A national audit of the management of HIV-2 in adults in the UK.

BACKGROUND: HIV-2 is rare in the UK. Many UK centres therefore only treat small numbers of people and there are few clinical trials to guide treatment. The British HIV Association (BHIVA) 2010 guidelines for management of HIV-2 formed the basis for this national audit, which aims to describe current practice and adherence to guidelines. METHODS: All UK centres providing HIV care were contacted via the BHIVA "Members Matters" newsletter, and asked to submit anonymised, retrospective data for individuals living with HIV-2 accessing care at their service. RESULTS: Thirty-five sites responded and data were analysed for 167 individuals. Nearly half of individuals accessed care at one of four large London centres (77/167, 46%).Most people living with HIV-2 have taken antiretroviral therapy (ART) (132/167, 79%). The most common reasons for initiating treatment were clinical disease (34/89, 38%) and pregnancy (11/89, 12%). Most treatment-naïve individuals were initiated on a protease inhibitor based regimen (70/89, 79%). The use of integrase strand transfer inhibitor based regimens has increased over time.A significant minority of patients did not have baseline drug resistance testing performed, despite having a detectable viral load (15/52, 29%). Virological failure occurred in a minority of individuals (21/132, 16%); the most common drug regimen change in this context was the addition of an integrase strand transfer inhibitor (12/26 regimen changes, 46%). CONCLUSIONS: Most individuals living with HIV-2 were managed according to national guidance, with key areas for improvement including the choice of ART, drug resistance testing and the management of virological failure. It is hoped that this national audit, performed in conjunction with the updated 2021 BHIVA guidelines will improve the care of individuals living with HIV-2 in the UK.

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.

Widespread rash as initial presentation of acute hepatitis E in a woman with well-controlled HIV.

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.

Incidence of and risk factors for tuberculosis among people with HIV on antiretroviral therapy in the United Kingdom.

OBJECTIVE: The United Kingdom has a low tuberculosis incidence and earlier combination antiretroviral therapy (cART) is expected to have reduced incidence among people with HIV. Epidemiological patterns and risk factors for active tuberculosis were analysed over a 20-year period among people accessing HIV care at sites participating in the UK CHIC observational study. DESIGN: Cohort analysis. METHODS: Data were included for individuals over 15 years old attending for HIV care between 1996 and 2017 inclusive, with at least 3 months follow-up recorded. Incidence rates of new tuberculosis events were calculated and stratified by ethnicity (white/Black/other) as a proxy for tuberculosis exposure. Poisson regression models were used to determine the associations of calendar year, ethnicity and other potential risk factors after cART initiation. RESULTS: Fifty-eight thousand seven hundred and seventy-six participants (26.3% women; 54.5% white, 32.0% Black, 13.5% other/unknown ethnicity; median (interquartile range) age 34 (29-42) years) were followed for 546 617 person-years. Seven hundred and four were treated for active tuberculosis [rate 1.3; 95% confidence interval (CI) 1.2-1.4/1000 person-years). Tuberculosis incidence decreased from 1.3 (1.2-1.5) to 0.6 (0.4-0.9)/1000 person-years from pre-2004 to 2011-2017. The decline among people of Black ethnicity was less steep than among those of white/other ethnicities, with incidence remaining high among Black participants in the latest period [2.1 (1.4-3.1)/1000 person-years]. Two hundred and eighty-three participants [191 (67%) Black African] had tuberculosis with viral load less than 50 copies/ml. CONCLUSION: Despite the known protective effect of cART against tuberculosis, a continuing disproportionately high incidence is seen among Black African people. Results support further interventions to prevent tuberculosis in this group.

Evaluating a pilot process for reviewing late HIV diagnoses in England and Wales.

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/mm3 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.

Evaluating cabotegravir/rilpivirine long-acting, injectable in the treatment of HIV infection: emerging data and therapeutic potential.

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.

Profile of cabotegravir and its potential in the treatment and prevention of HIV-1 infection: evidence to date.

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.

Short Communication: Diagnosis of Pneumocystis jirovecii Pneumonia by Detection of DNA in Blood and Oropharyngeal Wash, Compared with Sputum.

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.

Five years' real-life experience with raltegravir in a large HIV centre.

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.

Brief Report: The Effect of Antiretroviral Therapy and CD4 Count on Markers of Infectiousness in HIV-Associated Tuberculosis.

Clinical features of tuberculosis influence infectiousness. This cross-sectional study examined the effect of combination antiretroviral therapy (cART) and CD4 on sputum smear-positivity (SS+) and pulmonary cavitation among 1589 (1185/1589 HIV-positive) miners in South Africa. Proportions SS+ varied nonlinearly by CD4 with greatest proportions SS+ (55.3%) in the lowest stratum (<100 cells/µL). Adjusted prevalence ratio for SS+; on vs. off cART was 0.90 (95% confidence interval: 0.73 to 1.11). Proportions with cavitation varied linearly with CD4, with no independent cART effect (adjusted prevalence ratio 1.17; 95% confidence interval: 0.80 to 1.71). cART did not independently affect SS+ or cavitation but may increase infectiousness through CD4 recovery.

Raised Venous Lactate and Markers of Intestinal Translocation Are Associated With Mortality Among In-Patients With HIV-Associated TB in Rural South Africa.

INTRODUCTION: Case fatality among in-patients with HIV-associated tuberculosis (HIV-TB) in Africa is high. We investigated the factors associated with mortality in a rural South African hospital. METHODS: This was a prospective observational study of HIV-TB in-patients, with death by 8 weeks the endpoint. RESULTS: Of 99 patients (median CD4 count 72 cells/mm³), 32 (32%) died after median 8-day TB treatment. TB was diagnosed microbiologically in 75/99 and clinico-radiologically in 24, with no mortality difference between these groups [31% versus 38% (P = 0.53)]. Median venous lactate was 5.5 mmol/L (interquartile range 3.9-6.2) in those who died and 3.1 mmol/L (interquartile range 2.2-4.1) in survivors (P < 0.001). In multivariable analysis, lactate ≥4 mmol/L [adjusted odds ratio (aOR) 9.8, 95% confidence interval (CI): 3.0 to 32.2], Glasgow Coma Score <15 (aOR 6.6, 95% CI: 1.5 to 29.6), CD4 count <50 cells per cubic millimeter (aOR 5.5, 95% CI: 1.6 to 18.5), and age ≥50 (aOR 7.7, 95% CI: 1.2 to 46.9) independently predicted death. In a nested case-control study, comparing those who died versus CD4-matched survivors, median plasma lipopolysaccharide concentrations were 93 and 57 pg/mL (P = 0.026) and intestinal fatty acid-binding protein, 132 and 0 pg/mL (P = 0.002). CONCLUSIONS: Mortality was high and predicted by elevated lactate, likely reflecting a sepsis-syndrome secondary to TB or bacterial coinfection with intestinal barrier dysfunction appearing to contribute.

Clinical Relevance of Nontuberculous Mycobacteria Isolated from Sputum in a Gold Mining Workforce in South Africa: An Observational, Clinical Study.

BACKGROUND: The clinical relevance of nontuberculous mycobacteria (NTM), detected by liquid more than solid culture in sputum specimens from a South African mining workforce, is uncertain. We aimed to describe the current spectrum and relevance of NTM in this population. METHODS: An observational study including individuals with sputum NTM isolates, recruited at workforce tuberculosis screening and routine clinics. Symptom questionnaires were administered at the time of sputum collection and clinical records and chest radiographs reviewed retrospectively. RESULTS: Of 232 individuals included (228 (98%) male, median age 44 years), M. gordonae (60 individuals), M. kansasii (50), and M. avium complex (MAC: 38) were the commonest species. Of 38 MAC isolates, only 2 (5.3%) were from smear-positive sputum specimens and 30/38 grew in liquid but not solid culture. MAC was especially prevalent among symptomatic, HIV-positive individuals. HIV prevalence was high: 57/74 (77%) among those tested. No differences were found in probability of death or medical separation by NTM species. CONCLUSIONS: M. gordonae, M. kansasii, and MAC were the commonest NTM among miners with suspected tuberculosis, with most MAC from smear-negative specimens in liquid culture only. HIV testing and identification of key pathogenic NTM in this setting are essential to ensure optimal treatment.

Adverse events with isoniazid preventive therapy: experience from a large trial.

OBJECTIVES: We describe isoniazid-related adverse events in Thibela TB, a cluster-randomized study of community-wide isoniazid preventive therapy (IPT) among gold miners in South Africa, where HIV prevalence is estimated at 30%. METHODS: Consenting employees were screened prior to IPT for active tuberculosis and increased risk of isoniazid toxicity using a questionnaire and chest radiograph. Study-defined IPT-related adverse events were sought at each study visit: liver function tests were only performed if clinically indicated. In a substudy, we questioned consecutive participants at baseline and months 1, 3, and 6 concerning minor IPT-related adverse events. RESULTS: Among 24,221 participants (95.2% men, median age 40 years), 130 individuals had 132 study-defined adverse events (0.54%); 61 (0.25%) possible hypersensitivity rash, 50 (0.21%) peripheral neuropathy, 17 (0.07%) clinical hepatotoxicity, and four (0.02%) convulsions. Four events (two hepatotoxicity, one fatal, and two convulsions) fulfilled criteria for seriousness. Clinical hepatotoxicity was associated with consumption of alcohol [0.11 vs. 0.03% if no alcohol consumed, odds ratio 3.9 (95% confidence interval 1.2-12.1)], but not with sex, age, weight, or concurrent antiretroviral therapy. In the substudy, 324 of 498 (65.1%) participants reported better health since starting IPT; 180 of 324 (55.6%) reported that this was because of increased appetite. The frequency of specific minor symptoms was low among those taking IPT, and all symptoms were reported less often than at baseline. CONCLUSION: The risk of adverse events, particularly hepatotoxicity, was very low in this population. Our data suggest that clinical criteria can safely be used for screening prior to and monitoring during IPT.

Tuberculosis outcomes and drug susceptibility in individuals exposed to isoniazid preventive therapy in a high HIV prevalence setting.

OBJECTIVE: Despite World Health Organization recommendations, concerns about promoting resistance have impeded implementation of isoniazid preventive therapy (IPT) for tuberculosis (TB). We describe characteristics of TB in individuals previously exposed to IPT as part of 'Thibela TB', a cluster-randomized trial of community-wide IPT in gold miners in South Africa. DESIGN: Case series including participants who were dispensed IPT, attended at least one follow-up visit and were subsequently treated for TB. METHODS: TB episodes were detected through surveillance and through follow-up if IPT was stopped early. Drug susceptibility data were compared with TB episodes detected through surveillance in control clusters (where IPT use was minimal) and a laboratory substudy of mycobacterial sputum culture from TB suspects in control clusters. RESULTS: Among 126 eligible individuals (125 men, median age 43 years), median time from starting IPT to TB treatment was 316 days (interquartile range 174-491). Ninety-four of the 126 (75%) were first episodes. Eighty-nine of 103 (86%) tested HIV-infected, with the median CD4 cell count of 196 cells/microl (n = 51). Sixty-four of 108 (59%) with known treatment outcomes were cured or completed treatment. Among 71 isolates with drug susceptibility results available, 12.1% [95% confidence interval (CI) 5.0-23.3] and 7.7% (95% CI 0.2-36.0) from first and retreatment episodes, respectively, had isoniazid resistance, compared with 6.0% (95% CI 3.1-10.2) and 18.7% (95% CI 10.6-29.3) in control clusters and 11.8% (95% CI 8.2-16.3) among first TB episodes in the laboratory substudy. CONCLUSION: TB after recent IPT has prevalence of drug resistance similar to background and treatment outcomes typical of this setting. These data support wider implementation of IPT.