KEY RECOMMENDATIONS, RATIONALE, AND EVIDENCE SUMMARY

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Guidelines for Diagnosing and Managing Disseminated Histoplasmosis among People Living with HIV [Internet]. Washington (DC): Pan American Health Organization; 2020 Apr.

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Guidelines for Diagnosing and Managing Disseminated Histoplasmosis among People Living with HIV [Internet].

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3KEY RECOMMENDATIONS, RATIONALE, AND EVIDENCE SUMMARY

3.1. Diagnosis of disseminated histoplasmosis among people living with HIV

Disseminated histoplasmosis should be diagnosed among people living with HIV by detecting circulating Histoplasma antigens (conditional recommendation; low-certainty evidence).

3.1.1. Background and rationale

The traditional gold standard for diagnosing histoplasmosis is based on conventional laboratory tests (culture, histopathology, and special stains) (10, 16). However, these assays have important limitations, notably the need for laboratory infrastructure for handling isolates (Biosafety Level 3), the need for laboratory staff with appropriate training and experience, variable analytical performance of the tests and long turnaround time for diagnosis. Several weeks are required to undertake fungal culture, and this can lead to providing empirical treatment while awaiting the results, potentially adding unnecessary toxicity and associated costs to patient care (10, 16). Alternatively, people may die if treatment is delayed while awaiting culture confirmation (17). The Guideline Development Group was confident that this recommendation can be achieved in most countries, although financial and technical support may be needed in some settings to strengthen laboratory capacity to be able to provide adequate and timely testing. The Guideline Development Group also noted the need to strengthen implementation strategies (for example, educational programs) to improve the diagnosis of histoplasmosis (18) (Annex 2).

3.1.2. Systematic review

A systematic review and a meta-analysis compared the diagnostic accuracy of different laboratory approaches for disseminated histoplasmosis among people living with HIV (19). Studies were included for analysis if they demonstrated validation of Histoplasma laboratory assays among people living with HIV using culture or histopathological analysis to determine proven cases as defined by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group (20). Meta-analysis found that antigen detection tests have the highest analytical performance for diagnosing disseminated histoplasmosis among people living with HIV (overall sensitivity 95% and specificity 97%). Culture-based assays presented variable analytical performance in diagnosing disseminated histoplasmosis (overall sensitivity of 77% and unknown specificity). Antibody testing had high specificity but low sensitivity, probably because these people are highly immunosuppressed. Molecular testing through DNA detection showed high diagnostic accuracy (sensitivity 95% and specificity 99%), but the lack of consensus on techniques or procedures and the lack of availability of commercial kits makes implementing these types of assays difficult (19) (Annex 3).

Antigen detection assays were the most accurate method for diagnosing disseminated histoplasmosis among people living with HIV. These types of assays are commercially available as kits, which facilitates transfer of this assay to clinical laboratories. Using commercial assays reduces technical problems related to reproducibility and permits to undertake a better quality control. In addition, antigen testing can be performed in laboratories with lower level biosecurity (Biosafety Level 1 and 2 laboratories). In settings where Histoplasma antigen testing has been implemented, the number of diagnosed cases increased significantly, providing further evidence of the higher analytical performance of this type of assay (17, 18, 21, 22). In addition, the relative ease and speed with which these antigen assays can be performed and the use of non-invasive samples has reduced the time to diagnosis and the mortality associated with disseminated histoplasmosis among people living with HIV (17, 18, 21, 22). The main limitation is that commercial kits are only available in ELISA format, and point-of-care testing is needed to further reduce diagnostic delays. Further, assay distribution and costs need to be evaluated in each setting. Annex 4 summarizes the alternative commercially available assays for diagnosing histoplasmosis.

3.1.3. Recommendation

The Guideline Development Group recommends antigen detection assays to diagnose disseminated histoplasmosis among people living with HIV. This recommendation is based on the high diagnostic accuracy of Histoplasma antigen testing for these people and is also supported by preference for non-invasive testing and ease of use in resource-limited settings. The recommendation is conditional, since it is based on low-certainty evidence.

This recommendation applies to suspected disseminated histoplasmosis among people living with HIV. In the case of mucocutaneous infections, central nervous system, and pulmonary-only localizations of histoplasmosis may require complementary testing such as serum antibody tests or culture and histopathological analysis of different specimens, including tissue biopsy or body fluids.

3.2. Induction and maintenance antifungal treatment regimens for disseminated histoplasmosis among people living with HIV

3.2.1. Disseminated histoplasmosis classification definitions

The categories of disseminated histoplasmosis are defined as follows:

Severe or moderately severe histoplasmosis is defined as the presence of at least one sign or symptom involving vital organs: respiratory or circulatory failure, neurological signs, renal failure, coagulation anomalies and a general alteration of the WHO performance status greater than 2, in which the person is confined to a bed or chair more than half of the waking hours and only capable of limited self-care.
Mild to moderate histoplasmosis is defined as signs and symptoms that do not include the above features defining severity.

3.2.2. Induction therapy

Treating severe or moderately severe histoplasmosis among people living with HIV: liposomal amphotericin B, 3.0 mg/kg, for two weeks is recommended (conditional recommendation; very-low-certainty evidence).

Treating mild to moderate histoplasmosis among people living with HIV: itraconazole 200 mg three times daily for three days and then 200 mg twice daily is recommended (conditional recommendation, very-low-certainty evidence).

3.2.2.1. Background and rationale

Disseminated histoplasmosis among people living with HIV is a rapidly progressing, life-threatening infection that requires prompt treatment with antifungal medication. The standard treatment, deoxycholate amphotericin B has good treatment success rates (23) but is associated with considerable toxicity, especially infusion-related toxicity, renal failure, electrolyte abnormalities, and anemia (24, 25). The Guideline Development Group considered that not all regimens for treating moderate or severe disseminated histoplasmosis are consistently available in all resource-limited settings. The Guideline Development Group further recognized that there may be concerns about adverse events associated with some of the proposed treatments but was confident that the treatments recommended offer improved safety and tolerability compared with the alternatives; as such, the Guideline Development Group considered that the values and preferences overall favored the proposed interventions. In addition, the Guideline Development Group noted that therapeutic drug monitoring is proposed in some settings; however, the feasibility of implementing therapeutic drug monitoring and some treatment options depends on resource availability (26). However, the absence of therapeutic drug monitoring or of the first-line recommended treatment should not be a reason to not give treatment for disseminated histoplasmosis, a potentially fatal disease. Acceptability of treatment is a key issue because suboptimal adherence to using an antifungal drug is associated with treatment relapse and mortality among people living with HIV who have disseminated histoplasmosis (27, 28). The Guideline Development Group was confident that key stakeholders are likely to find this recommendation acceptable (Annex 2).

3.2.2.2. Systematic review

The systematic review identified four studies, including one randomized trial, that compared the efficacy of liposomal amphotericin B versus deoxycholate amphotericin B for induction therapy for moderately severe to severe disseminated histoplasmosis among people living with HIV (Annex 5). Compared with deoxycholate amphotericin B, the people treated with liposomal amphotericin B had improved clinical success (82% versus 56%), lower mortality (2% versus 13%) and less nephrotoxicity (9% versus 37%) (24, 29).

For treating people with less severe disease, fluconazole (800 mg daily for 12 weeks) was less effective than itraconazole (200 mg three times a day for three days and then 200 mg twice daily for 12 weeks) (30, 31). Moreover, triazoles all showed lower efficacy than polyenes among more severely ill people. Randomized trials of amphotericin B formulations compared with triazole antifungal agents have not been conducted (32).

3.2.2.3. Recommendations

Treating severe or moderately severe histoplasmosis among people living with HIV

Liposomal amphotericin B, 3.0 mg/kg for two weeks is recommended as the preferred treatment. This recommendation is conditional based on the very-low-certainty evidence (Annex 2).

Induction therapy should be given for two weeks. Because amphotericin B is associated with renal toxicity, the duration of therapy can be shortened based on clinical assessment of how the person responds to treatment.

Involvement of the central nervous system may require extending induction therapy or increasing dosage.

Alternative treatment for severe or moderately severe histoplasmosis among people living with HIV

In resource-limited settings where liposomal amphotericin B is unavailable, deoxycholate amphotericin B (0.7–1.0 mg/kg) should be administered for the initial two weeks. This is a conditional recommendation, based on very-low-certainty evidence because of imprecision and indirectness. For people with renal failure or at risk of renal injury, preventing and monitoring toxicity associated with deoxycholate amphotericin B are recommended (13).

Treating mild to moderate histoplasmosis among people living with HIV

Itraconazole 200 mg twice daily after a loading dose of 200 mg three times daily for three days is recommended. This is a conditional recommendation, based on very low certainty of evidence, because of imprecision and indirectness.

Based on the histoplasmosis treatment guidelines of the Infectious Diseases Society of America, this recommendation can be used for treating HIV-uninfected immunosuppressed individuals for disseminated histoplasmosis (25).

3.2.3. Maintenance therapy

Itraconazole 200 mg twice daily for 12 months is recommended (conditional recommendation; very-low-certainty evidence). Less than 12 months of therapy can be considered when the person is clinically stable, receiving antiretroviral therapy, has suppressed viral loads, and the immune status has improved (conditional recommendation, very-low-certainty evidence).

3.2.3.1. Background and rationale

After successful induction therapy for disseminated histoplasmosis among people living with HIV, rates of relapse can be as high as 90% among people not receiving maintenance therapy (32). Relapse occurs more frequently 6–18 months after discontinuing induction therapy. Reinfection can occur in regions that are hyperendemic for histoplasmosis (23). Antifungal maintenance therapy is therefore necessary to effectively suppress residual infection and prevent relapse. Treatment success rates are higher when maintenance therapy is with itraconazole (75%) compared with fluconazole (40%) (33, 34), although direct randomized comparisons are lacking. Itraconazole treatment 200 mg twice daily is usually preceded by a loading dose of 200 mg itraconazole thrice daily for three days to achieve steady-state itraconazole concentrations more rapidly (35). The efficacy and duration of such regimens required for people with central nervous system involvement is less clear.

The ideal duration of maintenance therapy has not been established and should be determined based on clinical judgment. Lifelong maintenance antifungal therapy has been recommended in some national guidelines, and relapses were usually associated with poor adherence to therapy, low itraconazole levels or central nervous system infection. Guidelines from the Infectious Diseases Society of America recommend maintenance therapy with azoles for one year (25).

3.2.3.2. Systematic review

The systematic review sought to compare the efficacy and safety of maintenance therapy with 12 months of oral itraconazole with shorter durations of maintenance therapy. The only study to report evidence on this comparison was a retrospective cohort study that compared a group in which maintenance therapy was discontinued (38 participants) with a group in which maintenance therapy was continued (59 participants) (28). The review authors judged the study to be at high risk of bias (29).

3.2.3.3. Recommendation

Itraconazole (200 mg twice daily) for one year is the recommended maintenance therapy. The recommendation is conditional, with very-low-certainty evidence because of imprecision and indirectness. The Guideline Development Group decided that the desirable effects of shortening the maintenance course were moderate and undesirable effects were trivial; there was no important uncertainty of values. The balance of effects was therefore judged to be in favor of the intervention, which was both feasible and acceptable. Itraconazole and dolutegravir, antiretroviral drug used in combination with two nucleoside reverse-transcriptase inhibitors for WHO-recommended first-line regimens, have no expected drug–drug interactions. Annex 7 presents more information on drug–drug interactions between itraconazole and antiretroviral drugs. The University of Liverpool’s drug interaction charts may also be consulted online at https://www.hiv-druginteractions.org (36).

Balancing the risk of relapse, drug–drug interactions, and side-effects, clinicians may opt for shorter courses (at least six months long) of maintenance therapy. The Guideline Development Group is aware that short maintenance therapy (3–6 months) has been used successfully for people receiving antiretroviral therapy, with suppressed viral loads, and clinically stable with immune recovery. Shortening the duration should be based on how the person responds to antiretroviral therapy with an undetectable viral load, some immune recovery, which can be defined as CD4 cell counts >200 cells/mm³, and clinical resolution of histoplasmosis. People with drug–drug interactions are more likely to benefit from shorter courses of maintenance therapy (28, 37). This conditional shortening of maintenance therapy was judged to be aligned with the values and preferences of people with disseminated histoplasmosis, physicians, and policy-makers (Annex 2). The Guideline Development Group recommendation for shortening maintenance therapy is conditional, with very-low-certainty evidence because of imprecision and indirectness.

3.3. Timing of antiretroviral therapy initiation

Antiretroviral therapy should be initiated as soon as possible among people with disseminated histoplasmosis for whom central nervous system involvement is not suspected or proven (conditional recommendation; very-low-certainty evidence).

3.3.1. Background and rationale

WHO guidelines recommend initiating antiretroviral therapy within seven days after HIV diagnosis and that people with advanced HIV disease be given priority for assessment and antiretroviral therapy initiation; these guidelines further recommend that antiretroviral therapy initiation should be offered on the same day to people who are ready to start (3). However, people presenting for the first time or those returning to care should undergo evaluation for opportunistic infections, in particular signs and symptoms of TB and cryptococcal meningitis, before antiretroviral therapy initiation is offered. Immediate antiretroviral therapy initiation is contraindicated among people living with HIV who have cryptococcal meningitis because of the increased mortality presumed to be caused by immune reconstitution inflammatory syndrome in the central nervous system, especially in the context of increased intracranial pressure (13, 3). Apart from the above situation, evidence indicates that starting antiretroviral therapy within 14 days of starting treatment for acute opportunistic infections (Pneumocystis jirovecii pneumonia, cryptococcal meningitis, and bacterial infections) reduced disease progression and death in individuals with other opportunistic infections (38) (Annex 2).

3.3.2. Systematic review

The systematic review sought to compare the outcomes of early versus delayed initiation of antiretroviral therapy. One randomized clinical trial with 282 participants met the inclusion criteria (39). Only 10 participants had HIV and a presumptive or confirmed diagnosis of disseminated histoplasmosis. By day 30, one of the seven people in the early arm and none of the three people in the late arm died. Based on this limited evidence, the efficacy and safety outcomes of early versus late initiation of antiretroviral therapy are unknown (29).

3.3.3. Recommendation

Antiretroviral therapy should not be delayed for people diagnosed with disseminated histoplasmosis who are administered antifungal therapy. The recommendation is conditional with very-low-certainty evidence. The Guideline Development Group considered that the risk of potential harms was minor. The recommendation was judged feasible and likely to be acceptable, with possible important uncertainty regarding values and preferences and the balance of effects. This recommendation is based on the balance between the substantial risk of dying from another opportunistic infection when delaying antiretroviral therapy and the low incidence of immune reconstitution inflammatory syndrome versus morbidity and mortality associated with immune reconstitution inflammatory syndrome among people living with HIV receiving antiretroviral therapy who have histoplasmosis. Immune reconstitution inflammatory syndrome appears to be uncommon among people with disseminated histoplasmosis following antiretroviral therapy initiation (38).

Most of the literature on immune reconstitution inflammatory syndrome is case reports or small case series, which cannot provide evidence on the incidence of immune reconstitution inflammatory syndrome or the optimal timing of antiretroviral therapy (Annex 2).

This recommendation regarding the timing of antiretroviral therapy only applies to people without central nervous system involvement, to avoid immune reconstitution syndrome in the central nervous system.

3.3.4. Managing immune response inflammatory syndrome associated with histoplasmosis

Immune reconstitution inflammatory syndrome associated with histoplasmosis is unusual, occurring at about 0.74 cases per 1,000 person-years among people living with HIV (38). Typically, immune reconstitution inflammatory syndrome occurs a median of 60 days after initiating antiretroviral therapy. The features of histoplasmosis-associated immune reconstitution inflammatory syndrome are non-specific and resemble disseminated histoplasmosis, with symptoms including fever, weight loss, cough, diarrhea and abdominal pain. Typically, antifungal therapy does not need to be adjusted. The following steps are recommended for managing immune reconstitution inflammatory syndrome associated with histoplasmosis:

continue antiretroviral therapy; and
ensure optimal antifungal therapy.

Short-course oral steroid therapy can be considered if there are life-threatening complications despite appropriate treatment of histoplasmosis. In these cases, it has been recommended that 1–2 mg/kg per day of prednisone or the equivalent be given for 1–2 weeks followed by dose-tapering for two weeks.

3.4. TB therapy for people coinfected with TB, HIV, and histoplasmosis

People living with HIV with TB and histoplasmosis coinfection should receive TB therapy according to WHO treatment guidelines (conditional recommendation; very-low-certainty evidence).

3.4.1. Background and rationale

TB and histoplasmosis coinfection is a challenge because the symptoms are non-specific. Coinfection is frequent although likely underestimated, since clinicians may stop investigation after initial diagnosis and thus fail to see coinfections. Depending on the local epidemiology, this situation may occur frequently among people living with HIV (8–38%), and screening should look for both diagnoses (12). When coinfections are diagnosed, this can lead to complex patient management, with drug–drug interactions that may affect HIV, TB, and histoplasmosis treatment. In particular, rifampicin results in reduced itraconazole levels, potentially leading to ineffective treatment for histoplasmosis (40) (Annex 6).

3.4.2. Systematic review

To address this concern, a systematic review was conducted to assess whether TB therapy should be adjusted for people coinfected with TB and histoplasmosis. This review found only two studies (including one case report) reporting on treatment outcomes among coinfected people (40, 41). The rationale for this recommendation therefore relies on the expertise of the Guideline Development Group and considers existing guidance on managing HIV and TB coinfection (Annex 2).

3.4.3. Recommendation

People living with HIV with TB and histoplasmosis coinfection should receive prompt treatment after diagnosis according to WHO treatment guidelines. The recommendation balances the risk for M. tuberculosis resistance and the risk of drug–drug interactions (rifampicin and itraconazole), leading to subtherapeutic itraconazole levels and potential ineffective treatment for histoplasmosis. The Guideline Development Group judged that there may be important variability in how much the people with histoplasmosis, physicians, and policy-makers value the main outcome but that the intervention was feasible and acceptable (Annex 2).

This recommendation has several possible resource implications. It is important to review potential antiretroviral therapy options for people with coinfection and to make necessary adjustments as recommended in WHO’s consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Because of the potential decrease in itraconazole levels related to some types of antiretroviral therapy, itraconazole drug levels should be monitored if possible (42). When histoplasmosis is not controlled because of interactions with rifampicin and itraconazole, clinicians may consider, depending on local context, extending the duration of amphotericin B induction therapy, once-weekly courses of amphotericin B, increasing the itraconazole dose and monitoring the blood level and toxicity and considering using other azole drugs (posaconazole, voriconazole, or fluconazole). Finally, clinicians can consider replacing rifampicin with rifabutin.

Treatment may need to be revised for people experiencing toxicity, drug-drug interactions, or for those with resistance profiles requiring protease inhibitors or second-line anti-TB drugs. When possible, antiretroviral resistance genotyping and M. tuberculosis drug susceptibility testing may assist clinical decisions. Itraconazole serum level testing may not be available in some areas.

3.5. Preventing, monitoring, and managing histoplasmosis among people living with HIV

3.5.1. Monitoring the toxicity of amphotericin B treatment

Drug toxicity and side-effects from amphotericin B therapy and drug–drug interactions associated with itraconazole use are important barriers to the successful treatment of people living with HIV who have histoplasmosis, especially in low- and middle-income countries (Annex 5).
Safe administration of amphotericin B formulations is a priority and may require referral to a center with resources available to manage toxicity.
Renal function should be evaluated to prevent, monitor, and manage toxicity such as nephrotoxicity, hypokalemia, infusion-related reactions and anemia.
Renal function should be measured to reduce the risk of kidney damage, including appropriate fluid and electrolyte reposition, in addition to drug infusion (for deoxycholate amphotericin B) over 4–6 hours (43).

3.5.1.1. Background and rationale

Adverse effects of amphotericin B therapy include renal toxicity, anemia, hypokalemia, hypomagnesemia and acute infusion-related reactions. A review of using amphotericin B formulations for treating people living with HIV for histoplasmosis found that nephrotoxicity was common (18%), as was infusion-related toxicity (36%) (24). In a study from Uganda among people with cryptococcal meningitis, proactive fluid and electrolyte management as part of amphotericin-based therapy was associated with improved survival (44).

The most common adverse reactions associated with itraconazole for treating people with histoplasmosis are nausea and vomiting, rash and pedal edema (31, 45). An important limitation to using itraconazole is variable bioavailability, and the guidelines of the Infectious Diseases Society of America recommend monitoring serum itraconazole levels for disseminated histoplasmosis (25). Serum concentrations are useful for determining whether itraconazole is adequately absorbed and may also be helpful in assessing adherence and the impact of drug–drug interactions. Toxicity has been associated with higher serum levels of itraconazole among people with aspergillosis (46).

3.5.2. Monitoring the treatment response

Clinical response, including resolution of fever, fatigue, and weight changes and other symptoms associated with disease severity (hypotension and hypoxia) should be assessed daily during the initial period of induction therapy (13).
Itraconazole blood levels, where available, should be monitored after two weeks of therapy. Blood levels of itraconazole between 1 and 2 μg/mL have been recognized as effective. Concentrations higher than 15 μg/mL has been related with development of toxic (42). Lack of capacity for drug monitoring should not be an obstacle to itraconazole treatment.
The co-occurrence of other opportunistic infections should be evaluated by clinical evaluation and using specific laboratory testing for other opportunistic infections (12, 47).

3.5.3. Diagnostic approach to persistent or recurrent symptoms

About 25% of the people with disseminated histoplasmosis have persistent or recurrent symptoms. Persistent symptoms may be caused by failure of induction or maintenance therapy (inadequate dose or duration) or concomitant infection, such as TB (12, 24, 47). Recurrent symptoms, reappearing after symptoms initially resolve, may occur from inadequate doses of maintenance therapy (drug level and drug interactions), failure of adherence, other concomitant illness, and immune reconstitution inflammatory syndrome (25).

It is important to review treatment history to determine whether drug regimen, dosing, or duration of therapy have contributed to treatment failure. Adherence to therapy, itraconazole drug levels, and potential drug interactions should be investigated.

Review patient adherence.
Perform relevant investigations for other concomitant illnesses such as TB, especially among people with CD4 cells counts <200 cells/mm³.
Consider paradoxical immune reconstitution inflammatory syndrome among people who have started antiretroviral therapy.
Monitor progress by using Histoplasma antigen testing following treatment initiation (25, 48).
Ensure appropriate drug levels, as necessary (42).

3.5.4. Managing relapse

In case of persistent or recurrent symptoms related to disseminated histoplasmosis, induction therapy should be restarted. It is important to ensure adherence to therapy and appropriate dose, drug levels, and duration.

Good practice statements

Measure Histoplasma urinary antigen and perform other complementary laboratory tests, such as culture (25, 48).
Restart induction or maintenance therapy (see subsection 3.2).
Prevent, manage, and monitor for drug toxicity.
Ensure appropriate drug levels, as necessary (42).

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