Residency · Residency · Infectiousdisease

HIV - Opportunistic Infections

Framework for Opportunistic Infections

CD4 Count Thresholds

The CD4 count serves as the clinical roadmap for predicting which opportunistic infections a patient is at risk for developing. At CD4 counts below 500, Kaposi sarcoma, tuberculosis at any CD4 level though with increased risk at lower counts, herpes zoster, and bacterial pneumonia become concerns. At CD4 counts below 200, Pneumocystis jirovecii pneumonia, mucocutaneous candidiasis, Cryptosporidium, and Microsporidium emerge as significant risks. At CD4 counts below 100, Toxoplasma gondii encephalitis, Cryptococcus neoformans meningitis, and disseminated histoplasmosis or coccidioidomycosis predominate. At the most profound level of immunosuppression with CD4 counts below 50, disseminated Mycobacterium avium complex, CMV retinitis and colitis, CNS lymphoma, and progressive multifocal leukoencephalopathy become the primary threats.

Principles of OI Management

The management of opportunistic infections rests on three integrated principles. First, the specific OI must be treated with appropriate antimicrobial therapy. Second, ART must be initiated, with the timing determined by the specific OI and the risk of immune reconstitution inflammatory syndrome. IRIS presents as paradoxical worsening of symptoms after ART initiation and is most common with tuberculosis, cryptococcal disease, and MAC. Third, both primary prophylaxis to prevent the first episode in patients below the CD4 threshold and secondary prophylaxis or maintenance therapy to prevent relapse after treatment must be implemented and discontinued appropriately when CD4 recovery is sustained on ART.

Pneumocystis jirovecii Pneumonia (PCP)

Clinical Presentation

PCP typically occurs at CD4 counts below 200 or when the CD4 percentage falls below 14 percent, and it remains the most common AIDS-defining illness. The presentation is characteristically subacute, evolving over days to weeks with progressive dyspnea, a dry nonproductive cough, fever, and hypoxia. Chest radiography demonstrates bilateral diffuse interstitial or ground-glass infiltrates, though the radiograph can be normal in 10 to 15 percent of cases. CT of the chest reveals ground-glass opacities, crazy-paving pattern, and upper-lobe predominance, though the distribution may differ in non-HIV PCP. The LDH is elevated above 500 IU/L in 90 percent of cases, and beta-D-glucan is elevated with sensitivity exceeding 90 percent.

Diagnosis

Induced sputum with immunofluorescent staining achieves sensitivity of 50 to 90 percent. Bronchoalveolar lavage with direct fluorescent antibody staining or PCR remains the gold standard with sensitivity exceeding 95 percent. Metagenomic next-generation sequencing has an increasing role in diagnosis. Pneumocystis cannot be cultured.

Treatment

Mild-to-moderate disease, defined by PaO2 above 70 or an A-a gradient below 35, is treated with TMP-SMX double-strength two tablets orally three times daily for 21 days. Moderate-to-severe disease, defined by PaO2 of 70 or below or an A-a gradient of 35 or above, requires TMP-SMX at 5 milligrams per kilogram of the trimethoprim component intravenously every 6 to 8 hours for 21 days, with transition to oral therapy when improving. Adjunctive corticosteroids are indicated when the PaO2 is below 70 or the A-a gradient is 35 or above, administered as prednisone 40 milligrams twice daily for 5 days, then 40 milligrams daily for 5 days, then 20 milligrams daily for 11 days. This steroid regimen reduces mortality from approximately 40 percent to 20 percent and must not be omitted. For patients intolerant of TMP-SMX, alternatives include primaquine plus clindamycin for moderate-to-severe disease, atovaquone 750 milligrams orally twice daily with food for mild disease only, and intravenous pentamidine for severe disease though with significant toxicity. G6PD testing must be performed before administering primaquine due to the risk of hemolytic anemia.

Prophylaxis

Primary prophylaxis is initiated when the CD4 count falls below 200 or the CD4 percentage is below 14 percent, with TMP-SMX double-strength one tablet orally daily as the preferred regimen, which also provides coverage against Toxoplasma. Alternatives include TMP-SMX single-strength daily, dapsone 100 milligrams daily with G6PD testing, atovaquone 1,500 milligrams orally daily, or aerosolized pentamidine 300 milligrams monthly. Prophylaxis can be discontinued when the CD4 count exceeds 200 for three or more months on ART.

<image>A chest imaging comparison panel for PCP pneumonia showing three images. Panel 1: "Chest X-ray" showing bilateral diffuse ground-glass infiltrates with relative apical sparing. Panel 2: "CT chest (axial)" showing extensive bilateral ground-glass opacities with areas of crazy-paving pattern. Panel 3: "CT chest (coronal)" showing the bilateral distribution with relative peripheral sparing. Include diagnostic workup boxes below: "LDH (typically >500), beta-D-glucan (>80 pg/mL), ABG (assess A-a gradient for steroid indication), induced sputum or BAL for DFA/PCR." Include a treatment decision point: "PaO2 ≤70 or A-a gradient ≥35 → ADD corticosteroids." Use standard radiology presentation style with arrows pointing to key findings.</image>

Toxoplasma Encephalitis

Clinical Features

Toxoplasma encephalitis typically occurs at CD4 counts below 100 and represents reactivation of latent Toxoplasma gondii infection. Patients present with headache, confusion, fever, focal neurologic deficits, and seizures. MRI demonstrates multiple ring-enhancing lesions with surrounding edema, preferentially located in the basal ganglia and at the gray-white junction. Toxoplasma IgG serology is positive in approximately 95 percent of cases, and a negative IgG makes the diagnosis unlikely.

Diagnosis

The diagnosis is typically presumptive, based on characteristic MRI findings in combination with positive Toxoplasma IgG serology, a CD4 count below 100, and clinical response to empiric therapy within 14 days. Brain biopsy is reserved for atypical presentations, negative serology, or failure to respond to therapy, with the differential diagnosis including CNS lymphoma, tuberculoma, and brain abscess. Thallium-201 SPECT or FDG-PET may help distinguish Toxoplasma, which shows decreased uptake, from lymphoma, which demonstrates increased uptake.

Treatment

Induction therapy consists of pyrimethamine with a 200 milligram loading dose followed by 50 to 75 milligrams orally daily plus sulfadiazine 1 to 1.5 grams orally four times daily plus leucovorin 10 to 25 milligrams orally daily for six weeks. TMP-SMX at 5 milligrams per kilogram of the trimethoprim component orally or intravenously twice daily is increasingly used as an alternative, particularly given intermittent pyrimethamine supply issues. After induction, chronic suppressive therapy continues with reduced doses until the CD4 count exceeds 200 for six or more months on ART. Corticosteroids are indicated for significant mass effect and should be tapered as clinically able.

Cryptococcal Meningitis

Clinical Presentation

Cryptococcal meningitis typically occurs at CD4 counts below 100 and presents as a subacute meningitis with headache, fever, and altered mental status evolving over days to weeks. Meningeal signs including nuchal rigidity are present in only approximately 30 percent of patients. Elevated intracranial pressure occurs in more than 50 percent of patients and represents a major cause of both morbidity and mortality.

Diagnosis

Serum and CSF cryptococcal antigen testing achieves sensitivity exceeding 99 percent and is the primary diagnostic test. CSF analysis shows lymphocytic pleocytosis, though the fluid may be acellular in severe immunosuppression, along with low glucose and elevated protein. Opening pressure is frequently elevated. India ink preparation has sensitivity of 60 to 80 percent. Fungal culture is the gold standard, with growth typically occurring in 3 to 7 days.

Treatment

The treatment protocol follows a three-phase approach. Induction consists of amphotericin B deoxycholate at 0.7 to 1 milligram per kilogram per day plus flucytosine at 100 milligrams per kilogram per day divided four times daily for two weeks. Liposomal amphotericin B at 3 to 4 milligrams per kilogram per day is preferred when available due to reduced nephrotoxicity. Consolidation consists of fluconazole 400 milligrams orally daily for eight weeks. Maintenance, or secondary prophylaxis, consists of fluconazole 200 milligrams orally daily until the CD4 count exceeds 100 for one year or more with viral load suppression and a minimum of one year of maintenance completed. The ACTT protocol for resource-limited settings employs a single high-dose of liposomal amphotericin at 10 milligrams per kilogram plus 14 days of flucytosine plus fluconazole. Intracranial pressure management is critical, requiring serial therapeutic lumbar punctures to maintain opening pressure below 20 centimeters of water, removing sufficient CSF to reduce opening pressure by 50 percent or to below 20, with daily lumbar punctures potentially needed initially and ventriculoperitoneal shunting for refractory cases.

ART Timing

ART should be deferred four to six weeks after starting antifungal therapy, as earlier ART initiation increases mortality. The COAT trial demonstrated six-week mortality of 45 percent with early ART versus 30 percent with deferred ART. All patients with CD4 counts below 100 should be screened for serum cryptococcal antigen before starting ART to identify subclinical disease, and if positive, meningitis must be ruled out before proceeding.

Mycobacterium avium Complex (MAC)

Clinical Features

Disseminated MAC typically occurs at CD4 counts below 50 and presents with fever, night sweats, weight loss, diarrhea, abdominal pain, and hepatosplenomegaly. Laboratory findings include anemia, elevated alkaline phosphatase, and positive AFB blood cultures, which may take one to two weeks for growth. Bone marrow involvement is common.

Treatment

The treatment backbone is clarithromycin 500 milligrams orally twice daily plus ethambutol 15 milligrams per kilogram orally daily, with rifabutin 300 milligrams daily considered for severe disease. Azithromycin 500 milligrams daily can substitute for clarithromycin if it is not tolerated. The minimum treatment duration is twelve months, with the additional requirement that the CD4 count has exceeded 100 for six or more months on ART. ART should be started within two weeks, as the IRIS risk is lower than with cryptococcal disease or tuberculosis.

Prophylaxis

Primary prophylaxis at CD4 counts below 50 consists of azithromycin 1,200 milligrams orally weekly or 600 milligrams twice weekly, and can be discontinued when the CD4 count exceeds 100 for three or more months on ART. Blood MAC cultures should be obtained before starting prophylaxis to rule out active disease.

Cytomegalovirus (CMV) Disease

CMV Retinitis

CMV retinitis is the most common CMV end-organ disease in AIDS, typically occurring at CD4 counts below 50. Patients present with painless vision loss, floaters, or scotomata, which may be unilateral or bilateral. Fundoscopic examination reveals the characteristic appearance of hemorrhages and white fluffy exudates described as a "pizza pie" or "cottage cheese and ketchup" pattern along the vascular arcades. The diagnosis is clinical, made by fundoscopic examination, with aqueous or vitreous PCR used for confirmation when the presentation is atypical.

Treatment

Sight-threatening disease in zone 1, near the macula or optic disc, requires intravitreal ganciclovir or foscarnet injection plus systemic therapy. Systemic treatment consists of valganciclovir 900 milligrams orally twice daily for 14 to 21 days for induction, followed by 900 milligrams daily for maintenance. Intravenous ganciclovir at 5 milligrams per kilogram every 12 hours for induction followed by 5 milligrams per kilogram daily for maintenance is the alternative parenteral approach. Foscarnet is used for ganciclovir-resistant CMV with UL97 mutations. Maintenance therapy can be discontinued when the CD4 count exceeds 100 for three to six months on ART with no active retinitis and ophthalmology clearance. Immune recovery uveitis, an inflammatory reaction as the CD4 count rises on ART, is treated with periocular or systemic corticosteroids.

<image>A fundoscopic comparison image showing four panels. Panel 1: "Normal fundus" with clear optic disc, macula, and vessels labeled. Panel 2: "CMV retinitis" showing characteristic 'pizza pie' appearance with white fluffy exudates and hemorrhages along vascular arcades, with zone 1 (sight-threatening, within 1500 microns of fovea or optic disc) marked. Panel 3: "Cotton wool spots" (HIV retinopathy) for comparison - small white lesions without hemorrhage. Panel 4: "Toxoplasma chorioretinitis" showing focal necrotizing lesion for differential diagnosis. Each panel should be labeled with key features and CD4 threshold. Use realistic fundoscopic photography style with annotations.</image>

Immune Reconstitution Inflammatory Syndrome (IRIS)

Types

Paradoxical IRIS occurs when a known OI that is being actively treated worsens after ART initiation, affecting 20 to 30 percent of patients with concurrent TB and HIV. Unmasking IRIS occurs when a subclinical OI becomes clinically apparent after ART-induced immune recovery.

Risk Factors

Risk factors for IRIS include a low baseline CD4 count below 50, a high baseline viral load, a short interval between OI treatment and ART initiation, and a rapid rise in CD4 count on ART.

Management

ART should be continued, as stopping ART worsens outcomes except in life-threatening IRIS situations. The underlying OI must be adequately treated if not already. Corticosteroids, specifically prednisone at 1 to 2 milligrams per kilogram per day, are indicated for severe IRIS, particularly TB-IRIS as demonstrated in the PredART trial. NSAIDs are appropriate for mild symptoms.

Prophylaxis Summary

Primary Prophylaxis Thresholds

Key Clinical Pearls

• TMP-SMX prophylaxis at CD4 <200 covers both PCP and Toxoplasma -- the most important single prophylactic intervention in HIV
• Adjunctive corticosteroids for PCP (when PaO2 ≤70) reduce mortality by 50% -- do not omit this
• For cryptococcal meningitis, defer ART 4-6 weeks (COAT trial) and aggressively manage intracranial pressure with serial LPs
• Screen all patients with CD4 <100 for serum CrAg before initiating ART -- identifies subclinical cryptococcal disease
• CMV retinitis is a clinical diagnosis made by fundoscopy -- if CD4 <50 and visual complaints, urgent ophthalmology evaluation is mandatory
• IRIS is usually managed by continuing ART and adding corticosteroids for severe cases -- stopping ART worsens outcomes
• CD4 count is the roadmap for OI risk and prophylaxis -- memorize the thresholds (200, 100, 50)

References

1. Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. NIH/CDC/IDSA. Updated 2024.
2. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis (COAT). N Engl J Med. 2014;370(26):2487-2498.
3. Briel M, Bucher HC, Boscacci R, et al. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection. Cochrane Database Syst Rev. 2006;(3):CD006150.
4. Meintjes G, Stek C, Blumenthal L, et al. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS (PredART). N Engl J Med. 2018;379(20):1915-1925.
5. Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. MMWR Recomm Rep. 2009;58(RR-4):1-207.

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