Multi-drug resistant tuberculosis in women

The World Health Organisation (WHO) estimates a staggering 8.6 million new tuberculosis cases every year (Global TB report, 2013).1 Seventy five percent of the 8.6 million cases are from the Africa region. More than 500 000 of these cases are new multi-drug resistant tuberculosis (MDR TB) that has doubled from 2009 as well as 2011 and this number is currently doubling annually. Many of these cases are primary MDR TB infection or re-infection rather than previously treated tuberculosis progressing to MRD TB.2 Evidence is growing for increased transmission in congregate settings and hospitals. Currently drug susceptible tuberculosis treatment rapidly induces negative transmission compared to multi- and extreme drug resistant tuberculosis treatment that is not effective and the patient can be positive for months and still transmitting disease.http://reference.sabinet.co.za/sa_epublication/medogam201

Vertical transmission of HIV among pregnant women who initially had false–negative rapid HIV tests in four South African antenatal clinics

INTRODUCTION : There is a risk of mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding. The aim of this study was to assess vertical transmission of HIV among pregnant women who initially had false–negative rapid HIV tests in South African antenatal care (ANC) clinics. METHODS : Pregnant participants were enrolled in a diagnostic study that used nucleic acid amplification testing (NAAT) to screen for early HIV infection among individuals who tested negative on rapid HIV tests used at the point-of-care (POC) facilities. Participants were enrolled from four ANC clinics in the Tshwane district of South Africa. All NAAT-positive participants were recalled to the clinics for further management. Vertical transmission was assessed among exposed infants whose HIV polymerase chain reaction (PCR) results were available. RESULTS : This study enrolled 8208 pregnant participants who tested negative on rapid HIV tests between 2013 and 2016. Their median age was 26 years (interquartile range [IQR]: 23–30). NAAT detected HIV infections in 0.6% (n = 49; 95% confidence interval {CI}: 0.5–0.8) of all study participants. The distribution of these infections among the four clinics ranged from 0.3%– 1.1%, but this was not statistically significant (p = 0.07). Forty-seven participants (95.9%) were successfully recalled and referred for antiretroviral treatment initiation as part of prevention of MTCT (PMTCT). Most women with newly diagnosed HIV infection presented for the first ANC visit in the second (61.9%, n = 26) and third (31.0%, n = 13) trimesters. HIV PCR results were available for thirty-two infants, three of whom tested positive (9.4%; 95% CI: 1.98–25.02). CONCLUSIONS : This study showed that supplemental HIV testing for pregnant women led to earlier linkage to the PMTCT programme. Inaccurate diagnosis of HIV infection at ANC clinics is likely to undermine the efforts of eliminating MTCT particularly in HIV-endemic settings.S1 Table. Characteristics of participants diagnosed with early or chronic HIV infection. Initial tests were performed from samples obtained at enrolment (i.e. after a negative rapid HIV test result). HIV viral load (VL) tests were performed first to screen for HIV infection, and all the serology tests were performed later. Follow-up (F/U) VL was only performed for participants who had an initial VL <5000 copies/ml [16]. Pt ID = participant’s study identity, F = female, gen = generation, ELISA = enzyme-linked immunosorbent assay, W. Blot = Western Blot, LAg = limiting antigen, Insuf = insufficient, LT = long term (chronic) infection, --- = not available (participant did not return for follow-up), + = positive,— = negative. Units: HIV VL = copies/ml; p24 antigen = cut-off index (COI); Genscreen ELISA = sample cut-off (S/CO); LAg avidity = normalized optical density (OD-n); LAg avidity <1.5 OD-n = early infection; LAg avidity >1.5 OD-n = LT (chronic) infection. ¥ = participant 6738 was previously misclassified as having chronic infection [16], but testing on her follow-up sample revealed low avidity antibodies consistent with early infection; this was confirmed on repeat testing of 6738 sample. P24 antigen, W. Blot and F/U LAg were not performed for the last participants identified with newly diagnosed HIV infection owing to cost limitations. This also applies to the F/U VL for participant 1692, as this was supposed to have been performed according to the diagnostic study protocol [14].This work was supported by SHM - South African Medical Research Council – Self Initiated Research (SA MRC-SIR) grant; SHM - Discovery Foundation grant; SHM - Hamilton Naki Clinical Scholarship; and TCQ - The Division of Intramural Research, NIAID, NIH.SHM - South African Medical Research Council – Self Initiated Research (SA MRC-SIR) grant; SHM - Discovery Foundation grant; SHM - Hamilton Naki Clinical Scholarship; and TCQ - The Division of Intramural Research, NIAID, NIH.http://www.plosone.orgam2020Internal Medicin

Vertical transmission of HIV among pregnant women who initially had false–negative rapid HIV tests in four South African antenatal clinics

INTRODUCTION : There is a risk of mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding. The aim of this study was to assess vertical transmission of HIV among pregnant women who initially had false–negative rapid HIV tests in South African antenatal care (ANC) clinics. METHODS : Pregnant participants were enrolled in a diagnostic study that used nucleic acid amplification testing (NAAT) to screen for early HIV infection among individuals who tested negative on rapid HIV tests used at the point-of-care (POC) facilities. Participants were enrolled from four ANC clinics in the Tshwane district of South Africa. All NAAT-positive participants were recalled to the clinics for further management. Vertical transmission was assessed among exposed infants whose HIV polymerase chain reaction (PCR) results were available. RESULTS : This study enrolled 8208 pregnant participants who tested negative on rapid HIV tests between 2013 and 2016. Their median age was 26 years (interquartile range [IQR]: 23–30). NAAT detected HIV infections in 0.6% (n = 49; 95% confidence interval {CI}: 0.5–0.8) of all study participants. The distribution of these infections among the four clinics ranged from 0.3%– 1.1%, but this was not statistically significant (p = 0.07). Forty-seven participants (95.9%) were successfully recalled and referred for antiretroviral treatment initiation as part of prevention of MTCT (PMTCT). Most women with newly diagnosed HIV infection presented for the first ANC visit in the second (61.9%, n = 26) and third (31.0%, n = 13) trimesters. HIV PCR results were available for thirty-two infants, three of whom tested positive (9.4%; 95% CI: 1.98–25.02). CONCLUSIONS : This study showed that supplemental HIV testing for pregnant women led to earlier linkage to the PMTCT programme. Inaccurate diagnosis of HIV infection at ANC clinics is likely to undermine the efforts of eliminating MTCT particularly in HIV-endemic settings.S1 Table. Characteristics of participants diagnosed with early or chronic HIV infection. Initial tests were performed from samples obtained at enrolment (i.e. after a negative rapid HIV test result). HIV viral load (VL) tests were performed first to screen for HIV infection, and all the serology tests were performed later. Follow-up (F/U) VL was only performed for participants who had an initial VL <5000 copies/ml [16]. Pt ID = participant’s study identity, F = female, gen = generation, ELISA = enzyme-linked immunosorbent assay, W. Blot = Western Blot, LAg = limiting antigen, Insuf = insufficient, LT = long term (chronic) infection, --- = not available (participant did not return for follow-up), + = positive,— = negative. Units: HIV VL = copies/ml; p24 antigen = cut-off index (COI); Genscreen ELISA = sample cut-off (S/CO); LAg avidity = normalized optical density (OD-n); LAg avidity <1.5 OD-n = early infection; LAg avidity >1.5 OD-n = LT (chronic) infection. ¥ = participant 6738 was previously misclassified as having chronic infection [16], but testing on her follow-up sample revealed low avidity antibodies consistent with early infection; this was confirmed on repeat testing of 6738 sample. P24 antigen, W. Blot and F/U LAg were not performed for the last participants identified with newly diagnosed HIV infection owing to cost limitations. This also applies to the F/U VL for participant 1692, as this was supposed to have been performed according to the diagnostic study protocol [14].This work was supported by SHM - South African Medical Research Council – Self Initiated Research (SA MRC-SIR) grant; SHM - Discovery Foundation grant; SHM - Hamilton Naki Clinical Scholarship; and TCQ - The Division of Intramural Research, NIAID, NIH.SHM - South African Medical Research Council – Self Initiated Research (SA MRC-SIR) grant; SHM - Discovery Foundation grant; SHM - Hamilton Naki Clinical Scholarship; and TCQ - The Division of Intramural Research, NIAID, NIH.http://www.plosone.orgam2020Internal Medicin

The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro

Polymyxins have previously been described to have activity against M. tuberculosis (MTB), but further research was abandoned due to systemic toxicity concerns to achieve the required MIC. Colistin methanesulfonate (CMS), a polymyxin, is well tolerated when inhaled directly into the lungs, resulting in high local concentrations. We report here for the first time, MIC and MBC data for CMS determined by the microtiter Alamar Blue assay (MABA). We also determined how the MIC would be affected by the presence of pulmonary surfactant (PS) and if any synergy with isoniazid (INH) and rifampicin (RIF) exists. The effect of CMS on the ultrastructure of MTB was also determined. The MIC for CMS was 16 mg/L, while the MBC was 256 mg/L. MIC for CMS in PS was antagonised by eight fold. For synergy, indifference was determined while time-kill assays revealed a greater killing effect when CMS was used together with INH. Ultrastructure analysis suggests that the disruption of the outer polysaccharide layer of MTB by CMS may lead to enhanced uptake of INH. Our findings may provide insight for further investigations of CMS against MTB.http://intl.elsevierhealth.com/journals/tube2016-07-30hb201

Molecular analysis of genetic mutations among cross-resistant second-line injectable drugs reveals a new resistant mutation in Mycobacterium tuberculosis

Mutations causing mono and cross-resistance among amikacin, kanamycin and capreomycin of second-line injectable drugs (SLIDs) namely are not well understood.We investigated 124 isolates of Mycobacterium tuberculosis for mutations within rrs, eis, tlyA and efflux pump (Rv1258c and Rv0194) genes involved in resistance towards SLIDs. The distribution of mutations across these genes were significantly different in strains with mono-resistance or cross-resistance. A new mutation G878A was found in rrs gene, among strains with capreomycin mono-resistant, or in strains with cross-resistance of capreomycin, kanamycin and amikacin. This mutation was associated with the Euro-American X3 lineage (P b 0.0001). Mutations in the two efflux genes Rv1258c and Rv0194 were confined to strains with only capreomycin/amikacin/kanamycin cross-resistance. Wefurther investigated the minimuminhibitory concentration of capreomycin on isolateswith newG878Amutation ranging from 8 μg/mL to 64 μg/mL. Inclusion of G878A on new molecular assays could increase the sensitivity of capreomycin resistance detection.Lesibana Malinga received PhD funding from National Research foundation (Innovation Fund) and University of Pretoria.http://www.elsevier.com/locate/diagmicrobiohb2016Internal Medicin

Impact of FDG PET on the management of TBC treatment

The AIM: of this study is to assess the potential impact of double-phase FDG PET versus routine staging in HIV-negative patients suffering from tuberculosis. PATIENTS, METHODS: 16 consecutive patients suffering from tuberculosis underwent contrast-enhanced CT and double-phase FDG PET imaging (45 min, 120 min). Early (E) and delayed (D) SUVmax values were determined for all identified lesions and % change in SUV calculated (ΔSUV). RESULTS: Seven patients presented with lung lesions on PET as well as CT (mean SUVmaxE 8.2, mean SUVmaxD 11.1, (p = 0.002), ΔSUV 35%. In two patients, lesions were judged as non-active on CT. In nine patients, 18 sites of LN involvement were identified on both early and delayed FDG PET images (mean SUVmaxE 6.3, mean SUVmaxD 7.9, (p = 0.0001), ΔSUV: 25%). 9 out of 18 sites of LN involvement, occurring in five patients, were missed on CT. In four of these five patients, sites of LN involvement were the only sites of extra-pulmonary involvement identified. In 6 out of 16 patients, pleural involvement was identified, respectively in 5 on FDG PET and in 6 on CT imaging (mean SUVmaxE 1.3, mean SUVmaxD 1.7, (p = 0.06), ΔSUV 21%). In 4 patients, osseous involvement was identified by both FDG PET and CT (mean SUVmaxE 7.2, mean SUVmaxD 10.7, (p = 0,06), ΔSUV 45%). Finally, in 3 patients, joint involvement was identified on both FDG PET as well as on CT imaging (mean SUVmaxE 4.7, mean SUVmaxD 5.2, ΔSUV 23%). FDG PET did not identify CTadditional sites of involvement that would have resulted in a prolonged treatment. CONCLUSION: In HIV-negative patients suffering from tuberculosis, FDG PET images suggested a more extensive involvement by Mycobacterium tuberculosis when compared to contrast enhanced CT.Ziel dieser Studie ist die Beurteilung eines möglichen Einflusses der 2-Phasen-FDG-PET im Vergleich zum Routine-Staging bei HIV-negativen Patienten mit Tuberkulose. PATIENTEN, METHODEN: Bei 16 aufeinanderfolgenden Patienten mit Tuberkulose wurden ein kontrastverstärktes CT sowie eine 2-Phasen-FDG-PET (45 min, 120 min) durchgeführt. Frühe (E) und späte (D) SUVmax-Werte wurden für alle dargestellten Läsionen bestimmt; die prozentuale Veränderung der SUV (ΔSUV) wurde berechnet. ERGEBNISSE: Bei sieben Patienten zeigten sich pulmonale Herde sowohl in der PET als auch im CT (mittlere SUVmaxE 8,2, mittlere SUVmaxD 11,1, (p = 0,002), ΔSUV 35%). Bei zwei Patienten wurden die Läsionen im CT als nicht aktiv beurteilt. Bei neun Patienten wurde sowohl in den frühen als auch in den späten FDG-PET-Aufnahmen ein Lymphknotenbefall an 18 Stellen identifiziert (mittlere SUVmaxE 6,3, mittlere SUVmaxD 7,9, (p = 0,0001), ΔSUV 25%). Bei fünf Patienten fehlten im CT 9 der 18 befallenen Lymphknoten. Bei vier dieser fünf Patienten stellte der Lymphknotenbefall die einzige extrapulmonale Beteiligung dar. Bei 6/16 Patienten wurde eine pleurale Beteiligung festgestellt, bei 5 in der FDG-PET bzw. bei 6 im CT (mittlere SUVmaxE 1,3, mittlere SUVmaxD 1,7, (p = 0,06), ΔSUV 21 %). Bei 4 Patienten wurde eine Knochenbeteiligung sowohl in der FDG-PET als auch im CT diagnostiziert (mittlere SUVmaxE 7,2, mittlere SUVmaxD 10,7, (p = 0,06), ΔSUV 45%). Schließlich wurde bei 3 Patienten ein Befall der Gelenke sowohl in der FDG-PET als auch im CT festgestellt (mittlere SUVmaxE 4,7, mittlere SUVmaxD 5,2, ΔSUV 23%). In der FDG-PET konnte kein über das CT hinausgehender Befall festgestellt werden, der zu längerer Behandlungsdauer geführt hätte. SCHLUSSFOLGERUNG: Bei HIV-negativen Patienten mit Tuberkulose können die FDG-PET-Aufnahmen einen ausgedehnteren Befall mit Mycobacterium tuberculosis vermuten lassen als das kontrastverstärkte CT

Systolic function evaluated with cardiovascular magnetic resonance imaging in HIV-infected patients

BACKGROUND : Of all areas worldwide, sub-Saharan Africa is worst affected by the HIV and/or AIDS epidemic. Cardiovascular manifestations are very common and are a powerful contributor to mortality, but often go undetected. Cardiovascular magnetic resonance (CMR) is the most reliable method of assessing cardiac function and morphology and, with this in mind, we initiated a cross-sectional study comparing CMR-determined morphological and functional parameters in asymptomatic HIV-infected patients who were not yet on treatment and early in the disease, with HIV-uninfected control patients. OBJECTIVES : To ascertain whether there were any morphological abnormalities or systolic functional impairments on CMR in untreated asymptomatic HIV-infected patients, compared with HIV-uninfected control individuals. METHODS : The CMR studies were performed using a 1.5-T whole-body clinical magnetic resonance 16-channel scanner (Achieva, Philips Medical Systems, Best, The Netherlands), using a cardiac five-element phased-array receiver coil (SENSE coil). Functional assessment was performed on 36 HIV-infected patients and the findings compared with 35 HIV-uninfected control patients who were matched for age and sex. RESULTS : There was no significant difference in systolic function between the HIV-uninfected and the HIV-infected patients. The left ventricular end diastolic mass (LVEDM) was slightly higher in the HIV-infected group, but this was statistically insignificant. CONCLUSION : No significant differences were found regarding the CMR systolic functional analysis and morphological parameters between the HIV-infected and the healthy volunteers.http://www.sajr.org.za/am2017Internal MedicineRadiolog

Sustaining essential healthcare in Africa during the COVID-19 pandemic

No abstract available.https://www.ingentaconnect.com/content/iuatld/ijtldhj2021Family MedicineImmunologyInternal MedicineMedical Microbiolog

Detection of acute and early HIV-1 infections in an HIV hyper-endemic area with limited resources

BACKGROUND: Two thirds of the world's new HIV infections are in sub-Saharan Africa. Acute HIV infection (AHI) is the time of virus acquisition until the appearance of HIV antibodies. Early HIV infection, which includes AHI, is the interval between virus acquisition and establishment of viral load set-point. This study aimed to detect acute and early HIV infections in a hyper-endemic setting. METHODS: This was a cross-sectional diagnostic study that enrolled individuals who had negative rapid HIV results in five clinics in South Africa. Pooled nucleic acid amplification testing (NAAT) was performed, followed by individual sample testing in positive pools. NAAT-positive participants were recalled to the clinics for confirmatory testing and appropriate management. HIV antibody, p24 antigen, Western Blot and avidity tests were performed for characterization of NAAT-positive samples. RESULTS: The study enrolled 6910 individuals with negative rapid HIV results. Median age was 27 years (interquartile range {IQR}: 23-31). NAAT was positive in 55 samples, resulting in 0.8% newly diagnosed HIV-infected individuals (95% confidence interval {CI}: 0.6-1.0). The negative predictive value for rapid HIV testing was 99.2% (95% CI: 99.0-99.4). Characterization of NAAT-positive samples revealed that 0.04% (95% CI: 0.000-0.001) had AHI, 0.3% (95% CI: 0.1-0.4) had early HIV infection, and 0.5% (95% CI: 0.5-0.7) had chronic HIV infection. Forty-seven (86%) of NAAT-positive participants returned for follow-up at a median of 4 weeks (IQR: 2-8). Follow-up rapid tests were positive in 96% of these participants. CONCLUSIONS: NAAT demonstrated that a substantial number of HIV-infected individuals are misdiagnosed at South African points-of-care. Follow-up rapid tests done within a 4 week interval detected early and chronic HIV infections initially missed by rapid HIV testing. This may be a practical and affordable strategy for earlier detection of these infections in resource-constrained settings. Newer molecular tests that can be used at the points-of-care should be evaluated for routine diagnosis of HIV in hyper-endemic settings.National Health Laboratory Service Research Trust (NHLS-RT) grant (www.nhls.ac. za), SHM and DJM. Federation of Infectious Diseases Societies of Southern Africa and GlaxoSmithKline (FIDSSA- GSK) grant (www.fidssa.co.za), University of Pretoria research assistant grant (www.up.ac.za) and research grant from GlaxoSmithKline, SHM. South African Medical Research Council Self Initiated Research (MRC-SIR) grant (www.mrc.ac.za), Discovery Foundation (www.tshikululu.org.za), SHM. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (www.nih.gov), TCQ and OL; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.http://www.plosone.orgam2016Internal MedicineMedical Microbiolog

A comparison of the pharmacokinetics of Aspen Ceftriaxone and Rocephin in community-acquired meningitis

BACKGROUND. Community-acquired bacterial meningitis (CABM) is a life-threatening condition that is common among immunocompromised individuals. Intravenous ceftriaxone, of which Rocephin (ROC) is the originator brand, is recommended as first-line therapy in South Africa. Despite concerns regarding therapeutic equivalence with generic agents, this is the first study that has been conducted comparing clinical pharmacokinetics (PK) of a generic ceftriaxone formulation with the originator. OBJECTIVE. To compare the PK and safety of Aspen Ceftriaxone (AC) and ROC in the treatment of adult CABM. METHODS. A total of 63 eligible patients were randomised 1:1 to receive 2 g of either medication twice daily for a duration based on the identity of the causative organism and their physician’s clinical judgment. The primary endpoint of this study was the comparison of clinical PK, specifically the concentrations of each drug in the cerebrospinal fluid with corresponding paired plasma samples. While this study was underpowered to assess efficacy, safety could be evaluated on the basis of reported adverse events. RESULTS. The two patient groups were epidemiologically similar. There were no statistically significant differences in PK between either agent, nor any difference with regard to safety. CONCLUSION. AC can be considered as equivalent to ROC with regard to PK and safety in patients with CABM.Aspen Pharmacare Ltd, SA.http://www.samj.org.zaam2014ay201