Two-drug regimens for the treatment of HIV in Africa.

Two-drug regimens for the treatment of HIV are increasingly available. The oral regimen of dolutegravir plus lamivudine is recommended as a preferred option in multiple national guidelines but is not currently included in WHO HIV treatment guidelines nor widely used in Africa. Long-acting injectable cabotegravir and rilpivirine is being rolled out in the USA, Europe, and Australia but its use in sub-Saharan Africa is currently restricted to clinical trials. Given the increasing life expectancy, rising prevalence of non-communicable diseases, and resulting polypharmacy among people living with HIV, there are potential advantages to the use of two-drug regimens, particularly in African women, adolescents, and older adults. This Viewpoint reviews existing evidence and highlights the risks, benefits, and key knowledge gaps for the use of two-drug regimens in settings using the public health approach in Africa. We suggest that a two-drug regimen of dolutegravir and lamivudine can be safely used as a switch option for virologically suppressed individuals in settings using the public health approach once chronic hepatitis B has been excluded. Individuals with HIV who are switched to two-drug regimens should receive a full course of hepatitis B vaccinations. More efficacy data is needed to support dolutegravir plus lamivudine combination in the test and treat approach, and long-acting cabotegravir and rilpivirine in the public health system in sub-Saharan Africa.

Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy.

After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77-GFPHI cells contain expanded TCR clonotypes, have elevated expression of co-stimulatory genes such as Tnfrsf4/OX40, and are functionally more protective than Nur77-GFPLO cells. By contrast, Nur77-GFPLO cells express markers of terminal exhaustion and cytotoxicity, and the trafficking receptor S1pr5, associated with vascular localization. A short course of immunotherapy targeting OX40+ cells transiently expands CD4 T cell numbers and shifts their phenotype towards parenchymal protective cells. Moreover, OX40 agonist immunotherapy decreases the lung bacterial burden and extends host survival, offering an additive benefit to antibiotics. CD4 T cells from the cerebrospinal fluid of humans with HIV-associated tuberculous meningitis commonly express surface OX40 protein, while CD8 T cells do not. Our data thus propose OX40 as a marker of recently activated CD4 T cells at the infection site and a potential target for immunotherapy in tuberculosis.

Cytomegalovirus viremia as a risk factor for mortality in HIV-associated cryptococcal and tuberculous meningitis.

OBJECTIVES: CMV viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-naïve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of patients with HIV-associated meningitis at 18 weeks. METHODS: We prospectively enrolled Ugandans with cryptococcal or TB meningitis into clinical trials in 2015-2019. We quantified CMV DNA concentrations from stored baseline plasma or serum samples from 340 participants. We compared 18-week survival between those with and without CMV viremia. RESULTS: We included 308 persons with cryptococcal meningitis and 32 with TB meningitis, of whom 121 (36%) had detectable CMV DNA. Baseline CD4+ T-cell counts (14 vs. 24 cells/µl; P = 0.07) and antiretroviral exposure (47% vs. 45%; P = 0.68) did not differ between persons with and without CMV viremia. The 18-week mortality was 50% (61/121) in those with CMV viremia versus 34% (74/219) in those without (P = 0.003). Detectable CMV viremia (adjusted hazard ratio [aHR] 1.60; 95% confidence interval [CI] 1.13-2.25; P = 0.008) and greater viral load (aHR 1.22 per log10 IU/ml increase; 95% CI 1.09-1.35; P <0.001) were positively associated with all-cause mortality through 18 weeks. CONCLUSION: CMV viremia at baseline was associated with a higher risk of death at 18 weeks among persons with HIV-associated cryptococcal or TB meningitis, and the risk increased as the CMV viral load increased. Further investigation is warranted to determine whether CMV is a modifiable risk contributing to deaths in HIV-associated meningitis or is a biomarker of immune dysfunction.

Evaluation of the BioFire® FilmArray® Meningitis/Encephalitis panel in an adult and pediatric Ugandan population.

BACKGROUND: Meningitis causes significant mortality in sub-Saharan Africa and limited diagnostics exist. We evaluated the utility of the BioFire® FilmArray® Meningitis/Encephalitis multiplex PCR panel (BioFire ME) in HIV-infected adults and HIV-infected and uninfected children presenting with suspected meningitis in Uganda. METHODS: We tested cerebrospinal fluid (CSF) using a stepwise meningitis diagnostic algorithm including BioFire ME. We determined the diagnostic performance of BioFire ME for cryptococcal meningitis, using cryptococcal antigen (CrAg) and CSF culture as reference standards, and assessed other central nervous system (CNS) pathogens identified by the panel. RESULTS: We evaluated 328 adult and 42 pediatric CSF specimens using BioFire ME. Of the adult CSF samples tested, 258 were obtained at baseline, and 70 were obtained from repeat lumbar punctures in cryptococcal meningitis. For Cryptococcus, sensitivity was 82%, specificity was 98%, PPV was 98%, and NPV was 79% in baseline specimens using CSF CrAg as the reference standard. Among follow-up specimens, a negative BioFire ME for Cryptococcus predicted CSF culture sterility with 84% NPV. Overall sensitivity was decreased at low fungal burdens: 29% for 0-99 Cryptococcus CFU/mL compared to 94% for ≥100 CFU/mL in baseline specimens. Other pathogens detected included E. Coli, H. influenzae, S. pneumoniae, CMV, enterovirus, HSV, HHV-6, and VZV. Two specimens tested positive for S. pneumoniae and one for Cryptococcus in the pediatric population. CONCLUSIONS: Multiplex PCR is a promising rapid diagnostic test for meningitis in adults and children in resource-limited settings. Cryptococcus at low fungal burdens in CSF may be missed by BioFire ME.

High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial.

BACKGROUND: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. METHODS: In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration, and grade 3-5 adverse events. RESULTS: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC0-24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P = .34). CONCLUSIONS: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC.

Fujifilm SILVAMP TB LAM Assay on Cerebrospinal Fluid for the Detection of Tuberculous Meningitis in Adults With Human Immunodeficiency Virus.

BACKGROUND: Tuberculous meningitis (TBM) has a high fatality rate, with inadequate diagnostic tests being a major contributor. The rollout of Xpert MTB/Rif and Xpert MTB/RIF Ultra (Xpert Ultra) have improved time-to-diagnosis with sensitivities similar to culture, yet test availability and sensitivity are inadequate. The TB lipoarabinomannan lateral flow assay (AlereLAM) offers ease of use, but its low sensitivity in cerebrospinal fluid (CSF) limits clinical utility for TBM. The Fujifilm SILVAMP TB LAM (FujiLAM) assay has excellent sensitivity in urine, but performance on cerebrospinal fluid is uncertain. METHODS: We conducted a prospective cohort study at Kiruddu National Referral Hospital in Kampala, Uganda, enrolling patients suspected to have TBM. CSF was tested using AlereLAM, Xpert Ultra, culture, and FujiLAM. Results were compared with 2 reference standards: probable and definite TBM or definite TBM alone by the uniform TBM case definition. RESULTS: Of 101 patients enrolled (95/101 HIV-positive), 34 had definite TBM and 24 had probable TBM. FujiLAM sensitivity on CSF was 52% (30/58) for definite or probable TBM compared with 55% (32/58) for Xpert Ultra. AlereLAM had lower sensitivity than FujiLAM in the subgroup of patients tested with both assays (14% [4/28] vs 50% [14/28]; P < .01). FujiLAM specificity was 98% (42/43) for patients without probable or definite TBM. CONCLUSIONS: FujiLAM showed higher sensitivity than AlereLAM, with sensitivity potentially approaching that of Xpert Ultra. FujiLAM could improve time-to-treatment-initiation, especially in settings where the more technical Xpert Ultra system might not be feasible. Large confirmatory studies are needed.

Cerebrospinal Fluid Bacillary Load by Xpert MTB/RIF Ultra Polymerase Chain Reaction Cycle Threshold Value Predicts 2-Week Mortality in Human Immunodeficiency Virus-Associated Tuberculous Meningitis.

BACKGROUND: The World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated polymerase chain reaction (PCR) assay, as the initial tuberculous meningitis (TBM) diagnostic test. The assay's PCR cycle threshold (Ct) values represent the number of PCR cycles required for probe signal to be detected (low Ct value = high bacillary load) and may approximate tuberculosis (TB) bacillary load. We measured the relationship between cerebrospinal fluid (CSF) TB bacillary load with mortality. METHODS: We prospectively enrolled 102 human immunodeficiency virus (HIV)-positive Ugandans with probable or definite TBM from April 2015 to August 2019. Xpert Ultra Ct tertiles and semi-quantitative categories were separately analyzed as predictors of 2-week mortality. We investigated associations between Ct and baseline clinical and CSF parameters. RESULTS: Subjects with Ct values in the low tertile (ie, high bacillary load) had 57% 2-week mortality-worse than the intermediate (17%) and high (25%) Ct tertiles and Xpert Ultra-negative (30%) probable TBM cases (P = .01). In contrast, the reported semi-quantitative Xpert Ultra categorization was less precise; with the medium to low category trending toward worse 2-week survival (42%) compared with very low (28%), trace (26%), and negative (30%) categories (P = .48). Ct tertile was significantly associated with baseline CSF lactate (P = .03). CONCLUSIONS: High CSF TB bacillary load, as measured by Xpert Ultra Ct tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TBM and is a better predictor than the reported Xpert Ultra semi-quantitative category. Xpert Ultra Ct values could identify TBM patients at increased risk of death who may benefit from enhanced supportive care.

Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis.

BACKGROUND: Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. METHODS: We evaluated 1201 human immunodeficiency virus-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic-symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. RESULTS: We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ≥5 white cells/µL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P = .91). CONCLUSIONS: Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. CLINICAL TRIALS REGISTRATION: NCT01802385.

Hepatitis C core antigen testing: a reliable, quick, and potentially cost-effective alternative to hepatitis C polymerase chain reaction in diagnosing acute hepatitis C virus infection.

Hepatitis C virus (HCV) is increasingly common among human immunodeficiency virus (HIV)-infected men who have sex with men. We evaluated the efficacy of HCV core antigen in diagnosing acute HCV in an HIV-infected cohort. Compared with HCV polymerase chain reaction, core antigen proved sensitive (100%) and specific (97.9%). As a quick, simple, and cost-effective test, it has considerable utility in screening for acute HCV.