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.

Associations of inter-annual rainfall decreases with subsequent HIV outcomes for persons with HIV on antiretroviral therapy in Southern Africa: a collaborative analysis of cohort studies.

BACKGROUND: Periods of droughts can lead to decreased food security, and altered behaviours, potentially affecting outcomes on antiretroviral therapy (ART) among persons with HIV (PWH). We investigated whether decreased rainfall is associated with adverse outcomes among PWH on ART in Southern Africa. METHODS: Data were combined from 11 clinical cohorts of PWH in Lesotho, Malawi, Mozambique, South Africa, Zambia, and Zimbabwe, participating in the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration. Adult PWH who had started ART prior to 01/06/2016 and were in follow-up in the year prior to 01/06/2016 were included. Two-year rainfall from June 2014 to May 2016 at the location of each HIV centre was summed and ranked against historical 2-year rainfall amounts (1981-2016) to give an empirical relative percentile rainfall estimate. The IeDEA-SA and rainfall data were combined using each HIV centre's latitude/longitude. In individual-level analyses, multivariable Cox or generalized estimating equation regression models (GEEs) assessed associations between decreased rainfall versus historical levels and four separate outcomes (mortality, CD4 counts < 200 cells/mm3, viral loads > 400 copies/mL, and > 12-month gaps in follow-up) in the two years following the rainfall period. GEEs were used to investigate the association between relative rainfall and monthly numbers of unique visitors per HIV centre. RESULTS: Among 270,708 PWH across 386 HIV centres (67% female, median age 39 [IQR: 32-46]), lower rainfall than usual was associated with higher mortality (adjusted Hazard Ratio: 1.18 [95%CI: 1.07-1.32] per 10 percentile rainfall rank decrease) and unsuppressed viral loads (adjusted Odds Ratio: 1.05 [1.01-1.09]). Levels of rainfall were not strongly associated with CD4 counts < 200 cell/mm3 or > 12-month gaps in care. HIV centres in areas with less rainfall than usual had lower numbers of PWH visiting them (adjusted Rate Ratio: 0.80 [0.66-0.98] per 10 percentile rainfall rank decrease). CONCLUSIONS: Decreased rainfall could negatively impact on HIV treatment behaviours and outcomes. Further research is needed to explore the reasons for these effects. Interventions to mitigate the health impact of severe weather events are required.

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.

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%.

Ensuring HIV-infected pregnant women start antiretroviral treatment: an operational cohort study from Lilongwe, Malawi.

OBJECTIVES: HIV-infected women identified through antenatal care (ANC) often fail to access antiretroviral treatment (ART), leaving them and their infants at risk for declining health or HIV transmission. We describe results of measures to improve uptake of ART among eligible pregnant women. METHODS: Between October 2006 and December 2009, interventions implemented at ANC and ART facilities in urban Lilongwe aimed to better link services for women with CD4 counts <250/µl. A monitoring system followed women referred for ART to examine trends and improve practices in referral completion, on-time ART initiation and ART retention. RESULTS: Six hundred and twelve women were ART eligible: 604 (99%) received their CD4 result, 344 (56%) reached the clinic, 286 (47%) started ART while pregnant and 261 (43%) were either alive on ART or transferred out after 6 months. Between 2006 and 2009, the median (IQR) time between CD4 blood draw and ART initiation fell from 41 days (17, 349) to 15 days (7,42) (P = 0.183); the proportion of eligible individuals starting ART while pregnant and retained for 6 months improved from 17% to 65% (P < 0.001). Delays generally shortened within the continuum of care from 2006 to 2009; however, time from CD4 blood draw to ART referral increased from 7 to 14 days. CONCLUSIONS: Referrals between facilities and delays through CD4 count measurements create bottlenecks in patient care. Retention improved over time, but delays within the linkage process remained. ART initiation at ANC plus use of point-of-care CD4 tests may further enhance ART uptake.

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.

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.

Growth response to antiretroviral treatment in HIV-infected children: a cohort study from Lilongwe, Malawi.

OBJECTIVE: Malnutrition is common in HIV-infected children in Africa and an indication for antiretroviral treatment (ART). We examined anthropometric status and response to ART in children treated at a large public-sector clinic in Malawi. METHODS: All children aged <15 years who started ART between January 2001 and December 2006 were included and followed until March 2008. Weight and height were measured at regular intervals from 1 year before to 2 years after the start of ART. Sex- and age-standardized z-scores were calculated for weight-for-age (WAZ) and height-for-age (HAZ). Predictors of growth were identified in multivariable mixed-effect models. RESULTS: A total of 497 children started ART and were followed for 972 person-years. Median age (interquartile range; IQR) was 8 years (4-11 years). Most children were underweight (52% of children), stunted (69%), in advanced clinical stages (94% in WHO stages 3 or 4) and had severe immunodeficiency (77%). After starting ART, median (IQR) WAZ and HAZ increased from -2.1 (-2.7 to -1.3) and -2.6 (-3.6 to -1.8) to -1.4 (-2.1 to -0.8) and -1.8 (-2.4 to -1.1) at 24 months, respectively (P < 0.001). In multivariable models, baseline WAZ and HAZ scores were the most important determinants of growth trajectories on ART. CONCLUSIONS: Despite a sustained growth response to ART among children remaining on therapy, normal values were not reached. Interventions leading to earlier HIV diagnosis and initiation of treatment could improve growth response.

Virologic failure and switch to second-line antiretroviral therapy in children with HIV in Lilongwe, Malawi: an observational cohort study.

BACKGROUND: As routine viral load testing among HIV-infected individuals on antiretroviral therapy (ART) expands, virologic failure (VF) among children in developing countries remains poorly understood. We assessed the rate of VF, the proportion failing who were subsequently switched to second-line ART and factors associated with VF among children ≤18 y. METHODS: An observation cohort study among 1312 children at two public clinics in Lilongwe, Malawi who initiated a first-line ART regimen between January 2014 and December 2017 and remained on treatment for ≥6 mo was conducted. Kaplan-Meier methods estimated the probabilities of VF. Univariable and multivariable Poisson regression models were used to explore predictors of VF. RESULT: Overall, 16% (208/1312) of children experienced VF with an incidence rate of 10.1 events per 100 person-years. Of the 208, 184 (88%) were switched to second-line ART: 68 (43%) switched the same day VF was confirmed and 106 (66%) switched within 90 d of confirmed VF. Use of a Nevirapine (NVP)-based regimen and initiating ART in 2016-2017 compared with 2014-2015 were independent predictors of VF. CONCLUSION: VF is common among children receiving ART. The findings suggest that VF can be reduced by phasing out NVP-based regimen and by ensuring optimal adherence to ART.

Cytomegalovirus Retinitis Screening and Treatment in Human Immunodeficiency Virus Patients in Malawi: A Feasibility Study.

BACKGROUND: Cytomegalovirus retinitis is a treatable cause of blindness in people with human immunodeficiency virus (HIV) typically with CD4 counts <50 cells/mm3. Diagnosis is with indirect fundoscopy, and treatment is with intravitreal ganciclovir injections or systemic therapy. However, diagnosis and treatment are not widely available in Malawi, which has an adult HIV prevalence estimated at 10.6%. This study aimed to establish the prevalence of cytomegalovirus retinitis among people with HIV in Malawi and the feasibility of screening. METHODS: Patients with CD4 counts <200 cells/mm3 were examined from 2 HIV clinics in Lilongwe and the main government hospital. Data were collected on antiretroviral therapy, ocular symptoms, and visual acuity. Fundoscopy was performed to investigate for features of cytomegalovirus retinitis. Retinal photographs were reviewed by an ophthalmologist. Patients diagnosed with cytomegalovirus retinitis were offered weekly ganciclovir injections, because systemic treatment was not available. RESULTS: Five of the 102 people with HIV screened had cytomegalovirus retinitis (4.9%). All affected patients had CD4 counts <50 cells/mm3 (mean, 15 cells/mm3; range, 3-22 cells/mm3). Visual acuity was unhelpful in identifying those with cytomegalovirus retinitis. Symptomatically, only blurred vision was useful. Two patients consented to treatment, 1 of which improved but relapsed after defaulting. CONCLUSIONS: Cytomegalovirus retinitis screening based on CD4 count is essential to early recognition because visual acuity and symptoms are unreliable. Cytomegalovirus retinitis is a significant yet neglected public health issue in Malawi. Oral valganciclovir is essential to reduce blindness and mortality in those diagnosed but is not yet available. Further screening and advocacy are needed.

Treatment outcomes of AIDS-associated Kaposi's sarcoma under a routine antiretroviral therapy program in Lilongwe, Malawi: bleomycin/vincristine compared to vincristine monotherapy.

PURPOSE: Despite Kaposi's sarcoma (KS) being the most prevalent AIDS-associated cancer in resource limited settings, optimal treatment options remain unknown. We assessed whether bleomycin/vincristine compared to vincristine monotherapy was associated with improved treatment outcomes for AIDS-associated KS among patients initiating combination antiretroviral therapy (cART) in Malawi. METHODS: All patients initiating cART and chemotherapy for AIDS-related KS were identified from an electronic data system from the HIV Lighthouse Clinic from 2002 to 2011. Treatment responses were compared between patients receiving vincristine monotherapy and vincristine/bleomycin. Binomial regression models were implemented to assess probability of tumor improvement for patients receiving vincristine/bleomycin compared to vincristine monotherapy after a complete cycle of chemotherapy (9-10 months). A chi-squared test was used to compare changes in CD4 count after six months of chemotherapy. RESULTS: Of 449 patients with AIDS-associated KS on chemotherapy, 94% received vincristine monotherapy and 6% received bleomycin/vincristine. Distribution of treatment outcomes was different: 29% of patients on vincristine experienced tumor improvement compared to 53% of patients on bleomycin/vincristine. Patients receiving bleomycin/vincristine were 2.25 (95% CI: 1.47, 3.44) times as likely to experience tumor improvement as to those on vincristine monotherapy. This value changed little after adjustment for age and baseline CD4 count: 2.46 (95% CI: 1.57, 3.86). Change in CD4 count was similar for patients receiving vincristine monotherapy and bleomycin/vincristine (p = 0.6). CONCLUSION: Bleomycin/vincristine for the treatment of AIDS-associated KS was associated with better tumor response compared to vincristine monotherapy without impairing CD4 count recovery. Replication in larger datasets and randomized controlled trials is necessary.

Are they really lost? "true" status and reasons for treatment discontinuation among HIV infected patients on antiretroviral therapy considered lost to follow up in Urban Malawi.

INTRODUCTION: Patients who are lost to follow-up (LTFU) while on antiretroviral therapy (ART) pose challenges to the long-term success of ART programs. We describe the extent to which patients considered LTFU are misclassified as true disengagement from care when they are still alive on ART and explain reasons for ART discontinuation using our active tracing program to further improve ART retention programs and policies. METHODS: We identified adult ART patients who missed clinic appointment by more than 3 weeks between January 2006 and December 2010, assuming that such patients would miss their doses of antiretroviral drugs. Patients considered LTFU who consented during ART registration were traced by phone or home visits; true ART status after tracing was documented. Reasons for ART discontinuation were also recorded for those who stopped ART. RESULTS: Of the 4,560 suspected LTFU cases, 1,384 (30%) could not be traced. Of the 3,176 successfully traced patients, 952 (30%) were dead and 2,224 (70%) were alive, of which 2,183 (99.5%) started ART according to phone-based self-reports or physical verification during in-person interviews. Of those who started ART, 957 (44%) stopped ART and 1,226 (56%) reported still taking ART at the time of interview by sourcing drugs from another clinic, using alternative ART sources or making brief ART interruptions. Among 940 cases with reasons for ART discontinuations, failure to remember (17%), too weak/sick (12%), travel (46%), and lack of transport to the clinic (16%) were frequently cited; reasons differed by gender. CONCLUSION: The LTFU category comprises sizeable proportions of patients still taking ART that may potentially bias retention estimates and misdirect resources at the clinic and national levels if not properly accounted for. Clinics should consider further decentralization efforts, increasing drug allocations for frequent travels, and improving communication on patient transfers between clinics to increase retention and adherence.

Managing HIV-infected children in a low-resource, public clinic: a comparison of nurse vs. clinical officer practices in ART refill, calculation of adherence and subsequent appointments.

BACKGROUND: In Malawi, as in other sub-Saharan African countries, nurses manage patients of all ages on antiretroviral treatment(ART). Nurse management of children is rarely studied.We compare ART prescribing between nurses and clinical officers during routine clinic visits at an urban, public clinic to inform policy in paediatric ART management. METHODS: Caregivers of children on first-line ART provided information about visit dates, pill counts, ART dosage and formulation to a nurse and, subsequently, to a clinical officer. Nurses and clinical officers independently calculated adherence, dosage based on body weight, and set next appointment date. Clinical officers, but not nurses, accessed an electronic data system that made the calculations for them based on information from prior visits, actual and expected pill consumption, and standard drug supplies. Nurses calculated with pen and paper. For numerical variables, Bland-Altman graphs plot differences of each nurse clinical officer pair against the mean, show the 95% limits of agreement (LoA), and also show the mean difference across all reviews. Kappa statistics assess agreement for categorical variables. RESULTS: A total of 704 matched nurse clinical officer reviews of 367 children attending the ART clinics between March and July 2010 were analyzed. Eight nurses and 18 clinical officers were involved; two nurses and five clinical officers managed 100 visits or more. Overall, there was a good agreement between the two cadres. Differences between nurses and clinical officers were within narrow LoA and mean differences showed little deviation from zero, indicating little skewing towards one cadre. LoA of adherence and morning and evening ART dosages varied from -24% to 24%, -0.4 to 0.4 and -0.41 to 0.40 tablets,respectively, with mean differences (95% CI) of 0.003 (-0.9, 0.91), -0.005 (-0.02, 0.01) and -0.009 (-0.02, 0.01). Next appointment calculations differed more between cadres with LoA from -40 to 42 days [mean difference: 0.96 days (95%CI:-0.6 to 2.5)], but agreement in the ART formulation prescribed was very good (kappa 0.93). CONCLUSIONS: Nurses' ART prescribing practices and calculations of adherence and next appointments are similar to clinical officers, although clinical officers used an electronic system. Our findings support the decision of Malawi's health officials to utilize nurses to manage paediatric ART patients.