@article{Ellis2019,

title = {Erratum to: The Changing Epidemiology of HIV-Associated Adult Meningitis, Uganda 2015–2017},

author = {Jayne Ellis and Ananta S. Bangdiwala and Fiona V. Cresswell and Joshua Rhein and Edwin Nuwagira and Kenneth Ssebambulidde and Lillian Tugume and Radha Rajasingham and Sarah C. Bridge and Conrad Muzoora and David B. Meya and David R. Boulware on behalf of the ASTRO-CM Team},

year  = {2019},

date = {2019-12-03},

journal = {Open Forum Infectious Diseases},

volume = {19},

number = {1},

pages = {982},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{P.2019,

title = {Piperaquine concentration and malaria treatment outcomes in Ugandan children treated for severe malaria with intravenous Artesunate or quinine plus Dihydroartemisinin-Piperaquine},

author = {Byakika-Kibwika P. and Ssenyonga R. and Lamorde M. and Blessborn D. and Tarning J. },

url = {https://link.springer.com/article/10.1186/s12879-019-4647-2},

doi = {doi: 10.1186/s12879-019-4647-2.},

year  = {2019},

date = {2019-12-03},

journal = {BMC Infectious Diseases},

volume = {19},

number = {1},

pages = {1025},

abstract = {Abstract



Background



Treatment for severe malaria must be prompt with effective parenteral antimalarial drugs for at least 24 h to achieve fast parasite clearance, and when the patient can tolerate oral therapy, treatment should be completed with effective artemisinin based combination therapy (ACT) for complete parasite clearance and to prevent recrudescence. We evaluated piperaquine concentration and malaria treatment outcomes among Ugandan children treated for severe malaria with intravenous artesunate (AS) or quinine (QN) plus dihydroartemisinin-piperaquine (DP), in Tororo District Hospital in Eastern Uganda.

Methods



Capillary blood piperaquine concentration data were obtained from a randomized clinical trial whose objective was to evaluate parasite clearance, 42-day parasitological treatment outcomes and safety, following treatment of severe malaria with intravenous AS or QN, plus artemether-lumefantrine or DP among children in Tororo District Hospital, in Eastern Uganda.

Results



Piperaquine concentration data from 150 participants who received DP were analyzed. Participants with unadjusted treatment failure had lower median day 7 capillary piperaquine concentration than those with treatment success (34.7 (IQR) (17.9–49.1) vs 66.7 (IQR) (41.8–81.9), p < 0.001), and lower than the recommended day 7 cut off level of 57 ng/mL. There was no difference in median capillary piperaquine concentrations among participants with re-infection and recrudescence (35.3 (IQR) (17.9–55.2) vs 34.8 (IQR) (18.1–45.1), p = 0.847). The risk of treatment failure was two times higher among children with low (< 57 ng/mL) day 7 capillary piperaquine concentration (relative risk: 2.1 CI 1.4–3.1), p < 0.001) compared to children with high day 7 capillary piperaquine concentrations (> 57 ng/mL).

Conclusion



Considering the low day 7 concentrations of piperaquine reported in the patients studied here, we suggest to adopt the recently recommended higher dose of DP in young children or a prolonged 5-day dosing in children living in malaria endemic areas who have suffered an initial episode of severe malaria in order to achieve adequate drug exposures for effective post-treatment prophylactic effects.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ellis2019b,

title = {The Changing Epidemiology of HIV-Associated Adult Meningitis, Uganda 2015–2017},

author = {Jayne Ellis and Ananta S Bangdiwala and Fiona V Cresswell and Joshua Rhein and Edwin Nuwagira and Kenneth Ssebambulidde and Lillian Tugume and Radha Rajasingham and Sarah C Bridge and Conrad Muzoora and David B Meya and David R Boulware },

url = {https://academic.oup.com/ofid/article/6/10/ofz419/5575986?login=true},

doi = {https://doi.org/10.1093/ofid/ofz419},

year  = {2019},

date = {2019-12-03},

journal = {Open Forum Infectious Diseases},

volume = {6},

number = {12},

abstract = {Abstract

Background



Central nervous system (CNS) infections remain a major public health problem in Sub-Saharan Africa, causing 15%–25% of AIDS-related deaths. With widespread availability of antiretroviral therapy (ART) and the introduction of improved diagnostics, the epidemiology of infectious meningitis is evolving.

Methods



We prospectively enrolled adults presenting with HIV-associated meningitis in Kampala and Mbarara, Uganda, from March 2015 to September 2017. Participants had a structured, stepwise diagnostic algorithm performed of blood cryptococcal antigen (CrAg), CSF CrAg, Xpert MTB/RIF for tuberculous (TB) meningitis (TBM), Biofire multiplex polymerase chain reaction, and traditional microscopy and cultures.

Results



We screened 842 consecutive adults with HIV presenting with suspected meningitis: 57% men, median age 35 years, median CD4 26 cells/mcL, and 55% presented on ART. Overall, 60.5% (509/842) were diagnosed with first-episode cryptococcal meningitis and 7.4% (62/842) with second episode. Definite/probable TB meningitis was the primary diagnosis in 6.9% (58/842); 5.3% (n = 45) had microbiologically confirmed (definite) TB meningitis. An additional 7.8% (66/842) did not meet the diagnostic threshold for definite/probable TBM but received empiric TBM therapy. Bacterial and viral meningitis were diagnosed in 1.3% (11/842) and 0.7% (6/842), respectively. The adoption of a cost-effective stepwise diagnostic algorithm allowed 79% (661/842) to have a confirmed microbiological diagnosis at an average cost of $44 per person.

Conclusions



Despite widespread ART availability, Cryptococcus remains the leading cause of HIV-associated meningitis. The second most common etiology was TB meningitis, treated in 14.7% overall. The increased proportion of microbiologically confirmed TBM cases reflects the impact of new improved molecular diagnostics.

bacterial meningitis, cryptococcal meningitis, HIV/AIDS, tuberculous meningitis, viral meningitis



Topic:



    polymerase chain reaction hiv bacterial meningitis meningitis epidemiology cryptococcal meningitis adult viral meningitis tuberculosis tuberculous meningitis uganda cryptococcus diagnosis },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Alhadab2019,

title = {Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis},

author = {Ali A. Alhadab and Joshua Rhein and Lillian Tugume and Abdu Musubire and Darlisha A. Williams and Mahsa Abassi and Melanie R. Nicol and David B. Meya and David R. Boulware and Richard C. Brundage on behalf of ASTRO-CM Study },

url = {https://link.springer.com/article/10.1007/s10928-019-09657-0},

doi = {https://doi.org/10.1007/s10928-019-09657-0},

year  = {2019},

date = {2019-12-01},

journal = {Journal of Pharmacokinetics and Pharmacodynamics },

volume = {46},

number = {6},

pages = {565-576},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Tugume2019,

title = {Perceived risk versus objectively measured risk of HIV acquisition: a cross-sectional study among HIV-negative individuals in Serodiscordant partnerships with clients attending an Urban Clinic in Uganda},

author = {Lillian Tugume, Timothy Ronald Muwonge, Edith Nakku Joloba, John Bosco Isunju & Flavia Matovu Kiweewa },

doi = {https://doi.org/10.1186/s12889-019-7929-0},

year  = {2019},

date = {2019-11-29},

journal = {BMC Public Health volume},

volume = {19},

number = {1591},

abstract = {Background



Acceptability of Pre-exposure Prophylaxis (PrEP) could be hampered by low self-perceived risk for HIV acquisition. Moreover, discordance between risk perception and actual risk of HIV acquisition is likely to occur. We assessed congruence between the level of self- perceived and that of objectively scored risk of HIV acquisition among HIV-negative individuals in discordant relationships.



Methods



This was a cross-sectional study among a representative sample of HIV-negative adult males and females whose partners were receiving antiretroviral therapy for at least 3 months from the Infectious Diseases Institute Clinic in Kampala, Uganda. Perceived risk was measured based on self-report using a numerical rating scale whereas objective risk was measured using a validated risk score tool. Congruence between perceived risk and objectively scored risk was evaluated using descriptive statistics and validity measures. Incongruence between the two phenomena was further evaluated using univariate and multivariate regression analyses.



Results



HIV-negative partners evaluated in this study were mostly male (64%) with a median age of 41 years (IQR 35 to 50). Majority (76.3%) of the partners perceived themselves as low risk for HIV acquisition. Similarly, most (93.8%) were objectively scored as low risk. However, nearly three quarters (72.7%) of partners who were objectively scored as high risk perceived themselves as being at low risk and all were men. The sensitivity and specificity of perceived risk for detecting the objectively measured risk was 27.3 and 76.5% respectively; area under ROC curve = 0.52; 95%CI (0.38, 0.66). The proportion of participants at high risk of HIV acquisition who perceived their risk as low was greater among those whose partners had detectable viral load compared to participants whose partners had undetectable viral load (PR = 0.51; 95%CI 0.29 to 0.90).



Conclusion



Incongruence between perceived and objectively measured risk of HIV acquisition does occur especially among individuals whose partners had a detectable viral load. PrEP counselling for serodiscordant couples should focus on explaining the consequence of detectable viral load in the HIV-positive partner on HIV transmission risk.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Manabe2019,

title = {A Parsimonious Host Inflammatory Biomarker Signature Predicts Incident Tuberculosis and Mortality in Advanced Human Immunodeficiency Virus},

author = {Yukari C Manabe, Bruno B Andrade, Nikhil Gupte, Samantha Leong, Manisha Kintali, Mitch Matoga, Cynthia Riviere, Wadzanai Samaneka, Javier R Lama, Kogieleum Naidoo, Yue Zhao, W Evan Johnson, Jerrold J Ellner, Mina C Hosseinipour, Gregory P Bisson, Padmini Salgame, Amita Gupta},

doi = {https://doi.org/10.1093/cid/ciz1147},

year  = {2019},

date = {2019-11-25},

journal = {Clinical Infectious Diseases},

volume = {71},

number = {10},

pages = {2645–2654},

abstract = {Background

People with advanced human immunodeficiency virus (HIV) (CD4 < 50) remain at high risk of tuberculosis (TB) or death despite the initiation of antiretroviral therapy (ART). We aimed to identify immunological profiles that were most predictive of incident TB disease and death.



Methods

The REMEMBER randomized clinical trial enrolled 850 participants with HIV (CD4 < 50 cells/µL) at ART initiation to receive either empiric TB treatment or isoniazid preventive therapy (IPT). A case-cohort study (n = 257) stratified by country and treatment arm was performed. Cases were defined as incident TB or all-cause death within 48 weeks after ART initiation. Using multiplexed immunoassay panels and ELISA, 26 biomarkers were assessed in plasma.



Results

In total, 52 (6.1%) of 850 participants developed TB; 47 (5.5%) died (13 of whom had antecedent TB). Biomarkers associated with incident TB overlapped with those associated with death (interleukin [IL]-1β, IL-6). Biomarker levels declined over time in individuals with incident TB while remaining persistently elevated in those who died. Dividing the cohort into development and validation sets, the final model of 6 biomarkers (CXCL10, IL-1β, IL-10, sCD14, tumor necrosis factor [TNF]-α, and TNF-β) achieved a sensitivity of 0.90 (95% confidence interval [CI]: .87–.94) and a specificity of 0.71(95% CI: .68–.75) with an area under the curve (AUC) of 0.81 (95% CI: .78–.83) for incident TB.



Conclusion

Among people with advanced HIV, a parsimonious inflammatory biomarker signature predicted those at highest risk for developing TB despite initiation of ART and TB preventive therapies. The signature may be a promising stratification tool to select patients who may benefit from increased monitoring and novel interventions.



Clinical Trials Registration

NCT01380080

tuberculosis, biomarker, antiretroviral therapy, early mortality



Topic:

hiv inflammatory markers biological markers plasma tuberculosis mortality 



Issue Section:

MAJOR ARTICLES AND COMMENTARIES },

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{AF2019,

title = {Schistosomiasis was not associated with higher HIV-1 plasma or genital set point viral loads among HIV seroconverters from four cohort studies},

author = {Bochner AF and Secor WE and Baeten JM and van Dam GJ and Szpiro AA and Njenga SM and Corstjens PLAM and Mackelprang RD and Mugo NR and Overbaugh J and Celum C and Mujugira A and McClelland RS and Barnabas RV. },

url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0007886},

doi = { https://doi.org/10.1371/journal.pntd.0007886},

year  = {2019},

date = {2019-11-20},

journal = {PLOS Neglected Tropical Diseases},

abstract = {Abstract



Background



Many regions of sub-Saharan Africa experience a high prevalence of both schistosomiasis and HIV-1, leading to frequent coinfection. Higher plasma HIV-1 viral loads are associated with faster disease progression and genital HIV-1 loads are a primary determinant of HIV-1 transmission risk. We hypothesized that schistosome infection would be associated with higher HIV-1 viral loads in plasma and genital samples.

Methods/Principal findings



We utilized data from individuals who HIV-1 seroconverted while enrolled in one of four prospective cohort studies. Plasma and genital viral loads collected 4–24 months after the estimated date of HIV-1 acquisition, but prior to antiretroviral therapy initiation, were included. Detection of circulating anodic antigen in archived blood samples, collected prior to HIV-1 seroconversion, identified participants with active schistosomiasis; immunoblots determined the schistosome species causing infection. Our analysis included 370 HIV-1 seroconverters with plasma viral load results, of whom 82 (22%) had schistosomiasis. We did not find a statistically significant association between schistosomiasis and higher HIV-1 set point plasma viral loads (-0.17 log10 copies/ml, 95% CI -0.38 to 0.03); S. mansoni infection was associated with a lower set point (-0.34 log10 copies/ml, 95% CI -0.58 to -0.09). We found no association between schistosomiasis and cervical (+0.07 log10 copies/swab, 95% CI -0.20 to 0.34) or vaginal (+0.11 log10 copies/swab, 95% CI -0.17 to 0.39) set point viral loads; S. haematobium infection was associated with lower cervical viral loads (-0.59 log10 copies/swab, 95% CI -1.11 to -0.06).

Conclusions/Significance



These results do not support the hypotheses that schistosome coinfection increases plasma or genital HIV-1 viral loads.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Seddon2019,

title = {Tuberculous meningitis: new tools and new approaches required},

author = {James A Seddon and Guy E Thwaites },

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871354/},

doi = {doi: 10.12688/wellcomeopenres.15591.1},

year  = {2019},

date = {2019-11-19},

journal = {Wellcome Open Research},

volume = {4},

pages = {181},

abstract = {Abstract



Tuberculous meningitis is the most severe form of tuberculosis and causes widespread mortality and morbidity. Understanding of the epidemiology and pathogenesis is incomplete, and the optimal diagnosis and treatment are poorly defined. To generate research collaboration and coordination, as well as to promote sharing of ideas and advocacy efforts, the International Tuberculous Meningitis Research Consortium was formed in 2009. During the most recent meeting of this group in Lucknow, India, in March 2019, the Consortium decided to bring together key articles on tuberculous meningitis in one supplement. The supplement covers recent scientific updates, expert perspectives on specific clinical challenges, consensus statements on how to conduct research, and a set of priorities for future investigation.

Keywords: Tuberculous meningitis, TBM, Tuberculosis, Consortium},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Richert-Spuhler2019,

title = {Pre-exposure prophylaxis differentially alters circulating and mucosal immune cell activation in herpes simplex virus type 2 seropositive women},

author = {Richert-Spuhler and Laura E.a and Pattacini, Lauraa and Plews, Margotb and Irungu, Elizabethc and Muwonge, Timothy R.d and Katabira, Ellye and Mugo, Nellyc,f,g and Meyers, Adrienne F.A.b,h and Celum, Connief,i,j and Baeten, Jared M.f,i,j and Lingappa, Jairam R.f,j,k and Lund, Jennifer M.},

url = {https://journals.lww.com/aidsonline/fulltext/2019/11150/pre_exposure_prophylaxis_differentially_alters.2.aspx},

doi = {doi: 10.1097/QAD.0000000000002323},

year  = {2019},

date = {2019-11-15},

journal = {AIDS},

volume = {33},

number = {14},

pages = {2125-2136},

abstract = {Abstract



Objective: 



Oral tenofovir-based pre-exposure prophylaxis (PrEP) is an important tool for prevention of new HIV infections, which also reduces subclinical herpes simplex virus type 2 (HSV-2) shedding and symptomatic lesions in HIV-negative, HSV-2-seropositive individuals. However, the impact of PrEP on mucosal immunity has not been examined in detail.



Design: 



Here we evaluate paired genital tissue and systemic immune profiles to characterize the immunological effects of PrEP in HIV-negative, HSV-2-seropositive African women sexually exposed to HIV.



Methods: 

We compared local and systemic innate and T-cell characteristics in samples collected during PrEP usage and 2 months after PrEP discontinuation.



Results: 

We found that frequencies of cervical CCR5+CD4+ cells, regulatory T cells, and tissue macrophages were significantly reduced during PrEP use compared with after PrEP discontinuation. In contrast, peripheral blood CD4+ and CD8+ T cells expressing markers of activation and trafficking were increased during PrEP usage.



Conclusion: 

Together, our data are consistent with PrEP altering immunity differentially in the female genital tract compared with circulation in HSV-2+ women. Further study including comparison with HSV-2 negative women is needed to define the overall impact and mechanisms underlying these effects. These results point to the critical need to study the human mucosal compartment to characterize immune responses to mucosal infections.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Martin2019,

title = {Bending the Arc towards Equitable Partnerships in Global Health and Applied Training},

author = {Nina A. Martin and Anna Kalbarczyk and Emily Nagourney and Abigail Reich and Bhakti Hansoti and Andrew Kambugu and Thomas C. Quinn and Yukari C. Manabe and Barbara Castelnuovo},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838765/},

doi = { doi: 10.5334/aogh.2564},

year  = {2019},

date = {2019-11-06},

journal = {Annals of Global Health},

volume = {85},

number = {1},

pages = {130},

abstract = {Abstract



Background:



Global health education has rapidly expanded in popularity, and many programs require applied practical experiences. Applied experiences are critical for global health training. Often a trainee from a high-income country travels to work with collaborators and partners in a low- or middle-income country. These experiences exist within partnerships between individuals and institutions that have varying objectives, including research, program implementation, or education. Attention is growing to ensure equity in these relationships in ways that are informed by the voices of collaborators and partners.



Objectives:



Understanding the experiences of LMIC collaborators in academic global health partnerships is essential. Our research aimed to capture views of our partners about factors impacting equitable global health partnerships.

Methods:



We conducted a small survey among global health collaborators and partners who host students on these experiences. Respondents were asked to rank enablers and barriers to equitable partnerships in priority order. Results were stratified by institutional affiliation and role.



Results:



Funding, time, engagement, and mutual opportunities for training are common enablers and barriers of global health partnerships. There were slight differences across different professional roles. Other reported factors that impact partnerships included language barriers, visa concerns, and identifying opportunities for collaboration.



Conclusions:



Our work highlights several barriers and enablers faced by partners that align with those reported across the global health education community. Equitable partnerships are possible and require substantial input at individual, interpersonal, and institutional levels. We reflect on two strategies to encourage partnership equity employed within our own work and discuss how these strategies can be applied more broadly.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Pastick2019b,

title = {Seizures in Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: Predictors and Outcomes},

author = { Katelyn A Pastick and Ananta S Bangdiwala and Mahsa Abassi and Andrew G Flynn and Bozena M Morawski and Abdu K Musubire and Prosperity C Eneh and Charlotte Schutz and Kabanda Taseera and Joshua Rhein and Kathy Huppler Hullsiek and Melanie R Nicol and Jose E Vidal and Noeline Nakasujja and Graeme Meintjes and Conrad Muzoora and David B Meya and David R Boulware},

url = {https://academic.oup.com/ofid/article/6/11/ofz478/5613202?login=true},

doi = {https://doi.org/10.1093/ofid/ofz478},

year  = {2019},

date = {2019-11-05},

journal = {Open Forum Infectious Diseases},

volume = {6},

number = {11},

abstract = {Abstract

Background



Seizures commonly occur in patients with cryptococcal meningitis, yet risk factors and outcomes related to seizures are not well described.

Methods



We performed post hoc analyses on participants prospectively enrolled in 3 separate human immunodeficiency virus (HIV)-associated cryptococcal meningitis clinical trials during 2010–2017. Documentation of seizures at presentation or during hospitalization and antiseizure medication receipt identified participants with seizures. We summarized participant characteristics by seizure status via Kruskal-Wallis and χ 2 tests. Cox proportional hazards models analyzed the relationship between seizures and mortality. We compared mean quantitative neurocognitive performance Z (QNPZ-8) scores, and individual domain z-scores, at 3-months using independent t tests.

Results



Among 821 HIV-infected cryptococcal meningitis participants, 28% (231 of 821) experienced seizures: 15.5% (127 of 821) experienced seizures at presentation, and 12.7% (104 of 821) experienced incident seizures. Participants with seizures at presentation had a significantly lower Glasgow coma scale ([GCS] <15; P < .001), CD4 count (<50 cells/mcL; P = .02), and higher cerebrospinal fluid (CSF) opening pressure (>25 cm H2O; P = .004) when compared with participants who never experienced seizures. Cerebrospinal fluid fungal burden was higher among those with seizures at presentation (125 000 Cryptococcus colony-forming units [CFU]/mL CSF) and with seizures during follow-up (92 000 CFU/mL) compared with those who never experienced seizures (36 000 CFU/mL, P < .001). Seizures were associated with increased 10-week mortality (adjusted hazard ratio = 1.45; 95% confidence interval, 1.11–1.89). Participants with seizures had lower neurocognitive function at 3 months (QNPZ-8 = −1.87) compared with those without seizures (QNPZ-8 = −1.36; P < .001).

Conclusions



Seizures were common in this HIV-associated cryptococcal meningitis cohort and were associated with decreased survival and neurocognitive function.

cohort studies, cryptococcal, cryptococcus, HIV, meningitis, seizures



Topic:



    hiv seizures cryptococcal meningitis cryptococcus mortality },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{E2019k,

title = {Cryptococcal antigenemia in HIV therapy-experienced Ugandans with virologic failure},

author = {Mpoza E and Rajasingham R and Tugume L and Rhein J and Nabaggala MS and Ssewanyana I and Nyegenye W and Kushemererwa GE and Mulema V and Kalamya J and Kiyaga C and Kabanda J and Ssali M and Boulware DR Meya DB. },

url = {https://researchonline.lshtm.ac.uk/id/eprint/4655311/1/ciz1069.pdf},

doi = {doi: 10.1093/cid/ciz1069},

year  = {2019},

date = {2019-11-03},

journal = {Clinical infectious diseases },

abstract = {Abstract:

Background: Detectable serum or plasma cryptococcal antigen (CrAg) precedes symptomatic cryptococcal meningitis. The World Health Organization (WHO) recommends CrAg screening for HIV infected peoplewith CD4<100cells/mcL initiating antiretroviral therapy (ART). However, an increasing proportionof cryptococcosis patients are now ART-experienced. Whether CrAg screening is cost-effective in those with virologic failureis unknown.Methods:  We retrospectively performed nationwide plasma CrAg testing amongART experiencedUgandan adults with virologic failure(≥1,000 copies/mL) using leftover plasma after viral load testingduring September 2017–January 2018. For those CrAg-positive, we obtained ARThistory, meningitis occurrence, and 6-month survival via medical recordreview. Results: Among1,186 subjectswith virologic failure, 35(3.0%)were CrAg-positive withmedian ART duration of 41months (IQR,10–84months). Among 25 subjects with 6-month outcomes,16(64%) survived,7(28%) died,and 2 (8%) were lost. Onesurvivorhad suffered cryptococcal meningitis two years prior.Two others developed cryptococcal meningitis and survived.Five survivors were known to have received fluconazole. Thus, meningitis-free survival at 6-months was61%(14/23). Overall, 91% (32/35) of CrAg-positive persons had viral load ≥5000 copies/mL compared with 64% (735/1,151) of CrAg-negative (Odds Ratio=6.0; 95%CI:1.8-19.8, P=0.001). CrAg prevalence was 4.2% (32/768) among those with viral loads ≥5000 copies/mLand 0.7% (3/419) among <5000 copies/mLConclusion:In addition to the CD4 thresholdof <100cells/mcL, reflexiveCrAg screening should be considered in persons failing ART in Uganda with viral loads ≥5000 copies/mL.Keywords: Cryptococcal antigenemia, virologic failure, ART experienced, HIVDownloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz1069/5611261 by London School of Hygiene & Tropical Medicine user on 25 November 2019

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Nabatanzi2019,

title = {Monocyte Dysfunction, Activation, and Inflammation After Long-Term Antiretroviral Therapy in an African Cohort},

author = {Rose Nabatanzi and Lois Bayigga and Stephen Cose and Sarah Rowland Jones and Moses Joloba and Glenda Canderan and Damalie Nakanjako},

url = {https://academic.oup.com/jid/article/220/9/1414/5536380?login=true},

doi = {https://doi.org/10.1093/infdis/jiz320},

year  = {2019},

date = {2019-11-01},

journal = {The Journal of Infectious Diseases},

volume = {220},

number = {1},

pages = {1414-1419},

abstract = {Abstract

Background



Monocyte dysfunction may persist during antiretroviral therapy (ART).

Methods



Frozen peripheral blood mononuclear cells of 30 human immunodeficiency virus (HIV)-infected ART-treated adults with sustained viral suppression and CD4 counts ≥500 cells/µL were consecutively analyzed for monocyte phenotypes and function.

Results



Nonclassical monocytes (CD14+, CD16++), interleukin (IL)-1β production, and expression of CD40 and CD86 were lower among ART-treated HIV-infected adults relative to age-matched HIV-negative adults (P = .01, P = .01, and P = .02, respectively). Intestinal fatty acid-binding protein, IL6, and soluble CD14 were higher among HIV-infected adults relative to HIV-negative adults (P = .0002, P = .04, and P = .0017, respectively).



Conclusions

Further investigation is required to understand drivers of persistent monocyte activation and dysfunction.

HIV infection, immune activation, immune responses, long-term antiretroviral therapy, sub-Saharan Africa



Topic:

phenotype hiv inflammation adult monocytes hiv infections anti-retroviral agents },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Castelnuovo2019,

title = {Reasons for first line ART modification over the years during the ART scale up in Uganda},

author = {B. Castelnuovo and F. Mubiru and I. Kalule and A. Kiragga },

url = {https://aidsrestherapy.biomedcentral.com/articles/10.1186/s12981-019-0246-y},

doi = {https://doi.org/10.1186/s12981-019-0246-y},

year  = {2019},

date = {2019-10-09},

journal = {AIDS Research and Therapy},

volume = {16},

number = {1},

pages = {31},

abstract = {Abstract

Background



During the initial scale up of ART in sub-Saharan Africa, prescribed regimens included drugs with high potential for toxicity (particularly stavudine). More recently a growing number of patients requires second line treatment due to treatment failure, especially following the expansion of viral load testing. We aim to determine the reasons and risk factors for modification of first line ART across the years.

Methods



We included patients started on standard first line ART (2NRTI + 1 NNRTI) between 2005 and 2016 at the Infectious Diseases Institute, Kampala, Uganda. We described the reasons for treatment modification categorized in (1) toxicity (2) treatment failure (3) other reason (new TB treatment, new pregnancy). We used Cox proportional hazard to identify factors associated with treatment modification due to toxicity.

Results



We included 14,261 patients; 9114 (63.9%), were female, the median age was 34 years (IQR: 29–40), 60.8% were in WHO stage 3 and 4. The median BMI and CD4 count were 21.9 (IQR: 19.6–24.8) and 188 cell/µL (IQR: 65–353) respectively; 27.5% were started on stavudine, 46% on zidovudine, and 26.5% on a tenofovir containing regimens. We observed 6248 ART modifications in 4868/14,261 patients (34.1%); 1615 were due to toxicity, 1077 to treatment failure, 1330 to contraindications, and 1860 patients following WHO recommendation of phasing out stavudine and substituting with another NRTI. Modification for drug toxicity declined rapidly after the phase out of stavudine (2008), while switches to second line regimes increased after the implementation of viral load monitoring (2015). Patients with normal BMI compared to underweight, (HR: 0.79, CI 0.69–0.91), with CD4 counts 200–350 cells/µL compared to < 200 cells/µL (HR: 0.81− CI 0.71–0.93), and started on zidovudine (HR: 0.51 CI 0.44–0.59) and tenofovir (HR: 0.16, CI 0.14–0.22) compared to stavudine were less likely to have ART modification due to toxicity. Older patients (HR: 1.14 per 5-year increase CI 1.11–1.18), those in WHO stage 3 and 4 (HR: 1.19, CI 1.06–1.34) were more likely to have ART modification due to toxicity.

Conclusions



Toxicity as reason for drugs substitution decreased over time mirroring the phase out of stavudine, while viral load expansion identified more patients in need of second line treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{C2019d,

title = {Evaluation of Infection Prevention and Control Readiness at Frontline Health Care Facilities in High-Risk Districts Bordering Ebola Virus Disease–Affected Areas in the Democratic Republic of the Congo — Uganda, 2018},

author = {Biedron C and Lyman M and Stuckey MJ and Homsy J and Lamorde M and Luvsansharav UO and Wilson K and Gomes D and Omuut W and Okware S and Semanda JN and Kiggundu R and Bulwadda D and Brown V and Nelson LJ and Driwale A and Fagan R and Park BJ and Smith RM. },

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776373/},

doi = { doi: 10.15585/mmwr.mm6839a4},

year  = {2019},

date = {2019-10-04},

journal = {MMWR, Morbidity and Mortality Weekly Report},

volume = {68},

number = {39},

pages = {851–854},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Neary2019,

title = {Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART},

author = { Megan Neary and Catherine A Chappell and Kimberly K Scarsi and Shadia Nakalema and Joshua Matovu and Sharon L Achilles and Beatrice A Chen and Marco Siccardi and Andrew Owen and Mohammed Lamorde},

url = {https://academic.oup.com/jac/article-abstract/74/10/3003/5531809},

doi = {https://doi.org/10.1093/jac/dkz298},

year  = {2019},

date = {2019-10-01},

journal = {Journal of Antimicrobial Chemotherapy},

volume = {74},

number = {10},

pages = {3003-3010},

abstract = {Abstract



Background

We previously demonstrated that etonogestrel concentrations were 82% lower in women using etonogestrel contraceptive implants plus efavirenz-based ART compared with women not receiving ART.



Objectives

To investigate the genetic contribution to this previously observed drug–drug interaction through studying SNPs in genes known to be involved in efavirenz, nevirapine or etonogestrel metabolism in the same group of women.

Patients and methods



Here, we present a secondary analysis evaluating SNPs involved in efavirenz, nevirapine and etonogestrel metabolism and associated etonogestrel pharmacokinetics among 57 women, 19 not receiving ART (control group), 19 receiving efavirenz- (600 mg daily) based ART and 19 receiving nevirapine- (200 mg twice daily) based ART. Associations between patient genotype and etonogestrel pharmacokinetic parameters were determined through univariate and multivariate linear regression. This study was registered at clinicaltrials.gov (NCT02082652).



Results

Within the control group, CYP2B6 983 T>C was associated with 27% higher etonogestrel Cmax and 28% higher AUC0–24weeks. In the efavirenz group CYP2B6 516 G>T was associated with 43% lower etonogestrel Cmin and 34% lower AUC0–24weeks. For participants receiving nevirapine, NR1I2 63396 C>T was associated with 39% lower etonogestrel Cmin and 37% lower AUC0–24weeks.



Conclusions

This study demonstrates the influence of pharmacogenetics on the extent of drug–drug interactions between etonogestrel and efavirenz- or nevirapine-based ART. Efavirenz plus the etonogestrel contraceptive implant results in a detrimental drug–drug interaction irrespective of patient genetics, which is worsened in women possessing variant alleles for these CYP2B6 SNPs.



Topic:

drug interactions efavirenz genotype nevirapine single nucleotide polymorphism genetics pharmacokinetics etonogestrel cytochrome p450 cyp2b6 enzyme cyp2b6 gene implants 



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kwizera2019,

title = {Performance of Lipoarabinomannan Assay using Cerebrospinal fluid for the diagnosis of Tuberculous meningitis among HIV patients},

author = {Richard Kwizera and Fiona V. Cresswell and Gerald Mugumya and Micheal Okirwoth and Ananta S. Bangdiwala and Darlisha A. Williams and Joshua Rhein and David R. Boulware and David B. Meya},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749932/},

doi = { doi: 10.12688/wellcomeopenres.15389.2},

year  = {2019},

date = {2019-09-30},

journal = {Wellcome Open Research},

volume = {4},

abstract = {Abstract



Background: The diagnostic utility of the Mycobacteria tuberculosis lipoarabinomannan (TB-LAM) antigen lateral flow assay on cerebrospinal fluid (CSF) for the diagnosis of tuberculous meningitis (TBM) has not been extensively studied and the few published studies have conflicting results.



Methods: Lumbar CSF from 59 HIV-positive patients with suspected TBM was tested with TB-LAM and Xpert MTB/Rif Ultra. The diagnostic performance of CSF TB-LAM was compared to positive CSF Xpert MTB/Rif Ultra (definite TBM) and a composite reference of probable or definite TBM according to the uniform case definition. 



Results: Of 59 subjects, 12 (20%) had definite TBM and five (9%) had probable TBM. With reference to definite TBM, CSF TB-LAM assay had a diagnostic sensitivity of 33% and specificity of 96%. When compared to a composite reference of definite or probable TBM, the sensitivity was 24% and specificity was 95%. There were two false positive tests with TB-LAM (3+ grade). In-hospital mortality in CSF TB-LAM positive patients was 17% compared to 0% in those with definite TBM by Xpert MTB/Rif Ultra but negative LAM.



Conclusions: Lumbar CSF TB-LAM has a poor performance in diagnosing TBM. Both urine TB-LAM and Xpert Ultra should be further investigated in the diagnosis of TBM.

Keywords: Tuberculous meningitis, extra-pulmonary TB, lipoarabinomannan, TB-LAM, Xpert MTB/Rif Ultra, HIV, Diagnostics, cerebrospinal fluid},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Shah2019,

title = {Multicenter Study of the Accuracy of the BD MAX™ MDR-TB Assay for Detection of Mycobacterium tuberculosis Complex and Mutations Associated with Resistance to Rifampin and Isoniazid},

author = {Maunank Shah and Sonia Paradis and Joshua Betz and Natalie Beylis and Renu Bharadwaj and Tatiana Caceres and Eduardo Gotuzzo and Moses Joloba and Vidya Mave and Lydia Nakiyingi and Mark P Nicol and Neeta Pradhan and Bonnie King and Derek Armstrong and Deborah Knecht  and Courtney E Maus and Charles K Cooper and Susan E Dorman and Yukari C Manabe},

doi = {doi: 10.1093/cid/ciz932. },

year  = {2019},

date = {2019-09-27},

journal = {Journal 	Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},

pages = {E-pub ahead of print},

abstract = {Abstract



BACKGROUND: Tuberculosis (TB) control is hindered by absence of rapid tests to identify Mycobacterium tuberculosis (MTB), and detect isoniazid (INH) and rifampin (RIF) resistance. We evaluated the accuracy of the BD MAX MDR-TB assay (BD MAX) in South Africa, Uganda, India, and Peru.



METHODS: Outpatient adults with signs and/or symptoms of pulmonary TB were prospectively enrolled. Sputum smear-microscopy and BD MAX were performed on a single raw sputum, which was then processed for mycobacterial culture and phenotypic drug susceptibility testing (DST), BD MAX and Xpert MTB/RIF (Xpert).



RESULTS: 1053 participants with presumptive TB were enrolled with median age of 35 (47% female; 32% HIV-infected, and 32% unknown HIV status). In microbiologically-confirmed TB patients, BD MAX sensitivity was 93% (262/282 [95% CI 89, 95]); specificity was 97% (593/610 [96, 98]) among participants with negative cultures on raw sputa. BD MAX sensitivity was 100% (175/175, [98,100]) for smear-positive samples (florescence smear-microscopy), and 81% (87/107, [73,88]) in smear-negative samples. Among participants with both BD MAX and Xpert, sensitivity was 91% (249/274, [87,94]) for BD MAX and 90% (246/274 [86,93]) for Xpert on processed sputa. Sensitivity and specificity for RIF resistance compared to phenotypic DST was 90% (9/10 [60,98]) and 95% (211/222 [91,97]), respectively. Sensitivity and specificity for detection of INH resistance was 82% (22/27 [63,92]) and 100% (205/205 [98,100]), respectively.



CONCLUSIONS: The BD MAX MDR-TB assay had high sensitivity and specificity for detection of MTB, and RIF and INH drug resistance and may be an important tool for rapid detection of TB and MDR-TB globally.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Waitt2019,

title = {Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study)},

author = { Catriona Waitt and Catherine Orrell and Stephen Walimbwa and Yashna Singh and Kenneth Kintu and Bryony Simmons and Julian Kaboggoza and Mary Sihlangu and Julie-Anne Coombs and Thoko Malaba and Josaphat Byamugisha and Alieu Amara and Joshua Gini and Laura Else and Christie Heiburg and Eva Maria Hodel and Helen Reynolds and Ushma Mehta and Pauline Byakika-Kibwika, and Andrew Hill and Landon Myer and Mohammed Lamorde, and Saye Khoo},

url = {https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002895},

doi = { https://doi.org/10.1371/journal.pmed.1002895},

year  = {2019},

date = {2019-09-20},

journal = {PLOS MEDICINE},

volume = {16},

number = {9},

abstract = {Abstract

Background



The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3).

Methods and findings



In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28–36 weeks of gestation, age 26 (19–42), weight 67kg (45–119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma.



No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3–8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum.

Conclusion



Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{YC2019,

title = {Group Mentorship Model to Enhance the Efficiency and Productivity of PhD Research Training in Sub-Saharan Africa. },

author = {Manabe YC and Nambooze H and Okello ES and Kamya MR and Katabira ET and Ssinabulya I and Kaddumukasa M and Nabunnya Y and Bollinger RC and Sewankambo NK. },

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748251/ },

doi = {10.29024/aogh.25},

year  = {2019},

date = {2019-09-19},

journal = {Annals of Global Health},

volume = {84},

number = {1},

pages = {170-175},

abstract = {INTRODUCTION:



High quality PhD training in sub-Saharan Africa is important to strengthen research evidence to advance development and health. Training a critical mass of independent investigators capable of original scientific research requires strong mentorship, research environments, and international networks. We sought to iteratively improve a PhD training model in Uganda through systems capacity building.

METHODS:



PhD students were selected through a rigorous competitive application and selection process, which included a written proposal and a face-to-face panel interview. The program provided administrative support, paid tuition fees, tools (space, equipment, research money), skills (short research courses on study design, biostatistics, manuscript and grant writing), and infrastructure (finance, grants management support, and lab infrastructure). Guidance to identify local and international mentorship was also provided in addition to two to three group meetings per year where data was presented and progress assessed by the program leaders in addition to available local mentors.

RESULTS:



Seventeen PhD students were selected, and fifteen will complete training through the MEPI-MESAU program. To date, 60% have completed, including 2 students who started 2 years into the program. So far, 169 publications have been published in the peer-reviewed literature. Our PhD students have supervised and mentored 65 Master's students, which illustrates the cascade effect of PhD training on the academic medical school environment.

CONCLUSIONS:



The systems capacity building approach to PhD training is an efficient and productive training model that allowed strong outputs at lower cost and with relatively few additional mentors to rapidly achieve a critical mass of independent scientists able to conduct original research and mentor others.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ahimbisibwe2019,

title = {Management of amphotericin-induced phlebitis among HIV patients with cryptococcal meningitis in a resource-limited setting: a prospective cohort study. },

author = {Cynthia Ahimbisibwe and Richard Kwizera and Jane Frances Ndyetukira and Florence Kugonza and Alisat Sadiq and Kathy Huppler Hullsiek and Darlisha A. Williams and Joshua Rhein and David R. Boulware and David B. Meya},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595678/},

doi = {doi: 10.1186/s12879-019-4209-7},

year  = {2019},

date = {2019-09-19},

journal = {BMC Infectious Diseases },

volume = {19},

number = {1},

pages = {558},

abstract = {BACKGROUND:



Amphotericin-induced phlebitis is a common infusion-related reaction in patients managed for cryptococcal meningitis. High-quality nursing care is critical component to successful cryptococcosis treatment. We highlight the magnitude and main approaches in the management of amphotericin-induced phlebitis and the challenges faced in resource-limited settings.

METHODS:



We prospectively determined the incidence of amphotericin-induced phlebitis during clinical trials in Kampala, Uganda from 2013 to 2018. We relate practical strategies and challenges faced in clinical management of phlebitis.

RESULTS:



Overall, 696 participants were diagnosed with HIV-related cryptococcal meningitis. Participants received 7-14 doses of intravenous (IV) amphotericin B deoxycholate 0.7-1.0 mg/kg/day for induction therapy through peripheral IV lines at a concentration of 0.1 mg/mL in 5% dextrose. Overall, 18% (125/696) developed amphotericin-induced phlebitis. We used four strategies to minimize/prevent the occurrence of phlebitis. First, after every dose of amphotericin, we gave one liter of intravenous normal saline. Second, we rotated IV catheters every three days. Third, we infused IV amphotericin over 4 h. Finally, early ambulation was encouraged to minimize phlebitis. To alleviate phlebitis symptoms, warm compresses were used. In severe cases, treatment included topical diclofenac gel and oral anti-inflammatory medicines. Antibiotics were used only when definite signs of infection developed. Patient/caregivers' education was vital in implementing these management strategies. Major challenges included implementing these interventions in participants with altered mental status and limited access to topical and oral anti-inflammatory medicines in resource-limited settings.

CONCLUSIONS:



Amphotericin-induced phlebitis is common with amphotericin, yet phlebitis is a preventable complication even in resource-limited settings.

TRIAL REGISTRATION:



The ASTRO-CM trial was registered prospectively. ClincalTrials.gov : NCT01802385 ; Registration date: March 1, 2013; Last verified: February 14, 2018.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Muhindo2019,

title = {Psychosocial correlates of regular syphilis and HIV screening practices among female sex workers in Uganda: a cross-sectional survey},

author = {Richard Muhindo and Barbara Castelnuovo and Andrew Mujugira and Rosalind Parkes-Ratanshi and Nelson K. Sewankambo and Juliet Kiguli and Nazarius Mbona Tumwesigye and Edith Nakku-Joloba },

url = {https://link.springer.com/article/10.1186/s12981-019-0244-0},

doi = {doi:10.1186/s12981-019-0244-0},

year  = {2019},

date = {2019-09-18},

journal = {AIDS Research and Therapy},

volume = {16},

number = {1},

pages = {28},

abstract = {Abstract



Background

Limited data are available regarding correlates of regular sexually transmitted infections (STIs) and HIV screening among female sex workers (FSW) in Sub-Saharan Africa. In this study, we aimed to assess the frequency of regular syphilis and HIV screening and the psychosocial correlates associated with screening among FSW in Uganda.



Methods

This cross-sectional correlational study was conducted among 441 FSW, aged 17–49 years. We enrolled FSW through peer referrals and ascertained self-reported data on number of serological tests for HIV, syphilis and other STIs in the prior 12 months using an interviewer-administered questionnaire. In addition, we assessed attitudes, norms, social influences and self-efficacy towards 3-monthly Syphilis and 6-monthly HIV testing. We estimated the correlates of regular STI and HIV testing using negative binomial regression.



Results

Of the respondents 420 (95.2%) reported to have ever taken an HIV test with 297 (67.4%) testing two or more times in the prior 12 months. Over half of the respondents (59%) reported ever taking a syphilis test with only 62 (14.1%) reporting testing three or more times in the prior 12 months. After adjusting for socio-demographics, attitude and norms, high perceived self-efficacy was associated with a 33% increase in the likelihood of repeated HIV testing [prevalence ratio (PR), 1.33, 95% confidence interval (CI) 1.15–1.53] while low perceived confidence was associated with a 25% decrease in the likelihood of repeated HIV testing (PR, 0.75, 95% CI 0.63–0.89). Similarly low attitudes and norms were associated with a decrease of 52.6% (PR, 0.47, 95% CI 0.37–0.61) and 47% (PR, 0.53, 95% CI 0.41–0.69) in the likelihood of repeated syphilis testing respectively.



Conclusion

Compared to HIV, uptake of repeated syphilis testing was very low. Correlates of HIV testing include; perceived self-efficacy amidst barriers and perceived confidence for HIV and low attitudes and accepting norms for syphilis. Health campaigns should emphasize overcoming barriers to HIV testing while promoting attitudes and norms including integration of serological syphilis testing and other STIs into HIV services.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Fairlie2019,

title = {Inclusion of pregnant women in antiretroviral drug research: what is needed to move forwards?},

author = {Lee Fairlie and Catriona Waitt andShahin Lockman and Michelle Moorhouse and Elaine J. Abrams and Polly Clayden and Marta Boffito and Saye Khoo and Helen Rees and Amandine Cournil and Willem Francois Venter and Celicia Serenata and Matthew Chersich},

url = {https://onlinelibrary.wiley.com/doi/full/10.1002/jia2.25372},

doi = { https://doi.org/10.1002/jia2.25372},

year  = {2019},

date = {2019-09-16},

journal = {Journal of the International AIDS Society},

volume = {22},

number = {9},

pages = {e25372},

abstract = {

Abstract

Introduction



To adequately ascertain drug safety and efficacy, drug trials need to include participants from all groups likely to receive the medication following approval. Pregnant women, however, are mostly excluded from trials, and women participating are often required to use highly effective contraception and taken off study product (even off study) if they conceive. There is little commercial incentive for including pregnant women in clinical trials, even when preclinical animal and human pharmacokinetic and safety data appear reassuring. With this conservative approach, large numbers of pregnant women are exposed to drug postlicensing with little known about drug safety and efficacy, and little done to systematically monitor outcomes of pregnancy exposure.

Discussion



The article focuses on antiretrovirals for treating and preventing HIV, and presents potential approaches which could extend to other therapeutic areas, to obtaining adequate and timely data to inform use of these drugs in this population. Most importantly the pregnancy risk profile of investigational agents can be systematically stratified from low to high risk, based on guidelines from regulatory bodies. This stratification can determine the progress through preclinical work with animals and non‐pregnant women to opportunistic studies among women who become pregnant on a clinical trial or within routine clinical treatment. Stratification can include pregnant women in clinical trials, concurrent with Phase II/III trials in non‐pregnant adults, and ultimately to postmarketing surveillance for outcomes in pregnant women and their infants. Each step can be enabled by clear criteria from international and local regulatory bodies on progression through study phases, standardized protocols for collecting relevant data, collaborative data sharing, pregnancy outcomes surveillance systems supported by committed funding for these endeavours.

Conclusions



A formalized step‐wise approach to including pregnant women in antiretroviral drug research should become the new norm. Systematic implementation of this approach would yield more timely and higher quality pregnancy dosing, safety and efficacy data. Through more vigorous action, regulatory bodies could responsibly overcome reluctance to include pregnant women in drug trials. Funders, researchers and programme implementers need to be galvanized to progressively include pregnant women in research – the use of newer, more effective drugs in women is at stake (349).

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zakumumpa2019,

title = {Understanding the persistence of vertical (stand-alone) HIV clinics in the health system in Uganda: a qualitative synthesis of patient and provider perspectives},

author = {Henry Zakumumpa and Joseph Rujumba and Japheth Kwiringira and Jepchirchir Kiplagat and Edith Namulema and Alex Muganzi },

url = {https://link.springer.com/article/10.1186/s12913-018-3500-4},

doi = {doi:10.1186/s12913-018-3500-4},

year  = {2019},

date = {2019-09-05},

journal = {BMC Health Services Research},

volume = {18},

number = {1},

pages = {690},

abstract = {Abstract

Background



Although there is mounting evidence and policy guidance urging the integration of HIV services into general health systems in countries with a high HIV burden, vertical (stand-alone) HIV clinics are still common in Uganda. We sought to describe the specific contexts underpinning the endurance of vertical HIV clinics in Uganda.

Methods



A qualitative research design was adopted. Semi-structured interviews were conducted with the heads of HIV clinics, clinicians and facility in-charges (n = 78), coupled with eight focus group discussions (64 participants) with patients from 16 health facilities purposively selected, from a nationally-representative sample of 195 health facilities across Uganda, because they run stand-alone HIV clinics. Data were analyzed by thematic approach as guided by the theory proposed by Shediac-Rizkallah & Bone (1998) which identifies; Intervention characteristics, organizational context, and broader environment factors as potentially influential on health programme sustainability.

Results



Intervention characteristics: Provider stigma was reported to have been widespread in the integrated care experience of participating health facilities which necessitated the establishment of stand-alone HIV clinics. HIV disease management was described as highly specialized which necessitated a dedicated workforce and vertical HIV infrastructure such as counselling rooms. Organizational context: Participating health facilities reported health-system capacity constraints in implementing integrated systems of care due to a shortage of ART-proficient personnel and physical space, a lack of laboratory capacity to concurrently conduct HIV and non-HIV tests and increased workloads associated with implementing integrated care. Broader environment factors: Escalating HIV client loads and external HIV funding architectures were perceived to have perpetuated verticalized HIV programming over the past decade.

Conclusion



Our study offers in-depth, contextualized insights into the factors contributing to the endurance of vertical HIV clinics in Uganda. Our analysis suggests that there is a complex interaction in supply-side constraints (shortage of ART-proficient personnel, increased workloads, laboratory capacity deficiencies) and demand-side factors (escalating demand for HIV services, psychosocial barriers to HIV care) as well as the specialized nature of HIV disease management which pose challenges to the integrated-health services agenda.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bongomin2019b,

title = {Getting Histoplasmosis on the Map of International Recommendations for Patients with Advanced HIV Disease },

author = {Felix Bongomin and Richard Kwizera and David W. Denning

},

url = {https://www.mdpi.com/2309-608X/5/3/80},

doi = {https://doi.org/10.3390/jof5030080},

year  = {2019},

date = {2019-09-02},

journal = {Journal of Fungi (Basel)},

volume = {5},

number = {3},

pages = {80},

abstract = {Abstract

Progressive disseminated histoplasmosis, caused by H. capsulatum, is a life-threatening illness and is an AIDS-defining opportunistic infection. It is neglected, worryingly under-diagnosed, and often misdiagnosed as cancer or tuberculosis with fatal consequences. Globally, over 100,000 cases of disseminated histoplasmosis have been estimated. In 2017, the World Health Organization (WHO) noted that disseminated histoplasmosis is a significant cause of mortality in AIDS patients. Through the rigorous efforts of the Global Action Fund for Fungal Infections (GAFFI) and partners, in 2019, the Histoplasma antigen test was included on the 2nd Edition of the WHO List of Essential Diagnostics. The drugs used in the treatment of histoplasmosis (amphotericin B and itraconazole) are on the WHO Essential Medicine List. The Manaus Declaration on histoplasmosis in the Americas and the Caribbean, where histoplasmosis kills more people with HIV than tuberculosis, advocates for universal access to rapid testing for histoplasmosis and availability of essential drugs for the treatment of histoplasmosis in every country by 2025. Hyperendemic areas are present in the Americas, Caribbean, Southeast Asia, and Latin America. In conclusion, histoplasmosis remains an important clinical and public health problem. To reduce HIV-associated mortality, disseminated histoplasmosis must be addressed through advocacy, increased awareness, and universal access to essential diagnostics and antifungal agents. View Full-Text

Keywords: histoplasmosis; HIV; Histoplasma antigen tests; itraconazole; amphotericin B },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ssebambulidde2019,

title = {Culture-negative cryptococcal meningitis},

author = {Kenneth Ssebambulidde and Caleb Skipper and Joshua Rhein},

url = {https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30442-6/fulltext},

doi = {https://doi.org/10.1016/S1473-3099(19)30442-6},

year  = {2019},

date = {2019-09-01},

journal = {The Lancet, Infectious Diseases Institute},

volume = {19},

number = {9},

pages = {929-930},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bongomin2019c,

title = {Essential in vitro diagnostics for advanced HIV and serious fungal diseases: international experts’ consensus recommendations},

author = {Felix Bongomin and Nelesh P. Govender and Arunaloke Chakrabarti and Florence Robert-Gangneux and David R. Boulware and Afia Zafar and Rita O. Oladele and Malcolm D. Richardson and Jean-Pierre Gangneux and Ana Alastruey-Izquierdo and Joel Bazira and Tom H. Boyles and Jahit Sarcarlal and Mathieu Nacher and Taminori Obayashi and William Worodria and Alessandro C. Pasqualotto and David B. Meya and Ben Cheng, Charlotte Sriruttan and Conrad Muzoora and Andrew Kambugu and Juan Luis Rodriguez Tudela and Alexander Jordan and Tom M. Chiller and David W. Denning },

year  = {2019},

date = {2019-09-01},

journal = {European Journal of Clinical Microbiology & Infectious Diseases},

volume = {38},

number = {9},

pages = {1581–1584},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Katende2019,

title = {Short‐course amphotericin B in addition to sertraline and fluconazole for treatment of HIV‐associated cryptococcal meningitis in rural Tanzania},

author = {Andrew Katende and Gladys Mbwanji and Diana Faini and Amina Nyuri and Aneth Vedastus Kalinjuma and Dorcas Mnzava and Katherine H. Hullsiek and Joshua Rhein and Maja Weisser and David B. Meya and David R. Boulware and Emilio Letang and KIULARCO Study Group },

url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/myc.12995},

doi = {https://doi.org/10.1111/myc.12995},

year  = {2019},

date = {2019-08-28},

journal = {Mycoses},

abstract = {

Summary

Background



Cryptococcal meningitis accounts for 15% of all AIDS mortality globally. Most cases in low‐ and middle‐income countries are treated with fluconazole monotherapy, which is associated with a high mortality. New available therapies are needed. Short‐course amphotericin B has been shown to be a safe and efficient therapeutic option. Sertraline has in vitro fungicidal activity against Cryptococcus and bi‐directional synergy with fluconazole.

Methods



We conducted an open‐label clinical trial to assess the safety and efficacy of sertraline 400 mg/day and fluconazole 1200 mg/day (n = 28) vs sertraline, fluconazole and additional 5 days of amphotericin B deoxycholate 0.7‐1 mg/kg (n = 18) for cryptococcal meningitis.

Results



Two‐week survival was 64% (18/28) without amphotericin and 89% (16/18) with amphotericin, and 10‐week survival was 21% (6/28) vs 61% (11/18), respectively (P = .012). The cerebrospinal fluid (CSF) Cryptococcus clearance rate was 0.264 log10 colony‐forming units (CFU)/mL of CSF/day (95% CI: 0.112‐0.416) without amphotericin and 0.473 log10 CFU/mL/day (95% CI: 0.344‐0.60) with short‐course amphotericin (P = .03). Sertraline was discontinued in one participant due to side effects. Four participants receiving amphotericin B experienced hypokalemia <2.4 mEq/L.

Conclusions



Short‐course amphotericin substantially increased CSF clearance and 10‐week survival. Adjunctive sertraline improved 2‐week CSF fungal clearance but did not improve 10‐week mortality compared with published data using fluconazole 1200 mg/day monotherapy (early fungicidal activity 0.15 log10 CFU/mL/day).

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{PL2019,

title = {AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study},

author = {Ponatshego PL and Lawrence DS and Youssouf N and Molloy SF and Alufandika M and Bango F and Boulware DR and Chawinga C and Dziwani E and Gondwe E and Hlupeni A and Hosseinipour MC and Kanyama C and Meya DB and Mosepele M and Muthoga C and Muzoora CK and Mwandumba H and Ndhlovu CE and Rajasingham R and Sayed S and Shamu S and Tsholo K and Tugume L and Williams D and Maheswaran H and Shiri T and Boyer-Chammard T and Loyse A and Chen T and Wang D and Lortholary O and Lalloo DG and Meintjes G and Jaffar S and Harrison TS and Jarvis JN and Niessen LW},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500286/pdf/bmjopen-2018-026288.pdf},

doi = {10.1136/bmjopen-2018-026288},

year  = {2019},

date = {2019-08-27},

journal = {BMJ Open},

volume = {9},

number = {4},

pages = {1-8},

abstract = {INTRODUCTION:



Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation.

METHODS AND ANALYSIS:



Country-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial.

ETHICS AND DISSEMINATION:



The AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings.

TRIAL REGISTRATION:



ISRCTN 7250 9687; Pre-results.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{L2019b,

title = {The Mouse Inhalation Model of Cryptococcus neoformans Infection Recapitulates Strain Virulence in Humans and Shows that Closely Related Strains Can Possess Differential Virulence},

author = {Mukaremera L and McDonald TR and Nielsen JN and Molenaar CJ and Akampurira A and Schutz C and Taseera K and Muzoora C and Meintjes G and Meya DB and Boulware DR andNielsen K},

url = {https://iai.asm.org/content/87/5/e00046-19},

doi = {10.1128/IAI.00046-19},

year  = {2019},

date = {2019-08-27},

journal = {Infection and Immunity },

volume = {87},

number = {5},

abstract = {Cryptococcal meningitis (CM) causes high rates of HIV-related mortality, yet the Cryptococcus factors influencing patient outcome are not well understood. Pathogen-specific traits, such as the strain genotype and degree of antigen shedding, are associated with the clinical outcome, but the underlying biology remains elusive. In this study, we examined factors determining disease outcome in HIV-infected cryptococcal meningitis patients infected with Cryptococcus neoformans strains with the same multilocus sequence type (MLST). Both patient mortality and survival were observed during infections with the same sequence type. Disease outcome was not associated with the patient CD4 count. Patient mortality was associated with higher cryptococcal antigen levels, the cerebrospinal fluid (CSF) fungal burden by quantitative culture, and low CSF fungal clearance. The virulence of a subset of clinical strains with the same sequence type was analyzed using a mouse inhalation model of cryptococcosis. We showed a strong association between human and mouse mortality rates, demonstrating that the mouse inhalation model recapitulates human infection. Similar to human infection, the ability to multiply in vivo, demonstrated by a high fungal burden in lung and brain tissues, was associated with mouse mortality. Mouse survival time was not associated with single C. neoformans virulence factors in vitro or in vivo; rather, a trend in survival time correlated with a suite of traits. These observations show that MLST-derived genotype similarities between C. neoformans strains do not necessarily translate into similar virulence either in the mouse model or in human patients. In addition, our results show that in vitro assays do not fully reproduce in vivo conditions that influence C. neoformans virulence.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bongomin2019,

title = {Cor pulmonale complicating chronic pulmonary aspergillosis with fatal consequences: Experience from Uganda.},

author = {Felix Bongomin and Richard Kwizera and Angella Atukunda and Bruce J.Kirenga},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614533/},

doi = { 10.1016/j.mmcr.2019.07.001},

year  = {2019},

date = {2019-08-26},

journal = {Medical Mycology Case Reports},

volume = {25},

number = {1},

pages = {22-24},

abstract = {Cor pulmonale is a rare complication of pulmonary aspergillosis (CPA). A 45-year-old Ugandan male with a history of recurrent community-acquired pneumonias was admitted with symptoms of progressive difficulty in breathing, chronic productive cough, non-exertional left sided chest pain and progressive weight loss occurring over a 12-month period. Chest CT scan and echocardiography confirmed the diagnosis of CPA with an aspergilloma complicating bronchiectasis, complicated with cor pulmonale. However, this was previously clinically misdiagnosed as PTB.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Nakalembe2019,

title = {Prevalence, correlates, and predictive value of high-risk human papillomavirus mRNA detection in a community-based cervical cancer screening program in western Uganda.},

author = { Miriam Nakalembe and Makanga Philippa and Mubiru Frank and Swanson Megan and Martin Jeffrey and Huchko Megan},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515623/pdf/13027_2019_Article_230.pdf},

doi = {10.1186/s13027-019-0230-0},

year  = {2019},

date = {2019-08-26},

journal = {Infectious Agents and Cancer},

volume = {14},

number = {14},

pages = {1-10},

abstract = {Background:



New strategies are needed to combat the high incidence of cervical cancer in resource-limited settings such as sub-Saharan Africa. Screening for high-risk human papillomavirus (hrHPV) DNA is sensitive for pre-cancer, but its lack of specificity results in substantial overtreatment in low resource settings where additional testing (e.g., colposcopy) is rarely available. Testing for hrHPV E6/E7 mRNA may enhance specificity, but little is known about its performance characteristics in resource-limited settings.

Methods:



In a series of community health fairs in rural Uganda, women aged 25 to 49 years provided self-collected vaginal samples, which were tested for hrHPV (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) E6/E7 mRNA with the Aptima® assay. Positive specimens underwent testing for HPV-16 and 18/45. After excluding pregnant women, all women testing positive for any hrHPV subsequently were offered cervical biopsy to determine pathology.

Results:



A total of 1892 women provided a vaginal sample for hrHPV testing during 24 health fairs. The median age was 34 years, HIV prevalence was 10, and 95% had not been previously screened. Prevalence of any hrHPV E6/E7 mRNA was 21% (95% confidence interval (CI): 19 to 23%); the prevalence of HPV-16 was 2.6%, HPV-18/45 1.9%, and HPV 16 and 18/45 were jointly found in 0.1% of the study population. Younger age, pregnancy and HIV-positivity were independently associated with any hrHPV infection. Of the 255 evaluable cervical biopsies, the positive predictive value of detecting any hrHPV E6/E7 mRNA for presence of cervical intraepithelial neoplasia grade 2 or higher ("CIN 2+") was 8.2% (95% CI: 5.1 to 12%). The positive predictive value associated with detection of HPV-16 mRNA (15%) or HPV-18/45 mRNA (15%) was only slightly higher.

Conclusion:



Among community-based women in Uganda, the prevalence of any hrHPV E6/E7 mRNA in vaginal samples was high, but the prevalence of the most oncogenic HPV types (16, 18, or 45) was substantially lower. Positive predictive value of hrHPV mRNA-positivity for CIN 2+ was also low, including when restricting to HPV 16/18/45-positivity. The findings emphasize the need to identify more specific screening approaches for cervical cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{FS2019,

title = {Longer-term effectiveness of protease-inhibitor-based second line antiretroviral therapy in four large sub-Saharan African clinics},

author = {Sarfo FS and Castelnuovo B and Fanti I and Feldt T and Incardona F and Kaiser R and Lwanga I and Marrone G and Sonnerborg A and Tufa TB and Zazzi M and De Luca A.},

url = {https://www.idi-makerere.com/wp-content/uploads/2019/08/10.1016@j.jinf_.2019.03.003-3.pdf},

doi = {10.1016/j.jinf.2019.03.003},

year  = {2019},

date = {2019-08-26},

journal = {The Journal of Infection},

volume = {75},

number = {5},

pages = {402-408},

abstract = {OBJECTIVES:



Data on the longer-term effectiveness of second line combination antiretroviral therapy (ART) in sub-Saharan Africa (SSA) are lacking. We sought to assess the probability and determinants of 2nd line ART failure in SSA.

METHODS:



A retrospective, multi-center study of 2nd line ART initiated between 2005 and 2017 at four ART centers in Ethiopia, Ghana and Uganda. Main outcome measure was virologic failure (VF) defined as VL>1000 copies/ml after >6 months on 2nd line therapy. Predictors of VF and virologic re-suppression on 2nd line were evaluated using Cox Proportional Hazards and multivariable logistic regression models, respectively.

RESULTS:



2191 subjects started 2nd line therapy, 61.5% females. Switching from 1st line (56.4% NVP-based, 70.3% including thymidine-analogues) to 2nd line therapy occurred after mean of 4.1 years. 98.9% of patients started boosted PI with NRTI backbone (TDF+3TC/FTC 67.3%, AZT+3TC 18.5%, others 14.2%). There were 267 (12.0%) VF with a 5-year estimated probability of 15.0% (95% CI 13.2-16.9). Key determinants of VF were concomitant rifampicin use (aHR 2.50 [95% CI 1.54-4.05]) and clinical/immunological failure versus virologic failure as reason for switching therapy (aHR, 0.53 [0.33-0.86]). 138 of 267 (51.7%) subsequently achieved virologic re-suppression and predictors included HIV RNA levels at 2nd-line failure: +1 log higher aOR 0.59 [0.43-0.80], experiencing change within 2nd line ART before VF: aOR 0.17 [0.05-0.56], and more recent calendar year of 2nd line initiation: aOR 0.85 [0.75-0.94].},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kwizera2019b,

title = { Performance of Lipoarabinomannan Assay using Cerebrospinal fluid for the diagnosis of Tuberculous meningitis among HIV patients [version 1; peer review: 2 approved] },

author = {Richard Kwizera and Fiona V. Cresswell and Gerald Mugumya and Micheal Okirwoth and Enock Kagimu and Ananta S. Bangdiwala and Darlisha A. Williams and Joshua Rhein and David R. Boulware and David B. Meya},

url = {https://wellcomeopenresearch.org/articles/4-123/v1},

doi = {https://doi.org/10.12688/wellcomeopenres.15389.1},

year  = {2019},

date = {2019-08-19},

journal = {Wellcome Open Research},

abstract = {Abstract

Background: The diagnostic utility of the Mycobacteria tuberculosis lipoarabinomannan (TB-LAM) antigen lateral flow assay on cerebrospinal fluid (CSF) for the diagnosis of tuberculous meningitis (TBM) has not been extensively studied and the few published studies have conflicting results.

Methods: Lumbar CSF from 59 HIV-positive patients with suspected TBM was tested with TB-LAM and Xpert MTB/Rif Ultra. The diagnostic performance of CSF TB-LAM was compared to positive CSF Xpert MTB/Rif Ultra (definite TBM) and a composite reference of probable or definite TBM according to the uniform case definition. 

Results: Of 59 subjects, 12 (20%) had definite TBM and five (9%) had probable TBM. With reference to definite TBM, CSF TB-LAM assay had a diagnostic sensitivity of 33% and specificity of 96%. When compared to a composite reference of definite or probable TBM, the sensitivity was 24% and specificity was 95%. There were two false positive tests with TB-LAM (3+ grade). In-hospital mortality in CSF TB-LAM positive patients was 17% compared to 0% in those with definite TBM by Xpert MTB/Rif Ultra but negative LAM.

Conclusions: Lumbar CSF TB-LAM has a poor performance in diagnosing TBM. Both urine TB-LAM and Xpert Ultra should be further investigated in the diagnosis of TBM





Keywords



Tuberculous meningitis, extra-pulmonary TB, lipoarabinomannan, TB-LAM, Xpert MTB/Rif Ultra, HIV, Diagnostics, cerebrospinal fluid

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Chesdachai2019,

title = {Minimum Inhibitory Concentration Distribution of Fluconazole Against Cryptococcus Species and the Fluconazole Exposure Prediction Model},

author = {Supavit Chesdachai and Radha Rajasingham and Melanie R Nicol and David B Meya and Felix Bongomin and Mahsa Abassi and Caleb Skipper and Richard Kwizera and Joshua Rhein and David R Boulware},

url = {https://academic.oup.com/ofid/article/6/10/ofz369/5550889?login=true},

doi = { https://doi.org/10.1093/ofid/ofz369},

year  = {2019},

date = {2019-08-17},

journal = {Open Forum Infectious Diseases},

volume = {6},

number = {10},

abstract = {Abstract



Background



Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100 mg to 2000 mg/day have been used. Prevalence of fluconazole nonsusceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentrations and area under the curve (AUC) relative to MIC to propose a rational fluconazole dosing strategy.

Method



We conducted a systematic review using the MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Then, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800mg/day coupled with fluconazole’s known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100 mg to 2000 mg via linear regression. The fluconazole AUC above MIC ratio were calculated using Monte Carlo simulation and using the MIC distribution elucidated during the systemic review.



Results



We summarized 21 studies with 11 049 clinical Cryptococcus isolates. Minimum inihibitory concentrations were normally distributed with a geometric mean of 3.4 µg/mL, median (MIC50) of 4 µg/mL, and 90th percentile (MIC90) of 16 µg/mL. The median MIC50 trended upwards from 4 µg/mL in 2000–2012 to 8 µg/mL in 2014–2018. Predicted subtherapeutic fluconazole concentrations (below MIC) would occur in 40% with 100 mg, 21% with 200 mg, and 9% with 400 mg. The AUC:MIC ratio >100 would occur in 53% for 400 mg, 74% for 800 mg, 83% for 1200 mg, and 88% for 1600 mg.

Conclusions



Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.

cryptococcal meningitis, Cryptococcus, fluconazole, fungal drug resistance, systematic review



Topic:

 fluconazole cryptococcus minimum inhibitory concentration measurement },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Pastick2019,

title = {Cryptococcosis in pregnancy and the postpartum period: Case series and systematic review with recommendations for management},

author = { Katelyn A Pastick and Elizabeth Nalintya and Lillian Tugume and Kenneth Ssebambulidde and Nicole Stephens and Emily E Evans and Jane Frances Ndyetukira and Edwin Nuwagira and Caleb Skipper and Conrad Muzoora and David B Meya and Joshua Rhein and David R Boulware and Radha Rajasingham},

url = {https://academic.oup.com/mmy/article/58/3/282/5549534?login=true},

doi = {https://doi.org/10.1093/mmy/myz084},

year  = {2019},

date = {2019-08-13},

journal = {Medical Mycology},

volume = {58},

number = {3},

pages = {282-292},

abstract = {Abstract



Cryptococcal meningitis causes 15% of AIDS-related deaths. Optimal management and clinical outcomes of pregnant women with cryptococcosis are limited to case reports, as pregnant women are often excluded from research. Amongst pregnant women with asymptomatic cryptococcosis, no treatment guidelines exist. We prospectively identified HIV-infected women who were pregnant or recently pregnant with cryptococcosis, screened during a series of meningitis research studies in Uganda from 2012 to 2018. Among 571 women screened for cryptococcosis, 13 were pregnant, one was breastfeeding, three were within 14 days postpartum, and two had recently miscarried. Of these 19 women (3.3%), 12 had cryptococcal meningitis, six had cryptococcal antigenemia, and one had a history of cryptococcal meningitis and was receiving secondary prophylaxis. All women with meningitis received amphotericin B deoxycholate (0.7–1.0 mg/kg). Five were exposed to 200–800 mg fluconazole during pregnancy. Of these five, three delivered healthy babies with no gross physical abnormalities at birth, one succumbed to meningitis, and one outcome was unknown. Maternal meningitis survival rate at hospital discharge was 75% (9/12), and neonatal/fetal survival rate was 44% (4/9) for those mothers who survived. Miscarriages and stillbirths were common (n = 4). Of six women with cryptococcal antigenemia, two received fluconazole, one received weekly amphotericin B, and three had unknown treatment courses. All women with antigenemia survived, and none developed clinical meningitis. We report good maternal outcomes but poor fetal outcomes for cryptococcal meningitis using amphotericin B, without fluconazole in the first trimester, and weekly amphotericin B in place of fluconazole for cryptococcal antigenemia.

Cryptococcus, pregnancy, HIV/AIDS, antifungal agents, systematic review

Topic:



    pregnancy hiv meningitis amphotericin b cryptococcal meningitis cryptococcosis fluconazole pregnancy trimester, first postpartum period cryptococcus hiv infections 



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Muwanguzi2019,

title = {Towards a definition of male partner involvement in the prevention of mother-to-child transmission of HIV in Uganda: a pragmatic grounded theory approach},

author = {Patience A. Muwanguzi and Louise K. Nassuna and Joachim G. Voss and Joanita Kigozi and Alex Muganzi and Tom Denis Ngabirano and Nelson Sewankambo and Damalie Nakanjako },

year  = {2019},

date = {2019-08-09},

journal = {BMC Health Services Research},

volume = {19},

number = {1},

pages = {557},

abstract = {Abstract



Background

Male partner involvement has been shown to increase mothers’ uptake of Prevention of Mother-to-Child Transmission of HIV (PMTCT) and improve maternal and infant HIV treatment outcomes. Currently, male involvement in PMTCT is measured primarily through men’s attendance at HIV testing and counselling which may not be a true reflection of their engagement. This study therefore set out to explore the meaning of male partner involvement and propose a definition and theoretical model of this concept in PMTCT in Uganda.



Methods

Eight focus group discussions and five in-depth interviews were conducted with couples at three public health facilities and community members in the health facility catchment areas in Uganda. The study employed a grounded theory approach underpinned by the pragmatic philosophical paradigm. Data were analyzed using the constant comparative method, performing three levels of open, axial, and selective coding.



Results

Of the 61 participants, 29 (48%) were male and the majority 39 (63.9%) were in long term marital relationships, while about half were self-employed 29 (47.5%). Three themes emerged for the meaning of male involvement in PMTCT (a) HIV treatment support (b) economic support and (c) psychosocial support. HIV treatment support included adherence support, couples’ HIV counseling and testing, and clinic attendance during and after pregnancy. Participants expressed that men were engaged in PMTCT when they offered economic support by providing basic needs and finances or when they included their female partners in financial planning for the family. Psychosocial support arose from the female participants who defined male involvement as family support, perceived societal recognition and emotional support. Emotional support also included the absence of harm resulting from women’s disclosure of HIV test results to their male partner.

Conclusions



This study proposes a new definition for male partner involvement in PMTCT in Uganda. The definition extends beyond men’s clinic attendance and HIV testing and counselling. Further research should seek to develop and validate tools to accurately measure male partner involvement as the next step in the development of interventions to improve PMTCT outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{tephanieWang2019,

title = {Association between common telomere length genetic variants and telomere length in an African population and impacts of HIV and TB},

author = {Stephanie Wang and Emily Chang and Patrick Byanyima and Peter Huang and Ingvar Sanyu and Emmanuel Musisi and Abdul Sessolo and J. Lucian Davis and William Worodria and Laurence Huang and Jue Lin and Inflammation, Aging, Microbes and Obstructive Lung Disease (I AM OLD) Study},

url = {https://www.nature.com/articles/s10038-019-0646-9},

doi = {https://doi.org/10.1038/s10038-019-0646-9},

year  = {2019},

date = {2019-08-06},

journal = {Journal of Human Genetics},

pages = {1033–1040},

abstract = {Abstract



Prior studies in predominantly European (Caucasian) populations have discovered common genetic variants (single nucleotide polymorphisms, SNPs) associated with leukocyte telomere length (LTL), but whether these same variants affect LTL in non-Caucasian populations are largely unknown. We investigated whether six genetic variants previously associated with LTL (TERC (rs10936599), TERT (rs2736100), NAF1 (7675998), OBFC1 (rs9420907), ZNF208 (rs8105767), and RTEL1 (rs755017)) are correlated with telomere length (TL) in peripheral blood mononuclear cells (PBMCs) in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). We found OBFC1 and the genetic sum score of the effect alleles across all six loci to be associated with shorter TL (adjusted for age, gender, HIV status, and smoking pack-years (p < 0.02 for both OBFC1 and the genetic sum score). In an analysis stratified by HIV status, the genetic sum score is associated with LTL in both groups with and without HIV. On the contrary, a stratified analysis according to TB status revealed that in the TB-positive subgroup, the genetic sum score is not associated with LTL, whereas the relationship remains in the TB-negative subgroup. The different impacts of HIV and TB on the association between the genetic sum score and LTL indicate different modes of modification and suggest that the results found in this cohort with HIV and TB participants may not be applied to the African general population. Future studies need to carefully consider these confounding factors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Miller2019,

title = {Educational Curricula and Programs in Adolescent Medicine for Health Workers in Low- and Middle-Income Countries: A Scoping Review},

author = {Kathleen K. Miller and Sarah Jane Brown and Betsy Pfeffer and Peter Olupot-Olupot and Sabrina Kitaka},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697283/},

doi = { doi: 10.4300/JGME-D-19-00052},

year  = {2019},

date = {2019-08-01},

journal = {Journal of Graduate Medical Education},

volume = {11},

number = {4 suppl},

pages = {64-72},

abstract = {Abstract

Background



Adolescent medicine (AM) has been increasingly recognized as critically important to the health of individuals during their transition to adulthood. On a global scale, AM is often underprioritized and underfunded. In low- and middle-income countries (LMICs), education and AM training is developing, and AM physicians often are from general medicine backgrounds.

Objective



The objective of our scoping review was to identify existing training curricula and educational tools designed to teach AM skills to health care workers in LMICs.

Methods



We followed PRISMA guidelines for scoping reviews for article identification and inclusion. Online databases, including MEDLINE, Embase, CINAHL, and Scopus, were used to identify papers. We included studies that took place in a LMIC, were available in English, and described any of the following: published educational curricula in AM, education-based intervention for HCWs that focused on AM, or a training opportunity in AM located in a LMIC.

Results



Our review includes 14 publications: 5 published curricula and 9 articles describing educational interventions or training opportunities in AM in LMICs. Curricula were relatively consistent in the topics included, although they varied in implementation and teaching strategies. The scholarly articles described educational materials and identified a number of innovative strategies for training programs.

Conclusions



Our review found existing high-quality AM curricula designed for LMICs. However, there is limited published data on their implementation and utilization. There is a continued need for funding and implementation of education in AM in resource-constrained settings.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{C2019c,

title = {Pharmacokinetic and pharmacodynamic considerations of rifamycin antibiotics for the treatment of tuberculosis},

author = {Sekaggya-Wiltshire C and Dooley KE. },

url = {https://www.tandfonline.com/doi/full/10.1080/17425255.2019.1648432},

doi = {https://doi.org/10.1080/17425255.2019.1648432},

year  = {2019},

date = {2019-08-01},

journal = {Expert Opinion on Drug Metabolism & Toxicology },

volume = {15},

number = {8},

pages = {615-618},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{M2019b,

title = {A new vision for bioethics training in global health},

author = {DeCamp M and Kalbarczyk A and Manabe YC and Sewankambo NK},

url = {https://www.thelancet.com/action/showPdf?pii=S1473-3099%2819%2930442-6},

doi = {DOI: 10.1016/S2214-109X(19)30273-6 },

year  = {2019},

date = {2019-08-01},

journal = {The Lancet, Global Health},

volume = {7},

number = {8},

pages = {e1002-e1003},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Tenforde2019,

title = {HIV-associated cryptococcal meningitis: ongoing challenges and new opportunities },

author = {Mark W Tenforde and Joseph N Jarvis 

},

url = {https://pubmed.ncbi.nlm.nih.gov/31345446/},

doi = {DOI: 10.1016/S1473-3099(19)30295-6 },

year  = {2019},

date = {2019-08-01},

journal = {The Lancet, Infectious Diseases Institute},

volume = {19},

number = {8},

pages = {793-794},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{J2019b,

title = {Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial},

author = {Rhein J and Huppler Hullsiek K and Tugume L. and Nuwagira E and Mpoza E and Evans EE and Kiggundu R and Pastick KA and Ssebambulidde K and Akampurira A and Williams DA and Bangdiwala AS and Abassi M, Musubire AK and Nicol MR and Muzoora C and Meya DB and Boulware DR and ASTRO-CM team},

year  = {2019},

date = {2019-08-01},

journal = {The Lancet Infectious Diseases},

volume = {19},

number = {8},

pages = {843-851},

abstract = {Summary

Background

 Identifying  new  antifungals  for  cryptococcal  meningitis  is  a  priority  given  the  inadequacy  of  current  therapy.  Sertraline  has  previously  shown  in  vitro  and  in  vivo  activity  against  cryptococcus.  We  aimed  to  assess  the  efficacy andcost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo.Methods In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either  adjunctive  sertraline  or  placebo.  Sertraline  was  administered  orally  or  via  nasogastric  tube  at  a  dose  of  400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was    18-week    survival,    analysed    by    intention-to-treat.    This    study    is    registered    with    ClinicalTrials.gov,    number NCT01802385.Findings Between  March  9,  2015,  and  May  29,  2017,  we  screened  842  patients  with  suspected  meningitis  and  enrolled  460  of  a  planned  550  participants,  at  which  point  the  trial  was  stopped  for  futility.  Three  patients  in  the  sertraline  group  and  three  patients  in  the  placebo  group  were  lost  to  follow-up  and  therefore  discontinued  before  study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log10 CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs0·47 –log10CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity.Interpretation Sertraline  did  not  reduce  mortality  and  should  not  be  used  to  treat  patients  with  HIV-associated  cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations.

Funding National Institutes of Health and Medical Research Council, Wellcome Trust.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Baluku2019,

title = {Prevalence of Malaria and TB Coinfection at a National Tuberculosis Treatment Centre in Uganda},

author = {Joseph Baruch Baluku and Sylvia Nassozi and Brian Gyagenda and Margret Namanda and Irene Andia-Biraro and William Worodria and Pauline Byakika-Kibwika},

url = {https://www.hindawi.com/journals/jtm/2019/3741294/},

doi = {https://doi.org/10.1155/2019/3741294},

year  = {2019},

date = {2019-07-25},

journal = {Journal of Tropical Medicine},

abstract = {Abstract



The prevalence of malaria and tuberculosis (TB) coinfection is not well established in countries that are highly burdened for both diseases. Malaria could impair TB containment and increase mortality of TB patients. The objective of this study was to determine the prevalence of malaria/TB coinfection among bacteriologically confirmed adult TB patients at a national TB treatment centre in Uganda. Using a cross-sectional study design we enrolled 363 bacteriologically confirmed adult TB patients, and data on demographics and medical history was collected. Blood samples were tested for malaria blood smear, rapid malaria diagnostic test (RDT), complete blood count, haematological film analysis, HIV serology, and CD4+ and CD8+ cell counts. Malaria was defined as either a positive blood smear or RDT. The study participants were mostly male (61.4%), with a median age of 31 (interquartile range, IQR: 25-39) years, and 35.8% were HIV positive. The prevalence of malaria was 2.2% (8/363) on the overall and 5% (3/58) among participants with rifampicin resistance. A triple infection of HIV, malaria, and rifampicin resistant TB was observed in 3 participants. The prevalence of malaria among TB patients is low, and further evaluation of the epidemiological, clinical, and immunological interaction of the two diseases is warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kalanzi2019,

title = {Prevalence and factors associated with dental caries in patients attending an HIV care clinic in Uganda: a cross sectional study},

author = {Dunstan Kalanzi and Harriet Mayanja-Kizza and Damalie Nakanjako and Catherine Lutalo Mwesigwa and Ronald Ssenyonga and Bennett T. Amaechi },

url = {https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-019-0847-9},

doi = {https://doi.org/10.1186/s12903-019-0847-9},

year  = {2019},

date = {2019-07-19},

journal = {BMC Oral Health},

volume = {19},

number = {1},

pages = {159},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bayiyana2019,

title = {Longitudinal Changes in CD4+, CD8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis},

author = {Alice Bayiyana and Samuel Okurut and Rose Nabatanzi and Godfrey Zziwa and David R. Boulware and Fredrick Lutwama and David Meya },

url = {https://www.mdpi.com/2309-608X/5/3/63},

doi = {https://doi.org/10.3390/jof5030063},

year  = {2019},

date = {2019-07-17},

journal = {Journal of Fungi (Basel)},

volume = {5},

number = {3},

pages = {63},

abstract = {Abstract

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection. View Full-Text

Keywords: HIV; T cell phenotypes; ART; cryptococcal meningitis },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Mwesiga2019,

title = {A cross-sectional mixed methods protocol to describe correlates and explanations for a long duration of untreated psychosis among patients with first episode psychosis in Uganda},

author = {Emmanuel Kiiza Mwesiga and Noeline Nakasujja and Linnet Ongeri and Aggrey Semeere and Rachel Loewy and Susan Meffert .},

url = {https://bmjopen.bmj.com/content/9/7/e028029.abstract},

doi = {http://dx.doi.org/10.1136/bmjopen-2018-028029},

year  = {2019},

date = {2019-07-16},

journal = {BMJ Open},

volume = {9},

number = {7},

abstract = {Abstract



Introduction Among patients with psychotic disorders, the ‘duration of untreated psychosis’ (DUP) is a predictor of key outcomes such as symptom remission and quality of life. In sub-Saharan Africa, DUP is up to five times longer than in high-income countries, with many patients going without antipsychotic medication for 5 years or longer. One contributor to this high DUP may relate to cultural norms that drive use of alternative and complementary therapies (ACTs) as first-line treatment strategies, rather than biomedical care with antipsychotic medicine. We aim to1 determine the prevalence and factors associated with DUP and ACT use in Uganda, and2 Identify factors that drive patient and family choices to use ACT as a first-line treatment strategy.



Methods and analysis We will leverage on an ongoing cohort study at the national psychiatric and teaching hospital in Uganda. The parent study is an observational cohort design following antipsychotic naïve adults with a first episode of psychosis without substance use, HIV/AIDS or syphilis. The embedded study will use a mixed methods design including quantitative assessment of parent study participants with the Nottingham Onset Schedule-DUP to determine the DUP. Qualitative assessment will focus on patient and caregiver perceptions and use of ACT and its impact on DUP among patients with psychosis using in-depth interviews.



Ethics and dissemination The study has received ethical approval from the school of medicine research and ethics committee of the college of health sciences at Makerere University. It has also received institutional support to perform the study from the Infectious Diseases Institute and Butabika hospital. Besides publication of the work in reputable peer-reviewed journals, we hope that this work will lead to evidence-based discussions on the need for early interventions to reduce DUP in Uganda.



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, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Gerstein2019,

title = {Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during Cryptococcus neoformans Infection},

author = {Aleeza C. Gerstein and Katrina M. Jackson and Tami R. McDonald and Yina Wang and Benjamin D. Lueck and Sara Bohjanen and Kyle D. Smith and Andrew Akampurira and David B. Meya and Chaoyang Xue and David R. Boulware and Kirsten Nielsen},

url = {https://mbio.asm.org/content/10/4/e01440-19.abstract},

doi = {DOI: 10.1128/mBio.01440-19},

year  = {2019},

date = {2019-07-16},

journal = {The American Society for Microbiology},

volume = {10},

number = {4},

abstract = {ABSTRACT



Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen’s characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined Cryptococcus neoformans isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants’ survival, meningitis disease parameters, immunologic phenotypes, and pathogen in vitro growth characteristics. We compared those clinical data to whole-genome sequences from 38 C. neoformans isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate Cryptococcus genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human Cryptococcus infections.



IMPORTANCE Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus Cryptococcus neoformans and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific C. neoformans genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related C. neoformans strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40 C. neoformans genes are associated with human disease. Surprisingly, many of these genes are specific to Cryptococcus and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify C. neoformans genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Masereka2019,

title = {Increasing retention of HIV positive pregnant and breastfeeding mothers on option-b plus by upgrading and providing full time HIV services at a lower health facility in rural Uganda},

author = {Enosk Mirembe Masereka and Tom Denis Ngabirano and Charles Peter Osingada and Christine Sekaggya Wiltshire and Barbara Castelnuovo and Agnes N. Kiragga },

url = {https://link.springer.com/article/10.1186/s12889-019-7280-5},

doi = {https://doi.org/10.1186/s12889-019-7280-5},

year  = {2019},

date = {2019-07-15},

journal = {BMC Public Health },

volume = {19},

number = {1},

pages = {950},

abstract = {Abstract



Background



Despite advancement in Prevention of Mother to Child Transmission (PMTCT) services, the rate of MTCT of HIV in sub-Saharan Africa is still high. This is partly due to low retention of HIV positive mothers in HIV care. We sought to determine the level of retention and the factors associated with retention among HIV positive pregnant and breastfeeding mothers following accreditation of an antiretroviral therapy (ART) clinic to offer full time ART services in one of the lower health facilities in rural Western Uganda.



Methods



This study was a mixed methods study conducted in 5 health centres in rural Western Uganda from 10th April to 10th May 2017. A total of 132 retained and non-retained HIV positive pregnant and breastfeeding mothers were recruited. A Mother was categorized as retained if she had not missed her ART appointments at antenatal or postnatal clinic for ≥3 consecutive months. Questionnaires were administered and four focus group discussions were held. We used descriptive statistics to understand characteristics of mothers and their levels of retention. Thematic analysis was used to analyze qualitative data.



Results



About a third (35.6%) of the mothers were aged 18–24 with a median age of 26 (IQR 23, minimum age of 16 and maximum age of 39). More than half, 73 (55.3%) of all mothers were in HIV care for 3–24 months and about 116(87.9%) of all mothers were retained in HIV care. This was an improvement from 53% reported in 2015. We found lack of formal education, lack of disclosure of HIV status to the spouse, perceived lack of confidentiality and self stigmatization as factors hindering retention. The desire to have an HIV free baby, fear of death and opportunistic infections, support from significant others and community groups were factors associated with retention.



Conclusions



We observed improved retention in lower health centres and to achieve 100% retention, we recommend interventions such as sensitizing HIV positive mothers on disclosure of HIV status to spouse, maintaining confidentiality of client information at the clinic, support to girl child education and formation of community support groups.



Trial registration



This study was retrospectively registered with the Uganda National Council for Science and Technology (UNCST), registration receipt number 10961 on the 9th March, 2018.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Brazier2019,

title = {Implementation of “Treat‐all” at adult HIV care and treatment sites in the Global IeDEA Consortium: results from the Site Assessment Survey},

author = {Ellen Brazier and Fernanda Maruri and Stephany N Duda and Olga Tymejczyk and C William Wester and Geoffrey Somi and Jeremy Ross and Aimee Freeman and Morna Cornell and Armel Poda and Beverly S Musick and Fujie Zhang and Keri N Althoff and Catrina Mugglin and April D Kimmel and Marcel Yotebieng and Denis Nash and IeDEA Consortium},

url = {https://onlinelibrary.wiley.com/doi/full/10.1002/jia2.25331},

doi = { https://doi.org/10.1002/jia2.25331},

year  = {2019},

date = {2019-07-12},

journal = {Journal of the International AIDS Society},

volume = {22},

number = {7},

pages = {e25331},

abstract = {

Abstract

Introduction



Since 2015, the World Health Organization (WHO) has recommended that all people living with HIV (PLHIV) initiate antiretroviral treatment (ART), irrespective of CD4+ count or clinical stage. National adoption of universal treatment has accelerated since WHO's 2015 “Treat All” recommendation; however, little is known about the translation of this guidance into practice. This study aimed to assess the status of Treat All implementation across regions, countries, and levels of the health care delivery system.

Methods



Between June and December 2017, 201/221 (91%) adult HIV treatment sites that participate in the global IeDEA research consortium completed a survey on capacity and practices related to HIV care. Located in 41 countries across seven geographic regions, sites provided information on the status and timing of site‐level introduction of Treat All, as well as site‐level practices related to ART initiation.

Results



Almost all sites (93%) reported that they had begun implementing Treat All, and there were no statistically significant differences in site‐level Treat All introduction by health facility type, urban/rural location, sector (public/private) or country income level. The median time between national policy adoption and site‐level introduction was one month. In countries where Treat All was not yet adopted in national guidelines, 69% of sites reported initiating all patients on ART, regardless of clinical criteria, and these sites had been implementing Treat All for a median period of seven months at the time of the survey. The majority of sites (77%) reported typically initiating patients on ART within 14 days of confirming diagnosis, with 60% to 62% of sites implementing Treat All in East, Southern and West Africa reporting same‐day ART initiation for most patients.

Conclusions



By mid‐ to late‐2017, the Treat All strategy was the standard of care at almost all IeDEA sites, including rural, primary‐level health facilities in low‐resource settings. While further assessments of site‐level capacity to provide high‐quality HIV care under Treat All and to support sustained viral suppression after ART initiation are needed, the widespread introduction of Treat All at the service delivery level is a critical step towards global targets for ending the HIV epidemic as a public health threat.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}