The impact of non-disclosure of HIV status and antiretroviral therapy on HIV recency testing and incidence algorithms.

BACKGROUND AND OBJECTIVES: Accurate HIV incidence estimates among blood donors are necessary to assess the effectiveness of programs aimed at limiting transfusion-transmitted HIV. We assessed the impact of undisclosed HIV status and antiretroviral (ARV) use on HIV recency and incidence estimates using increasingly comprehensive recent infection testing algorithms. MATERIALS AND METHODS: Using 2017 donation data from first-time and lapsed donors, we populated four HIV recency algorithms: (1) serology and limiting-antigen avidity testing, (2) with individual donation nucleic amplification testing (ID-NAT) added to Algorithm 1, (3) with viral load added to Algorithm 2 and (4) with ARV testing added to Algorithm 3. Algorithm-specific mean durations of recent infection (MDRI) and false recency rates (FRR) were calculated and used to derive and compare incidence estimates. RESULTS: Compared with Algorithm 4, progressive algorithms misclassified fewer donors as recent: Algorithm 1: 61 (12.1%); Algorithm 2: 14 (2.8%) and Algorithm 3: 3 (0.6%). Algorithm-specific MDRI and FRR values resulted in marginally lower incidence estimates: Algorithm 1: 0.19% per annum (p.a.) (95% confidence interval [CI]: 0.13%-0.26%); Algorithm 2: 0.18% p.a. (95% CI: 0.13%-0.22%); Algorithm 3: 0.17% p.a. (95% CI: 0.13%-0.22%) and Algorithm 4: 0.17% p.a. (95% CI: 0.13%-0.21%). CONCLUSION: We confirmed significant misclassification of recent HIV cases when not including viral load and ARV testing. Context-specific MDRI and FRR resulted in progressively lower incidence estimates but did not fully account for the context-specific variability in incidence modelling. The inclusion of ARV testing, in addition to viral load and ID-NAT testing, did not have a significant impact on incidence estimates.

Motivations for blood donation by HIV-positive individuals on antiretrovirals in South Africa: A qualitative study.

OBJECTIVES: We performed a mixed-methods study to explore the motivations associated with blood donation by donors with known, but undisclosed HIV-positive status and ARV use (HIV+/ARV+), seeking potential strategies to reduce such donations and mitigate risk for blood recipients. Here, we report predominantly the qualitative component. BACKGROUND: A safe and sustainable blood supply is dependent in part, on effective pre-donation donor assessment. We previously described failure by HIV+/ARV+ blood donors to disclose their status. Such donations may lead to transfusion-transmitted HIV. METHODS: The social ecological model provided the conceptual framework for this study. Previously identified HIV+/ARV+ donors were invited to complete a survey (including a validated stigma scale) and qualitative interview, which underwent inductive and deductive thematic analysis. RESULTS: We uncovered two primary motivational paths to HIV+/ARV+ blood donations: privacy and altruism. The latter included a motivation not previously reported in the literature: donating specifically for other people living with HIV (PLWH). The other primary factor was a lack of privacy. These accounts often included donors encountering donation opportunities when accompanied by people to whom they had not and did not plan to disclose their HIV status. Most were highly confident their donations would be identified as HIV-positive and discarded. CONCLUSION: We demonstrated a complex interaction between individual, social, cultural, and structural/policy factors in blood donations by PLWH who take ARV. Recommendations to limit HIV + ARV+ donations include: (1) Targeted communication strategies to increase knowledge among PLWH of their deferral from blood donation-without increasing stigma, and (2) development of procedures to assist those who feel unable to opt-out of donation due to privacy concerns.

Undisclosed HIV status and antiretroviral therapy use among South African blood donors.

BACKGROUND: Undisclosed antiretroviral drug (ARV) use among blood donors who tested HIV antibody positive, but RNA negative, was previously described by our group. Undisclosed ARV use represents a risk to blood transfusion safety. We assessed the prevalence of and associations with undisclosed ARV use among HIV-positive donors who donated during 2017. STUDY DESIGN AND METHODS: South African National Blood Service (SANBS) blood donors are screened by self-administered questionnaire, semi-structured interview, and individual donation nucleic acid amplification testing for HIV. Stored samples from HIV-positive donations were tested for ARV and characterized as recent/longstanding using lag avidity testing. RESULTS: Of the 1462 HIV-positive donations in 2017, 1250 had plasma availability for testing of which 122 (9.8%) tested positive for ARV. Undisclosed ARV use did not differ by gender (p = .205) or ethnicity (p = .505) but did differ by age category (p < .0001), donor (p < .0001), clinic type (p = .012), home province (p = .01), and recency (p < .0001). Multivariable logistic regression found older age (adjusted odds ratio [aOR] 3.73, 95% confidence interval [CI] 1.98-7.04 for donors >40 compared with those <21), first-time donation (aOR 5.24; 95% CI 2.48-11.11), and donation in a high HIV-prevalence province (aOR 9.10; 95% CI 2.70-30.72) compared with Northern Rural provinces to be independently associated with undisclosed ARV use. DISCUSSION: Almost 1 in 10 HIV-positive blood donors neglected to disclose their HIV status and ARV use. Demographic characteristics of donors with undisclosed ARV use differed from those noted in other study. Underlying motivations for nondisclosure among blood donors remain unclear and may differ from those in other populations with significant undisclosed ARV use.

Global survey of transfusion medicine curricula in medical schools: Challenges and opportunities.

BACKGROUND: Physician's knowledge in transfusion medicine (TM) is critical for patient safety. Therefore, ensuring that medical schools provide adequate education in TM is important. The aim of this study was to assess the status of TM education at a global level. STUDY DESIGN AND METHODS: A comprehensive anonymous survey to assess TM education in existing medical school curricula was developed. The survey was distributed to deans and educational leads of medical schools in a range of low-, medium-, high-, and very high-human development index (HDI) countries. It included 20 questions designed to assess specific domains including structure of TM curriculum and teaching faculty. RESULTS: The response rate was 53%. The majority of responding schools from very-high-HDI countries offered a 6-year curriculum after high school or a 4-year curriculum after college education, whereas most schools from medium-HDI countries offered a 5-year medical curriculum. A formal teaching program was available in only 42% of these schools in contrast to 94% of medical schools from very high-HDI. Overall, 25% of all medical schools did not offer structured TM teaching. When offered, most TM teaching was mandatory (95%) and integrated within the third and fourth year of medical school. Formal assessment of TM knowledge was done in 72% of all responding medical schools. More than half of the deans considered the TM education in their medical schools as inadequate. CONCLUSION: Despite its limitations, the current survey highlights significant gaps and opportunities of TM education at a global scale.

Correction to: Diagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis.

After publication of the original article [1], we were notified that there is a mistake in the article note.

Diagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis.

BACKGROUND: The WHO recently recommended the new Xpert MTB/RIF Ultra assay (Ultra) instead of the Xpert MTB/RIF assay because Ultra has improved sensitivity. We report the diagnostic accuracy of Ultra for tuberculous adenitis in a tuberculosis and HIV endemic setting. METHODS: We obtained fine-needle aspirates (FNA) and lymph node tissue by core-needle biopsy in adult patients with peripheral lymphadenopathy of >20 mm. Ultra and mycobacterial culture were performed on FNA and tissue specimens, with histological examination of tissue specimens. We assessed the diagnostic accuracy of Ultra against a composite reference standard of 'definite tuberculosis' (microbiological criteria) or 'probable tuberculosis' (histological and clinical criteria). RESULTS: We prospectively evaluated 99 participants of whom 50 were HIV positive: 21 had 'definite tuberculosis', 15 'probable tuberculosis' and 63 did not have tuberculosis (of whom 38% had lymphoma and 19% disseminated malignancy). Using the composite reference standard the Ultra sensitivity on FNA was 70% (95% CI 51-85; 21 of 30), and on tissue was 67% (45-84; 16/24) these were far superior to the detection of acid-fast bacilli on an FNA (26%; 7/27); AFB on tissue (33%; 8/24); or tissue culture (39%; 9/23). The detection of granulomas on histology had high senstivity (83%) but the lowest specficity. When compared with culture the Ultra on FNA had a sensitvity of 78% (40-97; 7/9) and tissue 90% (55-100; 9/10). CONCLUSIONS: Ultra performed on FNA or tissue of a lymph node had good sensitivity and high specificity. Ultra had a higher yield than culture and has the advantage of being a rapid test. Ultra on FNA would be an appropriate initial investigation for lymphadenopathy in tuberculosis endemic areas followed by a core biopsy for histopathology with a repeat Ultra on tissue if granulomas are present.

The determinants and impact of diagnostic delay in lymphoma in a TB and HIV endemic setting.

BACKGROUND: Little is known about the pathway to diagnosis of lymphoma in Sub-Saharan Africa, despite the increased risk of lymphoma in people living with HIV (PLHIV). The challenges of diagnosis in this setting include diagnostic confusion with extrapulmonary tuberculosis (EPTB), which commonly causes lymphadenopathy in PLHIV. METHODS: We analysed the time to diagnosis and treatment in patients using predetermined time intervals. Univariate and multivariable analyses were performed to determine the relationship between patient and disease-specific variables with delays to diagnosis. We were particularly interested in the impact of HIV, empiric tuberculosis therapy and fine-needle aspirate for cytology (FNAC) in contributing to delay. RESULTS: Patients (n = 163), 29% HIV-infected, waited a median of 4 weeks before seeking medical attention. It took a median of 7 weeks for the diagnosis of lymphoma to be made from the time the patient sought medical attention, termed the healthcare practitioner interval. In multivariable logistic regression analysis, diagnostic delay > 6 weeks was associated with late-stage disease (OR 2.3, 95% CI 1.1-5.2) and Hodgkin lymphoma (HL) (OR 3.0, 95% CI 1.1-8.0). HIV status was not associated with diagnostic delay (OR 0.9, 95% CI 0.3-2.2). The median time to diagnosis was a median of 4 weeks longer for patients on tuberculous (TB) therapy (n = 16, p = 0.28) and patients who underwent an FNAC (n = 63, p = 0.04). Where FNAC was performed, it was diagnostic for lymphoma in only 11%. Diagnostic delay was not associated with overall survival. CONCLUSIONS: Time-to-diagnosis of lymphoma in South Africa was similar to that reported from high-income countries and shows significant periods of delay between the onset of symptoms to diagnosis and treatment. The longest period of delay was in the health practitioner interval. Education regarding the significance of lymphadenopathy for both patients and health care practitioners and appropriate investigative steps preferably by best-practice algorithms specific to TB-endemic areas are needed to shorten the time-to-diagnosis of lymphoma.

Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd.

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

Determining the outcomes for clinicians completing a postgraduate diploma in transfusion medicine.

BACKGROUND: Much is known about outcomes and content of training programs in blood banking, but only a limited amount of formal research has been done on the outcomes required for a postgraduate training program aimed at medical doctors working in clinical practice. STUDY DESIGN AND METHODS: A formal qualitative and semi-quantitative research approach was followed to determine and test the factors considered important in determining the outcomes for clinicians completing a postgraduate diploma in transfusion medicine, and consisted of a literature survey, followed by semi-structured interviews and a Delphi survey. RESULTS: After a series of semi-structured interviews, based on an extensive literature survey, 42 factors were identified. These factors were categorized into eight groups and tested in a Delphi survey to determine which of these would be essential outcomes of a postgraduate training program in transfusion medicine. After three rounds of the Delphi survey, consensus was reached on 27 factors and stability on 14 factors. On one factor, neither consensus nor stability could be reached. Twenty-six factors were identified as essential outcomes. CONCLUSION: This research provides support for the essential outcomes to be considered in any postgraduate training program in transfusion medicine aimed at clinicians.

The difference in scope of practice between a specialist in transfusion medicine and the clinician who deals with transfusion on an ad hoc basis.

BACKGROUND: In designing a training program in transfusion medicine, a range of factors needs to be taken into account. One of these is delineating the scope of practice of students in order to ensure a program that will be appropriate in terms of content, level of difficulty, and the requirements of the student's working environment. Very little has been done in terms of scientifically studying the differences in scope of practice of a specialist in transfusion medicine compared to a clinician who deals with blood transfusion on an intermittent basis. STUDY DESIGN AND METHODS: A formal qualitative and semi-quantitative research approach was followed to determine and test the factors considered important in determining the difference in scope of practice between a specialist in transfusion medicine and the clinician who deals with transfusion on an ad hoc basis, and consisted of a literature survey, followed by semi-structured interviews and a Delphi survey. RESULTS: Nineteen factors were identified, through semi-structured interviews, as being particularly descriptive of the scope of practice of a full-time specialist in transfusion medicine that differentiated them from clinicians dealing with blood transfusion on an ad hoc basis. Nine factors were identified as being descriptive of the scope of practice of clinicians dealing with blood transfusion on an ad hoc basis, which differentiate them from full-time specialists in transfusion medicine. CONCLUSION: Designing a training program with the end in mind requires an understanding of the variable contexts within which clinicians, who deal with blood transfusion, work. The findings of this study provide a framework for planning a curriculum that takes such differing scopes of practice into account.

The impact of HIV-associated anaemia on the incidence of red blood cell transfusion: implications for blood services in HIV-endemic countries.

Cytopaenias, especially anaemia, are common in the HIV-infected population. The causes of HIV related cytopaenias are multi-factorial and often overlapping. In addition, many of the drugs used in the management of HIV-positive individuals are myelosuppresive and can both cause and exacerbate anaemia. Even though blood and blood products are still the cornerstone in the management of severe cytopaenias, how HIV may affect blood utilisation is not well understood. The impact of HIV/AIDS on blood collections has been well documented. As the threat posed by HIV on the safety of the blood supply became clearer, South Africa introduced progressively more stringent donor selection criteria, based on the HIV risk profile of the donor cohort from which the blood collected. The implementation of new testing technology in 2008 which significantly improved the safety of the blood supply enabled the removal of what was perceived by many as a racially based donor risk model. However, this new technology had a significant and sustained impact on the cost of blood and blood products in South Africa. In contrast, it would appear little is known of how HIV influences the utilisation of blood and blood products. Considering the high prevalence of HIV among hospitalised patients and the significant risk for anaemia among this group, there would be an expectation that the transfusion requirements of an HIV-infected patient would be higher than that of an HIV-negative patient. However, very little published data is available on this topic which emphasises the need for further large-scale studies to evaluate the impact of HIV/AIDS on the utilisation of blood and blood products and how the large-scale roll-out of ARV programs may in future play a role in determining the country's blood needs.

Postgraduate education in transfusion medicine in the absence of formal residency training: assessment of factors needed to develop and sustain a postgraduate diploma program.

BACKGROUND: Quality education in transfusion medicine is key to delivering a safe and cost-effective blood service, yet postgraduate residency programs are lacking in many resource-limited countries and regions. The first formal, accredited, postgraduate training program in transfusion medicine aimed at medical doctors was developed and implemented at the University of the Free State in Bloemfontein, South Africa, in 2008. In the context of high demand and limited resources, ensuring sustainability of postgraduate training programs is essential. STUDY DESIGN AND METHODS: A formal qualitative and semi-quantitative research approach was followed to determine and test the factors considered important in program sustainability, and consisted of a literature survey, followed by semi-structured interviews and a Delphi survey. RESULTS: Fifty-five factors were identified from the semi-structured interviews. During the Delphi survey, consensus was reached on 41 and stability declared on a further 13. These factors formed the basis of a structured model informing the sustainability aspects of a postgraduate program in transfusion medicine. CONCLUSION: Literature on program sustainability in the field of transfusion medicine is very limited. This study identified the key factors essential to the long-term viability of a postgraduate program in transfusion medicine and should find broad applicability in other resource-limited countries and regions. It is envisaged that this will enable such programs to reach a state of self-sufficiency while not being overly reliant on external funding and support.

Exchange transfusion as a life-saving intervention in three patients with different haematological malignancies with severe hyperleukocytosis where leukapheresis was not available.

Hyperleukocytosis is a rare but potentially serious complication of haematological malignancies. It is usually treated with rehydration, prevention of tumour lysis syndrome and the administration of cytotoxic therapy. Leukapheresis may be life-saving in emergency cases. In this article we describe how, in a resource-limited setting where leukapheresis was not available, manual exchange transfusion was utilised as a life-saving intervention in three patients with different haematological malignancies complicated by hyperleukocytosis. Further we outline the procedure that was carried out and evaluated possible complications associated with this rarely used practice.

WITHDRAWN: Exchange transfusion as a life-saving intervention in three patients with different haematological malignancies with severe hyperleukocytosis where leukapheresis was not available.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, 10.1016/j.transci.2013.09.003. The duplicate article has therefore been withdrawn.

Factors affecting the current status of transfusion medicine education in South Africa.

Education in transfusion medicine, aimed at clinical transfusion practice, is limited in most South African pre- and postgraduate medical training programs. A number of local and global factors impact on the need for and provision of transfusion medicine education programs in South Africa, which are discussed in this paper. A perspective is provided on the effects of issues such as global versus local training need, blood safety, appropriate use of blood in resource-restrained environments, the presence or absence of national blood policies, standardization of training, medical migration and workforce diversity. Harnessing support for the development of training programs for medical doctors and new opportunities for developing a career in transfusion medicine are discussed. Commentary is also provided on online learning, social networking and integration of modern paradigms of learning, such as screencasting and online learning, into teaching programs. This article should provide anyone in medical education or program development, in particular in the field of transfusion medicine, with an indication of the factors that should be considered when embarking on such an endeavor.

Focused investigations to expedite cancer diagnosis among patients with lymphadenopathy in a tuberculosis and HIV-endemic region.

PURPOSE: In tuberculosis (TB)-endemic areas, lymphadenopathy is frequently due to TB adenitis, but lymphoma and cancers are important differential diagnoses and critical to diagnose at the earliest opportunity. Key obstacles to lymphoma diagnosis include empiric TB treatment and difficulty accessing a biopsy. We report on a specialized clinic utilizing high-yield investigations for patients with lymphadenopathy. METHODS: This prospective interventional study investigated the utility of a core biopsy and the Xpert MTB/RIF Ultra (Ultra) on fine-needle aspirate (FNA) and tissue in a newly established lymph node biopsy clinic over 4 years. Electronic referral facilitated patient assessment within a week. Hematology fellows without specialist surgical or radiological expertise performed the biopsy on the first visit. RESULTS: In 277 patients, including 43% people with HIV, TB was the most frequent diagnosis (34%), followed by lymphoma (27%) and other cancers (17%). Patients were seen a median of 5 days [interquartile range (IQR) 2-8.5 days] from referral. Core biopsy provided sufficient tissue for diagnosis in 96% of patients with lymphoma (72/75) and 94% of patients with cancer (44/47). FNA Ultra had a sensitivity of 73.9% [34/46; 95% confidence interval (CI) 58.9-85.7], and tissue Ultra 73% (46/63; 95% CI 60.3-83.4). There were six false-positive Ultra tests, highlighting the value of histology to either support TB or make an alternative diagnosis. CONCLUSION: Core biopsies collected under the conditions described are safe and sensitive and can yield a rapid diagnosis. Combining Ultra and a core biopsy can accurately diagnose TB and cancer. This clinic provides an implementation model for resource-constrained and TB-endemic areas.

The International Prognostic Score and HIV status predict red cell concentrate transfusion needs in Hodgkin lymphoma.

Despite the burden of anemia among Hodgkin lymphoma (HL) patients, data evaluating red cell concentrate transfusion are limited. We retrospectively studied 285 newly diagnosed HL patients who received first-line adriamycin, bleomycin sulfate, vinblastine sulfate, and dacarbazine (ABVD) treatment at Groote Schuur Hospital, Cape Town. HIV prevalence in the cohort was 39.5% and 74.2% of patients had advanced stage HL. Patient prognosis was scored using the HL International Prognostic Score (IPS-7) and HL IPS-3. Seventy (24.6%) patients were transfused with a median of 2 (IQR 1-5) units per patient. Compared to HIV-negative patients, more HIV-positive patients were transfused (14.1% vs. 40.4%, p < .001) and received more units, median 2 (IQR 1-3) vs. 3 (IQR 2-5), p = .035. HL IPS-7 (OR 2.1, p < .001) and HL IPS-3 (OR 2.6, p < .001) were independently associated with transfusion. HL IPS-7, HL IPS-3, and HIV positivity remained associated with transfusion after adjusting for covariates. For patients with newly diagnosed HL, HL IPS-7, HL IPS-3, and HIV status predicted transfusion.

Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus).

Thrombotic thrombocytopenic purpura (TTP) is the prototypical microangiopathy characterized by disseminated microthromboses, hemolytic anemia, and ultimately organ dysfunction. A link with deficiency of the von Willebrand factor-cleaving protease (ADAMTS13) has been demonstrated, but additional genetic and/or environmental triggers are thought to be required to incite acute illness. Here we report that 4 days of ADAMTS13 functional inhibition is sufficient to induce TTP in the baboon (Papio ursinus), in the absence of inciting triggers because injections with an inhibitory monoclonal antibody (mAb) consistently (n = 6) induced severe thrombocytopenia (< 12 × 10(9)/L), microangiopathic hemolytic anemia, and a rapid rise in serum lactate dehydrogenase. Immunohistochemical staining revealed the characteristic disseminated platelet- and von Willebrand factor-rich thrombi in kidney, heart, brain, and spleen but not lungs. Prolonged inhibition (14 days, n = 1) caused myocardial ischemic damage and asplenia but not death. Control animals (n = 5) receiving equal doses of a noninhibitory anti-ADAMTS13 mAb remained unaffected. Our results provide evidence for a direct link between TTP and ADAMTS13 inhibition and for a mild disease onset. Furthermore, we present a reliable animal model of this disease as an opportunity for the development and validation of novel treatment strategies.