Lesson 3. Opportunistic Infections: Treatment

The introduction of effective antiretroviral therapy in the mid-1990s played a major role in the dramatic reduction in opportunistic infection-related morbidity and mortality.[1,2,3] Despite the widespread availability and use of potent antiretroviral therapy, individuals with HIV continue to suffer significant morbidity and mortality from opportunistic infections, defined as infections that are more frequent or severe due to immunosuppression. Most opportunistic infections now occur in people with undiagnosed HIV or in persons diagnosed with HIV who are not engaged in care. Because opportunistic infections continue to occur with potentially devastating consequences, clinicians should have a core understanding of the diagnosis, prevention, and treatment of opportunistic infections. This topic review provides an overview of treatment for the most common opportunistic infections based on the Adult and Adolescent OI Guidelines.[4]

Immune Reconstitution Syndrome

After initiation of effective antiretroviral therapy and during the early phases of immune reconstitution, a paradoxical worsening of certain clinical conditions can occur; this has been termed immune reconstitution inflammatory syndrome (IRIS).[5,6] Similarly, some patients with profound immunosuppression may have undiagnosed opportunistic infections that may be exposed as a result of an immune upregulation after starting antiretroviral therapy. This has been referred to as “unmasking” IRIS, a process whereby the immune system regains the capacity to recognize antigens and pathogens that previously it was too suppressed to confront. Although IRIS may develop in the context of various infections and/or AIDS-associated malignancies in patients with advanced HIV disease, the most commonly observed IRIS events involve disseminated Mycobacterium avium complex disease, cryptococcal meningitis, tuberculosis, progressive multifocal leukoencephalopathy, and cytomegalovirus retinitis.[7,8,9]

Pneumocystis pneumonia (PCP) is a leading cause of morbidity and mortality in people with HIV. The causative organism, Pneumocystis jirovecii, is classified as a fungus and was previously known as P. carinii.[10] Despite the organism name change, the acronym PCP is still widely used to denote Pneumocystis pneumonia. Individuals with HIV most often acquire P. jirovecii via the airborne route, and disease may occur either through a newly acquired infection or by reactivation of latent infection.[10] The risk of developing Pneumocystis pneumonia increases markedly when the CD4 count drops below 200 cells/mm³.[11,12,13] After the use of effective antiretroviral therapy became widespread, the incidence of Pneumocystis pneumonia dropped substantially.[1,2]

Clinical Manifestations

The most common clinical manifestations in patients with Pneumocystis pneumonia are a subacute nonproductive cough, progressive dyspnea (particularly dyspnea on exertion), and fever.[13,14] The pulmonary physical examination is usually normal, but in more advanced disease, rales may be present on auscultation. If untreated, individuals with Pneumocystis pneumonia may have progression of clinical disease with worsening dyspnea and hypoxemic respiratory failure.

Diagnosis

All persons with suspected Pneumocystis pneumonia should undergo evaluation to confirm the diagnosis. Nondefinitive tests can be used to support the diagnosis, but all persons with suspected Pneumocystis pneumonia should have a definitive diagnosis made.[14,15]

Nondefinitive Diagnostic Tests

The diagnosis of Pneumocystis pneumonia can be supported by several nonspecific tests.

• Chest Radiography and Chest Computed Tomography: In patients with suspected Pneumocystis pneumonia, chest imaging is almost always performed (Figure 1). In patients with Pneumocystis pneumonia, chest radiograph typically shows diffuse bilateral perihilar infiltrates; the appearance of these infiltrates is often described as ground glass and butterfly-shaped.[16,17] Approximately 15 to 20% of persons with Pneumocystis pneumonia have a normal chest radiograph, particularly those in the earlier phase of Pneumocystis pneumonia.[13,17,18] In some individuals with Pneumocystis pneumonia, pneumatoceles or cystic lesions develop; these may result in pneumothorax.[19,20] High-resolution chest computed tomography is more sensitive than chest radiography in detecting interstitial abnormalities.[16,21]
• Exercise Pulse Oximetry: Oxygen desaturation with exercise, as documented with continuous pulse oximetry, has been shown to be a feature of most persons with Pneumocystis pneumonia.[22]
• Laboratory Studies: Nonspecific laboratory findings that may support the diagnosis of Pneumocystis pneumonia include lactate dehydrogenase (LDH) greater than 500 mg/dL and a 1,3-beta-D-glucan level of 80 pg/mL or greater; the 1,3-beta-D-glucan is used for testing because it is a major component of the P. jirovecii cell wall.[23,24,25] Although the sensitivity of the beta-D-glucan test is high, the specificity is low because persons with HIV who have advanced immunosuppression are at risk for multiple other fungal pathogens that can also cause elevated beta-D-glucan levels.[25]

Definitive Diagnostic Tests

A definitive diagnosis of Pneumocystis pneumonia requires detection of organisms in respiratory secretions or tissue.[13,26] Several tests play a role in the definitive diagnosis of Pneumocystis pneumonia.

• Induced Sputum: An induced sputum sample using an ultrasonic saline nebulizer has a sensitivity for diagnosing Pneumocystis pneumonia that ranges from 50 to 90%, assuming the medical facility has experience with performing this test.[13,26] Expectorated sputum should not be submitted for diagnosis of Pneumocystis pneumonia due to low sensitivity.
• Bronchoscopy: A patient with a negative induced sputum should undergo bronchoscopy with bronchoalveolar lavage (BAL), which has a sensitivity of approximately 95%; some centers go directly to BAL as the initial test.[27]
• Transbronchial or Open-Lung Biopsy: A transbronchial biopsy or open-lung biopsy can further increase the yield but is rarely required because of the high yield with bronchoalveolar lavage.
• Detection of P. jirovecii Organisms in Sample: Many laboratories now consider the direct immunofluorescent stain as the procedure of choice for identifying P. jirovecii organisms; this test has higher sensitivity than other stains that can detect P. jirovecii (methenamine silver, Giemsa silver, and toluidine blue-O).[13,26,28,29] Although polymerase chain reaction (PCR) is a highly sensitive test for detecting P. jirovecii organisms, it does not accurately distinguish acute infection from colonization.[26,28,30,31]

Treatment of Pneumocystis Pneumonia

The prompt and appropriate treatment of Pneumocystis pneumonia is essential for having a good outcome for this potentially fatal opportunistic infection. If the diagnosis of Pneumocystis pneumonia is suspected, empiric treatment for Pneumocystis pneumonia should be started without delay while the diagnostic evaluation is underway.[15] Nontoxic-appearing individuals with suspected or diagnosed Pneumocystis pneumonia can receive treatment as an outpatient provided they have a documented PaO2 of 70 mm Hg or greater and a calculated alveolar-arterial gradient (A-a) gradient less than 35 mm Hg.[15] All the regimens used to treat Pneumocystis pneumonia require a duration of antimicrobial therapy for 21 days, assuming clinical improvement, although the recovery of functional status can often lag behind based on the degree of pulmonary scarring, immunosuppression, comorbidities, and/or development of IRIS.[15] Following the 21-course of therapy, patients should receive secondary prophylaxis.[15] The treatments for Pneumocystis pneumonia outlined below are based on recommendations in the Adult and Adolescent OI Guidelines.[15]

Treatment of Mild-to-Moderate Pneumocystis Pneumonia

Mild-to-moderate Pneumocystis pneumonia is defined as having a PaO2 of 70 mm Hg or greater and a calculated (A-a) gradient less than 35 (Table 1).[15] Individuals who are being considered for treatment as an outpatient should appear nontoxic and meet the criteria for mild-to-moderate Pneumocystis pneumonia. The preferred therapy for mild-to-moderate Pneumocystis pneumonia is oral trimethoprim-sulfamethoxazole, given in three divided daily doses.[15] If dapsone is used as an alternative therapy, it is advisable to check a glucose-6-phosphate dehydrogenase (G6PD) level prior to starting dapsone.

Treatment of Moderate-to-Severe PCP

Moderate-to-severe Pneumocystis pneumonia is defined by room air PaO2 less than 70 mm Hg or A-a gradient greater than or equal to 35 mm Hg (Table 2).[15] The preferred therapy is trimethoprim-sulfamethoxazole, but therapy for moderate-to-severe is usually started intravenously and then switched to oral therapy after clinical improvement.[15]

Use of Adjunctive Corticosteroids

For moderate-to-severe Pneumocystis pneumonia, defined as PaO2 of 70 mm Hg or greater and a calculated A-a gradient less than 35, adjunctive corticosteroids improve survival and should ideally be started as soon as antimicrobial treatment is started for Pneumocystis pneumonia (and no later than 72 hours after starting antimicrobial therapy).[13,15,32] The recommended corticosteroid regimen is prednisone 40 mg twice daily for days 1 to 5, prednisone 40 mg once daily for days 6 to 10, and prednisone 20 mg once daily for days 11 to 21. If parenteral therapy is needed, the dose of intravenous methylprednisolone is 80% of the oral prednisone dosage (i.e., 32 mg methylprednisolone = 40 mg prednisone).

Treatment in Pregnant Women

Trimethoprim-sulfamethoxazole is the preferred treatment for Pneumocystis pneumonia in pregnancy, as its benefits outweigh potential fetal risks, including a small first-trimester teratogenic risk.[15] For mild to moderate PCP, alternative options include atovaquone suspension, or dapsone plus trimethoprim if atovaquone is unavailable or not tolerated.[15] Due to the risk of hemolytic anemia in G6PD-deficient fetuses, primaquine or dapsone should only be used during pregnancy if no safer alternatives are available and the benefits outweigh the risks. Since trimethoprim is a folate antagonist, pregnant women who are taking trimethoprim-sulfamethoxazole or trimethoprim plus dapsone should also receive 4 mg/day of folic acid during the first trimester, then reduce to 0.4 mg after 12 weeks until 4–6 weeks postpartum or after breastfeeding ends.[15] An ultrasound at 18–20 weeks’ gestation is recommended to assess fetal anatomy, with possible follow-up imaging. During pregnancy, adjunctive corticosteroids should be used when indicated for HIV-related treatment, with close monitoring of maternal glucose, blood pressure, and fetal growth.[15]

Timing of Starting Antiretroviral Therapy

Individuals not on antiretroviral therapy who develop Pneumocystis pneumonia should start antiretroviral therapy within 2 weeks of the diagnosis of Pneumocystis pneumonia, if possible.[15] The recommendation to start antiretroviral therapy early is primarily based on data from a randomized, controlled trial that early initiation of antiretroviral therapy (median 12 days after start of acute opportunistic infection treatment) resulted in a lower incidence of progression to AIDS or death, as compared to deferred initiation (median 45 days after start of acute opportunistic infection treatment).[33]

Preventing Recurrence (Secondary Prophylaxis)

All persons with HIV who are diagnosed with Pneumocystis pneumonia should receive secondary prophylaxis beginning immediately after completion of the 21-day treatment course.[15] Individuals who do not receive secondary prophylaxis have a high risk for developing another episode of Pneumocystis pneumonia. The following table addresses the preferred and alternative regimens for secondary prophylaxis, criteria for discontinuing secondary prophylaxis, and indications for restarting secondary prophylaxis (Table 3).[15]

Toxoplasma gondii is a protozoan parasite that can infect humans and cause focal encephalitis, and more rarely, retinitis, pneumonitis, and disseminated disease. Most Toxoplasma disease in persons with HIV occurs from reactivation of latent organisms in the brain of patients who have a CD4 count less than 100 cells/mm³.[34,35] In the United States, the incidence of Toxoplasma encephalitis has decreased significantly with widespread use of antiretroviral therapy and prophylaxis with trimethoprim-sulfamethoxazole.[1,2] All individuals diagnosed with HIV should be tested for IgG antibody to T. gondii at their initial medical visit if their CD4 count is less than 200 cells/mm³.[36]

Clinical Manifestations

The central nervous system is by far the most common site for the development of toxoplasmosis. Extracerebral disease, such as pulmonary or ocular involvement, occurs in about 1 to 2% of individuals with AIDS and toxoplasmosis.[37] Individuals with AIDS and Toxoplasma encephalitis characteristically present with headache, confusion, fever, and/or focal neurologic deficits (Figure 2).[35,36] Approximately 30% of persons with HIV and Toxoplasma encephalitis develop seizures, and those with severe disease may present with more profound changes in mental status.[35,36] Abnormal findings on physical examination may include fever, hemiparesis, ataxia, altered consciousness, and cranial nerve palsies.

Diagnosis

Toxoplasma encephalitis is usually a presumptive diagnosis based on a combination of clinical manifestations, a positive serum anti-Toxoplasma antibody, and characteristic neuroradiographic findings.

• Anti-Toxoplasma Antibody: Among persons with acute Toxoplasma encephalitis, approximately 95% have detectable anti-Toxoplasma IgG antibodies using an enzyme-linked immunosorbent assay (ELISA), and approximately 85% have detectable antibodies using an indirect immunofluorescence assay (IFA) with a cutoff of greater than or equal to 1:16.[35]
• Brain Imaging: Contrast brain computed tomography (CT) scan shows enhancing lesions in approximately 90% of adults with HIV who have acute Toxoplasma encephalitis.[35] Individuals with AIDS and Toxoplasma encephalitis generally have multiple ring-enhancing lesions that often involve the basal ganglia (Figure 3).[35] Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT) for identifying Toxoplasma brain lesions and often shows multiple lesions when a CT scan has demonstrated only a solitary lesion. Since MRI is the more sensitive test, it is ideal to perform an MRI at the time the initial diagnosis is made and use this test to follow response to therapy.
• Analysis of Cerebrospinal Fluid: Ideally, a lumbar puncture should also be performed for T. gondii PCR testing on the cerebrospinal fluid (CSF) sample to help support the diagnosis; PCR for T. gondii in this setting has high specificity but low sensitivity, particularly once anti-toxoplasma therapy has been initiated.[38,39] In addition, CSF studies can help to investigate other conditions in the differential diagnosis.[40,41]
• Brain Biopsy: In some circumstances, such as an acute life-threatening presentation or failure to respond to therapy for toxoplasmosis, a definitive diagnosis is needed; this requires detection of T. gondii organism in a clinical sample usually obtained via a stereotactic CT-guided brain biopsy (with hematoxylin and eosin staining, or ideally immunoperoxidase staining).

Treatment of Toxoplasma Encephalitis

Initial Therapy for Toxoplasma Encephalitis

Individuals with suspected Toxoplasma encephalitis should immediately receive intensive high-dose anti-Toxoplasma therapy. The Adult and Adolescent OI Guidelines provide recommendations for preferred and alternative regimens for the initial treatment (Table 4).[36] The preferred first-line therapies for Toxoplasma encephalitis are pyrimethamine plus sulfadiazine plus leucovorin (using weight-based dosing) or trimethoprim-sulfamethoxazole.[34,42,43] Leucovorin is used in this regimen to prevent hematologic toxicity secondary to pyrimethamine. More recently, trimethoprim-sulfamethoxazole has increasingly been used as the preferred agent for treatment due to the extremely high cost of pyrimethamine.[44] The initial treatment is for at least 6 weeks. Longer duration for acute treatment may be required with severe disease, or if the response to treatment is incomplete at 6 weeks. Following the initial treatment course, persons with HIV and toxoplasmosis should transition to chronic maintenance therapy.

Treatment During Pregnancy

For pregnant women with suspected or confirmed Toxoplasma encephalitis during pregnancy, the treatment should be the same as that recommended for other adults with HIV.[36] For pregnant women with primary infection or symptomatic reactivation, treatment depends on the gestational age at the time of the acquisition or reactivation, and the treatment must consider prevention of congenital transmission. Given the complexity of managing toxoplasmosis in pregnancy, expert consultation with a specialist is recommended.[36]

Timing of Starting Antiretroviral Therapy

For persons with HIV who develop Toxoplasma encephalitis while not taking antiretroviral therapy, the optimal timing for initiating antiretroviral therapy remains unknown. Based on available data, most experts recommend starting antiretroviral therapy within 2 to 3 weeks of the diagnosis of Toxoplasma encephalitis.[36] This recommendation is primarily based on extrapolation of findings that showed early initiation of antiretroviral therapy reduces HIV progression and death in individuals with acute opportunistic infections.[33]

Response to Initial Therapy

More than 70% of individuals with HIV and Toxoplasma encephalitis have clinical and radiographic improvement within 14 days of receiving appropriate therapy for Toxoplasma encephalitis.[34,35,45] In one retrospective study, among patients with Toxoplasma encephalitis who eventually responded to anti-Toxoplasma therapy, 86% had improvement by day 7, and 91% had improvement (with respect to at least half of baseline abnormalities) by day 14 (Figure 4).[45] Thus, if by day 14, the person has not responded to therapy, the clinician should strongly consider a diagnosis other than Toxoplasma encephalitis and obtain further studies, typically including a brain biopsy, in an attempt to make a definitive or alternative diagnosis.[45]

Preventing Recurrence (Chronic Maintenance Therapy)

In the absence of chronic maintenance therapy for Toxoplasma encephalitis in persons not taking antiretroviral therapy, the rate of relapse after an initial episode of Toxoplasma encephalitis is high, with an incidence of 50 to 80% among persons surviving more than 6 to 12 months.[46] Thus, patients with Toxoplasma encephalitis who have successfully completed at least 6 weeks of acute therapy should transition to chronic maintenance therapy.[36] The preferred chronic maintenance regimens are the same as those used for initial therapy for Toxoplasma encephalitis but are administered at a lower dose.[36] Both of the preferred regimens are adequate for Pneumocystis pneumonia prophylaxis. The following table addresses chronic maintenance therapy (Table 5).[36]

In the era prior to effective antiretroviral therapy, Mycobacterium avium complex (MAC) infection was a common complication of advanced HIV disease.[47] Mycobacterium avium complex represents a group of nontuberculous mycobacteria that are ubiquitous in the environment; the mode of transmission for these organisms is thought to occur via the lungs or gastrointestinal tract, but preventing environmental exposure is not realistic.[48] Most persons who develop disseminated MAC have a CD4 count of less than 50 cells/mm³.[49] The incidence of disseminated MAC infection has declined dramatically since the early 1990s.[1,2,50] When cases of disseminated MAC occur, they usually involve individuals with HIV who have advanced immunosuppression and are unaware of their HIV diagnosis, or persons with HIV who are aware of their HIV diagnosis but not engaged in medical care.

Clinical Manifestations

The MAC-related clinical manifestations result from the huge burden of organisms, which interfere with tissue function and alter cytokine production.[51] Persons with disseminated MAC typically present with nonspecific symptoms, including fatigue, fever, weight loss, diarrhea, and abdominal pain (Figure 5).[52] Physical examination findings may reveal hepatomegaly, splenomegaly, or lymphadenopathy. Common abnormal laboratory studies include anemia, increased alkaline phosphatase (often with normal bilirubin and hepatic aminotransferase levels), and an increased serum lactate dehydrogenase level.[51,52,53] Abdominal CT scan abnormalities may include multiple large retroperitoneal and mesenteric lymph nodes, hepatomegaly, splenomegaly, and a thickened small bowel wall.[54]

Diagnosis

The definitive diagnosis of disseminated MAC is usually made by isolating the organism from a normally sterile body site.[48] Use of mycobacterial blood cultures to isolate MAC has become the preferred method of diagnosis: among persons with untreated disseminated MAC, obtaining two sets of blood cultures has a sensitivity of greater than 90%.[55,56] Growth from MAC blood cultures is slow, but usually occurs by day 14, at which point the exact Mycobacterium species can be identified using DNA probes. The diagnosis of disseminated MAC is sometimes made from a lymph node biopsy or a bone marrow biopsy.

Treatment of Disseminated MAC

Initial Therapy for Disseminated MAC

The Adult and Adolescent OI Guidelines recommend initial treatment for disseminated MAC with at least two active drugs, typically with a macrolide (clarithromycin or azithromycin) plus ethambutol.[48,57,58,59] Persons taking ethambutol require regular ophthalmologic examinations due to the risk of optic neuritis. Some experts would add a third or fourth medication in selected circumstances, such as with more severe MAC disease or when effective antiretroviral therapy is absent.[48] In most situations, the treatment regimen for disseminated MAC should be continued for a minimum of 12 months.[48] The following table outlines preferred therapy, considerations for adding rifabutin as a third medication, and considerations for adding a fourth drug (Table 6).[48]

Timing of Initiating Antiretroviral Therapy

Individuals newly diagnosed with disseminated MAC who are not on antiretroviral therapy should promptly start treatment for disseminated MAC and preferably start antiretroviral therapy at the same time that treatment for MAC is initiated.[48] Starting antiretroviral therapy at the same time as starting MAC treatment is recommended for two reasons: (1) to improve the treatment response to antimycobacterial therapy and (2) to lower the risk of developing other serious opportunistic infections. The antiretroviral regimens should be adjusted to minimize the risk of adverse drug interactions with the antimycobacterial medications.

MAC and Immune Reconstitution Inflammatory Syndrome (IRIS)

Mycobacterium avium complex IRIS is a potential complication following initiation of antiretroviral therapy in patients with disseminated MAC.[60] Persons with MAC-related IRIS usually present with intraabdominal lymphadenopathy or pulmonary-thoracic disease; the risk of death from MAC IRIS appears to be low, and the long-term prognosis is favorable.[60] The management of moderate-to-severe MAC IRIS-related symptoms should start with a nonsteroidal, antiinflammatory drug. If, however, there is no clinical improvement or initial symptoms are severe, then more aggressive treatment of IRIS is warranted, using systemic corticosteroid therapy with oral prednisone 20 to 40 mg daily for 4 to 8 weeks.[48] Severe MAC IRIS may require use of repeated or longer courses of corticosteroids. Antiretroviral therapy should typically be continued if MAC IRIS develops.

Preventing Recurrence (Chronic Maintenance Therapy)

The regimens for chronic maintenance therapy (secondary prophylaxis) in patients with MAC are exactly the same as those used for initial therapy.[48]

Discontinuing Chronic Maintenance Therapy

Discontinuing secondary MAC prophylaxis (chronic maintenance therapy) requires meeting all the following criteria:[48]

• Successful completion of at least 12 months of MAC therapy, and
• No signs or symptoms of MAC disease, and
• Sustained (at least 6 months) increase in CD4 count to greater than 100 cells/mm³ in response to antiretroviral therapy.

Restarting Chronic Maintenance Therapy

Secondary MAC prophylaxis should be restarted if a fully suppressive antiretroviral therapy regimen is not possible and the CD4 count is consistently less than 100 cells/mm³.[48]

Cryptococcosis is an opportunistic fungal infection that causes significant morbidity and mortality in persons with HIV who have advanced immunosuppression. In the United States, the incidence of cryptococcal antigenemia is 2.9% in adults with a CD4 count less than 100 cells/mm³ and 4.3% in those with less than 50 cells/mm³.[61] Most cryptococcal infections in persons with HIV are caused by Cryptococcus neoformans.[62] As with other opportunistic infections, the widespread use of highly active antiretroviral therapy has led to a decrease in the incidence of cryptococcal meningitis. Most cases are identified in persons with recently diagnosed HIV who have advanced immunosuppression, or in persons with established HIV who are not taking antiretroviral therapy.[63]

Clinical Manifestations

Cryptococcal meningitis occurs as a result of disseminated infection and typically manifests with a more indolent presentation than acute bacterial meningitis.[62] Most patients with early cryptococcal meningitis develop nonspecific symptoms consisting of fever and headache, and approximately 65 to 75% do not have classic signs of meningeal irritation early in their course of meningitis.[62] As the disease progresses, more neurologic-specific manifestations typically develop, including altered mental status, neck stiffness, or cranial nerve abnormalities (Figure 6).[64] Approximately 10% of individuals with disseminated cryptococcal disease have cutaneous manifestations that may resemble molluscum contagiosum.[65] Individuals with HIV can develop pulmonary cryptococcal disease, with or without central nervous system involvement.

Diagnosis

The diagnosis of cryptococcal meningitis is usually made by obtaining a positive cryptococcal antigen test on a cerebrospinal fluid (CSF) sample. Among persons with HIV who have cryptococcal meningitis, the cerebrospinal fluid and serum cryptococcal antigen test are positive in more than 95% of cases, often with a very high titer.[66,67,68] When there is strong clinical suspicion for cryptococcal meningitis but the CSF cryptococcal antigen test is negative, a prozone effect should be considered, and the sample should be diluted and retested to rule out a false-negative result caused by very high antigen levels. A positive serum cryptococcal antigen is not sufficient to diagnose central nervous system disease. Most experts would recommend performing a brain CT prior to lumbar puncture to evaluate for a brain mass lesion that could result in brain herniation during the procedure. Tests done on CSF should include cryptococcal antigen, fungal culture, glucose, protein, cell count with differential, Gram's stain, bacterial culture, and other studies as indicated. More than 50% of individuals with cryptococcal meningitis have fewer than 20 leukocytes/mm³ on the CSF cell count. Opening pressure should be measured at the time of lumbar puncture in all persons with suspected cryptococcal meningitis, since a significant proportion will have an elevated CSF pressure.[69]

Treatment of Cryptococcal Meningitis

The recommended treatment of cryptococcal meningitis involves three phases: induction therapy, consolidation therapy, and chronic maintenance therapy.[62] Serial monitoring of cryptococcal antigen (blood or CSF) to determine response to therapy has shown minimal benefit and is not recommended.[70]

Induction Therapy for Cryptococcal Meningitis

The recommended initial induction therapy for cryptococcal meningitis consists of either intravenous liposomal amphotericin B plus oral flucytosine or intravenous amphotericin B deoxycholate plus oral flucytosine (Table 7).[62] Liposomal amphotericin B has similar efficacy as amphotericin B deoxycholate but is associated with a lower risk of renal toxicity.[62,71,72] Flucytosine, when added to either liposomal amphotericin B or amphotericin B deoxycholate, results in more rapid CSF sterilization.[73] If flucytosine is used, it is ideal to check a flucytosine level after administering 3 to 5 doses of flucytosine, approximately 2 hours after taking the dose. The target serum flucytosine level is 25 to 100 mg/L. The flucytosine dose must be adjusted in persons with renal impairment.[62]

Management of Increased Intracranial Pressure

At the time induction therapy is started, cryptococcal meningitis is often associated with increased intracranial pressure (opening pressure greater than 20 cm H₂0). Appropriate management of increased intracranial pressure can improve survival and neurologic outcomes. In a retrospective study performed in the United States, investigators showed that patient outcomes strongly correlated with the use of serial lumbar punctures to manage increased intracranial pressure during the first 2 weeks of therapy for cryptococcal meningitis (Figure 7).[69] A more recent study of patients with acute cryptococcal meningitis in Africa also showed a marked survival benefit if therapeutic lumbar punctures were performed in persons with high opening presssure.[74] The following summarizes recommendations from the Adult and Adolescent OI Guidelines for managing elevation in intracranial pressure in persons with cryptococcal meningitis.[62]

• Lowering Opening Pressure at Initial Lumbar Puncture: If the opening pressure is elevated, the recommended approach is to remove ample cerebrospinal fluid (20 to 30 mL) to reduce the opening pressure to normal (less than 20 cm H₂0), or at least by 50% if not able to achieve a normal pressure with the removal of 20 to 30 mL.[62]
• Serial Lumbar Punctures: For persons with ongoing symptoms, such as headache or confusion, serial lumbar punctures with cerebrospinal fluid drainage may be required on a daily basis to maintain opening pressure less than 20 cm H₂0; daily lumbar punctures should be continued until the opening pressure normalizes and symptoms resolve.[62]
• Use of Lumbar Drains or Ventriculostomy: If the person initially has focal neurologic deficits, or serial lumbar punctures with the removal of cerebrospinal fluid fails to control increased intracranial pressures, a lumbar drain or ventriculostomy may be required.[62,75]
• Medical Therapy for Reducing Intracranial Pressure: For persons with acute cryptococcal meningitis, attempts to treat increased intracranial pressure with medical therapy, such as mannitol, acetazolamide, or corticosteroids, is not effective and is not recommended.[62,76]

Evaluation After Course of Induction Therapy

If there is substantial clinical improvement after completing the 2-week induction course, lumbar puncture should be performed (at or near the end of the induction therapy) to obtain cerebrospinal fluid fungal cultures.[62] If the patient does not improve clinically, then induction therapy should be continued until the cerebrospinal fluid cultures are negative.[62]

Consolidation Therapy for Cryptococcal Meningitis

After at least 2 weeks of successful initial induction therapy, patients who are clinically stable can start induction therapy with oral fluconazole 800 mg once daily while cerebrospinal fluid fungal cultures are pending (Table 8).[62] The consolidation regimen should be adjusted based on CSF fungal culture results.[62] The duration of consolidation therapy is 8 weeks from the time of negative cerebrospinal fluid culture.[62] Monitoring serum and/or cerebrospinal cryptococcal antigen titers is not recommended.[62]

Cryptococcal Meningitis and IRIS

A paradoxical worsening of cryptococcal meningitis occurs in up to 30% of persons with HIV who start antiretroviral therapy at the same time (or soon after) they start treatment for cryptococcal meningitis.[77] If cryptococcal meningitis-associated IRIS develops, it is often life-threatening. Baseline factors associated with an increased risk of developing cryptococcal meningitis-associated IRIS include lack of prior antiretroviral therapy, high baseline HIV RNA, low white blood cell count in cerebrospinal fluid, and a high cerebrospinal fluid fungal burden.[7] The challenge of such cases is differentiating between cryptococcal meningitis treatment failure, a new central nervous system disorder, or IRIS. Persons with IRIS typically have negative cerebrospinal fluid fungal cultures, whereas those with treatment failure will have positive cultures. If a new central nervous system problem and treatment failure are ruled out, and IRIS is the most likely diagnosis, antiretroviral therapy and antifungal therapy should be continued in conjunction with careful lowering of intracranial pressure, if indicated. Mild cases can be managed with nonsteroidal antiinflammatory medications, and most experts would use oral corticosteroids in severe cases.

Timing of Initiating Antiretroviral Therapy

To reduce the risk of IRIS in patients with cryptococcal meningitis, the Adult and Adolescent OI Guidelines recommend delaying initiation of antiretroviral therapy for 4 to 6 weeks after starting treatment for cryptococcal meningitis, ideally after negative CSF cryptococcal cultures have been obtained.[62] A 2014 study from Uganda and South Africa demonstrated that deferral of antiretroviral therapy for 5 weeks was associated with a significant improvement in survival, as compared with initiating antiretroviral therapy at 1 to 2 weeks, especially among patients with a low white blood cell count in the cerebrospinal fluid.[78] Several additional studies support the approach of deferring antiretroviral therapy for at least several weeks.[79,80]

Maintenance Therapy for Cryptococcal Meningitis

Maintenance therapy with fluconazole 200 mg once daily is required for at least 1 year after successful induction and consolidation treatment of cryptococcal meningitis.[62] Separate studies have shown that fluconazole is superior to intravenous amphotericin B and to oral itraconazole for chronic maintenance therapy, so the latter two are not recommended.[81,82] The following table addresses the preferred regimen for maintenance therapy, criteria for stopping maintenance therapy, and indications for restarting maintenance therapy (Table 9).[62]

Additional Treatment Considerations

The following summarizes the recommended treatment approach for: (1) cryptococcal infection that does not involve the lungs or central nervous system (CNS), (2) diffuse cryptococcal pulmonary disease, and (3) asymptomatic persons with isolated cryptococcal antigenemia.[62] Note that all asymptomatic persons with HIV who have cryptococcal antigenemia should have their CSF evaluated for occult cryptococcal meningitis.[62]

• Treating Non-CNS Extrapulmonary, Diffuse Pulmonary Disease, or Asymptomatic Patients with Isolated Cryptococcal Antigenemia (Serum LFA titer ≥1:640) Without Evidence of CNS Disease: The recommendation is to use the same treatment as recommended for cryptococcal meningitis, but without the need for follow-up lumbar puncture and CSF analysis.[62]

• Treating Non-CNS Focal Pulmonary Disease or Asymptomatic Patients with Isolated Cryptococcal Antigenemia (Serum LFA titer ≤1:320), Without Evidence of CNS Disease: The recommended treatment is fluconazole 400 to 800 mg PO daily for 10 weeks, followed by fluconazole 200 mg daily, with a total duration of therapy of 6 months.[62]

Cytomegalovirus (CMV) is a double-stranded DNA virus in the herpes family that can cause invasive disease, including retinitis, colitis, and central nervous system disease, in persons with HIV who have advanced immunosuppression (CD4 count less than 50 cells/mm³).[83,84] Among people with HIV, retinitis is the most common form of CMV end-organ disease. Typically, CMV disease in people with HIV occurs due to reactivation of latent CMV infection. Among men with HIV who have sex with men, CMV-positive antibody rates are greater than 90%. Following the widespread availability and use of effective antiretroviral therapy, the incidence of CMV retinitis has declined by more than 90%.[85,86,87]

Clinical Manifestations

Retinitis

Individuals with CMV retinitis most often develop one or more ocular manifestations commonly referred to as the four “F's”: floaters, flashes, field deficits, or failing vision.[88] These manifestations can represent loss of peripheral and/or central vision. Individuals with CMV retinitis do not have pain related to the lesions. Although only one eye is usually involved at the initial presentation, CMV disease can progress to affect the contralateral eye, particularly in individuals who are not on antiretroviral therapy.[89] On dilated funduscopic examination, the CMV-associated retinal lesions typically appear as yellow or white patches caused by retinal necrosis, with or without hemorrhage, usually following a vascular distribution; the findings of CMV retinitis should not be confused with findings caused by HIV retinopathy (Figure 8).[84]

Gastrointestinal

Odynophagia is usually the most prominent symptom associated with CMV esophagitis.[90] In addition, individuals with HIV and CMV colitis typically have weight loss, malaise, anorexia, abdominal pain, debilitating diarrhea (sometimes bloody), and potentially develop gastrointestinal perforation as a life-threatening complication.[91,92]

Neurologic

Less frequently, individuals with HIV and CMV infection can have neurologic manifestations, including myelitis, polyradiculomyelopathy, encephalitis, and ventriculitis.[93]

Pneumonia

Cytomegalovirus pneumonitis is rarely seen in individuals with HIV, in contrast to the high frequency seen among patients with other forms of profound immunosuppression, such as bone marrow transplantation. Cytomegalovirus pneumonitis, when present, usually manifests with fever, cough, and/or dyspnea.

Diagnosis

Most individuals with HIV and CMV retinitis, colitis, or other end-organ disease have CMV viremia that can be detected by PCR, antigen assays, or culture, but testing for CMV viremia is not recommended for the diagnosis of CMV-related end-organ disease.[84,86]

Retinitis

The diagnosis of CMV retinitis is a clinical diagnosis based on characteristic findings observed during a dilated funduscopic examination by an ophthalmologist.[84,86] With a handheld monocular direct ophthalmoscope, a clinician can visualize all of zone 1 (including the optic nerve head and the macula), less than half of zone 2, and none of zone 3 (Figure 9). Thus, all patients suspected of having CMV retinitis should see an ophthalmologist for a full retinal examination. Obtaining PCR of aqueous or vitreous specimens can be helpful but is not practical in most situations.

Gastrointestinal

The diagnosis of CMV esophagitis or colitis is suggested by observing mucosal ulcerations on endoscopy, but a definitive diagnosis requires characteristic biopsy findings showing intranuclear and intracytoplasmic inclusions.[92] Abdominal computed tomographic scans may show colonic thickening, but this finding is nonspecific.

Neurologic

The diagnosis of CMV central nervous system disease is usually made based on compatible clinical findings in conjunction with a positive cerebrospinal fluid PCR test for CMV.[94]

Pneumonia

Although CMV is commonly identified in bronchoalveolar lavage (BAL) fluid via nucleic acid testing in patients with HIV and low CD4 cell count, it has low diagnostic value.[86] In such cases, clinicians should consider alternative pathogens. The diagnosis requires radiologic findings (diffuse infiltrates) combined with histologic evidence of multiple CMV inclusion bodies in lung tissue.[86] In addition, a confirmed diagnosis of CMV pneumonitis requires exclusion of more common respiratory pathogens.[86]

Treatment

The Adult and Adolescent OI Guidelines recommendations for the treatment of CMV disease vary based on the organ system affected.[86]

Initial Treatment of CMV Retinitis

The treatment of CMV retinitis depends on whether the individual has sight-threatening retinitis or peripheral lesions; lesions are considered sight-threatening if they are within 1,500 microns of the fovea.[86] The preferred initial treatment for CMV retinitis consists of induction therapy with oral valganciclovir or intravenous ganciclovir.[86] If there is an immediate site-threatening lesion, many clinicians prefer induction with intravenous ganciclovir. In addition, with immediate site-threatening lesions, systemic therapy should be supplemented with repeated intravitreal injections of either ganciclovir or foscarnet, given every 7 days until lesion inactivity is achieved.[86] For small peripheral lesions that are not vision threatening, providing induction therapy with oral valganciclovir is usually sufficient.[86] Even if the ocular clinical manifestations are unilateral, systemic therapy helps to prevent disease in the contralateral eye. The following table summarizes preferred and alternative treatments for CMV retinitis, including treatment for sight-threatening and peripheral lesions (Table 10).[86]

Cytomegalovirus Retinitis and IRIS

The ocular form of CMV-associated IRIS, typically referred to as immune reconstitution uveitis, is characterized by inflammation in the anterior chamber or vitreous; vision loss from macular edema, cataracts, or epiretinal membranes can occur.[95,96,97,98] Immune reconstitution uveitis tends to occur in the first 3 months after starting antiretroviral therapy but can occur even years after treatment of acute CMV retinitis.[86] The risk of developing CMV-associated IRIS is highest when the CMV disease involves more than 30% of the retina.[99] The treatment of immune reconstitution uveitis typically consists of continued CMV treatment with the addition of corticosteroids (intravitreal or oral).[86,100]

Maintenance Therapy for CMV Retinitis

After completion of 14 to 21 days of induction therapy for CMV retinitis, persons should transition to chronic maintenance therapy.

• Preferred Therapy: The initial intravenous ganciclovir induction therapy should be followed by maintenance therapy with either oral valganciclovir 900 mg once daily or intravenous ganciclovir 5mg/kg once daily. If oral therapy was used for the initial therapy, it should be followed by maintenance therapy with oral valganciclovir 900 mg once daily.
• Alternative Therapy: If foscarnet or cidofovir is required for initial therapy, either can be continued for maintenance therapy, but expert consultation is advised since these agents are likely to cause significant toxicity if continued for prolonged periods of time.

Discontinuing Maintenance Therapy for CMV Retinitis

Chronic maintenance therapy for CMV retinitis can be discontinued when the following criteria are met:

• At least 3 to 6 months of CMV treatment has been completed, and
• No retinal lesions are active, and
• The CD4 count is above 100 cells/mm³ for 3 to 6 months in response to antiretroviral therapy, and
• An ophthalmologist has been consulted.

Note: After stopping maintenance therapy, ophthalmologic monitoring for early detection of CMV relapse should ideally be performed every 3 months to evaluate for early relapse of retinitis and to detect immune reconstitution uveitis. After sustained immune reconstitution has occurred, periodic ophthalmologic examinations should be performed as indicated and feasible. Monitoring CMV viral load in blood is not recommended as it has poor positive predictive value for retinitis relapse.

Restarting Chronic Maintenance Therapy

Chronic maintenance therapy should be restarted if the CD4 count decreases to less than 100 cells/mm³.

Treatment of CMV Esophagitis or Colitis

The following summarizes the Adult and Adolescent OI Guidelines recommendations for the preferred and alternative therapies for CMV esophagitis or colitis.[86] The preferred therapy is intravenous ganciclovir and the duration of therapy is 21 to 42 days or until clinical symptoms resolve (Table 11).[86]

Treatment of CMV Pneumonia and CMV Encephalitis

There are limited, mostly anecdotal, data for the treatment of CMV pneumonia and CMV neurological disease. The recommended treatment for CMV pneumonia consists of either intravenous ganciclovir or intravenous foscarnet.[86] For neurological disease, many clinical experts would initiate a combined antiviral intravenous regimen of ganciclovir and foscarnet, despite the toxicities associated with using these drugs simultaneously.[86] The duration of therapy for either of these disease entities is at least 21 days and should only occur after clinical improvement.

Adverse Effects Associated with CMV Therapy

Cytopenias (anemia, thrombocytopenia, neutropenia) are the most important toxicity associated with ganciclovir and valganciclovir use, but it can be managed by using granulocyte colony-stimulating factor (G-CSF).[86,101] During induction with ganciclovir or valganciclovir, a complete blood count and serum creatinine should be monitored at least twice weekly and then once weekly during maintenance. Foscarnet use can be associated with nephrotoxicity and electrolyte derangements. Toxicity monitoring during foscarnet therapy should include serum electrolytes and serum creatinine at least twice weekly during induction and once weekly while on maintenance treatment. Intravenous cidofovir use can lead to nephrotoxicity, ocular hypotony, and neutropenia. Aggressive intravenous fluid hydration and oral probenecid administration immediately prior to cidofovir dosing can help to attenuate renal issues.[86]

Timing of Initiating Antiretroviral Therapy

Among persons with HIV who develop CMV retinitis, the risk of developing CMV-associated IRIS is greater when antiretroviral therapy is immediately started versus deferring antiretroviral therapy until the CMV retinitis is initially controlled.[102] Individuals with newly diagnosed CMV who are not on antiretroviral therapy should promptly start treatment for CMV retinitis or CMV end-organ disease and then start antiretroviral therapy no more than 2 weeks later.[86] There is also a significant concern for the development of CMV-related IRIS in persons who have CMV neurologic disease.

Progressive multifocal leukoencephalopathy (PML) is a focal demyelinating disease of the central nervous system caused by reactivation of the John Cunningham (JC) virus in persons who have impaired immunity, most often in the setting of HIV-associated immunosuppression.[103] Infection with JC virus is common, and antibodies to JC virus are detected in more than 80% of humans worldwide.[104] Although the incidence of PML has decreased with the widespread use of effective antiretroviral therapy, mortality remains high for those persons with HIV who develop PML.[105,106]

Clinical Manifestations

Persons with HIV who develop PML typically present with subacute, progressive focal neuropsychiatric signs and symptoms, including cognitive disturbances, visual changes, limb paresis, hemisensory deficits, dysmetria, and ataxia.[104,107,108] The clinical presentation with PML may be difficult to distinguish from severe HIV-associated dementia or a slowly evolving stroke.[103,109] Approximately 15 to 20% of persons with PML will have at least one seizure.[110,111] Headache, fever, acute encephalopathy, and spinal cord manifestations are rare. In persons with AIDS, if immunosuppression is not reversed with antiretroviral therapy, PML will have a relentless progression and will lead to death within 6 months.[103]

Diagnosis

Brain biopsy is the gold standard for diagnosis, but it is not usually performed since a presumptive diagnosis can be made based on brain magnetic resonance imaging (MRI) findings. Brain MRI usually shows focal white matter lesions that correlate anatomically to the patient’s neurological deficits; these multiple high-signal intensity lesions are best seen on T2-weighted and FLAIR sequences (Figure 10).[103] In addition, 70 to 90% of persons with PML who are not taking antiretroviral therapy have a positive JC virus DNA PCR in the cerebrospinal fluid (this number drops to about 60% among persons who are taking antiretroviral therapy).[112] Detection of JC virus in the cerebrospinal fluid is not necessary to confirm the diagnosis of PML if the clinical picture and brain MRI findings are consistent with the diagnosis, but may support the diagnosis of PML in atypical cases. Plasma PCR detection of JC virus DNA can be a useful adjunct test, especially when CSF is not readily available, with the test having high specificity but relatively low sensitivity.[112,113]

Treatment

There is no specific antiviral therapy for JC virus.[103] The cornerstone for the treatment of PML in persons with HIV is antiretroviral therapy, with resultant immune restoration.[112] Antiretroviral therapy should promptly be initiated or optimized in all persons with HIV who are diagnosed with PML. Among those with HIV and PML who receive effective antiretroviral therapy, the 1-year survival rate is only 55 to 60%, and survivors often have some permanent neurologic deficits.[103,114] Multiple therapies have been attempted for treatment of PML in persons with HIV, but none (except for antiretroviral therapy-related immune reconstitution) has been shown to be effective (Table 12).[112] The following therapies should not be used to treat PML in persons with HIV: intravenous cytarabine, intrathecal cytarabine, cidofovir, mefloquine, mirtazapine, olanzapine, ziprasidone, cyproheptadine, risperidone, interferon-alfa, and check-point inhibitors, such as pembrolizumab.[112]

Timing of Initiating Antiretroviral Therapy

Individuals with HIV newly diagnosed with PML who are not on HIV antiretroviral therapy should immediately start on a fully suppressive antiretroviral therapy.[112] There is no rationale to delay therapy since there is no known effective antiviral therapy specific for PML that could be used to reduce the JC virus load prior to starting HIV antiretroviral therapy. Individuals diagnosed with PML who are taking antiretroviral therapy but do not have optimal suppression of HIV should receive a fully suppressive antiretroviral regimen.

Management of Immune Reconstitution Syndrome

Persons with HIV may develop PML immune reconstitution syndrome in the first weeks to months after starting antiretroviral therapy. The increased inflammation in the central nervous system may potentially cause mass effect and herniation. For individuals with a contrast-enhanced imaging that shows significant inflammation, use of corticosteroids can be considered.[112] There is no consensus on the dosage or duration of corticosteroids for PML IRIS; the Adult and Adolescent OI Guidelines suggest one approach modeled on treating flares of multiple sclerosis, which is to start with a 3- to 5-day course of intravenous methylprednisolone (1 gram per day) and then transition to oral prednisone 60 mg once daily and taper over 1 to 6 weeks.[112] Some experts recommend obtaining a brain MRI at 2 to 6 weeks after starting corticosteroid therapy to reevaluate edema and inflammation, which can inform the corticosteroid dosing schedule and establish a new radiographic baseline. Antiretroviral therapy should not be discontinued in this setting.[112]

Managing Treatment Failure

Clinical and radiographic improvement with PML typically takes at least several weeks. Treatment failure should be considered if there is continued clinical worsening despite at least 3 months of antiretroviral therapy, especially if HIV RNA levels are suppressed and CD4 counts improve.[112] If the person has not had a good HIV RNA response with antiretroviral therapy, it is very important to promptly address virologic failure and achieve virologic suppression as soon as possible.[112] If PML worsens despite fully suppressive antiretroviral therapy, unproven therapies may be considered with expert consultation, weighing potential toxicity against uncertain benefit.[112]

Esophageal candidiasis remains a significant cause of morbidity in persons with HIV, but the incidence has declined markedly since the widespread use of highly effective antiretroviral therapy.[85] When esophageal candidiasis occurs, it usually involves individuals with a CD4 cell count less than 100 cells/mm³.[115] Candida albicans is the most common species involved, but non-albicans species (C. dubliniensis, C. glabrata, C. tropicalis) can also cause disease.[116] In addition, Candida glabrata is associated with azole resistance among patients with advanced immunosuppression, particularly those who have received repeated or prolonged courses of oral fluconazole.[117,118,119]

Clinical Manifestations

Esophageal candidiasis usually causes retrosternal burning pain and odynophagia.[120,121] Persons with HIV and esophageal candidiasis often also have oropharyngeal candidiasis, which typically presents with painless, creamy white plaques or patches on the tongue, buccal mucosa, or pharynx that can be easily scraped off with a tongue blade.

Diagnosis

A presumptive diagnosis of esophageal candidiasis is based on typical clinical symptoms and response to empiric antifungal treatment.[120] A definitive diagnosis can be made with endoscopic evaluation with visualization and obtaining fungal culture (with speciation), but this approach is generally reserved for patients who do not respond within 7 days after starting antifungal therapy.[120,122] If endoscopy is performed, it should evaluate for other potential causes of esophagitis.

Treatment

Initial Therapy

For initial treatment of esophageal candidiasis, the preferred therapy should be oral or intravenous fluconazole.[120,123,124] The recommended initial course of treatment for esophageal candidiasis is 14 to 21 days.[120] Multiple alternative options are available (Table 13).[120]

Therapy During Pregnancy

During the first trimester of pregnancy, intravenous amphotericin B is recommended for the treatment of esophageal candidiasis.[120] Data derived from women with vulvovaginal candidiasis suggest that fluconazole should not be used in the first trimester due to the risk of spontaneous abortion and, with doses greater than 150 mg per day, the risk of cardiac septal closure defects.[125,126,127] Use of agents other than amphotericin B to treat esophageal candidiasis in pregnancy is not recommended, either due to inadequate data in pregnancy or known teratogenic effects.[120]

Timing of Starting Antiretroviral Therapy

Antiretroviral therapy should be initiated without delay in patients with Candida esophagitis.[120]

Chronic Suppressive Therapy

Chronic suppressive therapy for Candida is not recommended for persons with isolated episodes of esophageal candidiasis because therapy for acute episodes of disease is effective, mortality from candidiasis is low, drug interactions can occur, and suppressive therapy may increase drug-resistant species.[120] The use of chronic suppressive therapy for persons with esophageal candidiasis is usually limited to situations when individuals with a CD4 count less than 200 cells/mm³ have severe bouts of esophageal candidiasis or frequent recurrences.[120] If the decision is made to administer chronic suppressive therapy for patients with esophageal candidiasis, the recommended options are:

• Fluconazole 100 to 200 mg PO daily, or
• Posaconazole oral solution 400 mg PO twice daily, or
• Posaconazole tablet 300 mg PO daily

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum, which is endemic to the Central and South-Central United States (especially the Mississippi and Ohio River Valley areas), as well as to many regions of Latin America.[128,129] Histoplasma infections are acquired through inhalation, and asymptomatic extrapulmonary infection is common. Individuals with HIV who have a CD4 count below 150 cells/mm³ have an increased risk of developing symptomatic illness following acute infection, and most cases in nonendemic areas are attributed to reactivation of latent infection.[130,131] The incidence of symptomatic histoplasmosis declined after the introduction of potent antiretroviral therapy.[1]

Clinical Manifestations

Histoplasma infection can be asymptomatic or symptomatic, acute or chronic, and focal or disseminated. Disseminated disease often develops in persons with HIV, particularly in those who have a CD4 count of less than 150 cells/mm³.[129,130] Symptoms of disseminated histoplasmosis may include fever, fatigue, weight loss, hepatosplenomegaly, cough, chest pain, and dyspnea.[132] Approximately 50% of cases include respiratory complaints; chest radiography often shows diffuse or patchy opacities that can mimic Pneumocystis pneumonia (Figure 11). Less often, the chest radiograph shows focal infiltrates, nodules, or cavities. Persons with HIV and histoplasmosis may also have hepatosplenomegaly (25%), lymphadenopathy (25%), sepsis (10 to 20%), central nervous system involvement (10 to 20%), or gastrointestinal involvement (10 to 20%).[129] Some with disseminated disease may have oral lesions.[133] In rare situations, individuals with disseminated histoplasmosis may develop hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), which is a dysregulated immune response to infection that causes a multisystem illness characterized by fever, hepatosplenomegaly, and cytopenias.[134,135]

Diagnosis

The following summarizes the main laboratory tests used in diagnosing histoplasmosis.

• Histoplasma Antigen: Disseminated histoplasmosis in persons with HIV is usually diagnosed by detecting Histoplasma antigen in blood or urine (Figure 12).[129,136,137] Results with the Histoplasma antigen assay (on urine or serum samples) are typically available in 1 to 2 days. Evaluation of tests for the diagnosis of disseminated histoplasmosis in adults with HIV has shown that sensitivity was 100% with urinary antigen and 92% with serum antigen.[138]
• Serologic Testing: Testing for antibodies to H. capsulatum is not very useful for the diagnosis of disseminated histoplasmosis in persons with HIV.[136,137,139]
• Peripheral Blood Smear: In some cases, peripheral blood smears and biopsy samples of involved tissues may show budding yeasts (Figure 13).[140]
• Culture: Although more than 85% of adults with HIV and disseminated histoplasmosis will have a positive culture for H. capsulatum from a body source (blood, bone marrow, respiratory secretion, or skin lesions), obtaining a culture has limited clinical diagnostic utility since the organism usually takes several weeks to grow.[137]
• Bronchoalveolar Lavage Fluid: The detection of Histoplasma antigen in bronchoalveolar lavage fluid may be helpful for the diagnosis of acute pulmonary histoplasmosis infections.[136,141]
• Cerebrospinal Fluid: Typical cerebrospinal fluid findings among individuals with Histoplasma meningitis include lymphocytic pleocytosis, elevated protein, and low glucose. Confirming a diagnosis of Histoplasma meningitis can be challenging due to poor sensitivity of most diagnostic tests—fungal stains are usually negative, and cerebrospinal fungal cultures are positive in less than 40% of individuals. Cerebrospinal fluid testing for Histoplasma antibodies and antigen can aid with diagnosing Histoplasma meningitis, as detection of either Histoplasma antibodies or antigen in the cerebrospinal fluid confirms active central nervous system Histoplasma infection.[136,142] Often, a presumptive diagnosis of Histoplasma meningitis is made when an individual with CNS infection has evidence of disseminated histoplasmosis at another site and no other obvious etiology for their neurological symptoms.[136]

Treatment

The treatment of disseminated histoplasmosis in persons with HIV is based on the severity and type of disease, and level of immunosuppression.[136] Treatment consists of induction therapy, maintenance therapy, and long-term suppressive therapy. The duration of the induction period is at least 2 weeks for treatment of disseminated disease and 6 weeks for treatment of meningitis.[136] Liposomal amphotericin B is the preferred treatment for induction therapy for moderately severe to severe disease and meningitis, whereas itraconazole is preferred for treatment of less severe disseminated disease.[136] Acute pulmonary histoplasmosis in individuals with HIV and a CD4 count greater than 300 cells/mm³ should be managed the same as immunocompetent individuals.[136,143] The following table summarizes the Adult and Adolescent OI Guidelines recommendations for the treatment of severe disseminated histoplasmosis, less severe histoplasmosis or acute pulmonary histoplasmosis in individuals with a CD4 count less than 300 cells/mm³, and Histoplasma meningitis (Table 14).[136]

Monitoring Drug Levels

• Itraconazole: Serum itraconazole levels should be checked after 2 weeks of therapy, with a target itraconazole serum level of 1-2 µg/mL.[136] The risk of side effects and toxicities with itraconazole increases with serum levels greater than or equal to 5 µg/mL.[136,144] In general, oral itraconazole liquid formulation (administered on an empty stomach) is better absorbed, albeit less well tolerated, than the oral capsules.

• Voriconazole: For persons intolerant of itraconazole, alternative agents include posaconazole, voriconazole, or fluconazole.[145] If voriconazole is used, serum trough levels should be measured 5 days after treatment initiation. The therapeutic level is between 1 and 5 µg/mL; levels higher than 5 µg/mL can lead to drug toxicities, including neurotoxicity and hepatotoxicity.
• Posaconazole: Posaconazole serum levels should be measured 5 days after treatment initiation—the therapeutic level is greater than 1 µg/mL.

Timing of Initiating Antiretroviral Therapy

Individuals diagnosed with histoplasmosis should start on antiretroviral therapy as soon as possible after starting antifungal treatment for histoplasmosis. Available data suggest that IRIS infrequently occurs in persons with HIV who have disseminated histoplasmosis.[136,146]

Long-Term Suppressive Therapy

For individuals with severe disseminated disease or central nervous system infection, after at least 12 months of maintenance itraconazole therapy, the oral itraconazole dose should be reduced from 200 mg twice daily to 200 mg once daily for long-term suppressive therapy. The alternative for long-term suppressive therapy is oral posaconazole 300 mg daily, oral voriconazole 200 mg twice daily, or oral fluconazole 400 mg daily. The following table addresses the use of long-term suppressive therapy, criteria for discontinuing long-term suppressive therapy, and indications for restarting long-term suppressive therapy (Table 15).[136]

Coccidioidomycosis is caused by a soil-dwelling fungus, Coccidioides immitis, and may cause a wide spectrum of clinical diseases among individuals with HIV. The risk of developing symptomatic coccidioidomycosis in persons with HIV is significantly increased in persons with a CD4 count less than 250 cells/mm³ who live (or previously lived) in a region endemic for coccidioidomycosis. In persons with HIV, rates of coccidioidomycosis have been higher in Black individuals than in White persons.[147] The incidence of coccidioidomycosis has decreased in the era of potent antiretroviral therapy.[148]

Clinical Manifestations

In adults with a CD4 cell count greater than 250 cells/mm³, coccidioidomycosis typically presents as an acute or subacute localized pulmonary infection that mimics community-acquired pneumonia. Persons with lower CD4 counts may develop diffuse pneumonia with reticulonodular infiltrates (that may resemble Pneumocystis pneumonia) or disseminated extrapulmonary infection that may cause skin lesions, meningitis, or involve lymph nodes or the liver.[149,150,151] Cutaneous findings in acute coccidioidomycosis infection may include erythema multiforme or erythema nodosum, whereas cutaneous findings in disseminated disease may include papules, pustules, nodules, and ulcerated lesions.

Diagnosis

The initial evaluation of a person with suspected coccidioidomycosis should be guided by the clinical manifestations. The diagnosis is made based on the clinical presentation combined with laboratory testing that may include serologic tests, antigen testing, histologic staining, and fungal cultures.[150,152,153] A definitive diagnosis can be established with a positive culture of the organism from a clinical sample or by detecting spherules on histopathological examination of tissue.[150]

• Serologic Testing: For individuals with HIV who have symptoms consistent with coccidioidomycosis, serologic testing is the most frequently used test to make a presumptive diagnosis. A negative serologic test, however, does not exclude the diagnosis, since the formation of antibodies takes several weeks after initial infection.[150] As such, repeat serological testing should be performed every 1 to 2 weeks in individuals without a diagnosis who exhibit a clinical syndrome compatible with coccidioides disease.[150] For persons with HIV who have suspected coccidioidomycosis, the enzyme immunoassay (EIA) for IgG and IgM is the recommended initial diagnostic test, but the sensitivity of this test is significantly reduced in those with a low CD4 count.[150,154] Accordingly, serologic testing should not be considered reliable for ruling out coccidioidomycosis in persons with HIV who have advanced immunosuppression.[149,155] In addition, problems have been reported with false-positive IgM EIA Coccidioides serologic tests.[156] If the EIA test is positive (for either IgG or IgM), the result should be confirmed using immunodiffusion or complement fixation tests.[150]
• Antigen Testing: A Coccidioides antigen test is commercially available and can be performed on urine, serum, or other body fluids of individuals with active disease. This antigen test is most useful for the diagnosis of extra-thoracic disseminated coccidioidomycosis, especially coccidioidal meningitis.[150,155,157,158]
• Real-Time Polymerase Chain Reaction: To help establish a diagnosis of coccidioides, real-time PCR (RT-PCR) can be performed on formalin-fixed tissue or unfixed clinical specimens. Although there is a commercially available Coccidioides RT-PCR assay, it has not been approved by the FDA for use in people with HIV due to a lack of data in this population.[150,159]
• Fungal Culture: The diagnosis of coccidioidomycosis can be confirmed by isolating C. immitis from a clinical specimen (bronchoalveolar lavage fluid, cerebrospinal fluid, or tissue sample).[150] When performing fungal cultures in an attempt to isolate C. immitis, the microbiology laboratory must have established biocontainment procedures to prevent infection in laboratory staff.
• Staining: The diagnosis of coccidioidomycosis can be made by identifying characteristic Coccidioides spherules (8 to 10 microns in diameter) that contain multiple endospores (2 to 5 microns in diameter). Depending on the clinical sample, the staining may be performed on a wet mount (using saline or potassium hydroxide) of a sample or on a histopathology specimen (usually with hematoxylin and eosin staining).

Treatment

Initial Treatment

The Adult and Adolescent OI Guidelines recommended initial treatment of coccidioidomycosis is based on whether the disease is considered mild (e.g., focal pneumonia) or severe (e.g., disseminated or diffuse pulmonary disease) (Table 16).[150] For mild disease, the recommended treatment is fluconazole (400 mg once daily) or itraconazole (200 mg three times daily for 3 days, then twice daily); if bone or joint disease is present, itraconazole is preferred. For severe pulmonary disease or extrapulmonary disease, which both carry high mortality rates, the recommended therapy is amphotericin B deoxycholate (or lipid formulation of amphotericin B).[149,150] In persons with severe non-meningeal disease, initial therapy with an amphotericin B preparation should continue until clinical improvement has occurred, and then treatment can be switched to oral fluconazole or oral itraconazole. To treat coccidioidal meningitis, high-dose oral fluconazole (800-1,200 mg once daily) is recommended, in consultation with a specialist.[150]

Discontinuation of Therapy

Discontinuation of therapy for coccidioidomycosis depends on the type and severity of the coccidioidomycosis infection, the CD4 cell count, whether virologic suppression on antiretroviral therapy has been achieved, and if continued monitoring for recurrence can be performed using serial chest radiograph and coccidioidal serology (Table 17).[150]

Cryptosporidiosis is an intestinal infection caused by the protozoan parasite Cryptosporidium (Figure 14).[160,161] The life cycle of this organism in humans is complex, and all stages of development can take place within a single host.[160] Cryptosporidiosis can be transmitted through contaminated water sources (including swimming pools, lakes, and public water supplies), can persist despite chlorination, and can also be transmitted from person to person, especially among men who have sex with men.[162] In the current HIV era, the incidence of cryptosporidiosis in persons with HIV is very low (less than 1 case per 1,000 person-years).[1,162]

Clinical Manifestations

The incubation period for cryptosporidiosis is typically 7 to 10 days.[160] Infection of the gastrointestinal tract by Cryptosporidium impairs absorption and enhances secretion, typically manifesting as watery diarrhea and often accompanied by nausea, vomiting, and intestinal cramping. The severity and duration of disease depend on the host immune response, ranging from an asymptomatic or mild self-limited illness, to chronic low-level diarrhea, to a profuse cholera-like illness. For persons with HIV, the CD4 cell count is a strong predictor of illness severity (Figure 15).[163] In a retrospective analysis, adults with HIV and self-limited cryptosporidiosis had a mean CD4 count of 312 cells/mm³ versus a mean CD4 count of 57 cells/mm³ in those with persistent infection. In some cases, biliary complications (primarily cholangiopathy) can develop from Cryptosporidium infection.[164]

Diagnosis

Diagnostic testing for Cryptosporidium should be performed in persons with HIV and acute diarrhea, chronic diarrhea, or biliary tract disease, especially if their CD4 count is less than 200 cells/mm³.[160,164] The diagnosis can be made by identifying oocysts in stool or tissue; the recommended test to identify Cryptosporidium depends on the available tests at the laboratory used by the clinician (Figure 16).[165]

• Ova and Parasite Examination of Stool: Routine ova and parasite testing does not detect Cryptosporidium and thus should not be relied on to diagnose Cryptosporidium.
• Modified Acid-Fast Stain: The modified acid-fast stain, which stains the organism red, is the most common method used to detect Cryptosporidium on microscopic examination of a stool sample.
• Immunofluorescence Antigen Testing: Many centers now offer detection of Cryptosporidium using direct immunofluorescence antigen testing, most often with an enzyme-linked immunoassay (ELISA).
• Enteric Pathogen PCR Panel: Some laboratories now have a multiplex enteric pathogen panel for evaluating patients with diarrhea.[166] This test is a molecular assay that utilizes PCR technology. Most of these panels will detect common bacterial, viral, and parasitic pathogens. Many, but not all, include detection of Cryptosporidium. These multiplex molecular tests are often better than direct microscopy at detecting Cryptosporidium.[167,168,169]

Treatment

Treatment of cryptosporidiosis includes a combination of antiretroviral therapy-related immune reconstitution, supportive symptomatic therapy, and the use antimicrobial agents that have activity against Cryptosporidium (Table 18).[162]

• Antiretroviral Therapy and Immune Reconstitution: The most important aspect of treatment for cryptosporidiosis is immune restoration with antiretroviral therapy.
• Supportive Therapy: Since immune reconstitution may take months, supportive care plays a vital role in managing symptoms and may include oral rehydration, intravenous rehydration, replacement of electrolytes, and symptomatic treatment of diarrhea.
• Antimicrobial Therapy: Antimicrobial treatments have been studied, including nitazoxanide, paromomycin, or azithromycin, but none of these options has been consistently effective in the absence of antiretroviral therapy.[170,171,172,173,174] Some experts recommend giving a trial of nitazoxanide or paromomycin in addition to antiretroviral therapy, a recommendation based on a few studies that demonstrated improvement in diarrhea symptoms and reduced parasite burden in individuals with CD4 counts greater than 50 cells/mm³.[162,173,174,175]

• Timing of Antiretroviral Therapy: Since antiretroviral therapy is the mainstay of cryptosporidiosis treatment for patients with HIV, antiretroviral therapy should be started as soon as possible after the diagnosis of cryptosporidiosis.

Cystoisospora belli (formerly Isospora belli) is a parasite that primarily affects immunocompromised persons in tropical and subtropical areas of the world.[176,177] Infection is acquired via the ingestion of food or water that is contaminated with human feces that contain C. belli oocysts.[177,178] Most persons with HIV who develop cystoisosporiasis have a CD4 count less than 250 cells/mm³ and have current or past residence in a highly endemic geographic region. In the United States, most cases of cystoisosporiasis occur in the context of travel or immigration.[179,180,181,182]

Clinical Manifestations

Individuals with HIV and cystoisosporiasis typically develop watery diarrhea, nausea, vomiting, intestinal cramping, anorexia, and low-grade fever.[180] These symptoms often resemble those seen with other gastrointestinal opportunistic infections in persons with HIV. Several reports have documented cases of extraintestinal disease, including involvement of gallbladder, lymph nodes, and spleen, but such cases are rare.

Diagnosis

The diagnosis of cystoisosporiasis can be made by direct visualization of a stool sample, using a modified acid-fast stain on that shows oocysts that are relatively large (15 to 20 microns in diameter) (Figure 18).[183] The unsporulated Cystoisospora oocysts appear elliptical, with one or both ends slightly tapered.[177] Modified acid-fast staining of a stool sample can identify C. belli oocysts. In the early phase, oocysts have an internal granular mass and as they mature, one or two internal sporoblasts may be seen. The C. belli oocysts are approximately 30 by 15 microns in size and are distinctly larger and more oval than the C. parvum oocysts (4 to 6 microns in diameter) and Cyclospora spp. oocysts (6 to 10 microns in diameter).[177] Various techniques, other than modified acid-fast staining, have been used on wet mounts to identify C. belli, including bright-field microscopy, differential interference contrast, and ultraviolet fluorescence microscopy.[184] Polymerase chain reaction (PCR) methods, especially quantitative PCR (qPCR) for enteric pathogens, are increasingly used to diagnose C. belli due to their speed and ability to detect multiple parasites at once, offering a diagnostic advantage and greater efficiency than traditional microscopy.[184] These methods show high sensitivity (87–100%) and specificity (88–100%).[182,185]

Treatment

Treatment of Acute Infection

Treatment of acute cystoisosporiasis includes supportive care (rehydration and nutritional supplementation) and antimicrobial therapy targeted against C. belli (Table 19).[184]

• Preferred Therapy: Several treatment studies in persons with HIV showed good responses to trimethoprim-sulfamethoxazole.[180,181,186] Based on available data, the preferred acute therapy consists of trimethoprim-sulfamethoxazole (160/800 mg) 4 times daily for 10 days, with twice-daily dosing considered an acceptable option.[184] Some experts prefer to initiate treatment with trimethoprim-sulfamethoxazole (160/800 mg) twice daily and increase the dose to four times daily—if symptoms worsen or persist—and possibly extend the duration of acute therapy up to 4 weeks.
• Alternative Therapy: Alternatives include pyrimethamine or ciprofloxacin.[187] Note that pyrimethamine may not be easily available due to the extremely high cost of this medication.
• Timing of Initiating Antiretroviral Therapy: Antiretroviral therapy should be initiated when cystoisosporiasis treatment is started, unless there is concern that the antiretroviral therapy medications will not be absorbed well.[184]

Chronic Maintenance Therapy

Individuals with HIV and a CD4 count less than 200 cells/mm³ have a high rate of relapse with cystoisosporiasis and thus should receive chronic maintenance therapy with trimethoprim-sulfamethoxazole (160/800 mg) dosed either daily for 3 times weekly (Table 20).[184] Pyrimethamine or ciprofloxacin may be options for those unable to take trimethoprim-sulfamethoxazole.[184]

Discontinuing Chronic Maintenance Therapy

Chronic maintenance therapy for cystoisosporiasis in persons with HIV can be discontinued if the following criteria are met:

• The person has experienced a sustained increase in CD4 count to above 200 cells/mm³ for more than 6 months in response to antiretroviral therapy, and
• There is no evidence of active C. belli infection.

• Adults with HIV who have a CD4 count below 200 cells/mm³ are at significant risk of developing Pneumocystis pneumonia; the recommended therapy is trimethoprim-sulfamethoxazole, and the use of adjunctive corticosteroids improves survival for individuals with moderate-to-severe disease.
• Toxoplasma encephalitis is typically caused by reactivation of latent organisms in persons with a CD4 count below 100 cells/mm³. Toxoplasma encephalitis is usually a presumptive diagnosis based on characteristic clinical and neuroradiographic findings combined with a positive serum anti-Toxoplasma antibody.
• Mycobacterium avium complex is a non-tuberculous mycobacterial infection that can cause multiorgan disease in persons with a CD4 count of less than 50 cells/mm³. Therapy requires a prolonged course with at least two active drugs.
• Patients with cryptococcal meningitis typically have a CD4 count of less than 100 cells/mm³. Initial antifungal therapy with liposomal amphotericin B and flucytosine is recommended for the induction phase. All persons with elevated intracranial pressure should have this managed through serial therapeutic lumbar punctures with CSF removal.
• Cytomegalovirus (CMV) has the potential to cause retinitis in persons with HIV who have a CD4 count below 50 cells/mm³. Therapy usually consists of ocular injections of antiviral medications combined with systemic CMV therapy. Persons with HIV can also develop gastrointestinal and neurologic CMV infections.
• Progressive multifocal leukoencephalopathy (PML) is a focal demyelinating disease caused by the JC virus; immune restoration with antiretroviral therapy is the mainstay of therapy.
• Fungal opportunistic infections include Candida esophagitis, histoplasmosis and coccidioidomycosis. Candida esophagitis is typically treated with a course of oral fluconazole for 2 to 3 weeks whereas severe histoplasmosis and coccidioidomycosis requires initial treatment with liposomal amphotericin B and a longer duration of therapy.
• Multiple intestinal parasites (e.g., Cryptosporidium, Microsporidium, Cystoisospora) can cause intestinal disease in persons with HIV. Treatment generally includes supportive care and antiretroviral therapy to restore immune function.