to estimate the number of new HIV infections averted and the associated lifetime costs over 5 years if all HIV-positive temporary residents in Australia had access to ART and subsidised medical care was developed. Input data came from a cohort of 180 HIV-positive temporary residents living in Australia who are receiving free ART donated by pharmaceutical companies for up to 4 years. RESULTS: Expanding ART access to an estimated total 450 HIV+ temporary residents in Australia for 5 years could avert 80 new infections. The model estimated the total median discounted (5%) cost for ART and associated care to be A$36million, while the total savings in lifetime-discounted costs for the new infections averted was A$22million. CONCLUSIONS: It is estimated that expanded access to ART for all HIV-positive temporary residents in Australia will substantially reduce HIV transmission to their sexual partners at little additional cost. In the context of Australia's National HIV strategy and Australia's endorsement of global goals to provide universal access to ART for all people with HIV, this is an important measure to remove inequities in the provision of HIV-related treatment and care.

Assessing the Impacts of Integrated Decision Support Software on Sexual Orientation Recording, Comprehensive Sexual Health Testing, and Detection of Infections Among Gay and Bisexual Men Attending General Practice: Observational Study.

BACKGROUND: Gay and bisexual men are disproportionately affected by HIV and other sexually transmissible infections (STIs), yet opportunities for sexual health testing of this population are often missed or incomplete in general practice settings. Strategies are needed for improving the uptake and completeness of sexual health testing in this setting. OBJECTIVES: The goal of the research was to evaluate the impact of an intervention centered around integrated decision support software and routine data feedback on the collection of sexual orientation data and sexual health testing among gay and bisexual men attending general practice. METHODS: A study using before/after and intervention/comparison methods was undertaken to assess the intervention's impact in 7 purposively sampled Australian general practice clinics located near the urban centers of Sydney and Melbourne. The software was introduced at staggered points between April and August 2012; it used patient records to prompt clinicians to record sexual orientation and accessed pathology testing history to generate prompts when sexual health testing was overdue or incomplete. The software also had a function for querying patient management system databases in order to generate de-identified data extracts, which were used to report regularly to participating clinicians. We calculated summary rate ratios (SRRs) based on quarterly trends and used Poisson regression analyses to assess differences between the 12-month preintervention and 24-month intervention periods as well as between the intervention sites and 4 similar comparison sites that did not receive the intervention. RESULTS: Among 32,276 male patients attending intervention clinics, sexual orientation recording increased 19% (from 3213/6909 [46.50%] to 5136/9110 [56.38%]) during the intervention period (SRR 1.10, 95% CI 1.04-1.11, P<.001) while comprehensive sexual health testing increased by 89% (305/1159 [26.32%] to 690/1413 [48.83%]; SRR 1.38, 95% CI 1.28-1.46, P<.001). Comprehensive testing increased slightly among the 7290 gay and bisexual men attending comparison sites, but the increase was comparatively greater in clinics that received the intervention (SRR 1.12, 95% CI 1.10-1.14, P<.001). In clinics that received the intervention, there was also an increase in detection of chlamydia and gonorrhea that was not observed in the comparison sites. CONCLUSIONS: Integrated decision support software and data feedback were associated with modest increases in sexual orientation recording, comprehensive testing among gay and bisexual men, and the detection of STIs. Tests for and detection of chlamydia and gonorrhea were the most dramatically impacted. Decision support software can be used to enhance the delivery of sexual health care in general practice.