• ~39 million people living with HIV (PLHIV) worldwide (UNAIDS 2024 estimate)
• ~1.3 million new infections per year (declining from peak of 3.4 million in 1996)
• Sub-Saharan Africa carries the heaviest burden (~65% of all PLHIV)
• Since the introduction of combination ART (cART) in the mid-1990s, AIDS-related deaths have declined dramatically

In Hong Kong, the main risk groups are men who have sex with men (MSM) and heterosexual contacts ^[1][3].

• As of 2024, there are approximately 12,000+ reported HIV/AIDS cases cumulatively in HK
• MSM account for the majority of new diagnoses in recent years (~60–70%) ^[1]
• Heterosexual transmission remains significant (~25–30%)
• Injection drug use (IDU) accounts for a smaller but important proportion ^[1]
• Late diagnosis remains a problem — a significant proportion present with CD4 < 200 at first diagnosis ("late presenters")
• HIV-2 is very rare in Hong Kong; almost all cases are HIV-1 ^[1]

• Bimodal age distribution of new diagnoses: young MSM (20s–30s) and older heterosexual men (40s–50s)
• Male-to-female ratio approximately 4–5:1 in HK
• Vertical (mother-to-child) transmission is now very rare in HK due to screening and prophylaxis ^[1]

• Unprotected anal intercourse (highest per-act risk among sexual routes: receptive anal ~1.4%, insertive anal ~0.1%) ^[1]
• Unprotected vaginal intercourse (receptive vaginal ~0.08%, insertive vaginal ~0.04%)
• Presence of other STIs (especially ulcerative diseases like syphilis, HSV-2, chancroid) — disrupted mucosa + local inflammation recruit more CD4+ cells to the site ^[4]
• Multiple sexual partners
• Commercial sex without condom use

Why does HSV-2 increase HIV acquisition risk by 2–4×? ^[4] Because genital ulcers disrupt the mucosal barrier AND the inflammatory response recruits CD4+ T cells and dendritic cells to the ulcer site — the very cells HIV targets. This creates a "welcome mat" for HIV.

• Injection drug use (sharing needles/syringes) — per-act risk ~0.63% ^[1]
• Needle-stick injury (occupational) — per-act risk ~0.3% ^[1][3]
• Blood transfusion with contaminated blood — per-act risk > 90% (now extremely rare in HK due to screening) ^[1]
• Organ transplantation from infected donor

• In utero, intrapartum (during delivery), and postpartum (via breastfeeding) ^[1]
• Without intervention: 15–45% transmission rate
• With ART prophylaxis + elective C-section (if VL detectable) + avoidance of breastfeeding: < 1% ^[1]

• Higher viral load in the source = higher transmission risk (this is the single most important determinant) ^[1]
• Undetectable viral load = Untransmittable (U=U): validated by PARTNER study
• Circumcision reduces female-to-male transmission by ~50–60%
• Pre-exposure prophylaxis (PrEP) reduces risk by > 99% when taken consistently
• Co-infection with STIs (as above)

• CD4+ T cells are the "conductors of the immune orchestra" — they coordinate both cell-mediated and humoral immune responses
• They recognise antigens presented by MHC class II molecules on antigen-presenting cells (APCs)
• Subtypes:
  • Th1: activates macrophages, promotes cell-mediated immunity (critical for intracellular pathogens — TB, fungi, viruses)
  • Th2: promotes B-cell differentiation and antibody production
  • Th17: important for mucosal immunity and defence against extracellular bacteria and fungi
  • Treg: regulatory function, prevents autoimmunity
• Normal CD4 count: 500–1500 cells/μL ^[1]
• CD4 < 200 cells/μL = AIDS-defining threshold ^[1][2]

• Monocytes/Macrophages: express CD4 and CCR5; serve as viral reservoirs (long-lived)
• Dendritic cells (especially follicular dendritic cells): trap virus and present to CD4+ T cells in lymph nodes — ironically facilitating infection
• Microglial cells in the CNS: leads to HIV-associated neurocognitive disorders (HAND)

• Lymph nodes are the primary site of HIV replication during the asymptomatic phase
• Even when peripheral blood viral load is low, massive replication continues in lymphoid tissue (this explains why lymphadenopathy is common in HIV)
• GALT (Gut-Associated Lymphoid Tissue): massive CD4+ T-cell depletion occurs early in the gut, leading to disruption of the mucosal barrier and microbial translocation (chronic immune activation)

HIV belongs to the family Retroviridae, genus Lentivirus ^[1].

• "Retro-" → refers to reverse transcription (RNA → DNA, the reverse of the central dogma)
• "Lenti-" → Latin for "slow" — these viruses cause slowly progressive disease

Understanding the structure is critical because each component is a drug target:

Envelope (lipid bilayer from host cell membrane)
├── gp120 (surface glycoprotein) → binds CD4 receptor
├── gp41 (transmembrane glycoprotein) → mediates membrane fusion
│
Matrix (p17) → lines inner surface of envelope
│
Capsid (p24) → core protein, encloses the genome
│   ├── 2 copies of single-stranded RNA genome
│   ├── Reverse transcriptase (RT) → converts RNA to DNA
│   ├── Integrase → integrates viral DNA into host genome
│   └── Protease → cleaves polyproteins into functional proteins

This is the foundation for understanding ART — every drug class interrupts a specific step:

• HIV uses CD4 as its primary receptor but also requires a co-receptor ^[1]:
  • CCR5 (a chemokine receptor on macrophages and memory T cells): used by R5-tropic (macrophage-tropic) strains — predominant in early infection ^[1]
  • CXCR4 (on T cells): used by X4-tropic (T-cell-tropic) strains — associated with later disease and more rapid CD4 decline ^[1]
  • Dual-tropic viruses can use both

Individuals homozygous for the CCR5-Δ32 deletion are highly resistant to HIV-1 infection (because the virus cannot bind the co-receptor). This is found in ~1% of Northern Europeans. The "Berlin patient" (Timothy Ray Brown) was cured of HIV by receiving a bone marrow transplant from a CCR5-Δ32 homozygous donor. ^[1]

1. HIV crosses mucosal barriers and infects dendritic cells and CD4+ T cells at the site of entry ^[1]
2. Virus is transported to regional lymph nodes within 2 days
3. Massive viral replication occurs → viraemia peaks at 2–4 weeks post-exposure (viral load can reach millions of copies/mL) ^[1]
4. Widespread dissemination to all lymphoid organs, especially GALT ^[1]
5. Massive depletion of gut mucosal CD4+ T cells (the gut contains the majority of the body's CD4+ T cells — up to 60% are destroyed in the first few weeks)
6. Acute retroviral syndrome occurs in 40–90% of patients at this stage (see Clinical Features below) ^[1]
7. Immune response develops (CTLs + antibodies) → viral load decreases to a "set point" ^[1]

• After acute infection, the immune system partially controls viral replication
• The viral load stabilises at a "set point" — this set point is a strong predictor of disease progression ^[1]
• Higher set point → faster progression to AIDS
• The set point is determined by host immune responses (HLA type, CTL activity) and viral factors

• Clinically silent but immunologically and virologically ACTIVE ^[1]
• Massive viral turnover occurs in lymph nodes (10 billion virions produced/day, CD4 T cells destroyed and regenerated daily) ^[1]
• CD4 count declines gradually at a rate of ~50–80 cells/μL/year without treatment ^[1]
• The immune system compensates for a while by increasing CD4 production, but eventually the regenerative capacity is exhausted
• This phase lasts a median of 8–10 years without treatment ^[1][2]
• Some patients are "long-term non-progressors" (maintain high CD4 for > 10 years) or "elite controllers" (maintain undetectable VL without ART) — these are rare and related to host genetic factors (e.g., HLA-B57, HLA-B27)

Multiple mechanisms contribute:

1. Direct viral cytopathic effect: productive infection → cell lysis
2. Apoptosis of infected cells: viral proteins (especially Vpr) induce programmed cell death
3. Bystander apoptosis: uninfected CD4+ cells die due to chronic immune activation and exposure to viral proteins (gp120 binding to CD4 can trigger apoptosis even without productive infection)
4. CTL-mediated killing: cytotoxic T cells kill HIV-infected CD4+ cells
5. Syncytium formation: gp120/gp41 on infected cells binds CD4/co-receptors on uninfected cells → cell fusion → multinucleated giant cells that die
6. Pyroptosis: abortive infection of resting CD4+ cells triggers inflammatory cell death via caspase-1 activation → releases IL-1β → drives inflammation and attracts more CD4+ cells (a vicious cycle)
7. Thymic damage: HIV infects thymic epithelial cells → impairs new T-cell generation

This is now recognised as the central driver of disease progression:

• Chronic immune activation is caused by: ^[1]
  • Persistent viral replication
  • Microbial translocation from the damaged gut (LPS and other microbial products leak into the bloodstream)
  • Co-infections (CMV, EBV, etc.)
  • Residual viral proteins
• Leads to: T-cell exhaustion, accelerated ageing of the immune system, increased risk of non-AIDS events (cardiovascular disease, malignancy, neurocognitive decline) even when on ART

Without treatment: ^[1][2]

• Median time from infection to AIDS: ~8–10 years
• Median survival after AIDS diagnosis without treatment: ~1–2 years

Three phases of HIV infection: ^[2]

1. Acute infection (weeks)
2. Long period of asymptomatic phase (years)
3. Symptomatic AIDS phase ^[2]

This uses a matrix of CD4 count categories and clinical categories:

Any patient in category C or category 3 (CD4 < 200) has AIDS by CDC definition ^[1][2].

This is an exhaustive list — know the common ones in bold:

Opportunistic Infections:

• Pneumocystis jirovecii pneumonia (PCP) — most common OI in HIV ^[2]
• Oesophageal/tracheal/bronchial candidiasis
• Cerebral toxoplasmosis
• Cryptococcal meningitis
• CMV disease (retinitis, colitis, oesophagitis) — excluding liver, spleen, lymph nodes
• Mycobacterium avium complex (MAC/MAI) — disseminated
• Extrapulmonary or disseminated TB
• Progressive multifocal leukoencephalopathy (PML) — due to JC virus ^[5]
• Chronic intestinal cryptosporidiosis (> 1 month)
• Chronic intestinal isosporiasis (> 1 month)
• Disseminated histoplasmosis
• Disseminated coccidioidomycosis
• Talaromyces (Penicillium) marneffei — important in Southeast Asia/Southern China/Hong Kong ^[7]
• Recurrent Salmonella bacteraemia
• Recurrent bacterial pneumonia (≥2 episodes in 12 months)

Malignancies:

• Kaposi sarcoma — most common malignancy related to HIV ^[2] (caused by HHV-8)
• Primary CNS lymphoma (EBV-driven)
• Non-Hodgkin lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, primary effusion lymphoma)
• Invasive cervical cancer

Other:

• HIV wasting syndrome (involuntary weight loss > 10% + chronic diarrhoea or chronic weakness and fever)
• HIV encephalopathy (AIDS dementia complex)

Occurs 2–6 weeks after exposure in 40–90% of patients ^[1]. This is the time of peak viraemia before the immune response develops.

Think of it like a severe "mono-like" illness:

Symptoms (with pathophysiological basis):

Signs (with pathophysiological basis):

The acute retroviral syndrome is often missed because it mimics infectious mononucleosis (EBV), influenza, or secondary syphilis. Always have a high index of suspicion in patients with risk factors! ^[1]

• Patient is generally well
• May have persistent generalised lymphadenopathy (PGL) ^[1]: defined as palpable lymph nodes ≥ 1 cm at ≥ 2 non-contiguous extra-inguinal sites for ≥ 3 months
  • Why? Because lymph nodes are the primary site of viral replication — chronic antigenic stimulation causes follicular hyperplasia
  • Symmetrical, non-tender, rubbery, mobile nodes — most commonly cervical, axillary, occipital
  • PGL itself does NOT indicate progression
• Minor skin conditions may appear: seborrhoeic dermatitis (due to immune dysregulation), recurrent herpes simplex, warts, molluscum contagiosum
• Some patients develop haematological abnormalities: mild thrombocytopenia (immune-mediated — anti-platelet antibodies, similar mechanism to ITP)

As CD4 declines (typically 200–500), conditions appear that are not AIDS-defining but indicate immune compromise:

Symptoms and Signs (with pathophysiological basis):

IRIS occurs when a patient starts ART and the recovering immune system mounts an exaggerated inflammatory response against previously subclinical or treated OIs ^[1].

• Two types: ^[1]

  1. Paradoxical IRIS: worsening of a known, treated OI after starting ART
  2. Unmasking IRIS: previously undiagnosed OI becomes clinically apparent after ART initiation

• Typically occurs 2–12 weeks after starting ART ^[1]

• Risk factors: low baseline CD4 (especially < 50), high baseline VL, rapid immune recovery, pre-existing OI

• Common OIs involved: TB-IRIS (most common), MAC, cryptococcal meningitis, PML, KS, CMV

Why does IRIS happen? Before ART, the immune system was too weak to "see" the pathogen. When ART restores CD4+ T cells, they suddenly recognise the OI antigens and mount a massive inflammatory response — fever, lymphadenopathy, worsening of the OI symptoms.

The differential diagnosis of atypical lymphocytes / infectious mononucleosis-like syndromes includes: ^[8]

HIV infection can be associated with dysplastic haematopoiesis and variable cytopaenia ^[13] — this is important because it enters the DDx of MDS.

• Both HIV and syphilis are transmitted sexually and frequently co-exist ^[10]
• Secondary syphilis and acute HIV BOTH cause: generalised LAP, rash involving palms/soles, mucosal lesions, fever
• Always test for syphilis when diagnosing HIV, and always test for HIV when diagnosing syphilis ^[10]
• Syphilis can accelerate HIV progression, and HIV alters the natural history of syphilis (faster progression to neurosyphilis)

• Bidirectional relationship: HIV immunosuppression increases risk of TB activation; TB induces host TNF-α response which increases HIV viraemia ^[16]
• Co-infection leads to higher mortality than either alone ^[16]
• TB in the immunocompromised is harder to diagnose because many tests rely on intact host immune response (e.g., TST may be negative) ^[16]
• Recommendation: early bronchoscopy for respiratory specimen if pulmonary TB suspected in HIV ^[16]

• Share parenteral and sexual transmission routes
• HBV co-infection: tenofovir-based ART treats both; risk of HBV flare if ART containing tenofovir/emtricitabine is stopped
• HCV co-infection: more common in IVDU and MSM; accelerates liver fibrosis; genotypes 1 and 6 most common in HK ^[17]; DAAs are effective but check for drug interactions with ART

HIV tests have evolved over "generations" — each generation detects earlier markers and therefore shortens the window period:

Why is the 4th-generation test the current standard? Because during acute HIV infection, there is massive viral replication — p24 (capsid protein) is released into the blood before the immune system generates detectable antibodies ^[2]. By detecting p24 antigen AND antibodies simultaneously, the 4th-gen test closes most of the diagnostic "window."

This is the current standard approach used in most settings, including Hong Kong:

• In Hong Kong, voluntary counselling and testing (VCT) is available at Social Hygiene Service (SHS) clinics and NGO testing sites ^[1]
• Pre-test and post-test counselling is essential (informed consent before testing; discussion of result implications, window period, partner notification) ^[1]
• In HK, a reactive screening test is confirmed by a second method — typically the differentiation immunoassay or HIV-1 RNA ^[1]
• Rapid tests are available at some outreach sites but must be confirmed by laboratory-based tests ^[18]

For occupational exposure (needle-stick injury): ^[1][3]

Key principle: if the source is known HIV-positive or high-risk, start PEP as soon as possible (ideally within 1–2 hours), no later than 72 hours ^[1][3]. PEP details will be covered in the Management section.

This is critical because co-infections alter management and prognosis:

• Maternal IgG antibodies cross the placenta → serological tests (antibody-based) are UNRELIABLE until 18 months ^[1]
• Use HIV DNA PCR or HIV RNA PCR (virological tests) for diagnosis in infants
• Testing schedule: at birth, 4–6 weeks, and 4–6 months
• Two positive virological tests on separate samples confirm HIV infection in an infant

• Elite controllers maintain undetectable viral loads without ART
• They are HIV antibody-positive (4th-gen test will be reactive)
• Viral load may be undetectable or very low — does NOT mean they are uninfected
• CD4 counts are typically preserved

• Many patients in Hong Kong present late with CD4 < 200 and an AIDS-defining illness
• Always test for HIV in patients presenting with PCP, TB (especially extrapulmonary), candidiasis, cryptococcal meningitis, Kaposi sarcoma, unexplained weight loss, chronic diarrhoea, or persistent generalised lymphadenopathy ^[1][11]
• The OI itself may be the first clue to underlying HIV

• Traditional approach: "opt-in" — patient must specifically consent to HIV testing
• Modern approach (recommended by WHO, CDC): "opt-out" — HIV testing is offered as routine to all patients in healthcare settings, with the option to decline
• In HK, voluntary testing with informed consent remains the standard, but there is a push towards normalising HIV testing in clinical settings ^[1]

The current recommendation (WHO 2025, DHHS, BHIVA, IAS): START ART IN ALL HIV-POSITIVE INDIVIDUALS REGARDLESS OF CD4 COUNT ^[1][2].

This is based on landmark trials:

• START trial (2015): demonstrated benefit of immediate ART (at CD4 > 500) vs deferred ART — reduced serious AIDS and non-AIDS events by 57%
• TEMPRANO trial (2015): similar findings in West Africa
• Universal test-and-treat: the current global strategy — diagnose and start ART as early as possible

Why treat everyone regardless of CD4?

1. Clinical benefit: earlier treatment prevents immune damage, reduces non-AIDS events (CVD, renal disease, neurocognitive decline driven by chronic immune activation)
2. Prevention benefit: undetectable viral load = untransmittable (U=U) — ART prevents onward transmission
3. Public health benefit: reducing community viral load decreases epidemic spread

Exceptions / timing nuances for starting ART:

ART always involves a COMBINATION of drugs (cART — combination antiretroviral therapy), typically 2–3 agents from different classes ^[1].

Why combination therapy? HIV has an extraordinarily high mutation rate (due to error-prone reverse transcriptase — ~1 mutation per replication cycle). Monotherapy allows rapid selection of resistant mutants. Combining drugs with different mechanisms makes it virtually impossible for a single viral variant to be resistant to all drugs simultaneously. This is the same logic as TB treatment.

The backbone of modern ART: ^[1]

The WHO and most international guidelines now recommend INSTI-based regimens as preferred first-line ^[1]:

PrEP is the use of ART by HIV-negative individuals at high risk to prevent HIV acquisition ^[1].

Who should be offered PrEP? ^[1]

• MSM with inconsistent condom use, multiple partners, or history of STIs
• Serodiscordant couples (HIV+ partner not on ART or VL not suppressed)
• Transgender individuals at high risk
• IVDU (especially if sharing needles)
• Sex workers

If a person with HIV achieves and maintains an undetectable viral load ( < 200 copies/mL, ideally < 50) on ART, they CANNOT sexually transmit HIV ^[1].

This was proven by the PARTNER 1, PARTNER 2, and HPTN 052 studies — zero linked transmissions among thousands of serodiscordant couples when the HIV+ partner was virally suppressed.

Without intervention, MTCT risk is 15–45%. With comprehensive PMTCT, risk is < 1%. ^[1]

The most common cause of virological failure is non-adherence, NOT drug resistance ^[1]. Always assess and optimise adherence before assuming resistance. Adherence > 95% is needed for reliable viral suppression.

If first-line fails (INSTI-based): ^[1]

• Switch to a boosted PI-based regimen (e.g., DRV/r) + 2 new NRTIs (guided by resistance testing)
• If first-line was NNRTI-based (in settings still using NNRTIs first-line): switch to DTG-based regimen + optimised NRTI backbone

Third-line / salvage regimens (for multi-drug resistant HIV):

• Use newer agents: darunavir/r, dolutegravir (if not previously used), maraviroc (if R5-tropic), enfuvirtide, fostemsavir, ibalizumab (anti-CD4 monoclonal antibody), lenacapavir
• Always guided by resistance testing; aim for at least 2 fully active drugs in the new regimen

Different pathogens require different degrees of immunosuppression to cause disease. The CD4 count acts as a "gate" — as it drops lower, more "doors" open to increasingly aggressive pathogens:

Why is PCP the most common OI? ^[2] Pneumocystis jirovecii is ubiquitous — virtually all humans are exposed by age 2. A competent immune system (specifically CD4+ Th1 cells and alveolar macrophages) keeps it in check. When CD4 drops below 200, the alveolar immune defence collapses, and P. jirovecii proliferates in the alveoli, filling them with a characteristic foamy eosinophilic exudate → impaired gas exchange → progressive respiratory failure.

These are directly linked to the degree of immunosuppression and are considered AIDS-defining regardless of CD4 count:

With ART extending lifespans, these are now a leading cause of morbidity and mortality:

Key insight: With effective ART, AIDS-defining malignancies (KS, NHL) have decreased dramatically. However, non-AIDS-defining cancers (Hodgkin lymphoma, lung, liver, anal) now account for a growing proportion of cancer-related deaths in PLHIV.

1. Before ART: the immune system is too weak to "see" pathogens — high pathogen burden with minimal inflammation
2. After ART: rapid CD4+ T-cell recovery → newly functional T cells recognise abundant pathogen antigens → massive inflammatory response → clinical worsening
3. Essentially, it is a "too much, too fast" immune response

• Low baseline CD4 (especially < 50 cells/μL) ^[1]
• High baseline viral load
• Pre-existing OI at the time of ART initiation (especially with high pathogen burden)
• Rapid CD4 recovery and VL decline on ART
• Short interval between OI treatment and ART start

IRIS is NOT a reason to stop ART permanently — interrupting ART allows viral rebound, further CD4 decline, and ultimately death. The goal is to manage IRIS while continuing ART whenever possible.

This deserves special mention because it is a frequently tested exam point: ^[1]

• Occurs in ~5–8% of patients carrying HLA-B5701* ^[1]
• Multisystem reaction: fever, rash (maculopapular), GI symptoms (nausea, vomiting, diarrhoea, abdominal pain), respiratory symptoms (dyspnoea, cough), malaise
• Typically occurs within first 6 weeks of treatment
• Worsens with each dose — must stop immediately
• RECHALLENGE IS CONTRAINDICATED — can cause fatal anaphylactic-like reaction (hypotension, renal failure, death) ^[1]
• Prevention: test HLA-B5701 before prescribing; if positive, never use abacavir*

Management: Cardiovascular risk assessment (Framingham/QRISK), aggressive management of modifiable risk factors (smoking cessation, statins [avoid simvastatin/lovastatin with PIs — use atorvastatin or rosuvastatin instead], BP control, glycaemic control).

Pathophysiology of HAND: HIV crosses the BBB within monocytes ("Trojan horse" mechanism) and infects microglia and perivascular macrophages. These release neurotoxic factors (gp120, Tat, quinolinic acid, TNF-α) → neuronal injury, dendritic pruning, synaptic dysfunction. Even with suppressed VL in blood, the CNS may act as a sanctuary site with low-level viral replication.