Unraveling the biology of a fungal meningitis pathogen using chemical genetics.

The fungal meningitis pathogen Cryptococcus neoformans is a central driver of mortality in HIV/AIDS. We report a genome-scale chemical genetic data map for this pathogen that quantifies the impact of 439 small-molecule challenges on 1,448 gene knockouts. We identified chemical phenotypes for 83% of mutants screened and at least one genetic response for each compound. C. neoformans chemical-genetic responses are largely distinct from orthologous published profiles of Saccharomyces cerevisiae, demonstrating the importance of pathogen-centered studies. We used the chemical-genetic matrix to predict novel pathogenicity genes, infer compound mode of action, and to develop an algorithm, O2M, that predicts antifungal synergies. These predictions were experimentally validated, thereby identifying virulence genes, a molecule that triggers G2/M arrest and inhibits the Cdc25 phosphatase, and many compounds that synergize with the antifungal drug fluconazole. Our work establishes a chemical-genetic foundation for approaching an infection responsible for greater than one-third of AIDS-related deaths.

T cell susceptibility to HIV influences outcome of opportunistic infections.

During HIV infection, the timing of opportunistic infections is not always associated with severity of CD4 T cell depletion, and different opportunistic pathogens reactivate at different CD4 T cell thresholds. Here, we examine how differences in the phenotype and function of pathogen-specific CD4 T cells influence susceptibility to HIV infection. By focusing on three common opportunistic infections (Mycobacterium tuberculosis, human papillomavirus, and cytomegalovirus), we investigate how differential depletion of pathogen-specific CD4 T cells impacts the natural history of these pathogens in HIV infection. A broader understanding of this relationship can better inform treatment strategies against copathogens.

Pathogenesis of HIV-Related Lung Disease: Immunity, Infection, and Inflammation.

Despite anti-retroviral therapy (ART), human immunodeficiency virus-1 (HIV)-related pulmonary disease continues to be a major cause of morbidity and mortality for people living with HIV (PLWH). The spectrum of lung diseases has changed from acute opportunistic infections resulting in death to chronic lung diseases for those with access to ART. Chronic immune activation and suppression can result in impairment of innate immunity and progressive loss of T cell and B cell functionality with aberrant cytokine and chemokine responses systemically as well as in the lung. HIV can be detected in the lungs of PLWH and has profound effects on cellular immune functions. In addition, HIV-related lung injury and disease can occur secondary to a number of mechanisms including altered pulmonary and systemic inflammatory pathways, viral persistence in the lung, oxidative stress with additive effects of smoke exposure, microbial translocation, and alterations in the lung and gut microbiome. Although ART has had profound effects on systemic viral suppression in HIV, the impact of ART on lung immunology still needs to be fully elucidated. Understanding of the mechanisms by which HIV-related lung diseases continue to occur is critical to the development of new preventive and therapeutic strategies to improve lung health in PLWH.

Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

National Hospitalization Rates and In-Hospital Mortality Rates of HIV-Related Opportunistic Infections in the United States, 2011-2018.

BACKGROUND: Human immunodeficiency virus (HIV)-related opportunistic infections (OIs) cause substantial morbidity and mortality among people with HIV (PWH). US hospitalization and in-hospital mortality rates associated with OIs have not been published using data from the past decade. METHODS: We analyzed the National Inpatient Sample for the years 2011 through 2018. We used sociodemographic, financial, and hospital-level variables and identified hospitalizations for PWH and OI diagnoses. Using survey-weighted methods, we estimated all OI-related US hospitalization rates and in-hospital mortality per 100 000 PWH and modeled associated factors using survey-based multivariable logistic regression techniques. RESULTS: From 2011 to 2018, there were an estimated 1 710 164 (95% confidence interval [CI], 1 659 566-1 760 762) hospital discharges for PWH with 154 430 (95% CI, 148 669-159 717 [9.2%]) associated with an OI, of which 9336 (95% CI, 8813-9857; 6.0%) resulted in in-hospital mortality. Variables associated with higher odds of OI-related hospitalizations (compared to without an OI) included younger age, male sex, non-White race/ethnicity, and being uninsured (all likelihood ratio [LR] P < .001). Higher OI-related mortality was associated with older age (LR P < .001), male sex (LR P = .001), Hispanic race/ethnicity (LR P < .001), and being uninsured (LR P = .009). The OI-related hospitalization rate fell from 2725.3 (95% CI, 2266.9-3183.7) per 100 000 PWH in 2011 to 1647.3 (95% CI, 1492.5-1802.1) in 2018 (P < .001), but the proportion of hospitalizations with mortality was stable (5.9% in 2011 and 2018). CONCLUSIONS: Our findings indicate an ongoing need for continued funding of HIV testing, health insurance for all PWH, OI screening initiatives, review of current prophylaxis guidelines, and recruitment of more HIV clinicians.

Tracking Cryptococcal Meningitis to Monitor HIV Program Success During the Treat All Era: An Analysis of National Data in Botswana.

BACKGROUND: Cryptococcal meningitis (CM) causes substantial mortality in African countries with a high prevalence of human immunodeficiency virus (HIV), despite advances in disease management and increasing antiretroviral therapy (ART) coverage. Reliable diagnosis of CM is cheap and more accessible than other indicators of advanced HIV disease burden such as CD4 testing or investigation for disseminated tuberculosis; therefore, monitoring CM incidence has the potential to serve as a valuable metric of HIV programmatic success. METHODS: Botswana national meningitis surveillance data from 2015 to 2022 were obtained from electronic health records. All electronic laboratory records from cerebrospinal fluid samples analyzed within government healthcare facilities in Botswana were extracted from a central online repository. Adjustments for missing data were made through triangulation with prospective cohort study datasets. CM case frequency was enumerated using a case definition and incidence calculated using national census data. RESULTS: A total of 1744 episodes of CM were identified; incidence declined from 15.0 (95% confidence interval [CI], 13.4-16.7) cases/100 000 person-years in 2015 to 7.4 (95% CI, 6.4-8.6) cases/100 000 person-years in 2022. However, the rate of decline slowed following the introduction of universal treatment in 2016. The highest incidence was observed in men and individuals aged 40-44 years. The proportion of cases diagnosed through cryptococcal antigen testing increased from 35.5% to 86.3%. CONCLUSIONS: CM incidence has decreased in Botswana following expansion of ART coverage but persists at a stubbornly high incidence. Most cases are now diagnosed through the cheap and easy-to-use cryptococcal antigen test, highlighting the potential of using CM as key metric of program success in the Treat All era.

Systematic Review of Prevalence of Histoplasma Antigenuria in Persons with HIV in Latin America and Africa.

Histoplasmosis is a fungal disease associated with substantial mortality rates among persons with advanced HIV disease. Our systematic review synthesized data on the global prevalence of Histoplasma--caused antigenuria in persons with HIV. We searched PubMed/Medline, Embase, and Scopus databases on January 3, 2023, to identify cross-sectional and cohort studies evaluating Histoplasma antigenuria prevalence among adults with HIV infection. We calculated point estimates and 95% CIs to summarize prevalence. Of 1,294 studies screened, we included 15. We found Histoplasma antigenuria among 581/5,096 (11%; 95% CI 11%-12%) persons with HIV and 483/3,789 persons with advanced HIV disease (13%; 95% CI 12%-14%). Among persons with HIV and symptoms consistent with histoplasmosis, Histoplasma antigenuria prevalence was 14% (95% CI 13%-15%; 502/3,631 participants). We determined that persons with advanced HIV disease, inpatients, and symptomatic persons might benefit from a systematic approach to early detection of histoplasmosis using urine antigen testing.

Impact of HIV status on prognosis of malignancies among people living with HIV in Japan.

BACKGROUND: Antiretroviral therapy has reduced the incidence and mortality of AIDS-defining malignancies (ADM); however, non-AIDS-defining malignancies (NADM) are a major cause of death among people living with HIV (PLWH) today. Though current guidelines suggest that PLWH should receive the same treatment as the general population, there are limited studies focused on how HIV status affects the prognosis of cancers. The present study aimed to investigate the characteristics and prognosis of malignant diseases among PLWH in Japan. METHODS: Patients with HIV diagnosed with malignant diseases at our institution between 2011 and 2021 were retrospectively reviewed. RESULTS: There were 205 patients who were diagnosed with malignancies. Of these, 87 (42.4%) were diagnosed with ADM and 118 (57.6%) were diagnosed with NADM. Among 69 patients who received chemotherapy for ADM, 24 (34.8%) developed AIDS-defining opportunistic infections during treatment. In contrast, only one (1.8%) of the 56 patients administered chemotherapy for NADM developed AIDS-defining opportunistic infections. Complications of opportunistic infections at diagnosis of malignancies, low CD4+ T-cell count, positive HIV RNA, and nonadministration of antiretroviral therapy were associated with 5-year overall survival among patients with malignant lymphomas. However, the variables associated with HIV did not affect NADM prognosis. CONCLUSIONS: In this analysis, HIV status had a small impact on the prognosis of malignant diseases in PLWH. Few patients with NADM developed AIDS-defining opportunistic infections after receiving chemotherapy.

Microbiomes detected by cerebrospinal fluid metagenomic next-generation sequencing among patients with and without HIV with suspected central nervous system infection.

BACKGROUND: Opportunistic infections in the central nervous system (CNS) can be a serious threat to people living with HIV. Early aetiological diagnosis and targeted treatment are crucial but difficult. Metagenomic next-generation sequencing (mNGS) has significant advantages over traditional detection methods. However, differences in the cerebrospinal fluid (CSF) microbiome profiles of patients living with and without HIV with suspected CNS infections using mNGS and conventional testing methods have not yet been adequately evaluated. METHODS: We conducted a retrospective cohort study in the first hospital of Changsha between January 2019 and June 2022 to investigate the microbiomes detected using mNGS of the CSF of patients living with and without HIV with suspected CNS infections. The pathogens causing CNS infections were concurrently identified using both mNGS and traditional detection methods. The spectrum of pathogens identified was compared between the two groups. RESULTS: Overall, 173 patients (140 with and 33 without HIV) with suspected CNS infection were enrolled in our study. In total, 106 (75.7%) patients with and 16 (48.5%) patients without HIV tested positive with mNGS (p = 0.002). Among the enrolled patients, 71 (50.7%) with HIV and five (15.2%) without HIV tested positive for two or more pathogens (p < 0.001). Patients with HIV had significantly higher proportions of fungus (20.7% vs. 3.0%, p = 0.016) and DNA virus (59.3% vs. 21.2%, p < 0.001) than those without HIV. Epstein-Barr virus (33.6%) was the most commonly identified potential pathogen in the CSF of patients living with HIV using mNGS, followed by cytomegalovirus (20.7%) and torque teno virus (13.8%). The top three causative pathogens identified in patients without HIV were Streptococcus (18.2%), Epstein-Barr virus (12.1%), and Mycobacterium tuberculosis (9.1%). In total, 113 patients living with HIV were diagnosed as having CNS infections. The rate of pathogen detection in people living with HIV with a CNS infection was significantly higher with mNGS than with conventional methods (93.8% vs. 15.0%, p < 0.001). CONCLUSION: CSF microbiome profiles differ between patients living with and without HIV with suspected CNS infection. mNGS is a powerful tool for the diagnosis of CNS infection among people living with HIV, especially in those with mixed infections.

Cytomegalovirus infection among people living with HIV in Sweden: Case profiles, treatment strategies and patient outcomes at Karolinska University Hospital 2010-2020.

OBJECTIVES: In countries with access to early antiretroviral treatment (ART), opportunistic infections caused by cytomegalovirus (CMV) in people living with HIV (PLWH) are becoming increasingly rare. As potential complications are severe, it is critical to remain aware of this important diagnosis. However, clinical characteristics and prognosis of CMV infection in PLWH in the era of modern ART have not been well described. METHODS: Here, we compiled the clinical presentation, management and outcome of CMV infection in PLWH treated at the infectious diseases clinic of Karolinska University Hospital during 2010-2020. RESULTS: We identified 51 cases of active CMV infection, based on detection of CMV-DNA, mainly diagnosed in patients with CD4 T-cell count <200 cells/µL (86%). Median time from HIV diagnosis to detection of CMV infection was 16 days. In 20 cases (39%), CMV infection was symptomatic with retinitis identified as a manifestation in 70% of cases. Symptomatic CMV infection was treated for 73 (20-313) days upon diagnosis, mostly using valganciclovir. One-year mortality was 22% and was associated with longer time to ART initiation from HIV diagnosis and with comorbidities, but not with CMV-DNA levels or CD4 count. Immune reconstitution was not significantly compromised in patients with symptomatic CMV, although CD4/8 ratio tended to be lower in patients with systemic CMV infection. CONCLUSIONS: Retinitis remains the most common manifestation of symptomatic CMV infection in PLWH. Recognizing CMV infection is important, especially in the management of 'late presenters'. Adequate duration of antiviral therapy and appropriate follow-up must be ensured to avoid complications.

Direct antiglobulin (Coombs) test in HIV-positive Talaromycosis marneffei patients.

Talaromycosis marneffei (T.M) is the primary opportunistic infection of AIDS patients, and its morbidity and mortality are extremely high. To further clarify the disease characteristics of patients and provide a solid basis for in-depth exploration of their pathogenic mechanisms, we retrospectively summarized and analyzed their clinical data. We included all T.M patients tested for direct antiglobulin test (DAT) in the study. Interestingly, we found that AIDS-T.M patients had an extremely high rate of DAT positivity (92/127, 72.44%). In univariate analysis, a positive DAT was associated with blood culture of TM (P = .021), hypoproteinemia (P = .001), anemia (P = .001), thrombocytopenia (P = .003), sepsis (P = .007), and Sequential Organ Failure Assessment (SOFA) (P = .001). Hypoproteinemia, anemia, SOFA, APTT > 32.6 s, and AST > 40 U/l were studied by logistic regression. Logistic regression revealed that SOFA (OR = 1.311, P = .043), hypoproteinemia (OR = 0.308, P = .021), and anemia (OR = 0.19, P = .044) were associated with positive DAT. Positive DAT was associated with severe disease manifestations such as sepsis, and the DAT test is crucial in patients with fungemia.

Talaromycosis marneffei (T.M) is the primary opportunistic infection of AIDS patients and causes high morbidity and mortality. AIDS-T.M patients who were positive for direct antiglobulin test had higher manifestations of inflammation, abnormal liver function, coagulation dysfunction, and hematologic abnormalities.

Application of the estimand framework for an emulated trial using reference based multiple imputation to investigate informative censoring.

BACKGROUND: The ICH E9 (R1) addendum on Estimands and Sensitivity analysis in Clinical trials proposes a framework for the design and analysis of clinical trials aimed at improving clarity around the definition of the targeted treatment effect (the estimand) of a study. METHODS: We adopt the estimand framework in the context of a study using "trial emulation" to estimate the risk of pneumocystis pneumonia, an opportunistic disease contracted by people living with HIV and AIDS having a weakened immune system, when considering two antibiotic treatment regimes for stopping antibiotic prophylaxis treatment against this disease. A "while on treatment" strategy has been implemented for post-randomisation (intercurrent) events. We then perform a sensitivity analysis using reference based multiple imputation to model a scenario in which patients lost to follow-up stop taking prophylaxis. RESULTS: The primary analysis indicated a protective effect for the new regime which used viral suppression as prophylaxis stopping criteria (hazard ratio (HR) 0.78, 95% confidence interval [0.69, 0.89], p < 0.001). For the sensitivity analysis, when we apply the "jump to off prophylaxis" approach, the hazard ratio is almost the same compared to that from the primary analysis (HR 0.80 [0.69, 0.95], p = 0.009). The sensitivity analysis confirmed that the new regime exhibits a clear improvement over the existing guidelines for PcP prophylaxis when those lost to follow-up "jump to off prophylaxis". CONCLUSIONS: Our application using reference based multiple imputation demonstrates the method's flexibility and simplicity for sensitivity analyses in the context of the estimand framework for (emulated) trials.

Comprehensive risk factor predictions for 3-year survival among HIV-associated and disseminated cryptococcosis involving lungs and central nervous system.

BACKGROUND: The global mortality rate resulting from HIV-associated cryptococcal disease is remarkably elevated, particularly in severe cases with dissemination to the lungs and central nervous system (CNS). Regrettably, there is a dearth of predictive analysis regarding long-term survival, and few studies have conducted longitudinal follow-up assessments for comparing anti-HIV and antifungal treatments. METHODS: A cohort of 83 patients with HIV-related disseminated cryptococcosis involving the lung and CNS was studied for 3 years to examine survival. Comparative analysis of clinical and immunological parameters was performed between deceased and surviving individuals. Subsequently, multivariate Cox regression models were utilized to validate mortality predictions at 12, 24, and 36 months. RESULTS: Observed plasma cytokine levels before treatment were significantly lower for IL-1RA (p < 0.001) and MCP-1 (p < 0.05) when in the survivor group. Incorporating plasma levels of IL-1RA, IL-6, and high-risk CURB-65 score demonstrated the highest area under curve (AUC) value (0.96) for predicting 1-year mortality. For 1-, 2- and 3-year predictions, the single-factor model with IL-1RA demonstrated superior performance compared to all multiple-variate models (AUC = 0.95/0.78/0.78). CONCLUSIONS: IL-1RA is a biomarker for predicting 3-year survival. Further investigations to explore the pathogenetic role of IL-1RA in HIV-associated disseminated cryptococcosis and as a potential therapeutic target are warranted.

Disseminated mycobacterium genavense infection with central nervous system involvement in an HIV patient: a case report and literature review.

BACKGROUND: Immunodeficient patients, particularly HIV patients, are at risk of opportunistic infections. Nontuberculous mycobacteria can cause severe complications in immunodeficient patients. CASE PRESENTATION: We describe a 57-year-old HIV patient, primarily presented with coughs and constitutional symptoms, with a unique Mycobacterium genavense abdominal, pulmonary, and central nervous system infection, accompanied by intracranial masses. CONCLUSION: The diagnosis of NTM, including M. genavense, must always be considered by clinicians in immunodeficient patients, especially those with HIV, who have a compromised immune system.

Comparison of clinical outcomes of pulmonary nocardiosis between AIDS and non-AIDS patients.

BACKGROUND: Nocardia species can affect both immunocompetent and immunocompromised people. METHOD: This retrospective study, from 2009 to 2022, aims to compare the survival analyses of pulmonary nocardiosis in AIDS and non-AIDS patients in northeastern Thailand. RESULTS: A total of 215 culture-confirmed cases of pulmonary nocardiosis: 97 with AIDS and 118 without AIDS. The median CD4 count of AIDS patients was 11 cells/µL (range: 1-198), and 33% had concurrent opportunistic infections. 63.6% of 118 non-AIDS patients received immunosuppressive medications, 28.8% had comorbidities, and 7.6% had no coexisting conditions. Disseminated nocardiosis and pleural effusion were more prevalent among AIDS patients, whereas non-AIDS patients revealed more shock and respiratory failure. One hundred-fifty patients underwent brain imaging; 15 (10%) had brain abscesses. Patients with pulmonary nocardiosis have overall 30-day and 1-year mortality rates of 38.5% (95% CI: 32.3%, 45.4%) and 52.1% (95% CI: 45.6%, 58.9%), respectively. The Cox survival analysis showed that AIDS patients with disseminated nocardiosis had a 7.93-fold (95% CI: 2.61-24.02, p < 0.001) increased risk of death within 30 days compared to non-AIDS patients when considering variables such as age, Charlson comorbidity index, concurrent opportunistic infections, duration of illness, shock, respiratory failure, multi-lobar pneumonia, lung abscesses, and combination antibiotic therapy. While AIDS and pulmonary nocardiosis had a tendency to die within 30 days (2.09 (95% CI, 0.74-5.87, p = 0.162)). CONCLUSION: AIDS with pulmonary nocardiosis, particularly disseminated disease, is a serious opportunistic infection. Early diagnosis and empiric treatment with a multidrug regimen may be the most appropriate approach in a resource-limited setting.

Drug-resistant oral candidiasis in patients with HIV infection: a systematic review and meta-analysis.

BACKGROUND: Oral candidiasis (OC) is a prevalent opportunistic infection in patients with human immunodeficiency virus (HIV) infection. The increasing resistance to antifungal agents in HIV-positive individuals suffering from OC raised concerns. Thus, this study aimed to investigate the prevalence of drug-resistant OC in HIV-positive patients. METHODS: Pubmed, Web of Science, Scopus, and Embase databases were systematically searched for eligible articles up to November 30, 2023. Studies reporting resistance to antifungal agents in Candida species isolated from HIV-positive patients with OC were included. Baseline characteristics, clinical features, isolated Candida species, and antifungal resistance were independently extracted by two reviewers. The pooled prevalence with a 95% confidence interval (CI) was calculated using the random effect model or fixed effect model. RESULTS: Out of the 1942 records, 25 studies consisting of 2564 Candida species entered the meta-analysis. The pooled prevalence of resistance to the antifungal agents was as follows: ketoconazole (25.5%, 95% CI: 15.1-35.8%), fluconazole (24.8%, 95% CI: 17.4-32.1%), 5-Flucytosine (22.9%, 95% CI: -13.7-59.6%), itraconazole (20.0%, 95% CI: 10.0-26.0%), voriconazole (20.0%, 95% CI: 1.9-38.0%), miconazole (15.0%, 95% CI: 5.1-26.0%), clotrimazole (13.4%, 95% CI: 2.3-24.5%), nystatin (4.9%, 95% CI: -0.05-10.3%), amphotericin B (2.9%, 95% CI: 0.5-5.3%), and caspofungin (0.1%, 95% CI: -0.3-0.6%). Furthermore, there were high heterogeneities among almost all included studies regarding the resistance to different antifungal agents (I2 > 50.00%, P < 0.01), except for caspofungin (I2 = 0.00%, P = 0.65). CONCLUSIONS: Our research revealed that a significant number of Candida species found in HIV-positive patients with OC were resistant to azoles and 5-fluocytosine. However, most of the isolates were susceptible to nystatin, amphotericin B, and caspofungin. This suggests that initial treatments for OC, such as azoles, may not be effective. In such cases, healthcare providers may need to consider prescribing alternative treatments like polyenes and caspofungin. REGISTRATION: The study protocol was registered in the International Prospective Register of Systematic Reviews as PROSPERO (Number: CRD42024497963).

A complex case study: coexistence of multi-drug-resistant pulmonary tuberculosis, HBV-related liver failure, and disseminated cryptococcal infection in an AIDS patient.

BACKGROUND: Hepatitis B virus (HBV) infection can cause liver failure, while individuals with Acquired Immunodeficiency Virus Disease (AIDS) are highly susceptible to various opportunistic infections, which can occur concurrently. The treatment process is further complicated by the potential occurrence of immune reconstitution inflammatory syndrome (IRIS), which presents significant challenges and contributes to elevated mortality rates. CASE PRESENTATION: The 50-year-old male with a history of chronic hepatitis B and untreated human immunodeficiency virus (HIV) infection presented to the hospital with a mild cough and expectoration, revealing multi-drug resistant pulmonary tuberculosis (MDR-PTB), which was confirmed by XpertMTB/RIF PCR testing and tuberculosis culture of bronchoalveolar lavage fluid (BALF). The patient was treated with a regimen consisting of linezolid, moxifloxacin, cycloserine, pyrazinamide, and ethambutol for tuberculosis, as well as a combination of bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) for HBV and HIV viral suppression. After three months of treatment, the patient discontinued all medications, leading to hepatitis B virus reactivation and subsequent liver failure. During the subsequent treatment for AIDS, HBV, and drug-resistant tuberculosis, the patient developed disseminated cryptococcal disease. The patient's condition worsened during treatment with liposomal amphotericin B and fluconazole, which was ultimately attributed to IRIS. Fortunately, the patient achieved successful recovery after appropriate management. CONCLUSION: Enhancing medical compliance is crucial for AIDS patients, particularly those co-infected with HBV, to prevent HBV reactivation and subsequent liver failure. Furthermore, conducting a comprehensive assessment of potential infections in patients before resuming antiviral therapy is essential to prevent the occurrence of IRIS. Early intervention plays a pivotal role in improving survival rates.

Immune recovery uveitis: an ocular manifestation in HIV/AIDS receiving treatment.

PURPOSE OF REVIEW: This article intends to briefly discuss AIDS, summarize the current literature on immune recovery uveitis, describe its ocular manifestations and complications, and tackle its complex management. RECENT FINDINGS: The clinical picture of immune recovery uveitis is still evolving. Up to today, there are still no definite criteria for immune recovery uveitis, and although closely associated with cytomegalovirus retinitis and HIV/AIDS, there are several cases of similar intraocular response in non-HIV patients. The exact pathology for this paradoxical inflammatory reaction remains unclear; however, there is an interest in identifying biomarkers to determine underlying mechanisms and identify patients at risk. The management of this disease also remains a challenge and no standardized treatment approach exists currently. SUMMARY: Immune recovery uveitis is an important cause of visual morbidity particularly in HIV/AIDS patients receiving highly active antiretroviral. It is a paradoxical reaction that is frequently associated with a prior cytomegalovirus retinitis infection. Although it can be a transient and self-limiting process, there is a complex decision on the timing of antiviral treatment and the initiation of antiretroviral treatment to prevent immune recovery uveitis. Furthermore, a substantial challenge arises in balancingtreatment decisions for complications in refractory cases.

Mucosal leishmaniasis of the lips and cheeks: a first concomitant presentation of visceral and mucosal leishmaniasis in a patient living with HIV/AIDS in Monastir, Tunisia.

BACKGROUND: Visceral Leishmaniasis (VL) is the most severe and fatal disease if left untreated. In people living with HIV/AIDS (PLHA), VL is considered an emerging opportunistic infection. The aim of this manuscript was to report a first case in Tunisia of a concomitant presentation of visceral and oral leishmaniasis in a patient LHA. A systematic review of the literature was performed according to PRISMA guidelines, as well. CASE PRESENTATION: The patient, a 43-year-old heterosexual man, treated for HIV/AIDS was referred for macrocheilitis of the upper and lower lips. A noticeable nodular and painless swelling extending to the cheeks' mucosa was noted. The patient's poor oral hygiene was evident due to the presence of multiple dental caries. Histological analysis of the biopsied lower lip sample revealed the presence of numerous Leishmania amastigotes. The diagnosis of VL was clinically confirmed by the presence of a mild splenomegaly and pancytopenia and biologically by the identification of the parasite using PCR Lei and the species L. infantum involved using RFLP-PCR and culture. The treatment consisted of an intravenous administration of liposomal Amphotericin B (Ambisome®, 40 mg/kg/weight) for a period of 6 weeks. A favorable outcome was noted after one year with the resolution of clinical symptoms and a negative Leishmania blood PCR test. After 2 years, the patient remained asymptomatic but showed a positive Leishmania blood PCR test. Dolutegravir® was introduced in the patient's ART regimen. CONCLUSIONS: To the best of our knowledge, this is the first case report in Tunisia of atypical VL diagnosed through an uncommon oral location in an HIV/AIDS co-infected patient . Since VL is a severe and potentially fatal disease, it is essential for dentists to perform a thorough clinical examination and adopt a multidisciplinary approach in order to ensure an early diagnosis and an effective treatment outcome.

Safety of different amphotericin B formulations among AIDS patients with invasive fungal disease: a retrospective observational study.

We conducted a retrospective, observational study among acquired immune deficiency syndrome (AIDS) patients with cryptococcal meningitis or talaromycosis to assess AmB formulations-related adverse events (AEs). Total 205 eligible patients were enrolled. Of them, 139 received AmB therapy, 51 received liposomal AmB (L-AmB) therapy, and 15 received AmB cholesteryl sulfate complex (ABCD) therapy. The incidences of total AEs between the AmB, L-AmB and ABCD group had no significant differences. The ABCD group had significantly higher incidences of hepatotoxicity and hematological toxicity than the AmB and L-AmB groups. The incidence of grade 3-4 hematological toxicity in the ABCD group was significantly higher than that in the AmB and L-AmB groups. Multinomial logistic regression models showed that compared with AmB, ABCD had a higher risk for the occurrence of grade 3-4 hematological toxicity (aOR = 43.924, 95%CI 6.296-306.418; p < 0.001). We demonstrated that ABCD was more prone to hepatotoxicity and hematological toxicity than AmB and L-AmB among AIDS patients, which is worth noting.