Optimising DTwP-containing vaccine infant immunisation schedules (OptImms) - a protocol for two parallel, open-label, randomised controlled trials.

BACKGROUND: Universal immunisation is the cornerstone of preventive medicine for children, The World Health Organisation (WHO) recommends diphtheria-tetanus-pertussis (DTP) vaccine administered at 6, 10 and 14 weeks of age as part of routine immunisation. However, globally, more than 17 unique DTP-containing vaccine schedules are in use. New vaccines for other diseases continue to be introduced into the infant immunisation schedule, resulting in an increasingly crowded schedule. The OptImms trial will assess whether antibody titres against pertussis and other antigens in childhood can be maintained whilst adjusting the current Expanded Programme on Immunisation (EPI) schedule to provide space for the introduction of new vaccines. METHODS: The OptImms studies are two randomised, five-arm, non-inferiority clinical trials in Nepal and Uganda. Infants aged 6 weeks will be randomised to one of five primary vaccination schedules based on age at first DTwP-vaccination (6 versus 8 weeks of age), number of doses in the DTwP priming series (two versus three), and spacing of priming series vaccinations (4 versus 8 weeks). Additionally, participants will be randomised to receive their DTwP booster at 9 or 12 months of age. A further sub-study will compare the co-administration of typhoid vaccine with other routine vaccines at one year of age. The primary outcome is anti-pertussis toxin IgG antibodies measured at the time of the booster dose. Secondary outcomes include antibodies against other vaccine antigens in the primary schedule and their safety. DISCUSSION: These data will provide key data to inform policy decisions on streamlining vaccination schedules in childhood. TRIAL REGISTRATIONS: ISRCTN12240140 (Nepa1, 7th January 2021) and ISRCTN6036654 (Uganda, 17th February 2021).

Pre-pandemic SARS-CoV-2-specific IFN-γ and antibody responses were low in Ugandan samples and significantly reduced in HIV-positive specimens.

Introduction: We investigated whether prior SARS-CoV-2-specific IFN-γ and antibody responses in Ugandan COVID-19 pre-pandemic specimens aligned to this population's low disease severity. Methods: We used nucleoprotein (N), spike (S), NTD, RBD, envelope, membrane, SD1/2-directed IFN-γ ELISpots, and an S- and N-IgG antibody ELISA to screen for SARS-CoV-2-specific cross-reactivity. Results: HCoV-OC43-, HCoV-229E-, and SARS-CoV-2-specific IFN-γ occurred in 23, 15, and 17 of 104 specimens, respectively. Cross-reactive IgG was more common against the nucleoprotein (7/110, 15.5%; p = 0.0016, Fishers' Exact) than the spike (3/110, 2.72%). Specimens lacking anti-HuCoV antibodies had higher rates of pre-epidemic SARS-CoV-2-specific IFN-γ cross-reactivity (p-value = 0.00001, Fishers' exact test), suggesting that exposure to additional factors not examined here might play a role. SARS-CoV-2-specific cross-reactive antibodies were significantly less common in HIV-positive specimens (p=0.017; Fishers' Exact test). Correlations between SARS-CoV-2- and HuCoV-specific IFN-γ responses were consistently weak in both HIV negative and positive specimens. Discussion: These findings support the existence of pre-epidemic SARS-CoV-2-specific cellular and humoral cross-reactivity in this population. The data do not establish that these virus-specific IFN-γ and antibody responses are entirely specific to SARS-CoV-2. Inability of the antibodies to neutralise SARS-CoV-2 implies that prior exposure did not result in immunity. Correlations between SARS-CoV-2 and HuCoV-specific responses were consistently weak, suggesting that additional variables likely contributed to the pre-epidemic cross-reactivity patterns. The data suggests that surveillance efforts based on the nucleoprotein might overestimate the exposure to SARS-CoV-2 compared to inclusion of additional targets, like the spike protein. This study, while limited in scope, suggests that HIV-positive people are less likely than HIV-negative people to produce protective antibodies against SARS-CoV-2.

Acceptability and applicability of biometric iris scanning for the identification and follow up of highly mobile research participants living in fishing communities along the shores of Lake Victoria in Kenya, Tanzania, and Uganda.

BACKGROUND: Recruitment and retention of participants in research studies conducted in fishing communities remain a challenge because of population mobility. Reliable and acceptable methods for identifying and tracking participants taking part in HIV prevention and treatment research are needed. The study aims to assess the acceptability, and technical feasibility of iris scans as a biometric identification method for research participants in fishing communities. METHODS: This was a cross-sectional study conducted in eight fishing communities in Kenya, Tanzania, and Uganda, with follow-up after one month in a randomly selected subset of participants. All consenting participants had their iris scanned and then responded to the survey. RESULTS: 1,199 participants were recruited. The median age was 33 [Interquartile range (IQR) 24-42] years; 56% were women. The overall acceptability of iris scanning was 99%, and the success rate was 98%. Eighty one percent (n = 949) had a successful scan on first attempt, 116 (10%) on second and 113 (9%) after more than two attempts. A month later, 30% (n = 341) of participants were followed up. The acceptability of repeat iris scanning was 99% (n = 340). All participants who accepted repeat iris scanning had successful scans, with 307 (90%) scans succeeding on first attempt; 25 (7%) on second attempt, and 8 (2%) after several attempts. The main reason for refusing iris scanning was fear of possible side effects of the scan on the eyes or body. CONCLUSION: The acceptability and applicability of biometric iris scan as a technique for unique identification of research participants is high in fishing communities. However, successful use of the iris scanning technology in research will require education regarding the safety of the procedure.

Factors Associated with Short and Long Term Mobility and HIV Risk of Women Living in Fishing Communities Around Lake Victoria in Kenya, Tanzania, and Uganda: A Cross Sectional Survey.

Mobility is linked to negative HIV care continuum outcomes. We sought to understand factors associated with short and long term mobility among women in fishing communities in Kenya, Tanzania, and Uganda. From 2018 through 2019 we conducted a cross-sectional survey of women aged 15 years and above, randomly selected from a census of six fishing villages, around Lake Victoria. Data collected included: demographics, risky sexual behaviour on the most recent trip, and travel behaviour in the previous 4 months. Mobility was recorded as any overnight trip outside the participant's village. A two-level multinomial logistic regression model was used to determine the associated factors. A total of 901 participants were enrolled, of whom 645 (71.6%) reported travelling (53.4%; short and 18.2% long term trips). Five factors were associated with long term travel: age, travel purpose, frequency of travel, sexual behaviour while travelling, and destination. Trips made by women aged 46-75 years were less likely to be long term. Long term trips were more common if the trip was to visit, rather than to trade, and more common for women who reported one or two trips rather than three or more trips. Women who made long term trips were more likely to engage in unprotected sex while on a trip. Women who travelled to a regional town/district or another town/district were more likely to take long term trips. The factors associated with travel duration among women living in fishing communities could inform planning of future health care interventions in these communities.

Social networks, mobility, and HIV risk among women in the fishing communities of Lake Victoria.

BACKGROUND: Population mobility is a demonstrated barrier to reducing HIV incidence. A clear understanding of social networks and their influence on mobility among women in the fishing communities of Lake Victoria may contribute to tailoring effective interventions that suit the needs of these mobile women. METHODS: A cross-sectional qualitative methods study was conducted to understand mobility patterns among women resident and or working in fishing communities of Lake Victoria in Kenya, Tanzania, and Uganda. The study was conducted in six fishing communities from March 2018 to June 2019. The communities were purposively selected, based on population size (1000 people or more) and HIV prevalence of > 15% among women aged 18 years or older who had lived in the fishing community for at least six months. In-depth interviews were conducted with 24 key informants and 72 women from the sites in the three countries. Questions focused on women's social networks and other factors that fuelled or facilitated women's mobility as well as challenges they faced due to mobility. Data analysis followed a thematic framework approach. RESULTS: Different social groupings/networks existed among women in the fishing communities of Lake Victoria. These included female sex workers, women fish processors/traders, women bar workers/owners, restaurant workers, and family networks. Networks encouraged mobility, supporting finding work opportunities, but also increased sexual risks through partner changes. The benefits of networks included information sharing, financial support, and group protection, especially against violence. CONCLUSION: Social networks and groupings among women in the fishing communities of Lake Victoria could be useful in tailoring HIV prevention and HIV care interventions to suit the needs of these highly mobile populations.

Characterization of Near Full-Length Transmitted/Founder HIV-1 Subtype D and A/D Recombinant Genomes in a Heterosexual Ugandan Population (2006-2011).

Detailed characterization of transmitted HIV-1 variants in Uganda is fundamentally important to inform vaccine design, yet studies on the transmitted full-length strains of subtype D viruses are limited. Here, we amplified single genomes and characterized viruses, some of which were previously classified as subtype D by sub-genomic pol sequencing that were transmitted in Uganda between December 2006 to June 2011. Analysis of 5' and 3' half genome sequences showed 73% (19/26) of infections involved single virus transmissions, whereas 27% (7/26) of infections involved multiple variant transmissions based on predictions of a model of random virus evolution. Subtype analysis of inferred transmitted/founder viruses showed a high transmission rate of inter-subtype recombinants (69%, 20/29) involving mainly A1/D, while pure subtype D variants accounted for one-third of infections (31%, 9/29). Recombination patterns included a predominance of subtype D in the gag/pol region and a highly recombinogenic envelope gene. The signal peptide-C1 region and gp41 transmembrane domain (Tat2/Rev2 flanking region) were hotspots for A1/D recombination events. Analysis of a panel of 14 transmitted/founder molecular clones showed no difference in replication capacity between subtype D viruses (n = 3) and inter-subtype mosaic recombinants (n = 11). However, individuals infected with high replication capacity viruses had a faster CD4 T cell loss. The high transmission rate of unique inter-subtype recombinants is striking and emphasizes the extraordinary challenge for vaccine design and, in particular, for the highly variable and recombinogenic envelope gene, which is targeted by rational designs aimed to elicit broadly neutralizing antibodies.

Knowledge, Attitudes, and Practices Regarding COVID-19 among Healthcare Workers in Uganda: A Cross-Sectional Survey.

Healthcare workers (HCWs) are at high risk of COVID-19. However, data on HCWs' knowledge, attitudes, and practices (KAP) toward COVID-19 are limited. Between September and November 2020, we conducted a questionnaire-based COVID-19 KAP survey among HCWs at three hospitals in Uganda. We used Bloom's cut-off of ≥80% to determine sufficient knowledge, good attitude, and good practice, and multivariate Poisson regression with robust variance for statistical analysis. Of 717 HCWs invited to participate, 657 (91.6%) agreed and were enrolled. The mean age (standard deviation) of enrollees was 33.2 (10.2) years; most were clinical HCWs (64.7%) and had advanced secondary school/other higher-level education (57.8%). Overall, 83.9% had sufficient knowledge, 78.4% had a positive attitude, and 37.0% had good practices toward COVID-19. Factors associated with KAP were: Knowledge: being a clinical HCW (aRR: 1.12; 95% CI: 1.02-1.23) and previous participation in health research (aRR: 1.10; 95% CI: 1.04-1.17); Attitude: age > 35 years (aRR: 0.88; 95% CI: 0.79-0.98); Practice: being a clinical HCW (aRR: 1.91; 95% CI: 1.41-2.59). HCWs in Uganda have good knowledge and positive attitude but poor practices towards COVID-19. Differences in COVID-19 KAP between clinical and non-clinical HCWs could affect uptake of COVID-19 interventions including vaccination.

Willingness to participate in COVID-19 vaccine trials; a survey among a population of healthcare workers in Uganda.

BACKGROUND: Healthcare workers (HCWs) are at high risk of acquiring SARS-CoV-2 and COVID-19 and may therefore be a suitable population for COVID-19 vaccine trials. We conducted a survey to evaluate willingness-to-participate in COVID-19 vaccine trials in a population of HCWs at three hospitals in Uganda. METHODS: The survey was conducted between September and November 2020. Using a standardised questionnaire, data were collected on socio-demographics, previous participation in health research, COVID-19 information sources, underlying health conditions, and willingness-to-participate in COVID-19 vaccine trials. Data were analysed descriptively and a binomial generalised linear model with a log link function used to investigate factors associated with unwillingness to participate. RESULTS: 657 HCWs (female, 63%) were enrolled with a mean age of 33 years (Standard Deviation, 10). Overall willingness-to-participate was 70.2%. Key motivating factors for participation were: hope of being protected against COVID-19 (81.1%), altruism (73.3%), and the opportunity to get health care (26.0%). Selected hypothetical trial attributes reduced willingness-to-participate as follows: weekly-quarterly study visits over a 12-month period (70.2%-63.2%, P = 0.026); provision of approximately 50ml of blood at each study visit (70.2%-63.2%, P = 0.026); risk of mild-moderate local adverse reactions (70.2%-60.3%, P<0.001); chance of receiving candidate vaccine or placebo (70.2%-56.9%, P<0.001); and delay of pregnancy [Overall, 70.2%-57.1% P<0.001); Female, 62.8%-48.4% (P = 0.002); Male, 82.5%-71.5% (P = 0.003)]. Collectively, these attributes reduced willingness-to-participate from [70.2%-42.2% (P<0.001) overall; 82.5%-58.1% (P<0.001) in men; 62.8%-32.6% (P<0.001) in women]. Among individuals that were unwilling to participate, the commonest barriers were concerns over vaccine safety (54.6%) and fear of catching SARS-CoV-2 (31.6%). Unwillingness to participate was associated with being female (aRR 1.97, CI 1.46-2.67, P<0.001) and having university or other higher-level education (aRR 1.52, CI 1.05-2.2, P = 0.026). CONCLUSIONS: Willingness-to-participate in COVID-19 vaccine trials among HCWs in Uganda is high but may be affected by vaccine trial requirements and concerns about the safety of candidate vaccines.

Quality of life and associated factors among HIV positive patients after completion of treatment for Cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CCM) remains one of the leading causes of mortality among HIV infected patients. Due to factors such as the severity of CCM pathology, the quality of life (QOL) of patients post-treatment is likely to be poor. Few studies have reported on QOL of CCM patients post treatment completion. We used data collected among patients in the CryptoDex trial (ISRCTN59144167) to determine QOL and associated factors at week 10 and six months from treatment initiation. METHODOLOGY: CryptoDex was a double-blind placebo-controlled trial of adjunctive dexamethasone in HIV infected adults with CCM, conducted between 2013 and 2015 in six countries in Asia and Africa. QOL was determined using the descriptive and Visual Analog Scales (VAS) of the EuroQol Five-Dimension-Three-Level (EQ-5D-3L) tool. We derived index scores, and described these and the VAS scores at 10 weeks and 6 months; and used linear regression to determine the relationship between various characteristics and VAS scores at both time points. VAS scores were interpreted as very good (81-100), good (51-80), normal (31-50) and bad/very bad (0-30). RESULTS: Of 451 patients enrolled in the trial, 238 had QOL evaluations at week 10. At baseline, their mean age (SD) was 35.2(8.5) years. The mean index scores (SD) were 0.785(0.2) and 0.619(0.4) among African and Asian patients respectively at week 10, and 0.879(0.2) and 0.731(0.4) among African and Asian patients respectively at month six. The overall mean VAS score (SD) at 10 weeks was 57.2 (29.7), increasing significantly to 72(27.4) at month six (p<0.001). At week 10, higher VAS score was associated with greater weight (p = 0.007) and being African (p<0.001), while lower VAS score was associated with positive yeast culture at day 14 (p = 0.026). At month six, higher VAS score remained associated with African origin (p = 0.006) while lower VAS score was associated with positive yeast culture (p = 0.006). Lower VAS scores were associated with higher number of inpatient days at 10 weeks and 6 months (p = 0.003 and 0.002 respectively). CONCLUSION: QOL was good among patients that had completed therapy for CCM, but below perfect. Strategies to improve QOL among CCM survivors are required.

Short Communication: Validation of the Asante HIV-1 Rapid Recency Assay for Detection of Recent HIV-1 Infections in Uganda.

Point of care rapid recency testing for HIV-1 may be a cost-effective tool to identify recently infected individuals for incidence estimation, and focused HIV prevention through intensified contact tracing. We validated the Asante™ HIV-1 rapid recency® assay for use in Uganda. Archived specimens (serum/plasma), collected from longitudinally observed HIV-1 recently and long-term infected participants, were tested with the Asante HIV-1 rapid recency assay per manufacturer's instructions. Previously identified antiretroviral therapy (ART)-naive samples with known seroconversions within 6 months of follow-up were tested in independent laboratories: the Rakai Health Sciences Program (RHSP) and the Uganda Virus Research Institute HIV Reference Laboratory (UVRI-HRL). In addition, samples from participants who seroconverted within 6-18 months and samples from individuals with chronic HIV-1 infection of at least 18 months duration were classified into three categories: ART naive, ART exposed with suppressed viral loads, and ART exposed with detectable viremia. Of the 85 samples seroconverting in ≤6 months, 27 and 42 samples were identified as "recent" by the Asante HIV-1 rapid recency test at the RHSP laboratory and UVRI-HRL, corresponding to sensitivities of 32% and 49%, respectively. There was 72% agreement between the laboratories (Cohen's kappa = 0.481, 95% CI = 0.317-0.646, p < .0001). Specificity was 100% (200/200) among chronically infected ART-naive samples. The Asante HIV-1 rapid recency assay had low sensitivity for detection of recent HIV-1 infections in Uganda, with substantial interlaboratory variability due to differential interpretation of the test strip bands. Specificity was excellent. Assessment of assay performance in other settings is needed to guide decisions on test utility.

Determinants of two-year mortality among HIV positive patients with Cryptococcal meningitis initiating standard antifungal treatment with or without adjunctive dexamethasone in Uganda.

Globally, early initiation of antiretroviral therapy for HIV led to a reduction in the estimated mortality from cryptococcal meningitis (CCM) from 624,700 in 2009 to 181,100 in 2014. However, CCM remains one of the leading causes of mortality among HIV infected patients especially in sub-Saharan Africa where 75% of the deaths occur. Most of the studies evaluating mortality have reported short-term mortality (at or before 10 weeks of therapy). We determined mortality and associated factors among patients treated for CCM in the CryptoDex trial (ISRCTN59144167) in Uganda, and the effect of dexamethasone adjunctive therapy on mortality at two years. We conducted a retrospective cohort study between May 2017 and July 2017 to determine the long term survival (up to 2 years post-randomization) of all patients who had been enrolled into the CryptoDex trial in Uganda. The CryptoDex trial recruited between April 2013 and February 2015. We estimated mortality rates and determined factors affecting mortality at two years using Cox regression. The study followed up 211 participants, 127 (60.2%) of whom were male. Sixteen participants (7.58%) were diagnosed with HIV at the same admission when CCM was diagnosed. By two years following randomization 127 (60%) participants had died, a mortality rate of 67 deaths per 100 person-years. Mortality was associated with Glasgow coma score (GCS) below 15 (adjusted Hazard ratio (aHR) 1.77, 95% CI: 1.02-2.44), p = 0.040; weight (aHR 0.97, per 1 Kg increase; 95% CI: 0.94-0.99), p = 0.003; and presence of convulsions (aHR 2.31, 95% CI: 1.32-4.04), p = 0.004, while dexamethasone use and fungal burden had no effect. Long-term mortality in CCM patients remains high even among patients receiving recommended therapy. Strategies to improve long-term survival in CCM patients are urgently needed, especially targeting those with reduced GCS, low weight, and convulsions.

Pervasive and non-random recombination in near full-length HIV genomes from Uganda.

Recombination is an important feature of HIV evolution, occurring both within and between the major branches of diversity (subtypes). The Ugandan epidemic is primarily composed of two subtypes, A1 and D, that have been co-circulating for 50 years, frequently recombining in dually infected patients. Here, we investigate the frequency of recombinants in this population and the location of breakpoints along the genome. As part of the PANGEA-HIV consortium, 1,472 consensus genome sequences over 5 kb have been obtained from 1,857 samples collected by the MRC/UVRI & LSHTM Research unit in Uganda, 465 (31.6 per cent) of which were near full-length sequences (>8 kb). Using the subtyping tool SCUEAL, we find that of the near full-length dataset, 233 (50.1 per cent) genomes contained only one subtype, 30.8 per cent A1 (n = 143), 17.6 per cent D (n = 82), and 1.7 per cent C (n = 8), while 49.9 per cent (n = 232) contained more than one subtype (including A1/D (n = 164), A1/C (n = 13), C/D (n = 9); A1/C/D (n = 13), and 33 complex types). K-means clustering of the recombinant A1/D genomes revealed a section of envelope (C2gp120-TMgp41) is often inherited intact, whilst a generalized linear model was used to demonstrate significantly fewer breakpoints in the gag-pol and envelope C2-TM regions compared with accessory gene regions. Despite similar recombination patterns in many recombinants, no clearly supported circulating recombinant form (CRF) was found, there was limited evidence of the transmission of breakpoints, and the vast majority (153/164; 93 per cent) of the A1/D recombinants appear to be unique recombinant forms. Thus, recombination is pervasive with clear biases in breakpoint location, but CRFs are not a significant feature, characteristic of a complex, and diverse epidemic.

Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection.

Few human immunodeficiency virus (HIV)-infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, "viral control") in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51-2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3-9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3-3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1-2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0-3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines.

Factors affecting mortality among HIV positive patients two years after completing recommended therapy for Cryptococcal meningitis in Uganda.

BACKGROUND: Cryptococcal meningitis (CCM) remains a leading cause of mortality amongst HIV infected patients in sub-Saharan Africa. When patients receive recommended therapy, mortality at 10 weeks has been reported to vary between 20 to 36%. However, mortality rate and factors affecting mortality after completing recommended therapy are not well known. We investigated mortality rate, and factors affecting mortality at 2 years among CCM patients following completion of recommended CCM therapy in Uganda. METHODS: A retrospective cohort study was conducted among HIV infected patients that had completed 10 weeks of recommended therapy for CCM (2 weeks of intravenous amphotericin B 1mg/kg and 10 weeks of oral Fluconazole 800mg daily) in the CryptoDex trial (ISRCTN59144167) between 2013 and 2015. Survival analysis applying Cox regression was used to determine the mortality rate and factors affecting mortality at 2 years. RESULTS: This study followed up 112 participants for 2 years. Mean age (±SD) was 34.9 ± 8, 48 (57.1%) were female and 80 (74.8%) had been on ART for less than 1 year. At 2 years, overall mortality was 30.9% (20 deaths per 100 person-years). Majority of deaths (61.8%) occurred during the first 6 months. In multivariable analysis, mortality was associated with ever being re-admitted since discharge after hospital-based management of CCM (aHR = 13.33, 95% CI: 5.92-30.03), p<0.001; and self-perceived quality of life, with quality of life 50-75% having reduced risk compared to <50% (aHR = 0.21, 95% CI: 0.09-0.5), p<0.001, as well as >75% compared to <50% (HR = 0.29, 95% CI: 0.11-0.81), p = 0.018. CONCLUSION: There remains a considerable risk of mortality in the first two years after completion of standard therapy for CCM in resource-limited settings with risk highest during the first 6 months. Maintenance of patient follow up during this period may reduce mortality.

Do Intracerebral Cytokine Responses Explain the Harmful Effects of Dexamethasone in Human Immunodeficiency Virus-associated Cryptococcal Meningitis?

BACKGROUND: The CryptoDex trial showed that dexamethasone caused poorer clinical outcomes and slowed fungal clearance in human immunodeficiency virus-associated cryptococcal meningitis. We analyzed cerebrospinal fluid (CSF) cytokine concentrations from participants over the first week of treatment to investigate mechanisms of harm and test 2 hypotheses: (1) dexamethasone reduced proinflammatory cytokine concentrations, leading to poorer outcomes and (2) leukotriene A4 hydrolase (LTA4H) genotype influenced the clinical impact of dexamethasone, as observed in tuberculous meningitis. METHODS: We included participants from Vietnam, Thailand, and Uganda. Using the Luminex system, we measured CSF concentrations of the following: interferon γ, tumor necrosis factor (TNF) α, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant 1, macrophage inflammatory protein 1α, and interleukin 6, 12p70, 8, 4, 10, and 17. We determined the LTA4H genotype based on the promoter region single-nucleotide polymorphism rs17525495. We assessed the impact of dexamethasone on cytokine concentration dynamics and the association between cytokine concentration dynamics and fungal clearance with mixed effect models. We measured the influence of LTA4H genotype on outcomes with Cox regression models. RESULTS: Dexamethasone increased the rate TNF-α concentration's decline in (-0.13 log2pg/mL/d (95% confidence interval, -.22 to -.06 log2pg/mL/d; P = .03), which was associated with slower fungal clearance (correlation, -0.62; 95% confidence interval, -.83 to -.26). LTA4H genotype had no statistically significant impact on outcome or response to dexamethasone therapy. Better clinical outcomes were associated with higher baseline concentrations of interferon γ. CONCLUSIONS: Dexamethasone may slow fungal clearance and worsen outcomes by increasing TNF-α concentration's rate of decline.

Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis.

Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the central nervous system (CNS) is not known. A fluconazole PK study was conducted in 43 patients receiving oral fluconazole (usually 800 mg every 24 h [q24h]) in combination with amphotericin B deoxycholate (1 mg/kg q24h) for cryptococcal meningitis (CM). A four-compartment PK model was developed, and Monte Carlo simulations were performed for a range of fluconazole dosages. A meta-analysis of trials reporting outcomes of CM patients treated with fluconazole monotherapy was performed. Adjusted for bioavailability, the PK parameter means (standard deviation) were the following: clearance, 0.72 (0.24) liters/h; volume of the central compartment, 18.07 (6.31) liters; volume of the CNS compartment, 32.07 (17.60) liters; first-order rate constant from the central to peripheral compartment, 12.20 (11.17) h-1, from the peripheral to central compartment, 18.10 (8.25) h-1, from the central to CNS compartment, 35.43 (13.74) h-1, and from the CNS to central the compartment, 28.63 (10.03) h-1 Simulations of the area under concentration-time curve resulted in median (interquartile range) values of 1,143.2 (range, 988.4 to 1,378.0) mg · h/liter in plasma (AUCplasma) and 982.9 (range, 781.0 to 1,185.9) mg · h/liter in cerebrospinal fluid (AUCCSF) after a dosage of 1,200 mg q24h. The mean simulated ratio of AUCCSF/AUCplasma was 0.89 (standard deviation [SD], 0.44). The recommended dosage of fluconazole for CM induction therapy fails to attain the pharmacodynamic (PD) target in respect to the wild-type MIC distribution for C. neoformans The meta-analysis suggested modest improvements in both CSF sterility and mortality outcomes with escalating dosage. This study provides the pharmacodynamic rationale for the long-recognized fact that fluconazole monotherapy is an inadequate induction regimen for CM.

Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis.

There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h-1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h-1 The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144-168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.