# CD4 Count Thresholds & Opportunistic Infections

> What CD4 count thresholds predict which opportunistic infections?

The CD4 cutoffs that name each opportunistic infection, the current NIH rules for starting and stopping prophylaxis, CDC staging, ART timing, IRIS and HIV testing.

CD4 counts below 200 cells/mm³ predict Pneumocystis pneumonia; below 100, toxoplasmosis, cryptococcal meningitis and cryptosporidiosis; below 50, disseminated MAC, CMV retinitis and primary CNS lymphoma. Histoplasmosis risk rises below 150 and coccidioidomycosis risk below 250. Tuberculosis, bacterial pneumonia and Kaposi sarcoma occur at any count, so a normal number never excludes them.

## What CD4 count thresholds predict which opportunistic infections?

The CD4 count is the most important laboratory indicator of immune function in HIV, and the risk of each opportunistic infection climbs below its own threshold. Read the count before anything else in a stem, then climb down the ladder.

Some infections ignore the ladder. Tuberculosis occurs at any CD4 count, with risk rising as immunity falls. Bacterial pneumonia also occurs at any count, with the highest risk below 100. Herpes zoster is more common below 200 or with viremia. Kaposi sarcoma still appears in people whose virus is fully suppressed on ART, and most US cases occur in patients with high CD4 counts on ongoing ART.

Below **200**, *Pneumocystis jirovecii* pneumonia (PCP) appears: about 90% of cases occur under that line, as does most oral and esophageal candidiasis. Below **150**, disseminated histoplasmosis becomes a risk in endemic areas. Below **100** come *Toxoplasma* encephalitis (greatest risk under 50), cryptococcal disease (90% of cases) and chronic cryptosporidiosis. Below **50** come disseminated *Mycobacterium avium* complex (MAC), CMV end-organ disease, bacillary angiomatosis and primary CNS lymphoma. Related guides sit on the [Infectious Disease](/topics/infectious-disease) hub.

## The CD4 threshold table

The table lists fifteen conditions by CD4 threshold, with the clue that names each one and its first-line management.

| CD4 count (cells/mm³) | Condition | Classic clue | Key management |
| --- | --- | --- | --- |
| Any count | Tuberculosis | Below 200: no upper-lobe predilection, little cavitation, more extrapulmonary disease | TB therapy; ART within 2 weeks if CD4 <50, within 2-8 weeks if higher (later in TB meningitis) |
| Any count; risk highest <100 | Bacterial pneumonia | *S. pneumoniae* most common; two or more episodes in a year is AIDS-defining | Treat as community-acquired pneumonia; pneumococcal vaccines |
| Any count | Kaposi sarcoma (HHV-8) | Nontender hyperpigmented macules or nodules on skin and oral mucosa | ART alone for limited (T0) disease; add liposomal doxorubicin for advanced (T1) |
| <250 | Coccidioidomycosis | Southwestern US residence; new positive IgM or IgG | Fluconazole 400 mg daily if newly seropositive without disease |
| <200 | *Pneumocystis* pneumonia | Subacute dyspnea, dry cough, fever; bilateral ground-glass infiltrates | TMP-SMX for 21 days; prednisone if PaO₂ <70 mmHg or A-a gradient >=35 mmHg |
| <200, esophageal lower | Oral and esophageal candidiasis | Retrosternal pain and odynophagia; thrush may be absent | Fluconazole, 14-21 days for esophagitis |
| <200, occasionally higher | PML (JC virus) | Focal deficits progressing over weeks; white matter lesions, usually non-enhancing | ART; no specific antiviral exists |
| <150 | Disseminated histoplasmosis | Fever, weight loss, hepatosplenomegaly in endemic areas; urine or serum antigen | Liposomal amphotericin B, then itraconazole |
| <100 | *Toxoplasma* encephalitis | Headache, focal deficits, sometimes fever; multiple ring-enhancing lesions | Pyrimethamine + sulfadiazine + leucovorin, or TMP-SMX, for at least 6 weeks |
| <100 | Cryptococcal meningitis | Subacute headache and fever; meningismus in only a quarter to a third | Liposomal amphotericin B + flucytosine for 2 weeks, then fluconazole |
| <100 | Cryptosporidiosis | Watery diarrhea; oocysts on acid-fast stool stain | ART is the mainstay; nitazoxanide may be added to ART |
| <50 | Disseminated MAC | Fever, night sweats, weight loss, diarrhea, anemia, raised alkaline phosphatase | Clarithromycin or azithromycin plus ethambutol |
| <50 | CMV retinitis | Floaters, scotomata, peripheral field loss; fluffy yellow-white retinal lesions | Oral valganciclovir; add intravitreal ganciclovir or foscarnet if sight-threatening |
| <50 (median) | Bacillary angiomatosis (*Bartonella*) | Skin lesions that mimic Kaposi sarcoma; cats or body lice | Doxycycline or erythromycin |
| Very low, often <50 | Primary CNS lymphoma (EBV) | More often a single enhancing lesion; EBV DNA in CSF | Brain biopsy; ART plus radiation or high-dose methotrexate |

## Current US prophylaxis rules: when to start and when to stop

US prophylaxis rules come from the NIH Adult and Adolescent Opportunistic Infection guidelines, whose prophylaxis and discontinuation tables were last updated on May 27, 2026. Two current rules deserve emphasis: primary PCP prophylaxis is tied to a CD4 count below 200 in someone not yet on ART or just starting it, and MAC prophylaxis is not recommended when ART starts immediately.

| Infection | Start primary prophylaxis | Preferred regimen | Stop when |
| --- | --- | --- | --- |
| *Pneumocystis* pneumonia | CD4 <200 and not on ART or just starting it | TMP-SMX, one double-strength or single-strength tablet daily | CD4 >=200 for >=3 months on ART; can consider at CD4 100-200 with undetectable viral load for 3-6 months |
| *Toxoplasma* encephalitis | Toxoplasma IgG positive and CD4 <100 | TMP-SMX, one double-strength tablet daily | CD4 >200 for >3 months with suppressed viral load; can consider at 100-200 with undetectable viral load for 3-6 months |
| Disseminated MAC | CD4 <50 and not on ART, viremic on ART, or without a fully suppressive option; not if ART starts immediately | Azithromycin 1,200 mg weekly or clarithromycin 500 mg twice daily | Once on a fully suppressive ART regimen |
| Histoplasmosis | CD4 <150 plus occupational exposure or a hyperendemic area (over 10 cases per 100 person-years) | Itraconazole 200 mg daily | CD4 >=150 for 6 months on ART with an undetectable viral load |
| Coccidioidomycosis | New positive IgM or IgG, no active disease, CD4 <250 | Fluconazole 400 mg daily | CD4 >=250 with viral suppression |
| Latent tuberculosis | Positive screening test, active TB excluded and no prior treatment, at any CD4 count | Weekly isoniazid plus rifapentine for 12 weeks, or daily isoniazid plus rifampin for 3 months, each with pyridoxine | When the course is complete |

Restart PCP or toxoplasmosis prophylaxis if the CD4 count falls below 100 whatever the viral load, or sits at 100-200 with detectable virus. Restart MAC prophylaxis if the count drops below 50 without a fully suppressive regimen.

Three "no prophylaxis" rules are just as testable. Primary antifungal prophylaxis against cryptococcosis is not recommended; instead, newly diagnosed patients with CD4 ≤200 and no signs of meningitis are screened for serum cryptococcal antigen (CrAg). A positive result generally prompts a lumbar puncture. Normal CSF with a lateral-flow titer below 1:640 is treated preemptively with high-dose fluconazole plus ART, but a titer of 1:640 or higher is treated like cryptococcal meningitis even when the CSF is normal. Valganciclovir is not recommended to prevent CMV disease, even in patients with CMV viremia, and routine primary prophylaxis for candidiasis is not recommended either.

Drug choice carries its own traps. One double-strength TMP-SMX tablet daily prevents PCP and toxoplasmosis at once. Test G6PD before giving dapsone. Dapsone alone, aerosolized pentamidine and IV pentamidine are reserved for Toxoplasma-seronegative patients; dapsone with pyrimethamine and leucovorin, or atovaquone, are listed alternatives for both infections.

## How the CDC stages HIV, and what makes it AIDS

CDC surveillance staging uses the CD4 count first, uses the CD4 percentage only when the count is missing, and assigns stage 3 (AIDS) whenever a stage-3-defining opportunistic illness is diagnosed, regardless of the count, unless the stage 0 criteria are met. Stage 0 marks early infection: a negative or indeterminate HIV test within 180 days before the first confirmed positive result.

| Stage (age 6 and older) | CD4 count | CD4 percentage, used only without a count |
| --- | --- | --- |
| 1 | >=500 cells/µL | >=26% |
| 2 | 200-499 cells/µL | 14-25% |
| 3 (AIDS) | <200 cells/µL, or any stage-3-defining illness | <14% |

The stage-3-defining list in the 2014 case definition includes PCP, toxoplasmosis of the brain, extrapulmonary cryptococcosis, chronic intestinal cryptosporidiosis or isosporiasis, CMV disease and retinitis, disseminated or extrapulmonary MAC, tuberculosis, PML, Kaposi sarcoma, Burkitt, immunoblastic and primary brain lymphoma, invasive cervical cancer, recurrent pneumonia, recurrent *Salmonella* septicemia, disseminated or extrapulmonary histoplasmosis and coccidioidomycosis, chronic herpes simplex ulcers, HIV encephalopathy and HIV wasting syndrome. Candidiasis counts only in the esophagus, bronchi, trachea or lungs; oral thrush is not on the list.

## When ART starts, and when an infection delays it

ART is recommended for everyone with HIV regardless of CD4 count, started immediately or as soon as possible after diagnosis; same-day starts are one accepted strategy. Regimen choice is covered in [HIV antiretroviral drugs](/blog/hiv-antiretroviral-drugs-usmle).

Most opportunistic infections are not a reason to wait. ART should start within 2 weeks of a PCP diagnosis, and within 2 weeks of starting tuberculosis treatment when the CD4 count is below 50 (within 2-8 weeks at higher counts).

Meningitis is the exception. In cryptococcal meningitis, ART is generally deferred for 4 to 6 weeks after antifungal therapy begins, because a randomized trial found higher 6-month mortality with early ART (45% versus 30%). Tuberculous meningitis also warrants a short delay: ART starts once the meningitis is under control, after at least 2 weeks of TB treatment.

Suppression also protects partners: keeping the viral load below 200 copies/mL on ART prevents sexual transmission, the basis of Undetectable = Untransmittable.

## IRIS: worsening that means the immune system is recovering

Immune reconstitution inflammatory syndrome (IRIS) is a dysregulated inflammatory response to an opportunistic pathogen as ART restores immunity, usually within the first 6 months of treatment.

IRIS takes two forms. **Paradoxical** IRIS is worsening of an infection already diagnosed and on treatment; **unmasking** IRIS is a previously unrecognized infection that emerges after ART begins. Risk factors include starting ART at a CD4 count below 100 and starting it soon after treatment of an opportunistic infection. CMV, mycobacteria, *Cryptococcus*, JC virus and *Pneumocystis* are among the usual culprits.

In almost every case, continue ART and treat the inflammation; the NIH guidelines keep ART and antifungal therapy going even in IRIS after cryptococcal meningitis. Mild symptoms can be managed with NSAIDs or paracetamol, and severe lung or CNS involvement is likely to benefit from corticosteroids; for severe, unremitting MAC-associated IRIS, the guidelines allow prednisone 20-40 mg daily for 4-8 weeks. In tuberculosis, prednisone 40 mg daily for 2 weeks, then 20 mg daily for 2 weeks, is recommended to prevent paradoxical IRIS in high-risk patients: CD4 ≤100, starting ART within 30 days of TB treatment, responding to TB therapy, and without rifampin resistance, Kaposi sarcoma or active hepatitis B.

## Testing: diagnose with antigen/antibody, judge treatment by viral load

US laboratory diagnosis starts with a fourth-generation antigen/antibody combination immunoassay, which detects HIV-1 and HIV-2 antibodies plus p24 antigen. A reactive specimen goes to an HIV-1/HIV-2 antibody differentiation immunoassay, which replaced the Western blot; if that result is negative or indeterminate, an HIV-1 RNA test settles it.

Acute HIV presents with fever, lymphadenopathy, pharyngitis, rash, myalgia and arthralgia, and the laboratory signature is detectable HIV RNA or p24 antigen with a negative or indeterminate antibody result. According to CDC, nucleic acid tests usually detect HIV 10-33 days after exposure, laboratory antigen/antibody tests on venous blood 18-45 days, finger-stick antigen/antibody tests 18-90 days and antibody-only tests 23-90 days. CDC recommends testing everyone aged 13-64 at least once, and people at higher risk at least annually.

Infants under 18 months may carry transplacental maternal antibody, so diagnosis needs nucleic acid testing: for exposed infants at 14-21 days, 1-2 months and 4-6 months, plus at birth for all but those at low risk.

After diagnosis, two numbers do different jobs. Viral load is the most important indicator of response to ART, and adherent patients without drug resistance generally suppress within 8-12 weeks. The CD4 count is the key indicator of immune function and of the need for prophylaxis; an adequate response is a rise of 50-150 cells/mm³ in the first year. Virologic failure means failing to reach or keep HIV RNA below 200 copies/mL, and resistance testing is done on the failing regimen or within 4 weeks of stopping a non-long-acting regimen.

## Telling toxoplasmosis, CNS lymphoma and PML apart

Three focal brain processes dominate advanced HIV, and tempo, enhancement and one targeted test separate them.

| Feature | *Toxoplasma* encephalitis | Primary CNS lymphoma | PML |
| --- | --- | --- | --- |
| Usual CD4 | <100, highest risk <50 | Very low, often <50 | Usually <200, occasionally higher |
| Tempo | Hours to days | Hours to days | Steady progression over weeks |
| Imaging | Multiple ring-enhancing lesions, basal ganglia predilection, edema and mass effect | Ring-enhancing like toxoplasmosis, but more often a single lesion | White matter lesions without mass effect, usually non-enhancing |
| Key test | Toxoplasma IgG; a negative result makes it unlikely | EBV DNA in CSF, especially above 10,000 copies/mL | JC virus DNA in CSF |
| Next step | Empiric treatment; biopsy if no response | Brain biopsy | ART; no specific antiviral |

With ring-enhancing lesions and a positive Toxoplasma IgG, treat empirically. About 90% of patients respond clinically within 14 days; without a response, consider other diagnoses and strongly consider a brain biopsy. Cryptococcus usually presents as meningitis rather than a focal lesion, so its CSF picture belongs with the [meningitis differential](/blog/meningitis-bacterial-viral-fungal-usmle).

> **If you only remember one thing:** read the CD4 count first. Under 200 and not yet on ART: prevent PCP with TMP-SMX. Under 100 with a positive Toxoplasma IgG: the same TMP-SMX also prevents toxoplasmosis. Under 50: think MAC and CMV, but skip MAC prophylaxis when ART starts immediately. Any count: tuberculosis, bacterial pneumonia and Kaposi sarcoma. Viral load grades the drugs; CD4 grades the immune system.

## How this is tested on the exam

- **CD4 of 30, floaters and fluffy yellow-white retinal lesions.** Answer: CMV retinitis; oral valganciclovir, adding intravitreal ganciclovir or foscarnet if the lesion threatens vision.
- **New diagnosis, CD4 of 40, starting ART today.** Answer: TMP-SMX for PCP, which also covers toxoplasmosis if IgG is positive; screen serum CrAg; no MAC prophylaxis.
- **CD4 of 80, positive Toxoplasma IgG, several ring-enhancing basal ganglia lesions.** Answer: toxoplasmic encephalitis; pyrimethamine, sulfadiazine and leucovorin (or TMP-SMX), then reassess at two weeks.
- **Cryptococcal meningitis diagnosed this week in a patient not yet on ART.** Answer: liposomal amphotericin B plus flucytosine induction; defer ART for 4-6 weeks.
- **Fever and enlarging lymph nodes weeks after starting ART, with a falling viral load.** Answer: IRIS; continue ART and treat the unmasked infection.

## Common wrong-answer traps

- **Starting MAC prophylaxis in someone who begins ART immediately.** Current guidelines recommend against it, whatever the CD4 count.
- **Calling oral thrush AIDS-defining.** Esophageal, bronchial, tracheal or lung candidiasis is; oral thrush is not.
- **Starting ART on day one of cryptococcal meningitis.** Defer it 4-6 weeks after antifungals begin.
- **Stopping ART for IRIS.** Continue it and treat the inflammation; even IRIS after cryptococcal meningitis is managed without stopping ART.
- **Judging the regimen by the CD4 count.** Viral load measures the response; CD4 recovery takes months.
- **Giving valganciclovir because CMV is in the blood.** Primary prophylaxis is not recommended even with CMV viremia.
- **Using an antibody test in a young infant.** Before 18 months, maternal antibody can give a false positive, so use nucleic acid testing.
- **Prescribing dapsone without a G6PD test.** Check G6PD first.

## Sources

- NIH Adult and Adolescent OI Guidelines: [prophylaxis table](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/prophylaxis-prevent-first-episode), [stop and restart table](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/indications-discontinuing-and), [Pneumocystis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/pneumocystis), [toxoplasmosis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/toxoplasmosis), [MAC](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/disseminated), [cryptococcosis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis), [CMV](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cytomegalovirus), [tuberculosis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/mycobacterium), [histoplasmosis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/histoplasmosis), [coccidioidomycosis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/coccidioidomycosis), [PML](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/progressive), [candidiasis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/candidiasis), [cryptosporidiosis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptosporidiosis), [bartonellosis](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/bartonellosis), [bacterial pneumonia](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/community-acquired), [varicella-zoster](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/varicella-zoster), [HHV-8 and Kaposi sarcoma](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/human-herpesvirus)
- NIH Adult and Adolescent ART Guidelines: [starting ART](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/initiation-antiretroviral-therapy), [viral load and CD4 monitoring](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/plasma-hiv-1-rna-cd4-monitoring), [acute and recent HIV](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/acute-and-recent-early-hiv-infection), [virologic failure](https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/virologic-failure)
- NIH Perinatal Guidelines: [diagnosis of HIV in infants and children](https://clinicalinfo.hiv.gov/en/guidelines/perinatal/diagnosis-hiv-infection-infants-and-children)
- CDC: [2014 HIV surveillance case definition (MMWR)](https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm), [evaluation of the HIV diagnostic algorithm (MMWR 2013)](https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6224a2.htm), [HIV testing](https://www.cdc.gov/hiv/testing/index.html), [HIV Nexus testing guidance for clinicians](https://www.cdc.gov/hivnexus/hcp/diagnosis-testing/index.html)
- NCBI Bookshelf: [StatPearls, IRIS](https://www.ncbi.nlm.nih.gov/books/NBK567803/), [StatPearls, PML](https://www.ncbi.nlm.nih.gov/books/NBK560584/), [NCI PDQ, Kaposi sarcoma treatment](https://www.ncbi.nlm.nih.gov/books/NBK65897/), [NCI PDQ, AIDS-related lymphoma treatment](https://www.ncbi.nlm.nih.gov/books/NBK65743/)

HIV questions reward one reflex: read the CD4 count first. [Practice HIV/AIDS questions on StepGenie](https://dashboard.stepgenie.app/sign-up) and drill the thresholds, prophylaxis and CNS lesion split.

## Frequently asked questions

### Which CD4 counts trigger prophylaxis against opportunistic infections?

Under current NIH guidelines, start TMP-SMX against Pneumocystis when the CD4 count is below 200 in someone not on ART or just starting it, and against toxoplasmosis when it is below 100 with a positive Toxoplasma IgG. Give itraconazole below 150 to patients at high risk of histoplasmosis, and fluconazole below 250 after a new positive Coccidioides test without active disease. MAC prophylaxis below 50 is reserved for people who are not starting fully suppressive ART immediately.

### When can Pneumocystis and toxoplasmosis prophylaxis be stopped?

Stop primary Pneumocystis prophylaxis once ART has kept the CD4 count at 200 or above for at least 3 months; stopping can also be considered at 100 to 200 if the viral load has been undetectable for 3 to 6 months. Toxoplasmosis prophylaxis stops once the count has exceeded 200 for more than 3 months with suppressed virus, with the same 100 to 200 option. Restart either if the count falls below 100, or sits at 100 to 200 with detectable virus.

### Is MAC prophylaxis still recommended when the CD4 count is below 50?

Not for people who start ART immediately. The NIH guidelines recommend against primary prophylaxis for disseminated Mycobacterium avium complex in anyone who immediately initiates ART, regardless of CD4 count. Azithromycin 1,200 mg weekly or clarithromycin 500 mg twice daily is reserved for people with a CD4 count below 50 who are not on ART, remain viremic on ART, or have no fully suppressive option, and it stops once they are on a fully suppressive regimen.

### What CD4 count defines AIDS?

Under the CDC surveillance case definition, stage 3 HIV infection, or AIDS, is a CD4 count below 200 cells/µL in anyone aged 6 or older, or a CD4 percentage below 14% when no count is available. Any stage-3-defining opportunistic illness, such as Pneumocystis pneumonia, esophageal candidiasis, Kaposi sarcoma or toxoplasmosis of the brain, also establishes stage 3 regardless of the CD4 count. Oral thrush alone does not.

### How do you distinguish cerebral toxoplasmosis from primary CNS lymphoma?

Both can produce ring-enhancing brain lesions at very low CD4 counts, but toxoplasmosis usually causes multiple lesions with a basal ganglia predilection in a patient with positive Toxoplasma IgG, while lymphoma more often presents as a single lesion and is suggested by Epstein-Barr virus DNA in the CSF. Treat suspected toxoplasmosis empirically; about 90% of patients respond within 14 days, and failure to respond should prompt other diagnoses and a brain biopsy.

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