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HIV and Opportunistic Infections: ART, Prophylaxis, and AIDS-Defining Illnesses

Infectious Disease10 min read1,998 wordsadvancedUpdated 3/13/2026

Contents

Human Immunodeficiency Virus (HIV) is a retrovirus that selectively targets CD4+ T-helper cells, leading to progressive immunosuppression and the development of Acquired Immunodeficiency Syndrome (AIDS). [KEY_CONCEPT] The hallmark of HIV infection is the depletion of CD4+ T cells, with AIDS defined by a CD4+ count <200 cells/μL or the presence of AIDS-defining opportunistic infections or malignancies.

Epidemiology:

Global prevalence: approximately 38 million people living with HIV worldwide
Most common transmission routes: sexual contact, parenteral exposure, vertical transmission
Highest risk groups: men who have sex with men, intravenous drug users, sex workers

Pathophysiology: HIV primarily infects cells expressing the CD4 receptor, including:

CD4+ T-helper cells (primary target)
Macrophages and monocytes
Dendritic cells
Microglial cells in the CNS

[CLINICAL_PEARL] The viral life cycle involves reverse transcription of viral RNA into DNA, integration into the host genome, and subsequent viral replication. This process is targeted by different classes of antiretroviral therapy.

Natural History:

Acute HIV syndrome (2-4 weeks post-infection): flu-like illness
Clinical latency (2-10 years): asymptomatic period with ongoing viral replication
AIDS (CD4+ <200 cells/μL): opportunistic infections and malignancies

[HIGH_YIELD] Without treatment, the median time from HIV infection to AIDS is approximately 8-10 years, with significant individual variation based on viral load, host factors, and access to care.

HIV infection presents with a spectrum of clinical manifestations that correlate with the degree of immunosuppression, primarily measured by CD4+ T cell count.

WHO Clinical Staging System:

Stage	CD4+ Count	Clinical Features	Examples
1	>500 cells/μL	Asymptomatic or mild symptoms	Persistent lymphadenopathy
2	350-500 cells/μL	Moderate symptoms	Oral candidiasis, recurrent bacterial infections
3	200-349 cells/μL	Severe symptoms	Pulmonary TB, severe bacterial pneumonia
4 (AIDS)	<200 cells/μL	Life-threatening conditions	PCP, CMV retinitis, disseminated MAC

Constitutional Symptoms:

Fever and night sweats
Unintentional weight loss (>10% baseline)
Chronic diarrhea
Fatigue and malaise

Organ System Manifestations:

Pulmonary (CD4+ <200):

Pneumocystis jirovecii pneumonia (PCP): most common AIDS-defining illness
Bacterial pneumonia (S. pneumoniae, H. influenzae)
Tuberculosis (pulmonary and extrapulmonary)

Gastrointestinal:

Oral candidiasis (thrush)
Esophageal candidiasis
Cytomegalovirus (CMV) colitis
Cryptosporidium diarrhea

Neurological (CD4+ <100):

HIV-associated neurocognitive disorder (HAND)
Cryptococcal meningitis
Progressive multifocal leukoencephalopathy (PML)
CMV encephalitis

Dermatological:

Kaposi's sarcoma (HHV-8)
Seborrheic dermatitis
Molluscum contagiosum
Herpes zoster (shingles)

[CLINICAL_PEARL] The presence of oral candidiasis in a young, otherwise healthy adult should prompt HIV testing, as it often indicates significant immunosuppression.

[HIGH_YIELD] CD4+ count is the most important predictor of opportunistic infection risk, with specific thresholds for different pathogens.

HIV Diagnostic Algorithm:

Initial Screening Test ├── HIV-1/2 Antigen/Antibody Immunoassay (4th generation) │ ├── Reactive → HIV-1/HIV-2 Antibody Differentiation Immunoassay │ │ ├── HIV-1 (+) → HIV-1 Confirmed │ │ ├── HIV-2 (+) → HIV-2 Confirmed │ │ └── Indeterminate → HIV-1 Nucleic Acid Test (NAT) │ │ ├── Detectable → Acute HIV-1 Infection │ │ └── Not Detectable → HIV Negative* │ └── Non-reactive → HIV Negative (if no clinical suspicion) │ └── Consider repeat testing if high clinical suspicion

Laboratory Monitoring Parameters:

Baseline Assessment:

CD4+ T cell count and percentage
HIV RNA viral load (copies/mL)
Complete blood count with differential
Comprehensive metabolic panel
Hepatitis B and C serologies
Syphilis serology (RPR/VDRL)
Tuberculin skin test or interferon-gamma release assay

Ongoing Monitoring:

CD4+ count: every 3-6 months (can extend to annually if stable on ART with suppressed viral load and CD4+ >300)
Viral load: every 3-6 months, target <50 copies/mL
Resistance testing: if viral load >1000 copies/mL on ART

Opportunistic Infection Screening Thresholds:

CD4+ Count	Recommended Screening	Prophylaxis Indication
<200 cells/μL	PCP prophylaxis	TMP-SMX daily
<100 cells/μL	Toxoplasma serology	TMP-SMX (if IgG+)
<50 cells/μL	CMV retinal exam	Consider prophylaxis
Any count	Annual TB screening	INH if LTBI+

Drug Resistance Testing:

Genotypic resistance testing: recommended at baseline and treatment failure
Phenotypic resistance testing: reserved for complex resistance patterns
Integrase resistance testing: if planning integrase inhibitor-based regimen

[HIGH_YIELD] HIV diagnosis requires confirmation with a supplemental test due to potential false positives with screening assays. The 4th generation assays detect both antibodies and p24 antigen, reducing the window period.

[CLINICAL_PEARL] Viral load suppression to <50 copies/mL is the goal of ART and typically achieved within 12-24 weeks of initiating effective therapy.

Current ART Guidelines: The goal of ART is to achieve and maintain viral suppression (HIV RNA <50 copies/mL) while reconstituting immune function and preventing HIV transmission.

First-Line ART Regimens (2023 Guidelines):

Preferred Regimens:

Bictegravir/tenofovir alafenamide/emtricitabine (B/TAF/FTC)
Dolutegravir + tenofovir alafenamide/emtricitabine (DTG + TAF/FTC)
Dolutegravir + tenofovir disoproxil fumarate/emtricitabine (DTG + TDF/FTC)

Alternative Regimens:

Efavirenz/tenofovir alafenamide/emtricitabine (EFV/TAF/FTC)
Rilpivirine/tenofovir alafenamide/emtricitabine (RPV/TAF/FTC) - if viral load <100,000
Darunavir/cobicistat + tenofovir alafenamide/emtricitabine

ART Initiation Criteria:

HIV Diagnosis Confirmed ├── Immediate ART Initiation ("Treatment as Prevention") │ ├── All HIV-positive patients regardless of CD4+ count │ ├── Special Populations: │ │ ├── Pregnant women │ │ ├── AIDS-defining illness │ │ ├── HIV nephropathy │ │ └── Hepatitis B co-infection │ └── Patient Readiness Assessment: │ ├── Understanding of lifelong therapy │ ├── Adherence counseling │ └── Drug interaction review

Monitoring ART Response:

Virologic Response:

Expected viral load decline: 1-1.5 log₁₀ copies/mL by 4-8 weeks
Target: <50 copies/mL by 12-24 weeks
Virologic failure: confirmed viral load >200 copies/mL after 24 weeks

Immunologic Response:

CD4+ count typically increases by 50-150 cells/μL in first year
Slower response in patients with baseline CD4+ <200 cells/μL
[CLINICAL_PEARL] CD4+ response may be blunted in older patients and those with advanced disease

Drug Interactions and Contraindications:

Drug Class	Key Interactions	Monitoring
Protease Inhibitors	Statins, anticoagulants, rifamycins	Liver enzymes, drug levels
NNRTIs	Rifamycins, proton pump inhibitors	Rash, hepatotoxicity
Integrase Inhibitors	Antacids, iron supplements	Generally well-tolerated
Entry Inhibitors	Limited interactions	CCR5 tropism testing

Treatment Failure Management:

Confirm adherence issues
Review drug interactions
Obtain resistance testing if viral load >1000 copies/mL
Consider expert consultation for complex resistance

[HIGH_YIELD] Modern ART regimens are highly effective with >95% of treatment-naive patients achieving viral suppression. Single-tablet regimens improve adherence and clinical outcomes.

[KEY_CONCEPT] "Undetectable = Untransmittable" (U=U): Patients with suppressed viral loads cannot sexually transmit HIV, making ART a powerful prevention tool.

Primary Prophylaxis Guidelines: Primary prophylaxis prevents the first occurrence of opportunistic infections in HIV patients with severe immunosuppression.

Pneumocystis jirovecii Pneumonia (PCP):

Indication: CD4+ <200 cells/μL or CD4+ percentage <14%
First-line: Trimethoprim-sulfamethoxazole (TMP-SMX) 1 DS tablet daily
Alternatives: Dapsone 100mg daily, Atovaquone 1500mg daily, Aerosolized pentamidine 300mg monthly
Discontinuation: CD4+ >200 cells/μL for >3 months on ART

Toxoplasma gondii:

Indication: CD4+ <100 cells/μL AND Toxoplasma IgG positive
First-line: TMP-SMX 1 DS tablet daily (also covers PCP)
Alternatives: Dapsone 50mg daily + pyrimethamine 50mg weekly + leucovorin 25mg weekly
Discontinuation: CD4+ >200 cells/μL for >3 months on ART

Mycobacterium avium Complex (MAC):

Indication: CD4+ <50 cells/μL
First-line: Azithromycin 1200mg weekly or Clarithromycin 500mg twice daily
Alternative: Rifabutin 300mg daily
Discontinuation: CD4+ >100 cells/μL for >3 months on ART

Cytomegalovirus (CMV):

Indication: CD4+ <50 cells/μL (controversial)
Screening: Ophthalmologic examination every 6 months
Prophylaxis: Not routinely recommended due to toxicity

Prophylaxis Decision Algorithm:

CD4+ Count Assessment ├── CD4+ <200 cells/μL │ ├── Start PCP prophylaxis (TMP-SMX) │ └── Check Toxoplasma IgG │ └── If positive → Continue TMP-SMX (covers both) ├── CD4+ <100 cells/μL │ ├── Continue PCP/Toxoplasma prophylaxis │ └── Consider TB screening intensification └── CD4+ <50 cells/μL ├── Continue previous prophylaxis ├── Start MAC prophylaxis (Azithromycin) └── CMV retinal screening every 6 months

Secondary Prophylaxis (Maintenance Therapy): Prevents recurrence after successful treatment of opportunistic infections.

Infection	Maintenance Therapy	Duration
PCP	TMP-SMX 1 DS daily	Until CD4+ >200 x 3 months
Toxoplasmosis	Sulfadiazine + pyrimethamine + leucovorin	Until CD4+ >200 x 6 months
MAC	Clarithromycin + ethambutol	Until CD4+ >100 x 12 months
CMV retinitis	Valganciclovir or ganciclovir	Until CD4+ >100 x 6 months
Cryptococcosis	Fluconazole 200mg daily	Until CD4+ >100 x 12 months

Immune Reconstitution Inflammatory Syndrome (IRIS): Paradoxical worsening of opportunistic infections after starting ART due to immune reconstitution.

Risk Factors:

Low baseline CD4+ count (<50 cells/μL)
High baseline viral load
Rapid CD4+ increase after ART initiation
Recent opportunistic infection treatment

Management:

Continue ART in most cases
Treat underlying opportunistic infection
Consider corticosteroids for severe IRIS
NSAIDs for mild inflammatory symptoms

[HIGH_YIELD] TMP-SMX provides prophylaxis against both PCP and Toxoplasma, making it the preferred agent when both are indicated.

[CLINICAL_PEARL] Discontinuation of prophylaxis is based on immune reconstitution (sustained CD4+ increase) rather than viral load suppression alone.

AIDS-Defining Conditions: The CDC defines AIDS by the presence of specific opportunistic infections, malignancies, or severe immunosuppression (CD4+ <200 cells/μL) in HIV-positive patients.

Major AIDS-Defining Illnesses by System:

Pulmonary:

Pneumocystis jirovecii pneumonia (PCP)
- Presentation: dyspnea, dry cough, fever, bilateral infiltrates
- Diagnosis: induced sputum or BAL with direct fluorescence
- Treatment: TMP-SMX ± corticosteroids (if PaO₂ <70 or A-a gradient >35)

Gastrointestinal:

Esophageal candidiasis
- Presentation: dysphagia, odynophagia, retrosternal chest pain
- Diagnosis: clinical + response to antifungal therapy
- Treatment: fluconazole 200-400mg daily x 14-21 days
Chronic cryptosporidiosis (>1 month)
- Presentation: chronic watery diarrhea, weight loss
- Diagnosis: acid-fast staining of stool or antigen detection
- Treatment: nitazoxanide + ART for immune reconstitution

Central Nervous System:

Cryptococcal meningitis
- Presentation: headache, fever, altered mental status
- Diagnosis: CSF India ink, antigen, culture
- Treatment: amphotericin B + flucytosine x 2 weeks, then fluconazole
Toxoplasma encephalitis
- Presentation: focal neurologic deficits, seizures, altered consciousness
- Diagnosis: brain imaging (ring-enhancing lesions) + serology
- Treatment: sulfadiazine + pyrimethamine + leucovorin

Comparison of CNS AIDS-Defining Illnesses:

Feature	Toxoplasmosis	Cryptococcal Meningitis	PML	CMV Encephalitis
CD4+ threshold	<100 cells/μL	<100 cells/μL	<200 cells/μL	<50 cells/μL
Imaging	Ring-enhancing lesions	Minimal enhancement	White matter lesions	Periventricular enhancement
CSF findings	Mild pleocytosis	High opening pressure	Normal	Mild pleocytosis
Treatment	Sulfadiazine/pyrimethamine	Amphotericin B/flucytosine	ART (no specific therapy)	Ganciclovir/foscarnet

Malignancies:

Kaposi's sarcoma (HHV-8)
- Presentation: violaceous skin lesions, lymphadenopathy, visceral involvement
- Treatment: ART + chemotherapy (liposomal doxorubicin) for extensive disease
Primary CNS lymphoma
- Presentation: focal neurologic symptoms, mass lesion on imaging
- Diagnosis: brain biopsy (EBV-positive B-cell lymphoma)
- Treatment: high-dose methotrexate-based chemotherapy + radiation

Immune Reconstitution Inflammatory Syndrome (IRIS):

Unmasking IRIS:

Manifestation of previously subclinical opportunistic infection after ART initiation
Typically occurs within first 3 months of ART
Common pathogens: TB, cryptococcosis, CMV, hepatitis B

Paradoxical IRIS:

Worsening of treated opportunistic infection after ART initiation
Results from restored inflammatory response to residual antigens
Management: continue ART, optimize OI treatment, consider corticosteroids

Long-term Complications:

Non-AIDS Defining Conditions:

Cardiovascular disease (2-fold increased risk)
Non-AIDS malignancies (anal, lung, liver, Hodgkin lymphoma)
Bone disease (osteoporosis, osteonecrosis)
Kidney disease (HIV nephropathy, ART toxicity)
Neurocognitive impairment (HIV-associated neurocognitive disorder)

ART-Related Complications:

Lipodystrophy and metabolic syndrome
Bone loss and fractures
Renal toxicity (tenofovir)
Hepatotoxicity
Drug interactions

[HIGH_YIELD] The presence of any AIDS-defining illness establishes an AIDS diagnosis regardless of CD4+ count and requires immediate ART initiation.

[CLINICAL_PEARL] IRIS is a sign of immune recovery and generally indicates ART effectiveness, but requires careful monitoring and symptomatic management.

High-Yield Key Points

HIV diagnosis requires confirmation with supplemental testing; 4th generation assays detect both antibodies and p24 antigen, reducing window period

ART should be initiated immediately in all HIV-positive patients regardless of CD4+ count ("Treatment as Prevention" strategy)

PCP prophylaxis with TMP-SMX is indicated when CD4+ <200 cells/μL and provides dual coverage for Toxoplasma when CD4+ <100 cells/μL

Viral load suppression to <50 copies/mL is the primary goal of ART and prevents HIV transmission (U=U concept)

IRIS represents immune reconstitution and typically occurs within 3 months of ART initiation in patients with low baseline CD4+ counts

AIDS-defining illnesses have specific CD4+ thresholds: PCP (<200), Toxoplasma (<100), MAC and CMV (<50 cells/μL)

Modern integrase inhibitor-based regimens achieve >95% viral suppression rates with improved tolerability compared to older regimens

HIV and Opportunistic Infections: ART, Prophylaxis, and AIDS-Defining Illnesses

Overview & Pathophysiology

**Human Immunodeficiency Virus (HIV)** is a retrovirus that selectively targets CD4+ T-helper cells, leading to progressive immunosuppression and the development of **Acquired Immunodeficiency Syndrome (AIDS)**. [KEY_CONCEPT] The hallmark of HIV infection is the depletion of CD4+ T cells, with AIDS defined by a CD4+ count  200 cells/μL or the presence of AIDS-defining opportunistic infections or malignancies.

**Epidemiology:**
- Global prevalence: approximately 38 million people living with HIV worldwide
- Most common transmission routes: sexual contact, parenteral exposure, vertical transmission
- Highest risk groups: men who have sex with men, intravenous drug users, sex workers

**Pathophysiology:**
HIV primarily infects cells expressing the CD4 receptor, including:
- CD4+ T-helper cells (primary target)
- Macrophages and monocytes
- Dendritic cells
- Microglial cells in the CNS

[CLINICAL_PEARL] The viral life cycle involves reverse transcription of viral RNA into DNA, integration into the host genome, and subsequent viral replication. This process is targeted by different classes of antiretroviral therapy.

**Natural History:**
1. **Acute HIV syndrome** (2-4 weeks post-infection): flu-like illness
2. **Clinical latency** (2-10 years): asymptomatic period with ongoing viral replication
3. **AIDS** (CD4+  200 cells/μL): opportunistic infections and malignancies

[HIGH_YIELD] Without treatment, the median time from HIV infection to AIDS is approximately 8-10 years, with significant individual variation based on viral load, host factors, and access to care.

Clinical Presentation & Staging

**HIV Diagnostic Algorithm:**


Initial Screening Test
├── HIV-1/2 Antigen/Antibody Immunoassay (4th generation)
│   ├── Reactive → HIV-1/HIV-2 Antibody Differentiation Immunoassay
│   │   ├── HIV-1 (+) → HIV-1 Confirmed
│   │   ├── HIV-2 (+) → HIV-2 Confirmed
│   │   └── Indeterminate → HIV-1 Nucleic Acid Test (NAT)
│   │       ├── Detectable → Acute HIV-1 Infection
│   │       └── Not Detectable → HIV Negative*
│   └── Non-reactive → HIV Negative (if no clinical suspicion)
│       └── Consider repeat testing if high clinical suspicion


**Laboratory Monitoring Parameters:**

**Baseline Assessment:**
- CD4+ T cell count and percentage
- HIV RNA viral load (copies/mL)
- Complete blood count with differential
- Comprehensive metabolic panel
- Hepatitis B and C serologies
- Syphilis serology (RPR/VDRL)
- Tuberculin skin test or interferon-gamma release assay

**Ongoing Monitoring:**
- CD4+ count: every 3-6 months (can extend to annually if stable on ART with suppressed viral load and CD4+  300)
- Viral load: every 3-6 months, target  50 copies/mL
- Resistance testing: if viral load  1000 copies/mL on ART

**Opportunistic Infection Screening Thresholds:**

| CD4+ Count | Recommended Screening | Prophylaxis Indication |
|------------|----------------------|------------------------|
|  200 cells/μL | PCP prophylaxis | TMP-SMX daily |
|  100 cells/μL | Toxoplasma serology | TMP-SMX (if IgG+) |
|  50 cells/μL | CMV retinal exam | Consider prophylaxis |
| Any count | Annual TB screening | INH if LTBI+ |

**Drug Resistance Testing:**
- **Genotypic resistance testing**: recommended at baseline and treatment failure
- **Phenotypic resistance testing**: reserved for complex resistance patterns
- **Integrase resistance testing**: if planning integrase inhibitor-based regimen

[HIGH_YIELD] HIV diagnosis requires confirmation with a supplemental test due to potential false positives with screening assays. The 4th generation assays detect both antibodies and p24 antigen, reducing the window period.

[CLINICAL_PEARL] Viral load suppression to  50 copies/mL is the goal of ART and typically achieved within 12-24 weeks of initiating effective therapy.

**Current ART Guidelines:**
The goal of ART is to achieve and maintain viral suppression (HIV RNA  50 copies/mL) while reconstituting immune function and preventing HIV transmission.

**First-Line ART Regimens (2023 Guidelines):**

**Preferred Regimens:**
- **Bictegravir/tenofovir alafenamide/emtricitabine** (B/TAF/FTC)
- **Dolutegravir + tenofovir alafenamide/emtricitabine** (DTG + TAF/FTC)
- **Dolutegravir + tenofovir disoproxil fumarate/emtricitabine** (DTG + TDF/FTC)

**Alternative Regimens:**
- Efavirenz/tenofovir alafenamide/emtricitabine (EFV/TAF/FTC)
- Rilpivirine/tenofovir alafenamide/emtricitabine (RPV/TAF/FTC) - if viral load  100,000
- Darunavir/cobicistat + tenofovir alafenamide/emtricitabine

**ART Initiation Criteria:**


HIV Diagnosis Confirmed
├── Immediate ART Initiation ("Treatment as Prevention")
│   ├── All HIV-positive patients regardless of CD4+ count
│   ├── Special Populations:
│   │   ├── Pregnant women
│   │   ├── AIDS-defining illness
│   │   ├── HIV nephropathy
│   │   └── Hepatitis B co-infection
│   └── Patient Readiness Assessment:
│       ├── Understanding of lifelong therapy
│       ├── Adherence counseling
│       └── Drug interaction review


**Monitoring ART Response:**

**Virologic Response:**
- Expected viral load decline: 1-1.5 log₁₀ copies/mL by 4-8 weeks
- Target:  50 copies/mL by 12-24 weeks
- Virologic failure: confirmed viral load  200 copies/mL after 24 weeks

**Immunologic Response:**
- CD4+ count typically increases by 50-150 cells/μL in first year
- Slower response in patients with baseline CD4+  200 cells/μL
- [CLINICAL_PEARL] CD4+ response may be blunted in older patients and those with advanced disease

**Drug Interactions and Contraindications:**

| Drug Class | Key Interactions | Monitoring |
|------------|------------------|------------|
| Protease Inhibitors | Statins, anticoagulants, rifamycins | Liver enzymes, drug levels |
| NNRTIs | Rifamycins, proton pump inhibitors | Rash, hepatotoxicity |
| Integrase Inhibitors | Antacids, iron supplements | Generally well-tolerated |
| Entry Inhibitors | Limited interactions | CCR5 tropism testing |

**Treatment Failure Management:**
- Confirm adherence issues
- Review drug interactions
- Obtain resistance testing if viral load  1000 copies/mL
- Consider expert consultation for complex resistance

[HIGH_YIELD] Modern ART regimens are highly effective with  95% of treatment-naive patients achieving viral suppression. Single-tablet regimens improve adherence and clinical outcomes.

[KEY_CONCEPT] "Undetectable = Untransmittable" (U=U): Patients with suppressed viral loads cannot sexually transmit HIV, making ART a powerful prevention tool.

**Primary Prophylaxis Guidelines:**
Primary prophylaxis prevents the first occurrence of opportunistic infections in HIV patients with severe immunosuppression.

**Pneumocystis jirovecii Pneumonia (PCP):**
- **Indication**: CD4+  200 cells/μL or CD4+ percentage  14%
- **First-line**: Trimethoprim-sulfamethoxazole (TMP-SMX) 1 DS tablet daily
- **Alternatives**: Dapsone 100mg daily, Atovaquone 1500mg daily, Aerosolized pentamidine 300mg monthly
- **Discontinuation**: CD4+  200 cells/μL for  3 months on ART

**Toxoplasma gondii:**
- **Indication**: CD4+  100 cells/μL AND Toxoplasma IgG positive
- **First-line**: TMP-SMX 1 DS tablet daily (also covers PCP)
- **Alternatives**: Dapsone 50mg daily + pyrimethamine 50mg weekly + leucovorin 25mg weekly
- **Discontinuation**: CD4+  200 cells/μL for  3 months on ART

**Mycobacterium avium Complex (MAC):**
- **Indication**: CD4+  50 cells/μL
- **First-line**: Azithromycin 1200mg weekly or Clarithromycin 500mg twice daily
- **Alternative**: Rifabutin 300mg daily
- **Discontinuation**: CD4+  100 cells/μL for  3 months on ART

**Cytomegalovirus (CMV):**
- **Indication**: CD4+  50 cells/μL (controversial)
- **Screening**: Ophthalmologic examination every 6 months
- **Prophylaxis**: Not routinely recommended due to toxicity

**Prophylaxis Decision Algorithm:**


CD4+ Count Assessment
├── CD4+  200 cells/μL
│   ├── Start PCP prophylaxis (TMP-SMX)
│   └── Check Toxoplasma IgG
│       └── If positive → Continue TMP-SMX (covers both)
├── CD4+  100 cells/μL
│   ├── Continue PCP/Toxoplasma prophylaxis
│   └── Consider TB screening intensification
└── CD4+  50 cells/μL
    ├── Continue previous prophylaxis
    ├── Start MAC prophylaxis (Azithromycin)
    └── CMV retinal screening every 6 months


**Secondary Prophylaxis (Maintenance Therapy):**
Prevents recurrence after successful treatment of opportunistic infections.

| Infection | Maintenance Therapy | Duration |
|-----------|-------------------|----------|
| PCP | TMP-SMX 1 DS daily | Until CD4+  200 x 3 months |
| Toxoplasmosis | Sulfadiazine + pyrimethamine + leucovorin | Until CD4+  200 x 6 months |
| MAC | Clarithromycin + ethambutol | Until CD4+  100 x 12 months |
| CMV retinitis | Valganciclovir or ganciclovir | Until CD4+  100 x 6 months |
| Cryptococcosis | Fluconazole 200mg daily | Until CD4+  100 x 12 months |

**Immune Reconstitution Inflammatory Syndrome (IRIS):**
Paradoxical worsening of opportunistic infections after starting ART due to immune reconstitution.

**Risk Factors:**
- Low baseline CD4+ count ( 50 cells/μL)
- High baseline viral load
- Rapid CD4+ increase after ART initiation
- Recent opportunistic infection treatment

**Management:**
- Continue ART in most cases
- Treat underlying opportunistic infection
- Consider corticosteroids for severe IRIS
- NSAIDs for mild inflammatory symptoms

[HIGH_YIELD] TMP-SMX provides prophylaxis against both PCP and Toxoplasma, making it the preferred agent when both are indicated.

[CLINICAL_PEARL] Discontinuation of prophylaxis is based on immune reconstitution (sustained CD4+ increase) rather than viral load suppression alone.

**AIDS-Defining Conditions:**
The CDC defines AIDS by the presence of specific opportunistic infections, malignancies, or severe immunosuppression (CD4+  200 cells/μL) in HIV-positive patients.

**Major AIDS-Defining Illnesses by System:**

**Pulmonary:**
- **Pneumocystis jirovecii pneumonia (PCP)**
  - Presentation: dyspnea, dry cough, fever, bilateral infiltrates
  - Diagnosis: induced sputum or BAL with direct fluorescence
  - Treatment: TMP-SMX ± corticosteroids (if PaO₂  70 or A-a gradient  35)

**Gastrointestinal:**
- **Esophageal candidiasis**
  - Presentation: dysphagia, odynophagia, retrosternal chest pain
  - Diagnosis: clinical + response to antifungal therapy
  - Treatment: fluconazole 200-400mg daily x 14-21 days

- **Chronic cryptosporidiosis ( 1 month)**
  - Presentation: chronic watery diarrhea, weight loss
  - Diagnosis: acid-fast staining of stool or antigen detection
  - Treatment: nitazoxanide + ART for immune reconstitution

**Central Nervous System:**
- **Cryptococcal meningitis**
  - Presentation: headache, fever, altered mental status
  - Diagnosis: CSF India ink, antigen, culture
  - Treatment: amphotericin B + flucytosine x 2 weeks, then fluconazole

- **Toxoplasma encephalitis**
  - Presentation: focal neurologic deficits, seizures, altered consciousness
  - Diagnosis: brain imaging (ring-enhancing lesions) + serology
  - Treatment: sulfadiazine + pyrimethamine + leucovorin

**Comparison of CNS AIDS-Defining Illnesses:**

| Feature | Toxoplasmosis | Cryptococcal Meningitis | PML | CMV Encephalitis |
|---------|---------------|-------------------------|-----|------------------|
| CD4+ threshold |  100 cells/μL |  100 cells/μL |  200 cells/μL |  50 cells/μL |
| Imaging | Ring-enhancing lesions | Minimal enhancement | White matter lesions | Periventricular enhancement |
| CSF findings | Mild pleocytosis | High opening pressure | Normal | Mild pleocytosis |
| Treatment | Sulfadiazine/pyrimethamine | Amphotericin B/flucytosine | ART (no specific therapy) | Ganciclovir/foscarnet |

**Malignancies:**
- **Kaposi's sarcoma (HHV-8)**
  - Presentation: violaceous skin lesions, lymphadenopathy, visceral involvement
  - Treatment: ART + chemotherapy (liposomal doxorubicin) for extensive disease

- **Primary CNS lymphoma**
  - Presentation: focal neurologic symptoms, mass lesion on imaging
  - Diagnosis: brain biopsy (EBV-positive B-cell lymphoma)
  - Treatment: high-dose methotrexate-based chemotherapy + radiation

**Immune Reconstitution Inflammatory Syndrome (IRIS):**

**Unmasking IRIS:**
- Manifestation of previously subclinical opportunistic infection after ART initiation
- Typically occurs within first 3 months of ART
- Common pathogens: TB, cryptococcosis, CMV, hepatitis B

**Paradoxical IRIS:**
- Worsening of treated opportunistic infection after ART initiation
- Results from restored inflammatory response to residual antigens
- Management: continue ART, optimize OI treatment, consider corticosteroids

**Long-term Complications:**

**Non-AIDS Defining Conditions:**
- Cardiovascular disease (2-fold increased risk)
- Non-AIDS malignancies (anal, lung, liver, Hodgkin lymphoma)
- Bone disease (osteoporosis, osteonecrosis)
- Kidney disease (HIV nephropathy, ART toxicity)
- Neurocognitive impairment (HIV-associated neurocognitive disorder)

**ART-Related Complications:**
- Lipodystrophy and metabolic syndrome
- Bone loss and fractures
- Renal toxicity (tenofovir)
- Hepatotoxicity
- Drug interactions

[HIGH_YIELD] The presence of any AIDS-defining illness establishes an AIDS diagnosis regardless of CD4+ count and requires immediate ART initiation.

[CLINICAL_PEARL] IRIS is a sign of immune recovery and generally indicates ART effectiveness, but requires careful monitoring and symptomatic management.