Today, we are comparing HIV clinical practice guidelines from the World Health Organization (WHO) and the Department of Health and Human Services (DHHS). While both of these guidelines were developed to guide clinicians on managing individuals with HIV, the WHO guideline focuses on individuals with advanced HIV disease, while the DHHS guidelines provides broader, infection-specific recommendations across a wide range of opportunistic infections.
For this side-by-side comparison, we are taking a focused look at opportunistic infections addressed in both documents. We encourage you to review the full-text version available at the links below for the most complete look at these publications.
Guidelines for Comparison
| Item | Management of Advanced HIV Disease | Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV |
|---|---|---|
| Authoring Organization | World Health Organization (WHO) | Department of Health and Human Services (DHHS) |
| Publication Date | December 2025 | February 2026 |
| Links | Summary / Full Text | Summary / Full Text |
Key Takeaways
Package of Care of HIV Disease
- WHO recommends a standardized package of care for individuals with advanced HIV disease, while DHHS provides infection specific preventive recommendations.
Cryptococcal Disease Management
- Induction therapy for both WHO and DHHS recommend liposomal amphotericin B along with flucytosine for 14 days.
- For alternative induction regimen, WHO recommends a course of amphotericin B deoxycholate and flucytosine, followed by seven days of fluconazole. DHHS recommends Amphotericin B lipid complex plus flucytosine, or Amphotericin B deoxycholate plus flucytosine, followed by fluconazole.
- For consolidation and maintenance therapy, both the WHO and DHHS recommend fluconazole.
Histoplasmosis
- Both WHO and DHHS recommend itraconazole for maintenance therapy for histoplasmosis, though dosage differs between society's recommendations.
Treatment of Kaposi's sarcoma
- Both WHO and DHHS recommend initiating antiretroviral therapy for managing disease.
Side-by-Side Comparison of Guidelines
| Item | WHO | DHHS |
|---|---|---|
| Providing a Package of Care for HIV Disease | A package of interventions including screening, treatment and/or prophylaxis for major opportunistic infections, rapid ART initiation and intensified adherence support interventions should be offered to everyone presenting with advanced HIV disease. | Immunizations (e.g., against Salmonella serotype Typhi) should be recommended in advance of travel to relevant locations. Antimicrobial prophylaxis to prevent bacterial enteric illness is not routinely recommended, including for travelers. In rare cases—such as for immunosuppressed travelers (depending on their level of immunosuppression, the region of travel, and the trip’s duration)—antimicrobial prophylaxis with rifaximin or azithromycin should be offered. Because of toxicity associated with fluoroquinolone use (e.g., CDI, tendinitis) and increasing rates of antimicrobial resistance among enteric bacterial pathogens outside of the United States, routine use of fluoroquinolones for prophylaxis is discouraged. During pregnancy, azithromycin is the preferred agent for prophylaxis. |
| CD4 Testing for Identifying HIV Disease | CD4 testing is recommended as the preferred method to identify advanced HIV disease among people living with HIV. In settings in which CD4 testing is not yet available, WHO clinical staging can be used to identify advanced HIV disease. | Not addressed. |
| Interventions to Provide at Hospital Discharge | Hospitalized people with HIV may be provided interventions to support transitions to outpatient careand reduce avoidable readmissions. Interventions may include: Pre-discharge goal setting; Medication review; Transitional care planning; Telephone follow-up; Home visits by health-care providers and/or peer supporters; Individualized support. | Not addressed. |
| Diagnosis of Cryptococcal Meningitis | For adults, adolescents and children living with HIV suspected of having a first episode of cryptococcal meningitis, prompt lumbar puncture with measurement of cerebrospinal fluid (CSF) opening pressure and rapid cryptococcal antigen assay is recommended as the preferred diagnostic approach. The following diagnostic approaches are recommended according to the context. Settings with ready access to and no contraindication for lumbar puncture. 1. If both access to a cryptococcal antigen assay (either lateral flow assay or latex agglutination assay)and rapid results (less than 24 hours) are available: lumbar puncture with rapid CSF cryptococcal antigenassay is the preferred diagnostic approach. 2. If access to a cryptococcal antigen assay is not available and/or rapid results are not available, lumbar puncture with CSF India ink test examination is the preferred diagnostic approach. Settings without immediate access to lumbar puncture or when lumbar punctureis clinically contraindicated. 1. If both access to a cryptococcal antigen assay and rapid results (less than 24 hours) are available, rapid serum, plasma or whole blood cryptococcal antigen assays are the preferred diagnostic approaches. 2. If a cryptococcal antigen assay is not available and/or rapid access to results is not ensured, prompt referral for further investigation and treatment is appropriate. | Not addressed. |
| Prevention and Screening for Cryptococcal Meningitis | Overarching principle screening for plasma, serum or whole blood cryptococcal antigen is the optimal approach for guiding resources in a public health approach and is the preferred approach for identifying infection when managing people 10 years and older presenting with advanced HIV disease. Screening for cryptococcal antigen followed by pre-emptive antifungal therapy among cryptococcal antigen–positive people to prevent the development of invasive cryptococcal disease is recommended before initiating or reinitiating antiretroviral therapy (ART) for adults and adolescents living with HIV who have a CD4 cell count <100 cells/mm3. This may be considered at a higher CD4 cell count threshold of >200 cells/mm3. All people living with HIV with a positive cryptococcal antigen screening should be carefully evaluated for signs and symptoms of meningitis and undergo lumbar puncture, if feasible, with CSF examination and India ink or CSF cryptococcal antigen assay to exclude meningitis. India ink has low sensitivity and a negative result on India ink should be confirmed by CSF cryptococcal antigen testing or CSF culture. When cryptococcal antigen screening is not available, fluconazole primary prophylaxis should be given to adults and adolescents living with HIV who have a CD4 cell count <100 cells/mm3. This may be considered at a higher CD4 cell count threshold of <200 cells/mm3. | Not addressed. |
| Induction Therapy - Cryptococcal Disease | A single high dose (10 mg/kg) of liposomal amphotericin B with 14 days of flucytosine (100 mg/kg perday divided into four doses per day) and fluconazole (1200 mg/daily for adults; 12 mg/kg per day forchildren and adolescents up to a maximum of 800 mg daily) should be used as the preferred inductionregimen for treating people with cryptococcal meningitis. | Irrespective of which regimen is used, patients must be followed carefully in the hospital for at least 7 days and ideally 14 days. LP should be performed at Day 7 and Day 14 to ensure an appropriate clinical response and culture sterility. If increased ICP is documented, daily LP should be performed until the pressure is decreased into the normal range and symptoms have abated. Preferred Regimens: In the United States and other settings where daily monitoring of electrolytes and kidney function and administration of electrolytes and IV fluid is possible: Liposomal amphotericin B 3–4 mg/kg IV once daily plus flucytosine 25 mg/kg PO four times a day for 2 weeks. In resource-limited health care systems, as recommended by the World Health Organization: Liposomal amphotericin B 10 mg/kg IV as a single dose on Day 1, followed by flucytosine 25 mg/kg PO four times a day plus fluconazole 1,200 mg PO daily for 2 weeks. Additional Studied Regimens (Duration of Therapy: 2 Weeks): Amphotericin B deoxycholate 0.7–1.0 mg/kg IV once daily plus flucytosine 25 mg/kg PO four times a day. Liposomal amphotericin B 3–4 mg/kg IV once daily plus fluconazole 800–1,200 mg PO once daily. Amphotericin B deoxycholate 0.7–1.0 mg/kg IV once daily plus fluconazole 800–1,200 mg PO once daily. Fluconazole 1,200 mg PO or IV once daily plus flucytosine 25 mg/kg PO four times a day. If the patient has not improved clinically or remains clinically unstable, continue or start (liposomal amphotericin B or amphotericin B deoxycholate) plus flucytosine induction therapy until the CSF culture is confirmed to be negative. Additional Considerations CSF opening pressure should always be measured when an LP is performed. Repeated therapeutic LPs are essential to manage symptomatic increased ICP and have a survival benefit. Corticosteroids should not be used routinely during induction therapy unless used for management of IRIS. Corticosteroids, acetazolamide, and mannitol are ineffective in reducing ICP and are not recommended. |
| Alternative Induction Regimes – Cryptococcal Disease | If liposomal amphotericin is not available: A seven-day course of amphotericin B deoxycholate (1 mg/kg per day) and flucytosine (100 mg/kg per day, divided into four doses per day) followed by seven days of fluconazole (1200 mg daily for adults and 12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily). If no amphotericin formulation is available: 14 days of fluconazole (1200 mg daily, 12 mg/kg per day for children and adolescents) and flucytosine (100 mg/kg per day, divided into four doses per day). Note: Fluconazole and flucytosine is the only recommended oral combination regimen and has been associated with lower mortality compared with amphotericin B deoxycholate and fluconazole. If flucytosine is not available: 14 days of liposomal amphotericin B (3–4 mg/kg per day) and fluconazole (1200 mg daily, 12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily). If liposomal amphotericin B and flucytosine are not available: 14 days of amphotericin B deoxycholate (1 mg/kg per day) and fluconazole (1200 mg daily, 12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily). Note: Flucytosine-containing regimens are superior, and steps should be taken to ensure access to this drug. | Alternative Regimens Amphotericin B lipid complex 5 mg/kg IV daily plus flucytosine 25 mg/kg PO four times a day for 2 weeks, or Amphotericin B deoxycholate 1 mg/kg IV daily plus flucytosine 25 mg/kg PO four times a day for 1 week, followed by fluconazole 1,200 mg PO daily for an additional week. Note: The flucytosine dose should be adjusted in renal impairment and ideally use TDM. |
| Use of Adjunctive Systemic Corticosteroids in Treating People with Cryptococcal Meningitis | Routine use of adjunctive corticosteroid therapy during the induction phase is not recommended in treating adults, adolescents and children who have HIV-associated cryptococcal meningitis. | Not addressed. |
| Consolidation - Cryptococcal Disease | Fluconazole (800 mg daily for adults or 6–12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily) is recommended for the consolidation phase (for eight weeks following the induction phase). | Perform LP after 1 week and/or 2 weeks of induction therapy to document the culture is negative. After 2 weeks of induction therapy, people who are clinically stable may be switched to consolidation therapy while awaiting culture results. Duration of consolidation therapy should be for at least 8 weeks after receiving CSF culture at 2 weeks is negative. Preferred Regimen Fluconazole 800 mg PO daily For clinically stable patients, continue fluconazole 800 mg until CSF cultures are known to be sterile and ART has been initiated; dose then can be reduced to 400 mg PO daily. If CSF remains positive in a clinically stable patient after 2 weeks of induction therapy, use one of the following two options for an additional 2 weeks before reducing the dose to fluconazole 800 mg PO daily: Fluconazole 1,200 mg PO daily plus flucytosine 25 mg/kg PO four times a day for an additional 2 weeks, or Fluconazole 1,200 mg PO daily for an additional 2 weeks. Alternative Regimen Itraconazole 200 mg PO twice a day, if fluconazole is not available or not tolerated. |
| Maintenance - Cryptococcal Disease | Fluconazole (200 mg daily for adults or 6 mg/kg per day for adolescents and children) is recommended for the maintenance phase until immune reconstitution (CD4> 200 cells/mm3) and suppression of viral loads on ART. | Preferred Regimen Fluconazole 200 mg PO once daily for ≥1 year from initiation of antifungal therapy. Alternative Regimen Itraconazole 200 mg PO twice a day, if fluconazole is not available or not tolerated. If susceptibility studies have been performed and the fluconazole MIC is ≥16 µg/mL, the fluconazole dose may be increased to 400 mg daily. Criteria for Stopping Maintenance Therapy At least 1 year from initiation of antifungal therapy, and patient remains asymptomatic from cryptococcal infection, and CD4 count ≥100 cells/mm3 and suppressed HIV RNA in response to effective ART. Restarting Maintenance Therapy If CD4 count declines to <100 cells/mm3. |
| Timing of ART - Cryptococcal Disease | Immediate ART initiation is not recommended among adults, adolescents and children living with HIV who have cryptococcal meningitis because of the risk of increased mortality and should be deferred 4–6 weeks from the initiation of antifungal treatment. | Not addressed. |
| Diagnosis of Disseminated Histoplasmosis Among People Living with HIV | Among people living with HIV, disseminated histoplasmosis should be diagnosed by detectingcirculating Histoplasma antigens. | Not addressed. |
| Induction Therapy - Histoplasmosis | Treating people living with HIV for severe or moderately severe histoplasmosis: liposomal amphotericin B, 3.0 mg/kg, for two weeks is recommended. In settings in which liposomal amphotericin B is unavailable, deoxycholate amphotericin B, 0.7–1.0 mg/kg, is recommended for two weeks. Treating people living with HIV for mild to moderate histoplasmosis: itraconazole 200 mg three times daily for three days and then 200 mg twice daily is recommended. | Treating Severe Disseminated Disease Induction Therapy (≥2 Weeks or Until Clinically Improved) Preferred Therapy: Liposomal amphotericin B 3 mg/kg IV daily Alternative TherapyAmphotericin B lipid complex 5 mg/kg IV daily. Alternative Therapy Note: These recommendations are based on limited clinical data for people who are intolerant to itraconazole and only moderately ill. Posaconazole 300 mg extended-release tablet PO twice daily for 1 day, then 300 mg PO once daily ,or Voriconazole 400 mg PO twice daily for 1 day, then 200 mg PO twice daily, or Fluconazole 800 mg PO once daily (Cll). Treating Mild-to-Moderate Disseminated Disease or Acute Pulmonary Histoplasmosis in People With CD4 <300 cells/mm3Induction and Maintenance Therapy (≥12 Months) Preferred Therapy: Itraconazole 200 mg PO three times a day for 3 days, then 200 mg PO two times a day. Alternative Therapy: Posaconazole 300 mg extended-release tablet PO twice daily for 1 day, then 300 mg PO once daily, or Voriconazole 400 mg PO twice daily for 1 day, then 200 mg PO twice daily, or Fluconazole 800 mg PO once daily. |
| Maintenance Therapy — Histoplasmosis | Itraconazole 200 mg twice daily for 12 months is recommended. Less than 12 months of therapy can be considered when the person is clinically stable, receiving ART, has suppressed viral load and the immune status has improved. | Preferred Therapy: Itraconazole 200 mg PO three times a day for 3 days, then 200 mg PO two times a day. |
| Timing of ART - Histoplasmosis | ART should be initiated as soon as possible among people with disseminated histoplasmosis for whom central nervous system involvement is not suspected or proven. | Not addressed. |
| TB Treatment for People with TB, HIV and Histoplasmosis | People living with HIV who also have TB and histoplasmosis coinfection should receive TB therapyaccording to WHO treatment guidelines. | Not addressed. |
| Treating Histoplasma Meningitis | Not addressed. | Induction Therapy (4–6 Weeks Depending on Symptom Resolution and Improvement of CSF Findings) Preferred Therapy: Liposomal amphotericin B 5 mg/kg IV daily. Alternative Therapy: Amphotericin B deoxycholate 0.7–1.0 mg/kg IV daily. Maintenance Therapy (≥12 Months and Until Resolution of Abnormal CSF Findings) Preferred Therapy: Itraconazole 200 mg PO two or three times a day. Alternative Therapy: Note: These recommendations are based on limited clinical data for people who are intolerant to itraconazole and only moderately ill. Voriconazole 400 mg PO twice daily for 1 day, then 200 mg PO twice daily ,or Fluconazole 800 mg PO once daily ¾for people who cannot tolerate both itraconazole and voriconazole. |
| Long-Term Suppressive Therapy - Histoplasmosis | Not addressed. | Indications Severe disseminated or CNS infection after completing maintenance therapy for ≥12 months of treatment , or relapse despite appropriate initial therapy (after reinduction therapy). Preferred Therapy: Itraconazole 200 mg PO once daily. Alternative Therapy Note: These recommendations are based on limited clinical data for people who are intolerant to itraconazole. Fluconazole 400 mg PO once daily, or Voriconazole 200 mg PO twice daily, or Posaconazole 300 mg PO daily Criteria for Discontinuing Long-Term Suppressive Therapy Receipt of azole treatment for >1 year, and negative fungal blood cultures, and serum or urine Histoplasma antigen below the level of quantification, and undetectable HIV viral load on stable ART, and CD4 count ≥150 cells/mm3 and on ART for ≥6 months. Indication for Restarting Long-Term Suppressive Therapy CD4 count <150 cells/mm3. |
| Preventing Development of Kaposi Sarcoma | Not addressed. | Administer ART to all people with HIV to reduce the likelihood that KS will develop. |
| Pharmacological Treatment of Kaposi’s Sarcoma | WHO suggests paclitaxel or pegylated liposomal doxorubicin for pharmacological treatment for peopleliving with HIV with Kaposi’s sarcoma. | Not addressed. |
| Treatment of Kaposi’s Sarcoma | In HIV-infected adults, adolescents and children diagnosed with mild or moderate Kaposi sarcoma, immediate ART initiation is recommended. Severe or Symptomatic Disease: In HIV-infected adults, adolescents and children diagnosed with severe symptomatic Kaposi sarcoma, immediate ART initiation in combination with systemic chemotherapy is recommended. | Treatment for HHV-8-associated diseases should be undertaken in consultation with guidance from both oncology and infectious disease specialists, with additional input from centers specifically caring for people with HIV and cancer. Among people with HIV, all HHV-8-specific treatments should be given with ART, which is an essential component of managing these diseases. ART given concurrently with chemotherapy for HHV-8 malignancies should be chosen to minimize drug–drug interactions and additive toxicities. Kaposi Sarcoma ACTG StageT0 (localized involvement of skin and/or lymph nodes and/or minimal oral disease only): ART alone, or ART plus liposomal doxorubicin, if disease does not respond to ART alone; or ACTG stage T1 [extensive and/or symptomatic KS skin lesions, extensive oral disease, tumor-associated edema, and/or ulceration or any visceral involvement]: Preferred Therapy: ART plus liposomal doxorubicin. Alternative Therapy: ART plus paclitaxel, if liposomal doxorubicin is not available, or to treat recurrence after treatment with liposomal doxorubicin, or ART with oral pomalidomide plus thromboprophylaxis (e.g., low-dose aspirin 81 mg daily). Note: Concurrent use of systemic corticosteroids or other immunosuppressants in patients with KS should either be avoided or used under close observation, given the potential for exacerbation of KS. |
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