**6. Treatment**

Patients with CD4 count > 300 cells/mm3 who develop acute pulmonary histoplasmosis must be treated as immunocompetent persons [91].

Progressive disseminated histoplasmosis in HIV-infected patients is a life-threatening infection that requires always treatment, as the mortality rate in untreated infection is very high (up to 100%) [91].

Several guidelines have been released with recommendations for treatment for disseminated form of histoplasmosis in people living with HIV: IDSA, DHHS, EACS, WHO. According to the last one published in 2020, the treatment is related to the form of the infection considering that:



The preferred regimen for severe or moderate-severe form as induction therapy is intravenous liposomal amphotericin B (3 mg/kg/day) for up to two weeks, as this formulation has demonstrated better outcomes than standard deoxycholate formulation in terms of rapid and complete response (82% versus 56%), lower mortality (2% versus 13%), and nephrotoxicity (9% versus 37%) [92]. Clinical improvement (resolution of fever and no need for ventilatory support, or vasopressors) must be followed by step-down therapy to itraconazole 200 mg three times a day for 3 days, and then 200 mg twice a day for at least 12 months as maintenance treatment [1, 91, 93].

If liposomal formulation is not available, standard deoxycholate amphotericin B must be initiated in dose of 0.7–1.0 mg/kg/day with close monitoring of the renal function and electrolytes. Dose reduction or rapid switch to itraconazole is needed if the patient develops nephrotoxicity despite proactive fluids and electrolytes replacement or other toxicities (anemia and toxic-related infusion).

Intravenous amphotericin B lipid complex at 5 mg/kg/day is an alternative option but it demonstrated a lower efficacy than two previous options [18] in AIDS patients with PDH.

Itraconazole is preferred for induction and maintenance therapy for mild or mild to moderate forms of histoplasmosis in HIV-infected patients. After 3 days of 200 mg three times a day as loading dose, 200 mg twice a day must be continued for at least 12 months, with dose adjustment based on drug-drug interaction with ARV and itraconazole serum concentration [1, 91, 93]. Itraconazole must be administrated with food or low-pH beverages (such as cola) in order to increase absorption. Liquid itraconazole is preferred due to better absorption if it is well tolerated. Blood level must be measured after 2 weeks of treatment (time to reach steady state) to verify if achieving optimal concentration between 1 and 2 mcg/ml. Serum concentrations could be useful in case of drug-drug interactions or to assess the adherence of the patient. Higher concentration (>15 mcg/ml) is correlated with toxicities. Most adverse events in HIV-infected patients are nausea, vomiting, rash, and pedal edema.

Like all the triazoles, itraconazole exhibits multiple drug interactions, most notably with cytochrome P450-inducing drugs [94]. Before starting treatment, these potential drug-drug interactions must be evaluated as HIV infection must be treated as well. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as Efavirenz (EFV), Nevirapine (NVP), and Etravirine (ETR) reduce itraconazole blood level; meanwhile, Doravirine (DOR) display only low interactions and co-administration does not require TDM for itraconazole like for previous ones. Boosted protease inhibitors (PIs) such as lopinavir (LPV/r), atazanavir (ATZ/r), darunavir (DRV/r or DRV/c) increase itraconazole blood level so must be avoided or TDM is needed to avoid toxicities. Integrase inhibitors (INSTI) such as Raltegravir or Dolutegravir have no interaction so are safe to prescribe them in association with itraconazole but, due to cobicistat, Elvitegravir will increase itraconazole level [95] and must be avoided. Tuberculosis medication's rifampicin and rifabutin, potent inducers of cytochrome P450 (CYP) enzymes and transporters, decrease the level of itraconazole; on the other hand, itraconazole may increase the blood levels of rifabutin [94, 95].

If itraconazole cannot be administrated, alternative therapy must be considered for treating less severe disseminated disease. Posaconazole is the preferred antifungal

## *HIV-Associated Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.111389*

for treating H. capsulatum as it demonstrates high efficacy in patients who failed other fungicidal medication [96]. Posaconazole treatment duration ranged from 6 weeks to 48 weeks depending on the clinical form and was followed by successful clinical outcomes [97]. Serum level must be measured after 5 days in order to reach steady state to determine if the drug has adequate absorption (concentration must be >1 mcg/ mL). Fluconazole 800 mg once daily is associated with a slower decline of antigenuria than itraconazole [98] and with a higher rate of resistance emergence in HIV-infected patients due to a single point mutation [99], so is no longer recommended as maintenance therapy [100]. Voriconazole was associated with increased mortality in the first 42 days when compared to itraconazole in a retrospective cohort in which have been included 24.7% HIV-infected patients with disseminated histoplasmosis [101]. Isavuconazole could be an alternative to Posaconazole and cases have been published with good outcome [102], but there are not enough data to generate a conclusion.

The maintenance therapy with itraconazole in AIDS-associated disseminated histoplasmosis must be 12 months in order to suppress residual infection and to prevent relapses. Is safe to discontinue itraconazole after 12 months when CNS involvement is absent, CD4 counts are more than 150 cells/mm3 , HIV-RNA is suppressed under cART, and Histoplasma antigenuria is less than 2 ng/mL [35], otherwise must be continued with 200 mg/day for the entire life as long-term suppressive therapy [91, 93]. In some cases, itraconazole can be replaced by Posaconazole XR 300 mg/day (best option), Fluconazole 400 mg/day, or Voriconazole 200 mg/day.

A special approach must be considered for H. capsulatum meningitis. The induction therapy with intravenous liposomal amphotericin B 5 mg/kg/day must be longer, for 4–6 weeks, followed by itraconazole 200 mg two or three times a day for more than 12 months with dosage adjusted not to exceed 10 mcg/mL [91, 93]. The maintenance treatment with Itraconazole must be continued till the resolution of CNS abnormal findings with negative antigen and culture of CSF when CD4 count recovered as HIV viral load became undetectable. Itraconazole could be replaced in case of intolerance by Posaconazole as alternative best option, Fluconazole, or Voriconazole.

All guidelines recommend monitoring treatment response by performing antigen level at the initiation of antifungal medication; at the end of amphotericin B induction phase, at 3, 6, and 12 months and when it is decided the cessation of therapy [1, 91, 93]. Any increase in antigen level must be followed by a comprehensive evaluation considering adherence to antifungal and ARV treatment. TDM for itraconazole level is required, and also CD4 count and HIV-RNA determination as relapses are related to non-adherence [35].

Antiretroviral therapy should be initiated as soon as possible if CNS involvement is not suspected or confirmed [1, 91]. In order to avoid drug-drug interaction with any triazole, INSTI-based regimen (DTG or RAL) are preferred as first-line therapy or doravirine (DOR) as NNRTI-based regimen. Immune reconstitution inflammatory syndrome (IRIS) is uncommon in HIV-infected people with histoplasmosis with an incidence rate of 0.74 cases/1000 HIV-infected person-years [76]; thus, the cART should not be delayed. The management of IRIS associated with histoplasmosis is to continue antiretroviral treatment as well as antifungal therapy with short term of oral steroids associated (Prednison 1 mg/kg per day) if there are life-threatening complications. If patient is naïve to cART, a two-week delay is recommended before starting medication; meanwhile, induction antifungal therapy is in place.

The most challenging situation for clinicians is treatment of histoplasmosis/ tuberculosis co-occurrence in HIV-infected patients as currently, there are no guidelines or recommendations targeting all three infections. Tuberculosis must be treated according WHO, DHHS, EACS guidelines, but due to drug-drug interactions, especially in HIV heavily pretreated patients requiring protease inhibitors regimens or in case of MDR-tuberculosis, clinicians must seek experts advise. Due to drug-drug interactions between itraconazole—rifampin or rifabutin—some ARV drugs, TDM for itraconazole must be perform on a regular basis. Results from a case series study conducted in Columbia on 12 PLHIV determined investigators to recommend fluoroquinolone instead of rifampicin use for TB as three patients treated with rifampicin had undetectable levels of itraconazole [78]. Another challenge is delaying initiation of ARV therapy up to 14 days as CD4 count is frequent less than 200 cells/mm3 , due to the associated risk of developing IRIS [76].
