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Opportunistic infections associated with human immunodeficiency virus (HIV) represent a major source of morbidity and mortality in advanced HIV infection despite modern antiretroviral therapy. Clinical presentation spans localized mucocutaneous disease to life-threatening pulmonary, neurologic, gastrointestinal, and disseminated syndromes. Diagnosis requires careful correlation of epidemiologic context, immunologic status, radiologic findings, and microbiologic or histopathologic confirmation. Delays in recognition frequently lead to irreversible complications such as neurologic sequelae, blindness from cytomegalovirus retinitis, chronic pulmonary impairment, or death. Early HIV infection diagnosis, sustained viral suppression, and appropriate prophylaxis remain central to prevention. However, structural barriers, stigma, low health literacy, and comorbid substance use disorders continue to drive late presentation and complex clinical courses. The course enables the participant to recognize key clinical patterns of HIV-associated opportunistic infections, interpret relevant diagnostic studies, and apply current guideline-based treatment and prophylaxis strategies. Emphasis falls on integrating antiretroviral initiation or optimization with infection-specific therapy while anticipating immune reconstitution inflammatory syndrome. The participant learns how collaboration among clinicians, nurses, pharmacists, social workers, case managers, and mental health professionals enhances outcomes through medication reconciliation, monitoring for toxicities and drug–drug interactions, adherence support, and targeted patient education. Interprofessional case coordination supports timely diagnosis, reduces avoidable hospitalizations, and promotes retention in HIV care. Objectives: Apply current evidence-based guidelines for diagnosing and managing opportunistic infections in advanced human immunodeficiency virus infection. Differentiate opportunistic infections from noninfectious mimickers and malignancies. Implement strategies that minimize drug-drug interactions and toxicities across antiretroviral and opportunistic infection regimens. Develop effective communication and collaboration workflows among clinicians, nurses, pharmacists, and other interprofessional team members to optimize outcomes for persons living with human immunodeficiency virus infection.

Implement strategies that minimize drug-drug interactions and toxicities across antiretroviral and opportunistic infection regimens. Develop effective communication and collaboration workflows among clinicians, nurses, pharmacists, and other interprofessional team members to optimize outcomes for persons living with human immunodeficiency virus infection. Access free multiple choice questions on this topic.

Human immunodeficiency virus (HIV) is a retrovirus that targets CD4+ T lymphocytes, progressively weakening the immune system. In individuals with chronic HIV infection who are not receiving antiretroviral therapy, whether due to late diagnosis, loss to follow-up, or, less commonly, treatment failure, CD4+ T-cell counts decline, which increases susceptibility to certain infections that rarely cause disease in immunocompetent hosts. These pathogens, widely referred to as opportunistic infections, exploit the profound immunodeficiency associated with low CD4+ counts, taking advantage of impaired cellular immunity to establish infection. Opportunistic infections typically emerge when the absolute CD4+ count falls below 200 cells/mm³, or when the relative count is less than 14%, reflecting significant immune compromise. Please see StatPearls' companion resource, "HIV and AIDS," for further information.

Common opportunistic infections in HIV infection include those caused by Toxoplasma gondii, Pneumocystis jirovecii, Candida species, Cryptococcus neoformans, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare complex, herpes simplex viruses (HSV) 1 and 2, varicella-zoster virus (VZV), and cytomegalovirus (CMV). These pathogens are notable for their high prevalence in this population and the need for prompt treatment. Other less common opportunistic infections may also affect individuals with HIV infection, sometimes within specific exposure or geographic epidemiologic contexts, including Leishmania species, Trypanosoma cruzi, Bartonella species, Listeria monocytogenes, Histoplasma capsulatum, Coccidioides species, and Cryptosporidium species. Specific opportunistic agents in HIV infection do not cause infection but rather neoplastic or preneoplastic conditions, such as Kaposi sarcoma (associated with human herpesvirus 8 [HHV-8]), lymphomas (Epstein-Barr virus [EBV]), human papillomavirus (HPV)–associated lesions, or demyelinating diseases like progressive multifocal leukoencephalopathy (PML) caused by the John Cunningham (JC) virus. Furthermore, persons living with HIV have a higher incidence of many infections that are not strictly opportunistic, including bacterial pathogens like Streptococcus pneumoniae and Neisseria meningitidis, and viral infections such as influenza. Moreover, HIV infection shares overlapping epidemiologic pathways with other infections, including sexually transmitted infections (hepatitis A, B, C; syphilis) and infections associated with intravenous drug use (eg, Staphylococcus aureus, hepatitis C).

Globally, approximately 40.8 million people are living with HIV infection as of 2024, with an adult prevalence of approximately 0.7% among individuals 15 to 49 years of age.[World Health Organization, Global Situation and Trends. 2025] Approximately 1.2 million people in the United States were living with diagnosed and undiagnosed HIV infection at the end of 2022.[CDC. Surveillance Report. 2024] Current antiretroviral therapy (ART) has considerably reduced the incidence of HIV-related opportunistic infections. Trends in the US and Europe from 1996 to 2020 have revealed that acquired immunodeficiency syndrome (AIDS) as a cause of mortality in patients with HIV infection has decreased from 49% to 16%. In contrast, cardiovascular and other noninfectious causes of death are more prevalent.[1] However, many patients are still diagnosed in later stages of HIV infection, while others have discontinued therapy or do not have viral suppression for other reasons. When CD4+ counts fall below 200 cells/mm³ (14%), they remain at high risk of opportunistic infections. In the US, the most common opportunistic infections are herpesviral infections, salmonelae infections, candidiasis, toxoplasmosis, Pneumocystis jirovecii pneumonia (PJP), and tuberculosis (TB).[Hiv.gov. Opportunistic Infections. 2025] While PJP, esophageal candidiasis, and herpesvirus infections occur at similar rates worldwide, rates of other opportunistic infections vary by geographic region or population group. In sub-Saharan Africa, Southeast Asia, and South America, TB is a leading cause of opportunistic infections in HIV infection.[WHO. Global Tuberculosis Report. 2024] In the Americas, histoplasmosis is highly endemic and a frequent cause of opportunistic infections.[2] The vast majority of Coccidioides species infections occur in endemic zones such as California, Arizona, Mexico, and Central America.[3] Additionally, PJP is more common in heterosexual individuals, Kaposi sarcoma is more common in men who have sex with men, and TB is frequently associated with injection drug use.

Opportunistic infections in persons with HIV infection often arise from microorganisms that inhabit the human body before progressing to disease. Fungi such as Pneumocystis jirovecii and Candida albicans can colonize the respiratory and gastrointestinal tracts of otherwise healthy individuals, respectively. In persons with HIV infection and advanced immunosuppression, however, these organisms can invade tissues and organs, leading to clinical syndromes such as PJP, oral candidiasis, or esophageal candidiasis. Other pathogens, including Mycobacterium tuberculosis, Cryptococcus neoformans, HSV-1, VZV, and CMV, are typically acquired earlier in life and can persist in a latent state for weeks, months, or even years, with control maintained by an intact immune system. When CD4+ T-lymphocyte counts decline, these agents exploit immune failure and disseminate to vital organs, leading to hallmark opportunistic infections in advanced HIV infection, such as pulmonary or extrapulmonary tuberculosis, cryptococcal meningitis, disseminated herpesviral infections, or CMV retinitis.

Opportunistic infections in individuals with HIV infection typically present with organ- or system-specific signs and symptoms but may simultaneously affect multiple organs. Infection with TB is the most prominent example of this systemic involvement. Furthermore, coinfection with multiple opportunistic infections in a single patient is not uncommon, further complicating diagnosis and highlighting the limitations of a symptom-based approach alone.[4][5] Pulmonary Disease Pulmonary symptoms, fever, unintentional weight loss, and fatigue developing over weeks to months, particularly when accompanied by night sweats or a productive cough, strongly suggest TB. In contrast, PJP typically evolves over several days to a few weeks and is characterized by a nonproductive cough, fatigue with exertion, and tachypnea. In appropriate epidemiological contexts, fungal infections such as histoplasmosis or coccidioidomycosis should also be considered, as they may present with fever, cough, pleuritic chest pain, and dyspnea. See StatPearls' companion resources, "Tuberculosis Overview," "Pneumocystis jirovecii Pneumonia," "Histoplasmosis," and "Coccidioidomycosis" for further information. Neurologic Manifestations Neurologic complications are frequent and often life-threatening. Headache, confusion, or seizures associated with focal neurological deficits may indicate toxoplasmosis encephalitis (TE), while subacute meningitis with headache and malaise suggests cryptococcal meningitis. These entities can overlap clinically with tuberculous meningitis, which may present either as subacute meningitis or a focal mass lesion. Progressive multifocal leukoencephalopathy (PML, caused by the JC virus) can affect any region of the central nervous system (CNS) and may present with hemiparesis, aphasia, hemisensory deficits, or ataxia, typically progressing over days to weeks. Cytomegalovirus infection can cause encephalitis, characterized by delirium, cognitive decline, or somnolence; however, CMV retinitis remains its most common clinical manifestation. Infection with VZV may produce CNS vasculopathy, stroke, or encephalitis, while spinal involvement with paraparesis, sensory loss, or sphincter dysfunction is most often associated with TB or herpesvirus infection. Gastrointestinal and Hepatobiliary Involvement

Neurologic complications are frequent and often life-threatening. Headache, confusion, or seizures associated with focal neurological deficits may indicate toxoplasmosis encephalitis (TE), while subacute meningitis with headache and malaise suggests cryptococcal meningitis. These entities can overlap clinically with tuberculous meningitis, which may present either as subacute meningitis or a focal mass lesion. Progressive multifocal leukoencephalopathy (PML, caused by the JC virus) can affect any region of the central nervous system (CNS) and may present with hemiparesis, aphasia, hemisensory deficits, or ataxia, typically progressing over days to weeks. Cytomegalovirus infection can cause encephalitis, characterized by delirium, cognitive decline, or somnolence; however, CMV retinitis remains its most common clinical manifestation. Infection with VZV may produce CNS vasculopathy, stroke, or encephalitis, while spinal involvement with paraparesis, sensory loss, or sphincter dysfunction is most often associated with TB or herpesvirus infection. Gastrointestinal and Hepatobiliary Involvement Oropharyngeal and esophageal candidiasis are the most frequent gastrointestinal opportunistic infections in advanced HIV disease. Diarrhea is also common and can result from HIV enteropathy or a variety of bacterial, parasitic, or viral pathogens (eg, Salmonella, Shigella, and Campylobacter species; and parasites such as Giardia lamblia, Cryptosporidium, and Microsporidia species). Cytomegalovirus colitis or proctitis may cause abdominal pain, diarrhea, or bleeding. In contrast, hepatobiliary complications, including hepatomegaly or cholestasis, often arise in disseminated mycobacterial infection, fungal disease, Cryptosporidium or Microsporidia infection, or CMV-associated cholangiopathy. Mucocutaneous Involvement

Oropharyngeal and esophageal candidiasis are the most frequent gastrointestinal opportunistic infections in advanced HIV disease. Diarrhea is also common and can result from HIV enteropathy or a variety of bacterial, parasitic, or viral pathogens (eg, Salmonella, Shigella, and Campylobacter species; and parasites such as Giardia lamblia, Cryptosporidium, and Microsporidia species). Cytomegalovirus colitis or proctitis may cause abdominal pain, diarrhea, or bleeding. In contrast, hepatobiliary complications, including hepatomegaly or cholestasis, often arise in disseminated mycobacterial infection, fungal disease, Cryptosporidium or Microsporidia infection, or CMV-associated cholangiopathy. Mucocutaneous Involvement Mucocutaneous findings often provide critical diagnostic clues. HSV-1 and HSV-2 infections produce localized or disseminated, sparse, and distributed mucocutaneous lesions that are painful, vesicular, and ulcerative. In contrast, disseminated VZV infection can be multidermatomal or systemic, unlike in immunocompetent patients, which affects one dermatome. Primary varicella infection can cause substantial morbidity in patients with HIV infection, including visceral dissemination, especially to the lung, causing pneumonitis. Kaposi sarcoma (associated with HHV-8) presents with infiltrating, violaceous mucocutaneous lesions on the skin and mucous membranes (especially the palate and gingiva) and may involve visceral organs. In contrast, bacillary angiomatosis (Bartonella species) mimics many cutaneous lesions and is frequently accompanied by fever. This condition can also present as a hematogenously disseminated infection, with night sweats and weight loss. Molluscum contagiosum, cryptococcosis, histoplasmosis, and coccidioidomycosis can also produce widespread or atypical skin lesions in advanced HIV infection. See StatPearls' companion resource, "Kaposi Sarcoma," for further information. Hematologic and Systemic Disease Lymphadenopathy, hepatosplenomegaly, and cytopenias may indicate disseminated mycobacterial or fungal infection, visceral leishmaniasis, CMV, or parvovirus B19 infection. Epstein-Barr–associated lymphoma and HHV-8–associated multicentric Castleman disease are neoplastic complications of advanced immunosuppression that present similarly and further blur the boundary between infection and malignancy in HIV infection.

In PJP, chest radiography may reveal bilateral, diffuse, symmetrical interstitial or alveolar infiltrates. Ground-glass or hazy opacities are typical on thoracic CT, which provides higher resolution than radiography. Patients are usually hypoxemic with normal or low arterial partial pressure of carbon dioxide (CO2) due to hyperventilation. Please see StatPearls' companion resource, "Pneumocystis jirovecii Pneumonia," for further information. Blood analysis may reveal mild anemia, traditionally associated with untreated HIV infection or concomitant esophageal candidiasis (due to occult blood loss), and an elevated lactate dehydrogenase, which is a marker with low specificity but relatively high sensitivity for PJP.[6] Arterial blood gas analysis typically shows hypoxemia with respiratory alkalosis.[7] The most relevant diagnostic tests are detection of Pneumocystis antigen (by immunofluorescent staining) or DNA (by polymerase chain reaction), either in induced sputum or in bronchoalveolar lavage collected during bronchoscopy; the latter offers the greatest sensitivity.[8] In pulmonary TB, the chest x-ray may demonstrate a typical pattern, similar to patients without HIV infection, with upper lobe infiltrates and cavitary lesions. However, in patients with severe immunosuppression, the x-ray may be atypical, with involvement of the lower and middle lung zones, diffuse interstitial or miliary patterns (resulting from hematogenous spread), hilar and mediastinal lymphadenopathy, and pleural effusion, but less often cavitary disease or consolidation.[9] Pneumothorax and hydropneumothorax can develop in advanced disease, typically coexisting with parenchymal lesions, such as thick-walled cavities.[10][11] Thoracic CT may demonstrate intrathoracic lymphadenopathy with central low attenuation and rim enhancement (necrotic nodes), tree-in-bud nodularity (indicating endobronchial spread), and miliary nodules (< 2 mm, diffuse, as seen in miliary tuberculosis) not clearly visualized on x-ray. Please see StatPearls' companion resource, "Tuberculosis Overview," for further information.

In pulmonary TB, the chest x-ray may demonstrate a typical pattern, similar to patients without HIV infection, with upper lobe infiltrates and cavitary lesions. However, in patients with severe immunosuppression, the x-ray may be atypical, with involvement of the lower and middle lung zones, diffuse interstitial or miliary patterns (resulting from hematogenous spread), hilar and mediastinal lymphadenopathy, and pleural effusion, but less often cavitary disease or consolidation.[9] Pneumothorax and hydropneumothorax can develop in advanced disease, typically coexisting with parenchymal lesions, such as thick-walled cavities.[10][11] Thoracic CT may demonstrate intrathoracic lymphadenopathy with central low attenuation and rim enhancement (necrotic nodes), tree-in-bud nodularity (indicating endobronchial spread), and miliary nodules (< 2 mm, diffuse, as seen in miliary tuberculosis) not clearly visualized on x-ray. Please see StatPearls' companion resource, "Tuberculosis Overview," for further information. Extrapulmonary tuberculosis usually coexists with pulmonary disease, including peripheral lymphadenopathy with ultrasonographic findings of heterogeneous echotexture and necrosis or caseation; intraabdominal lymphadenopathy; intestinal wall thickening or narrowing; ascites; or peritoneal thickening with contrast enhancement. Extrapulmonary TB is more commonly seen in patients living with HIV and more advanced HIV infections.[12][13][14][15] In miliary tuberculosis, the liver may reveal innumerable millimetric hypodense nodules on abdominal ultrasonography and CT. Results from blood analysis may be nonspecific with normocytic anemia and an elevated erythrocyte sedimentation rate. In disseminated or miliary TB infection, liver cytolysis and cholestasis may reflect the presence of tuberculous granulomas.[16] The most useful and rapid tests are acid-fast bacilli detection in sputum smears and molecular testing (nucleic acid amplification testing for M tuberculosis). Sensitivity ranges from 50% to 90%, and it increases further when the sample is obtained via bronchoalveolar lavage.[8][17] Blood and urine cultures (in specific media) can identify M tuberculosis in disseminated disease. Biopsies from affected areas (eg, lymph node, pleura, peritoneum) can reveal characteristic histological findings, such as epithelioid granulomas and Langerhans giant cells. Results from blood testing may also enable microbial identification via acid-fast bacilli staining, culture, or nucleic acid amplification testing. Tuberculosis infection occasionally poses a greater diagnostic challenge because microbiological identification results are sometimes negative or delayed (eg, cultures may take several weeks to yield positive results). Central nervous system investigations are relevant, as TB CNS disease occurs up to 8 times more often in patients living with HIV infection compared to patients with intact immunity.[13]

Extrapulmonary tuberculosis usually coexists with pulmonary disease, including peripheral lymphadenopathy with ultrasonographic findings of heterogeneous echotexture and necrosis or caseation; intraabdominal lymphadenopathy; intestinal wall thickening or narrowing; ascites; or peritoneal thickening with contrast enhancement. Extrapulmonary TB is more commonly seen in patients living with HIV and more advanced HIV infections.[12][13][14][15] In miliary tuberculosis, the liver may reveal innumerable millimetric hypodense nodules on abdominal ultrasonography and CT. Results from blood analysis may be nonspecific with normocytic anemia and an elevated erythrocyte sedimentation rate. In disseminated or miliary TB infection, liver cytolysis and cholestasis may reflect the presence of tuberculous granulomas.[16] The most useful and rapid tests are acid-fast bacilli detection in sputum smears and molecular testing (nucleic acid amplification testing for M tuberculosis). Sensitivity ranges from 50% to 90%, and it increases further when the sample is obtained via bronchoalveolar lavage.[8][17] Blood and urine cultures (in specific media) can identify M tuberculosis in disseminated disease. Biopsies from affected areas (eg, lymph node, pleura, peritoneum) can reveal characteristic histological findings, such as epithelioid granulomas and Langerhans giant cells. Results from blood testing may also enable microbial identification via acid-fast bacilli staining, culture, or nucleic acid amplification testing. Tuberculosis infection occasionally poses a greater diagnostic challenge because microbiological identification results are sometimes negative or delayed (eg, cultures may take several weeks to yield positive results). Central nervous system investigations are relevant, as TB CNS disease occurs up to 8 times more often in patients living with HIV infection compared to patients with intact immunity.[13] Opportunistic infections of the CNS almost always require lumbar puncture and CNS imaging for prognostication. But because of the frequency of space-occupying lesions in patients with immunosuppression, a head CT is recommended before lumbar puncture to reduce the risk of brain herniation. Predictive clinical signs of space-occupying lesions and herniation risk include decreased level of consciousness, history of CNS disease, papilledema, focal neurological deficits, and seizures, reinforcing the need for CT prior to lumbar puncture.[18][19] In TE, imaging results are usually diagnostic, typically showing multiple contrast-enhancing lesions (often ring-enhancing) with a predilection for the basal ganglia. Atypical presentations include a unique lesion, diffuse encephalitis, ventriculitis, obstructive hydrocephalus, brain hemorrhage, and meningitis.[20] Cerebrospinal fluid polymerase chain reaction for Toxoplasma gondii is highly specific but low in sensitivity; therefore, a negative test result in the presence of typical imaging findings should not exclude TE or the need for empirical treatment.[21]

Opportunistic infections of the CNS almost always require lumbar puncture and CNS imaging for prognostication. But because of the frequency of space-occupying lesions in patients with immunosuppression, a head CT is recommended before lumbar puncture to reduce the risk of brain herniation. Predictive clinical signs of space-occupying lesions and herniation risk include decreased level of consciousness, history of CNS disease, papilledema, focal neurological deficits, and seizures, reinforcing the need for CT prior to lumbar puncture.[18][19] In TE, imaging results are usually diagnostic, typically showing multiple contrast-enhancing lesions (often ring-enhancing) with a predilection for the basal ganglia. Atypical presentations include a unique lesion, diffuse encephalitis, ventriculitis, obstructive hydrocephalus, brain hemorrhage, and meningitis.[20] Cerebrospinal fluid polymerase chain reaction for Toxoplasma gondii is highly specific but low in sensitivity; therefore, a negative test result in the presence of typical imaging findings should not exclude TE or the need for empirical treatment.[21] In cryptococcal meningitis or meningoencephalitis, cryptococcal antigen is readily detected in CSF and serum. Positive blood culture results occur in up to 75% of patients with HIV and cryptococcal meningitis.[22] CSF findings may show a normal or elevated white blood cell count, mononuclear predominance, normal-to-low glucose levels, and elevated protein levels. The opening pressure of the lumbar puncture should always be measured, as values greater than 25 cm H2O are associated with a poorer prognosis.[23][24][25] In CNS TB, contrast-enhanced CT or MRI typically demonstrates meningeal enhancement, enhancing parenchymal lesions (tuberculomas and abscesses), hydrocephalus, and infarction. Most patients also have pulmonary tuberculosis.[26] The CSF findings in TB meningitis show lymphocytic pleocytosis (50–500 cells/µL), markedly elevated protein levels, and profoundly low glucose levels, often described as lymphocytic biochemical dissociation, typically lower than in cryptococcal meningitis. Culture and nucleic acid amplification testing for M tuberculosis should be performed on the CSF sample.

In CNS TB, contrast-enhanced CT or MRI typically demonstrates meningeal enhancement, enhancing parenchymal lesions (tuberculomas and abscesses), hydrocephalus, and infarction. Most patients also have pulmonary tuberculosis.[26] The CSF findings in TB meningitis show lymphocytic pleocytosis (50–500 cells/µL), markedly elevated protein levels, and profoundly low glucose levels, often described as lymphocytic biochemical dissociation, typically lower than in cryptococcal meningitis. Culture and nucleic acid amplification testing for M tuberculosis should be performed on the CSF sample. The diagnosis of progressive multifocal leukoencephalopathy (PML) is based on clinical and neuroradiologic findings. MRI reveals white matter lesions that are hyperintense on T2-weighted images and hypointense on T1-weighted sequences, corresponding to the clinical deficits.[27] A positive polymerase chain reaction for JC virus in CSF, together with the typical clinical and radiological findings, establishes a definitive diagnosis.[EACS Guidelines. Progressive Multifocal Leukoencephalopathy. 2024] Histopathology may show perivascular mononuclear inflammatory infiltration.[28] Epstein-Barr virus–related Burkitt lymphoma, which occurs in advanced HIV disease, can be associated with biopsy findings of a starry sky appearance.[29] CMV retinitis is usually diagnosed clinically by an experienced ophthalmologist on the basis of characteristic retinal changes. CMV and other herpesvirus infections in the CNS require polymerase chain reaction testing on CSF for confirmation.[hiv.gov. Cytomegalovirus. 2025]

The diagnosis of progressive multifocal leukoencephalopathy (PML) is based on clinical and neuroradiologic findings. MRI reveals white matter lesions that are hyperintense on T2-weighted images and hypointense on T1-weighted sequences, corresponding to the clinical deficits.[27] A positive polymerase chain reaction for JC virus in CSF, together with the typical clinical and radiological findings, establishes a definitive diagnosis.[EACS Guidelines. Progressive Multifocal Leukoencephalopathy. 2024] Histopathology may show perivascular mononuclear inflammatory infiltration.[28] Epstein-Barr virus–related Burkitt lymphoma, which occurs in advanced HIV disease, can be associated with biopsy findings of a starry sky appearance.[29] CMV retinitis is usually diagnosed clinically by an experienced ophthalmologist on the basis of characteristic retinal changes. CMV and other herpesvirus infections in the CNS require polymerase chain reaction testing on CSF for confirmation.[hiv.gov. Cytomegalovirus. 2025] Endoscopy can identify esophageal candidiasis (white or yellowish adherent plaques or pseudomembranes on the mucosa) and CMV esophagitis or colitis (mucosal ulcers with histology showing intranuclear inclusion bodies).[30] Detection of CMV viremia by polymerase chain reaction occurs in both end-organ and non–end-organ states; therefore, a positive result does not always indicate target-organ disease.[31] However, in patients with severe immunosuppression (CD4+ < 50 cells/µL), CMV viremia, in the setting of clinical suspicion of retinitis, colitis, esophagitis, or encephalitis, supports the diagnosis of CMV infection with target-organ involvement.[32] Cytomegalovirus viremia can also serve as a marker of treatment response.[32] In addition to CMV, investigation of diarrhea should include stool culture and microscopic examination for ova, cysts, and parasites using specific stains. Antigen tests can also detect Giardia lamblia, Cryptosporidium species, and microsporidia.

Endoscopy can identify esophageal candidiasis (white or yellowish adherent plaques or pseudomembranes on the mucosa) and CMV esophagitis or colitis (mucosal ulcers with histology showing intranuclear inclusion bodies).[30] Detection of CMV viremia by polymerase chain reaction occurs in both end-organ and non–end-organ states; therefore, a positive result does not always indicate target-organ disease.[31] However, in patients with severe immunosuppression (CD4+ < 50 cells/µL), CMV viremia, in the setting of clinical suspicion of retinitis, colitis, esophagitis, or encephalitis, supports the diagnosis of CMV infection with target-organ involvement.[32] Cytomegalovirus viremia can also serve as a marker of treatment response.[32] In addition to CMV, investigation of diarrhea should include stool culture and microscopic examination for ova, cysts, and parasites using specific stains. Antigen tests can also detect Giardia lamblia, Cryptosporidium species, and microsporidia. Mucocutaneous herpesvirus infections are usually diagnosed clinically. Confirmatory polymerase chain reaction on swabs from exudative lesions (HSV-1, HSV-2, and VZV) may be performed and provides the highest specificity, but should not delay treatment in severe infection. Bartonellosis can be diagnosed by histopathology of tissue biopsies from cutaneous lesions in patients with Bartonella henselae infection. Stains will be Gram-negative and acid-fast negative. Numerous bacilli may be seen using modified silver stains (eg, Warthin-Starry stain).[33] In coccidioidomycosis, diagnosis can be made by isolating the organism in culture or by visualizing spherules on histopathology of tissue or body fluids.[34] Serology is helpful in patients with HIV infection and milder immunosuppression, although very low CD4+ counts (< 100 cells/µL) may yield false-negative results.[35] Antigen testing can also aid diagnosis, but significant cross-reactivity with Histoplasma species limits specificity; therefore, results must be interpreted in the appropriate clinical and geographic context.

In coccidioidomycosis, diagnosis can be made by isolating the organism in culture or by visualizing spherules on histopathology of tissue or body fluids.[34] Serology is helpful in patients with HIV infection and milder immunosuppression, although very low CD4+ counts (< 100 cells/µL) may yield false-negative results.[35] Antigen testing can also aid diagnosis, but significant cross-reactivity with Histoplasma species limits specificity; therefore, results must be interpreted in the appropriate clinical and geographic context. Disseminated histoplasmosis can be diagnosed by detecting histoplasma antigen in blood or urine, although sensitivity is lower in pulmonary disease.[36] Peripheral blood smears may show organisms within white blood cells. Culture is slow, requiring weeks for growth, but has positive results from bone marrow, blood, or respiratory secretions in > 85% of patients with AIDS.[37] CSF cultures are rarely positive, but antigen or antibody detection in CSF is diagnostic in approximately 70% of cases of meningitis.[38] In the evaluation of patients with HIV infection and suspected opportunistic infections involving lymph nodes or bone marrow, the diagnostic workup should include lymph node biopsy and bone marrow aspirate or biopsy with microbiological (direct and cultural), histopathological, and molecular studies, to exclude entities such as disseminated mycobacterial infection, leishmaniasis, or hematologic neoplasms.

Treatment of opportunistic infections is generally guided by microbial diagnosis; however, empiric therapy is occasionally necessary (eg, in a clinically deteriorating patient with suspected PJP infection or in a patient with suspected TE who has a contraindication to lumbar puncture). A high index of suspicion should be maintained in patients with HIV infection who present with typical clinical, radiologic, and laboratory findings, especially in newly diagnosed patients with low CD4+ counts; in patients who recently started ART (immune reconstitution inflammatory syndrome may unmask opportunistic infections); or in previously diagnosed patients who have disengaged from care. The CD4+ cell count is central, and while awaiting that result, indirect clues to advanced HIV disease include weight loss/cachexia, oropharyngeal candidiasis, suspected Kaposi sarcoma lesions, anemia, and lymphopenia. Bartonella species, the cause of bacillary angiomatosis, can be readily treated with doxycycline 100 mg orally or intravenously twice daily, or, when oral medication is not tolerated or when pregnant, with erythromycin 500 mg orally or intravenously every 6 hours. Alternatives to erythromycin include other macrolides, such as azithromycin 100 mg orally once daily or clarithromycin 500 mg orally twice daily. In cases involving the CNS or other severe manifestations, doxycycline 100 mg orally or intravenously twice daily may be combined with rifampin 300 mg orally or intravenously twice daily for at least 3 months. In rare cases of Bartonella endocarditis, induction with doxycycline and rifampin is often required for 6 weeks, followed by stepdown to oral doxycycline 100 mg twice daily for three or more months, unless there are severe manifestations of endocarditis or CNS infection. Suppressive doses of doxycycline or a macrolide may be required in cases of relapse after a primary course of therapy.[hiv.org. Bartonellosis. 2025]

Bartonella species, the cause of bacillary angiomatosis, can be readily treated with doxycycline 100 mg orally or intravenously twice daily, or, when oral medication is not tolerated or when pregnant, with erythromycin 500 mg orally or intravenously every 6 hours. Alternatives to erythromycin include other macrolides, such as azithromycin 100 mg orally once daily or clarithromycin 500 mg orally twice daily. In cases involving the CNS or other severe manifestations, doxycycline 100 mg orally or intravenously twice daily may be combined with rifampin 300 mg orally or intravenously twice daily for at least 3 months. In rare cases of Bartonella endocarditis, induction with doxycycline and rifampin is often required for 6 weeks, followed by stepdown to oral doxycycline 100 mg twice daily for three or more months, unless there are severe manifestations of endocarditis or CNS infection. Suppressive doses of doxycycline or a macrolide may be required in cases of relapse after a primary course of therapy.[hiv.org. Bartonellosis. 2025] The preferred treatment for PJP is co-trimoxazole (trimethoprim/sulfamethoxazole, administered at a trimethoprim dose of 15–20 mg/kg/d).[39] In mild to moderate disease, it can be given orally; in moderate to severe disease, intravenous administration is recommended. If the arterial partial pressure of oxygen is less than 70 mm Hg on room air, adjunctive corticosteroid therapy should be initiated with prednisolone 40 mg orally twice daily, as this reduces inflammation and hypoxemia, thereby reducing the risk of respiratory failure and overall mortality.[40] Alternative regimens include primaquine plus clindamycin, dapsone plus trimethoprim, or atovaquone.[hiv.org. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. 2025] Importantly, efforts to obtain microbiological confirmation should not delay initiation of therapy in patients with HIV infection and low CD4+ counts who present with typical radiologic findings of PJP and risk of clinical deterioration.

The preferred treatment for PJP is co-trimoxazole (trimethoprim/sulfamethoxazole, administered at a trimethoprim dose of 15–20 mg/kg/d).[39] In mild to moderate disease, it can be given orally; in moderate to severe disease, intravenous administration is recommended. If the arterial partial pressure of oxygen is less than 70 mm Hg on room air, adjunctive corticosteroid therapy should be initiated with prednisolone 40 mg orally twice daily, as this reduces inflammation and hypoxemia, thereby reducing the risk of respiratory failure and overall mortality.[40] Alternative regimens include primaquine plus clindamycin, dapsone plus trimethoprim, or atovaquone.[hiv.org. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. 2025] Importantly, efforts to obtain microbiological confirmation should not delay initiation of therapy in patients with HIV infection and low CD4+ counts who present with typical radiologic findings of PJP and risk of clinical deterioration. Clinicians usually make every effort to obtain microbiologic identification, or at least a typical histologic finding suggestive of TB, before initiating antituberculous therapy. This caution is essential because TB treatment carries significant toxicity, requires strict adherence over several months, and because other opportunistic infections and neoplasms may mimic TB clinical presentation. For this reason, empirical treatment is rarely started, being reserved for patients with severe disease (eg, respiratory failure, shock) and a clinical picture highly suggestive of TB infection. Once a smear demonstrates acid-fast bacilli, antituberculous treatment should be initiated promptly. Standard first-line oral therapy consists of isoniazid 5 mg/kg/d (usual dose 300 mg/day), rifampicin 10 mg/kg/d (usual dose 600 mg/d), pyrazinamide 20 to 25 mg/kg/d (1000-2000 mg/d), ethambutol 15 to 20 mg/kg/day (800-1600 mg/d), and pyridoxine 25 to 50 mg/d, all given once a day orally. Rapid molecular (genotypic) drug-susceptibility tests for rifampicin and isoniazid are now widely available and useful for anticipating phenotypic resistance and guiding therapy. Culture-based (phenotypic) drug susceptibility remains indispensable for confirming molecular resistance results, ruling out false-positive or false-negative results, and detecting resistance not identified by genotypic assays (eg, pyrazinamide, ethambutol, or uncommon mutations affecting rifampicin and isoniazid).[41][42] In TB meningitis, dexamethasone 0.3 to 0.4 mg/kg/d should be used because it is associated with lower mortality and morbidity.[hiv.org. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. 2025]

Clinicians usually make every effort to obtain microbiologic identification, or at least a typical histologic finding suggestive of TB, before initiating antituberculous therapy. This caution is essential because TB treatment carries significant toxicity, requires strict adherence over several months, and because other opportunistic infections and neoplasms may mimic TB clinical presentation. For this reason, empirical treatment is rarely started, being reserved for patients with severe disease (eg, respiratory failure, shock) and a clinical picture highly suggestive of TB infection. Once a smear demonstrates acid-fast bacilli, antituberculous treatment should be initiated promptly. Standard first-line oral therapy consists of isoniazid 5 mg/kg/d (usual dose 300 mg/day), rifampicin 10 mg/kg/d (usual dose 600 mg/d), pyrazinamide 20 to 25 mg/kg/d (1000-2000 mg/d), ethambutol 15 to 20 mg/kg/day (800-1600 mg/d), and pyridoxine 25 to 50 mg/d, all given once a day orally. Rapid molecular (genotypic) drug-susceptibility tests for rifampicin and isoniazid are now widely available and useful for anticipating phenotypic resistance and guiding therapy. Culture-based (phenotypic) drug susceptibility remains indispensable for confirming molecular resistance results, ruling out false-positive or false-negative results, and detecting resistance not identified by genotypic assays (eg, pyrazinamide, ethambutol, or uncommon mutations affecting rifampicin and isoniazid).[41][42] In TB meningitis, dexamethasone 0.3 to 0.4 mg/kg/d should be used because it is associated with lower mortality and morbidity.[hiv.org. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. 2025] The preferred treatment for TE is a pyrimethamine 200 mg oral loading dose, followed by 50 to 75 mg/d orally, plus sulfadiazine 1000 to 1500 mg orally every 6 hours, combined with folinic acid 10 to 25 mg/d orally to prevent hematologic toxicity. Induction therapy is at least 6 weeks, followed by chronic maintenance at lower doses until immune reconstitution is achieved (CD4+ > 200 cells/µL for > 6 months on ART).[hiv.org. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. 2025] In Europe, the European AIDS Clinical Society (EACS) guidance lists co-trimoxazole also as a preferred regimen, at 5 mg trimethoprim/kg component twice daily (intravenously or orally) plus the corresponding sulfamethoxazole dose. Results from a recent meta-analysis indicate that this regimen is as effective as, and potentially safer than, pyrimethamine-based regimens. Moreover, in settings with pyrimethamine supply constraints or cost limitations, co-trimoxazole should be preferred.[EACS Guidelines. Toxoplasma gondii encephalitis. 2025]. Occasionally, patients with TE with more severe disease or those who have a contraindication to a lumbar puncture due to the risk of brain herniation, TE-directed therapy should be started empirically.

The preferred treatment for TE is a pyrimethamine 200 mg oral loading dose, followed by 50 to 75 mg/d orally, plus sulfadiazine 1000 to 1500 mg orally every 6 hours, combined with folinic acid 10 to 25 mg/d orally to prevent hematologic toxicity. Induction therapy is at least 6 weeks, followed by chronic maintenance at lower doses until immune reconstitution is achieved (CD4+ > 200 cells/µL for > 6 months on ART).[hiv.org. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. 2025] In Europe, the European AIDS Clinical Society (EACS) guidance lists co-trimoxazole also as a preferred regimen, at 5 mg trimethoprim/kg component twice daily (intravenously or orally) plus the corresponding sulfamethoxazole dose. Results from a recent meta-analysis indicate that this regimen is as effective as, and potentially safer than, pyrimethamine-based regimens. Moreover, in settings with pyrimethamine supply constraints or cost limitations, co-trimoxazole should be preferred.[EACS Guidelines. Toxoplasma gondii encephalitis. 2025]. Occasionally, patients with TE with more severe disease or those who have a contraindication to a lumbar puncture due to the risk of brain herniation, TE-directed therapy should be started empirically. The preferred induction therapy for cryptococcal meningitis is liposomal amphotericin B 3 to 4 mg/kg intravenously once daily plus flucytosine 25 mg/kg orally every 6 hours, for at least 2 weeks (or until CSF sterilization), followed by a consolidation phase with fluconazole 400 to 800 mg orally daily for 8 weeks.[WHO. Guidelines for Diagnosing, Preventing, and Managing Cryptococcal Disease Among Adults, Adolescents, and Children Living with HIV. 2022] If flucytosine is unavailable, an alternative is amphotericin B plus high-dose fluconazole (eg, 800–1200 mg/d). There is no specific antiviral therapy proven effective for PML. The cornerstone is prompt initiation or optimization of ART to achieve immune reconstitution, and early control of HIV infection is the key determinant of outcomes.

The preferred induction therapy for cryptococcal meningitis is liposomal amphotericin B 3 to 4 mg/kg intravenously once daily plus flucytosine 25 mg/kg orally every 6 hours, for at least 2 weeks (or until CSF sterilization), followed by a consolidation phase with fluconazole 400 to 800 mg orally daily for 8 weeks.[WHO. Guidelines for Diagnosing, Preventing, and Managing Cryptococcal Disease Among Adults, Adolescents, and Children Living with HIV. 2022] If flucytosine is unavailable, an alternative is amphotericin B plus high-dose fluconazole (eg, 800–1200 mg/d). There is no specific antiviral therapy proven effective for PML. The cornerstone is prompt initiation or optimization of ART to achieve immune reconstitution, and early control of HIV infection is the key determinant of outcomes. Oropharyngeal candidiasis is treated with topical nystatin or fluconazole 100 mg orally once daily for 7 to 14 days, and esophageal candidiasis is treated with fluconazole 200 to 400 mg orally once daily for 14 to 21 days.[43] Cytomegalovirus retinitis is treated with valganciclovir 900 mg orally twice daily for 14 to 21 days (induction), or ganciclovir 5 mg/kg intravenously every 12 hours, followed by maintenance dosing of valganciclovir 900 mg/day orally, continued until immune recovery (CD4+ > 100 cells/µL for ≥ 3–6 months). For sight-threatening lesions (macula, optic nerve), intravitreal ganciclovir or foscarnet may be required as adjunctive therapy.[44] Cytomegalovirus colitis and esophagitis are treated with the same dose of valganciclovir or ganciclovir. Cryptosporidiosis, which causes diarrhea, is managed by initiating and optimizing antiretroviral therapy to restore immune function. Supportive treatment (fluids, nutrition, electrolyte correction) is essential. Nitazoxanide, 50 to 1000 mg orally twice daily for at least 2 weeks, may be used; however, efficacy is variable in immunocompromised hosts. Azithromycin and rifaximin, alone or in combination with nitazoxanide, have been used with some effectiveness, particularly in other patients with compromised immunity.[45] The preferred therapy for severe mucocutaneous HSV infection is acyclovir 5 mg/kg intravenously every 8 hours until clinical improvement, then transition to oral therapy (eg, acyclovir 400 mg orally three times daily, valacyclovir 1 g orally twice daily, or famciclovir 500 mg orally twice daily) to complete a total course of 7 to 14 days, or longer in extensive disease.[CDC. Sexually Transmitted Infections Treatment Guidelines 2021]

Oropharyngeal candidiasis is treated with topical nystatin or fluconazole 100 mg orally once daily for 7 to 14 days, and esophageal candidiasis is treated with fluconazole 200 to 400 mg orally once daily for 14 to 21 days.[43] Cytomegalovirus retinitis is treated with valganciclovir 900 mg orally twice daily for 14 to 21 days (induction), or ganciclovir 5 mg/kg intravenously every 12 hours, followed by maintenance dosing of valganciclovir 900 mg/day orally, continued until immune recovery (CD4+ > 100 cells/µL for ≥ 3–6 months). For sight-threatening lesions (macula, optic nerve), intravitreal ganciclovir or foscarnet may be required as adjunctive therapy.[44] Cytomegalovirus colitis and esophagitis are treated with the same dose of valganciclovir or ganciclovir. Cryptosporidiosis, which causes diarrhea, is managed by initiating and optimizing antiretroviral therapy to restore immune function. Supportive treatment (fluids, nutrition, electrolyte correction) is essential. Nitazoxanide, 50 to 1000 mg orally twice daily for at least 2 weeks, may be used; however, efficacy is variable in immunocompromised hosts. Azithromycin and rifaximin, alone or in combination with nitazoxanide, have been used with some effectiveness, particularly in other patients with compromised immunity.[45] The preferred therapy for severe mucocutaneous HSV infection is acyclovir 5 mg/kg intravenously every 8 hours until clinical improvement, then transition to oral therapy (eg, acyclovir 400 mg orally three times daily, valacyclovir 1 g orally twice daily, or famciclovir 500 mg orally twice daily) to complete a total course of 7 to 14 days, or longer in extensive disease.[CDC. Sexually Transmitted Infections Treatment Guidelines 2021] For disseminated or severe coccidioidomycosis, fluconazole 400 to 800 mg orally once daily is the preferred regimen. In rapidly progressive disease, initial therapy with amphotericin B may be considered, followed by step-down to fluconazole. The duration of treatment is typically longer than 12 months, guided by response and immunologic recovery. Preferred induction therapy in disseminated histoplasmosis is liposomal amphotericin B 3 mg/kg intravenously daily for 2 weeks or until clinical improvement, followed by itraconazole 200 mg orally three times daily for 3 days, then 200 mg orally twice daily for at least 12 months.[EACS Guidelines. Histoplasmosis. 2025] Preferred therapy for bacillary angiomatosis is erythromycin 500 mg orally four times daily, or doxycycline 100 mg orally twice daily, for at least 3 months and until CD4 recovery. Liposomal amphotericin B 4 mg/kg intravenously daily on days 1 to 5, 10, 17, 24, 31, and 38 is the preferred treatment for severe disseminated fungal disease.

For disseminated or severe coccidioidomycosis, fluconazole 400 to 800 mg orally once daily is the preferred regimen. In rapidly progressive disease, initial therapy with amphotericin B may be considered, followed by step-down to fluconazole. The duration of treatment is typically longer than 12 months, guided by response and immunologic recovery. Preferred induction therapy in disseminated histoplasmosis is liposomal amphotericin B 3 mg/kg intravenously daily for 2 weeks or until clinical improvement, followed by itraconazole 200 mg orally three times daily for 3 days, then 200 mg orally twice daily for at least 12 months.[EACS Guidelines. Histoplasmosis. 2025] Preferred therapy for bacillary angiomatosis is erythromycin 500 mg orally four times daily, or doxycycline 100 mg orally twice daily, for at least 3 months and until CD4 recovery. Liposomal amphotericin B 4 mg/kg intravenously daily on days 1 to 5, 10, 17, 24, 31, and 38 is the preferred treatment for severe disseminated fungal disease. Initiation of ART in the setting of an acute, AIDS-associated opportunistic infection or malignancy can improve immune function and potentially enhance treatment success. In cryptosporidiosis, microsporidiosis, and progressive multifocal leukoencephalopathy, ART improves immune function and clinical outcomes. In TB infection outside of the CNS, initiating ART during antituberculosis treatment confers a significant survival advantage. For most opportunistic infections, ART can be initiated within 2 weeks of treatment initiation, with notable exceptions being CNS TB and cryptococcosis; ART is usually delayed until 4 to 6 weeks after treatment initiation.[hiv.gov. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. 2025] Immune Reconstitution Inflammatory Syndrome Immune reconstitution inflammatory syndrome refers to either a paradoxical worsening of a known opportunistic infection or unmasking of a previously undiagnosed infection following immune recovery after ART initiation. The syndrome is characterized by overt inflammatory signs that cannot be explained simply by the natural course of the disease or by drug toxicity.[EACS Guidelines. Immune Reconstitution Inflammatory Syndrome (IRIS) 2024]

Immune reconstitution inflammatory syndrome refers to either a paradoxical worsening of a known opportunistic infection or unmasking of a previously undiagnosed infection following immune recovery after ART initiation. The syndrome is characterized by overt inflammatory signs that cannot be explained simply by the natural course of the disease or by drug toxicity.[EACS Guidelines. Immune Reconstitution Inflammatory Syndrome (IRIS) 2024] Prevention strategies for immune reconstitution inflammatory syndrome vary depending on the underlying opportunistic infection. For tuberculosis infection outside the  CNS, prophylactic prednisone (40 mg/d for 2 weeks, then 20 mg/d for 2 weeks) may be considered in patients with CD4+ less than 100 cells/µL who begin ART within 30 days of anti-TB therapy and whose regimen is optimal and clinically effective. In persons with TB meningitis, adjuvant steroids are always recommended, and ART initiation is usually delayed for 4 weeks after antituberculous initiation. In cryptococcal meningitis, the risk of paradoxical immune reconstitution inflammatory syndrome is mitigated by using an optimal fungicidal regimen and delaying ART initiation by 4 to 6 weeks. Only in severe cryptococcal meningitis associated with immune reconstitution inflammatory syndrome are adjunctive corticosteroids used. Immune reactions associated with cryptococcosis reduce the risk of unmasking an immune reconstitution inflammatory syndrome in asymptomatic patients with HIV infection who are not on treatment and have CD4+ less than 100 cells/µL; a screen for cryptococcal antigen in the blood should be performed. If positive, patients should undergo lumbar puncture; if negative, preemptive therapy should be initiated with oral fluconazole 800 mg/day for 2 weeks, followed by 400 mg/day for 8 weeks.[EACS Guidelines. Immune Reconstitution Inflammatory Syndrome (IRIS). 2024] When immune reconstitution inflammatory syndrome occurs, most cases resolve over several weeks while continuing ART and opportunistic infection-specific therapy, without the need to discontinue ART.

Respiratory Because of its characteristic radiological appearance, PJP can be mistaken for community-acquired pneumonia, especially when caused by atypical organisms. Viral pneumonia can mimic influenza and SARS-CoV-2 infection. Chest radiographs of PJP may also be misinterpreted as cryptococcal pneumonia, which typically shows alveolar consolidation and ground-glass opacities.[46] Pulmonary TB that presents radiographically with cavitation and significant exudate (pericavitation or a liquid level) complicates the distinction between superinfected TB cavitation and a bacterial pulmonary abscess. Cavitation or pulmonary lesions may also be misinterpreted as signs of malignancy, which should be excluded during evaluation.[47] Pulmonary nodules and small cavitations in the lung may occasionally be mistaken for vasculitis or septic emboli, typical of gram-positive bacteremia or endocarditis.[47] To complicate matters, these clinical entities are also more common in populations with similar risk factors for TB, such as immunosuppressed persons, persons experiencing homelessness, and persons who use alcohol and drugs. A pleural effusion should raise the possibility of a neoplasm, such as non–small-cell lung cancer or lymphoma (eg, diffuse large B-cell lymphoma, Burkitt lymphoma), both of which are more common in patients with HIV infection. Neurological When evaluating meningitis, clinicians should consider other common agents of community-acquired meningitis, namely pneumococci, meningococci (typically associated with petechial and purpuric rash), and Listeria monocytogenes, which primarily affects immunosuppressed patients. Listeria monocytogenes infection appears radiographically as leptomeningeal enhancement, occasionally with small abscesses, most commonly in the brainstem. Persons living with HIV infection can also have brain lesions secondary to Aspergillus species, neurosyphilis (syphilitic gummas), and Histoplasma capsulatum infection.[48]

When evaluating meningitis, clinicians should consider other common agents of community-acquired meningitis, namely pneumococci, meningococci (typically associated with petechial and purpuric rash), and Listeria monocytogenes, which primarily affects immunosuppressed patients. Listeria monocytogenes infection appears radiographically as leptomeningeal enhancement, occasionally with small abscesses, most commonly in the brainstem. Persons living with HIV infection can also have brain lesions secondary to Aspergillus species, neurosyphilis (syphilitic gummas), and Histoplasma capsulatum infection.[48] Typically, contrast-enhancing lesions of TE can be challenging to distinguish from CNS abscess, neurocysticercosis, tuberculomas, and primary and secondary CNS cancers, including glioblastoma and metastases. Cryptococcal meningitis should be included in the differential diagnosis, particularly when the presentation involves altered consciousness secondary to increased intracranial pressure.[49] Furthermore, PML is challenging to differentiate clinically and radiographically from HIV encephalopathy. However, PML rarely presents with behavioral changes, dementia, or encephalopathy and is more likely to present with focal motor deficits, visual deficits, and acute cognitive impairment, features that are usually distinct from those of HIV encephalopathy.[50] Consultation with a neuroradiologist will help distinguish subtle radiological findings, including the number and location of lesions and the characteristics of contrast enhancement. Other Suspicion of CMV proctitis should also prompt evaluation for sexually transmitted infections that can present similarly, such as Chlamydia trachomatis and syphilis. However, TB colitis can also occur and can be difficult to distinguish from inflammatory bowel disease without a biopsy.[51] Lymphadenopathy caused by an opportunistic infection should be distinguished from the generalized lymphadenopathy common in the acute or early stages of HIV infection. Lymphomas, such as Burkitt lymphoma and diffuse large B-cell lymphoma, should be considered in the differential diagnosis of persistent and diffuse lymphadenopathy.

The prognosis of opportunistic infections in AIDS remains poor despite earlier HIV infection diagnoses, greater viral suppression, and the availability of more potent and safer antiretroviral drugs. For example, while opportunistic infection-related hospitalization rates among persons living with HIV infection in the US have declined, mortality among those hospitalized with an opportunistic infection has not decreased accordingly. Contributing factors likely include late presentation with advanced HIV disease, delays in recognizing opportunistic infections in hospitalized patients, limited access to advanced diagnostic tools, insufficient availability of infectious diseases or HIV specialists, and suboptimal implementation of opportunistic infections treatment and prophylaxis guidelines for diverse populations. In the US, factors associated with increased odds of opportunistic infection-related hospitalization include younger age, male sex, racial and ethnic minority groups, and lack of insurance, while higher opportunistic infection mortality has been reported in older patients, men, Hispanic populations, and those without insurance coverage.[54] Sepsis remains a major risk factor for mortality with opportunistic infection in persons living with HIV infection in resource-limited settings, with mortality rates as high as 57% within 6 months of initial presentation.[55][56]

With TB meningitis, the risk of death is as high as 25%, and the risk of neurological sequelae occurs in approximately 50%.[57] Cryptococcal meningitis is responsible for 15% of AIDS-related deaths globally.[58]  Residual neurologic morbidity (eg, cognitive impairment, vision loss, and complications of raised intracranial pressure) is common. Progressive multifocal leukoencephalopathy (PML, caused by the JC virus) continues to carry a poor prognosis in HIV infection despite ART, with reported 1-year mortality rates of approximately 30% to 50%. Long-term complications include cognitive impairment, sensory deficits, motor deficits, and coordination disturbances. Please see StatPearls' companion resource, "Progressive Multifocal Leukoencephalopathy," for further information. Similarly, CMV end-organ disease (retinitis, colitis, pneumonitis) in advanced HIV infection is associated with significant morbidity and increased risk of death, particularly in resource-limited settings or when diagnosis and treatment are delayed. Cytomegalovirus-related retinitis may cause debilitating, typically permanent vision loss, which is largely preventable with routine ophthalmologic monitoring in immunosuppressed patients and timely ART initiation in persons with HIV infection. Despite advances in antiviral treatment, the visual prognosis of CMV-related retinitis remains poor. Poor prognosis is associated with retinal detachment during treatment, macular involvement, and poor overall health.[59] Although outcomes have improved with ART, Kaposi sarcoma still carries substantial morbidity and mortality when advanced or untreated. Results from studies demonstrate function-limiting sequelae, including cutaneous or visceral lesions, lymphedema, and pulmonary or gastrointestinal involvement.

Prevention of HIV-related complications depends on continuous, patient-centered education delivered by an interdisciplinary team. Persons with advanced disease often face the dual challenge of complex treatment regimens for both HIV and opportunistic infections, while also navigating frequent follow-ups, potential adverse effects, and the psychosocial burden of their diagnosis.[60] These challenges are frequently magnified by stigma, language barriers, low health literacy, and socioeconomic hardship, which may hinder engagement in care. To address these barriers, education must go beyond information delivery to actively promote understanding, empowerment, and adherence. Clinicians, nurses, and pharmacists each play complementary roles: clinicians provide diagnostic and treatment guidance; nurses reinforce education at the bedside and monitor for early signs of complications; pharmacists ensure medication reconciliation, counsel on adverse effects, and optimize regimen adherence. Interdisciplinary communication and patient-tailored strategies, such as simplified regimens, mobile reminders, or pill organizers, are critical to support retention in care. Beyond the clinic, community-based programs, peer support groups, and family engagement can strengthen patient confidence and resilience. These networks help counter misinformation, reduce isolation, and provide practical strategies for day-to-day management. By combining medical expertise with psychosocial support and by leveraging the complementary skills of clinicians, nurses, pharmacists, and community resources, education becomes a tool not only for adherence but also for empowerment, ultimately improving survival, reducing disability, and enhancing quality of life in persons living with HIV infection.

Management of HIV infection is best accomplished through an interprofessional team of healthcare professionals, including infectious disease specialists, pharmacists, and nurses. In addition, other specialists may be involved, such as physical therapists, psychologists, psychiatrists, pneumologists, neurologists, and neurosurgeons. This approach offers the best opportunity for optimal patient care and therapeutic success. Continuous communication among these professionals is necessary to anticipate and monitor potential adverse effects and ensure adherence to the follow-up plan. Patients with advanced HIV disease often need multiple medications from several drug classes, with complex safety profiles and drug-drug interactions, which expose them to increased toxicities. Every medical, nursing, and pharmacy interaction with the patient should emphasize the importance of adherence to antiretroviral therapy, chemoprophylaxis against opportunistic infections, and regular examinations, and should explain the risks of nonadherence. Interpreters and cultural liaison officers may be needed to bridge communication gaps between clinicians and patients. Care should be taken to address beliefs and specific language, cultural, and social barriers that can affect the comprehension of health recommendations, especially within populations with lower health literacy, migrants, and members of racial or ethnic minority groups. Safe sex practices and education on safe needle disposal and injection practices among persons who inject drugs are highly encouraged to reduce the spread of HIV infection. Individuals with substance use disorders should be referred to drug rehabilitation clinics. Another component of this education is preparing patients for the possibility of immune reconstitution inflammatory syndrome. For individuals initiating ART at very low CD4+ counts, nurses and clinicians should explain that temporary worsening of symptoms or new inflammatory events may occur, reflecting immune recovery rather than treatment failure. Framing this inflammatory reaction as an anticipated and manageable complication helps to reduce anxiety, prevent treatment discontinuation, and maintain patient trust in the care plan.