A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis (The LASER-TBM Trial) (preprint)

ABSTRACT Background Drug regimens which include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in Tuberculous Meningitis (TBM). Safety data on their use in combination and in the context of HIV is needed to inform clinical trial design. Methods We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. Results 52 participants were randomised. 59% had mild disease (MRC Grade 1) vs 39% (Grade 2) vs 2% (Grade 3). 33% of participants had microbiologically-confirmed TBM; vs 41% ‘possible’ or 25% ‘probable’. AESI or death occurred in 10/16 (arm 3) vs 4/14 (arm 2) vs 6/20 (arm 1) ( p=0 . 083 ). The cumulative proportion of AESI or death (Kaplan-Meier method) demonstrated worse outcomes in arm 3 vs arm 1 ( p=0 . 04 ), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (Modified Rankin Scale) at day 56 between the three arms. Conclusions High-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly aspirin, is outweighed by mortality or morbidity benefit. SUMMARY In this phase 2a randomised control trial we demonstrate that high-doserifampicin and adjunctive linezolid is safe in adult HIV-associated tuberculous meningitis. Larger studies are required to evaluate potential toxicity with aspirin, in relation to benefit on morbidity and mortality.

Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa (preprint)

ObjectiveWe aimed to compare clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. MethodsWe included public sector patients aged [≥]20 years with laboratory-confirmed COVID-19 between 1-21 May 2022 (BA.4/BA.5 wave) and equivalent prior wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination and prior infection. ResultsAmong 3,793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio [aHR] 1.12; 95% confidence interval [CI] 0.93; 1.34). Both Omicron waves had lower risk of severe outcomes than previous waves. Prior infection (aHR 0.29, 95% CI 0.24; 0.36) and vaccination (aHR 0.17; 95% CI 0.07; 0.40 for boosted vs. no vaccine) were protective. ConclusionDisease severity was similar amongst diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to prior infection and vaccination, both of which were strongly protective.

Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa (preprint)

Objectives: We aimed to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection, and whether protection against severe disease conferred by prior infection and/or vaccination was maintained. Methods: In this cohort study, we included public sector patients aged [≥]20 years with a laboratory confirmed COVID-19 diagnosis between 14 November-11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalization or death and any hospitalization or death (all [≤]14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. Results: We included 5,144 patients from wave four and 11,609 from prior waves. Risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted Hazard Ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR:0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58). Conclusions: In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for an approximately 25% reduced risk of severe hospitalization or death compared to Delta.

Change in profile of COVID-19 deaths in the Western Cape during the fourth wave (preprint)

Fewer COVID-19 deaths have been reported in this fourth wave, with clinicians reporting less admissions due to severe COVID-19 pneumonia when compared to previous waves. We therefore aimed to rapidly compare the profile of deaths in wave 4 with wave 3 using routinely collected data on admissions to public sector hospitals in the Western Cape province of South Africa. Findings show that there have been fewer COVID-19 pneumonia deaths in the Omicron-driven fourth wave compared to the third wave, which confirms anecdotal reports and lower bulk oxygen consumption by hospitals in the province.

COVID-19 In-Hospital Mortality in South Africa: The Intersection of Communicable and Non-Communicable Chronic Diseases in a High HIV Prevalence Setting (preprint)

Background: The interaction between COVID-19, non-communicable diseases, and chronic infectious diseases such as HIV and tuberculosis (TB) are unclear, particularly in low- and middle-income countries in Africa. We investigated this interaction using a nationally representative hospital surveillance system for laboratory-confirmed COVID-19 hospital admissions in South Africa.Methods: Using DATCOV data, we describe the demographic characteristics, clinical features, and in-hospital mortality among individuals admitted to public and private hospitals with COVID-19 during 5 March to 11 August 2020. Multivariable logistic regression models were used to assess the role of HIV-status and underlying comorbidities on in-hospital COVID-19 mortality.Findings: Hospital admissions peaked at 1,560 admissions per day, in late July. Among the 41,877 individuals admitted with laboratory-confirmed COVID-19, 7,662 (18.3%) died. Comorbidities were documented in 27,555 (65.8%) individuals, most commonly observed were hypertension (36.8%), diabetes (29.6%), obesity (19.7%), and HIV (8.7%); TB was reported in 0.7% of individuals. Increased risk of in-hospital mortality was associated with HIV and TB, as well as other described risk factors for COVID-19, such as increasing age, male sex, non-White race (Black, mixed and Indian race), chronic underlying conditions particularly hypertension, diabetes and obesity. In addition, HIV-infected individuals with immunosuppression had increased risk of mortality (adjusted odds ratio 2.2; 95% confidence interval 1.6-3.1). Among HIV-infected individuals, the prevalence of other comorbidities associated with severe COVID-19 outcomes was 39.9%. The effect of multiple comorbidities on mortality was similar in HIV-infected and -uninfected individuals.Interpretation: These data provide a better understanding of the interaction of non-communicable diseases, chronic infectious diseases like HIV and TB and COVID-19. Increasing age and presence of chronic underlying comorbidities (particularly hypertension and diabetes) are important additional factors associated with COVID-19 mortality in a middle-income African setting and are common among HIV-infected individuals. HIV- and TB-infected individuals, particularly those with additional comorbidities, would benefit from COVID-19 prevention programmes, as well as early referral and treatment.Funding Statement: DATCOV is funded by the National Institute for Communicable Diseases (NICD) and the South African National Government. No additional funding was obtained towards the completion of this analysis and the development of this manuscript.Declaration of Interests: The authors declare that there are no conflicts of interest.Ethics Approval Statement: The Human Research Ethics Committee (Medical), University of the Witwatersrand, approved the project protocol as part of a national surveillance program (M160667). This activity was reviewed by the U.S. Centers for Disease Control and Prevention (CDC) and was conducted consistent with applicable federal law and CDC policy. All personal identifying information was de-linked for our analysis and stored in a secure server.

COVID-19 in-hospital mortality in South Africa: the intersection of communicable and non-communicable chronic diseases in a high HIV prevalence setting (preprint)

Background: The interaction between COVID-19, non-communicable diseases, and chronic infectious diseases such as HIV and tuberculosis (TB) are unclear, particularly in low- and middle-income countries (LMIC) in Africa. We investigated this interaction using a nationally representative hospital surveillance system in South Africa. Methods: A national surveillance system for laboratory-confirmed COVID-19 hospital admissions (DATCOV) was established. Using DATCOV data, we describe the demographic characteristics, clinical features, and in-hospital mortality among individuals admitted to public and private hospitals with COVID-19 during 5 March to 11 August 2020. Multivariable logistic regression models were used to compare individuals who were HIV-infected and HIV-uninfected and determine the factors associated with in-hospital mortality. Findings: Hospital admissions peaked at 1,560 admissions per day, in late July. Among the 41,877 individuals admitted with laboratory-confirmed COVID-19, 7,662 (18.3%) died. Comorbidities were documented in 27,555 (65.8%) individuals, most commonly observed were hypertension (36.8%), diabetes (29.6%), obesity (19.7%), and HIV (8.7%); TB was reported in 0.7% of individuals. Increased risk of in-hospital mortality was associated with HIV and TB, as well as other described risk factors for COVID-19, such as increasing age, male sex, non-White race (Black, mixed and Indian race), chronic underlying conditions particularly hypertension, diabetes and obesity. In addition, HIV-infected individuals with immunosuppression had increased risk of mortality (adjusted odds ratio 2.2; 95% confidence interval 1.6-3.1). Among HIV-infected individuals, the prevalence of other comorbidities associated with severe COVID-19 outcomes was 39.9%. The effect of multiple comorbidities on mortality was similar in HIV-infected and -uninfected individuals. Interpretation: These data provide a better understanding of the interaction of non-communicable diseases, chronic infectious diseases like HIV and TB and COVID-19. Increasing age and presence of chronic underlying comorbidities (particularly hypertension and diabetes) are important additional factors associated with COVID-19 mortality in a middle-income African setting and are common among HIV-infected individuals. HIV- and TB-infected individuals, particularly those with additional comorbidities, would benefit from COVID-19 prevention and treatment programmes.