Comorbidity in context: Part 2. Ethicolegal considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa.

The COVID-19 pandemic has brought discussions around the appropriate and fair rationing of scare resources to the forefront. This is of special importance in a country such as South Africa (SA), where scarce resources interface with high levels of need. A large proportion of the SA population has risk factors associated with worse COVID-19 outcomes. Many people are also potentially medically and socially vulnerable secondary to the high levels of infection with HIV and tuberculosis (TB) in the country. This is the second of two articles. The first examined the clinical evidence regarding the inclusion of HIV and TB as comorbidities relevant to intensive care unit (ICU) admission triage criteria. Given the fact that patients with HIV or TB may potentially be excluded from admission to an ICU on the basis of an assumption of lack of clinical suitability for critical care, in this article we explore the ethicolegal implications of limiting ICU access of persons living with HIV or TB. We argue that all allocation and rationing decisions must be in terms of SA law, which prohibits unfair discrimination. In addition, ethical decision-making demands accurate and evidence-based strategies for the fair distribution of limited resources. Rationing decisions and processes should be fair and based on visible and consistent criteria that can be subjected to objective scrutiny, with the ultimate aim of ensuring accountability, equity and fairness.

Comorbidity in context: Part 1. Medical considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa.

Infectious diseases pandemics have devastating health, social and economic consequences, especially in developing countries such as South Africa. Scarce medical resources must often be rationed effectively to contain the disease outbreak. In the case of COVID-19, even the best-resourced countries will have inadequate intensive care facilities for the large number of patients needing admission and ventilation. The scarcity of medical resources creates the need for national governments to establish admission criteria that are evidence-based and fair. Questions have been raised whether infection with HIV or tuberculosis (TB) may amplify the risk of adverse COVID-19 outcomes and therefore whether these conditions should be factored in when deciding on the rationing of intensive care facilities. In light of these questions, clinical evidence regarding inclusion of these infections as comorbidities relevant to intensive care unit admission triage criteria is investigated in the first of a two-part series of articles. There is currently no evidence to indicate that HIV or TB infection on their own predispose to an increased risk of infection with SARS-CoV-2 or worse outcomes for COVID-19. It is recommended that, as for other medical conditions, validated scoring systems for poor prognostic factors should be applied. A subsequent article examines the ethicolegal implications of limiting intensive care access of persons living with HIV or TB.

Consent for critical care research after death from COVID-19: Arguments for a waiver.

Pandemics challenge clinicians and scientists in many ways, especially when the virus is novel and disease expression becomes variable or unpredictable. Under such circumstances, research becomes critical to inform clinical care and protect future patients. Given that severely ill patients admitted to intensive care units are at high risk of mortality, establishing the cause of death at a histopathological level could prove invaluable in contributing to the understanding of COVID-19. Postmortem examination including autopsies would be optimal. However, in the context of high contagion and limited personal protective equipment, full autopsies are not being conducted in South Africa (SA). A compromise would require tissue biopsies and samples to be taken immediately after death to obtain diagnostic information, which could potentially guide care of future patients, or generate hypotheses for finding needed solutions. In the absence of an advance written directive (including a will or medical record) providing consent for postmortem research, proxy consent is the next best option. However, obtaining consent from distraught family members, under circumstances of legally mandated lockdown when strict infection control measures limit visitors in hospitals, is challenging. Their extreme vulnerability and emotional distress make full understanding of the rationale and consent process difficult either before or upon death of a family member. While it is morally distressing to convey a message of death telephonically, it is inhumane to request consent for urgent research in the same conversation. Careful balancing of the principles of autonomy, non-maleficence and justice becomes an ethical imperative. Under such circumstances, a waiver of consent, preferably followed by deferred proxy consent, granted by a research ethics committee in keeping with national ethics guidance and legislation, would fulfil the basic premise of care and research: first do no harm. This article examines the SA research ethics framework, guidance and legislation to justify support for a waiver of consent followed by deferred proxy consent, when possible, in urgent research after death to inform current and future care to contain the pandemic in the public interest.

HIV and haematopoiesis.

Human immunodeficiency virus (HIV) infection not only leads to a compromised immune system, but also disrupts normal haematopoiesis, resulting in the frequent manifestation of cytopenias (anaemia, thrombocytopenia and neutropenia). Although there is a definite association between the severity of cytopenia and HIV disease stage, this relationship is not always linear. For example, cytopenias such as thrombocytopenia may occur during early stages of infection. The aetiology of these haematological abnormalities is complex and multifactorial, including drug-induced impaired haematopoiesis, bone marrow suppression due to infiltration of infectious agents or malignant cells, HIV-induced impaired haematopoiesis, and several other factors. In this review, we describe the frequencies of anaemia, thrombocytopenia and neutropenia reported for HIV-infected, treatment-naïve cohorts studied in eastern and southern sub-Saharan African countries. We present a rational approach for the use of diagnostic tests during the workup of HIV-infected patients presenting with cytopenia, and discuss how HIV impacts on haematopoietic stem/progenitor cells (HSPCs) resulting in impaired haematopoiesis. Finally, we describe the direct and indirect effects of HIV on HSPCs which result in defective haematopoiesis leading to cytopenias.

HIV as a Cause of Immune Activation and Immunosenescence.

Systemic immune activation has emerged as an essential component of the immunopathogenesis of HIV. It not only leads to faster disease progression, but also to accelerated decline of overall immune competence. HIV-associated immune activation is characterized by an increase in proinflammatory mediators, dysfunctional T regulatory cells, and a pattern of T-cell-senescent phenotypes similar to those seen in the elderly. These changes predispose HIV-infected persons to comorbid conditions that have been linked to immunosenescence and inflamm-ageing, such as atherosclerosis and cardiovascular disease, neurodegeneration, and cancer. In the antiretroviral treatment era, development of such non-AIDS-defining, age-related comorbidities is a major cause of morbidity and mortality. Treatment strategies aimed at curtailing persistent immune activation and inflammation may help prevent the development of these conditions. At present, the most effective strategy appears to be early antiretroviral treatment initiation. No other treatment interventions have been found effective in large-scale clinical trials, and no adjunctive treatment is currently recommended in international HIV treatment guidelines. This article reviews the role of systemic immune activation in the immunopathogenesis of HIV infection, its causes and the clinical implications linked to immunosenescence in adults, and the therapeutic interventions that have been investigated.

HIV drug resistance levels in adults failing first-line antiretroviral therapy in an urban and a rural setting in South Africa.

OBJECTIVES: Urban and rural HIV treatment programmes face different challenges in the long-term management of patients. There are few studies comparing drug resistance profiles in patients accessing treatment through these programmes. The aim of this study was to perform such a comparison. METHODS: HIV drug resistance data and associated treatment and monitoring information for adult patients failing first-line therapy in an urban and a rural programme were collected. Data were curated and managed in SATuRN RegaDB before statistical analysis using Microsoft Excel 2013 and stata Ver14, in which clinical parameters, resistance profiles and predicted treatment responses were compared. RESULTS: Data for 595 patients were analysed: 492 patients from a rural setting and 103 patients from an urban setting. The urban group had lower CD4 counts at treatment initiation than the rural group (98 vs. 126 cells/µL, respectively; P = 0.05), had more viral load measurements performed per year (median 3 vs. 1.4, respectively; P < 0.01) and were more likely to have no drug resistance mutations detected (35.9% vs. 11.2%, respectively; P < 0.01). Patients in the rural group were more likely to have been on first-line treatment for a longer period, to have failed for longer, and to have thymidine analogue mutations. Notwithstanding these differences, the two groups had comparable predicted responses to the standard second-line regimen, based on the genotypic susceptibility score. Mutations accumulated in a sigmoidal fashion over failure duration. CONCLUSIONS: The frequency and patterns of drug resistance, as well the intensity of virological monitoring, in adults with first-line therapy failure differed between the urban and rural sites. Despite these differences, based on the genotypic susceptibility scores, the majority of patients across the two sites would be expected to respond well to the standard second-line regimen.

Blood-borne infections in healthcare workers in South Africa.

The risks associated with infection of healthcare workers and students with blood-borne pathogens, specifically HIV, hepatitis B virus and hepatitis C virus, are often neglected. South Africa (SA) currently has no official policies or guidelines in place for the prevention and management of these infections. This article reviews the available data and international guidelines with regard to infected healthcare practitioners and makes minimum recommendations for the SA setting.

Missed opportunities for accessing HIV care among Tshwane tuberculosis patients under different models of care.

OBJECTIVE: To compare access to human immunodeficiency virus (HIV) care for tuberculosis (TB) patients in settings with antiretroviral treatment (ART) and TB care under one roof ('semi-integrated sites') and in settings with geographically separately rendered care in Tshwane, South Africa. METHODS: Historical cohort study of patients registered with TB at 46 TB treatment points, with follow-up until the end of anti-tuberculosis treatment. ART initiation for HIV-positive TB patients was established through linkage of TB register patient identifiers to the electronic ART register. Data analysis entailed univariate and multivariate competing risk analysis. RESULTS: The records of 636 and 1297 patients for semi-integrated and separate facilities, respectively, were reviewed. Cotrimoxazole prophylactic therapy and recording of CD4 count were lower in semi-integrated than in separate facilities, but the reverse was true for referral to HIV-related care. A higher percentage of patients started ART in the semi-integrated than in the separate facilities (70.5% vs. 44.6%, P < 0.001). In competing risk analysis (with death and lost to follow-up as competing risks), attending a semi-integrated facility (sub-hazard ratio [SHR] 2.49, 95%CI 1.06-5.88) and TB case load > 401 (SHR 1.45, 95%CI 1.04-2.03) were associated with increased ART initiation. CONCLUSIONS: ART and TB treatment under one roof appears to facilitate ART initiation for HIV-positive TB patients.