HIV (Human Immunodeficiency Virus)

Overview

HIV is a retrovirus (Lentivirus family) that targets CD4+ T-lymphocytes, macrophages, and dendritic cells, progressively destroying cell-mediated immunity. Untreated, it leads to Acquired Immunodeficiency Syndrome (AIDS). Two types exist: HIV-1 (global, more virulent) and HIV-2 (predominantly West Africa, slower progression).

Transmission

Route	Key Details
Sexual contact	Most common globally; receptive anal intercourse carries highest per-act risk
Blood-borne	IV drug use, transfusions, needle-stick injuries
Vertical (mother-to-child)	In utero, intrapartum, or via breastfeeding
Healthcare personnel to patient	Extremely rare; mostly linked to substance use diversion

Risk is proportional to viral load — an undetectable viral load renders transmission effectively impossible (U=U: Undetectable = Untransmittable).

Pathophysiology

HIV binds CD4 receptors and CCR5/CXCR4 co-receptors on T-helper cells. The viral life cycle proceeds through:

Binding & fusion to CD4+ T-cell
Reverse transcription (RNA → DNA via reverse transcriptase)
Integration into host genome (provirus)
Replication and transcription
Assembly & budding of new virions

Normal HIV replication (Panel A) vs. disrupted life cycle in elite controllers and long-term nonprogressors (Panel B), showing failure of viral replication due to host genetic factors, restriction proteins (e.g., TRIM5α), or strong immune responses.

Progressive CD4+ T-cell depletion leads to immunosuppression. AIDS is defined as CD4 count < 200 cells/μL or the presence of an AIDS-defining illness.

Clinical Stages

1. Acute HIV Infection (2–4 weeks post-exposure)

Flu-like syndrome: fever, lymphadenopathy, pharyngitis, rash, myalgias, headache
Very high viral load; highly infectious
Often missed or misdiagnosed as mononucleosis

2. Chronic HIV Infection (Clinical Latency)

Asymptomatic or mild lymphadenopathy
Ongoing viral replication; CD4 count slowly declines
Can last years (median ~10 years untreated)

3. AIDS (CD4 < 200 cells/μL)

Susceptibility to opportunistic infections (OIs) and AIDS-defining malignancies

AIDS-Defining Conditions (Selected)

CD4 Threshold	Opportunistic Infections
< 500	Oral/vaginal candidiasis, TB, Kaposi sarcoma, lymphoma
< 200	Pneumocystis jirovecii pneumonia (PCP), Toxoplasmosis
< 100	Cryptococcal meningitis, disseminated MAC
< 50	CMV retinitis, disseminated MAC

Diagnosis

4th-generation Ag/Ab combination immunoassay — initial test of choice (detects both p24 antigen and antibodies)
HIV-1/HIV-2 differentiation immunoassay — confirmatory
HIV RNA PCR (viral load) — confirms acute infection when antibodies are not yet present; also used to monitor treatment
CD4+ T-cell count — staging, treatment decisions, OI prophylaxis thresholds

Management

Antiretroviral Therapy (ART)

Per Harrison's Principles of Internal Medicine (21st Ed., p. 5957), ART should be initiated as soon as possible following HIV diagnosis. The primary goals are:

Suppress viral load to undetectable (< 50 copies/mL)
Restore/preserve CD4 count
Prevent OIs and transmission

Note: A brief delay (several weeks) may be warranted before initiating ART in cases of cryptococcal or TB meningitis, to reduce the risk of severe Immune Reconstitution Inflammatory Syndrome (IRIS).

ART Drug Classes

Class	Mechanism	Examples
NRTIs	Inhibit reverse transcriptase (chain termination)	Tenofovir (TDF/TAF), Emtricitabine (FTC), Abacavir (ABC)
NNRTIs	Non-competitive reverse transcriptase inhibition	Efavirenz, Rilpivirine, Doravirine
PIs	Inhibit HIV protease	Darunavir, Atazanavir (+ ritonavir/cobicistat boost)
INSTIs	Inhibit integrase	Dolutegravir, Bictegravir, Raltegravir
Entry inhibitors	Block CCR5 or fusion	Maraviroc, Enfuvirtide

Preferred first-line regimens typically consist of 2 NRTIs + 1 INSTI (e.g., Bictegravir/TAF/FTC as a single daily tablet).

OI Prophylaxis (by CD4 threshold)

CD4 Count	Prophylaxis
< 200	TMP-SMX for PCP
< 100	TMP-SMX also covers Toxoplasma; add if seropositive
< 50	Azithromycin for MAC

Prevention

PrEP (Pre-Exposure Prophylaxis): TDF/FTC (Truvada) or TAF/FTC (Descovy) daily, or on-demand (2-1-1 regimen) — highly effective in high-risk individuals
PEP (Post-Exposure Prophylaxis): 28-day course started within 72 hours of exposure
Condom use, harm reduction programs, needle exchange
MTCT prevention: ART during pregnancy, elective C-section if viral load > 1000 copies/mL, avoidance of breastfeeding where safe alternatives exist

Prognosis

With modern ART, people living with HIV who are diagnosed early and maintain viral suppression have a near-normal life expectancy. The key predictors of outcome are:

Time to ART initiation
Adherence to therapy
CD4 count nadir
Presence of co-infections (HBV, HCV, TB)

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