Screening for invasive fungal disease using non-culture-based assays among inpatients with advanced HIV disease at a large academic hospital in South Africa.

INTRODUCTION: Despite widespread access to antiretroviral therapy (ART), the burden of advanced HIV disease in South Africa is high. This translates into an increased risk of AIDS-related opportunistic infections, including invasive mycoses. METHODS: Using a limited number of non-culture-based diagnostic assays, we aimed to determine the prevalence of invasive mycoses and tuberculosis among hospitalised adults with very advanced HIV (CD4 counts < 100 cells/µL) at a large academic hospital. We conducted interviews and prospective medical chart reviews. We performed point-of-care finger stick and serum cryptococcal antigen lateral flow assays; serum (1 → 3) ß-D-glucan assays; urine Histoplasma galactomannan antigen enzyme immunoassays and TB lipoarabinomannan assays. RESULTS: We enrolled 189 participants from 5280 screened inpatients. Fifty-eight per cent were female, with median age 37 years (IQR: 30-43) and median CD4 count 32 cells/µL (IQR: 13-63). At enrolment, 60% (109/181) were receiving ART. Twenty-one participants (11%) had a diagnosis of an invasive mycosis, of whom 53% (11/21) had cryptococcal disease. Thirteen participants (7%) had tuberculosis and a concurrent invasive mycosis. ART-experienced participants were 60% less likely to have an invasive mycosis than those ART-naïve (adjusted OR: 0.4; 95% CI 0.15-1.0; P = .03). Overall in-hospital mortality was 13% (invasive mycosis: 10% [95% CI 1.2-30.7] versus other diagnoses: 13% (95% CI 8.4-19.3)). CONCLUSIONS: One in ten participants had evidence of an invasive mycosis. Diagnosis of proven invasive fungal disease and differentiation from other opportunistic infections was challenging. More fungal-specific screening and diagnostic tests should be applied to inpatients with advanced HIV disease.

Epidemiologic Shift in Candidemia Driven by Candida auris, South Africa, 2016-20171.

Candida auris is an invasive healthcare-associated fungal pathogen. Cases of candidemia, defined as illness in patients with Candida cultured from blood, were detected through national laboratory-based surveillance in South Africa during 2016-2017. We identified viable isolates by using mass spectrometry and sequencing. Among 6,669 cases (5,876 with species identification) from 269 hospitals, 794 (14%) were caused by C. auris. The incidence risk for all candidemia at 133 hospitals was 83.8 (95% CI 81.2-86.4) cases/100,000 admissions. Prior systemic antifungal drug therapy was associated with a 40% increased adjusted odds of C. auris fungemia compared with bloodstream infection caused by other Candida species (adjusted odds ratio 1.4 [95% CI 0.8-2.3]). The crude in-hospital case-fatality ratio did not differ between Candida species and was 45% for C. auris candidemia, compared with 43% for non-C. auris candidemia. C. auris has caused a major epidemiologic shift in candidemia in South Africa.

Clinical diagnosis of sensory neuropathy in HIV patients treated with tenofovir: A 6-month follow-up study.

BACKGROUND: Sensory neuropathy (SN) is a common and often painful neurological condition associated with HIV-infection and its treatment. However, data on the incidence of SN in neuropathy-free individuals initiating combination antiretroviral therapies (cART) that do not contain the neurotoxic agent stavudine are lacking. AIMS: We investigated the 6-month incidence of SN in ART naïve individuals initiating tenofovir (TDF)-based cART, and the clinical factors associated with the development of SN. METHODS: 120 neuropathy-free and ART naïve individuals initiating cART at a single center in Johannesburg, South Africa were enrolled. Participants were screened for SN using clinical signs and symptoms at study enrolment and approximately every 2-months for a period of ~6-months. Diagnostic criteria for symptomatic SN was defined by the presence of at least one symptom (pain/burning, numbness, paraesthesias) and at least two clinical signs (reduced vibration sense, absent ankle reflexes or pin-prick hypoaesthesia). Diagnostic criteria for asymptomatic SN required at least two clinical signs only (as above). RESULTS: A total of 88% of the cohort completed three visits within the 6-month period. The 6-month cumulative incidence of neuropathy was 140 cases per 1000 patients (95% CI: 80-210) at an incidence rate of 0.37 (95% CI: 0.2-0.5) per person year. Height and active tuberculosis (TB) disease were independently associated with the risk of developing SN (P < .05). INTERPRETATION: We found that within the first 6 months of starting cART, incident SN persists in the post-stavudine era, with 11 (9%) of individuals developing asymptomatic SN, and 9 (8%) developing symptomatic SN.

Psychological Factors Associated With Painful Versus Non-Painful HIV-Associated Sensory Neuropathy.

HIV-associated sensory neuropathy (HIV-SN) is a common, and frequently painful complication of HIV, but factors that determine the presence of pain are unresolved. We investigated: (i) if psychological factors associated with painful (n = 125) versus non-painful HIV-SN (n = 72), and (ii) if pain and psychological factors affected quality of life (QoL). We assessed anxiety and depression using the Hopkins Symptoms Checklist-25. Pain catastrophizing and QoL were assessed using the Pain Catastrophizing Scale and Euroqol-5D, respectively. Presence of neuropathy was detected using the Brief Neuropathy Screening Tool, and pain was characterised using the Wisconsin Brief Pain Questionnaire. Overall, there was a high burden of pain, depression and anxiety in the cohort. None of the psychological variables associated with having painful HIV-SN. Greater depressive symptoms and presence of pain were independently associated with lower QoL. In those participants with painful HIV-SN, greater depressive symptom scores were associated with increased pain intensity. In conclusion, in a cohort with high background levels of psychological dysfunction, psychological factors do not predict the presence of pain, but both depression and presence of pain are associated with poor quality of life.

Imputing the Direct and Indirect Effectiveness of Childhood Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease by Surveying Temporal Changes in Nasopharyngeal Pneumococcal Colonization.

The limited capability in most low- to middle-income countries to study the benefit of pneumococcal conjugate vaccine (PCV) in protecting against invasive pneumococcal disease (IPD) calls for alternate strategies to assess this. We used a mathematical model to predict the direct and indirect effectiveness of PCV by analyzing serotype-specific colonization prevalence and IPD incidence prior to and following childhood PCV immunization in South Africa. We analyzed IPD incidence from 2005 to 2012 and colonization studies undertaken in human immunodeficiency virus (HIV)-uninfected and HIV-infected child-mother dyads from 2007 to 2009 (pre-PCV era), in 2010 (7-valent PCV era), and in 2012 (13-valent PCV era). We compared the model-predicted changes in IPD incidence with observed changes in IPD incidence, according to HIV status, in children aged 3 months-5 years and in women aged 18-45 years. We observed reductions in vaccine-serotype colonization and IPD due to vaccine serotypes among children and women after PCV introduction. Using the changes in vaccine-serotype colonization data, the model-predicted changes in vaccine-serotype IPD incidence rates were similar to the observed changes in PCV-unvaccinated children and adults, but not among children under age 24 months. Surveillance of colonization prior to and following PCV use can be used to impute the indirect protection afforded by PCV in unvaccinated age groups, including those in high-HIV-prevalence settings.

Contrasting predictors of poor antiretroviral therapy outcomes in two South African HIV programmes: a cohort study.

BACKGROUND: Many national antiretroviral therapy (ART) programmes encourage providers to identify and address baseline factors associated with poor treatment outcomes, including modifiable adherence-related behaviours, before initiating ART. However, evidence on such predictors is scarce, and providers judgement may often be inaccurate. To help address this evidence gap, this observational cohort study examined baseline factors potentially predictive of poor treatment outcomes in two ART programmes in South Africa, with a particular focus on determinants of adherence. METHODS: Treatment-naïve patients starting ART were enrolled from a community and a workplace ART programme. Potential baseline predictors associated with poor treatment outcomes (defined as viral load > 400 copies/ml or having discontinued treatment by six months) were assessed using logistic regression. Exposure variables were organised for regression analysis using a hierarchical framework. RESULTS: 38/227 (17%) of participants in the community had poor treatment outcomes compared to 47/117 (40%) in the workplace. In the community, predictors of worse outcomes included: drinking more than 20 units of alcohol per week, having no prior experience of chronic medications, and consulting a traditional healer in the past year (adjusted odds ratio [aOR] 15.36, 95% CI 3.22-73.27; aOR 2.30, 95%CI 1.00-5.30; aOR 2.27, 95% CI 1.00-5.19 respectively). Being male and knowing someone on ART were associated with better outcomes (aOR 0.25, 95%CI 0.09-0.74; aOR 0.44, 95%CI 0.19-1.01 respectively). In the workplace, predictors of poor treatment outcomes included being uncertain about the health effects of ART and a traditional healer's ability to treat HIV (aOR 7.53, 95%CI 2.02-27.98; aOR 4.40, 95%CI 1.41-13.75 respectively). Longer pre-ART waiting time (2-12 weeks compared to <2 weeks) predicted better treatment outcomes (aOR 0.13, 95% CI 0.03-0.56). CONCLUSION: Baseline predictors of poor treatment outcomes were largely unique to each programme, likely reflecting different populations and pathways to HIV care. In the workplace, active promotion of HIV testing may have extended ART to individuals who, without provider initiation, would not have spontaneously sought care. As provider-initiated testing makes ART available to individuals less motivated to seek care, patients may need additional adherence support, especially addressing uncertainty about the health benefits of ART.

Antiretroviral Therapy Outcomes in Patients with Severe Mental Illness.

A retrospective cohort analysis was performed to describe outcomes and retention in care on antiretroviral therapy (ART) of 53 patients with severe mental illness (SMI). Diagnoses were psychosis secondary to HIV (24 patients), psychosis not otherwise specified (12), mania with or without psychosis (9), depression with psychotic features (4), and schizophrenia and bipolar mood disorder (2 each). The median baseline CD4 count was 66/mm(3) and viral load was 5.4 log10 copies/mL. Thirteen (25%) patients were lost to follow-up (10 within 6 months), 3 were transferred out, and 3 died. By week 96, 29 (85%) of 34 (64%) patients still in care had a viral load <400 copies/mL and 26 (76%) a viral load <25 copies/mL. Median CD4 count increased to 307/mm(3). Twenty-seven of 34 patients discontinued antipsychotic medication. Patients with SMI and advanced HIV infection responded well to ART. The first 6 months was important for retention in care.

Pharmacological treatment of painful HIV-associated sensory neuropathy.

BACKGROUND: HIV-associated sensory neuropathy (HIV-SN) is a common and frequently painful complication of HIV infection and its treatment. However, few data exist describing the frequency, type and dosage of pain medications patients are receiving in the clinic setting to manage the painful symptoms of HIV-SN. OBJECTIVE: To report on analgesic prescription for painful HIV-SN and factors influencing that prescription in adults on combination antiretroviral therapy. METHODS: Using validated case ascertainment criteria to identify patients with painful HIV-SN, we recruited 130 HIV-positive patients with painful HIV-SN at Chris Hani Baragwanath Hospital, Johannesburg, South Africa. Demographic and clinical data (including current analgesic use) were collected on direct questioning of the patients and review of the medical files. RESULTS: We found significant associations, of moderate effect size, between higher pain intensity and lower CD4 T-cell counts with prescription of analgesic therapy. Factors previously identified as predicting analgesic treatment in HIV-positive individuals (age, gender, level of education) were not associated with analgesic use here. Consistent with national guidelines, amitriptyline was the most commonly used agent, either alone or in combination therapy. Importantly, we also found that despite the relatively high analgesic treatment rate in this setting, the majority of patients described their current level of HIV-SN pain as moderate or severe. CONCLUSION: Our findings highlight the urgent need for both better analgesic options for HIV-SN pain treatment and ongoing training and support of clinicians managing this common and debilitating condition.

Evaluation of parent-child pairs on antiretroviral therapy in separate adult and pediatric clinics.

In Africa, HIV infection is considered a family disease. A retrospective cohort analysis was performed to describe the characteristics and outcome in 35 parent-child pairs taking antiretroviral therapy (ART) in separate adult and pediatric HIV clinics. In 26 pairs, ART was first initiated in children. Baseline median CD4 count was 122/mm(3) in adults and 376/mm(3) in children. World Health Organization stage 3 or 4 disease affected 49% of adults and 83% of children. In all, 3 parents and 1 child died. Hospitalization, poor adherence, missed appointments, or regimen change affected >50% of pairs on ART. Following tuberculosis diagnosis in their parents, 2 of the 5 children were not investigated. By week 104, 29 (83%) pairs remained on ART, and 69% of patients on ART were virologically suppressed. Parent-child pairs with advanced HIV infection had good outcomes when cared for in separate clinics. Establishing lines of communication between clinics is important. Family-centered services may provide more integrated care.

Extrapulmonary tuberculosis among adults: experience at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.

BACKGROUND: Extrapulmonary tuberculosis (EPTB) occurs in 15 - 20% of immunocompetent and 20 - 70% of HIV-infected patients with tuberculosis. There are few recent incidence data for EPTB. METHODS: Adults (N=2 963) with culture-proven EPTB seen over 2 years at Chris Hani Baragwanath Academic Hospital, the main referral hospital serving Soweto, Johannesburg, South Africa, were retrospectively studied for pattern and incidence. RESULTS: The commonest sites of EPTB were the pleura (39.1%), lymph nodes (31.0%), blood (21.8%), meninges (7.3%), and peritoneum (2.9%). Disseminated tuberculosis occurred in 25.0%. The median age was 33 years (range 18 - 87 years). Males comprised 53.2% overall, with a female majority in the peritonitis group. For Soweto, the incidence of adult EPTB was 88.6/100 000 population, rising to 139.4/100 000 and 125.7/100 000 in the 25 - 34-year and 35 - 44-year age groups, respectively. There was no secondary peak in the elderly (17.9/100 000). CONCLUSIONS: This retrospective cohort showed a high incidence of EPTB, most marked in the 25 - 44-year age group. Culture of extrapulmonary sites is of importance to confirm diagnosis of tuberculosis and to ensure antituberculosis drug susceptibility testing.

Candidemia among adults in Soweto, South Africa, 1990-2007.

BACKGROUND: Studies on candidemia occurring among adults in Southern African are limited. We aimed to document the epidemiology of candidemia among adults in Soweto. METHODS: This was a retrospective hospital-based study in three discrete periods, involving 9 years, from 1990 to 2007. RESULTS: Two hundred and sixty-six patients were identified. Case rates were 2.8 cases/10 000 admissions in 1998-2002 and 3.6 episodes/10 000 hospitalizations in 2005-2007. In 1990, Candida albicans caused 62% and Candida tropicalis caused 23% of episodes. In 2005-2007, major species were C. albicans (46%), Candida parapsilosis (25%), and Candida glabrata (23%), with little change compared to 1998-2002. Major predisposing conditions were abdominal surgery (43%), HIV infection (19% in 2005-2007), trauma (16%), diabetes mellitus (12%), and cancer (8%). General wards superseded intensive care as the major diagnostic setting in 2005-2007. The crude mortality was 60%. Among 22 HIV-infected patients with a median CD4 cell count of 68/µl, three were of community-onset. C. albicans caused 73% of cases. Five patients had another predisposing condition and five had central venous catheters. The mortality was 73%. CONCLUSIONS: Soweto has a pattern of Candida species different from other continents. HIV infection and trauma were important predisposing conditions.

Profile of cause of death assigned to adults on antiretroviral therapy in Soweto.

This retrospective cohort study describes causes of death in 305 patients (baseline median CD4 count 26/µl) from 2 943 adults on antiretroviral therapy. Acute sepsis (20%), tuberculosis (18%) and Mycobacterium avium complex (MAC) bacteraemia (14%) were the most common causes. Mortality owing to the disease was 66% for MAC bacteraemia and 23% for non-Hodgkin's lymphoma. In 37 patients dying beyond one year on ART, virological failure was present in 11 (30%), and non-HIV-related causes of death occurred in 10. The main causes were acute sepsis (6), tuberculosis (7) and chronic medical conditions (5). Initiating ART at higher CD4 counts should reduce early mortality.

Antiretroviral outcomes in South African prisoners: a retrospective cohort analysis.

BACKGROUND AND METHODS: Little is known about antiretroviral therapy (ART) outcomes in prisoners in Africa. We conducted a retrospective review of outcomes of a large cohort of prisoners referred to a public sector, urban HIV clinic. The review included baseline characteristics, sequential CD4 cell counts and viral load results, complications and co-morbidities, mortality and loss to follow-up up to 96 weeks on ART. FINDINGS: 148 inmates (133 male) initiated on ART were included in the study. By week 96 on ART, 73% of all inmates enrolled in the study and 92% of those still accessing care had an undetectable viral load (<400 copies/ml). The median CD4 cell count increased from 122 cells/mm(3) at baseline to 356 cells/mm(3) by 96 weeks. By study end, 96 (65%) inmates had ever received tuberculosis (TB) therapy with 63 (43%) receiving therapy during the study: 28% had a history of TB prior to ART initiation, 33% were on TB therapy at ART initiation and 22% developed TB whilst on ART. Nine (6%) inmates died, 7 in the second year on ART. Loss to follow-up (LTF) was common: 14 (9%) patients were LTF whilst still incarcerated, 11 (7%) were LTF post-release and 9 (6%) whose movements could not be traced. 16 (11%) inmates had inter-correctional facility transfers and 34 (23%) were released of whom only 23 (68%) returned to the ART clinic for ongoing follow-up. CONCLUSIONS: Inmates responded well to ART, despite a high frequency of TB/HIV co-infection. Attention should be directed towards ensuring eligible prisoners access ART programs promptly and that inter-facility transfers and release procedures facilitate continuity of care. Institutional TB control measures should remain a priority.

A comparison of cases of paediatric-onset and adult-onset cryptococcosis detected through population-based surveillance, 2005-2007.

OBJECTIVE: We compared the epidemiology of laboratory-confirmed paediatric cryptococcal disease with adult-onset disease in the South African population. METHODS: The study was an active, prospective, population-based, laboratory-based surveillance in South Africa. We compared cases of paediatric cryptococcosis (<15 years) with cases of adult-onset cryptococcosis that were reported to the surveillance programme between 1 January 2005 and 31 December 2007. The case definition was based on a positive India ink test, cryptococcal antigen test or cryptococcal culture. Clinical case data were obtained at enhanced surveillance sites. RESULTS: Of 16,192 incident episodes of cryptococcosis in South Africa, 361 (2%) episodes occurred among children. In 2007, incidence was one and 19 cases per 100,000 persons in the general paediatric and adult populations and was 47 and 120 cases per 100,000 persons for HIV-infected children and adults, respectively. Among children, a bimodal peak in incidence was evident in the less than 1-year age group and in the 5 age group. Most children (64%) and adults (63%) were severely immunocompromised (CD4 T-lymphocyte cell count < 50 cells/µl) at the time of diagnosis. On multivariable analysis, children were significantly more likely than adults to be male, diagnosed on blood culture, infected with Cryptococcus gattii, treated with amphotericin B and admitted for a longer stay in hospital. CONCLUSION: This series of 361 cases of paediatric cryptococcosis is by far the largest described to date. The diagnosis of cryptococcosis should be considered in the paediatric HIV-infected population, especially among those who are severely immunocompromised.

Persistent high burden of invasive pneumococcal disease in South African HIV-infected adults in the era of an antiretroviral treatment program.

BACKGROUND: Highly active antiretroviral treatment (HAART) programs have been associated with declines in the burden of invasive pneumococcal disease (IPD) in industrialized countries. The aim of this study was to evaluate trends in IPD hospitalizations in HIV-infected adults in Soweto, South Africa, associated with up-scaling of the HAART program from 2003 to 2008. METHODS: Laboratory-confirmed IPD cases were identified from 2003 through 2008 through an existing surveillance program. The period 2003-04 was designated as the early-HAART era, 2005-06 as the intermediate-HAART era and 2007-08 as the established-HAART era. The incidence of IPD was compared between the early-HAART and established-HAART eras in HIV-infected and-uninfected individuals. RESULTS: A total of 2,567 IPD cases among individuals older than 18 years were reported from 2003 through 2008. Overall incidence of IPD (per 100,000) did not change during the study period in HIV-infected adults (207.4 cases in the early-HAART and 214.0 cases in the established-HAART era; p = 0.55). IPD incidence, actually increased 1.16-fold (95% CI: 1.01; 1.62) in HIV-infected females between the early-and established-HAART eras (212.1 cases and 246.2 cases, respectively; p = 0.03). The incidence of IPD remained unchanged in HIV-uninfected adults across the three time periods. CONCLUSION: Despite a stable prevalence of HIV and the increased roll-out of HAART for treatment of AIDS patients in our setting, the burden of IPD has not decreased among HIV-infected adults. The study indicates a need for ongoing monitoring of disease and HAART program effectiveness to reduce opportunistic infections in African adults with HIV/AIDS, as well as the need to consider alternate strategies including pneumococcal conjugate vaccine immunization for the prevention of IPD in HIV-infected adults.

Contrasting reasons for discontinuation of antiretroviral therapy in workplace and public-sector HIV programs in South Africa.

Abstract We investigated reasons for clinical follow-up and treatment discontinuation among HIV-infected individuals receiving antiretroviral therapy (ART) in a public-sector clinic and in a workplace clinic in South Africa. Participants in a larger cohort study who had discontinued clinical care by the seventh month of treatment were traced using previously provided locator information. Those located were administered a semistructured questionnaire regarding reasons for discontinuing clinical follow-up. Participants who had discontinued antiretroviral therapy were invited to participate in further in-depth qualitative interviews. Fifty-one of 144 (35.4%) in the workplace cohort had discontinued clinical follow-up by the seventh month of treatment. The median age of those who discontinued follow-up was 46 years and median educational level was five years. By contrast, only 16.5% (44/267) of the public-sector cohort had discontinued follow-up. Among them the median age was 37.5 years and median education was 11 years. Qualitative interviews were conducted with 17 workplace participants and 10 public-sector participants. The main reasons for attrition in the workplace were uncertainty about own HIV status and above the value of ART, poor patient-provider relationships and workplace discrimination. In the public sector, these were moving away and having no money for clinic transport. In the workplace, efforts to minimize the time between testing and treatment initiation should be balanced with the need to provide adequate baseline counseling taking into account existing concepts about HIV and ART. In the public sector, earlier diagnosis and ART initiation may help to reduce early mortality, while links to government grants may reduce attrition.

HIV/AIDS and antiretroviral treatment knowledge, attitudes, beliefs, and practices in HIV-infected adults in Soweto, South Africa.

A cross-sectional study of knowledge, attitudes, beliefs, and practices (KABPs) toward HIV and antiretroviral therapy (ART) was conducted in Soweto, South Africa, using a standardized validated questionnaire. Of 105 HIV clinic patients evaluated, 70% of whom were not on ART, 89% had good knowledge about the cause of HIV infection and 83% knew about modes of transmission. Fifty-nine percent reported they were not worried about ART side effects. Sixty-five percent agreed that missing ART doses can lead to disease progression. Ninety percent had disclosed their HIV serostatus to 1 or more persons, but only 62% of those with a current sexual partner reported having told that partner. Approximately 80% reported that if they were taking ART, they would not be worried about family or friends finding out. Forty-nine percent believed that ART can cure HIV, a belief that was associated with a low level of education (P<0.001). Overall, knowledge of the cause of HIV/AIDS, modes of transmission, and importance of ART adherence was good in our study population. Further research is warranted to assess the extent to which this knowledge and attendant attitudes predict ART adherence levels. The low rate of HIV serostatus disclosure to sexual partners calls for multidimensional interventions to reduce HIV-related stigma.