Advances in Antiretroviral Therapy for Patients with Human Immunodeficiency Virus-Associated Tuberculosis.

Tuberculosis is one of the most common opportunistic infections and a prominent cause of death in patients with human immunodeficiency virus (HIV) infection, in spite of near-universal access to antiretroviral therapy (ART) and tuberculosis preventive therapy. For patients with active tuberculosis but not yet receiving ART, starting ART after anti-tuberculosis treatment can complicate clinical management due to drug toxicities, drug-drug interactions and immune reconstitution inflammatory syndrome (IRIS) events. The timing of ART initiation has a crucial impact on treatment outcomes, especially for patients with tuberculous meningitis. The principles of ART in patients with HIV-associated tuberculosis are specific and relatively complex in comparison to patients with other opportunistic infections or cancers. In this review, we summarize the current progress in the timing of ART initiation, ART regimens, drug-drug interactions between anti-tuberculosis and antiretroviral agents, and IRIS.

HIV-associated disseminated cryptococcosis-An unusual clinical and diagnostic picture with successful cure by single dose liposomal amphotericin B treatment.

BACKGROUND: Cryptococcosis is an invasive, opportunistic fungal infection seen especially in human immunodeficiency virus (HIV) infected patients. Cryptococcal meningitis (CM) is the second leading cause of mortality in HIV patients. We report a case of disseminated cryptococcosis presenting with altered mental status in a newly diagnosed HIV infection. METHODS AND RESULTS: A 50-year-old with a short history of altered mental sensorium and a history of low-grade fever and weight loss for few months presented at a tertiary care hospital in North India. He was detected positive for HIV-1. Cryptococcal antigen (CRAG) was positive in Cerebrospinal fluid (CSF), and negative in serum. The fungal culture in CSF was sterile while the fungal blood culture grew Cryptococcus neoformans. The patient was treated with single high-dose Liposomal Amphotericin B (LAmB) therapy followed by Fluconazole and Flucytosine for the next two weeks followed by fluconazole daily for consolidation and maintenance therapy. Antiretroviral therapy (ART) was started 4 weeks after induction therapy. After 6 months, the patient is doing fine. CONCLUSION: Single dose LAmB along with the backbone of fluconazole and flucytosine appears promising in disseminated cryptococcal infection in HIV-infected individuals.

HIV and skin infections.

HIV infection alters the skin microbiome and predisposes to a wide range of cutaneous infections, from atypical presentations of common skin infections to severe disseminated infections involving the skin that are AIDS-defining illnesses. Bacterial infection of the skin, most commonly caused by Staphylococcus aureus, occurs frequently and can result in bacteremia. Nontuberculous mycobacterial infections that are usually localized to the skin may disseminate, and guidance on the treatment of these infections is limited. Herpes simplex can be severe, and less common presentations such as herpetic sycosis and herpes vegetans have been reported. Severe herpes zoster, including disseminated infection, requires intravenous antiviral treatment. Viral warts can be particularly difficult to treat, and in atypical or treatment-resistant cases a biopsy should be considered. Superficial candidosis occurs very commonly in people living with HIV, and antifungal resistance is an increasing problem in non-albicans Candida species. Systemic infections carry a poor prognosis. In tropical settings the endemic mycoses including histoplasmosis are a problem for people living with HIV, and opportunistic infections can affect those with advanced HIV in all parts of the world. Most cutaneous infections can develop or worsen as a result of immune reconstitution in the weeks to months after starting antiretroviral therapy. Direct microscopic examination of clinical material can facilitate rapid diagnosis and treatment initiation, although culture is important to provide microbiological confirmation and guide treatment.

Recurrent Cryptococcal Meningitis in a Late Presenter of HIV: A Rare Case Report and Review of Literature.

BACKGROUND The highly active antiretroviral treatment (HAART) and the primary prophylaxis in newly diagnosed people living with HIV (PLHIV) have reduced the incidence of opportunistic infections such as cryptococcal meningitis (CM). Relapse of CM is associated with increased morbidity and mortality. The aim of the present case presentation is to report the clinical progress relapse of CM in a man who was a late presenter PLHIV, 1 year after ART initiation with increased CD4 cell count, undetectable viral load, and excellent compliance after disruption of secondary antifungal prophylaxis. CASE REPORT One year after initial diagnosis of HIV and CM, the patient had no neurological or other symptoms, and viral suppression and increased CD4 cell count were achieved. After the completion of 12 months of secondary prophylaxis with fluconazole, an episode of partial seizure with secondary generalization occurred, followed by a short-term memory loss. Magnetic resonance imaging (MRI) indicated a focal lesion in right frontal-parietal brain region. Lumbar puncture was conducted and Cryptococcus neoformans non-resistant to fluconazole was isolated. He received antiepileptic treatment, induction antifungal treatment with liposomal amphotericin and fluconazole, consolidation treatment with fluconazole, and secondary prophylaxis with fluconazole, as in the first episode of CM. One year after the relapse, antiepileptic treatment and secondary prophylaxis with fluconazole continues and no new episode has been reported. The diagnosis of immune reconstitution inflammatory syndrome (IRIS)-related relapse of CM cannot be excluded. CONCLUSIONS Further studies are needed for the evaluation of parameters such as duration of secondary prophylaxis and treatment options for induction and consolidation therapy to reduce the relapse rate of CM.

[Role of glucocorticoids in pneumocystis pneumonia in patients with non-HIV infection/AIDS (HIV/AIDS) and related mechanisms].

Pneumocystis pneumonia (PCP) is an opportunistic infection caused by Pneumocystis carinii and is the most common fungal infection in HIV/AIDS patients. With the routine use of antiretroviral therapy (ART), the incidence of PCP infection in HIV/AIDS patients has decreased and the prognosis has improved significantly. On the other hand, the use of chemoradiotherapy and immunotherapy in patients with cancer, post-transplantation and autoimmune diseases are increasing dramatically, which has led to a similar increase in the incidence of PCP in these non-HIV/AIDS patients. There is a global shift in research on PCP from HIV-infected co-infected PCP (HIV-PCP) to non-HIV-infected co-infected PCP. The clinical course of non-HIV-PCP is rapid and severe, and the morbidity and mortality rates are higher than those of HIV-PCP. Studies have shown that 90% of non-HIV-PCP patients have a history of glucocorticoid use prior to infection, such as in patients with hematologic malignancies, solid organ transplants, and rheumatic diseases, and that long-term high-dose glucocorticoid use is an important risk for PCP susceptibility. Clinical practice has shown that PCP often occurs during the tapering of glucocorticoids, and a higher proportion of patients develop diffuse pulmonary lesions and, in more severe cases suffer from life-threatening acute respiratory failure. The pathogenesis of non-HIV infections associated with PCP is not yet clarified, and there is a lack of effective therapeutic practices that require further investigation.

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023.

BACKGROUND: The European AIDS Clinical Society (EACS) guidelines were revised in 2023 for the 19th time, and all aspects of HIV care were updated. KEY POINTS OF THE GUIDELINES UPDATE: Version 12.0 of the guidelines recommend the same six first-line treatment options for antiretroviral treatment (ART)-naïve adults as versions 11.0 and 11.1: tenofovir-based backbone plus an unboosted integrase inhibitor or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. The long-acting section has been expanded in the ART and drug-drug interaction (DDI) panels. Tables for preferred and alternative ART in children and adolescents have been updated, as has the section on prevention of vertical transmission, particularly with new guidance for breastfeeding. A new DDI table has been included for the ART and anti-infective drugs used for opportunistic infections, sexually transmitted infections, and other infectious conditions; lenacapavir has been included in all DDI tables. New sections on alcohol use and patient-reported outcome measures (PROMs) have been included in the comorbidity panel, in addition to updates on many relevant topics, such as new resource guidance for deprescribing in people with HIV. Other sections, including travel, cognitive impairment, cancer screening, sexual health, and diabetes have also been revised extensively. The algorithm for the management of acute hepatitis C virus infection has been removed, as current guidelines recommend immediate treatment of all people with recently acquired hepatitis C virus. Updates on vaccination for hepatitis B virus and recommendations for simplification to tenofovir-free two-drug regimens in people with isolated anti-hepatitis B core antibodies are provided. In the opportunistic infections and COVID-19 panel, guidance on the management of COVID-19 in people with HIV has been updated according to the most up-to-date evidence, and a new section on monkeypox has been added. CONCLUSIONS: In 2023, the EACS guidelines were updated extensively and now include several new sections. The recommendations are available as a free app, in interactive web format, and as a pdf online.

Immune-related neurodegeneration in the midbrain causes pulmonary dysfunction in murine cryptococcal IRIS.

Cryptococcal immune reconstitution inflammatory syndrome (C-IRIS) is a condition that affects immunosuppressed individuals recruited to antiretroviral therapy. In a recent publication, Kawano and colleagues used a mouse model to demonstrate that pulmonary dysfunction, one of the fatal complications of C-IRIS, is caused by T cell-driven neurodegeneration in a vital medullary nucleus of the brain responsible for respiratory control.

Coexistence of Cryptococcal Fungemia and Pneumocystis jirovecii Pneumonia in an HIV-Infected Patient: A Case Report.

INTRODUCTION: Opportunistic infections caused by bacteria and fungi are common in human immunodeficiency virus (HIV)-infected patients. Cryptococcus neoformans and Pneumocystis jirovecii are the most common opportunistic infections in immunosuppressed individuals, but their coexistence is rare. To our knowledge, this is the first case presented in Turkey involving the coexistence of C.neoformans fungemia and P.jirovecii pneumonia. CASE PRESENTATION: A 26-year-old male patient presented with a cachectic appearance, cough, sputum, weakness, shortness of breath, and a weight loss of 15 kg in the last three months. It was learned that the patient was diagnosed with HIV three years ago, did not go to follow-ups, and did not use the treatments. CD4 cell count was 7/mm3 (3.4%), CD8 cell count was 100 (54%) mm3, and HIV viral load was 5670 copies/mL. In thorax computed tomography (CT), increases in opacity in diffuse ground glass density in both lungs and fibroatelectasis in lower lobes were observed. With the prediagnosis of P. jiroveci pneumonia, the HIV-infected patient was given trimethoprim-- sulfamethoxazole 15 mg/kg/day intravenously (i.v.). On the 4th day of the patient's hospitalization, mutiplex PCR-based rapid syndromic Biofire (Film Array) blood culture identification 2 (BCID2) test (Biomerieux, France) was applied for rapid identification from blood culture. C. neoformans was detected in the blood culture panel. The treatment that the patient was taking with the diagnosis of C. neoformans fungemia was started at a dose of liposomal amphotericin B 5 mg/kg/- day + fluconazole 800 mg/day. CONCLUSION: While the incidence of opportunistic infections has decreased with antiretroviral therapy (ART), it remains a problem in patients who are unaware of being infected with HIV or who fail ART or refuse treatment. High fungal burden, advanced age, low CD4+ cell count, and being underweight are risk factors for mortality in HIV-positive patients. Our case was a cachectic patient with a CD4 count of 7 cells/mm3. Despite the early and effective treatment, the course was fatal.

Joint Modeling of Longitudinal Outcome and Competing Risks: Application to HIV/AIDS Data.

BACKGROUND: Tuberculosis (TB) and human immunodeficiency virus (HIV) are major public health challenges globally, and the number of TB infections and death caused by HIV are high because of HIV/ TB co-infection. On the other hand, CD4 count plays a significant role in TB/HIV co-infections. We used a joint model of longitudinal outcomes and competing risks to identify the potential risk factors and the effect of CD4 cells on TB infection and death caused by HIV in HIV-infected patients. STUDY DESIGN: This was a retrospective cohort study. METHODS: The current study was performed on 1436 HIV+patients referred to Behavioral Diseases Counseling Centers in Kermanshah Province during 1998-2019. In this study, joint modeling was used to identify the effect of potential risk factors and CD4 cells on TB and death caused by HIV. RESULTS: The results demonstrated that the decreasing CD4 cell count was significantly associated with an increased risk of death, while it had no significant relation with the risk of TB. In addition, patients with TB were at a higher risk of death. Based on the results, a significant relationship was found between CD4 count and sex, marital status, education level, antiretroviral therapy (ART), time, and the interaction between time and ART. Further, people infected with HIV through sexual relationships were at higher risk of TB, while those with a history of imprisonment who received ART or were infected with HIV through drug injection had a lower risk of TB. CONCLUSION: The findings revealed that the decreasing CD4 count had a significant association with an increased risk of death caused by HIV. However, it was not significantly related to the risk of TB. Finally, patients with TB were at higher risk of death caused by HIV.

Brain opportunistic infections and tumors in people living with HIV - still a challenge in efficient antiretroviral therapy era.

The aim of the study was to evaluate the incidence of brain opportunistic pathologies and survival in patients living with HIV from a Romanian tertiary center. A 15-year prospective observational study of brain opportunistic infections diagnosed in HIV-infected patients was performed at Victor Babes Hospital, Bucharest, between January 2006 and December 2021. Characteristics and survival were compared related to modes of HIV acquisition and type of opportunistic infection. A total of 320 patients were diagnosed with 342 brain opportunistic infections (incidence 9.79 per 1000 person-years), 60.2% males with median age at diagnosis of 31 years (IQR 25, 40). Median CD4 cell count and VL were 36/µL (IQR 14, 96) and 5.1 log10 copies/mL (IQR 4, 5.7) respectively. The routes of HIV acquisition were heterosexual (52.6%), parenteral route in early childhood (31.6%), injecting drug use (12.9%), men having sex with men (1.8%), and vertical (1.2%). The most common brain infections were progressive multifocal leukoencephalopathy (31.3%), cerebral toxoplasmosis (26.9%), tuberculous meningitis (19.3%), and cryptococcal meningitis (16.7%). Patients infected by parenteral mode in early childhood were younger at diagnosis of both opportunistic infection and HIV (p < 0.001 and p < 0.001, respectively), developed more frequently PML (p < 0.001), and had the lowest early (p = 0.002) and late (p = 0.019) mortality rates. Risk factors for shorter survival were age > 30 years (p = 0.001), injecting drug use (p = 0.003), CD4 + < 100/µL (p = 0.007), and VL > 5 log10 copies/mL at diagnosis (p < 0.001). The incidence and mortality rate of brain opportunistic infections were high and did not decrease significantly during the study period, due to late presentation or non-adherence to ART.

Review: The application of corticosteroids in cryptococcal meningitis.

Cryptococcal meningitis (CM) is a serious disease with high morbidity and mortality. Although the patients who received corticosteroids were at high risk of having CM, corticosteroids also have been used as an adjunct to antifungal drugs for treating people with CM in some situations (such as immune reconstitution inflammatory syndrome, cerebral cyptococcoma, et al.). Here, we summarize the current knowledge on the application of the corticosteroids in CM, aiming to help clinicians to reasonably use corticosteroids in patients with CM.

Human Immunodeficiency Virus: Opportunistic Infections and Beyond.

Human immunodeficiency virus (HIV) infection causes substantial morbidity and mortality worldwide. Although antiretroviral therapy (ART) has changed the epidemiology of HIV in the last 20 years with increased survival and decreasing incidence of opportunistic infections (OI), CNS OI remain a major cause of morbidity. Improved survival has also increased neurological presentations due to co morbid conditions, treatment related side effects and inflammatory syndromes. Being familiar with the imaging findings, the impact of ART and interpretation of imaging in the context of clinical and laboratory findings is important for radiologists as well as clinicians in the management of HIV-infected patients.

Cryptococcal meningitis with atypical paradoxical inflammatory reactions after antifungal treatment in acquired immune deficiency syndrome: A case report.

Cryptococcal meningitis (CM) is a life-threatening disease that primarily affects patients with human immunodeficiency virus (HIV). Antifungal therapy with antiretroviral treatment (ART) usually leads to the clinical remission of CM; however, in some cases, these treatments exacerbate intracranial inflammation because of paradoxical inflammatory reaction or immune reconstitution inflammatory syndrome (IRIS). Here we report two CM cases that presented atypical clinical courses attributed to paradoxical inflammatory reactions. The first case was a 43-year-old man with headache and vertigo diagnosed with CM and HIV. The patient's CM not only was refractory to the antifungal combination therapy of liposomal amphotericin B (L-AMB) and fluconazole (FLCZ) but suddenly worsened because of a paradoxical inflammatory reaction after 18 days of treatment. He passed away from brain herniation on day 23. The second case was a 43-year-old man diagnosed with CM and HIV. After receiving antifungal therapy and ART, the patient's status was stable for more than 3 years with undetectable HIV-RNA. He suddenly presented with brain inflammation and was diagnosed with IRIS due to CM (CM-IRIS). His brain lesions were migratory and refractory to various antifungal therapies such as L-AMB, FLCZ, flucytosine, and intrathecal amphotericin B. Although the cryptococcal antigen in the patient's cerebrospinal fluid gradually diminished after continuous antifungal therapies, his cognitive function declined, and right hemiparesis persisted. These two cases of CM presented atypical clinical courses, presumably because of paradoxical inflammatory reactions. It should be noted that the onset of CM-IRIS may not necessarily depend on the timing of ART initiation.

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies.

BACKGROUND: Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence. METHODS: We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate. RESULTS: 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/µL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/µL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/µL; IQR: 47-142; WBC: 45 cells/µL; IQR: 8-128). Among those with CSF WBC <5 cells/µL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/µL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS. CONCLUSIONS: Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results. CLINICAL TRIALS REGISTRATION: NCT01802385.

CE: HIV-Associated Kaposi Sarcoma in the Combination Antiretroviral Therapy Era.

ABSTRACT: Kaposi sarcoma is a tumor caused by Kaposi sarcoma herpesvirus, also known as human herpesvirus 8. Its occurrence is associated with an immunocompromised state. Kaposi sarcoma that occurs among people living with HIV (PLWH) is known as epidemic Kaposi sarcoma. Despite the decline in HIV-associated complications because of the introduction of combination antiretroviral therapy two decades ago, Kaposi sarcoma continues to affect PLWH worldwide. It affects young African American men more than other age and racial groups and can result in multiorgan dysfunction, leading to short-term and chronic debilitating symptoms as well as death. While some patients with epidemic Kaposi sarcoma are managed as outpatients, others may require higher levels of care and their acuity may fluctuate throughout their life span. Therefore, nurses, regardless of their specialty, may experience caring for a patient with epidemic Kaposi sarcoma at some point in their career. Learning about this condition and the needs of patients who have it will help nurses provide effective care. Here, the authors describe Kaposi sarcoma in general as well as the epidemiology, characteristics, and management of epidemic Kaposi sarcoma. They also describe specific nursing considerations in the care of PLWH who have the disease.

Gastrointestinal Talaromyces marneffei infection in a patient with AIDS: A case report and systematic review.

Talaromyces marneffei is a thermally dimorphic fungus that affects multiple organs and frequently invades immunocompromised individuals. However, only a few studies have reported the presence of intestinal infection associated with T. marneffei. Herein, we reported a case of intestinal T. marneffei infection in a man who complained of a 1-month history of intermittent fever, abdominal pain, and diarrhea. The result of the human immunodeficiency virus antibody test was positive. Periodic acid-Schiff and Gomorrah's methylamine silver staining of the intestinal biopsy tissue revealed T. marneffei infection. Fortunately, the patient's symptoms rapidly resolved with prompt antifungal treatment. In addition, we summarized and described the clinical characteristics, management, and outcomes of patients with intestinal T. marneffei infection. A total of 29 patients were identified, the majority of whom (65.52%) were comorbid with acquired immunodeficiency syndrome. The main clinical features included anemia, fever, abdominal pain, diarrhea, weight loss, and lymphadenopathy. The transverse and descending colon, ileocecum, and ascending colon were the most common sites of lesions. A considerable number of patients (31.03%) developed intestinal obstruction, intestinal perforation, and gastrointestinal bleeding. Of the 29 patients, six underwent surgery, 23 survived successfully with antifungal treatment, five died of T. marneffei infection, and one died of unknown causes. T. marneffei intestinal infection should be considered when immunodeficient patients in endemic areas present with non-specific symptoms, such as fever, abdominal pain, and diarrhea. Appropriate and timely endoscopy avoids delays in diagnosis. Early aggressive antifungal therapy improves the clinical outcomes of patients.

Clinical Oral Condition Analysis and the Influence of Highly Active Antiretroviral Therapy on Human Salivary Microbial Community Diversity in HIV-Infected/AIDS Patients.

The purpose of this study was to assess the clinical oral status and investigate the effect of highly active antiretroviral therapy (HAART) on oral flora diversity in human immunodeficiency virus (HIV)-infected/acquired immune deficiency syndrome (AIDS) patients. We first recorded and analyzed the demographic indicators of 108 HIV-infected patients and assessed their periodontal health, dental health and oral lesion status by oral examination. Besides, we compared the changes in salivary microbial communities of healthy controls, before and after treatment of HAART-processed AIDS patients by Roche 454 sequencing and RT-qPCR. In HIV-infected/AIDS patients, age, sex, marital status, income level, smoking and oral health behaviors had an effect on periodontal clinical indicators; age and marital status were correlated with dental clinical indicators; most of them were accompanied by oral manifestations, mainly including candidiasis albicans, salivary gland disease, AIDS-associated periodontitis, and oral ulcers. Besides, a total of 487 species were detected in the saliva of AIDS patients. The microbial communities of HAART-unprocessed AIDS patients significantly differed from those processed patients, with 112 unique microbial species. More importantly, a large number of conditioned pathogens were also detected in the saliva samples of AIDS patients, which may be associated with opportunistic infections. Therefore, HAART might have a crucial role in salivary microecological balance in AIDS patients. And these patients should pay attention to the maintenance of oral health, and the early initiation of HAART may be important for the development of oral lesions.