Monkeypox Virus Infection in Humans across 16 Countries - April-June 2022.

BACKGROUND: Before April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. METHODS: We formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. RESULTS: We report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having ≤10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. CONCLUSIONS: In this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.

Monkeypox.

Monkeypox is a zoonotic illness caused by the monkeypox virus, an Orthopoxvirus in the same genus as the variola, vaccinia, and cowpox viruses. Since the detection of the first human case in the Democratic Republic of the Congo in 1970, the disease has caused sporadic infections and outbreaks, mainly restricted to some countries in west and central Africa. In July, 2022, WHO declared monkeypox a Public Health Emergency of International Concern, on account of the unprecedented global spread of the disease outside previously endemic countries in Africa and the need for global solidarity to address this previously neglected disease. The 2022 outbreak has been primarily associated with close intimate contact (including sexual activity) and most cases have been diagnosed among men who have sex with men, who often present with novel epidemiological and clinical characteristics. In the 2022 outbreak, the incubation period ranges from 7 days to 10 days and most patients present with a systemic illness that includes fever and myalgia and a characteristic rash, with papules that evolve to vesicles, pustules, and crusts in the genital, anal, or oral regions and often involve the mucosa. Complications that require medical treatment (eg, antiviral therapy, antibacterials, and pain control) occur in up to 40% of patients and include rectal pain, odynophagia, penile oedema, and skin and anorectal abscesses. Most patients have a self-limited illness; between 1% and 13% require hospital admission (for treatment or isolation), and the case-fatality rate is less than 0·1%. A diagnosis can be made through the presence of Orthopoxvirus DNA in PCRs from lesion swabs or body fluids. Patients with severe manifestations and people at risk of severe disease (eg, immunosuppressed people) could benefit from antiviral treatment (eg, tecovirimat). The current strategy for post-exposure prophylaxis or pre-exposure prophylaxis for people at high risk is vaccination with the non-replicating modified vaccinia Ankara. Antiviral treatment and vaccines are not yet available in endemic countries in Africa.

Mpox in people with advanced HIV infection: a global case series.

BACKGROUND: People living with HIV have accounted for 38-50% of those affected in the 2022 multicountry mpox outbreak. Most reported cases were in people who had high CD4 cell counts and similar outcomes to those without HIV. Emerging data suggest worse clinical outcomes and higher mortality in people with more advanced HIV. We describe the clinical characteristics and outcomes of mpox in a cohort of people with HIV and low CD4 cell counts (CD4 <350 cells per mm3). METHODS: A network of clinicians from 19 countries provided data of confirmed mpox cases between May 11, 2022, and Jan 18, 2023, in people with HIV infection. Contributing centres completed deidentified structured case report sheets to include variables of interest relevant to people living with HIV and to capture more severe outcomes. We restricted this series to include only adults older than 18 years living with HIV and with a CD4 cell count of less than 350 cells per mm3 or, in settings where a CD4 count was not always routinely available, an HIV infection clinically classified as US Centers for Disease Control and Prevention stage C. We describe their clinical presentation, complications, and causes of death. Analyses were descriptive. FINDINGS: We included data of 382 cases: 367 cisgender men, four cisgender women, and ten transgender women. The median age of individuals included was 35 (IQR 30-43) years. At mpox diagnosis, 349 (91%) individuals were known to be living with HIV; 228 (65%) of 349 adherent to antiretroviral therapy (ART); 32 (8%) of 382 had a concurrent opportunistic illness. The median CD4 cell count was 211 (IQR 117-291) cells per mm3, with 85 (22%) individuals with CD4 cell counts of less than 100 cells per mm3 and 94 (25%) with 100-200 cells per mm3. Overall, 193 (51%) of 382 had undetectable viral load. Severe complications were more common in people with a CD4 cell count of less than 100 cells per mm3 than in those with more than 300 cells per mm3, including necrotising skin lesions (54% vs 7%), lung involvement (29% vs 0%) occasionally with nodules, and secondary infections and sepsis (44% vs 9%). Overall, 107 (28%) of 382 were hospitalised, of whom 27 (25%) died. All deaths occurred in people with CD4 counts of less than 200 cells per mm3. Among people with CD4 counts of less than 200 cells per mm3, more deaths occurred in those with high HIV viral load. An immune reconstitution inflammatory syndrome to mpox was suspected in 21 (25%) of 85 people initiated or re-initiated on ART, of whom 12 (57%) of 21 died. 62 (16%) of 382 received tecovirimat and seven (2%) received cidofovir or brincidofovir. Three individuals had laboratory confirmation of tecovirimat resistance. INTERPRETATION: A severe necrotising form of mpox in the context of advanced immunosuppression appears to behave like an AIDS-defining condition, with a high prevalence of fulminant dermatological and systemic manifestations and death. FUNDING: None.

Multicentre service evaluation of injectable cabotegravir and rilpivirine delivery and outcomes across 12 UK clinics (SHARE LAI-net).

INTRODUCTION: Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics. METHODS: Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia. RESULTS: In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV. CONCLUSION: In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure.

Staff disability data in UK higher education: Evidence from EDI reports.

OBJECTIVES: To explore how higher education institutions (HEIs) make transparent the data they collect on staff disability, and how this relates to existing equality, diversity and inclusion (EDI) charters. DESIGN: Descriptive cross-sector quantitative study based on UK HEIs. SETTING: Higher education sector in the UK. PARTICIPANTS: 162 HEIs across the UK with information extracted from the Higher Education Statistics Agency (HESA), each institution's website and Advance HE. PRIMARY AND SECONDARY OUTCOME MEASURES: Availability of a publicly available EDI report. Type of information on staff disability identified within the EDI report and level of detail, the latter derived from the number of different types of information provided in the report. Athena SWAN and Disability Confident award level for each HEI were used as a proxy for the sector's commitment to EDI. RESULTS: Under a quarter of HEIs do not have an open EDI report online. The majority of Athena SWAN award holders make their EDI reports publicly available, which is similar by Disability Confident status. Russell Group universities are more likely to have a publicly available report. Regionally, EDI report availability is lowest in London. The level of detail with regards to staff disability varies, with more than half of institutions providing 'little detail' and just under a third 'some detail'. Athena SWAN award holders and Disability Confident members are twice as likely to provide 'some detail' than those which do not hold an award. CONCLUSIONS: Challenges remain to obtain a clear picture of staff with disabilities within higher education. The lack of both uniformity and transparency in EDI reporting with respect to disability hinders the ability to quantify staff with disabilities within higher education, develop meaningful interventions and address inequities more widely.

Expanded Multivariable Models to Assist Patient Selection for Long-Acting Cabotegravir + Rilpivirine Treatment: Clinical Utility of a Combination of Patient, Drug Concentration, and Viral Factors Associated With Virologic Failure.

BACKGROUND: Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants. METHODS: Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population-baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination). RESULTS: Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses. CONCLUSIONS: The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA.

Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.

BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.

Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.

BACKGROUND: Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection. METHODS: We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm). RESULTS: At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. CONCLUSIONS: Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.).

Estimating the global impact of coronavirus disease 2019 on people living with HIV.

PURPOSE OF REVIEW: The COVID-19 pandemic and public health response have directly and indirectly affected broader health outcomes, especially for those with existing chronic conditions, including HIV. We examine our current understanding of the global impact of COVID-19 on people with HIV (PWH). RECENT FINDINGS: The interaction between COVID-19 and HIV is complex, making it challenging to estimate its true impact on PWH. Evidence to date does not suggest that HIV confers a higher risk of acquiring SARS-CoV-2. However, once acquired, HIV increases the risk of severe COVID-19 and mortality, particularly in immunosuppressed viraemic individuals and in the context of traditional COVID-19 risk factors, including disparities in social determinants of health. In addition, COVID-19 vaccines may be less effective in the context of HIV infection with additional doses needed. The consequences of disruption of access to essential prevention and treatment services because of the pandemic are becoming evident and will likely adversely affect outcomes, risking decades of progress. SUMMARY: Given the increased mortality risk and reduced vaccine effectiveness seen in PWH, specific prevention and support measures are needed, including prioritization of vaccination and boosters, funding to mitigate the impact of pandemic and enabling integrated healthcare delivery during pandemics will be critical.

Public understanding and awareness of and response to monkeypox virus outbreak: A cross-sectional survey of the most affected communities in the United Kingdom during the 2022 public health emergency.

OBJECTIVES: Our objective was to examine the public response to public health and media messaging during the human monkeypox virus (MPXV) outbreak in the UK, focusing on at-risk communities. METHODS: A co-produced, cross-sectional survey was administered in June and July 2022 using community social media channels and the Grindr dating app. Basic descriptive statistics, logistic regression, and odds ratio p values are presented. RESULTS: Of 1932 survey respondents, 1750 identified as men, 88 as women, and 64 as gender non-conforming. Sexual identity was described as gay/lesbian/queer (80%), bisexual (12%), heterosexual (4%), and pansexual (2%); 39% were aged <40 years; 71% self-identified as White, 3% as Black, 8% as Asian, 2%as LatinX, and 11% as 'Mixed or Other' heritage groups. In total, 85% were employed and 79% had completed higher education. A total of 7% of respondents identified themselves as living with HIV. Overall, 34% reported limited understanding of public health information, 52% considered themselves at risk, 61% agreed that people with MPXV should isolate for 21 days, 49% reported they would first attend a sexual health clinic if symptomatic, 86% reported they would accept a vaccine, and 59% believed that MPXV originated from animals. The most trusted sources of information were healthcare professionals (37%), official health agencies (29%), and mainstream media (12%). CONCLUSIONS: Vaccine acceptability was very high, yet the understanding and acceptance of public health information varied. Social determinants of health inequalities already shaping the UK landscape risk were compounded in this new emergency. Engagement with structurally disadvantaged members of affected communities and better dissemination of public health messaging by trusted healthcare professionals are essential for the public health response.

Experiences of initiating rapid antiretroviral therapy among people newly diagnosed with HIV in East London: a qualitative study.

OBJECTIVES: We aimed to explore the experiences of people who initiated rapid antiretroviral therapy (ART) within 7 days of HIV diagnosis, as part of routine care in London. METHODS: Using purposive sampling, 18 in-depth, semistructured interviews were conducted between December 2020 and September 2021 with people who started rapid ART at Barts Health NHS Trust. Participants aged 22-69 years included 15 cisgender men and three cisgender women. Five identified as heterosexual and 13 as gay and bisexual and other men who have sex with men. Ethnic identities: six White Non-UK, five White UK, three Black Caribbean, two South Asian and two East Asian. Interviews explored feelings about the new HIV diagnosis, attitudes to rapid ART including barriers to and facilitators of starting. Thematic analysis of transcribed interviews was undertaken. RESULTS: Four themes were identified: (1) being offered rapid ART is acceptable; (2) it is a way of taking control of their health; (3) the need for information and support and (4) an individualised approach to care. Reasons for starting included getting well, staying well and reducing the likelihood of passing on HIV. Facilitators included being given comprehensive information about treatment and managing potential side-effects and a supportive clinical team. Support specified included a non-judgemental attitude, approachability, reassurance, encouragement and information about peer support. Most participants expressed they could not understand why people would not begin treatment, but suggested needing more time to decide and denial of diagnosis as possible barriers. CONCLUSIONS: To our knowledge, this is the first qualitative study exploring the experiences of people initiating rapid ART in the UK. It was deemed acceptable to an ethnically diverse, predominantly male sample of people newly diagnosed with HIV. Future research should include strategies to recruit a more gender diverse sample and those who declined or stopped rapid ART.

Opening the door on entry inhibitors in HIV: Redefining the use of entry inhibitors in heavily treatment experienced and treatment-limited individuals living with HIV.

INTRODUCTION: Entry inhibitors are a relatively new class of antiretroviral therapy and are typically indicated in heavily treatment experienced individuals living with HIV. Despite this, there is no formal definition of 'heavily treatment experienced'. Interpretation of this term generally includes acknowledgement of multidrug resistance and reflects the fact that patients in need of further treatment options may have experienced multiple lines of therapy. However, it fails to recognize treatment limiting factors including contraindications, age-associated comorbidities, and difficulty adhering to regimens. METHODS: This manuscript follows a roundtable discussion and aims to identify the unmet needs of those living with HIV who are in need of further treatment options, to broaden the definition of heavily treatment experienced and to clarify the use of newer agents, with an emphasis on the potential role of entry inhibitors, in this population. RESULTS/CONCLUSIONS: Within the entry inhibitor class, mechanisms of action differ between agents; resistance to one subclass does not confer resistance to others. Combinations of entry inhibitors should be considered in the same regimen, and if lack of response is seen to one entry inhibitor another can be tried. When selecting an entry inhibitor, physicians should account for patient preferences and needs as well as agent-specific clinical characteristics. Absence of documented multidrug resistance should not exclude an individual from treatment with an entry inhibitor; entry inhibitors are a valuable treatment option for all individuals who are treatment limited or treatment exhausted. We should advocate for additional clinical trials that help define the role of entry inhibitors in people with exhausted/limited ART options other than drug resistance.

Bone mineral density, kidney function and participant-reported outcome measures in women who switch from tenofovir disoproxil emtricitabine and a nonnucleoside reverse transcriptase inhibitor to abacavir, lamivudine and dolutegravir.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG). METHODS: We conducted a randomized controlled trial in which women aged ≥ 40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. We analysed changes in BMD at the hip and lumbar spine from baseline to week 96 using linear regression, and markers of bone turnover and kidney function using repeated measures mixed effects models with multiple imputation for missing data. We conducted exploratory analyses of weight, mental health, sleep and symptoms attributed to HIV infection and antiretroviral therapy. RESULTS: Ninety-one women [mean (standard deviation) age 50.4 (6.6) years] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in BMD at the lumbar spine (but not the neck of the femur or the total hip), bone resorption markers and proteinuria (total protein, albumin and retinol-binding protein) and modest weight gain without changes in body mass index. Although mean anxiety, depression and sleep scores did not differ between the two study arms, anxiety, depression and sleep disturbance at baseline predicted ABC/3TC/DTG discontinuation for neuropsychiatric side effects [odds ratios (95% confidence intervals) 11.9 (2.0-71.6), 16.0 (2.6-97.9) and 10.0 (1.8-56.0), respectively]. CONCLUSIONS: Switching from TDF/FTC/NNRTI to ABC/3TC/DTG improved the BMD of the lumbar spine and kidney function. These benefits need to be balanced against modest weight gain and the need for antiretroviral therapy substitutions in a proportion of participants.

Clinical outcomes of patients with and without HIV hospitalized with COVID-19 in England during the early stages of the pandemic: a matched retrospective multi-centre analysis (RECEDE-C19 study).

BACKGROUND: The contribution of HIV to COVID-19 outcomes in hospitalized inpatients remains unclear. We conducted a multi-centre, retrospective matched cohort study of SARS-CoV-2 PCR-positive hospital inpatients analysed by HIV status. METHODS: HIV-negative patients were matched to people living with HIV (PLWH) admitted from 1 February 2020 to 31 May 2020 up to a 3:1 ratio by the following: hospital site, SARS-CoV-2 test date ± 7 days, age ± 5 years, gender, and index of multiple deprivation decile ± 1. The primary objective was clinical improvement (two-point improvement or better on a seven-point ordinal scale) or hospital discharge by day 28, whichever was earlier. RESULTS: A total of 68 PLWH and 181 HIV-negative comparators were included. In unadjusted analyses, PLWH had a reduced hazard of achieving clinical improvement or discharge [adjusted hazard ratio (aHR) = 0.57, 95% confidence interval (CI): 0.39-0.85, p = 0.005], but this association was ameliorated (aHR = 0.70, 95% CI: 0.43-1.17, p = 0.18) after additional adjustment for ethnicity, frailty, baseline hypoxaemia, duration of symptoms prior to baseline, body mass index (BMI) categories and comorbidities. Baseline frailty (aHR = 0.79, 95% CI: 0.65-0.95, p = 0.011), malignancy (aHR = 0.37, 95% CI 0.17, 0.82, p = 0.014) remained associated with poorer outcomes. The PLWH were more likely to be of black, Asian and minority ethnic background (75.0% vs 48.6%, p = 0.0002), higher median clinical frailty score [3 × interquartile range (IQR): 2-5 vs, 2 × IQR: 1-4, p = 0.0069), and to have a non-significantly higher proportion of active malignancy (14.4% vs 9.9%, p = 0.29). CONCLUSIONS: Adjusting for confounding comorbidities and demographics in a matched cohort ameliorated differences in outcomes of PLWH hospitalized with COVID-19, highlighting the importance of an appropriate comparison group when assessing outcomes of PLWH hospitalized with COVID-19.

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority Trial.

BACKGROUND: Doravirine (DOR) is a nonnucleoside reverse-transcriptase inhibitor. In the phase 3 DRIVE-AHEAD trial in treatment-naive adults with human immunodeficiency virus type 1 (HIV-1) infection, DOR demonstrated noninferior efficacy compared with efavirenz (EFV) and superior profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96. METHODS: DRIVE-AHEAD is a phase 3, multicenter, double-blind, noninferiority trial in antiretroviral treatment-naive adults with HIV-1 RNA ≥1000 copies/mL. Participants were randomized to a daily fixed-dose tablet of DOR (100 mg), lamivudine (3TC; 300 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) (DOR/3TC/TDF) or EFV (600 mg), emtricitabine (FTC; 200 mg) and TDF (300 mg) (EFV/FTC/TDF). The efficacy end point of interest at week 96 was the proportion of participants with HIV-1 RNA levels <50 copies/mL (Food and Drug Administration Snapshot Approach) with a predefined noninferiority margin of 10% to support week 48 results. Safety end points of interest included prespecified neuropsychiatric adverse events and the mean change in fasting lipids at week 96. RESULTS: Of 734 participants randomized, 728 received study drugs and were included in analyses. At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF vs 73.6% of EFV/FTC/TDF participants, with a treatment difference of 3.8% (95% confidence interval, -2.4% to 10%). Virologic failure rates were low and similar across treatment arms, with no additional resistance to DOR observed between weeks 48 and 96. Prespecified neuropsychiatric adverse events and rash were less frequent in DOR/3TC/TDF than in EFV/FTC/TDF participants through week 96. At week 96, fasting low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol (HDL-C) levels increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group; the mean changes from baseline in total cholesterol/HDL-C ratio were similar. CLINICAL TRIALS REGISTRATION: NCT02403674.

Decline in Hepatitis C Virus (HCV) Incidence in Men Who Have Sex With Men Living With Human Immunodeficiency Virus: Progress to HCV Microelimination in the United Kingdom?

BACKGROUND: Modeling of the London hepatitis C virus (HCV) epidemic in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV) suggested that early access to direct-acting antiviral (DAA) treatment may reduce incidence. With high rates of linkage to care, microelimination of HCV within MSM living with HIV may be realistic ahead of 2030 World Health Organization targets. We examined trends in HCV incidence in the pre- and post-DAA eras for MSM living with HIV in London and Brighton, United Kingdom. METHODS: A retrospective cohort study was conducted at 5 HIV clinics in London and Brighton between 2013 and 2018. Each site reported all acute HCV episodes during the study period. Treatment timing data were collected. Incidence rates and reinfection proportion were calculated. RESULTS: A total of.378 acute HCV infections were identified, comprising 292 first infections and 86 reinfections. Incidence rates of acute HCV in MSM living with HIV peaked at 14.57/1000 person-years of follow-up (PYFU; 95% confidence interval [CI], 10.95-18.20) in 2015. Rates fell to 4.63/1000 PYFU (95% CI, 2.60 to 6.67) by 2018. Time from diagnosis to starting treatment declined from 29.8 (2013) to 3.7 months (2018). CONCLUSIONS: We observed a 78% reduction in the incidence of first HCV episode and a 68% reduction in overall HCV incidence since the epidemic peak in 2015, which coincides with wider access to DAAs in England. Further interventions to reduce transmission, including earlier access to treatment and for reinfection, are likely needed for microelimination to be achieved in this population.

Weight Change Following Antiretroviral Therapy Switch in People With Viral Suppression: Pooled Data from Randomized Clinical Trials.

BACKGROUND: We sought to identify factors associated with weight gain in randomized clinical trials of antiretroviral therapy (ART) switch. METHODS: We explored the effects of demographic factors, clinical characteristics, and ART on weight gain in a pooled analysis of 12 prospective clinical trials, wherein virologically suppressed people living with human immunodeficiency virus (PWH) were randomized to switch or remain on a stable baseline regimen (SBR). RESULTS: Both PWH randomized to switch ART (n = 4166) and those remaining on SBR (n = 3150) gained weight. Median weight gain was greater in those who switched (1.6 kg, interquartile range [IQR], -.05 to 4.0 vs 0.4 kg, [IQR], -1.8 to 2.4 at 48 weeks, P < .0001), with most weight gain occurring in the first 24 weeks after switch. Among baseline demographic and clinical characteristics, only younger age and lower baseline body mass index were associated with any or ≥10% weight gain. By week 48, 4.6% gained ≥10% weight (6.4% of switch and 2.2% of SBR), the greatest risk was with switch from efavirenz (EFV) to rilpivirine (RPV) or elvitegravir/cobicistat and switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF). Switch from abacavir to TAF was associated with less weight gain than switch from TDF to TAF and was not associated with increased risk for ≥10% weight gain. CONCLUSIONS: Moderate weight gain after ART switch was common and usually plateaued by 48 weeks. Baseline ART was a predictor of post-switch weight gain; participants who switched off of EFV and TDF had the greatest weight gain. The biological mechanisms that underlie the differential effects of switching ART agents on weight and associated clinical implications require further study.

Long-acting injectable HIV therapies: the next frontier.

PURPOSE OF REVIEW: There has been significant development of long-acting injectable therapy for the management of HIV in recent years that has the potential to revolutionise HIV care as we know it. This review summarises the data and outlines the potential challenges in the field of long-acting antiretroviral therapy (ART). RECENT FINDINGS: In recent years, monthly and two monthly long-acting injectable ART in the form of cabotegravir and rilpivirine has shown safety and efficacy in large-scale phase 3 randomised control trials. Also, agents with novel mechanisms of action, such as Lenacapavir, have been tested in early-phase studies and are currently being tested in phase 2-3 clinical trials; if successful, this may allow six-monthly dosing schedules. SUMMARY: However, despite evidence that suggests that these therapies are efficacious and acceptable to patients, the challenge of integrating these agents into our current healthcare infrastructure and making these novel agents cost-effective and available to the populations most likely to benefit remains. The next frontier for long-acting therapy will be to introduce these agents in a real-world setting ensuring that the groups most in need of long-acting therapy are not left behind.

Short-Duration Pan-Genotypic Therapy With Glecaprevir/Pibrentasvir for 6 Weeks Among People With Recent Hepatitis C Viral Infection.

BACKGROUND AND AIMS: Among treatment-naive individuals with chronic hepatitis C viral (HCV) infection and without cirrhosis, glecaprevir/pibrentasvir for 8 weeks is recommended. The aim of this analysis was to evaluate the efficacy of glecaprevir/pibrentasvir for 6 weeks in people with acute and recent HCV infection. APPROACH AND RESULTS: In this open-label, single-arm, multicenter, international pilot study, adults with recent HCV (duration of infection < 12 months) received glecaprevir/pibrentasvir 300/120 mg daily for 6 weeks. Primary infection was defined by first positive anti-HCV antibody and/or HCV RNA within 6 months of enrollment and either acute clinical hepatitis within the past 12 months (symptomatic seroconversion illness or alanine aminotransferase > 10 × upper limit of normal) or anti-HCV antibody seroconversion within 18 months. Reinfection was defined as new positive HCV RNA within 6 months of enrollment and evidence of prior spontaneous or treatment-induced clearance. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12). Thirty men (median age 43 years, 90% men who have sex with men) received treatment, of whom 77% (n = 23) were human immunodeficiency virus-positive, 47% (n = 14) had ever injected drugs, and 13% (n = 4) had HCV reinfection. The majority had HCV genotype 1 (83%, n = 25), followed by genotype 4 (10%, n = 3) and genotype 3 (7%, n = 2). At baseline, median estimated duration of infection was 29 weeks (range 13, 52) and median HCV RNA was 6.2 log10 IU/mL (range 0.9, 7.7). SVR12 in the intention-to-treat and per-protocol populations was achieved in 90% (27/30) and 96% (27/28), respectively. There was one case of relapse, and there were two cases of nonvirological failure (death, n = 1; loss to follow-up, n = 1). No treatment-related serious adverse events were seen. CONCLUSIONS: Glecaprevir/pibrentasvir for 6 weeks was highly effective among people with acute and recent HCV infection, supporting further evaluation of shortened-duration pan-genotypic therapy in this setting.

Once-daily Doravirine in Human Immunodeficiency Virus Type 1-Infected, Antiretroviral-naive Adults: An Integrated Efficacy Analysis.

BACKGROUND: Doravirine (DOR) demonstrated noninferior efficacy to darunavir plus ritonavir (DRV+r) and efavirenz (EFV) in 2 ongoing phase 3 trials: DRIVE-FORWARD (NCT02275780) and DRIVE-AHEAD (NCT02403674). METHODS: This prespecified analysis pooled efficacy data through the first 48 weeks of DRIVE-FORWARD and DRIVE-AHEAD from the DOR groups (DOR/lamivudine [3TC]/tenofovir disoproxil fumarate [TDF] or DOR [100 mg daily] with emtricitabine [FTC]/TDF or abacavir [ABC]/3TC [n = 747]) compared with DRV+r (800/100 mg daily) with FTC/TDF or ABC/3TC (n = 383) or EFV/FTC/TDF (600/200/300 mg daily; n = 364). Efficacy assessments included the proportion of participants with human immunodeficiency virus type 1 (HIV-1) RNA <50 copies/mL and change in CD4+ T-cell count. RESULTS: At week 48, DOR demonstrated noninferior efficacy to DRV+r and EFV, with 84.1% of DOR-treated participants achieving HIV-1 RNA <50 copies/mL compared with 79.9% of the DRV+r and 80.8% of the EFV groups. Results were similar across demographic/prognostic subpopulations, including baseline plasma HIV-1 RNA, gender, race, and HIV-1 subtype. Mean increases from baseline in CD4+ T-cell count through 48 weeks were 195.5 cells/mm3 for DOR, 185.6 cells/mm3 for DRV+r, and 188.4 cells/mm3 for EFV/FTC/TDF. CONCLUSIONS: DOR, as a single entity (in combination with other antiretroviral agents) and as a fixed-dose combination (DOR/3TC/TDF), demonstrated noninferior efficacy to DRV+r and EFV as assessed by the proportion of HIV-1-infected, treatment-naive adults with HIV-1 RNA <50 copies/mL. CLINICAL TRIALS REGISTRATION: NCT02275780 and NCT02403674.