*2.2.1 Histoplasmosis treatment in HIV patients*

Histoplasmosis is an AIDS-defining illness presenting as an invasive form [20]. The most frequent disease in these patients is progressive disseminated histoplasmosis (PDH), where the fungus spreads to other body parts, resulting in high mortality if not treated early [19, 20].

Patients with HIV may require life-long therapy depending on CD4 counts and the status of anti-retroviral treatment [7, 10]. The immunosuppression state is a factor that predisposes the infection due to the CD4+ T-lymphocyte-mediated immunity being compromised [19].

In the first few years of the AIDS pandemic, histoplasmosis carried a high risk for mortality because of the lack of efficacy of ketoconazole. Amphotericin B was effective initially, but in 60% cases experienced relapsed after stopped of treatment. Two treatment phases are recommended: initial induction and long-term maintenance therapy [6].

The IDSA recommended treatment is: a one-to-two-week induction therapy, with liposomal amphotericin B, 3 mg/kg/day for severe disease or itraconazole, a 3-day loading dose of 3x200mg, and then long-term maintenance itraconazole therapy, 200 mg daily, for a minimum period of 12 months [7].

The CDC/NIH and WHO/PAHO guidelines recommend induction for two weeks rather than the 1-to-2-week period advised by the IDSA [7, 20].

In the 2021 Guideline Development Group for Diagnosing And Managing Disseminated Histoplasmosis Among People Living With HIV, three recommendations address the induction and maintenance therapy for histoplasmosis among PLHIV. "The preferred treatment for severe or moderately severe disease is liposomal amphotericin B, 3.0 mg/kg for two weeks" (GRADE classified this recommendation as conditional with very-low-certainty evidence).

"For mild and moderate histoplasmosis, the preferred treatments are itraconazole 200 mg twice a day after an initial dose of 200 mg three times per day for three consecutively days" (GRADE classified this recommendation as conditional with very-low-certainty evidence). For maintenance therapy, the recommended doses are itraconazole 200 mg twice daily for 12 months (GRADE classified this recommendation as conditional with very-low-certainty evidence). Shorter treatment duration can be considered in clinically stable patients that receive antiretroviral treatment that suppressed the viral load with improvement in immune status. (GRADE classified this recommendation as conditional with very-low-certainty evidence) [20].

Global guidelines for the diagnosis and management of endemic mycoses recommended L-AmB as the drug of choice for induction therapy for patients with

advanced HIV and moderate-to-severe histoplasmosis, or patients who are sufficiently ill to require hospitalization. However, when L-AmB is not available, other AmB formulations are acceptable alternatives [20].

Liposomal or deoxycholate amphotericin B was more effective in AIDS patients with histoplasmosis (excluding those with CNS involvement) than amphotericin B lipid complex, with one-year survival of 81% and 56%, respectively [22, 23].

Alternative azole options recommended by the NIH/CDC include posaconazole 300 mg x2 for one day, then 300 mg daily; voriconazole 400 mg x2 for one day, then 200 mg bid; or the least desirable option, fluconazole 800 mg daily [6].

Global guideline for the diagnosis and management of endemic mycoses, in individuals with less severe disease, voriconazole is not routinely recommended, and fluconazole has a lower success rate than itraconazole and highlighted the fluconazole resistance in patients receiving fluconazole therapy [21, 23].

Isavuconazole is a newer antifungal triazole used for the treatment of both invasive aspergillosis and mucormycosis with in vitro demonstrated activity against *H. capsulatum*. It could be the best alternative to posaconazole because of its excellent sensitivity, including isolates resistant to fluconazole or voriconazole [24].

A recent Cochrane analysis concluded that the optimum maintenance regimen for histoplasmosis had not been determined (no published study has compared <12 months to >12 months of maintenance treatment) but 95% were relapse-free after 1 year for patients treated with itraconazole, 200 or 400 mg daily [25]. Because of potential toxicity and the need for intravascular access, weekly or biweekly amphotericin B deoxycholate has rarely been used [20, 25, 26].

A complex presentation of disseminated histoplasmosis infection involves the central nervous system (CNS). CNS manifestations can include meningitis involving the basilar meninges, acute meningitis, encephalitis, small ring-enhancing lesions, abscess, and stroke due to infected emboli [27]. Meningitis poses additional challenges in treatment. Liposomal amphotericin B for 4–6 weeks, followed by itraconazole for at least one year, is recommended [27, 28]. IDSA guidelines recommend prophylaxis with itraconazole for as long as the CD4 count remains low (> 150/mm3) in areas where the incidence of histoplasmosis is of >10 cases per 100 person-years. When efavirenz and itraconazole are administered together, itraconazole levels fall by 40%, so higher doses are required [7], and thus, their administration should be closely monitorized.

HIV-associated immune reconstitution inflammatory syndrome (IRIS) is an essential early complication of antiretroviral therapy initiation, associated with considerable morbidity and mortality, particularly in patients who start antiretroviral treatment with advanced immunosuppression [29, 30].

Numerous infective and noninfective conditions are associated with IRIS in HIV infection, including histoplasmosis. Some authors described a higher incidence of disseminated histoplasmosis among patients that recently started antiretroviral therapy, suggesting that this treatment can lead to unmasking IRIS [29]. Patients who manifest findings of IRIS while receiving effective antiretroviral therapy at the time of diagnosis should continue it and begin treatment for histoplasmosis with amphotericin B or itraconazole [29].

Supportive management may be required, including intravenous fluids and oxygen therapy. Various anti-inflammatory agents have been used to treat paradoxical and unmasking IRIS, including corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). The role of corticosteroids remains unclear but could be appropriate in patients with more severe manifestations [29, 30].

In 2019, the WHO included *Histoplasma* antigen tests as an essential diagnostic in endemic areas or non-endemic areas as a reference test for imported cases of histoplasmosis, and by 2025, every country should have access to rapid testing for histoplasmosis. Additionally, itraconazole and both formulations of amphotericin B should be available in the public sector [23, 26].

In the first year, levels of antigenuria and antigenemia should be monitored for early diagnosis of failure or relapse. After successful immune reconstitution and an increase in CD4 count (to more than 150/μL), secondary prevention can be stopped if the patient has received a minimum six-month course of antiretroviral treatment and at least 12 months of antifungal therapy, antigen, and blood culture-negative [7, 11, 29]. However, literature data recommend continuing prophylaxis until the clinical and laboratory results normalize [29]. Monitoring drug interaction in patients with HIV under antiretroviral treatment and histoplamosis is necessary, as these interactions are sometimes diminish efficacy and safety in patients taking these drugs, and they are at risk of toxicity or ineffectiveness from drug interactions. This observation might be useful for patients with advanced disease where possible resistant viruses with limited antiretroviral options [31].

### *2.2.2 Histoplasmosis secondary to immunosuppressive treatment*

Histoplasmosis secondary to TNF-α inhibitor therapy requires discontinuation of the tumor necrosis factor-α blocker during antifungal treatment [22, 32, 33].

Pharmacological immunosuppression with TNF-α inhibitor might be reinstituted after an excellent clinical response after 12 months of anti-histoplasmosis therapy and a negative antigen test [23]. Oral itraconazole, as an antifungal for *H. capsulatum*, could inhibit the CYP3A4 pathway and could decrease steroid metabolites [32]. A growing number of biologics targeting cytokines are available, including inhibitors of the proinflammatory mediators such as tumor necrosis factor-alpha (anti-TNF α), interleukin (IL)-1b (canakinumab), IL-1R (anakinra), IL-6R (tocilizumab), as well as T-cell co-stimulation (abatacept) and B-cells (rituximab) but with an increased risk for development of opportunistic infections [34]. TNF is essential for the formation of granuloma and the prevention of granulomatous infections such as tuberculosis and histoplasmosis [32, 33].

For long-term suppressive therapy, each of the four guidelines recommends itraconazole. A dose of 200 mg daily is advised by IDSA, whereas the CDC/NIH recommends 200 mg x2. Alternative options in rank order include posaconazole 300 mg extended-release capsule daily; voriconazole 200 mg x2; or fluconazole 400 mg daily [7].

### *2.2.3 Histoplasmosis in solid organ transplant recipients*

In the field of solid organ transplantation (SOT), T-cell immune dysfunction can also be significant, and the infection can be difficult to predict but remains a rare infection in post-transplant settings, even in endemic areas [34].

Solid organ transplant (SOT) recipients and other immunocompromised hosts have a propensity for severe infection, inclusive of extrapulmonary and disseminated disease. The infections in SOT recipients are best categorized as mild, moderate, or severe [35].

Clinical disseminated histoplasmosis in solid organ transplant (SOT) recipients is nonspecific and rare, with the highest risk period in the first year after transplant, although cases have been reported up to 20 years after transplantation [36]. One-third occurred in the first year, and almost half in the first two years after the transplant [34].

## *Histoplasmosis: An Overview Treatment of Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.110365*

Given the low incidence of histoplasmosis in healthy donors and the rarity of reported donor transmission events, routine donor screening is not indicated, nor the pre-transplant screening for histoplasmosis in transplant candidates, nor even in endemic areas [36]. Donor-derived histoplasmosis is rare, but this confirmed transmission has been reported [34]. Even without clear evidence of dissemination, SOT recipients with histoplasmosis should generally be treated as disseminated disease [5].

The American Society of Transplantation (AST) guidelines recommend at least 1 to 2 weeks of amphotericin B and step down to oral itraconazole. ITZ monotherapy could be used in mild to moderate disease, and longer courses of AmB therapy are recommended for patients with central nervous system (CNS) disease (i.e., 4 to 6 weeks). Irrespective of initial disease severity, antifungal therapy should be continued for a minimum of 12 months or more in patients necessitating continued high-level immunosuppression after a relapsed disease or in CNS involvement. Fluconazole (FCZ) or newer-generation azoles, including voriconazole (VCZ), isavuconazole (ISZ), and posaconazole (PCZ), has been used as an alternative in patients with ITZ intolerance [35]. Once the diagnosis of histoplasmosis is made, immunosuppressive medication should be reduced, although the optimal timing and strategy in this regard are unknown [36]. In patients taking concomitant itraconazole and tacrolimus, concentrations should be assessed to ensure that concentrations are within the narrow therapeutic window or to avoid increased tacrolimus serum levels with potential side effects because of excessive immunosuppression and toxicity (nephrotoxicity and neurotoxicity). Additional pharmacokinetic (PK) and drug–drug interaction considerations must be assessed in kidney transplant patients. Treatment of histoplasmosis with L-AmB comes with nephrotoxicity concerns and possible allograft loss. In the presence of subsequent acute kidney injury, treatment with liposomal amphotericin B (L-AmB) should be associated with concomitant administration of renin-angiotensin system blockers, catecholamines, or immunosuppressants, L-AmB doses ≥3.5 mg/kg/day, and serum potassium <3.5 mEq/L immediately before L-AmB administration [37].
