Immune reconstitution inflammatory syndrome associated with dermatophytoses in two HIV-1 positive patients in rural Tanzania: a case report

Immune reconstitution inflammatory syndrome associated with dermatophytoses (tinea-IRIS) may cause considerable morbidity. Yet, it has been scarcely reported and is rarely considered in the differential diagnosis of HIV associated cutaneous lesions in Africa. If identified, it responds well to antifungals combined with steroids. We present two cases of suspected tinea-immune reconstitution inflammatory syndrome from a large HIV clinic in rural Tanzania.; A first case was a 33 years-old female newly diagnosed HIV patient with CD4 count of 4 cells/μL (0 %), normal complete blood count, liver and renal function tests was started on co-formulated tenofovir/emtricitabine/efavirenz and prophylactic cotrimoxazole. Two weeks later she presented with exaggerated inflammatory hyperpigmented skin plaques with central desquamation, active borders and scratch lesions on the face, trunk and lower limbs. Tinea-IRIS was suspected and fluconazole (150 mg daily) and prednisolone (1 mg/Kg/day tapered down after 1 week) were given. Her symptoms subsided completely after 8 weeks of treatment, and her next CD4 counts had increased to 134 cells/μL (11 %). The second case was a 35 years-old female newly diagnosed with HIV. She had 1 CD4 cell/μL (0 %), haemoglobin 9.8 g/dl, and normal renal and liver function tests. Esophageal candidiasis and normocytic-normochromic anaemia were diagnosed. She received fluconazole, prophylactic cotrimoxazole and tenofovir/emtricitabine/efavirenz. Seven weeks later she presented with inflammatory skin plaques with elevated margins and central hyperpigmentation on the trunk, face and limbs in the frame of a good general recovery and increased CD4 counts (188 cells/μL, 6 %). Tinea-IRIS was suspected and treated with griseofulvin 500 mg daily and prednisolone 1 mg/Kg tapered down after 1 week, with total resolution of symptoms in 2 weeks.; The two cases had advanced immunosuppression and developed de-novo exaggerated manifestation of inflammatory lesions compatible with tinea corporis and tinea facies in temporal association with antiretroviral treatment initiation and good immunological response. This is compatible with unmasking tinea-IRIS, and reminds African clinicians about the importance of considering this entity in the differential diagnosis of patients with skin lesions developing after antiretroviral treatment initiation

High failure rates of protease inhibitor-based antiretroviral treatment in rural Tanzania - a prospective cohort study

Poor adherence to antiretroviral drugs and viral resistance are the main drivers of treatment failure in HIV-infected patients. In sub-Saharan Africa, avoidance of treatment failure on second-line protease inhibitor therapy is critical as treatment options are limited.; In the prospective observational study of the Kilombero & Ulanga Antiretroviral Cohort in rural Tanzania, we assessed virologic failure (viral load ≥1,000 copies/mL) and drug resistance mutations in bio-banked plasma samples 6-12 months after initiation of a protease inhibitor-based treatment regimen. Additionally, viral load was measured before start of protease inhibitor, a second time between 1-5 years after start, and at suspected treatment failure in patients with available bio-banked samples. We performed resistance testing if viral load was ≥1000 copies/ml. Risk factors for virologic failure were analyzed using logistic regression.; In total, 252 patients were included; of those 56% were female and 21% children. Virologic failure occurred 6-12 months after the start of a protease inhibitor in 26/199 (13.1%) of adults and 7/53 of children (13.2%). The prevalence of virologic failure did not change over time. Nucleoside reverse transcriptase inhibitors drug resistance mutation testing performed at 6-12 months showed a positive signal in only 9/16 adults. No cases of resistance mutations for protease inhibitors were seen at this time. In samples taken between 1-5 years protease inhibitor resistance was demonstrated in 2/7 adults. In adult samples before protease inhibitor start, resistance to nucleoside reverse transcriptase inhibitors was detected in 30/41, and to non-nucleoside reverse-transcriptase inhibitors in 35/41 patients. In 15/16 pediatric samples, resistance to both drug classes but not for protease inhibitors was present.; Our study confirms high early failure rates in adults and children treated with protease inhibitors, even in the absence of protease inhibitors resistance mutations, suggesting an urgent need for adherence support in this setting

A decade of HIV care in rural Tanzania: Trends in clinical outcomes and impact of clinic optimisation in an open, prospective cohort

OBJECTIVES: Our objectives were to describe trends in enrolment and clinical outcomes in the open, prospective Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) in the Morogoro region of southern Tanzania, and identify strengths and areas for improvement in the care of HIV-positive individuals in rural Tanzania. METHODS: We included adults (>/=15 years) and children (<15 years) enrolled in the cohort in 2005-2014. The cohort underwent significant changes from autumn 2012 to optimise care. We evaluated mortality and loss to follow-up (LTFU) using competing risks methods, ART usage, opportunistic infections (OI), co-infections and laboratory abnormalities. RESULTS: Overall, 7010 adults and 680 children were enrolled; enrolment peaked in 2008 but has increased steadily since 2011. Among adults (65% female; median age 37 [interquartile range 31-45] years), the proportion referred from hospital wards quadrupled in 2013-14 versus earlier years. 653 (9%) adults died and 2648 (38%) were LTFU; the five-year cumulative probabilities of death and LTFU were 10.3% and 44.0%, respectively. Among children, 69 (10%) died and 225 (33%) were LTFU. The corresponding five-year probabilities were 12.1% and 39.6%. Adult ART use (regardless of eligibility) increased from 5% in 2005 to 89% in 2014 (similarly among children), with 9% on second-line therapy in 2014 (17% of children). OI diagnoses increased over time; tuberculosis prevalence at enrolment quadrupled from 6% in 2011 to 26% in 2014. The proportion of newly-enrolled participants assessed for laboratory abnormalities peaked at nearly 100% in 2014 (from a minimum of 24%), yet abnormality prevalences remained fairly constant. CONCLUSIONS: In this cohort, ART usage improved dramatically and is approaching targets of 90%. Improved screening led to increases in detection of OIs and laboratory abnormalities, suggesting that a large number of these co-morbidities previously went undetected and untreated. Further work will address the high LTFU rates and implications for mortality estimates, and the management and outcomes of co-morbidities

Stigma-directed services (Stig2Health) to improve 'linkage to care' for people living with HIV in rural Tanzania: study protocol for a nested pre-post implementation study within the Kilombero and Ulanga Antiretroviral Cohort.

Background: HIV-related stigma is a major barrier to the timely linkage and retention of patients in HIV care in sub-Saharan Africa, where most people living with HIV/AIDS reside. In this implementation study we aim to evaluate the effect of stigma-directed services on linkage to care and other health outcomes in newly diagnosed HIV-positive patients. Methods: In a nested project of the Kilombero and Ulanga Antiretroviral Cohort in rural Tanzania, we conduct a prospective observational pre-post study to assess the impact of a bundle of stigma-directed services for newly diagnosed HIV positive patients. Stigma-directed services, delivered by a lay person living with HIV, are i) post-test counseling, ii) post-test video-assisted teaching, iii) group support therapy and group health education, and iv) mobile health. Patients receiving stigma services (enrolled from 1 st February 2020 to 31 st August 2021) are compared to a historical control receiving the standard of care (enrolled from 1 st July 2017 to 1 st February 2019). The primary outcome is 'linkage to care'. Secondary endpoints are retention in care, viral suppression, death and clinical failure at 6-12 months (up to 31 st August 2022). Self-reported stigma and depression are assessed using the Berger Stigma scale and the PHQ-9 questionnaire, respectively. The sample size calculation was based on cohort data from 2018. Assuming a pre-intervention cohort of 511 newly diagnosed adults of whom 346 (68%) were in care and on antiretroviral treatment (ART) at 2 months, a 10% increase in linkage (from 70 to 80%), a two-sided type I error rate of 5%, and 90% power, 321 adults are required for the post-implementation group. Discussion: We expect that integration of stigma-directed services leads to an increase of proportions of patients in care and on ART. The findings will provide guidance on how to integrate stigma-directed services into routine care in rural sub-Saharan Africa

Cohort profile: the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO): a prospective HIV cohort in rural Tanzania

The Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) is a single-site, open and ongoing prospective cohort of people living with human immunodeficiency virus (PLWHIV) established in 2005 at the Chronic Diseases Clinic of Ifakara (CDCI), within the Saint Francis Referral Hospital (SFRH) in Ifakara, Tanzania. The objectives of KIULARCO are to (i) provide patient and cohort-level information on the outcomes of HIV treatment; (ii) provide cohort-level information on opportunistic infections and comorbidities; (iii) evaluate aspects of human immunodeficiency virus (HIV) care and treatment that have national or international policy relevance; (iv) provide a platform for studies on improving HIV care and treatment in sub-Saharan Africa; and (v) contribute to generating local capacity to deal with the challenges posed by the HIV/AIDS pandemic in this region. Moreover, KIULARCO may serve as a model for other healthcare settings in rural sub-Saharan Africa. Since 2005, all patients diagnosed with HIV at the Saint Francis Referral Hospital are invited to participate in the cohort, including non-pregnant adults, pregnant women, adolescents, children and infants. The information collected includes demographics, baseline and follow-up clinical data, laboratory data, medication history, drug toxicities, diagnoses and outcomes. Real-time data are captured during the patient encounter through an electronic medical record system that allowed transition to a paperless clinic in 2013. In addition, KIULARCO is associated with a biobank of cryopreserved plasma samples and cell pellets collected from all participants before and at different time-points during antiretroviral treatment. Up to the end of 2016, 12 185 PLWHIV have been seen at the CDCI; 9218 (76%) of whom have been enrolled into KIULARCO and 6965 (76%) of these have received ART from the clinic. Patients on ART attend at least every 3 months, with laboratory monitoring every 6 months. KIULARCO data have been used to generate relevant information regarding ART outcomes, opportunistic infections, non-AIDS comorbidities, prevention of mother-to-child transmission of HIV, paediatric HIV, and mortality and retention in care. Requests for collaborations on analyses can be submitted to the KIULARCO scientific committee. KIULARCO provides a framework for improving the quality of care of people living with HIV in sub-Saharan Africa, to generate relevant information to evaluate ART programmes and to build local capacity to deal with HIV/AIDS. The comprehensiveness of the data collected, together with the biobank spanning over ten years has created a unique research platform in rural sub-Saharan Africa

Ultrasound in managing extrapulmonary tuberculosis: a randomized controlled two-center study

Patients with clinically suspected tuberculosis are often treated empirically, as diagnosis - especially of extrapulmonary tuberculosis - remains challenging. This leads to an overtreatment of tuberculosis and to underdiagnosis of possible differential diagnoses.; This open-label, parallel-group, superiority randomized controlled trial is done in a rural and an urban center in Tanzania. HIV-positive and -negative adults (≥18 years) with clinically suspected extrapulmonary tuberculosis are randomized in a 1:1 ratio to an intervention- or control group, stratified by center and HIV status. The intervention consists of a management algorithm including extended focused assessment of sonography for HIV and tuberculosis (eFASH) in combination with chest X-ray and microbiological tests. Treatment with anti-tuberculosis drugs is started, if eFASH is positive, chest X-ray suggests tuberculosis, or a microbiological result is positive for tuberculosis. Patients in the control group are managed according national guidelines. Treatment is started if microbiology is positive or empirically according to the treating physician. The primary outcome is the proportion of correctly managed patients at 6 months (i.e patients who were treated with anti-tuberculosis treatment and had definite or probable tuberculosis, and patients who were not treated with anti-tuberculosis treatment and did not have tuberculosis). Secondary outcomes are the proportion of symptom-free patients at two and 6 months, and time to death. The sample size is 650 patients.; This study will determine, whether ultrasound in combination with other tests can increase the proportion of correctly managed patients with clinically suspected extrapulmonary tuberculosis, thus reducing overtreatment with anti-tuberculosis drugs.; PACTR, Registration number: PACTR201712002829221, registered December 1st 2017

Prevalence and Evolution of Renal Impairment in People Living With HIV in Rural Tanzania

Background: We assessed the prevalence, incidence, and predictors of renal impairment among people living with HIV (PLWHIV) in rural Tanzania. Methods: In a cohort of PLWHIV aged >/=15 years enrolled from January 2013 to June 2016, we assessed the association between renal impairment (estimated glomerural filtration rate < 90 mL/min/1.73 m(2)) at enrollment and during follow-up with demographic and clinical characteristcis using logistic regression and Cox proportional hazards models. Results: Of 1093 PLWHIV, 172 (15.7%) had renal impairment at enrollment. Of 921 patients with normal renal function at baseline, 117 (12.7%) developed renal impairment during a median follow-up (interquartile range) of 6.2 (0.4-14.7) months. The incidence of renal impairment was 110 cases per 1000 person-years (95% confidence interval [CI], 92-132). At enrollment, logistic regression identified older age (adjusted odds ratio [aOR], 1.79; 95% CI, 1.52-2.11), hypertension (aOR, 1.84; 95% CI, 1.08-3.15), CD4 count <200 cells/mm(3) (aOR, 1.80; 95% CI, 1.23-2.65), and World Health Organization (WHO) stage III/IV (aOR, 3.00; 95% CI, 1.96-4.58) as risk factors for renal impairment. Cox regression model confirmed older age (adjusted hazard ratio [aHR], 1.85; 95% CI, 1.56-2.20) and CD4 count <200 cells/mm(3) (aHR, 2.05; 95% CI, 1.36-3.09) to be associated with the development of renal impairment. Conclusions: Our study found a low prevalence of renal impairment among PLWHIV despite high usage of tenofovir and its association with age, hypertension, low CD4 count, and advanced WHO stage. These important and reassuring safety data stress the significance of noncommunicable disease surveillance in aging HIV populations in sub-Saharan Africa

Sonography to rule out tuberculosis in sub-Saharan Africa: a prospective observational study

Patients with suspected tuberculosis are often overtreated with antituberculosis drugs. We evaluated the diagnostic value of the focused assessment with sonography for HIV-associated tuberculosis (FASH) in rural Tanzania.; In a prospective cohort study, the frequency of FASH signs was compared between patients with confirmed tuberculosis and those without tuberculosis. Clinical and laboratory examination, chest x-ray, Xpert MTB/RIF assay, and culture from sputum, sterile body fluids, lymph node aspirates, and Xpert MTB/RIF urine assay was done.; Of 191 analyzed patients with a 6-month follow-up, 52.4% tested positive for human immunodeficiency virus, 21.5% had clinically suspected pulmonary tuberculosis, 3.7% had extrapulmonary tuberculosis, and 74.9% had extrapulmonary and pulmonary tuberculosis. Tuberculosis was microbiologically confirmed in 57.6%, probable in 13.1%, and excluded in 29.3%. Ten of eleven patients with splenic or hepatic hypoechogenic lesions had confirmed tuberculosis. In a univariate model, abdominal lymphadenopathy was significantly associated with confirmed tuberculosis. Pleural- and pericardial effusion, ascites, and thickened ileum wall lacked significant association. In a multiple regression model, abnormal chest x-ray (odds ratio [OR] = 6.19; 95% confidence interval [CI], 1.96-19.6;; P; &lt; .002), ≥1 FASH-sign (OR = 3.33; 95% CI, 1.21-9.12;; P; = .019), and body temperature (OR = 2.48; 95% CI, 1.52-5.03;; P; = .001 per °C increase) remained associated with tuberculosis. A combination of ≥1 FASH sign, abnormal chest x-ray, and temperature ≥37.5°C had 99.1% sensitivity (95% CI, 94.9-99.9), 35.2% specificity (95% CI, 22.7-49.4), and a positive and negative predictive value of 75.2% (95% CI, 71.3-78.7) and 95.0% (95% CI, 72.3-99.3).; The absence of FASH signs combined with a normal chest x-ray and body temperature <37.5°C might exclude tuberculosis

Non-communicable diseases in people living with HIV in rural Africa: tackling the double burden

In 2019, there were around 38 million people living with HIV (PLHIV) worldwide. For the past decade, new HIV infections have been reduced by 23% and AIDS-related deaths have been reduced by 39% worldwide. All these achievements were possible mainly due to discovery and global rollout of antiretroviral therapies (ART), reduction in stigma and a global effort for funding to tackle the HIV epidemic. Sub-Saharan Africa is the most affected WHO region with around 20.7 million (54%) PLHIV. Since 2010, in the region, new HIV infections have been reduced by 38% and AIDS-related deaths have been reduced by 49%. This accomplishment was possible mostly due to extensive vertical HIV testing and treatment programs. Each year, more than 41 million people die from non-communicable diseases (NCDs) worldwide. More than 15 millions of these deaths are premature deaths (people aged between 30-69 years) and 85% occur in lower- and middle-income countries. The most common NCDs that cause deaths are cardiovascular diseases, cancers, respiratory diseases, and diabetes mellitus. The risk factors for most NCDs can be grouped as behaviour or metabolic risk factors. The most common modifiable behaviour risk factors are harmful tobacco use, excessive alcohol consumption, eating unhealthy diet, physical inactivity, overweight and obesity. Other metabolic risk factors are raised blood cholesterol, and raised fasting blood glucose. In sub-Saharan Africa, with the rapid demographic changes, an epidemiological transition from infectious diseases to non-communicable and chronic diseases can be observed. By 2030, mortality due to NCD is projected to surpass the mortality from combined infectious, neonatal, maternal and nutritional diseases. Therefore, there is an urgent need for innovative ways to tackle this double burden of diseases on the African continent. The overall goal of this doctoral thesis was to summarise the burden of non-communicable diseases in sub-Saharan Africa. Additionally, data from rural Tanzania was used to estimate the burden of renal impairment, excessive weight gain and different comorbidities among HIV-infected patients receiving antiretroviral treatment. The first study described the burden of the most relevant etiologies for NCDs in sub-Saharan Africa, which are arterial hypertension, heart diseases, diabetes mellitus and chronic kidney diseases. The review emphasized the importance of using a multifactorial approach, with emphasis on strengthening the existing health care systems to facilitate early diagnosis, treatment and management of NCDs. Furthermore, the review highlighted an urgent need for robust high- 2 quality evidence directed at informing national stakeholders on the key drivers of NCDs across Africa. The second study assessed the prevalence, incidence and predictors of renal impairment among PLHIV receiving ritonavir-boosted protease inhibitors (bPI). Renal impairment was present in 7.6% of participants at the switch from first-line to bPI. Among participants with normal kidney function at the time of switch, 7.4% developed renal impairment after a median time of 3.5 years. The study reported risk associated with renal impairment at switch to be older age, low body mass index (BMI) <18.5 kg/m2 and arterial hypertension. Hence, this study highlighted the high burden of renal impairment among patients who are switched from first-line to bPI in rural sub-Saharan Africa and stress the importance of clinical monitoring of renal function for patients using ART. The third study evaluated the weight change among newly diagnosed PLHIV starting treatment with either dolutegravir-based or efavirenz-based regimen in rural Tanzania. Additionally, it assessed risk factors associated with increased body weight ≥10% after 12 months of treatment. Initiating a dolutegravir-based ART regimen was associated with more weight gain compared to efavirenz-based regimens during the first 12 months of treatment, confirming observations from industrialized settings. Weight gain of ≥10% was associated with use of dolutegravir, level of immunosuppression, BMI at ART initiation and being female. The fourth article is a letter to the editor that discussed the rollout of dolutegravir-based antiretroviral therapy in sub-Saharan Africa and its public health implications. The letter highlighted the lack of studies to evaluate long-term side effects of dolutegravir-based regimens among PLHIV living in sub-Saharan Africa. At the time, it was vital since there were studies that demonstrated excessive weight in PLHIV either starting treatment with dolutegravir-based regimens or those who were switched from other regimens to dolutegravir-based regimen. Therefore, this letter set the basis for the third study to evaluate weight gain in patients starting ART in rural Tanzania. The fifth study investigated the age-related causes of morbidity and mortality of people living with HIV in rural Tanzania. Prevalence and incidence of different comorbidities in patients starting antiretroviral treatment was evaluated. The results showed that anaemia, arterial hypertension and undernutrition are the most relevant comorbidities with different age-associated frequencies and impact on death/LTFU in this population. The sixth study is a study protocol for an open-label, three-arm, parallel randomized controlled trial conducted at two rural hospitals in Lesotho and Tanzania. The clinical trial compares the 3 efficacy and cost-effectiveness of three antihypertensive treatment strategies among HIV-positive and negative participants. The primary endpoint is the proportion of participants reaching the target blood pressure at 12 weeks. The results from this trial will help to identify the most effective and cost-effective treatment strategies for uncomplicated arterial hypertension among people of African descent living in rural sub-Saharan Africa. The seventh article is an editorial that discussed the challenges for HIV-infected adolescents during transition from paediatric to adult HIV clinics in Africa. The editorial addressed the challenge of high HIV prevalence and incidence among adolescents and young adults in sub-Saharan Africa. The editorial stressed an urgent need to ensure that the transition policy from paediatric to adult-centred clinics is part of health care management for HIV-infected adolescents and young adults in Africa. In conclusion, the studies included in this thesis highlight the double burden of infectious diseases and non-communicable diseases in sub-Saharan Africa. The lessons learnt will help to inform future guidelines on the importance of clinical monitoring of people living with HIV once they start antiretroviral treatment. The results highlighted the urgent need to improve pharmacovigilance systems in the region to monitor side effects of new drugs. Finally, the results from this thesis stress the importance that future research from local context to tackle the double burden of diseases in the region

Non-communicable diseases on the Rise in sub-Saharan Africa, the underappreciated threat of a dual disease burden

In sub-Saharan Africa, the burden of non-communicable diseases (NCDs) remains under appreciated, but emerging evidence suggests it to be substantial. NCDs such as arterial hypertension, heart diseases, diabetes mellitus and chronic kidney diseases are especially relevant, and put additional strain on the already challenged health systems in this region. Moreover, NCDs appear to be associated with higher mortality and morbidity rates and are more common in younger population groups, in people from sub-Saharan Africa when compared to more developed countries. In this review, we summarize the current literature on the burden of NCDs in sub-Saharan Africa, and highlight the clinical implications of the most relevant etiologies, i.e. arterial hypertension, heart diseases, diabetes mellitus and chronic kidney diseases