@article{Hongler2018,

title = {Comparison of Löwenstein–Jensen and BACTEC MGIT 960 culture for Mycobacterium tuberculosis in people living with HIV},

author = {J Hongler, J Musaazi, B Ledergerber, N Eberhard, C Sekaggya-Wiltshire, PM Keller, J Fehr, B Castelnuovo},

doi = {https://doi.org/10.1111/hiv.12635},

year  = {2018},

date = {2018-07-03},

journal = {HIV Medicine},

volume = {19},

number = {9},

pages = {654-661},

abstract = {

Objectives



The aim of the study was to clarify how HIV infection affects tuberculosis liquid and solid culture results in a resource-limited setting.



Methods



We used baseline data from the Study on Outcomes Related to Tuberculosis and HIV Drug Concentrations in Uganda (SOUTH), which included 268 HIV/tuberculosis (TB)-coinfected individuals. Culture results from Löwenstein–Jensen (LJ) solid culture and mycobacteria growth indicator tube (MGIT) liquid culture systems and culture-based correlates for bacillary density from the sputum of HIV/TB-coinfected individuals at baseline were analysed.



Results



Of 268 participants, 243 had a CD4 cell count available and were included in this analysis; 72.2% of cultures showed growth on solid culture and 82.2% in liquid culture systems (P < 0.015). A higher CD4 cell count was predictive of LJ positivity [adjusted odds ratio (OR) 1.14; 95% confidence interval (CI) 1.03–1.25 per 50 cells/μL increase; P = 0.008]. The same, but insignificant trend was observed for MGIT positivity (adjusted OR 1.09; 95% CI 0.99–1.211 per 50 cells/μL increase; P = 0.094). A higher CD4 cell count was associated with a higher LJ colony-forming unit grade (adjusted OR 1.14; 95% CI 1.05–1.25 per 50 cells/μL increase; P = 0.011) and a shorter time to MGIT positivity [adjusted hazard ratio (HR) 1.08; 95% CI 1.04–1.12 per 50 cells/μL increase; P < 0.001].



Conclusions



In a resource-limited setting, the MGIT liquid culture system outperformed LJ solid culture in terms of culture yield and dependence on CD4 cell counts in HIV/TB-coinfected individuals. We therefore suggest considering an adaptation of diagnostic algorithms: when resources allow only one culture method to be performed, we recommend that MGIT liquid culture should be used exclusively in HIV-positive individuals as a first-line culture method, to reduce costs and make TB culture results accessible to more patients in resource-limited settings.

},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Walter2018,

title = {Does discovery of differentially culturable M tuberculosis really demand a new treatment paradigm? Longitudinal analysis of DNA clearance from sputum},

author = {Nicholas D. Walter, Camille M. Moore, Xavier A. Kayigire, Christian Dide-Agossou, William Worodria, Laurence Huang, Charles K. Everett, Gary S. Schoolnik, Payam Nahid & J. Lucian Davis },

doi = {https://doi.org/10.1186/s12879-018-3213-7},

year  = {2018},

date = {2018-07-03},

journal = {BMC Infectious Diseases },

volume = {18},

number = {293},

abstract = {Background

According to the traditional tuberculosis (TB) treatment paradigm, the initial doses of treatment rapidly kill most Mycobacterium tuberculosis (Mtb) bacilli in sputum, yet many more months of daily treatment are required to eliminate a small, residual subpopulation of drug-tolerant bacilli. This paradigm has recently been challenged following the discovery that up to 90% of Mtb bacilli in sputum are culturable only with growth-factor supplementation. These “differentially culturable” bacilli are hypothesized to be more drug-tolerant than routinely culturable bacilli. This hypothesis implies an alternative paradigm in which TB treatment does not rapidly reduce the total Mtb population but only the small, routinely culturable subpopulation. To evaluate these competing paradigms, we developed a culture-independent method for quantifying the viable fraction of Mtb bacilli in sputum during treatment.



Methods

We used GeneXpert MTB/RIF to quantify Mtb DNA in sputa collected longitudinally from Ugandan adults taking standard 4-drug treatment for drug-susceptible pulmonary TB. We modeled GeneXpert cycle thresholds over time using nonlinear mixed-effects regression. We adjusted these models for clearance of DNA from killed-but-not-yet-degraded bacilli, assuming clearance half-lives ranging from 0 to 1.25 days. We used a convolution integral to quantify DNA from viable bacilli only, and converted cycle thresholds to Mtb genomic equivalents. We replicated our results in a South African cohort.



Results

We enrolled 41 TB patients in Uganda. Assuming a DNA-clearance half-life of 0 days, genomic equivalents of viable sputum bacilli decreased by 0.22 log/day until 8.8 days, then by 0.07 log/day afterwards. Assuming a DNA-clearance half-life of 1.25 days, genomic equivalents of viable bacilli decreased by 0.36 log/day until 5.0 days, then by 0.06 log/day afterwards. By day 7, viable Mtb had decreased by 97.2–98.8%. We found similar results for 19 TB patients in South Africa.



Discussion

Using a culture-independent method, we found that TB treatment rapidly eliminates most viable Mtb in sputum. These findings are incompatible with the hypothesis that differentially culturable bacilli are drug-tolerant.



Conclusions

A culture-independent method for measuring viable Mtb in sputum during treatment corroborates the traditional TB treatment paradigm in which a rapid bactericidal phase precedes slow, elimination of a small, residual bacillary subpopulation.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Cresswell2018c,

title = {Tuberculous meningitis diagnosis and outcomes during the Xpert MTB/Rif era: a 6.5-year cohort study in Uganda},

author = {Fiona V. Cresswell, Ananta S. Bangdiwala, Nathan C. Bahr, Emily Trautner, Edwin Nuwagira, Jayne Ellis, Radha Rajasingham, Joshua Rhein, Darlisha A. Williams, Conrad Muzoora, Alison M. Elliott, David B. Meya and David R. Boulware},

doi = {10.12688/wellcomeopenres.14610.2},

year  = {2018},

date = {2018-07-03},

journal = {Wellcome Open Research},

volume = {3},

number = {64},

abstract = {Background: 

Tuberculous meningitis (TBM), a leading cause of meningitis in sub-Saharan Africa, is notoriously difficult to diagnose. In our Ugandan setting TB diagnostics have evolved rapidly in recent years, with introduction of Xpert MTB/Rif (Xpert) in 2011 and culture in 2013. We aim to describe the impact of improved TBM diagnostics at two Ugandan hospitals between 2010 and 2017.



Methods: 

Adults presenting with meningitis (headache and objective meningism) were assessed for eligibility for enrolment in two consecutive trials investigating cryptococcal meningitis. Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy, routine liquid-media culture and Xpert on large volume CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen (crAg). In a post-hoc analysis of three prospective cohorts, we compare rates of microbiologically confirmed TBM and hospital outcomes over time.



Results: 

1672 predominantly HIV-infected adults underwent lumbar puncture, of which 33% (558/1672) had negative CSF crAg and 12% (195/1672) were treated for TBM. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P<0.01) and there was a decline in in-hospital mortality from 57% to 41% (P=0.27). Adjusting for definite TBM and antiretroviral therapy, and using imputed data, the odds of dying were nearly twice as high in cohort one (adjusted odds ratio 1.7, 95% CI 0.7 to 4.4) compared to cohort three.  Sensitivity of Xpert was 63% (38/60) and culture was 65% (39/60) against a composite reference standard.



Conclusions: 

Since 2010, as TBM diagnostics have evolved, microbiologically-confirmed TBM diagnoses have increased significantly. There has been a non-significant decline in TBM in-hospital mortality but due to multiple possible confounding factors it is not possible to conclude what has driven this decline in mortality.



Keywords: 

Tuberculous meningitis, TBM, HIV, diagnosis, outcomes},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Abdallah2018,

title = {Stroke in Human Immunodeficiency Virus-infected Individuals in Sub-Saharan Africa (SSA): A Systematic Review},

author = {Amir Abdallah, Jonathan L. Chang, Cumara B. O'Carroll, Abdu Musubire, Felicia C. Chow, Anthony L. Wilson, Mark J. Siedner},

doi = {https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.02.016},

year  = {2018},

date = {2018-07-01},

journal = {Journal of Stroke and Cerebrovascular Diseases},

volume = {27},

number = {7},

pages = {1828-1836},

abstract = {Background

Human immunodeficiency virus (HIV) infection is associated with worse outcomes after stroke, but this association is less well-described in sub-Saharan Africa (SSA). We reviewed literature on stroke among people living with HIV (PLWH) in SSA.



Methods

We systematically reviewed published literature for original clinical stroke studies conducted in SSA that included PLWH. We included studies that reported data on presenting characteristics, risk factors, and/or outcomes after stroke.



Results

Seventeen studies (N = 478) met inclusion criteria. At the time of stroke presentation, PLWH had a median age ranging from 32 to 43 years. Subjects had low CD4 counts (median CD4, 108-225 cells/µl), and most were antiretroviral therapy-naïve. Fever, seizures, and concurrent opportunistic infections were common at presentation. Ischemic stroke accounted for up to 96% of strokes, which were mostly located in the anterior circulation territory. In studies comparing PLWH with HIV-uninfected individuals, PLWH had more frequent coagulopathy, greater stroke severity, (72% versus 36% National Institutes of Health Stroke Scale >13, P = .02), longer hospital length of stay (30.5 versus <10 days), and a higher 30-day mortality rate (23% versus 10.5%, P = .007).



Conclusion

Stroke in PLWH in SSA occurs at a young age, in those with advanced disease, and is associated with worse outcomes than in HIV-uninfected comparators. Stroke in young individuals in the region should prompt HIV testing, and ongoing efforts to promote early antiretroviral therapy initiation might also help decrease stroke incidence, morbidity, and mortality in the region.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Chammartin2018,

title = {Outcomes of Patients Lost to Follow-up in African Antiretroviral Therapy Programs: Individual Patient Data Meta-analysis},

author = {Frédérique Chammartin, Kathrin Zürcher, Olivia Keiser, Ralf Weigel, Kathryn Chu, Agnes N Kiragga, Cristina Ardura-Garcia, Nanina Anderegg, Christian Laurent, Morna Cornell, Hannock Tweya, Andreas D Haas, Brian D Rice, Elvin H Geng, Matthew P Fox, James R Hargreaves, Matthias Egger},

doi = {https://doi.org/10.1093/cid/ciy347},

year  = {2018},

date = {2018-06-08},

journal = {Clinical Infectious Diseases},

volume = {67},

number = {11},

pages = {1643–1652},

abstract = {Background

Low retention on combination antiretroviral therapy (cART) has emerged as a threat to the Joint United Nations Programme on human immunodeficiency virus (HIV)/AIDS (UNAIDS) 90-90-90 targets. We examined outcomes of patients who started cART but were subsequently lost to follow-up (LTFU) in African treatment programs.



Methods

This was a systematic review and individual patient data meta-analysis of studies that traced patients who were LTFU. Outcomes were analyzed using cumulative incidence functions and proportional hazards models for the competing risks of (i) death, (ii) alive but stopped cART, (iii) silent transfer to other clinics, and (iv) retention on cART.



Results

Nine studies contributed data on 7377 patients who started cART and were subsequently LTFU in sub-Saharan Africa. The median CD4 count at the start of cART was 129 cells/μL. At 4 years after the last clinic visit, 21.8% (95% confidence interval [CI], 20.8%–22.7%) were known to have died, 22.6% (95% CI, 21.6%–23.6%) were alive but had stopped cART, 14.8% (95% CI, 14.0%–15.6%) had transferred to another clinic, 9.2% (95% CI, 8.5%–9.8%) were retained on cART, and 31.6% (95% CI, 30.6%–32.7%) could not been found. Mortality was associated with male sex, more advanced disease, and shorter cART duration; stopping cART with less advanced disease andlonger cART duration; and silent transfer with female sex and less advanced disease.



Conclusions

Mortality in patients LTFU must be considered for unbiased assessments of program outcomes and UNAIDS targets in sub-Saharan Africa. Immediate start of cART and early tracing of patients LTFU should be priorities.

HIV, antiretroviral therapy, loss to follow-up, mortality, sub-Saharan Africa



Topic:

hiv africa south of the sahara cd4 count determination procedure follow-up mortality anti-retroviral agents lost to follow-up transfer technique },

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Bahr2018b,

title = {Delta-like 1 protein, vitamin D binding protein and fetuin for detection of Mycobacterium tuberculosis meningitis},

author = {Nathan C Bahr, Ryan Halupnick, Grace Linder, Reuben Kiggundu, Henry W Nabeta, Darlisha A Williams, Abdu K Musubire, Bozena M Morawski, Srinand Sreevatsan, David B Meya, Joshua Rhein & David R Boulware},

doi = {https://doi.org/10.2217/bmm-2017-0373},

year  = {2018},

date = {2018-06-01},

journal = {Biomarkers in Medicine},

volume = {2},

number = {7},

abstract = {Aim: Tuberculosis meningitis (TBM) diagnosis is difficult, new biomarkers are needed. We evaluated the diagnostic utility of delta-like 1 protein (DLL1), vitamin D binding protein (VDBP) and fetuin. Methods: Biomarker concentrations were measured by ELISA in cryopreserved cerebrospinal fluid from 139 HIV-infected Ugandans with suspected meningitis. TBM was diagnosed by GeneXpert MTB/Rif or culture. Cohort diagnoses included TBM (n = 22), cryptococcal (n = 71), or aseptic meningitis (n = 16) and no meningitis (n = 30). Results: DLL1 (cut-off value 1150 pg/ml) provided 32% sensitivity and 98% specificity. Adding fetuin, cryptococcal antigen and IFN-γ resulted in sensitivities of 36, 63 and 76% with specificities of 98, 90 and 92%, respectively. VDBP (cut-off value 2.0 μg/ml) provided 81% sensitivity and 68% specificity while fetuin (cut-off value 2 μg/ml) provided a sensitivity of 86% and specificity of 68%. Conclusion: CSF DLL1, VDBP and fetuin exhibited fair diagnostic performance for TBM diagnosis.



Keywords:

biomarkersMycobacterium tuberculosisTB meningitis},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Collaborators2018,

title = {Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study},

author = {The Polaris Observatory Collaborators},

url = {https://www.sciencedirect.com/science/article/abs/pii/S2468125318300566},

year  = {2018},

date = {2018-06-01},

volume = {3},

number = {6},

pages = {383-403},

abstract = {Background



The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate viral hepatitis by 2030. Although no virological cure exists for hepatitis B virus (HBV) infection, existing therapies to control viral replication and prophylaxis to minimise mother-to-child transmission make elimination of HBV feasible. We aimed to estimate the national, regional, and global prevalence of HBsAg in the general population and in the population aged 5 years in 2016, as well as coverage of prophylaxis, diagnosis, and treatment.



Methods

In this modelling study, we used a Delphi process that included a literature review in PubMed and Embase, followed by interviews with experts, to quantify the historical epidemiology of HBV infection. We then used a dynamic HBV transmission and progression model to estimate the country-level and regional-level prevalence of HBsAg in 2016 and the effect of prophylaxis and treatment on disease burden.



Findings

We developed models for 120 countries, 78 of which were populated with data approved by experts. Using these models, we estimated that the global prevalence of HBsAg in 2016 was 3·9% (95% uncertainty interval [UI] 3·4–4·6), corresponding to 291 992 000 (251 513 000–341 114 000) infections. Of these infections, around 29 million (10%) were diagnosed, and only 4·8 million (5%) of 94 million individuals eligible for treatment actually received antiviral therapy. Around 1·8 (1·6–2·2) million infections were in children aged 5 years, with a prevalence of 1·4% (1·2–1·6). We estimated that 87% of infants had received the three-dose HBV vaccination in the first year of life, 46% had received timely birth-dose vaccination, and 13% had received hepatitis B immunoglobulin along with the full vaccination regimen. Less than 1% of mothers with a high viral load had received antiviral therapy to reduce mother-to-child transmission.



Interpretation

Our estimate of HBV prevalence in 2016 differs from previous studies, potentially because we took into account the effect of infant prophylaxis and early childhood vaccination, as well as changing prevalence over time. Although some regions are well on their way to meeting prophylaxis and prevalence targets, all regions must substantially scale-up access to diagnosis and treatment to meet the global targets.



Funding

John C Martin Foundation.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Nalintya2018,

title = {A Prospective Evaluation of a multisite Cryptococcal Screening and Treatment program in HIV clinics in Uganda},

author = {Elizabeth Nalintya, David B Meya, Sarah Lofgren, Kathy Huppler Hullsiek, David R Boulware, and Radha Rajasingham},

doi = {doi: 10.1097/QAI.0000000000001669},

year  = {2018},

date = {2018-06-01},

journal = {J Acquir Immune Defic Syndr.},

volume = {78},

number = {2},

pages = {231–238},

abstract = {Background

Cryptococcus is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) is detectable in blood before meningitis onset, and predicts death. CrAg screening amongst those with advanced HIV, and treatment of those CrAg+ with fluconazole has demonstrated survival benefit. However, implementation and widespread uptake have been slow outside of clinical trials.



Methods

We designed a CrAg screening program for routine care that incorporated intensive education and training of clinic staff. We evaluated programmatic implementation, including time to initiation of fluconazole, time to initiation of antiretroviral therapy (ART), and 6-month clinical outcomes.



Results

Between December 2015 to January 2017, 1440 persons were screened at 11 HIV clinics in Kampala, and CRAG+ prevalence was 6.5% (n=94/1440) among adults with a CD4<100 cells/μL. Of those CrAg+, 7 of 94 (7%) persons died or were lost prior to further clinic evaluation. Fifty-three (56%) were asymptomatic and had six-month survival of 87% (46/53). Of CrAg+ persons, 28% (26/94) were symptomatic at time of clinic return. The majority had confirmed cryptococcal meningitis, and 54% (14/26) of the symptomatic CrAg+ persons were dead or lost at 6 months. Of the 7 symptomatic persons who declined lumbar puncture for further evaluation, all were dead or lost by 6 months.



Conclusion

All asymptomatic CrAg+ persons identified by our screening program who returned to clinic, initated fluconazole and ART in a timely manner. Despite this, 27% of CrAg+ (asymptomatic and symptomatic) identified on routine screening were dead or lost to follow up at 6 months, even with preemptive therapy for those asymptomatic, and standard amphotericin-based treatment for meningitis.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Rhein2018,

title = {Detrimental Outcomes of Unmasking Cryptococcal Meningitis With Recent ART Initiation },

author = {Joshua Rhein, Kathy H Hullsiek, Emily E Evans, Lillian Tugume, Edwin Nuwagira, Kenneth Ssebambulidde, Reuben Kiggundu, Edward Mpoza, Abdu K Musubire, Ananta S Bangdiwala, Nathan C Bahr, Darlisha A Williams, Mahsa Abassi, Conrad Muzoora, David B Meya, David R Boulware, ASTRO-CM study team },

doi = { https://doi.org/10.1093/ofid/ofy122},

year  = {2018},

date = {2018-05-24},

journal = {Open Forum Infectious Diseases},

volume = {8},

number = {8},

pages = {ofy122},

abstract = {Background

Increased antiretroviral therapy (ART) availability has been associated with more patients developing cryptococcosis after ART initiation. Despite this changing epidemiology, data regarding cryptococcal meningitis in those already receiving ART are limited. We compared clinical presentations and outcomes among ART-naïve and ART-experienced Ugandans.



Methods

We prospectively enrolled 605 HIV-infected persons with first-episode cryptococcal meningitis from August 2013 to May 2017 who received amphotericin-based combination therapy. We classified participants by ART status and ART duration and compared groups for 2-week survival.



Results

Overall, 46% (281/605) of participants were receiving ART at presentation. Compared with those not receiving ART, those receiving ART had higher CD4 counts (P < .001) and lower cerebrospinal fluid fungal burdens (P < .001). Of those receiving ART, 56% (156/281) initiated ART within 6 months, and 18% (51/281) initiated ART within 14 days. Two-week mortality did not differ by ART status (27% in both ART-naïve and ART-experienced%; P > .99). However, 47% (24/51) of those receiving ART for ≤14 days died within 2 weeks, compared with 19% (20/105) of those receiving ART for 15–182 days and 26% (32/125) of those receiving ART for >6 months (P < .001). Among persons receiving ART for >6 months, 87% had HIV viral loads >1000 copies/mL.



Conclusions

Cryptococcosis after ART initiation is common in Africa. Patients initiating ART who unmask cryptococcal meningitis are at a high risk of death. Immune recovery in the setting of central nervous system infection is detrimental, and management of this population requires further study. Implementing pre-ART cryptococcal antigen screening is urgently needed to prevent cryptococcal meningitis after ART initiation.

antiretroviral therapy, cryptococcal meningitis, cryptococcus, HIV, immune reconstitution inflammatory syndrome



Topic:

hiv cryptococcal meningitis cryptococcosis mortality anti-retroviral agents 



},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Esteves2018,

title = {The wide utility of rabbits as models of human diseases},

author = {Pedro J. Esteves, Joana Abrantes, Hanna-Mari Baldauf, Lbachir BenMohamed, Yuxing Chen, Neil Christensen, Javier González-Gallego, Lorenzo Giacani, Jiafen Hu, Gilla Kaplan, Oliver T. Keppler, Katherine L. Knight, Xiang-Peng Kong, Dennis K. Lanning, Jacques Le Pendu, Ana Lemos de Matos, Jia Liu, Shuying Liu, Ana M. Lopes, Shan Lu, Sheila Lukehart, Yukari C. Manabe, Fabiana Neves, Grant McFadden, Ruimin Pan, Xuwen Peng, Patricia de Sousa-Pereira, Ana Pinheiro, Masmudur Rahman, Natalie Ruvoën-Clouet, Selvakumar Subbian, Maria Jesús Tuñón, Wessel van der Loo, Michael Vaine, Laura E. Via, Shixia Wang & Rose Mage },

doi = {https://doi.org/10.1038/s12276-018-0094-1},

year  = {2018},

date = {2018-05-22},

journal = {Experimental & Molecular Medicine },

abstract = {Studies using the European rabbit Oryctolagus cuniculus contributed to elucidating numerous fundamental aspects of antibody structure and diversification mechanisms and continue to be valuable for the development and testing of therapeutic humanized polyclonal and monoclonal antibodies. Additionally, during the last two decades, the use of the European rabbit as an animal model has been increasingly extended to many human diseases. This review documents the continuing wide utility of the rabbit as a reliable disease model for development of therapeutics and vaccines and studies of the cellular and molecular mechanisms underlying many human diseases. Examples include syphilis, tuberculosis, HIV-AIDS, acute hepatic failure and diseases caused by noroviruses, ocular herpes, and papillomaviruses. The use of rabbits for vaccine development studies, which began with Louis Pasteur’s rabies vaccine in 1881, continues today with targets that include the potentially blinding HSV-1 virus infection and HIV-AIDS. Additionally, two highly fatal viral diseases, rabbit hemorrhagic disease and myxomatosis, affect the European rabbit and provide unique models to understand co-evolution between a vertebrate host and viral pathogens.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Verma2018,

title = {Tuberculosis in advanced HIV infection is associated with increased expression of IFNγ and its downstream targets},

author = {Sheetal Verma, Peicheng Du, Damalie Nakanjako, Sabine Hermans, Jessica Briggs, Lydia Nakiyingi, Jerrold J. Ellner, Yukari C. Manabe & Padmini Salgame },

doi = {https://doi.org/10.1186/s12879-018-3127-4},

year  = {2018},

date = {2018-05-15},

journal = {BMC Infectious Diseases},

volume = {18},

pages = {220},

abstract = {Background



Tuberculosis (TB) is the major cause of death in Human Immunodeficiency Virus (HIV)-infected individuals. However, diagnosis of TB in HIV remains challenging particularly when HIV infection is advanced. Several gene signatures and serum protein biomarkers have been identified that distinguish active TB from latent infection. Our study was designed to assess if gene expression signatures and cytokine levels would distinguish active TB in advanced HIV.



Methods



We conducted a case-control study of whole blood RNA-Seq and plasma cytokine/chemokine analysis in HIV-infected with CD4+ T cell count of ≤ 100 cells/μl, with and without active TB. Next, the overlap of the differentially expressed genes (DEG) with the published signatures was performed and then receiver operator characteristic (ROC) analysis was done on small gene discriminators to determine their performance in distinguishing TB in advanced HIV. ELISA was performed on plasma to evaluate cytokine and chemokine levels.



Results



Hierarchical clustering of the transcriptional profiles showed that, in general, HIV-infected individuals with TB (TB-HIV) clustered separately from those without TB. IPA indicated that the TB-HIV signature was characterized by an increase in inflammatory signaling pathways. Analysis of overlaps between DEG in our data set with published TB signatures revealed that significant overlap was seen with one TB signature and one TB-IRIS signature. ROC analysis revealed that transcript levels of FcGR1A (AUC = 0.85) and BATF2 (AUC = 0.82), previously reported as consistent single gene classifiers of active TB irrespective of HIV status, performed successfully even in advanced HIV. Plasma protein levels of IFNγ, a stimulator of FcGR1A and BATF2, and CXCL10, also up-regulated by IFNγ, accurately classified active TB (AUC = 0.98 and 0.91, respectively) in advanced HIV. Neither of these genes nor proteins distinguished between TB and TB-IRIS.



Conclusions



Gene expression of FcGR1A and BATF2, and plasma protein levels of IFNγ and CXCL10 have the potential to independently detect TB in advanced HIV. However, since other lung diseases were not included in this study, these final candidates need to be validated as specific to TB in the advanced HIV population with TB.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Buhikire2018,

title = {Reaching the First 90 in Uganda: Predictors of Success in Contacting and Testing the Named Sexual Partners of HIV+ Index Clients in Kiboga District.},

author = {Katherine Buhikire, Joachim Voss, Joanita Kigozi, Patience Nyakato, Nickson Ankunda, Brenda Kalebbo, Michael Musiitwa, Alex Muganzi, Nelson K. Sewankambo & Damalie Nakanjako },

doi = {https://doi.org/10.1007/s10461-018-2137-y},

year  = {2018},

date = {2018-05-12},

journal = {AIDS and Behavior},

volume = {22},

pages = {2458–2467},

abstract = {Assisted partner notification programs represent one strategy for targeted HIV testing and treatment of exposed individuals in high-risk populations. This study of a pilot Partner Services program in rural Uganda describes predictors of successful contact tracings and testing of partners of HIV+ individuals and possible barriers to contact. Partner contact tracing data was extracted from registers at seven Ministry of Health facilities between May and October 2016, to inform program implementation and scale up. A total of 464 HIV+ index clients named 660 sexual partners; 334/660 (51%) were contacted, 193/334 (58%) tested for HIV, and 61/193 (32%) tested HIV+. Current relationship status predicted contact [AOR = 0.23; (95% CI 0.15, 0.37), p < 0.0001] and testing [AOR = 0.19; (95% CI 0.09, 0.36), p < 0.0001]. Partner contact information type was associated with contact (p < 0.0001), and assisted disclosure with testing (p < 0.0001). Partner contact tracing is an effective means of identifying undiagnosed HIV infections.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Diehl2018,

title = {Cerebral Oximetry for Detecting High-mortality Risk Patients with Cryptococcal Meningitis},

author = {John W Diehl, Katherine H Hullsiek, Michael Okirwoth, Nicole Stephens, Mahsa Abassi, Joshua Rhein, David B Meya, David R Boulware, Abdu K Musubire, ASTRO-CM Trial Team },

doi = {https://doi.org/10.1093/ofid/ofy105},

year  = {2018},

date = {2018-05-08},

journal = {Open Forum Infectious Diseases},

volume = {5},

number = {6},

pages = {ofy105},

abstract = {Background



Cryptococcus is the commonest cause of adult meningitis in Africa, with 50%–70% experiencing increased intracranial pressure. Cerebral oximetry is a noninvasive near-infrared spectroscopy technology to monitor percent regional cerebral tissue oxygenation (rSO2). We assessed if cerebral oximetry predicts meningitis mortality.



Methods



We performed cerebral oximetry within 14 days of cryptococcal meningitis diagnosis on 121 Ugandans from April 2016 to September 2017. We evaluated baseline rSO2 association with mortality by multivariable logistic regression and correlation with other clinical factors. We compared groups formed by initial rSO2 <30% vs ≥30% for longitudinal change with mixed effects models. We measured change in %rSO2 before and after lumbar puncture (LP).



Results



The median initial rSO2 (interquartile range) was 36% (29%–42%), and it was <30% in 29% (35/121). For 30-day mortality, the unadjusted odds ratio (per 5% increase in rSO2) was 0.73 (95% confidence interval [CI], 0.58 to 0.91; P = .005). Those with initial rSO2 <30% had 3.4 (95% CI, 1.5 to 8.0) higher odds of 30-day mortality than those with initial rSO2 ≥30%. Hemoglobin correlated with initial rSO2 (rho = .54; P < .001), but rSO2 did not correlate with pulse oximetry, intracranial pressure, cerebral perfusion pressure, or quantitative cerebrospinal fluid culture, and rSO2 was unchanged pre/post–lumbar punctures. The longitudinal rSO2 measurements change was 15% (95% CI, 12% to 18%) lower in the group with initial rSO2 <30%.



Conclusions



Individuals with cryptococcal meningitis and low cerebral oximetry (rSO2 < 30%) have high mortality. Cerebral oximetry may be useful as a prognostic marker of mortality. Targeted interventions to improve rSO2 should be tested in trials to try to decrease mortality in meningitis.

cerebrovascular circulation, cryptococcal meningitis, hemodynamic monitoring, mortality, oximetry, physiologic monitoring



Topic:



meningitis cryptococcal meningitis hemoglobin brain diagnosis mortality diagnostic spinal puncture oximetry, pulse cerebral perfusion pressure tissue oxygenation transcranial cerebral oximetry },

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Freemen2018,

title = {Smartphone Confocal Microscopy for Imaging Cellular Structures In Human Skin in Vivo. },

author = {Esther E Freemen and Aggrey Semeere and Hany Osman and Gary Peterso and Milind Rajadhyaksha,and Salvador Gonzalez and Jeffrey N Martin and R. Rox Anderson and Guillermo J Tearney and Dongkyun Kang},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Smartphone-Confocal-Microscopy-for-Imaging-Cellular-Structures-In-Human-Skin-in-Vivo.-4.pdf},

doi = {10.1364/BOE.9.001906},

year  = {2018},

date = {2018-04-20},

journal = { BIOMEDICAL OPTICS EXPRESS },

volume = {9},

number = {4},

pages = {1906–1915},

abstract = { We report development of a low-cost smartphone confocal microscope and its first demonstration of in vivo human skin imaging. The smartphone confocal microscope uses a slit aperture and diffraction grating to conduct two-dimensional confocal imaging without using any beam scanning devices. Lateral and axial resolutions of the smartphone confocal microscope were measured as 2 and 5 µm, respectively. In vivo confocal images of human skin revealed characteristic cellular structures, including spinous and basal keratinocytes and papillary dermis. Results suggest that the smartphone confocal microscope has a potential to examine cellular details in vivo and may help disease diagnosis in resource-poor settings, where conducting standard histopathologic analysis is challenging. © 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement OCIS codes: (170.1790) Confocal microscopy; (170.1870) Dermatology. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Nyakato2018,

title = {Correction of estimates of retention in care among a cohort of HIV-positive patients in Uganda in the period before starting ART: a sampling-based approach},

author = {Patience Nyakato and Agnes N Kiragga and Andrew Kambugu and John Bradley and Kathy Baisley},

url = {https://bmjopen.bmj.com/content/8/4/e017487.long},

year  = {2018},

date = {2018-04-20},

journal = {BMJ Open},

volume = {8},

number = {4},

abstract = {OBJECTIVE:



The aim of this study was to use a sampling-based approach to obtain estimates of retention in HIV care before initiation of antiretroviral treatment (ART), corrected for outcomes in patients who were lost according to clinic registers.

DESIGN:



Retrospective cohort study of HIV-positive individuals not yet eligible for ART (CD4 >500).

SETTING:



Three urban and three rural HIV care clinics in Uganda; information was extracted from the clinic registers for all patients who had registered for pre-ART care between January and August 2015.

PARTICIPANTS:



A random sample of patients who were lost according to the clinic registers (>3 months late to scheduled visit) was traced to ascertain their outcomes.

OUTCOME MEASURES:



The proportion of patients lost from care was estimated using a competing risks approach, first based on the information in the clinic records alone and then using inverse probability weights to incorporate the results from tracing. Cox regression was used to determine factors associated with loss from care.

RESULTS:



Of 1153 patients registered for pre-ART care (68% women, median age 29 years, median CD4 count 645 cells/µL), 307 (27%) were lost according to clinic records. Among these, 195 (63%) were selected for tracing; outcomes were ascertained in 118 (61%). Seven patients (6%) had died, 40 (34%) were in care elsewhere and 71 (60%) were out of care. Loss from care at 9 months was 30.2% (95% CI 27.3% to 33.5%). After incorporating outcomes from tracing, loss from care decreased to 18.5% (95% CI 13.8% to 23.6%).

CONCLUSION:



Estimates of loss from HIV care may be too high if based on routine clinic data alone. A sampling-based approach is a feasible way of obtaining more accurate estimates of retention, accounting for transfers to other clinics.



© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Burnett2018b,

title = {Synergistic Impact of Training Followed by On-Site Support on HIV Clinical Practice: A Mixed-Design Study in Uganda With Pre/Post and Cluster-Randomized Trial Components},

author = {Burnett, Sarah M.; Mubiru, Norbert ; Imani, Peace; Mbonye, Martin K.; Fisher, Leigh ; Colebunders, Robert; Manabe, Yukari C. ; Weaver, Marcia R. },

doi = {doi: 10.1097/QAI.0000000000001630},

year  = {2018},

date = {2018-04-15},

journal = {JAIDS Journal of Acquired Immune Deficiency Syndromes},

volume = {77},

number = {5},

pages = {467-475},

abstract = {

Background: 

Task shifting can expand antiretroviral therapy access, but little is known about effective approaches to improve clinical practice among midlevel practitioners (MLPs) such as clinical officers, nurses, and midwives. The Integrated Infectious Diseases Capacity Building Evaluation compared training alone with training combined with on-site support (OSS).



Methods: 

Two MLPs each from 36 health facilities attended the 5-week Integrated Management of Infectious Disease training. After training, 18 facilities randomly assigned to arm A received OSS for 9 months, whereas 18 arm B facilities did not. Clinical faculty assessed MLP HIV clinical practice on 6 tasks: history taking, physical examination, laboratory investigations, diagnosis, treatment, and patient education. We analyzed the effect of training alone and training combined with OSS as the pre/post change within each arm. We analyzed the incremental effect of OSS with a difference-in-difference analysis that compared changes between arms.



Results: 

Training alone and training combined with OSS significantly improved clinical practice in patient history taking (13% and 24% increase, respectively), physical examination (54% and 71%), laboratory investigations (32% and 20%), and diagnosis (31% and 51%). Combined training and OSS also improved patient education significantly (72% increase). Effect sizes for training combined with OSS were larger than for training alone except for laboratory investigations, and the effects were robust in sensitivity analyses. The incremental effect of OSS on diagnosis was significant [adjusted relative risk = 1.23; 95% confidence interval = 1.00 to 1.50].



Conclusions: 

Combined training and OSS improved MLP HIV clinical practice over training alone and can contribute to continued expansion of access to antiretroviral therapy.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Nabatanzi2018,

title = {Effects of HIV infection and ART on phenotype and function of circulating monocytes, natural killer, and innate lymphoid cells},

author = {Rose Nabatanzi, Stephen Cose, Moses Joloba, Sarah Rowland Jones & Damalie Nakanjako },

doi = {https://doi.org/10.1186/s12981-018-0194-y},

year  = {2018},

date = {2018-03-15},

journal = {AIDS Research and Therapy },

volume = {15},

number = {1},

abstract = {HIV infection causes upregulation of markers of inflammation, immune activation and apoptosis of host adaptive, and innate immune cells particularly monocytes, natural killer (NK) and innate lymphoid cells (ILCs). Although antiretroviral therapy (ART) restores CD4 T-cell counts, the persistent aberrant activation of monocytes, NK and ILCs observed likely contributes to the incomplete recovery of T-cell effector functions. A better understanding of the effects of HIV infection and ART on the phenotype and function of circulating monocytes, NK, and ILCs is required to guide development of novel therapeutic interventions to optimize immune recovery.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Wandeler2018,

title = {Issues with measuring hepatitis prevalence in resource-limited settings},

author = {Gilles Wandeler, Patrick A Coffie, Mark H Kuniholm, Ponsiano Ocama and Matthias Egger},

doi = {https://doi.org/10.1016/S0140-6736(18)30463-X},

year  = {2018},

date = {2018-03-03},

journal = {The Lancet },

volume = {391},

number = {10123},

pages = {835-836},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Cresswell2018,

title = {Absence of Cerebrospinal Fluid Pleocytosis in Tuberculous Meningitis is a Common Occurrence in HIV Co-infection and a Predictor of Poor Outcomes },

author = {Fiona V Cresswell and Ananta S Bangdiwala and David B Meya and Nathan C Bahr and Jose E Vidal and M. Estée Török, Le Thi Phuong and Thao Guy E Thwaites and David R Boulwar},

url = {https://www.ijidonline.com/article/S1201-9712(18)30015-8/fulltext},

doi = {10.1016/j.ijid.2018.01.014.},

year  = {2018},

date = {2018-03-01},

journal = {International Jouranl of Infectious Deseases},

volume = {67},

pages = {77-78},

abstract = {We read with interest the article by Erdem et al. reporting absence of cerebrospinal fluid (CSF) pleocytosis (≤5 cells/l) in 3% (19/507) of HIV-negative tuberculous meningitis (TBM) patients (Erdem et al., 2017). 

We wish to highlight both the significance and higher incidence of acellular CSF among HIV-infected adults with TBM. In reviewing 85 microbiologically-confirmed, HIV-associated TBM cases in Uganda, 33% (28/85) had acellular CSF. Acellular CSF was also commonly reported among other HIV-infected microbiologically-confirmed TBM cohorts: 26% (5/19) in Zimbabwe, 19% (20/108) in Brazil, and 21% (18/91) in Argentina (Table1)(Cecchini et al., 2007, Croda et al., 2010, Hakim et al., 2000, Vidal et al., 2010). Prevalence of acellular CSF correlated with the severity of immunosuppression in the Argentinian cohort and occurred twice as often in CD4 counts <50 cells/l(33%, 9/28) than with >50 cells/ (15%, 5/31) (Cecchini et al., 2009). In Vietnam, acellular CSF is less common (4%, 20/461) despite advanced immunosuppression (median CD4 39 cells). Variation between cohorts may be attributable to variable time to CSF analysis, M. tuberculosis strain type, or genetic differences in host immune responses between geographically distinct cohorts (Caws et al., 2008). },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Becker2018,

title = {Detection of tuberculosis patterns in digital photographs of chest X-ray images using Deep Learning: feasibility study },

author = {Becker, A. S. ; Blüthgen, C. ; Phi van, V. D. ; Sekaggya-Wiltshire, C. ; Castelnuovo, B. ; Kambugu, A. ; Fehr, J. ; Frauenfelder, T. },

doi = {https://doi.org/10.5588/ijtld.17.0520},

year  = {2018},

date = {2018-03-01},

journal = {International Union Against Tuberculosis and Lung Disease},

volume = {22},

number = {3},

pages = {328-335(8)},

abstract = {OBJECTIVE: To evaluate the feasibility of Deep Learning-based detection and classification of pathological patterns in a set of digital photographs of chest X-ray (CXR) images of tuberculosis (TB) patients.



MATERIALS AND METHODS: In this prospective, observational study, patients with previously diagnosed TB were enrolled. Photographs of their CXRs were taken using a consumer-grade digital still camera. The images were stratified by pathological patterns into classes: cavity, consolidation, effusion, interstitial changes, miliary pattern or normal examination. Image analysis was performed with commercially available Deep Learning software in two steps. Pathological areas were first localised; detected areas were then classified. Detection was assessed using receiver operating characteristics (ROC) analysis, and classification using a confusion matrix.



RESULTS: The study cohort was 138 patients with human immunodeficiency virus (HIV) and TB co-infection (median age 34 years, IQR 28–40); 54 patients were female. Localisation of pathological areas was excellent (area under the ROC curve 0.82). The software could perfectly distinguish pleural effusions from intraparenchymal changes. The most frequent misclassifications were consolidations as cavitations, and miliary patterns as interstitial patterns (and vice versa).



CONCLUSION: Deep Learning analysis of CXR photographs is a promising tool. Further efforts are needed to build larger, high-quality data sets to achieve better diagnostic performance. },

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Namiiro2018,

title = {Molecular tests expedite the diagnosis of multidrug-resistant tuberculosis in childhood},

author = {Namiiro, S. ; Wobudeya, E. ; Colebunders, R. ; Worodria, W.},

doi = {https://doi.org/10.5588/ijtld.17.0507},

year  = {2018},

date = {2018-03-01},

journal = {International Union Against Tuberculosis and Lung Disease},

volume = {22},

number = {3},

pages = {349-350(2)},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Okoboi2018b,

title = {Correlation between Co-Therapy of Efavirenz-Based ART and Pregnancy among HIV-Positive Women on Hormonal Contraceptive Implants at TASO Tororo-Uganda: A Retrospective Review},

author = {Stephen Okoboi, Ajambo Eunice, Ronald Oceng and Bernard Etukoit},

doi = {DOI: 10.4172/2155-6113.1000759},

year  = {2018},

date = {2018-02-28},

journal = {Journal of AIDS & Clinical Research},

volume = {9},

number = {2},

abstract = {Background: 

We examined the association between EFV and non-EFV based ART regimens and pregnancy

outcomes among women who were on HCI in a peri-urban HIV clinic in Tororo, Uganda.



Methods: 

We reviewed and extracted routinely collected data from the TASO Tororo HIV clinic family planning

register. All women >18 years of age and on ART who received HCI between January, 2012 and June, 2014 were

included in the study.



Results: 

Of the 148 women reviewed 9 (6.1%) conceived. All women who conceived were on an EFV-based

regimen, while none of the women on non-EFV based regimens conceived (p=0.0003).



Conclusion: 

We observed a significant association (p=0.0003) between HIV-positive HCI users on EFV-based

ART regimens as compared to HIV-positive HCI users on non-EFV based ART regimens.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Lamorde2018b,

title = {Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics of Efavirenz 400 mg Once Daily During Pregnancy and Post-Partum},

author = {Mohammed Lamorde, Xinzhu Wang, Megan Neary, Elisa Bisdomini, Shadia Nakalema, Pauline Byakika-Kibwika, Jackson K Mukonzo, Waheed Khan, Andrew Owen, Myra McClure, Marta Boffito},

doi = {https://doi.org/10.1093/cid/ciy161},

year  = {2018},

date = {2018-02-23},

journal = {Clinical Infectious Diseases},

volume = {67},

number = {5},

pages = {785–790},

abstract = {Background

A clinical trial showed that efavirenz 400 mg once daily (EFV400) is as effective as the standard adult dose. World Health Organization recommends EFV400 as an alternative first-line agent, but data are lacking in the third trimester of pregnancy (TT). We investigated the pharmacokinetics, efficacy, and CYP2B6 pharmacogenetics in HIV-infected women (WLWH) on EFV400 during TT and post-partum (PP).



Methods

An open-label 2-center study (United Kingdom, Uganda) was conducted in WLWH receiving antiretroviral regimens containing efavirenz 600 mg, who had their efavirenz dose reduced to EFV400. Weekly therapeutic drug monitoring (TDM), steady-state pharmacokinetic profiles (TT and PP), safety, virological efficacy, and CYP2B6 polymorphisms at positions 516 (C > T) and 938 (T > C) were evaluated.



Results

Twenty-five WLWH of African origin were enrolled. All had viral loads <50 copies/mL at baseline, which were maintained throughout the study. No infant was HIV infected. No WLWH were withdrawn due to low EFV400 TDM results. Geometric mean ratios (TT/PP; 90% confidence interval) for EFV400 maximum observed plasma concentration, area under the curve, and plasma concentration measured 24 hours after the observed dose were 0.97 (.85–1.10), 0.87 (.76–.99), and 0.77 (.65–.91), respectively. Five of 25 WLWH were slow metabolizers.



Conclusions

Although EFV400 pharmacokinetic parameters were slightly lower for TT compared with PP values, efavirenz concentrations exceeded cutoff levels established by the study and those measured in antiretroviral-naive patients receiving EFV400 in ENCORE1. All subjects maintained a viral load <50 copies/mL, suggesting that EFV400 can be used in pregnant WLWH.

low-dose efavirenz, pharmacokinetics, pregnancy



Topic:

pregnancy efavirenz pharmacogenetics pharmacokinetics 



Issue Section:

Articles and Commentaries },

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Castelnuovo2018,

title = {Antiretroviral treatment Long-Term (ALT) cohort: a prospective cohort of 10 years of ART-experienced patients in Uganda},

author = {Barbara Castelnuovo and Frank Mubiru and Agnes N Kiragga and Rachel Musomba and Olive Mbabazi and Paul Gonza and Andrew Kambugu and Rosalind Parks Ratanshi},

url = {https://bmjopen.bmj.com/content/8/2/e015490.long},

year  = {2018},

date = {2018-02-21},

journal = {BMJ Open},

volume = {8},

number = {2},

abstract = {Purpose Little information is available on patients on antiretroviral treatment (ART) after a long-term period from sub-Saharan Africa, with the longest follow-up and related outcomes being after 10 years on ART. At the Infectious Diseases Institute (IDI) (Kampala, Uganda), we set up a cohort of patients already on ART for 10 years at the time of enrolment, who will be followed up for additional 10 years.



Participants A prospective observational cohort of 1000 adult patients previously on ART for 10 years was enrolled between May 2014 and September 2015. Patients were eligible for enrolment if they were in their consecutive 10th year of ART regardless of the combination of drugs for both first- and second-line ART. Data were collected at enrolment and all annual study visits. Follow-up visits are scheduled once a year for 10 years. Biological samples (packed cells, plasma and serum) are stored at enrolment and follow-up visits.



Findings to date Out of 1000 patients enrolled, 345 (34.5%) originate from a pre-existing research cohort at IDI, while 655 (65.5%) were enrolled from the routine clinic. Overall, 81% of the patients were on first line at the time of the enrolment in the ART long-term cohort, with the more frequent regimen being zidovudine plus lamivudine plus nevirapine (44% of the cohort), followed by zidovudine plus lamivudine plus efavirenz (22%) and tenofovir plus lamivudine or emtricitabine plus efavirenz (10%). At cohort enrolment, viral suppression was defined as HIV-RNA <400 copies/mL was 95.8%.



Future plans Through collaboration with other institutions, we are planning several substudies, including the evaluation of the risk for cardiovascular diseases, the assessment of bone mineral density, screening for liver cirrhosis using fibroscan technology and investigation of drug–drug interactions between ART and common drugs used for non-communicable diseases.



This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Nakiyingi2018,

title = {Performance of loop-mediated isothermal amplification assay in the diagnosis of pulmonary tuberculosis in a high prevalence TB/HIV rural setting in Uganda},

author = {Lydia Nakiyingi and Prossy Nakanwagi and Jessica Briggs and Tifu Agaba and Frank Mubiru and Mark Mugenyi and Willy Ssengooba and Moses L. Joloba and Yukari C. Manabe},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Performance-of-loop-mediated-isothermal-amplification-assay-in-the-diagnosis-of-pulmonary-tuberculosis-in-a-high-prevalence-TB-or-HIV-rural-setting-in-Uganda.pdf},

doi = { 10.1186/s12879-018-2992-1},

year  = {2018},

date = {2018-02-21},

journal = { BMC Infectious Diseases },

volume = {18},

number = {1},

pages = {87},

abstract = {BACKGROUND:



Smear microscopy lacks sensitivity especially in HIV co-infection, resulting in undiagnosed tuberculosis (TB) and high mortality. The loop-mediated isothermal amplification (TB-LAMP) assay can be staged with minimal infrastructure, is rapid, low cost and detection can be with the naked eye. We assessed feasibility and performance of Eiken TB-LAMP test at point-of-need in TB diagnosis in a high prevalence TB/HIV rural setting in Uganda.

METHODS:



From October 2013-February 2014, TB-LAMP testing was performed on sputum specimens from outpatient presumptive TB adults at a district hospital and two low-level health centers in Kiboga District where smear microscopy is the available routine diagnostic option. TB-LAMP was performed by a technician after a week of training in the district hospital. The technician had no prior experience in the technology. Samples from the low-level health centers were transported to the district hospital for TB-LAMP.

RESULTS:



Of the 233 presumptive TB (126 at hospital); 113 (48.5%) were HIV-infected; 129 (55%) male; median age 40 (IQR 30-53). Compared to MTB culture, overall sensitivity and specificity of TB-LAMP were 55.4% (95 CI 44.1-66.3) and 98.0% (95 CI 94.3-99.6) respectively. Among HIV-infected participants, TB-LAMP sensitivity and specificity were 52.3% (95 CI 36.7-67.5%) and 97.1% (95 CI 89.9-99.6) respectively; and 24.4% (95% CI 12.9-39.5) and 98.6% (95% CI 95.1-99.8) respectively among smear-negatives. TB-LAMP sensitivity and specificity were 62.2% (95% CI 44.8-77.5) and 97.8% (95% CI 92.1-99.7) in the hospital setting where central testing occurred compared to 50.0% (95% CI 34.9-65.1) and 98.4% (95% CI 91.2-100) respectively in low-level health centers where specimens were transported centrally.

CONCLUSIONS:



In this high prevalence TB/HIV rural setting, TB-LAMP performs better than conventional smear microscopy in diagnosis of MTB among presumptive TB patients although the sensitivity is lower than that reported by the World Health Organization. TB-LAMP can easily be performed following a short training period and in absence of sophisticated infrastructure and expertise.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Castelnuovo2018b,

title = {Describing the retention in care of human immunodeficiency virus positive young adults who transition from adolescent to adult care},

author = {Barbara Castelnuovo, Frank Mubiru, Shadia Nakalema, Adelline Twimukye and Agnes Kiragga

},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Describing-the-retention-in-care-of-human-immunodeficiency-virus-positive-young-adults-who-transition-from-adolescent-to-adult-care.pdf},

doi = {10.1093/inthealth/ihx063.},

year  = {2018},

date = {2018-02-01},

journal = {International Health},

volume = {10},

number = {4},

pages = {318-320},

abstract = {Background:



There is a high rate of lost to programme (LTP) in human immunodeficiency virus (HIV)-positive young adults transitioning from paediatric/adolescent to adult care.

Methods:



We describe and identify risk factors for LTP in all patients 18-23 y of age at the Infectious Diseases Institute (Kampala, Uganda) from 2010 to 2014.

Results:



A total of 260 of 907 young adults (28.6%) became LTP. Among those on antiretroviral treatment, 39.3% became LTP. We found that the only risk factor associated with LTP was being in World Health Organization stage 3 or 4.

Conclusion:



There is a need for tracing studies to evaluate the true vital status of LTP in this group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Nakiwala2018,

title = {Neutrophil activation and enhanced release of granule products in HIV-TB immune reconstitution inflammatory syndrome},

author = {Justine K Nakiwala, Naomi F Walker, Collin R Diedrich, William Worodria, Graeme Meintjes, Robert J Wilkinson, Harriet Mayanja-Kizza, Robert Colebunders, Luc Kestens, Katalin A Wilkinson and David M Lowe},

doi = {doi: 10.1097/QAI.0000000000001582},

year  = {2018},

date = {2018-02-01},

journal = {J Acquir Immune Defic Syndr.},

volume = {77},

number = {2},

pages = {221–229},

abstract = {Background

Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) remains incompletely understood. Neutrophils are implicated in tuberculosis pathology but detailed investigations in TB-IRIS are lacking. We sought to further explore the biology of TB-IRIS and in particular the role of neutrophils.



Setting

Two observational, prospective cohort studies in HIV/TB co-infected patients starting antiretroviral therapy, one to analyze gene expression and subsequently one to explore neutrophil biology.



Methods

nCounter gene expression analysis was performed in TB-IRIS patients (n=17) versus antiretroviral-treated HIV/TB co-infected controls without IRIS (n=17) in Kampala, Uganda. Flow cytometry was performed in TB-IRIS patients (n=18) and controls (n=11) in Cape Town, South Africa to determine expression of neutrophil surface activation markers, intracellular cytokines and Human Neutrophil Peptides (HNP). Plasma neutrophil Elastase and HNP1-3 were quantified using ELISA. Lymph node immunohistochemistry was performed on three further TB-IRIS cases.



Results

There was a significant increase in gene expression of S100A9 (p=0.002), NLRP12 (p=0.018), COX-1 (p=0.025) and IL-10 (p=0.045) two weeks after ART initiation in Ugandan TB-IRIS patients versus controls, implicating neutrophil recruitment. IRIS patients in both cohorts demonstrated increases in blood neutrophil count, plasma HNP and elastase concentrations from ART initiation to week two. CD62L (L-selectin) expression on neutrophils increased over 4 weeks in South African controls while IRIS patients demonstrated the opposite. Intense staining for the neutrophil marker CD15 and IL-10 was seen in necrotic areas of TB-IRIS patients’ lymph nodes.



Conclusion

Neutrophils in TB-IRIS are activated, recruited to sites of disease and release granule contents, contributing to pathology.

Keywords: Tuberculosis, HIV-1, neutrophils, immune reconstitution inflammatory syndrome, IRIS},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Cabral2018,

title = {Intimate partner violence and self-reported pre-exposure prophylaxis (PrEP) interruptions among HIV-negative partners in HIV serodiscordant couples in Kenya and Uganda},

author = {Alejandra Cabral, Jared Baeten, Kenneth Ngure, Jennifer Velloza, Josephine Odoyo, Jessica Haberer, Connie Celum, Timothy Muwonge, Stephen Asiimwe, Renee Heffron,},

doi = {doi: 10.1097/QAI.0000000000001574},

year  = {2018},

date = {2018-02-01},

journal = {J Acquir Immune Defic Syndr.},

volume = {77},

number = {2},

pages = {154-159},

abstract = {Background



Oral pre-exposure prophylaxis (PrEP) is effective for HIV prevention and PrEP delivery studies are investigating ways to deliver PrEP with high adherence. However, in many settings with high HIV burden, intimate partner violence (IPV) is reported often and could be a barrier to effective PrEP use. We examined the association between IPV and interruptions in PrEP use.



Methods

We analyzed data from 1,013 serodiscordant heterosexual couples enrolled in a large PrEP demonstration project in Kenya and Uganda, the Partners Demonstration Project. At quarterly study visits, HIV-negative participants receiving PrEP were asked about interruptions in their PrEP use and experiences with IPV. The association between IPV and PrEP interruptions was analyzed using multivariable generalized estimating equations.



Results

At baseline and follow-up there were 53 visits with reports of abuse by 49 HIV-negative partners, including physical, economic, and verbal IPV. Interruptions in PrEP use were reported at 328 visits (7.1% of all visits) by 249 people. The median length of PrEP interruption was 28 days (interquartile range [IQR]: 7–45). The frequency of PrEP interruptions among those reporting IPV was 23.8% and those without IPV was 6.9%. PrEP interruption was significantly associated with IPV after adjustment for age and frequency of sexual intercourse (adjusted OR=2.6, 95% CI 1.2–6.0).



Conclusion

IPV was more likely to be reported at visits when PrEP interruptions were also reported, which may have implications for sustained adherence to PrEP. Within PrEP delivery programs, there may be opportunities to assess individual safety and well-being in order to bolster adherence.



Keywords: 

Intimate Partner Violence, Pre-exposure prophylaxis, HIV, adherence, serodiscordant couples, Africa},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Mujugira2018,

title = {High Levels of Viral Suppression Among East African HIV-Infected Women and Men in Serodiscordant Partnerships Initiating Antiretroviral Therapy with High CD4 Counts and During Pregnancy},

author = {Andrew Mujugira, Jared M. Baeten, Lara Kidoguchi, Jessica Haberer, Connie Celum, Deborah Donnell, Kenneth Ngure, Elizabeth A. Bukusi, Nelly Mugo, Stephen Asiimwe, Josephine Odoyo, Edna Tindimwebwa, Nulu Bulya, Elly Katabira, Renee Heffron, and for the Partners Demonstration Project Team},

doi = {https://doi.org/10.1089/aid.2017.0020},

year  = {2018},

date = {2018-02-01},

journal = {AIDS Research and Human Retroviruses},

volume = {34},

number = {2},

pages = {140-147},

abstract = {Abstract

People who are asymptomatic and feel healthy, including pregnant women, may be less motivated to initiate antiretroviral therapy (ART) or achieve high adherence. We assessed whether ART initiation, and viral suppression 6, 12, and 24 months after ART initiation, were lower in HIV-infected members of serodiscordant couples who initiated during pregnancy or with higher CD4 counts. We used data from the Partners Demonstration Project, an open-label study of the delivery of integrated pre-exposure prophylaxis and ART (at any CD4 count) for HIV prevention among high-risk HIV serodiscordant couples in Kenya and Uganda. Differences in viral suppression (HIV RNA <400 copies/ml) among people initiating ART at different CD4 count levels (≤350, 351–500, and >500 cells/mm3) and during pregnancy were estimated using Poisson regression. Of 865 HIV-infected participants retained after becoming eligible for ART during study follow-up, 95% initiated ART. Viral suppression 24 months after ART initiation was high overall (97%), and comparable among those initiating ART at CD4 counts >500, 351–500, and ≤350 cells/mm3 [96% vs. 97% vs. 97%; relative risk (RR) 0.98; 95% confidence interval (CI): 0.93–1.03 for CD4 > 500 vs. <350 and RR 0.99; 95% CI: (0.93–1.06) for CD4 351–500 vs. ≤350]. Viral suppression was as likely among women initiating ART primarily to prevent perinatal transmission as ART initiation for other reasons (p = .9 at 6 months and p = .5 at 12 months). Nearly all HIV-infected partners initiating ART were virally suppressed by 24 months, irrespective of CD4 count or pregnancy status. These findings suggest that people initiating ART at high CD4 counts or due to pregnancy can adhere to ART as well as those starting treatment with symptomatic HIV disease or low CD4 counts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Heffron2018,

title = {Pre-exposure prophylaxis for HIV-negative persons with partners living with HIV: uptake, use, and effectiveness in an open-label demonstration project in East Africa},

author = {Renee Heffron, Kenneth Ngure, Josephine Odoyo, Nulu Bulya, Edna Tindimwebwa, Ting Hong, Lara Kidoguchi, Deborah Donnell, Nelly R. Mugo, Elizabeth A. Bukusi, Elly Katabira, Stephen Asiimwe, Jennifer Morton, Susan Morrison, Harald Haugen, Andrew Mujugira, Jessica E. Haberer, Norma C. Ware, Monique A. Wyatt, Mark A. Marzinke, Lisa M. Frenkel, Connie Celum, Jared M. Baeten and The Partners Demonstration Project Team},

doi = { doi: 10.12688/gatesopenres.12752.2},

year  = {2018},

date = {2018-01-30},

journal = {Gates Open Research},

volume = {1},

number = {3},

abstract = {Methods

The PrEP delivery model integrated PrEP into HIV treatmentservices, prioritizing PrEP use for HIV-negative partners within serodiscordant couples before and during the first 6 months after the partner living with HIV initiated antiretroviral therapy (ART). We measured PrEP uptake through pharmacy records and adherence to PrEP through medication event monitoring system (MEMS) bottle caps and quantification of tenofovir in plasma among a random sample of participants. We estimated HIV infections prevented using a counterfactual cohort simulated from the placebo arm of a previous PrEP

clinical trial.



Results:

We enrolled 1,010 HIV serodiscordant couples that were naïve toResults ART and PrEP. Ninety-seven percent of HIV-negative partners initiated PrEP. Objective measures suggest high adherence: 71% of HIV-negative participants took ≥80% of expected doses, as recorded via MEMS, and 81% of plasma samples had tenofovir detected. Four incident HIV infections were observed (incidence rate=0.24 per 100 person-years), a 95% reduction (95% CI 86-98%, p<0.0001) in HIV incidence, relative to estimated HIV incidence for the population in the absence of PrEP integrated into HIV treatment services.





Conclusions: 

PrEP uptake and adherence were high and incident HIV wasConclusions rare in this PrEP demonstration project for African HIV-negative individuals whose partners were known to be living with HIV. Delivery of PrEP to HIV-negative partners within HIV serodiscordant couples was feasible and should be prioritized for wide-scale implementation.



Keywords

HIV prevention, HIV serodiscordant couples, PrEP, ART},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{IeDEA2018,

title = {Global Trends in CD4 Cell Count at the Start of Antiretroviral Therapy: Collaborative Study of Treatment Program},

author = {IeDEA, COHERE Cohort },

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Global-Trends-in-CD4-Cell-Count-at-the-Start-of-Antiretroviral-Therapy-Collaborative-Study-of-Treatment-Program.pdf},

doi = {10.1093/cid/cix915},

year  = {2018},

date = {2018-01-25},

journal = {Clinical Infectious Diseases},

volume = {66},

number = {6},

pages = { 893–903},

abstract = {Background



Early initiation of combination antiretroviral therapy (cART), at higher CD4 cell counts, prevents disease progression and reduces sexual transmission of human immunodeficiency virus (HIV). We describe the temporal trends in CD4 cell counts at the start of cART in adults from low-income, lower-middle-income, upper-middle-income, and high-income countries (LICs, LMICs, UMICs, and HICs, respectively).

Methods



We included HIV-infected individuals aged ≥16 years who started cART between 2002 and 2015 in a clinic participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) or the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE). Missing CD4 cell counts at the start of cART were estimated through multiple imputation. Weighted mixed-effect models were used to smooth trends in median CD4 cell counts.

Results



A total of 951855 adults from 16 LICs, 11 LMICs, 9 UMICs, and 19 HICs were included. Overall, the modeled median CD4 cell count at the start of cART increased from 2002 to 2015, from 78/µL (95% confidence interval, 58–104/µL) to 287/µL (250–328/µL) in LICs, from 99/µL (71–140/µL) to 234/µL (192–285/µL) in LMICs, from 71/µL (49–104/µL) to 311/µL (255–379/µL) in UMICs, and from 161/µL (143–181/µL) to 327/µL (286–372/µL) in HICs. In LICs, LMICs, and UMICs, the increase was more pronounced in women; in HICs, the opposite was observed.

Conclusions



Median CD4 cell counts at the start of cART increased in all income groups, but generally remained below 350/μL in 2015. Substantial additional efforts and resources are required to achieve earlier diagnosis, linkage to care, and initiation of cART.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Vululi2018,

title = {Prevalence of lower limb deep venous thrombosis among adult HIV positive patients attending an outpatient clinic at Mulago Hospital},

author = {Sosthene Tsongo Vululi and Samuel Bugeza and Muyinda Zeridah and Henry Ddungu and Akello Betty Openy and Mubiru Frank and Rosalind Parkes‑Ratanshi

},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Prevalence-of-lower-limb-deep-venous-thrombosis-among-adult-HIV-positive-patients-attending-an-outpatient-clinic-at-Mulago-Hospital.pdf},

doi = {10.1186/s12981-018-0191-1},

year  = {2018},

date = {2018-01-25},

journal = {AIDS Research and Therapy},

volume = {13},

number = {1},

abstract = {BACKGROUND:



Deep venous thrombosis (DVT) and its major complication pulmonary embolism (PE) are collectively known as venous thromboembolism. In Uganda, the prevalence of DVT among HIV patients has not been previously published. The aim of the study was to determine the prevalence and sonographic features of lower limb deep venous thrombosis among HIV positive patients on anti-retroviral treatment (ART).

METHODS:



This was a cross sectional study in which HIV positive patients on ART were recruited from an out-patient HIV clinic at Mulago National Referral Hospital. Patients were randomly selected and enrolled until a sample size of 384 was reached. Study participants underwent compression and Doppler ultrasound studies of both lower limb deep veins using Medison Sonoacer7 ultrasound machine.

RESUTS:



We found a prevalence of DVT of 9.1% (35 of 384 participants) among HIV patients on ART. The prevalence of latent (asymptomatic) DVT was 2.3%. Among 35 patients with DVT, 42.8% had chronic DVT; 31.1% had acute DVT and the rest had latent DVT. Among the risk factors, the odds of occurrence of DVT among patients with prolonged immobility were 4.81 times as high as in those with no prolonged immobility (p = 0.023; OR = 4.81; 95% CI 1.25-18.62). Treatment with second line anti-retroviral therapy (ART) including protease inhibitors (PIs) was associated with higher odds of DVT occurrence compared with first line ART (p = 0.020; OR = 2.38; 95% CI 1.14-4.97). The odds of DVT occurrence in patients with a lower CD4 count (< 200 cells/µl) were 5.36 times as high as in patients with CD4 counts above 500 cells/µl (p = 0.008). About 48.6% patients with DVT had a low risk according to Well's score.

CONCLUSION:



DVT was shown in nearly 10% of HIV patients attending an out-patient clinic in an urban setting in Uganda. Risk factors included protease inhibitors in their ART regimen, prolonged immobility, and low CD4 count (< 200 cells/µl). Clinicians should have a low threshold for performing lower limb Doppler ultrasound scan examination on infected HIV patients on ART who are symptomatic for DVT. Therefore, clinicians should consider anti-coagulant prophylaxis and lower deep venous ultrasound screening of patients who are on second line ART regimen with low CD4 cell counts and/or with prolonged immobility or hormonal contraception.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kalema2018,

title = {Predictors and short-term outcomes of recurrent pulmonary tuberculosis, Uganda: a cohort study},

author = {Nelson Kalema, Christina Lindan, Dave Glidden, Samuel D. Yoo, Achilles Katamba, Andama Alfred, Winceslaus Katagira, Patrick Byanyim, Emmanuel Musisi, Sylvia Kaswabuli, Sanyu Ingvar, Josephine Zawedde, Christina Yoon, Irene Ayakaka, J. Lucian Davis, Laurence Huang, William Worodria, and Adithya Cattamanchi},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Predictors-and-short-term-outcomes-of-recurrent-pulmonary-tuberculosis-Uganda-a-cohort-study.pdf},

year  = {2018},

date = {2018-01-22},

journal = {South African repository journal},

volume = {23},

number = {4},

pages = {106-112},

abstract = {Introduction:



Recurrent tuberculosis (TB) occurring >2 years after completing treatment for a prior TB episode is most often due to reinfection with a new strain of M. tuberculosis.

Objectives:



We determined the prevalence and outcome of late recurrent TB among hospitalized patients in Kampala, Uganda.

Methods:



We conducted a retrospective analysis of patients admitted to Mulago Hospital who had cough of >2 weeks' duration and completed TB treatment >2 years prior to admission. All patients had mycobacterial culture performed on two sputum specimens and vital status ascertained 2-months post-enrollment. We performed modeling to identify predictors of recurrent TB and of survival.

Results:



Among 234 patients, 84 (36%) had recurrent TB. Independent predictors included younger age (aOR=0.64, 95% CI=0.42-0.97, p=0.04), chest pain >2 weeks (aOR=3.32, 95% CI=1.38-8.02, p=0.007), severe weight loss ≥5 kilograms (aOR=4.88, 95% CI=1.66-14.29, p=0.004) and presence of ≥1 WHO danger sign of severe illness (aOR=3.55, 95% CI=1.36-9.29, p=0.01). Two-month mortality was 17.8% (95% CI=10.5-29.2%), and was higher among patients not initiated on TB treatment (aHR=16.67, 95% CI=1.18-200, p=0.04), not on ART if HIV-positive (aHR=16.99, 95% CI=1.17-246.47, p=0.04) and with a history of smoking (aHR=1.20, 95% CI=1.03-1.40, p=0.02).

Conclusion:



The high prevalence of late recurrent TB likely reflects high levels of TB transmission in Kampala. Increased use of empiric TB treatment and early ART treatment initiation if HIV-positive should be considered in patients with a prior history of TB, particularly if young, with weight loss ≥5kgs, chest pain >2 weeks or ≥1 WHO danger sign of severe illness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Roberts2018,

title = {Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug–drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART},

author = { Owain Roberts, Rajith K R Rajoli, David J Back, Andrew Owen, Kristin M Darin, Courtney V Fletcher, Mohammed Lamorde, Kimberly K Scarsi, Marco Siccardi},

doi = {https://doi.org/10.1093/jac/dkx515},

year  = {2018},

date = {2018-01-22},

journal = {Journal of Antimicrobial Chemotherapy},

volume = {73},

number = {4},

pages = {1004–1012},

abstract = {Background

HIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low levonorgestrel exposure and unintended pregnancy.



Objectives

To investigate clinically applicable dose-adjustment strategies to overcome the known drug–drug interaction (DDI) between levonorgestrel and efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach.



Methods

A PBPK model was qualified against clinical data to predict levonorgestrel plasma concentrations when standard-dose (150 mg) levonorgestrel implants were administered alone (control group), as well as when standard-dose or increased-dose (300 mg) levonorgestrel implants were coadministered with either 600 or 400 mg of efavirenz.



Results

No difference was seen between in vivo clinical and PBPK-model-simulated levonorgestrel plasma concentrations (P > 0.05). Simulated levonorgestrel plasma concentrations were ∼50% lower at 48 weeks post-implant-placement in virtual individuals receiving standard-dose levonorgestrel with either 600 or 400 mg of efavirenz compared with the control group (efavirenz:control geometric mean ratio = 0.42 and 0.49, respectively). Conversely, increased-dose levonorgestrel in combination with either 600 or 400 mg of efavirenz was sufficient to restore levonorgestrel concentrations to levels similar to those observed in the 150 mg levonorgestrel control group 48 weeks post-implant-placement (efavirenz:control geometric mean ratio = 0.86 and 1.03, respectively).



Conclusions

These results suggest that the clinically significant DDI between efavirenz and levonorgestrel is likely to persist despite efavirenz dose reduction, whereas dose escalation of implantable levonorgestrel may represent a successful clinical strategy to circumvent efavirenz–levonorgestrel DDIs and will be of use to inform clinical trial design to assess coadministration of efavirenz and levonorgestrel implants.



Topic:

plasma drug concentration drug interactions efavirenz contraceptive agents levonorgestrel implants 



Issue Section:

ORIGINAL RESEARCH },

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Dorman2018,

title = {Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study},

author = {Susan E Dorman and Samuel G Schumacher and David Alland and Pamela Nabeta and Derek T Armstrong and Bonnie King and Sandra L Hall and Soumitesh Chakravorty and Daniela M Cirillo and Nestani Tukvadze, and Nino Bablishvili and Wendy Stevens and Lesley Scott and Camilla Rodrigues and Mubin I Kazi and Moses Joloba and Lydia Nakiyingi and Mark P Nicol and Yonas Ghebrekristos and Irene Anyango and Wilfred Murithi and Reynaldo Dietze and Renata Lyrio Peres and Alena Skrahina and Vera Auchynka and Kamal Kishore Chopra and Mahmud Hanif and Xin Liu and Xing Yuan, and Catharina C Boehme and Jerrold J Ellner and Claudia M Denkinger},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Xpert-MTBRIF-Ultra-for-detection-of-Mycobacterium.pdf},

doi = {10.1016/S1473-3099(17)30691-6 },

year  = {2018},

date = {2018-01-21},

journal = {Lancent},

volume = {18},

number = {1},

pages = { 76-84},

abstract = {Background The Xpert MTB/RIF assay is an automated molecular test that has improved the detection of tuberculosis and rifampicin resistance, but its sensitivity is inadequate in patients with paucibacillary disease or HIV. Xpert MTB/RIF Ultra (Xpert Ultra) was developed to overcome this limitation. We compared the diagnostic performance of Xpert Ultra with that of Xpert for detection of tuberculosis and rifampicin resistance.

Methods In this prospective, multicentre, diagnostic accuracy study, we recruited adults with pulmonary tuberculosis symptoms presenting at primary health-care centres and hospitals in eight countries (South Africa, Uganda, Kenya, India, China, Georgia, Belarus, and Brazil). Participants were allocated to the case detection group if no drugs had been taken for tuberculosis in the past 6 months or to the multidrug-resistance risk group if drugs for tuberculosis had been taken in the past 6 months, but drug resistance was suspected. Demographic information, medical history, chest imaging results, and HIV test results were recorded at enrolment, and each participant gave at least three sputum specimen on 2 separate days. Xpert and Xpert Ultra diagnostic performance in the same sputum specimen was compared with culture tests and drug susceptibility testing as reference standards. The primary objectives were to estimate and compare the sensitivity of Xpert Ultra test with that of Xpert for detection of smear-negative tuberculosis and rifampicin resistance and to estimate and compare Xpert Ultra and Xpert specificities for detection of rifampicin resistance. Study participants in the case detection group were included in all analyses, whereas participants in the multidrug-resistance risk group were only included in analyses of rifampicin-resistance detection.

Findings Between Feb 18, and Dec 24, 2016, we enrolled 2368 participants for sputum sampling. 248 participants were excluded from the analysis, and 1753 participants were distributed to the case detection group (n=1439) and the multidrug-resistance risk group (n=314). Sensitivities of Xpert Ultra and Xpert were 63% and 46%, respectively, for the 137 participants with smear-negative and culture-positive sputum (difference of 17%, 95% CI 10 to 24); 90% and 77%, respectively, for the 115 HIV-positive participants with culture-positive sputum (13%, 6·4 to 21); and 88% and 83%, respectively, across all 462 participants with culture-positive sputum (5·4%, 3·3 to 8·0). Specificities of Xpert Ultra and Xpert for case detection were 96% and 98% (–2·7%, –3·9 to –1·7) overall, and 93% and 98% for patients with a history of tuberculosis. Xpert Ultra and Xpert performed similarly in detecting rifampicin resistance.

Interpretation For tuberculosis case detection, sensitivity of Xpert Ultra was superior to that of Xpert in patients with paucibacillary disease and in patients with HIV. However, this increase in sensitivity came at the expense of a decrease in specificity.

Funding Government of Netherlands, Government of Australia, Bill & Melinda Gates Foundation, Government of the UK, and the National Institute of Allergy and Infectious Diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Otiti-Sengeri2018,

title = {Elevated inflammatory cytokines in aqueous cytokine profile in HIV-1 infected patients with cataracts in Uganda},

author = {Juliet Otiti-Sengeri, Robert Colebunders, Steven J. Reynolds, Musa Muwonge, Getrude Nakigozi, Valerian Kiggundu, Fred Nalugoda, Damalie Nakanjako},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Elevated-inflammatory-cytokines-in-aqueous-cytokine-profile-in-HIV-1-infected-patients-with-cataracts-in-Uganda.pdf},

year  = {2018},

date = {2018-01-19},

journal = {BMC Ophthalmology},

volume = {18},

number = {1},

abstract = {BACKGROUND:



Cataracts occur earlier among HIV-infected adults and this is attributed to various intraocular inflammatory processes that result in early degeneration. In this study we purposed to investigate whether HIV infected individuals with cataracts develop heightened intraocular inflammatory processes compared to their HIV negative counterparts by determining the concentration of 8 cytokines in the aqueous humour of HIV-positive adults with cataracts and their HIV-negative counterparts.

METHODS:



A cross-sectional study was conducted among consecutive adults with cataracts that were operated in an ophthalmology surgical camp in western Uganda. We determined levels of Granulocyte macrophage stimulating factor (GM-CSF), interleukin 6 (IL-6), interleukin 8 (IL-8), tumour necrotic factor alpha (TNF-a), interferon gamma (IFN-g), interleukin 4 (IL-4), interleukin 2 (IL-2), and interleukin (IL-10) in the aqueous fluid using a multiplexed cytokine analysis. Data was entered in the SPSS version 10 and analyzed using STATA statistical software version 7.0. Categorical and continuous variables were compared using the χ2 test, Fisher's exact test and the Student's t-test. Bonferroni correction was used to cater for multiple comparison of p values for the various cytokines.

RESULTS:



The 50 adults that underwent cataract surgery were outdoor peasants with similar exposure hours to UV radiation. The HIV-positive patients were younger {median age 43 years (SD 11.741)} compared to the HIV -negative patients {median age 66.5 years (SD 21.4)}. The mean CD4+ T cell count of the HIV-positive patients was 161 cells /mm3, and 12(48%) had started anti-retroviral therapy (ART). Pro inflammatory cytokines, GM-CSF, IL-8 and IL-10 were significantly higher among HIV-positive individuals (p = 0.001, 0.030, < 0.001 respectively). HIV-positive individuals on ART also showed significantly higher levels of GM-CSF, IL-8 and IL - 10 (p = 0.002, 0.021, < 0.001 respectively). TNF-a and IL-4 were significantly higher among those with a CD4+ T cell count greater than 200cells/mm3 compared to those with CD4+ T cell count less than 200 cells/mm3 (p = 0.022, 0.032 respectively).

CONCLUSION:



Cataracts among HIV-positive adults were associated with higher intraocular inflammation relative to the healthy elderly individuals with cataracts. There is need to explore the potential role of intra-ocular anti-inflammatory agents in the management of cataracts among HIV positive patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Holmes2018,

title = {Increased prevalence of pregnancy and comparative risk of program attrition among individuals starting HIV treatment in East Africa.},

author = {Charles B. Holmes, Constantin T. Yiannoutsos, Batya Elul, Elizabeth Bukusi, John Ssali, Andrew Kambugu, Beverly S. Musick, Craig Cohen, Carolyn Williams, Lameck Diero, Nancy Padian, Kara K. Wools-Kaloustian},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Increased-prevalence-of-pregnancy-and-comparative-risk-of-program-attrition-among-individuals-starting-HIV-treatment-in-East-Africa.pdf},

doi = {10.1371/journal.pone.0190828},

year  = {2018},

date = {2018-01-17},

journal = {PloS One},

volume = {13},

number = {1},

abstract = {BACKGROUND:



The World Health Organization now recommends initiating all pregnant women on life-long antiretroviral therapy (ART), yet there is limited information about the characteristics and program outcomes of pregnant women already on ART in Africa. Our hypothesis was that pregnant women comprised an increasing proportion of those starting ART, and that sub-groups of these women were at higher risk for program attrition.

METHODS AND FINDINGS:



We used the International Epidemiology Databases to Evaluate AIDS- East Africa (IeDEA-EA) to conduct a retrospective cohort study including HIV care and treatment programs in Kenya, Uganda, and Tanzania. The cohort consecutively included HIV-infected individuals 13 years or older starting ART 2004-2014. We examined trends over time in the proportion pregnant, their characteristics and program attrition rates compared to others initiating and already receiving ART. 156,474 HIV-infected individuals (67.0% women) started ART. The proportion of individuals starting ART who were pregnant women rose from 5.3% in 2004 to 12.2% in 2014. Mean CD4 cell counts at ART initiation, weighted for annual program size, increased from 2004 to 2014, led by non-pregnant women (annual increase 20 cells/mm3) and men (17 cells/mm3 annually), with lower rates of change in pregnant women (10 cells/mm3 per year) (p<0.0001). There was no significant difference in the cumulative incidence of program attrition at 6 months among pregnant women starting ART and non-pregnant women. However, healthy pregnant women starting ART (WHO stage 1/2) had a higher rate of attrition rate (9.6%), compared with healthy non-pregnant women (6.5%); in contrast among women with WHO stage 3/4 disease, pregnant women had lower attrition (8.4%) than non-pregnant women (14.4%). Among women who initiated ART when healthy and remained in care for six months, subsequent six-month attrition was slightly higher among pregnant women at ART start (3.5%) compared to those who were not pregnant (2.4%), (absolute difference 1.1%, 95% CI 0.7%-1.5%).

CONCLUSIONS:



Pregnant women comprise an increasing proportion of those initiating ART in Africa, and pregnant women starting ART while healthy are at higher risk for program attrition than non-pregnant women. As ART programs further expand access to healthier pregnant women, further studies are needed to better understand the drivers of loss among this high risk group of women to optimize retention.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Rachel2018,

title = {Uptake of hepatitis B-HIV co-infection screening and management in a resource limited settin},

author = {Musomba Rachel, Castelnuovo Barbara, Claire Murphy, Charlene Komujuni, Patience Nyakato, Ponsiano Ocama, Mohammed Lamorde, Philippa Easterbrooka, Rosalind Parkes Ratanshi},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Uptake-of-hepatitis-B-HIV-co-infection-screening-and-management-in-a-resource-limited-setting.pdf},

doi = {10.1186/s41124-017-0030-3},

year  = {2018},

date = {2018-01-06},

journal = { BMC Hepatology, Medicine and Policy},

abstract = {Background: WHO hepatitis B guidelines recommend testing all new HIV patients, treating them accordingly or providing immunization. At the Infectious Diseases Institute (IDI) following an audit done in 2012, only 46% patients had been screened for hepatitis B with variable management plans therefore new internal guidelines were implemented. This study describes the uptake of hepatitis B screening and management of patients with hepatitis B and HIV con-infection after the implementation. Methods: Data included for all HIV positive patients in care at IDI by October 2015. Data are expressed as median with interquartile range (IQR) and percentages were compared using the chi square test. Statistical analysis was performed using STATA version 13. The IDI laboratory upper limit of normal for alanine aminotransferase (ALT) and aspartate aminotransferase (ASTs) was 40 IU/ml. Results: Number of hepatitis B screening tests increased from 800 by 2012 to 1400 in 2015. By 2015 8042/8604(93.5%) patients had been screened for hepatitis B. Overall hepatitis B positive were 359 (4.6%). 166 (81.4%) hepatitis B positives were switched to a tenofovir (TDF) containing regimen. Conclusion: Our study confirms the importance of screening for hepatitis B and of using ART regimens containing tenofovir in hepatitis B co-infected patients. Whilst our program has made improvements in care still 18.6% of patients with hepatitis B were not on tenofovir regimens, 98.1% had no hepatitis B viral loads done. Clinicians should recognize the potential for hepatitis B in HIV positive patients and the importance of early diagnosis and treatment to ensure optimal management of cases and follow up.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Mpoza2018,

title = {Evaluation of a point-of-care immunoassay test kit ‘StrongStep’ for cryptococcal antigen detection},

author = {Edward Mpoza and Liliane Mukaremera and Didas Atwebembere Kundura and Andrew Akampurira and Tonny Luggya and Kiiza Kandole Tadeo and Katelyn A. Pastick and Sarah C. Bridgt, Lillian Tugume and Reuben Kiggundu and Abdu K. Musubire and Darlisha A. Williams and Conrad Muzoora and Elizabeth Nalintya and Radha Rajasingham and Joshua Rhein and David R. Boulware and David B. Meya and Mahsa Abassi},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Evaluation-of-a-point-of-care-immunoassay-test-kit-StrongStep-for-cryptococcal-antigen-detection..pdf},

doi = {10.1371/journal.pone.0190652},

year  = {2018},

date = {2018-01-05},

journal = {PloS One},

volume = {13},

number = {1},

abstract = {BACKGROUND:



HIV-associated cryptococcal meningitis is the leading cause of adult meningitis in Sub-Saharan Africa, accounting for 15%-20% of AIDS-attributable mortality. The development of point-of-care assays has greatly improved the screening and diagnosis of cryptococcal disease. We evaluated a point-of-care immunoassay, StrongStep (Liming Bio, Nanjing, Jiangsu, China) lateral flow assay (LFA), for cryptococcal antigen (CrAg) detection in cerebrospinal fluid (CSF) and plasma.

METHODS:



We retrospectively tested 143 CSF and 77 plasma samples collected from HIV-seropositive individuals with suspected meningitis from 2012-2016 in Uganda. We prospectively tested 90 plasma samples collected from HIV-seropositive individuals with CD4 cell count <100 cells/μL from 2016-2017 as part of a cryptococcal antigenemia screening program. The StrongStep CrAg was tested against a composite reference standard of positive Immy CrAg LFA (Immy, Norman, OK, USA) or CSF culture with statistical comparison by McNemar's test.

RESULTS:



StrongStep CrAg had a 98% (54/55) sensitivity and 90% (101/112) specificity in plasma (P = 0.009, versus reference standard). In CSF, the StrongStep CrAg had 100% (101/101) sensitivity and 98% (41/42) specificity (P = 0.99). Adjusting for the cryptococcal antigenemia prevalence of 9% in Uganda and average cryptococcal meningitis prevalence of 37% in Sub-Saharan Africa, the positive predictive value of the StrongStep CrAg was 50% in plasma and 96% in CSF.

CONCLUSIONS:



We found the StrongStep CrAg LFA to be a sensitive assay, which unfortunately lacked specificity in plasma. In lower prevalence settings, a majority of positive results from blood would be expected to be false positives.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Waitt2018,

title = {Plasma and breast milk pharmacokinetics of emtricitabine, tenofovir and lamivudine using dried blood and breast milk spots in nursing African mother–infant pairs},

author = {Catriona Waitt, Adeniyi Olagunju, Shadia Nakalema, Isabella Kyohaire, Andrew Owen, Mohammed Lamorde, Saye Khoo},

year  = {2018},

date = {2018-01-04},

journal = {Journal of Antimicrobiol Chemotherapy},

volume = {73},

number = {4},

pages = {1013-1019},

abstract = {Background:



Breast milk transfer of first-line ART from mother to infant is not fully understood.

Objectives:



To determine the concentrations of lamivudine, emtricitabine and tenofovir in maternal blood, breast milk and infant blood from breastfeeding mother-infant pairs.

Methods:



Intensive pharmacokinetic sampling of maternal dried blood spots (DBS), dried breast milk spots (DBMS) and infant DBS from 30 Ugandan and 29 Nigerian mothers receiving first-line ART and their infants was conducted. DBS and DBMS were collected pre-dose and at 5-6 timepoints up to 12 h following observed dosing. Infant DBS were sampled twice during this period. Lamivudine, emtricitabine and tenofovir were quantified using LC-MS/MS, with non-compartmental analysis to calculate key pharmacokinetic parameters.

Results:



Peak concentrations in breast milk from women taking lamivudine and emtricitabine occurred later than in plasma (4-8 h compared with 2 h for lamivudine and 2-4 h for emtricitabine). Consequently, the milk-to-plasma (M:P) ratio of lamivudine taken once daily was 0.95 (0.82-1.15) for AUC0-12, whereas for AUC12-20 this was 3.04 (2.87-4.16). Lamivudine was detectable in 36% (14/39) of infants [median 17.7 (16.3-22.7) ng/mL]. For 200 mg of emtricitabine once daily, the median M:P ratio was 3.01 (2.06-3.38). Three infants (19%) had measurable emtricitabine [median 18.5 (17.6-20.8) ng/mL]. For 300 mg of tenofovir once daily, the median M:P ratio was 0.015 (0-0.03) and no infant had measurable tenofovir concentrations.

Conclusions:



Emtricitabine and lamivudine accumulate in breast milk and were detected in breastfeeding infants. In contrast, tenofovir penetrates the breast milk to a small degree, but is undetectable in breastfeeding infants.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hakim2018,

title = {Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial.},

author = {James G Hakim, Jennifer Thompson, Cissy Kityo, Anne Hoppe, Andrew Kambugu, Joep J van Oosterhout, Abbas Lugemwa, Abraham Siika, Raymond Mwebaze, Aggrey Mweemba, George Abongomera, Margaret J Thomason, Philippa Easterbrook, Peter Mugyenyi, A Sarah Walker, Nicholas I Paton},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Europe-Africa-Research-Network-for-Evaluation-of-Second-line-Therapy-EARNEST-Trial-Team.-Lopinavir-plus-nucleoside-reverse-transcriptase-inhibitors-lopinavir-plus-raltegravir-or-lopi.pdf},

doi = {10.1016/S1473-3099(17)30630-8},

year  = {2018},

date = {2018-01-02},

volume = {18},

number = {1},

pages = {47-57},

abstract = {BACKGROUND:



Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.

METHODS:



We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.

FINDINGS:



Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.

INTERPRETATION:



Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.

FUNDING:



European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{H2018,

title = {Antimicrobial Drug  Resistance in Blood Culture Isolates at a Tertiary  Hospital, Uganda.},

author = {Kajumbula H, Fujita AW, Mbabazi O, Najjuka C, Izale C, Akampurira A, Aisu S, Lamorde M, Walwema R, Bahr NC, Meya DB, Boulware DR, Manabe YC.},

url = {https://wwwnc.cdc.gov/eid/article/24/1/17-1112_article},

doi = {10.3201/eid2401.},

year  = {2018},

date = {2018-01-01},

journal = {Emerging Infectious Diseases},

volume = {24},

number = {1},

abstract = {We summarize antimicrobial drug resistance (AMR) patterns from blood cultures at a tertiary hospital in Uganda. High rates of resistance to first-line antibiotic drugs were observed among Staphylococcus aureus and gram-negative organisms. Microbiology services with susceptibility testing should be strengthened to support standardized reporting of AMR data in sub-Saharan Africa.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Byakika-Kibwika2017,

title = {Intravenous artesunate plus Artemisnin based Combination Therapy (ACT) or intravenous quinine plus ACT for treatment of severe malaria in Ugandan children: a randomized controlled clinical trial},

author = {Pauline Byakika-Kibwika and Jane Achan and Mohammed Lamorde and Carine Karera-Gonahasa and Agnes N. Kiragga and Harriet Mayanja-Kizza and Noah Kiwanuka and Sam Nsobya and Ambrose O. Talisuna and Concepta Merry},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Intravenous-artesunate-plus-Artemisnin-based-Combination-Therapy-ACT-or-intravenous-quinine-plus-ACT-for-treatment-of-severe-malaria-in-Ugandan-children-a-randomized-controlled-clinical.pdf},

doi = {10.1186/s12879-017-2924-5},

year  = {2017},

date = {2017-12-28},

journal = {BMC Infectious Diseases},

volume = {17},

number = {1},

pages = {794},

abstract = {Background:

Severe malaria is a medical emergency associated with high mortality. Adequate treatment requires initial parenteral therapy for fast parasite clearance followed by longer acting oral antimalarial drugs for cure and prevention of recrudescence. 

Methods: 

In a randomized controlled clinical trial, we evaluated the 42-day parasitological outcomes of severe malaria treatment with intravenous artesunate (AS) or intravenous quinine (QNN) followed by oral artemisinin based combination therapy (ACT) in children living in a high malaria transmission setting in Eastern Uganda. Results: We enrolled 300 participants and all were included in the intention to treat analysis. Baseline characteristics were similar across treatment arms. The median and interquartile range for number of days from baseline to parasite clearance was significantly lower among participants who received intravenous AS (2 (1–2) vs 3 (2–3), P<0. 001). Overall, 63.3% (178/281) of the participants had unadjusted parasitological treatment failure over the 42-day follow-up period. Molecular genotyping to distinguish re-infection from recrudescence was performed in a sample of 127 of the 178 participants, of whom majority 93 (73.2%) had re-infection and 34 (26.8%) had recrudescence. The 42 day risk of recrudescence did not differ with ACT administered. Adverse events were of mild to moderate severity and consistent with malaria symptoms. Conclusion: In this high transmission setting, we observed adequate initial treatment outcomes followed by very high rates of malaria re-infection post severe malaria treatment. The impact of recurrent antimalarial treatment on the long term efficacy of antimalarial regimens needs to be investigated and surveillance mechanisms for resistance markers established since recurrent malaria infections are likely to be exposed to sub-therapeutic drug concentrations. More strategies for prevention of recurrent malaria infections in the most at risk populations are needed. 

Trial registration: The study was registered with the Pan African Clinical Trial Registry (PACTR201110000321348). 

Keywords: Artesunate, Quinine, Artemisinin combination therapy, Severe malaria, Re-infection

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Mahsa Abassi2017,

title = {Cryptococcal Disease in the Era of "Test and Treat": Is There Cause for Concern?},

author = {Mahsa Abassi, Joshua Rhein, David B. Meya, David R. Boulwar },

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777480/},

doi = {10.1093/ofid/ofx274},

year  = {2017},

date = {2017-12-26},

journal = {Open Forum Infectious Diseases},

volume = {5},

number = {51},

pages = {ofx274},

abstract = {Treatment of cryptococcosis requires deferred initiation of antiretroviral therapy (ART). Early ART initiation may be detrimental in the context of cryptococcal infection by increasing the risk of immune reconstitution inflammatory syndrome (IRIS). We present 3 cases where early ART initiation in the presence of unrecognized cryptococcal disease had fatal outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Abassi2017b,

title = {Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda},

author = {  Mahsa Abassi and Bozena M. Morawski Gertrude Nakigozi and Noeline Nakasujja and Xiangrong Kong and David B. Meya Kevin Robertson Ronald and Gray Maria and J. Wawer Ned Sacktor and David R. Boulware},

doi = {10.1007/s13365-016-0505-9},

isbn = {1355-0284},

year  = {2017},

date = {2017-12-19},

journal = {Journal of NueroVirology},

volume = {23},

number = {3},

pages = {369-375},

abstract = {In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/μL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid β42. Individuals with CD4 351–500 cells/μL (N = 40) had significantly higher CSF levels of interleukin (IL)-1β, amyloid β42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Flynn2017,

title = {Socioeconomic position and ten-year survival and virologic outcomes in a Ugandan HIV cohort receiving antiretroviral therapy},

author = {Andrew G. Flynn and Godwin Anguzu and Frank Mubiru and Agnes N. Kiragga and Moses Kamya and David B. Meya and David R. Boulware and Andrew Kambugu and Barbara C. Castelnuovo

},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Socioeconomic-position-and-ten-year-survival-and-virologic-outcomes-in-a-Ugandan-HIV-cohort-receiving-antiretroviral-therapy.pdf},

doi = {10.1371/journal. pone.0189055},

year  = {2017},

date = {2017-12-15},

journal = {PloS One},

abstract = {Lifelong ART is essential to reducing HIV mortality and ending the epidemic, however the interplay between socioeconomic position and long-term outcomes of HIV-infected persons receiving antiretroviral therapy (ART) in sub-Saharan Africa is unknown. Furthering the understanding of factors related to long-term ART outcomes in this important region will aid the successful scale-up of ART programs. We enrolled 559 HIV-infected Ugandan adults starting ART in 2004–2005 at the Infectious Diseases Institute in Kampala, Uganda and followed them for 10 years. We documented baseline employment status, regular household income, education level, housing description, physical ability, and CD4 count. Viral load was measured every six months. Proportional hazard regression tested for associations between baseline characteristics and 1) mortality, 2) virologic failure, and 3) mortality or virologic failure as a composite outcome. Over ten years 23% (n = 127) of participants died, 6% (n = 31) were lost-to-follow-up and 23% (107/472) experienced virologic treatment failure. In Kaplan-Meier analysis we observed an association between employment and mortality, with the highest cumulative probability of death occurring in unemployed individuals. In univariate analysis unemployment and disease severity were associated with mortality, but in multivariable analysis the only association with mortality was disease severity. We observed an association between higher household income and an increased incidence of both virologic failure and the combined outcome, and an association between self-employment and lower incidence of virologic failure and the combined outcome when compared to unemployment. Formal education level and housing status were unrelated to outcomes. It is feasible to achieve good ten-year survival, retention-in-care, and viral suppression in a socioeconomically diverse population in a resource-limited setting. Unemployment appears to be related to adverse 10-year ART outcomes. A low level of formal education does not appear to be a barrier to successful long-term ART.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Haberer2017,

title = {Context matters: PrEP adherence is associated with sexual behavior among HIV serodiscordant couples in East Africa},

author = {Jessica E. Haberer, MD, MS, Kenneth Ngure, PhD, MPH, MSc, Timothy Muwonge, MBChB, MPH, Nelly Mugo, Elly Katabira, Renee Heffron, Nicholas Musinguzi, David R. Bangsberg, Connie Celum, Jared M. Baeten and the Partners Mobile Adherence to PrEP (PMAP) Team},

doi = {doi: 10.1097/QAI.0000000000001548},

year  = {2017},

date = {2017-12-15},

journal = {J Acquir Immune Defic Syndr. },

volume = {76},

number = {5},

pages = {488–492},

abstract = {Background

Short message service (SMS) surveys are a promising tool for understanding whether pre-exposure prophylaxis (PrEP) adherence aligns with risk for HIV acquisition— a concept known as prevention-effective adherence.



Methods

The Partners Demonstration Project was an open-label study of integrated PrEP and antiretroviral therapy (ART) delivery among high-risk HIV serodiscordant couples in East Africa. HIV-uninfected partners were offered PrEP until their HIV-infected partner had taken ART for ≥6 months. At 2 study sites, HIV-uninfected partners were offered enrollment into the Partners Mobile Adherence to PrEP (PMAP) sub-study based on ongoing PrEP use, personal cell phone ownership, and ability to use SMS. SMS surveys asked about PrEP adherence and sexual activity in the prior 24 hours; these surveys were sent daily for the 7 days prior and 7 days after routine study visits in the Partners Demonstration Project.



Results

The PMAP sub-study enrolled 373 HIV-uninfected partners; 69% were male and mean age was 31 years. Participants completed 17,030 of 23,056 SMS surveys sent (74%) with a mean of 47 surveys per participant over 9.8 months of follow-up. While HIV-infected partner use of ART was <6 months, mean reported PrEP adherence was 92% on surveys concurrently reporting sex within the serodiscordant partnership and 84% on surveys reporting no sex (p<0.001).



Discussion

SMS surveys provided daily assessment of concurrent PrEP adherence and sexual behavior. Higher PrEP adherence was temporally associated with increased risk for HIV acquisition.



Keywords: HIV, pre-exposure prophylaxis (PrEP), SMS, adherence},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Musubire2017,

title = {A Systematic Review of  Non-Traumatic Spinal Cord  injuries in Sub-Saharan Africa and  a Proposed Diagnostic Algorithm  for Resource-Limited Settings},

author = {Abdu Kisekka Musubire, David B. Meya, Paul R. Bohjanen, Elly Tebasooke Katabira, Patrice Barasukana, David R. Boulware, Ana-Claire Meyer},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/A-Systematic-Review-of-Non-Traumatic-Spinal-Cord-Injuries-in-Sub-Saharan-Africa-and-a-Proposed-Diagnostic-Algorithm-for-Resource-Limited-Settings.pdf},

doi = {10.3389/fneur.2017.00618.},

year  = {2017},

date = {2017-12-08},

journal = {Frontiers in Neurology},

volume = {8},

number = {618},

abstract = {Background: Non-traumatic myelopathy is common in Africa and there are geographic differences in etiology. Clinical management is challenging due to the broad differential diagnosis and the lack of diagnostics. The objective of this systematic review is to determine the most common etiologies of non-traumatic myelopathy in sub-Saharan Africa to inform a regionally appropriate diagnostic algorithm. Methods: We conducted a systemic review searching Medline and Embase databases using the following search terms: “Non traumatic spinal cord injury” or “myelopathy” with limitations to epidemiology or etiologies and Sub-Saharan Africa. We described the frequencies of the different etiologies and proposed a diagnostic algorithm based on the most common diagnoses. Results: We identified 19 studies all performed at tertiary institutions; 15 were retrospective and 13 were published in the era of the HIV epidemic. Compressive bone lesions accounted for more than 48% of the cases; a majority were Pott’s disease and metastatic disease. No diagnosis was identified in up to 30% of cases in most studies; in particular, definitive diagnoses of non-compressive lesions were rare and a majority were clinical diagnoses of transverse myelitis and HIV myelopathy. Age and HIV were major determinants of etiology. Conclusion: Compressive myelopathies represent a majority of non-traumatic myelopathies in sub-Saharan Africa, and most were due to Pott’s disease. Non-compressive myelopathies have not been well defined and need further research in Africa. We recommend a standardized approach to management of non-traumatic myelopathy focused on identifying treatable conditions with tests widely available in low-resource settings.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kibirige2017,

title = {Access to affordable medicines and diagnostic tests for asthma and COPD in sub Saharan Africa: the Ugandan perspective},

author = {Davis Kibirige and Leaticia Kampiire and David Atuhe and Raymond Mwebaze and Winceslaus Katagira and Winters Muttamba and Rebecca Nantanda and William Worodria and Bruce Kirenga},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Access-to-affordable-medicines-and-diagnostic-tests-for-asthma-and-COPD-in-sub-Saharan-Africa-the-Ugandan-perspectiv.pdf},

doi = { 10.1186/s12890-017-0527-y},

year  = {2017},

date = {2017-12-08},

journal = {BMC Pulmonary Medicine},

volume = {17},

number = {1},

pages = {179},

abstract = {Background: Equitable access to affordable medicines and diagnostic tests is an integral component of optimal clinical care of patients with asthma and chronic obstructive pulmonary disease (COPD). In Uganda, we lack contemporary data about the availability, cost and affordability of medicines and diagnostic tests essential in asthma and COPD management. Methods: Data on the availability, cost and affordability of 17 medicines and 2 diagnostic tests essential in asthma and COPD management were collected from 22 public hospitals, 23 private and 85 private pharmacies. The percentage of the available medicines and diagnostic tests, the median retail price of the lowest priced generic brand and affordability in terms of the number of days’ wages it would cost the least paid public servant were analysed. Results: The availability of inhaled short acting beta agonists (SABA), oral leukotriene receptor antagonists (LTRA), inhaled LABA-ICS combinations and inhaled corticosteroids (ICS) in all the study sites was 75%, 60.8%, 46.9% and 45.4% respectively. None of the study sites had inhaled long acting anti muscarinic agents (LAMA) and inhaled long acting beta agonist (LABA)-LAMA combinations. Spirometry and peak flow-metry as diagnostic tests were available in 24.4% and 6.7% of the study sites respectively. Affordability ranged from 2.2 days’ wages for inhaled salbutamol to 17.1 days’ wages for formoterol/budesonide inhalers and 27.8 days’ wages for spirometry. Conclusion: Medicines and diagnostic tests essential in asthma and COPD care are not widely available in Uganda and remain largely unaffordable. Strategies to improve access to affordable asthma and COPD medicines and diagnostic tests should be implemented in Uganda. Keywords: Access, Medicines, Diagnostic tests, Asthma, COPD, Sub Saharan Africa, Uganda

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Castelnuovo2017,

title = {Challenges in Assessing Outcomes among Infants of Pregnant HIV-Positive Women Receiving ART in Uganda},

author = {Barbara Castelnuovo and Frank Mubiru and Ivan Kalule and Shadia Nakalema and Agnes Kiragga},

url = {https://www.idi-makerere.com/wp-content/uploads/2018/07/Challenges-in-Assessing-Outcomes-among-Infants-of-Pregnant-HIV-Positive-Women-Receiving-ART-in-Uganda.pdf},

doi = {10.1155/2017/3202737},

year  = {2017},

date = {2017-12-07},

journal = {AIDS Research and Treatment},

abstract = {Since 2012, the WHO recommends lifelong ART with TDF+FTC/3TC+EFV for all HIV-positive pregnant and breastfeeding women (Option B-plus). In this analysis we describe the proportion of early and late transmission in mothers with high retention in Kampala, Uganda. We included 700 pregnant women from January 2012 to August 2014 with a follow-up extended to August 2016; the median age was 31 years (IQR: 26-35), 36.3% in WHO stage 3/4; median CD4 count was 447 cells/μL (IQR: 301-651) and 73.3% were already on ART for a median time of 28 (IQR: 10-57) months; 52% infants were male and median weight was 3.2 Kg (IQR: 2.5-3.5). Five hundred and sixty-five (80.7%) infants had at least one test for HIV; 22 (3.1%) infants died, all with unknown serostatus; 3 tested positive at week 6 and one additional at months 12 and 18. Two of the mothers of the 4 HIV-positive infants were ART-naïve at the time of pregnancy. We report very low documented HIV transmission comparable with those reported in clinical trials settings; however, demonstrating the efficacy of Option B-plus in terms of averted transmission in routine settings is challenging since high proportion of infants do not have documented HIV tests.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}