Efficacy and safety of artemisinin-based combination therapy, and molecular markers for artemisinin and piperaquine resistance in Mainland Tanzania.

BACKGROUND: Artemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment of uncomplicated malaria in most malaria endemic countries, including Tanzania. Unfortunately, there have been reports of artemisinin resistance and ACT failure from South East Asia highlighting the need to monitor therapeutic efficacy of ACT in these countries as recommended by World Health Organization. METHODS: Open-label single arm studies in mainland Tanzania were conducted in nine sentinel sites in 2011, 2012 and 2015 to assess the efficacy and safety of artemether/lumefantrine (AL) and artesunate/amodiaquine (ASAQ) using 28 days follow-up and dihydroartemisinin/piperaquine (DHAPQ) using 42 days follow-up. Mutations in the propeller domain of the Plasmodium falciparum kelch 13 (k13) gene and amplification of the P. falciparum plasmepsin 2 (pm2) gene, associated with artemisinin and piperaquine (PQ) resistance, were also investigated. RESULTS: Of the 428 patients enrolled, 328 patients provided study endpoint. For AL, the PCR corrected per-protocol analysis showed adequate clinical and parasitological response (ACPR) of 90.3% (n = 28; 95% CI 74.2-98.0) in Kyela 2012, 95.7% (n = 22; 95% CI 78.1-99.0) in Chamwino, 100% in Muheza (n = 29; 95% CI 88.1-100), 100% in Nagaga (n = 39; 95% CI 91.0-100) and Kyela 2015 (n = 60; 95% CI 94.0-100). For ASAQ, PCR corrected ACPR of 98% (n = 49; 95% CI 89.4-99.9) and 100% (n = 25; 95% CI 86.3-100) were observed in 2011 in Ujiji and Kibaha, respectively. For DHAPQ, the ACPR was 100% (n = 71; 95% CI 94.9-100). Of the 235 samples with genetic interpretable results, only 7 (3%) had non-synonymous k13 mutations. None of these are candidate or validated markers of artemisinin resistance and all patients carrying these alleles cleared the parasites on day 3. Of the DHAPQ group, 10% (3/29) of the samples with interpretable results had pm2 multiple copies and none of them was associated with treatment failure. CONCLUSION: All the tested ACT in mainland Tanzania were highly efficacious and none of validated k13 mutants associated with artemisinin resistance was observed. However, three isolates with multiple copy numbers of pm2 gene associated with PQ resistance among the limited samples tested successfully calls for further investigation. Trial registration Number ACTRN12615000159550. Registered 18th February 2015, https://www.anzctr.org.au/trial/MyTrial.aspx.

Hypertension, kidney disease, HIV and antiretroviral therapy among Tanzanian adults: a cross-sectional study.

BACKGROUND: The epidemics of HIV and hypertension are converging in sub-Saharan Africa. Due to antiretroviral therapy (ART), more HIV-infected adults are living longer and gaining weight, putting them at greater risk for hypertension and kidney disease. The relationship between hypertension, kidney disease and long-term ART among African adults, though, remains poorly defined. Therefore, we determined the prevalences of hypertension and kidney disease in HIV-infected adults (ART-naive and on ART >2 years) compared to HIV-negative adults. We hypothesized that there would be a higher hypertension prevalence among HIV-infected adults on ART, even after adjusting for age and adiposity. METHODS: In this cross-sectional study conducted between October 2012 and April 2013, consecutive adults (>18 years old) attending an HIV clinic in Tanzania were enrolled in three groups: 1) HIV-negative controls, 2) HIV-infected, ART-naive, and 3) HIV-infected on ART for >2 years. The main study outcomes were hypertension and kidney disease (both defined by international guidelines). We compared hypertension prevalence between each HIV group versus the control group by Fisher's exact test. Logistic regression was used to determine if differences in hypertension prevalence were fully explained by confounding. RESULTS: Among HIV-negative adults, 25/153 (16.3%) had hypertension (similar to recent community survey data). HIV-infected adults on ART had a higher prevalence of hypertension (43/150 (28.7%), P = 0.01) and a higher odds of hypertension even after adjustment (odds ratio (OR) = 2.19 (1.18 to 4.05), P = 0.01 in the best model). HIV-infected, ART-naive adults had a lower prevalence of hypertension (8/151 (5.3%), P = 0.003) and a lower odds of hypertension after adjustment (OR= 0.35 (0.15 to 0.84), P = 0.02 in the best model). Awareness of hypertension was ≤ 25% among hypertensive adults in all three groups. Kidney disease was common in all three groups (25.6% to 41.3%) and strongly associated with hypertension (P <0.001 for trend); among hypertensive participants, 50/76 (65.8%) had microalbuminuria and 20/76 (26.3%) had an estimated glomerular filtration rate (eGFR) <60 versus 33/184 (17.9%) and 16/184 (8.7%) participants with normal blood pressure. CONCLUSIONS: HIV-infected adults on ART >2 years had two-fold greater odds of hypertension than HIV-negative controls. HIV-infected adults with hypertension were rarely aware of their diagnosis but often have evidence of kidney disease. Intensive hypertension screening and education are needed in HIV-clinics in sub-Saharan Africa. Further studies should determine if chronic, dysregulated inflammation may accelerate hypertension in this population.

Short-term and long-term cardiovascular risk, metabolic syndrome and HIV in Tanzania.

OBJECTIVE: To compare short-term and long-term cardiovascular disease (CVD) risk scores and prevalence of metabolic syndrome in HIV-infected adults receiving and not receiving antiretroviral therapy (ART) to HIV-negative controls. METHODS: A cross-sectional study including 151 HIV-infected, ART-naive, 150 HIV-infected on ART and 153 HIV-negative adults. Traditional cardiovascular risk factors were determined by standard investigations. The primary outcome was American College of Cardiology/American Heart Association Atherosclerotic CVD (ASCVD) Risk Estimator lifetime CVD risk score. Secondary outcomes were ASCVD 10-year risk, Framingham risk scores, statin indication and metabolic syndrome. RESULTS: Compared with HIV-negative controls, more HIV-infected adults on ART were classified as high lifetime CVD risk (34.7% vs 17.0%, p<0.001) although 10-year risk scores were similar, a trend which was similar across multiple CVD risk models. In addition, HIV-infected adults on ART had a higher prevalence of metabolic syndrome versus HIV-negative controls (21.3% vs 7.8%, p=0.008), with two common clusters of risk factors. More than one-quarter (28.7%) of HIV-infected Tanzanian adults on ART meet criteria for statin initiation. CONCLUSIONS: HIV-infected ART-treated individuals have high lifetime cardiovascular risk, and this risk seems to develop rapidly in the first 3-4 years of ART as does the development of clusters of metabolic syndrome criteria. These data identify a new subgroup of low short-term/high-lifetime risk HIV-infected individuals on ART who do not currently meet criteria for CVD risk factor modification but require further study.

Glucose Metabolism Disorders, HIV and Antiretroviral Therapy among Tanzanian Adults.

INTRODUCTION: Millions of HIV-infected Africans are living longer due to long-term antiretroviral therapy (ART), yet little is known about glucose metabolism disorders in this group. We aimed to compare the prevalence of glucose metabolism disorders among HIV-infected adults on long-term ART to ART-naïve adults and HIV-negative controls, hypothesizing that the odds of glucose metabolism disorders would be 2-fold greater even after adjusting for possible confounders. METHODS: In this cross-sectional study conducted between October 2012 and April 2013, consecutive adults (>18 years) attending an HIV clinic in Tanzania were enrolled in 3 groups: 153 HIV-negative controls, 151 HIV-infected, ART-naïve, and 150 HIV-infected on ART for ≥ 2 years. The primary outcome was the prevalence of glucose metabolism disorders as determined by oral glucose tolerance testing. We compared glucose metabolism disorder prevalence between each HIV group vs. the control group by Fisher's exact test and used multivariable logistic regression to determine factors associated with glucose metabolism disorders. RESULTS: HIV-infected adults on ART had a higher prevalence of glucose metabolism disorders (49/150 (32.7%) vs.11/153 (7.2%), p<0.001) and frank diabetes mellitus (27/150 (18.0%) vs. 8/153 (5.2%), p = 0.001) than HIV-negative adults, which remained highly significant even after adjusting for age, gender, adiposity and socioeconomic status (OR = 5.72 (2.78-11.77), p<0.001). Glucose metabolism disorders were significantly associated with higher CD4+ T-cell counts. Awareness of diabetes mellitus was <25%. CONCLUSIONS: HIV-infected adults on long-term ART had 5-fold greater odds of glucose metabolism disorders than HIV-negative controls but were rarely aware of their diagnosis. Intensive glucose metabolism disorder screening and education are needed in HIV clinics in sub-Saharan Africa. Further research should determine how glucose metabolism disorders might be related to immune reconstitution.

High prevalence of tuberculosis among adults with fever admitted at a tertiary hospital in north-western Tanzania.

Tuberculosis is a leading cause of death in developing countries where HIV is endemic. This hospital based study was done to estimate the magnitude of pulmonary and extra-pulmonary tuberculosis and to determine predictors of tuberculosis among febrile adults admitted at Bugando Medical Centre (BMC), Mwanza, Tanzania. A total of 346 adults febrile patients admitted in medical wards were studied. Sputum for AFB microscopy and chest X-rays was used to diagnose tuberculosis. Clinical features were collected using standardized data collection tool. HIV testing and CD4 counts were determined. Data were analyzed using STATA version 11 software. Of 346 febrile adults patients 116 (33.5%) were diagnosed to have tuberculosis; of which 79 (68.1%) and 37 (31.9%) had pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis, respectively. Smear negative PTB were more common in HIV positive than in HIV negative patients (50% vs. 18.5%, p=0.007). Extra-pulmonary tuberculosis was more common in HIV positive patients than pulmonary tuberculosis (86.4% vs. 13.6%), p=0.000 1). On multivariate logistic regression analysis the predictors of tuberculosis were; age above 35 years (OR =2.38, p=0.007), cardinal symptoms (OR=37, p<0.0001), pleural effusion (OR=24, p=0.0001), and HIV status (OR =3.2, p=0.0001). Of 79 patients with PTB, 48 (60.7%) were AFB smear positive and 31 (39.3%) were AFB smear negative. HIV patients with smear negative tuberculosis had significantly lower CD4 count than IV patients with smear positive tuberculosis (63.5 cells/µl versus 111.5 cells/µl) [Mann-Whitney test p=0.0431]]. No different in mortality was observed between patients with TB and those without TB admitted in BMC medical wards (28.5% vs. 23.0%, p= 0.13 18). Tuberculosis is the commonest cause of fever among adults patients admitted at BMC and is predicted by age above 35 years, positive HIV status, cardinal PTB symptoms, and pleural effusion. Routinely TB screening is highly recommended among adults with fever, cough, night sweating and wasting in countries where HIV is endemic.

High prevalence of Non-typhoid salmonella bacteraemia among febrile HIV adult patients admitted at a tertiary Hospital, North-Western Tanzania.

BACKGROUND: Bacterial blood stream infections constitute a significant public-health problem and it is an important cause of morbidity and mortality in HIV infected patients. Little is known in developing countries regarding salmonella bacteraemia among HIV patients. The purpose of this study was to determine the bacterial pathogens causing blood stream infection among febrile adults attending in a tertiary hospital North-Western, Tanzania. METHODS: A prospective cross-sectional study involving 346 consecutive, febrile adult patients admitted at Bugando Medical Centre was conducted. Demographic and other data were collected using standardized questionnaires. Blood culture was done followed by susceptibility testing using disc diffusion method. HIV testing was also performed as per Tanzania national algorithm and total white blood cell counts and CD4+ counts determined. RESULTS: Of 346 febrile adult patients 33 (9.5%) had blood stream infections. The common isolates were Salmonella spp 13(39.4%), Escherichia coli 8 (24.2%), Streptococcus pneumonia 5(15.2%), Staphylococcus aureus 4(12.1%), Citrobacter spp 1(3%), Streptococcus pyogenes 1(3%) and Klebsiella pneumonia 1(3%). A total of 156 (45.1%) patients were HIV infected; of whom 12/156 (7.6%) were infected by non-typhoid Salmonella spp compared to 1/190 (0.5%) of non-HIV infected patients (RRR 11.2, p=0.029) infected with Salmonella typhi. HIV infected patients with bacteraemia had significantly lower CD4+ count than those without bacteraemia (median 28 vs. 88 cells/ml, p=0.01). Patients with salmonella bacteraemia had significantly lower median of WBC than those with non-salmonella as well as those without bacteraemia (median, 3.6 vs. 17.5 vs. 9.8x109, p=0.0001). All Salmonella spp were sensitive to ceftriaxone and imipenem, while being 84%, 69.2%, 38% and 8% resistant to chloramphenicol, ampicillin, sulphamethaxazole/trimethoprim and ciprofloxacin respectively. Predictors of mortality were HIV infection (OR 2.3, p=0.006), Glasgow coma score of less than 15 (OR 3.4, p=0.0001) and night sweats (OR 2.4, p=0.014). CONCLUSION: Non-typhoid Salmonella spp that are highly resistant to common antibiotics are predominant cause of bacterial blood stream infection among HIV patients attending Bugando Medical Centre. Continuous surveillance and intervention strategies should be put in place to monitor and manage cases of bloodstream infections in HIV-positive patients in Mwanza, Tanzania.

Typhoid intestinal perforations at a University teaching hospital in Northwestern Tanzania: A surgical experience of 104 cases in a resource-limited setting.

BACKGROUND: Typhoid intestinal perforation is still prevalent in many developing countries. Despite the advances in the management, the outcome in these patients in resource limited countries is still very poor. This study was to review our experiences on the surgical management of typhoid intestinal perforation and to determine the prognostic factors for mortality in our local setting. METHODS: This was a combined retrospective and prospective study of patients who were operated for typhoid intestinal perforation at Bugando Medical Centre between August 2006 and September 2011. Data collected were analyzed using SPSS computer software version 15. RESULTS: A total of 104 patients were studied representing 8.7% of typhoid fever cases. Males were affected twice more than the females (2.6:1). Their ages ranged from 8 to 76 years with a median age of 18.5 years. The peak age incidence was in the 11-20 years age group. Fever and abdominal pain were the most common presenting symptoms and majority of the patients (80.8%) perforated between within 14 days of illness. Chest and abdominal radiographs revealed pneumoperitonium in 74.7% of cases. Ultrasound showed free peritoneal collection in 85.7% of cases. Nine (10.2%) patients were HIV positive with a median CD4+ count of 261 cells/µl. The perforation-surgery interval was more than 72 hours in 90(86.5%) patients. The majority of patients (84.6%) had single perforations and ileum was the most common part of the bowel affected occurring in 86.2% of cases. Simple closure of the perforations was the most commonly performed procedure accounting for 78.8% of cases. Postoperative complication rate was 39.4% and surgical site infection was the most frequent complication in 55.5% of cases. Mortality rate was 23.1% and it was statistically significantly associated with delayed presentation, inadequate antibiotic treatment prior to admission, shock on admission, HIV positivity, low CD4 count (< 200 cells/µl), high ASA classes (III-V), delayed operation, multiple perforations, severe peritoneal contamination and presence of postoperative complications (P < 0.001). The median overall length of hospital stay was 28 days. CONCLUSION: Typhoid intestinal perforation is still endemic in our setting and carries high morbidity and mortality. This study has attempted to determine the factors that statistically influence mortality in typhoid perforation in our environment. Appropriate measures focusing at these factors are vital in order to deliver optimal care for these patients in this region.

In vitro activity of cefepime against extended spectrum p-lactamase-producing Escherichia coli and Klebsiella pneumoniae from clinical specimens at Bugando Medical Centre, Mwanza, Tanzania.

There is an increase in isolation of extended spectrum beta-lactamase (ESBL) producing isolates from clinical samples worldwide. In developing countries the treatment option of ESBL producing isolates is limited. Recently fourth generation cephalosporins have been introduced for use in Tanzania. This study was done to determine in vitro activity of cefepime against ESBL producing clinical isolates. Disc diffusion testing was performed to 235 ESBL producing isolates; of which 73 (31%) were Escherichia coli and 162 (69%) Klebsiella pneumoniae. The sensitivity rate of E. coli and K pneumoniae to cefepime were 15.1% and 4.3%, respectively (P=0.012); intermediate sensitivity rate was observed in 13.7% for E. coli and 19.8% for K. pneumoniae. The mean zones of inhibition diameter among sensitive isolates were 24.9mm and 20.0mm for E coli and K. pneumonia, respectively (P=0.0085). Cefepime is less active against ESBL producing organisms; hence the use.of this drug should be guided using local resistance profile.

Surgical management of Diabetic foot ulcers: A Tanzanian university teaching hospital experience.

BACKGROUND: Diabetic foot ulcers (DFUs) pose a therapeutic challenge to surgeons, especially in developing countries where health care resources are limited and the vast majority of patients present to health facilities late with advanced foot ulcers. A prospective descriptive study was done at Bugando Medical Centre from February 2008 to January 2010 to describe our experience in the surgical management of DFUs in our local environment and compare with what is known in the literature. FINDINGS: Of the total 4238 diabetic patients seen at BMC during the period under study, 136 (3.2%) patients had DFUs. Males outnumbered females by the ratio of 1.2:1. Their mean age was 54.32 years (ranged 21-72years). Thirty-eight (27.9%) patients were newly diagnosed diabetic patients. The majority of patients (95.5%) had type 2 diabetes mellitus. The mean duration of diabetes was 8.2 years while the duration of DFUs was 18.34 weeks. Fourteen (10.3%) patients had previous history of foot ulcers and six (4.4%) patients had previous amputations. The forefoot was commonly affected in 60.3% of cases. Neuropathic ulcers were the most common type of DFUs in 57.4% of cases. Wagner's stage 4 and 5 ulcers were the most prevalent at 29.4% and 23.5% respectively. The majority of patients (72.1%) were treated surgically. Lower limb amputation was the most common surgical procedure performed in 56.7% of cases. The complication rate was (33.5%) and surgical site infection was the most common complication (18.8%). Bacterial profile revealed polymicrobial pattern and Staphylococcus aureus was the most frequent microorganism isolated. All the microorganisms isolated showed high resistance to commonly used antibiotics except for Meropenem and imipenem, which were 100% sensitive each respectively. The mean hospital stay was 36.24 ± 12.62 days (ranged 18-128 days). Mortality rate was 13.2%. CONCLUSION: Diabetic foot ulceration constitutes a major source of morbidity and mortality among patients with diabetes mellitus at Bugando Medical Centre and is the leading cause of non-traumatic lower limb amputation. A multidisciplinary team approach targeting at good glycaemic control, education on foot care and appropriate footware, control of infection and early surgical intervention is required in order to reduce the morbidity and mortality associated with DFUs. Due to polymicrobial infection and antibiotic resistance, surgical intervention must be concerned.