Point-of-care ultrasound to inform antiviral treatment initiation in chronic hepatitis B virus infection in low-resource settings - the PUSH protocol.

BACKGROUND: Chronic Hepatitis B (CHB) is prevalent worldwide and most related deaths occur in low-resource settings. Antiviral treatment of CHB is indicated in those with significant liver disease and markers of viral replication. However, recommended diagnostics such as elastography (a non-invasive imaging measure of fibrosis/cirrhosis) or HBV viral load are often lacking in these settings, which creates barriers to treatment. Point-of-care clinical B-mode ultrasound (US) has potential to overcome implementation barriers in HBV care programs in low-resource settings. METHODS: We describe a Point-of-care US protocol for Hepatitis ("PUSH") to check for signs of cirrhosis and hepatocellular carcinoma in the liver of people with CHB. We performed a prospective observational study applying the protocol, first by trainee clinicians and then by trainers, in consecutive patients referred to our clinic for CHB treatment eligibility assessment. All patients additionally underwent physical examination, liver function tests (LFTs) and platelet counts. We describe the PUSH training approach and performance of the protocol. RESULTS: Four clinicians and 111 adult patients with HBV infection were included in the development of PUSH. Using US, liver complications of HBV were documented in 31 (27.9%) patients; including cirrhosis in 15 patients, HCC with cirrhosis in 13, and HCC without cirrhosis in 3. Patients with sonographic findings had significantly more clinical symptoms also their LFTs were higher and more frequently indicative for HBV treatment. Of 28 patients with sonographic diagnosis of cirrhosis, 23 (82.1%) showed a nodular liver surface, 24 (85.7%) a coarse echotexture, 20 (71.4%) scarce vessels, and 9 (32.1%) an enlarged caudate lobe. Overall concordance of the findings between assessment of trainees and experienced sonographers was high, ranging from 90 to 95%; trainees were not blinded to clinical and laboratory findings. CONCLUSION: Ultrasound can facilitate same-day initiation of antiviral therapy for chronic HBV monoinfection in a resource-limited setting and a streamlined protocol-driven liver ultrasound can be feasibly used by front line clinicians managing HBV.

Point-of-care ultrasound for tuberculosis and HIV-revisiting the focused assessment with sonography for HIV-associated tuberculosis (FASH) protocol and its differential diagnoses.

BACKGROUND: The 'Focused assessment with sonography for HIV-associated tuberculosis' (FASH) protocol has been applied and researched for over a decade in HIV-infected patients with suspected extra-pulmonary tuberculosis. Interpretation of target FASH features may be challenging as they can also indicate alternative opportunistic diseases. OBJECTIVES: The primary aim of the review was summarizing the accumulated evidence on the diagnostic accuracy of the FASH protocol including description of diagnoses of target FASH features. SOURCES: Literature was searched using PubMed, Google Scholar, and publications referencing the original FASH publications; data from identified studies were compiled with data from studies identified by a preceding Cochrane review. A meta-analysis was performed based on a generalized linearized mixed model. Data on differential diagnoses were compiled by literature review and retrospective evaluation of clinical data. CONTENT: We identified ten studies; abdominal target FASH features were most studied. Sensitivity and specificity estimates were 39% (95% CI 25-54) and 89% (95% CI 83-96) for enlarged lymph nodes (ten studies), and 30% (95% CI 16-45%) and 93% (95% CI 89-98%) for hypoechoic spleen lesions (eight studies). In people living with HIV differential diagnoses of target FASH features are multiple and primarily include other opportunistic infections and malignancies such as non-tuberculous mycobacterial infection, bacillary angiomatosis, hepato-splenic brucellosis, meliodiosis, visceral leishmaniasis, invasive fungal infections, and lymphoma as well as Kaposi sarcoma. Ultrasound-guided diagnostic sampling may assist obtention of a definitive diagnosis. IMPLICATIONS: On the basis of current evidence, although limited by methodology, and personal experience, we recommend basic ultrasound training, including the FASH protocol and ultrasound-guided diagnostic interventions, for all healthcare providers working with people living with HIV in resource-limited settings.

POINT-OF-CARE ULTRASOUND FOR TUBERCULOSIS IN YOUNG CHILDREN WITH SEVERE ACUTE MALNUTRITION.

Point-of-care ultrasound (POCUS) to diagnose tuberculosis (TB) was assessed in 131 children under 5 years old hospitalized with severe acute malnutrition. Of these, 23% had confirmed or unconfirmed TB and 5% were HIV-infected. There were no POCUS findings associated with TB diagnosis. POCUS visualization quality was satisfactory for 65% and examination acceptability was "good" for 52%.

Reduction in mortality from HIV-related CNS infections in routine care in Africa (DREAMM): a before-and-after, implementation study.

BACKGROUND: Four decades into the HIV epidemic, CNS infection remains a leading cause of preventable HIV-related deaths in routine care. The Driving Reduced AIDS-associated Meningo-encephalitis Mortality (DREAMM) project aimed to develop, implement, and evaluate pragmatic implementation interventions and strategies to reduce mortality from HIV-related CNS infection. METHODS: DREAMM took place in five public hospitals in Cameroon, Malawi, and Tanzania. The main intervention was a stepwise algorithm for HIV-related CNS infections including bedside rapid diagnostic testing and implementation of WHO cryptococcal meningitis guidelines. A health system strengthening approach for hospitals was adopted to deliver quality care through a co-designed education programme, optimised clinical and laboratory pathways, and communities of practice. DREAMM was led and driven by local leadership and divided into three phases: observation (including situational analyses of routine care), training, and implementation. Consecutive adults (aged ≥18 years) living with HIV presenting with a first episode of suspected CNS infection were eligible for recruitment. The primary endpoint was the comparison of 2-week all-cause mortality between observation and implementation phases. This study completed follow-up in September, 2021. The project was registered on ClinicalTrials.gov, NCT03226379. FINDINGS: From November, 2016 to April, 2019, 139 eligible participants were enrolled in the observation phase. From Jan 9, 2018, to March 25, 2021, 362 participants were enrolled into the implementation phase. 216 (76%) of 286 participants had advanced HIV disease (209 participants had missing CD4 cell count), and 340 (69%) of 494 participants had exposure to antiretroviral therapy (ART; one participant had missing ART data). In the implementation phase 269 (76%) of 356 participants had a probable CNS infection, 203 (76%) of whom received a confirmed microbiological or radiological diagnosis of CNS infection using existing diagnostic tests and medicines. 63 (49%) of 129 participants died at 2 weeks in the observation phase compared with 63 (24%) of 266 in the implementation phase; and all-cause mortality was lower in the implementation phase when adjusted for site, sex, age, ART exposure (adjusted risk difference -23%, 95% CI -33 to -13; p<0·001). At 10 weeks, 71 (55%) died in the observation phase compared with 103 (39%) in the implementation phase (-13%, -24 to -3; p=0·01). INTERPRETATION: DREAMM substantially reduced mortality from HIV-associated CNS infection in resource-limited settings in Africa. DREAMM scale-up is urgently required to reduce deaths in public hospitals and help meet Sustainable Development Goals. FUNDING: European and Developing Countries Clinical Trials Partnership, French Agency for Research on AIDS and Viral Hepatitis. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.

A prospective cohort study identifies two types of HIV+ Kaposi Sarcoma lesions: proliferative and inflammatory.

Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH) in many countries where KS-associated herpesvirus is endemic. Treatment has changed little in 20 years, but the disease presentation has. This prospective cohort study enrolled 122 human immunodeficiency virus (HIV) positive KS patients between 2017 and 2019 in Malawi. Participants were treated with bleomycin, vincristine and combination antiretroviral therapy, the local standard of care. One-year overall survival was 61%, and progression-free survival was 58%. The 48-week complete response rate was 35%. RNAseq (n = 78) differentiated two types of KS lesions, those with marked endothelial characteristics and those enriched in inflammatory transcripts. This suggests that different KS lesions are in different disease states consistent with the known heterogeneous clinical response to treatment. In contrast to earlier cohorts, the plasma HIV viral load of KS patients in our study was highly variable. A total of 25% of participants had no detectable HIV; all had detectable KSHV viral load. Our study affirms that many KS cases today develop in PLWH with well-controlled HIV infection and that different KS lesions have differing molecular compositions. Further studies are needed to develop predictive biomarkers for this disease.

Blood pressure changes during tenofovir-based antiretroviral therapy among people living with HIV in Lilongwe, Malawi: results from the prospective LighTen Cohort Study.

BACKGROUND: Sub-Saharan Africa is one of the regions in the world with the highest numbers of uncontrolled hypertension as well as people living with HIV/AIDS (PLHIV). However, the association between hypertension and antiretroviral therapy is controversial. METHODS: Participant demographics, medical history, laboratory values, WHO clinical stage, current medication, and anthropometric data were recorded at study entry and during study visits at 1, 3, 6 months, and every 6 months thereafter until month 36. Patients who stopped or changed their antiretroviral therapy (tenofovir, lamivudine, efavirenz) were censored on that day. Office blood pressure (BP) was categorized using ≥ 2 measurements on ≥ 2 occasions during the first three visits. Factors associated with systolic and mean BP were analyzed using bivariable and multivariable multilevel linear regression. RESULTS: 1,288 PLHIV (751 females, 58.3%) could be included and 832 completed the 36 months of observation. Weight gain and a higher BP level at study entry were associated with an increase in BP (p < 0.001), while female sex (p < 0.001), lower body weight at study entry (p < 0.001), and high glomerular filtration rate (p = 0.009) protected against a rise in BP. The rate of uncontrolled BP remained high (73.9% vs. 72.1%) and despite indication treatment, adjustments were realized in a minority of cases (13%). CONCLUSION: Adherence to antihypertensive treatment and weight control should be addressed in patient education programs at centers caring for PLHIV in low-resources settings like Malawi. Together with intensified training of medical staff to overcome provider inertia, improved control rates of hypertension might eventually be achieved. TRIAL REGISTRATION: NCT02381275.

Case Report: Role of Point-of-Care Ultrasound in the Diagnosis of Bacillary Angiomatosis.

Clinical skin manifestations are commonly seen in resource-limited settings, but they are frequently misdiagnosed due to the lack of microbiological tests with ensuing stigma and long-term disability. The adoption of portable ultrasound devices, which extend physical examination in the hands of trained clinicians, has partially improved the situation. Specific protocols, such as focused assessment with sonography for HIV-associated tuberculosis (FASH), have led to simplified diagnostic pathways. Here we describe a case of bacillary angiomatosis in a patient with advanced HIV disease presenting with subacute unusual cutaneous lesions. The patient also presented with significant weight loss, anemia, and prostration. Highly sensitive rapid tests for tuberculosis and cryptococcosis were negative, and CD4 count was very low. Ultrasound scanning (US) and biopsy of the cutaneous lesions finally led to diagnosis and treatment. This report illustrates the benefits of integrating ultrasound-based protocols with clinical skills, as the diagnosis was suspected based on clinical presentation and US and confirmed by pathology. The importance of adoption of US protocols by infectious diseases clinicians is discussed.

Ultrasound findings in Kaposi sarcoma patients: overlapping sonographic features with disseminated tuberculosis.

BACKGROUND: Focused Assessment with Sonography for HIV-associated TB (FASH) is a diagnostic tool for extra-pulmonary tuberculosis (TB) in symptomatic patients with advanced HIV. As Kaposi's sarcoma (KS) is also prevalent in this patient population, changes due to KS may mimic TB findings and clinical interpretation of target FASH findings can be challenging. We aimed to describe sonographic findings in patients with KS. METHODS: We performed a prospective observational study at Lighthouse clinic at Kamuzu Central Hospital, Lilongwe, Malawi, in consecutive patients with newly diagnosed KS, without known diagnosis of TB, referred for paclitaxel treatment. All patients underwent FASH and abdominal ultrasound to assess for effusions and changes in liver and spleen, as well as systematic sonographic assessment for lymphadenopathy. RESULTS: We included 30 patients. We found inguinal lymph nodes using ultrasound in 20 patients; in 3 (10%) additionally abdominal lymph nodes were found. Pathological effusions were seen in eight patients (27%): pericardial effusion in one (3%), pleural effusion in six (20%) and ascites in four (13%) patients. We found focal spleen lesions in three (10%) patients. Most of these lesions were echogenic, but in one patient, we saw hypoechoic lesions with an echogenic center. In three (10%) patients an unusual "sponge-like pattern" of the splenic vasculature was found. Six (20%) patients had echogenic focal lesions in the liver resembling hemangiomas, individual lesions showing a hypoechoic center. In two patients echogenic portal fields were seen. CONCLUSIONS: The majority of patients with newly diagnosed KS demonstrate sonographic features of disease, predominantly lymphadenopathy. Effusions were observed in a significant minority, as well as focal lesions in liver or spleen, which commonly resemble hemangiomas, but hypoechoic lesions were also observed and can easily be mistaken for extra-pulmonary TB. A 'sponge-like pattern' of the spleen should not be confused with micro-abscesses. In conclusion, this case series illustrates the diverse nature of ultrasound features in patients with KS, which can be difficult to distinguish from other opportunistic diseases, including TB.

"Sponge pattern" of the spleen: a rarely described high-frequency ultrasound pattern in HIV-positive patients.

BACKGROUND: The spleen is frequently scanned in workup of infections. Hypoechoic splenic micro-abscesses are known signs of disseminated tuberculosis in HIV co-infected patients. The spleen of HIV patients is thus often scanned using high-frequency transducers. METHODS AND FINDINGS: We describe a reticulo-nodular "sponge pattern" in the spleen of an HIV-positive patient with Hodgkin's lymphoma. Disseminated throughout the spleen, very small (1.5-2.0 mm) hypoechoic lesions having a branching reticulo-nodular distribution were seen. The lesions partly, but not entirely, follow splenic vasculature. Review of stored images of other patients identified 15 more cases showing a similar pattern. All patients were HIV positive, almost all with CD4 counts below 200 cells/mm3. Seven (44%) were additionally diagnosed with HHV-8-associated diseases, but the pattern was seen with various underlying opportunistic infections. DISCUSSION AND CONCLUSION: After comparison with spleen microscopic anatomy, we hypothesize that the white pulp of spleens in our patients is hyperplastic or otherwise changed in consistency to be better visible by high-frequency ultrasound. Concomitant human herpesvirus-8 infection may be another cause of this visible white pulp. While we can only speculate about the etiology of the splenic "sponge pattern," it needs to be recognized as it may be misinterpreted as splenic micro-abscesses of disseminated infections, like tuberculosis in severely immune-compromised patients.

Virological Findings and Treatment Outcomes of Cases That Developed Dolutegravir Resistance in Malawi's National HIV Treatment Program.

Millions of Africans are on dolutegravir-based antiretroviral therapy (ART), but few detailed descriptions of dolutegravir resistance and its clinical management exist. We reviewed HIV drug resistance (HIVDR) testing application forms submitted between June 2019 and October 2022, data from the national HIVDR database, and genotypic test results. We obtained standardized ART outcomes and virological results of cases with dolutegravir resistance, and explored associations with dolutegravir resistance among individuals with successful integrase sequencing. All cases were on two nucleoside reverse transcriptase inhibitors (NRTIs)/dolutegravir, and had confirmed virological failure, generally with prolonged viremia. Among 89 samples with successful integrase sequencing, 24 showed dolutegravir resistance. Dolutegravir resistance-associated mutations included R263K (16/24), E138K (7/24), and G118R (6/24). In multivariable logistic regression analysis, older age and the presence of high-level NRTI resistance were significantly associated with dolutegravir resistance. After treatment modification recommendations, four individuals (17%) with dolutegravir resistance died, one self-discontinued ART, one defaulted, and one transferred out. Of the 17 remaining individuals, 12 had follow-up VL results, and 11 (92%) were <1000 copies/mL. Twenty-four cases with dolutegravir resistance among 89 individuals with confirmed virological failure suggests a considerable prevalence in the Malawi HIV program. Successful management of dolutegravir resistance was possible, but early mortality was high. More research on the management of treatment-experienced individuals with dolutegravir resistance is needed.

Dolutegravir Resistance in Malawi's National HIV Treatment Program.

Dolutegravir HIV drug resistance (HIVDR) data from Africa remain sparse. We reviewed HIVDR results of Malawians on dolutegravir-based antiretroviral therapy (November 2020-September 2021). Of 6462 eligible clients, 33 samples were submitted to South Africa, 27 were sequenced successfully, and 8 (30%) had dolutegravir HIVDR. Malawi urgently requires adequate HIVDR testing capacity.

Implementing Advanced HIV Disease Care for Inpatients in a Referral Hospital in Malawi - Demand, Results and Cost Implications.

Setting: 100 bed medical ward in referral hospital, Lilongwe, Malawi. Objective: HIV positive patients admitted to hospital often have advanced HIV disease (AHD) and are at risk for mortality. WHO guidelines suggest a package of care for AHD; these are often not implemented, especially in inpatient settings. We describe an implementation model for AHD care, its outcomes in routine care and provide cost estimates. Design: An "AHD care room" was established staffed by HIV counselor, nurse, and clinical officer allowing Provider Initiated Testing and Counseling, diagnostic testing for AHD and ensuring availability of HIV and TB drugs for rapid treatment initiation. Results: In the observation period from January to December 2020, a total of 1549 medical inpatients were tested for HIV (coverage 77.1%); 69 tested positive (yield 4.5%). The total proportion of HIV positive was 32.3% (638 already on ART and 69 newly diagnosed). CD4+ testing was done in 460 medical inpatients (65.1%); 245 (53.2%) were below 200 cells/ml and thus met definition of AHD. A total of 238 received S-CrAg tests; 39 (16.3%) were positive; 62 (28.3%) of 219 U-LAM tests were positive. The cost per identification of HIV positive patient was US$ 110.8; per AHD diagnosis between US$ 17.1 to 78.9; per positive S-CrAg test US$ 18.5 and per positive U-LAM test US$ 17.5. Conclusion: Our model successfully implemented AHD services according to WHO guidelines and provides basic costing data. Similar services could be implemented in other hospitals in LMICs.

Educational Content and Acceptability of Training Using Mobile Instant Messaging in Large HIV Clinics in Malawi.

Background: In resource-limited settings, many HIV-infected patients with advanced HIV-related disease need specialized care not represented in guidelines. Training opportunities for healthcare providers on advanced HIV care are limited. The aim of this study was to evaluate the educational content and acceptability of mobile instant messaging (MIM) as a training and telemedicine tool for HIV care providers in Malawi. Methods: At the Lighthouse Clinic, Malawi, a MIM group using WhatsApp® was created for clinical officers and moderated by an infectious disease consultant. Questions encountered in the clinics as well as educational cases were posted; identifying data was not to be posted. MIM conversation was analyzed and in-depth interviews with users on its perceptions were performed. Results: MIM was utilized by 25 clinical officers and five physicians with an average of 2.3 threads/week over the observation period of 15 months. Discussed topics related to tuberculosis (25 threads), adverse drug reaction (22 threads), antiretroviral treatment (21 threads), cryptococcal meningitis (12 threads), and drug dosing/logistics. In 20% of the threads at least one image file was shared (mainly pictures of skin conditions and chest X-rays). In-depth interviews showed that clinical officers appreciated MIM group as a telemedicine consulting and training tool. Conclusion: MIM was a successful and well-accepted telemedicine tool for support and training of clinical officers providing HIV care in a resource-limited setting. MIM may be integrated in training strategies to expand the knowledge of HIV care providers.

Sonographic findings in visceral leishmaniasis - A narrative review.

BACKGROUND: Visceral leishmaniasis (VL) is predominantly a neglected tropical parasitic disease but may also be acquired by travellers. We aimed at summarizing knowledge on sonographic presentation of VL to better understand sonographic features of VL. METHODS: PubMed was searched for studies and case reports presenting original data on sonographic findings of VL, published before August 13th, 2019. Demographic, clinical, and sonographic data were extracted and summarized in a qualitative approach. RESULTS: A total of 36 publications were included in this review; 27 of these were case reports and the remainder were prospective or retrospective studies. No study reported systematic cross-sectional comparative imaging. Overall, publications reported on 512 patients with VL of whom 12 were reported HIV-infected. Spleno- and hepatomegaly were the most frequently reported findings. Further relevant and repeatedly reported findings were splenic and hepatic lesions, abdominal lymphadenopathy, pleural and pericardial effusion and ascites. Reported focal splenic lesions were heterogeneous in size, shape, and echogenicity. Several publications reported gradual diminution and resolution of sonographic findings with VL treatment. CONCLUSION: Available literature on sonographic findings of VL is limited. Available reports indicate that spleno- and hepatomegaly, free fluid, abdominal lymphadenopathy, and focal splenic lesions may be common sonographic features in patients with VL. Because of the apparent overlap of sonographic features of VL, extrapulmonary tuberculosis and other conditions, interpretation of sonographic findings needs to be made with particular caution.

Near Point-of-Care HIV Viral Load: Targeted Testing at Large Facilities.

INTRODUCTION: Point-of-care (POC) technologies in resource-limited settings can circumvent challenges of centralized laboratory testing, improving clinical management. However, higher device costs and uncertain indications for use have inhibited scaling up POC modalities. To address this gap, we investigated the feasibility and cost of targeted near-POC viral load (VL) testing in 2 large HIV clinics in Lilongwe, Malawi. METHODS: VL testing using GeneXpert was targeted for patients suspected of treatment failure or returning to care after a previously elevated VL (>1000 copies/mL). Descriptive analysis of retrospective clinical and cost data is presented. RESULTS: Two thousand eight hundred thirteen near-POC VL tests were conducted. One thousand five hundred eleven (54%) tests were for patients for whom results and reason for the test were documented: 57% (794/1389) of tests were to confirm a previously high VL, and 33% (462/1389) were due to clinical indications. Sixty-one percent (926/1511) of patients had a high VL, of whom 78% (719/926) had a recorded clinical action: 77% (557/719) switched to second line antiretroviral therapy, and 15% (194/719) were referred for intensive adherence counseling. Eighty-two percent (567/687) of patients received a clinical action on the same day as testing. The "all-in" cost was $33.71 for a valid POC VL test, compared with an international benchmark for a centralized VL test of $28.62. CONCLUSION: Targeted, near-POC VL testing was feasible and consistently enabled prompt clinical action. The difference between the "all-in" cost of near-POC VL and centralized testing of $5.09 could be further reduced in an optimized national program by combining targeted near-POC testing and centralized testing.

Point-of-Care Ultrasound in the Diagnosis of Melioidosis in Laos.

Melioidosis is endemic in many rural areas in Southeast Asia where facilities for culture and identification of Burkholderia pseudomallei are often limited. We performed a prospective observational study in patients presenting with fever to Mahosot Hospital, the primary referral hospital in Laos, to establish whether the detection of abscesses on ultrasound could support a presumptive diagnosis of melioidosis. All patients underwent ultrasound examination to detect abscesses in the liver, spleen, prostate, or, if indicated, subcutaneous tissue. We enrolled 153 patients, including 18 patients with melioidosis. Of these, 11 (61%) had an abscess at one or more sites, including five (28%) with splenic and/or liver abscesses. Absence of abscesses cannot rule out melioidosis, but the positive predictive value of abscesses for melioidosis was high at 93% (88-96%). Therefore, in endemic areas, the presence of abscesses in febrile patients should prompt empiric antibiotic therapy for melioidosis even in the absence of culture confirmation.