Search

Thomas Whitfield, Adele Torkington, Clare van Halsema North West Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK Abstract: Modern antiretroviral therapy has demonstrated effectiveness in preexposure prophylaxis (PrEP) and treatment of HIV infection. There is a demand for prevention and treatment regimens that could overcome challenges of improving adherence, toxicity, and dosing convenience. Cabotegravir is an integrase strand transfer inhibitor and an analog of dolutegravir. Unlike dolutegravir, cabotegravir has a long half-life and can be formulated into a long-acting nanosuspension for parenteral administration. Initial pharmokinetic studies in humans have demonstrated adequate drug levels with intramuscular (IM) administration at 4 weekly and 8 weekly intervals, with few interactions with commonly used concomitant medications. Preliminary animal PrEP studies have shown that IM cabotegravir can prevent simian/HIV acquisition from rectal, vaginal, and intravenous challenge. Currently, there are two ongoing Phase II studies assessing cabotegravir as a PrEP agent in humans: ÉCLAIR and HPTN077. Cabotegravir has been studied in combination with rilpivirine as long-acting IM maintenance therapy. The Long-Acting Antiretroviral Treatment Enabling study demonstrated that those switching to oral cabotegravir/rilpivirine once virologically suppressed were more likely to maintain suppression than those continuing standard efavirenz-based therapy (82% vs 71% at 24 weeks). Initial results of the Long-Acting Antiretroviral Treatment Enabling-2 study of parenteral regimens found that 12 weeks after randomization to parenteral or oral regimens, there was no difference in proportions virologically suppressed on cabotegravir/rilpivirine daily orally vs IM every 4 weeks or 8 weeks (91% vs 94% vs 95%). The injections were well tolerated as, although they caused injection site pain in most recipients, most participants reported satisfaction with parenteral therapy. Cabotegravir offers a new member of the integrase strand transfer inhibitor class with potential for alternative mode of delivery. We await Phase III studies to define its efficacy and real-world experience to learn which patient groups stand to benefit most from the novel mode of delivery of treatment and PrEP. Keywords: integrase inhibitor, long-acting antiretroviral therapy, preexposure prophylaxis

Cristina Fernandez,1 Clare L van Halsema1,21Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK; 2Faculty of Education, Liverpool School of Tropical Medicine, Liverpool, UKAbstract: Cabotegravir and rilpivirine long-acting injectable antiretroviral therapy for the treatment of HIV-1 infection brings promise of a new mode of delivery and potential solutions to some problems of oral therapy, but also new challenges and unanswered questions. Adding to the increasing body of evidence for newer two-drug combinations, phase II and phase III trial data to date demonstrate cabotegravir and rilpivirine combination injectable therapy to be non-inferior to selected oral triple-therapy alternatives. Most importantly, this therapy is reported to be acceptable to individuals taking the 4-weekly or 8-weekly injections, despite frequent injection-site reactions. Key outstanding questions include management of missed or delayed dosing, drug interactions and management of virological failure, as well as the efficacy of cabotegravir and rilpivirine in all HIV-1 subtypes. We describe clinical evidence to date and efficacy and challenges in selected populations, including women; those with prior virological failure; individuals with a history of difficulty adhering to oral therapy and individuals with co-infections. We await real-world data and longer-term evidence while moving forward to this new era of antiretroviral therapy.Keywords: antiretroviral therapy, integrase inhibitors, non-nucleoside reverse transcriptase inhibitors

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., (© 2021 British HIV Association.)

Sporadic, acute hepatitis E is increasingly common in the United Kingdom, associated with travel or locally acquired. A 45-year-old woman with well-controlled HIV presented with a widespread, polymorphic rash and transaminitis. Acute genotype 3 hepatitis E infection was confirmed and resolved without intervention. A review of the literature reveals a number of atypical presentations of acute autochthonous hepatitis E. Clinicians should consider testing for hepatitis E in the presence of nonspecific symptoms and deranged liver function tests.

Late HIV diagnosis is associated with significant mortality in people living with HIV (PLWH) and high numbers of missed opportunities (MO) for earlier testing have been identified. A pilot of a national late diagnosis review process (LDRP) was undertaken in 15 HIV services evaluating the feasibility of LDRP implementation, as a patient safety initiative. All newly diagnosed PLWH with CD4 counts <200 cells/mm 3 were included, and healthcare episodes within 5 years of presentation reviewed. Of 127 patients identified, 40 (31.5%) had MO and were more often white, UK-born and suffered more serious harm around diagnosis. Of these, four were designated serious incidents (undergoing root cause analysis) and eight were serious learning events. Engagement with services where MO occurred was challenging, however 75% of services found the LDRP sustainable. Widespread implementation of the LDRP should enable progress with training and policy changes within external services, enabling earlier HIV diagnosis and preventing deaths., (© Royal College of Physicians 2020. All rights reserved.)

Molecular diagnostic methods on lower respiratory specimens for Pneumocystis pneumonia (PCP) are recommended, but specimens can be difficult to obtain. This study examined the diagnostic use of PCP polymerase chain reaction (PCR) on oropharyngeal wash (OPW) and blood versus sputum (spontaneous and induced) to find faster, simpler, and less invasive diagnostic methods. We prospectively recruited consenting adults with symptoms consistent with PCP. Real-time PCR targeted the Pneumocystis mitochondrial large subunit ribosomal RNA gene, using the aforementioned specimens. Clinical data were collected from routine records. Forty-five participants provided 45 sputa, 31 OPW, and 41 blood samples. Median age was 39 years and 41 (91%) were male, with median CD4 count being 64 cells/μL. Sputum PCR was positive in 27/45 (60%) participants. Comparative sensitivity of OPW was 9/19 (47%, 95% confidence interval [CI] 23-71) and blood 12/24 (50%, 95% CI 29-71) participants, both with specificity 100%. Including only samples obtained ≤2 days after start of treatment, sensitivity of OPW was 80% (8/10, 95% CI 51-100), that of blood was 57% (8/14, 95% CI 29-86), and that of combined tests was 88% (14/16, 95% CI 70-100). In 14/16 individuals with PCP and specimens obtained ≤2 days after start of treatment, diagnosis was possible using nonrespiratory samples. Despite moderate sensitivity of individual tests, combined PCP PCR on early blood and OPW specimens had high sensitivity and could reduce the need for invasive procedures. There were no false-positive results on nonrespiratory samples. Sampling and laboratory methods use routine technology and so require few additional resources.

Raltegravir was the first licensed integrase inhibitor. Real-life experience is informative and complements trial data. We therefore evaluated raltegravir use in adults in a large HIV treatment centre. From pharmacy and departmental HIV database records, we identified all adults taking ≥1 dose of raltegravir from first availability to the end of November 2012. Data were collected using a standardised case report form. Two hundred and fifteen individuals provided 502 patient-years (median 2.6 years/person) of raltegravir use. Of 215 individuals, 166 (77%) were male, median age 43 years; 189 (88%) were antiretroviral therapy (ART)-experienced and 26 (12%) ART-naive, with median baseline CD4 counts of 324 and 54 cells/µL, respectively. Of ten individuals using once-daily raltegravir, four, with good adherence remained virologically suppressed after a median 28 months, four stopped against medical advice, one stopped to simplify and one failed virologically. In hepatitis co-infection, 35 individuals (92 patient-years) took raltegravir without evidence of hepatotoxicity. Six women started raltegravir during pregnancy for intensification (5/6) or switch for tolerability without complications. Of ten individuals stopping raltegravir after virological failure, 2/4 with successful sequencing showed resistance. Raltegravir appears safe and effective, without evidence of toxicity above that in published trials, including in pregnancy and co-infections. Once-daily dosing seems effective where adherence is good., (© The Author(s) 2015.)