HIV/AIDS

01Pathophysiology

HIV is a retrovirus that carries two copies of single-stranded RNA. After entry into the host, the viral enzyme reverse transcriptase converts viral RNA into double-stranded DNA. This proviral DNA is then integrated into the host cell genome by the enzyme integrase, allowing the virus to hijack the cell's machinery for replication.

The virus enters host cells by binding its envelope glycoprotein gp120 to the CD4 receptor on the surface of T-helper lymphocytes. A second binding event occurs with a co-receptor, either CCR5 (used predominantly during early infection, macrophage-tropic strains) or CXCR4 (used in later-stage disease, T-cell-tropic strains). After fusion (mediated by gp41), the viral contents are released into the cell. Understanding these steps is critical because each one represents a pharmacologic target: CCR5 antagonists (maraviroc), fusion inhibitors (enfuvirtide), NRTIs and NNRTIs (reverse transcriptase), integrase inhibitors (dolutegravir, bictegravir), and protease inhibitors (atazanavir, darunavir).

The natural history of HIV infection progresses through three phases. The acute retroviral syndrome phase occurs 2 to 6 weeks after exposure, during which the virus replicates explosively and the viral load peaks (often exceeding ${10}^{6}10^6$ copies/mL). CD4 counts drop sharply. This is why the patient develops a mononucleosis-like illness with high fever, pharyngitis, rash, and lymphadenopathy. The immune system partially controls the virus, establishing a viral set point that predicts the rate of disease progression.

During the clinical latency phase, the patient is largely asymptomatic, but the virus continues to replicate at low levels and progressively destroys CD4+ T cells at a rate of approximately 50 to 80 cells/microL per year without treatment. This phase can last 8 to 10 years.

When the CD4 count falls below 200 cells/microL, the patient meets the definition of AIDS and becomes vulnerable to opportunistic infections (OIs) and malignancies that a competent immune system would normally control. The progressive loss of cell-mediated immunity explains the entire spectrum of clinical disease: the lower the CD4 count, the more severe and unusual the infections.

02Classification and Clinical Manifestation

The clinical manifestations of HIV/AIDS are best understood by the CD4 count threshold at which each opportunistic condition typically appears. This table is extremely high-yield.

The CDC staging system classifies HIV by both CD4 count and clinical status:

Key AIDS-defining conditions to memorize include: PCP, Kaposi sarcoma, primary CNS lymphoma, non-Hodgkin lymphoma (Burkitt, immunoblastic), invasive cervical carcinoma, CMV retinitis, esophageal candidiasis, disseminated MAC, Toxoplasma encephalitis, Cryptococcal meningitis, chronic Cryptosporidium or Isospora diarrhea (> 1 month), progressive multifocal leukoencephalopathy, HIV encephalopathy, and HIV wasting syndrome.

03Diagnostic Workup

The current diagnostic algorithm follows a three-step sequence. Step one is the 4th-generation Ag/Ab combination assay, which is the recommended initial screening test for all patients. If this test is reactive, the lab reflexively performs step two: the HIV-1/HIV-2 antibody differentiation immunoassay. If step two confirms HIV-1 or HIV-2 antibodies, the diagnosis is established. If step two is negative or indeterminate (which occurs in very early infection when p24 antigen is present but antibodies have not yet developed), step three is performed: an HIV-1 RNA PCR (nucleic acid test). A detectable RNA confirms acute HIV-1 infection.

The older Western blot has been removed from the recommended algorithm because it is less sensitive during acute infection and takes longer to become positive.

Baseline laboratory evaluation at diagnosis should include: CD4 count and percentage, HIV-1 RNA viral load, genotypic resistance testing, HLA-B*5701, complete blood count, comprehensive metabolic panel (including renal and hepatic function), fasting lipid panel, fasting glucose or HbA1c, urinalysis, hepatitis A/B/C serologies, Toxoplasma IgG, syphilis screen (RPR or VDRL), tuberculosis screening (interferon-gamma release assay or tuberculin skin test), cervical or anal Pap smear, and pregnancy test in women of reproductive age.

A commonly tested concept: a patient presents with a mononucleosis-like syndrome (fever, pharyngitis, lymphadenopathy, rash) with a negative monospot (heterophile antibody) test. The next best step is an HIV Ag/Ab combination assay (and/or HIV RNA PCR if acute infection is strongly suspected). This is one of the most classic vignette setups.

04Management and Treatment

Opportunistic Infection Prophylaxis

Alternatives for patients with sulfonamide allergy (unable to take TMP-SMX): dapsone 100 mg daily (check G6PD first), atovaquone 1500 mg daily with food, or aerosolized pentamidine 300 mg once monthly via nebulizer (for PCP only, does not cover Toxoplasma).

ART Principles

ART regimens consist of a backbone (two nucleoside/nucleotide reverse transcriptase inhibitors, or NRTIs) combined with a third agent (an INSTI, a boosted protease inhibitor, or an NNRTI). Current guidelines strongly favor INSTI-based regimens due to high efficacy, high barrier to resistance (for dolutegravir and bictegravir), good tolerability, and few drug interactions.

The most commonly tested backbone combinations are emtricitabine/tenofovir disoproxil fumarate (TDF) and emtricitabine/tenofovir alafenamide (TAF). TDF is associated with nephrotoxicity and decreased bone mineral density. TAF has improved renal and bone safety but may increase lipids. An alternative backbone is abacavir/lamivudine, but this requires a negative HLA-B*5701 result and should be avoided in patients with high cardiovascular risk.

Exceptions to Immediate ART Initiation

In certain OIs, starting ART too quickly risks immune reconstitution inflammatory syndrome (IRIS), a paradoxical worsening of symptoms as the recovering immune system mounts an inflammatory response against residual pathogen antigens. The key exceptions are:

Prevention: Pre-Exposure Prophylaxis (PrEP)

Prevention: Post-Exposure Prophylaxis (PEP)

PEP must be initiated within 72 hours of exposure and continued for 28 days. The preferred regimen is emtricitabine/TDF + dolutegravir (or raltegravir). Baseline HIV testing of the exposed individual is required before starting PEP, and follow-up testing is done at 4 to 6 weeks, 3 months, and 6 months.

Pregnancy

ART should be continued (or initiated) in all pregnant women with HIV. Preferred regimens include dolutegravir-based combinations (now considered safe throughout pregnancy per updated guidelines, though earlier concerns about neural tube defects at periconception led to caution). Efavirenz should be avoided (teratogenicity). If the maternal viral load is > 1000 copies/mL (or unknown) near delivery, intravenous zidovudine is administered during labor. The newborn receives zidovudine syrup for 4 to 6 weeks (and additional agents if the mother's viral load was not suppressed). In resource-rich settings, breastfeeding is avoided due to the risk of transmission. Cesarean delivery is recommended if viral load is > 1000 copies/mL at 38 weeks.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most commonly tested "gotcha" in HIV questions is failing to recognize acute retroviral syndrome. The vignette will describe a young, sexually active patient presenting with a mononucleosis-like illness (fever, pharyngitis, lymphadenopathy, diffuse rash) and a negative monospot test. Many students instinctively select EBV or another viral syndrome and move on. The correct next step is to order an HIV Ag/Ab combination assay (or HIV RNA if acute infection is strongly suspected and antibody tests may still be negative). Remember: the monospot being negative is the signal, not a throwaway detail.

Another frequent trap involves when to start ART in the setting of an opportunistic infection. Students often default to "start ART immediately in everyone." While this is generally true, cryptococcal meningitis is the critical exception. Starting ART too early in cryptococcal meningitis causes severe, potentially fatal IRIS (paradoxical clinical worsening due to immune reconstitution). The correct answer is to treat the cryptococcal infection first (amphotericin B + flucytosine induction, then fluconazole consolidation) and delay ART for 4 to 6 weeks.

A third trap involves CD4-based prophylaxis thresholds. Students may confuse the cutoffs or forget that TMP-SMX at the standard dose covers both PCP and Toxoplasma prophylaxis, making it a two-for-one answer. When the CD4 falls below 50, the additional prophylaxis needed is azithromycin for MAC, which is a separate drug.

Students also miss the HLA-B*5701 testing requirement before prescribing abacavir. Failing to test leads to a potentially fatal hypersensitivity reaction. If the vignette mentions a new ART regimen containing abacavir and the patient develops fever, rash, GI symptoms, and respiratory complaints within the first 6 weeks, think abacavir hypersensitivity. The drug must be permanently discontinued and never rechallenged.

Finally, recognize that the "U = U" (Undetectable = Untransmittable) principle is testable. A patient on stable ART with a consistently undetectable viral load (< 200 copies/mL for >= 6 months) has effectively no risk of sexual transmission. This concept is important for counseling-based questions.

The core competency being tested across HIV/AIDS questions is threefold: (1) pattern recognition of acute and chronic presentations, (2) correct sequencing of the diagnostic algorithm (screening, then confirmatory, then RNA if needed), and (3) management logic, particularly around when to start ART, which prophylaxis corresponds to which CD4 threshold, and which drugs require pre-treatment testing (HLA-B*5701 for abacavir, G6PD for dapsone, co-receptor tropism for maraviroc).