The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Background 
In 2015, Zimbabwe introduced third-line antiretroviral therapy (ART) through four designated treatment centers; three government clinics in Harare and Bulawayo, and Newlands Clinic (NC), operated by a private voluntary organization in Harare. We describe characteristics of patients receiving third line ART and analyzed treatment outcomes in this national programme as of 31 December 2018.


Methods 
We described the population using proportions for categorical variables, and medians and interquartile ranges for continuous variables. Patients from NC, where data were more complete, were followed from the date of starting third-line ART until death, transfer, loss to follow up or 31 December 2018.


Results 
A total of 209 patients had ever received third-line ART: 124 at NC and 85 from the three government clinics. HIV genotype results were available for 89 (72%) patients at NC and fourteen (16.5%) patients in the government clinics. Median duration of third line ART (years) in the government clinics was 2.3 (IQR:0.6–3.4), 1.3 (IQR: 0.7–1.7) and 1 (0.6–1.9). Of the 67 patients who received third line ART in the government clinics for at least six months, 53 (79%) had most recent viral load (VL) < 1000 copies/ml. Data on other treatment outcomes from government clinics were incomplete.

From NC: a total of 109 (88%) patients were still in care, 13 (10.5%) had died and 2 (1.5%) were transferred. Median duration of third-line ART was 1.4 years (IQR: 0.6–2.8). Among the 111 NC patients who had received third-line ART for at least 6 months, 83 (75%) had a VL <50 copies/ml and 106 (95.5%) had a VL <1000 copies/ml.


Conclusion 
Our findings demonstrate that, with comprehensive care, patients failing second-line ART can achieve high rates of virological suppression on third-line regimens. There is need to decentralize the provision of third-line ART in Zimbabwe. More needs to be done to improve completeness of data in the government clinics.

/pdf/zimbabwe-s-national-third-line-antiretroviral-therapy-1rlbi3mvi0.pdf

Zimbabwe's national third-line antiretroviral therapy program: Cohort description and treatment outcomes

Patients in sub-Saharan Africa generally have poor anticoagulation control. We review the potential reasons for this poor control, as well as the potential solutions. Challenges include the affordability and centralisation of anticoagulation care, problems with access to medicines and international normalised ratio monitoring, the lack of locally validated standardized dosing protocols, and low levels of anticoagulation knowledge among healthcare workers and patients. Increasing numbers of patients will need anticoagulation in the future because of the increasing burden of noncommunicable disease in the region. We propose that locally developed "warfarin care bundles" which address multiple anticoagulation challenges in combination may be the most appropriate solution in this setting currently.

Improving anticoagulation in sub-Saharan Africa: What are the challenges and how can we overcome them?

Warfarin remains the oral anticoagulant of choice in sub-Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose-initiation model in sub-Saharan Black-African patients. For the development cohort, we used data from 364 patients who were recruited from 8 outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was undertaken using the International Warfarin Pharmacogenetics Consortium (IWPC) dataset (690 black patients). Four predictors (age, weight, target International Normalized Ratio range, and HIV status) were included in the final model, which achieved mean absolute errors (MAEs; mean of absolute differences between true dose and dose predicted by the model) of 11.6 (95% confidence interval (CI) 10.4-12.8) and 12.5 (95% CI 11.6-13.4) mg/week in the development and validation cohorts, respectively. Two other clinical models, IWPC and Gage, respectively, obtained MAEs of 12.5 (95% CI 11.3-13.7) and 12.7 (95% CI 11.5-13.8) mg/week in the development cohort, and 12.1 (95% CI 11.2-13.0) and 12.2 (95% CI 11.4-13.1) mg/week in the validation cohort. Compared with fixed dose-initiation, our model decreased the percentage of patients at high risk of suboptimal anticoagulation by 7.5% (1.5-13.7%) and 11.9% (7.1-16.8%) in the development and validation cohorts, respectively. The clinical utility of this model will be tested in a prospective study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ Warfarin dosing remains challenging due to a highly variable clinical response for a given dose. WHAT QUESTION DID THIS STUDY ADDRESS? ☑ Can a clinical dose-initiation model be developed and validated for sub-Saharan Black-African patients? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ☑ We have developed the first warfarin dose-initiation clinical model for Black-African patients in Uganda and South Africa. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ☑ We will be implementing and validating this model in a prospective cohort to inform future large-scale implementation. More optimized dosing should improve the quality of warfarin anticoagulation in these two developing countries.

Developing and Validating a Clinical Warfarin Dose-Initiation Model for Black-African Patients in South Africa and Uganda.

Patients infected with the human immunodeficiency virus (HIV) are more prone to systemic inflammation and pathological clotting, and many may develop deep vein thrombosis (DVT) as a result of this dysregulated inflammatory profile. Coagulation tests are not routinely performed unless there is a specific reason. We recruited ten healthy control subjects, 35 HIV negative patients with deep vein thrombosis (HIV negative-DVT), and 13 HIV patients with DVT (HIV positive-DVT) on the primary antiretroviral therapy (ARV) regimen-emtricitabine, tenofovir and efavirenz. Serum inflammatory markers, haematological results, viscoelastic properties using thromboelastography (TEG) and scanning electron microscopy (SEM) of whole blood (WB) were used to compare the groups. The DVT patients (HIV positive and HIV negative) had raised inflammatory markers. The HIV positive-DVT group had anaemia in keeping with anaemia of chronic disorders. DVT patients had a hypercoagulable profile on the TEG but no significant difference between HIV negative-DVT and HIV positive-DVT groups. The TEG analysis compared well and supported our ultrastructural results. Scanning electron microscopy of DVT patient’s red blood cells (RBCs) and platelets demonstrated inflammatory changes including abnormal cell shapes, irregular membranes and microparticle formation. All the ultrastructural changes were more prominent in the HIV positive-DVT patients. Although there were trends that HIV-positive patients were more hypercoagulable on functional tests (viscoelastic profile) compared to HIV-negative patients, there were no significant differences between the 2 groups. The sample size was, however, small in number. Morphologically there were inflammatory changes in patients with DVT. These ultrastructural changes, specifically with regard to platelets, appear more pronounced in HIV-positive patients which may contribute to increased risk for hypercoagulability and deep vein thrombosis.

/pdf/comparison-of-pathological-clotting-using-haematological-1z8g0301eg.pdf

Comparison of pathological clotting using haematological, functional and morphological investigations in HIV‑positive and HIV‑negative patients with deep vein thrombosis

Deep venous thrombosis (DVT) and its major complication pulmonary embolism (PE) are collectively known as venous thromboembolism In Uganda, the prevalence of DVT among HIV patients has not been previously published The aim of the study was to determine the prevalence and sonographic features of lower limb deep venous thrombosis among HIV positive patients on anti-retroviral treatment (ART) This was a cross sectional study in which HIV positive patients on ART were recruited from an out-patient HIV clinic at Mulago National Referral Hospital Patients were randomly selected and enrolled until a sample size of 384 was reached Study participants underwent compression and Doppler ultrasound studies of both lower limb deep veins using Medison Sonoacer7 ultrasound machine We found a prevalence of DVT of 91% (35 of 384 participants) among HIV patients on ART The prevalence of latent (asymptomatic) DVT was 23% Among 35 patients with DVT, 428% had chronic DVT; 311% had acute DVT and the rest had latent DVT Among the risk factors, the odds of occurrence of DVT among patients with prolonged immobility were 481 times as high as in those with no prolonged immobility (p = 0023; OR = 481; 95% CI 125–1862) Treatment with second line anti-retroviral therapy (ART) including protease inhibitors (PIs) was associated with higher odds of DVT occurrence compared with first line ART (p = 0020; OR = 238; 95% CI 114–497) The odds of DVT occurrence in patients with a lower CD4 count (< 200 cells/µl) were 536 times as high as in patients with CD4 counts above 500 cells/µl (p = 0008) About 486% patients with DVT had a low risk according to Well’s score DVT was shown in nearly 10% of HIV patients attending an out-patient clinic in an urban setting in Uganda Risk factors included protease inhibitors in their ART regimen, prolonged immobility, and low CD4 count (< 200 cells/µl) Clinicians should have a low threshold for performing lower limb Doppler ultrasound scan examination on infected HIV patients on ART who are symptomatic for DVT Therefore, clinicians should consider anti-coagulant prophylaxis and lower deep venous ultrasound screening of patients who are on second line ART regimen with low CD4 cell counts and/or with prolonged immobility or hormonal contraception

/pdf/prevalence-of-lower-limb-deep-venous-thrombosis-among-adult-3i7xoaks1r.pdf

Sosthene Tsongo Vululi

Papers

Prevalence of lower limb deep venous thrombosis among adult HIV positive patients attending an outpatient clinic at Mulago Hospital.