RNA interference (RNAi)-based medicines offer precise targeting of virtually any transcript, making them an appealing new drug class for immuno-oncology. While RNAi therapies are highly effective in non-dividing cells, their efficacy in rapidly dividing cells, crucial for immuno-oncology, remains largely unexplored. Previous data suggest that full chemical modification of short interfering RNAs (siRNAs) in dividing cells has not consistently extended silencing duration, unlike in non-dividing cells. The present study explores key factors influencing the duration of effect of RNAi-based therapeutics (siRNAs) in dividing cancer and immune cells. Saturation of intracellular depots, a strategy to prolong silencing duration in non-dividing hepatocytes, had minimal impact on siRNA effect duration in dividing cells. However, modifying the guide strand with a 5 '-(E)-vinylphosphonate significantly extended siRNA silencing duration to over 30 days both in vitro and in vivo. Our findings enable the rational design of the chemical architecture and administration regimens of RNAi-based therapies in immuno-oncology.

Abstract Background RENOIR is a phase 3 randomized, double-blinded, placebo-controlled study evaluating Vaccine Efficacy (VE) to prevent lower respiratory tract illness (LRTI) in adults ≥ 60 years of age during 2 RSV seasons in Northern and Southern Hemisphere countries (NCT05035212). End of RSV Season 1 (EoS1) analysis demonstrated VE of 88.9% for RSV-associated Lower Respiratory Tract Illness (LRTI-RSV) with 3+ symptoms, VE of 65.1% for LRTI-RSV with 2+ symptoms, and VE of 62.2% for all Acute Respiratory Illness (ARI)-RSV events including LRTI-RSV 2+ and 3+ events. We sought to understand the ARI symptom distribution (e.g. upper respiratory versus lower) among all RSV confirmed endpoints, and the characterization of medical diagnoses provided for these endpoints by clinicians. Methods As per study protocol, ARI is an illness involving 1 or more of 7 respiratory illness symptoms lasting more than 1 day: new/increased sore throat, cough, nasal congestion, nasal discharge, wheezing, sputum production, shortness of breath during the RSV season. Participants with ARI symptoms obtain a nasal self-swab within 7 days of onset for RT-PCR testing and undergo virtual or in-person evaluation. Clinical diagnoses are collected at medically attended visits or by investigator assessment. Additional Study Definitions: LRTI is an ARI with at least 2 or 3 signs/symptoms: new or increased cough, wheezing, sputum production, shortness of breath, tachypnea lasting more than 1 day. ARI-RSV and LRTI RSV is an RT-PCR confirmed ARI or LRTI. Results At EoS1, respiratory symptoms trended lower for cough, sputum production, wheezing, shortness of breath, and tachypnea in RSVpreF recipients compared to placebo recipients. Of these wheezing, shortness of breath, and tachypnea are considered as more severe symptoms. Diagnoses of bronchitis, Influenza-like illness, and pneumonia were less common in RSVpreF recipients compared to placebo recipients. Conclusion The reduction of more severe LRTI-RSV symptoms and diagnoses amongst all ARI-RSV events in vaccine recipients reflects the higher VE against more severe RSV disease observed in the RENOIR study. The vaccine impacts symptoms that are associated with lower respiratory involvement. Disclosures Gonzalo Pérez Marc, M.D., GSK: Grant/Research Support|Merck: Grant/Research Support|Moderna: Expert Testimony|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Edward E. Walsh, MD, Icosavax: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Moderna: Advisor/Consultant|Pfizer: Grant/Research Support Elliot N. DeHaan, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Agnieszka Zareba, MD PhD, Pfizer: Employee|Pfizer: Stocks/Bonds|Pfizer: Stocks/Bonds Qin Jiang, PhD, Pfizer: Employee|Pfizer: Employee|Pfizer: Stocks/Bonds|Pfizer: Stocks/Bonds Kumar Ilangovan, MD, MSPH, MMCi, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Daniel P. Eiras, MD, MPH, Pfizer, Inc.: Stocks/Bonds Tarek Mikati, MD,MPH, Pfizer: Stocks/Bonds Elena Kalinina, PhD, Pfizer: Pfizer employee|Pfizer: Stocks/Bonds David Cooper, PhD, Pfizer, Inc.: Stocks/Bonds Annaliesa S. Anderson, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Kena A. Swanson, Ph.D., Pfizer: Employee|Pfizer: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Alejandra C. Gurtman, M.D., Pfizer: Employee|Pfizer: Stocks/Bonds Beate Schmoele-Thoma, MD, Pfizer: Stocks/Bonds

Abstract Background Respiratory Syncytial Virus (RSV)-related disease poses an economic burden due to a substantial amount of health care utilization (HCU). RENOIR is a phase 3 global, multicenter, randomized, double-blinded, placebo-controlled study evaluating vaccine efficacy (VE) in adults ≥60 years of age during two RSV seasons in Northern and Southern Hemisphere countries (Argentina, Canada, Finland, Japan, Netherlands, South Africa, and USA) (NCT05035212). VE at the end of the first RSV surveillance season (EOS1) against ARI-RSV, Lower Respiratory Tract Illness (LRTI)-RSV with ≥2 symptoms (2+ LRTI-RSV), and LRTI-RSV with ≥3 symptoms (3+ LRTI-RSV) was 62.2% (44.4, 74.9), 65.1% (35.9, 82.0), and 88.9% (53.6, 98.7), respectively. Methods HCU data and concomitant corticosteroid or antibiotic use were collected during the RSV season for Acute Respiratory Illness (ARI) events (defined as more than 1 day of new or increased cough, nasal congestion/discharge, sore throat, wheezing, sputum production, or shortness of breath). A pre-planned analysis of HCU at EOS1 was performed to assess HCU among participants receiving RSVpreF vs. placebo. Results A higher proportion of RSV-associated HCU was associated with more severe symptoms (43.0%, 60.3%, and 75% for ARI-RSV, 2+ LRTI-RSV, and 3+ LRTI-RSV, respectively). Medically attended (MA) VE was similar to VE for all first-episode cases with MA ARI-RSV 65.1% (35.9, 82.0), MA 2+ LRTI-RSV 70.4% (33.0, 88.4), MA 3+ LRTI-RSV 84.6% (32.0, 98.3). Most RSV-associated HCU were outpatient visits, with more in the placebo arm. A higher proportion of placebo arm participants with RSV cases had an RSV-associated emergency room visit. For ARI-RSV, there were 3 hospitalizations in the placebo arm and none in the RSVpreF arm. The placebo arm had higher antibiotic (11.8 - 55.6% higher) or corticosteroid (2.8 – 44.4% higher) use compared to the RSVpreF arm for ARI- or LRTI-RSV events. Table 1 Vaccine Efficacy of RSVpreF Against First Episode of RSV Cases in the First RSV Season – Evaluable Efficacy Population Table 2 Healthcare Resource Utilization Associated With RSV Cases in the First RSV Season Table 3 Prespecified Category of Concomitant Medication Uses for RSV Cases in the First RSV Season Conclusion RSVpreF reduced overall HCU and antibiotic or corticosteroid treatment for RSV-associated illnesses. The highest VE among MA RSV-associated cases was for MA 3+ LRTI-RSV. These findings suggest that RSVpreF may reduce RSV-related healthcare needs in older adults, thus alleviating this burden on health systems. Disclosures Edward E. Walsh, MD, Icosavax: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Moderna: Advisor/Consultant|Pfizer: Grant/Research Support Kumar Ilangovan, MD, MSPH, MMCi, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Agnieszka Zareba, MD PhD, Pfizer: Employee|Pfizer: Stocks/Bonds|Pfizer: Stocks/Bonds Qin Jiang, PhD, Pfizer: Employee|Pfizer: Employee|Pfizer: Stocks/Bonds|Pfizer: Stocks/Bonds Gonzalo Pérez Marc, M.D., GSK: Grant/Research Support|Merck: Grant/Research Support|Moderna: Expert Testimony|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Elliot N. DeHaan, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Michael Patton, B.Sc., Pfizer Inc.: Employee|Pfizer Inc.: Stocks/Bonds Yanqing Kan, MS, Pfizer: Pfizer's employee|Pfizer: Stocks/Bonds Daniel P. Eiras, MD, MPH, Pfizer, Inc.: Stocks/Bonds Tarek Mikati, MD,MPH, Pfizer: Stocks/Bonds Elena Kalinina, PhD, Pfizer: Pfizer employee|Pfizer: Stocks/Bonds David Cooper, PhD, Pfizer, Inc.: Stocks/Bonds Annaliesa S. Anderson, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Kena A. Swanson, Ph.D., Pfizer: Employee|Pfizer: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Alejandra C. Gurtman, M.D., Pfizer: Employee|Pfizer: Stocks/Bonds Beate Schmoele-Thoma, MD, Pfizer: Stocks/Bonds

The newly emerged Omicron SARS-CoV-2 has several distinct sublineages including BA.1, BA.2, and BA.3. BA.1 accounts for the initial surge and is being replaced by BA.2, whereas BA.3 is at a low prevalence at this time. Here we report the neutralization of BNT162b2-vaccinated sera (collected 1 month after dose 3) against the three Omicron sublineages. To facilitate the neutralization testing, we have engineered the complete BA.1, BA.2, or BA.3 spike into an mNeonGreen USA-WA1/2020 SRAS-CoV-2. All BNT162b2-vaccinated sera neutralize USA-WA1/2020, BA.1-, BA.2-, and BA.3-spike SARS-CoV-2s with titers of >20; the neutralization geometric mean titers (GMTs) against the four viruses are 1211, 336, 300, and 190, respectively. Thus, the BA.1-, BA.2-, and BA.3-spike SARS-CoV-2s are 3.6-, 4.0-, and 6.4-fold less efficiently neutralized than the USA-WA1/2020, respectively. Our data have implications in vaccine strategy and understanding the biology of Omicron sublineages.

BNT162b2-elicited human sera neutralize the currently dominant Delta SARS-CoV-2 variant. Here, we report the ability of 20 human sera, drawn 2 or 4 weeks after two doses of BNT162b2, to neutralize USA-WA1/2020 SARS-CoV-2 bearing variant spikes from Delta plus (Delta-AY.1, Delta-AY.2), Delta-∆144 (Delta with the Y144 deletion of the Alpha variant), Lambda, B.1.1.519, Theta, and Mu lineage viruses. Geometric mean plaque reduction neutralization titers against Delta-AY.1, Delta-AY.2, and Mu viruses are slightly lower than against USA-WA1/2020, but all sera neutralize the variant viruses to titers of ≥80, and neutralization titers against the Delta-∆144, Lambda, B.1.1.519 and Theta variants not significantly reduced relative to those against USA-WA1/2020. The susceptibility of Delta plus, Lambda, B.1.1.519, Theta, Mu, and other variants to neutralization by the sera indicates that antigenic change has not led to virus escape from vaccine-elicited neutralizing antibodies and supports ongoing mass immunization with BNT162b2 to control the variants and to minimize the emergence of new variants.

Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor. We generated isogenic N501 and Y501 SARS-CoV-2. Twenty human sera from the mRNA-based vaccine BNT162b2 trial exhibited equivalent neutralizing titers to the N501 and Y501 viruses.

OBJECTIVE:Development of immunogens that elicit an anti-HIV-1 broadly neutralizing antibody (bnAb) response will be a key step in the development of an effective HIV-1 vaccine. Although HIV-1 bnAb epitopes have been identified and mechanisms of action studied, current HIV-1 envelope-based immunogens do not elicit HIV-1 bnAbs in humans or animal models. A better understanding of how HIV-1 bnAbs arise during infection and the clinical factors associated with bnAb development may be critical for HIV-1 immunogen design efforts. DESIGN AND METHODS:Longitudinal plasma samples from the treatment-naive control arm of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) primary HIV-1 infection cohort were used in an HIV-1 pseudotype neutralization assay to measure the neutralization breadth, potency and specificity of bnAb responses over time. RESULTS:In the SPARTAC cohort, development of plasma neutralization breadth and potency correlates with duration of HIV infection and high viral loads, and typically takes 3-4 years to arise. bnAb activity was mostly directed to one or two bnAb epitopes per donor and more than 60% of donors with the highest plasma neutralization having bnAbs targeted towards glycan-dependent epitopes. CONCLUSION:This study highlights the SPARTAC cohort as an important resource for more in-depth analysis of bnAb developmental pathways.

The impact of HIV infection on the burden of gastrointestinal pathogens in Myanmar is poorly defined. Stools of 103 HIV-infected and 105 HIV-uninfected adult outpatients at a tertiary referral hospital in Yangon were examined microscopically. Stool antigen tests for Helicobacter pylori infection were positive in 63/103 (61%) HIV-infected and 61/105 (58%) HIV-uninfected patients (P = 0.65). Soil-transmitted helminth infections were much less common, occurring in 9/103 (9%) HIV-infected and 13/103 (13%) HIV-uninfected patients (P = 0.50). One HIV-uninfected patient had Giardia duodenalis, but there were no cases of Strongyloides stercoralis, Entamoeba histolytica, Capillaria philippinensis, Isospora, Cyclospora, or Schistosoma infection in the entire cohort. Despite the high prevalence of H. pylori, only 1/208 (0.5%) had ever received eradication, compared with 159/208 (76%) who had ever been dewormed. Helicobacter pylori appears to be an underappreciated pathogen in Myanmar. Its strong association with gastric cancer and peptic ulcer disease necessitates a more aggressive approach to its management.

Medical comorbidities occur in more persons with HIV than without HIV. We used a nationally representative 10% sample of 2016 Pharmaceutical Benefits Scheme (PBS) dispensing data to compare the proportions of antiretroviral therapy (ART)-purchasing and non-ART-purchasing patients who also purchased prescriptions for medical comorbidities. Each patient who purchased ART was compared with two gender- and age group-matched patients who did not purchase ART in the same year. We calculated the proportions of patients who also purchased coprescriptions used for hypertension, dyslipidemia, diabetes, cancer, low bone mineral density, and mental health, defined using PBS medication coding categories, and the resulting odds ratios. A total of 1,973 ART-purchasing patients in our sample were matched to 3,946 non-ART-purchasing patients. Compared with non-ART-purchasing patients, a greater proportion of ART-purchasing patients also purchased medications for dyslipidemia (19.8% vs. 16.6%; p-value = .003), low bone mineral density (1.5% vs. 0.8%; p-value = .02), and mental health (29.1% vs. 15.3%; p-value < .0001); a lower proportion purchased diabetes medications (4.8% vs. 6.5%; p-value = .009). These differences remained when our analysis was restricted to persons >55 years of age. Rates of multimorbidity (dispensed ≥2 medications for chronic conditions) were also higher among ART-purchasing patients (19.0% vs. 15.9%; p-value = .003). Using a nationally representative sample of prescription dispensing data, we found that higher proportions of ART-purchasing patients purchased coprescriptions for common comorbidities compared with non-ART-purchasing patients. Our finding that ART-purchasing patients purchased fewer diabetes medications is surprising, but may reflect differences in population characteristics between our two groups.

Background Treatment guidelines for antiretroviral therapy (ART) have evolved to emphasize newer regimens that address ageing-related comorbidities. Using national Australian dispensing data we compare ART regimens with Australian HIV treatment guidelines in the context of treated comorbidities. Methods The study population included all individuals in a 10% sample of national data from the Australian Pharmaceutical Benefits Scheme (PBS) who purchased a prescription of ART during 2016. We defined each patient’s most recently dispensed ART regimen and characterized them to evaluate regimen complexity and adherence to national HIV treatment guidelines. We then analyzed ART regimens in the context of other co-prescriptions purchased for defined comorbidities. Results The 1995 patients in our sample purchased 212 different ART regimens during 2016; 1524 (76.4%) purchased one of the top ten most common regimens of which 62.3% were integrase strand transfer inhibitor-based. Among the 1786 (90%) patients that purchased the most common regimens, 83.7% purchased a regimen recommended by the guidelines for initial antiretroviral therapy and 11.4% purchased antiretrovirals that are not recommended for initial therapy; < 1% of the entire cohort purchased medications not recommended for use. While most patients purchased optimal ART regimens with low potential for significant drug interactions, regimen choices in the setting of risk factors for heart disease, renal disease and low bone mineral density appeared suboptimal. Conclusions Australian HIV providers are prescribing ART regimens in accordance with updated treatment guidelines, but could further optimize regimens in the setting of important medical comorbidities.

BACKGROUND AND AIM:There is little published research to examine the best approach to the management of Helicobacter pylori in Myanmar. This study aimed to determine the relative efficacy and tolerability of sequential eradication therapy compared to Myanmar's current recommendation of a concomitant four drug regimen. METHODS:Patients were screened for H. pylori using monoclonal Stool Antigen Testing (SAT). Those testing positive were randomized 1:1 to receive receive Myanmar's first-line regimen of 14 days of concomitant rabeprazole, clarithromycin, amoxycillin and tinidazole (140 pills, cost US$23) or 10 days of sequential rabeprazole, clarithromycin, amoxycillin and tinidazole (60 pills, cost US$10). Adherence and adverse effects were recorded, and the efficacy of the regimens assessed with repeat SAT. RESULTS:Of the 1011 patients screened for H. pylori infection, 313 (31%) tested positive. There was no statistical difference in the cure rates of the two regimens in either intention-to-treat: 128/157 (82%; 95% confidence interval (CI): 75-87%) receiving sequential therapy versus 123/156 (79%; 95% CI: 72-85%) receiving concomitant therapy (P = 0.55) or per-protocol analysis: 125/131 (95%; 95% CI: 90-98) receiving sequential therapy versus 121/130 (93%; 95% CI: 87-96) receiving concomitant therapy (P = 0.42). Side effects of therapy were reported in 54/157 (47%) patients taking sequential therapy compared with 62/156 (53%) taking concomitant therapy, but this difference did not reach statistical significance (P = 0.33). CONCLUSIONS:In this high-burden, resource-poor setting, less expensive sequential therapy was as effective and as well tolerated as the currently recommended concomitant four drug regimen for eradication of H. pylori.

Background: Subject C135 is one of the members of the Sydney Blood Bank Cohort, infected in 1981 through transfusion with attenuated nef/3' long terminal repeat (LTR)-deleted HIV-1, and has maintained undetectable plasma viral load and steady CD4 cell count, in the absence of therapy. Uniquely, C135 combines five factors separately associated with control of viraemia: nef/LTR-deleted HIV-1, HLA-B57, HLA-DR13, heterozygous CCR 5 Delta 32 genotype and vigorous p24-stimulated peripheral blood mononuclear cell (PBMC) proliferation. Therefore, we studied in detail viral burden and immunological responses in this individual. Methods: PBMC and gut and lymph node biopsy samples were analysed for proviral HIV-1 DNA by real-time and nested PCRs, and nef/LTR alleles by nested PCR. HIV-specific antibodies were studied by Western blotting, and CD4+ and CD8+ T lymphocyte responses were measured by proliferation and cytokine production in vitro. Results: PBMC samples from 1996, but not since, showed amplification of nef alleles with gross deletions. Infectious HIV-1 was never recovered. Proviral HIV-1 DNA was not detected in recent PBMC or gut or lymph node biopsy samples. C135 has a consistently weak antibody response and a substantial CD4+ T cell proliferative response to a previously described HLA-DR13-restricted epitope of HIV-1 p24 in vitro, which augmented a CD8+ T cell response to an immunodominant HLA-B57-restricted epitope of p24, while his T cells show reduced levels of CCR 5. Conclusions: Subject C135' s early PCR and weak antibody results are consistent with limited infection with a poorly replicating nef/LTR-deleted strain of HIV-1. With his HLA-B57-restricted gag-specific CD8 and helper HLA-DR13-restricted CD4 T cell proliferative responses, C135 appears to have cleared his HIV-1 infection 37 years after transfusion.

Kirby MSD HIV Comorbidity Analysis - PBS Code References. This spreadsheet contains the groupings of medications used to determine comorbidity classifications (XLSX 162 kb)

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 log(10) copies of HIV DNA per 10(6) 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.

Introduction: There are few data about the range of strategies used to prevent sexual HIV transmission within gay male serodiscordant couples. We examined HIV prevention strategies used by such couples and compared differences between countries. Methods: Opposites Attract was a cohort study of male serodiscordant couples in Australia, Brazil and Thailand, from May 2014 (Australia) or May 2016 (Brazil/Thailand) to December 2016. At visits, HIV-positive partners had viral load (VL) tested; HIV-negative partners reported sexual behaviour and perceptions of their HIV-positive partner's VL results. Within-couple acts of condomless anal intercourse (CLAI) were categorized by strategy: condom-protected, biomedically protected (undetectable VL and/or pre-exposure prophylaxis [PrEP]), or not protected by either (HIV-negative partners engaging in insertive CLAI, receptive CLAI with withdrawal, or receptive CLAI with ejaculation). Results: A total of 343 couples were included in this analysis (153 in Australia, 93 in Brazil and 97 in Thailand). Three-quarters of HIV-positive partners were consistently virally suppressed (<200 copies/mL) during follow-up, and HIV-negative partners had correct perceptions of their partner's VL result for 76.5% of tests. One-third of HIV-negative partners used daily PrEP during follow-up. Over follow-up, 73.8% of couples had CLAI. HIV-negative partners reported 31,532 acts of anal intercourse with their HIV-positive partner. Of these, 46.7% were protected by condoms, 48.6% by a biomedical strategy and 4.7% of acts were not protected by these strategies. Australian couples had fewer condom-protected acts and a higher proportion of biomedically protected acts than Brazilian and Thai couples. Of the 1473 CLAI acts where the perceived VL was detectable/unknown and were not protected by PrEP (4.7% of all acts), two-thirds (n = 983) were when the HIV-negative partner was insertive (strategic positioning). Of the 490 acts when the HIV-negative partner was receptive, 261 involved withdrawal and 280 involved ejaculation. Thus, <1% of acts were in the highest risk category of receptive CLAI with ejaculation. Conclusions: Couples used condoms, PrEP or perceived undetectable VL for prevention in the majority of anal intercourse acts. Only a very small proportion of events were not protected by these strategies. Variation between countries may reflect differences in access to HIV treatment, education, knowledge and attitudes.

BACKGROUND:Indonesia has had low uptake of HIV testing and treatment. We did a study to estimate the cascade of HIV care in key populations and identify predictors of outcomes at key cascade steps. METHODS:We used an observational cohort study design to recruit and follow up men who have sex with men (MSM), female sex workers, transgender women (known as waria in Indonesia), and people who inject drugs (PWID) diagnosed with HIV in four locations in Indonesia: Bali, Bandung, Jakarta, and Yogyakarta. Recruitment, baseline, and follow-up visits were done at collaborating clinical services, including both primary care sites and hospitals. Inclusion criteria for participants included identifying as a member of a key population, age 16 years or older, not previously tested positive for HIV, and HIV positivity at baseline. All participants were offered treatment as per national guidelines, with the addition of viral load testing and completion of study-specific forms. Estimates were calculated of proportions of participants linked to care, commencing treatment, adherent to treatment, and who achieved virological suppression. We used logistic regression to investigate characteristics associated with antiretroviral therapy (ART) initiation and viral suppression and Cox regression to identify factors associated with loss to follow-up. This study is registered with ClinicalTrials.gov, NCT03429842. FINDINGS:Between Sept 15, 2015, and Sept 30, 2016, 831 individuals were enrolled in the study, comprising 637 (77%) MSM, 116 (14%) female sex workers, 27 (3%) waria, and 51 (6%) PWID. Of those enrolled, 703 (84·6%, 95% CI 82·1-87·1) were linked to HIV care and 606 (86·2%, 83·7-88·8) who were linked with care started ART. Among participants who started treatment, 457 (75·4%, 71·8-78·9) were retained in care, of whom 325 (71·1%, 66·7-75·2) had a viral load test about 6 months after enrolment, with 294 (90·5%, 86·7-93·4) of those tested (294 [35%, 32·1-38·7] of the original cohort) virally suppressed. 146 (24%) of 606 who started treatment were lost to follow-up. People who enrolled at sites that offered both testing and treatment had a higher likelihood of treatment initiation than those who enrolled at sites offering testing only (p<0·0001 by multivariate analysis), and participants who had been linked to care and had a high school or university education were significantly more likely to achieve viral suppression than those with a primary school or lower level of education (p≤0·029 by mulivariate analysis). INTERPRETATION:HIV cascade data among key populations in Indonesia show very poor rates of retention in treatment and viral suppression. Site and individual characteristics associated with initiating and continuing treatment suggest an urgent need to develop and implement effective interventions to support patients in achieving viral suppression among all people with HIV. FUNDING:Australian Government Department of Foreign Affairs and Trade, WHO, and Indonesian Government.

Background: Resource constraints in low and middle-income countries necessitate practical approaches to optimizing antiretroviral therapy outcomes. We hypothesised that an untimed plasma lopinavir concentration (UPLC) at week 12 would predict loss of virological response in those taking lopinavir as part of a second-line antiretroviral regimen. Methods: We measured plasma lopinavir concentration at week 12 on stored samples from the SECOND-LINE study. We characterized UPLC as: detectable and optimal (≥1000 &mgr;g/l); detectable but suboptimal (≥25 to < 1000 &mgr;g/l); and undetectable (<25 &mgr;g/l). We used Cox regression to explore the relationship between UPLC and loss of virological response over 48 weeks and backwards stepwise logistic regression to explore the relationship between UPLC and other predictors of virological failure at week 48. Results: At week 48, we observed virological failure in 15/32 (47%) and 53/485 (11%) of patients with undetectable and detectable UPLC, respectively, P < 0.001. Both suboptimal [adjusted hazard ratio (HR) 2.94; 95% confidence interval (CI) 1.54–5.62; P = 0.001], and undetectable (adjusted HR 3.55; 95% CI 1.89–6.64; P < 0.001) UPLC were associated with higher rates of loss of virological response over 48 weeks. In multivariate analysis, an independent association with virological failure at week 48 and undetectable UPLC was observed after adjustment (odds ratio 5.48; 95% CI 2.23–13.42; P < 0.01). Conclusion: In low and middle-income countries implementing a public health approach to antiretroviral therapy treatment, an untimed plasma drug concentration may provide a practical method for early identification of patients with inadequate medication adherence and facilitate timely corrective interventions to prevent virological failure.

dimensionality of the space of output statistics), Latin Hypercube Sampling and sequential Approximate Bayesian Computation (to explore the parameter space in a time-efficient manner) and multivariate emulation (to interpolate output statistics for regions of the parameter space that have not been sampled explicitly).

Background. Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods. The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results. Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions. Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.

BACKGROUND:Rheumatic heart disease (RHD) is a major cause of premature death in low and middle-income countries. The greatest barrier to RHD control is neglect of the disease in national health policies and a lack of prevalence data that might inform control efforts. Myanmar is making remarkable progress against many infectious diseases, but there are almost no data to define the clinical burden of RHD in the country. This prospective audit was performed in an adult medical ward of a tertiary-referral hospital in Yangon, to gain an insight into the prevalence of RHD in Myanmar. PRINCIPAL FINDINGS:All patients admitted to the ward between May 1, 2016 and April 30, 2017 were eligible for enrolment. RHD was confirmed in 96 patients who were admitted on 134 occasions, representing 1.1% of the 12,172 adult medical admissions during the study period. This compared with 410 (3.4%) admissions with HIV and 14 (0.1%) with malaria. Patients with RHD had a median age of 44 years (interquartile range: 35-59); 70 (73%) were female. Only one patient had ever had surgery despite 79 (82%) meeting criteria for intervention; 54 (56%) patients were not receiving any regular clinician review. Prior to hospitalisation only 18 (19%) patients were receiving regular penicillin. Only 8 (19%) of the 42 women <50 years were using contraception. Of 49 patients who had been hospitalised previously, 22 (45%) were receiving no regular therapy. During the study three (3.1%) patients died, and 28 (29%) were lost to follow-up. Of the 65 (68%) alive and retained in care, 21 (32%) were still experiencing moderate-severe RHD-related symptoms at the study's end. CONCLUSIONS:There is a significant and unmet clinical burden of RHD in Myanmar. A national RHD programme would improve patient care, reducing morbidity and mortality from this preventable disease.