HIV

 

• Background

  Virology and pathophysiology

  • A single-stranded, RNA retrovirus. Usually HIV1, with HIV2 limited to parts of Africa.
  • Transmitted by sex (including oral), IV drug use, blood transfusions, and vertically.
  • Attaches to CD4 T cells and macrophages, then integrates into DNA, and moves to lymph nodes.
  • In active cells, it replicates then is released to infect new cells. In inactive cells, it lies dormant until reactivation.
  • CD4 destruction is primarily due to apoptosis of uninfected bystander cells.

  Time course of infection

  • 1-6 weeks post-infection, seroconversion illness occurs, similar to infectious mononucleosis.
  • Then latent as the immune system mounts partial response but CD4 counts drop progressively from the healthy level of around 800 cells/mm3. During this period, 30% develop persistent (>3 months) generalised lymphadenopathy.
  • After around 10 years, infections and cancers begin to develop.
  • Most infections are 'opportunistic', in the sense that in most people they are innocuous organisms. Other infections are simply more severe manifestations of infections that non-HIV carriers may get.
  • Other aspects of disease are due to the HIV infection itself: HIV dementia, HIV peripheral neuropathy, HIV wasting syndrome.
  • CDC staging by CD4 count: stage 1 ≥500, stage 2 <500, stage 3 <200 (or stage-3-defining opportunistic infection).

  AIDS

  • The term acquired-immunodeficiency syndrome (AIDS) was traditionally used to described a CD4 count <200 or the presence of an AIDS-defining illness. These are now the CDC criteria for stage 3 HIV.
  • AIDS-related complex (ARC) is an associated term, describing weight loss, fever, diarrhoea, and minor infections, occurring before AIDS criteria are met.
  • The term AIDS is now less used in clinical practice. This partly reflects the huge decline in AIDS (due to cART), but also the possible stigma surrounding the term. More practically, it is more useful to refer to specific CD4 counts, viral load, and infection history to give a picture of someone's clinical condition, than the non-specific 'AIDS'.
  • Advanced or late-stage HIV may be useful alternative terms to 'AIDS'.

• Signs and symptoms

  Seroconversion illness

  • Lymphadenopathy
  • Pharyngitis
  • Systemic: fever, malaise.
  • Pain: myalgia, headache.
  • Maculopapular rash.
  • Lasts 1-2 weeks.

  Presentations by system

  Respiratory:

  • Pneumocystis jiroveci pneumonia (PJP or PCP). Fungal infection. Causes dry cough, sweats, SOB and desaturation on exertion, but no chest signs.
  • Other fungal infections: Aspergillus, Cryptococcus, Histoplasma.
  • TB: pulmonary TB or atypical and disseminated forms such as miliary TB and TB meningitis.
  • Strep and Staph pneumonia.
  • CMV

  Neurological:

  • Toxoplasma encephalitis: protozoal infection. Focal neurological signs.
  • Cryptococcal meningitis: fungal infection. Causes insidious, chronic meningitis, usually without stiff neck.
  • Primary cerebral lymphoma.
  • Progressive multifocal leukoencephalopathy (PML): JC virus infection.
  • HIV dementia: neurological decline in multiple domains, in the absence of other infection.
  • HIV peripheral neuropathy.

  Skin:

  • Kaposi's sarcoma: due to human herpesvirus 8. Purple papules on the face, mouth, back, lower limbs, or genitalia. Can also affect GI and respiratory tract.
  • Multi-dermatomal zoster (shingles).
  • Recalcitrant psoriasis.

  Mouth:

  • Oral and oesophageal candidiasis.
  • Oral hairy leukoplakia: non-malignant white growths on lateral tongue due to EBV.
  • HSV and aphthous mouth ulcers.

  GI:

  • Cryptosporidiosis: protozoa. Chronic diarrhoea.
  • CMV colitis.
  • HIV wasting syndrome: unexplained weight loss >10%.
  • Mycobacterium avium complex (MAC): GI, lung, or disseminated.
  • Fungal: Cryptococcus, Histoplasma.
  • Other bacteria: Salmonella, Shigella.
  • Hepatitis B and C.

  Cancer:

  • B-cell lymphoma. EBV-related.
  • Cervical and anal cancers. HPV-related.
  • Lung cancer.
  • Head and neck cancers.

  Eye:

  • CMV retinitis. Mozzarella pizza sign on fundoscopy.

  Infections by CD4 level

  • 200-500: TB, candida, VZV, Kaposi's, other pneumonias.
  • 100-200: PCP, histoplasmosis, PML.
  • 50-100: atypical TB, CMV retinitis/colitis, toxoplasmosis, cryptosporidiosis, cryptococcal meningitis.
  • <50: MAC.

• Investigations

  Diagnosis:

  • Serum HIV combined antibody + p24 antigen test to screen, then confirm with Western Blot. 50% detectable within 1 month of infection, and nearly all by 6 months.
  • If +ve, screen for: TB (tuberculin skin test), hepatitis A-C, syphilis, Toxoplasma, CMV.
  • Genotype testing to guide drug treatment.
  • Pregnancy test for women.
  • Baseline bloods: FBC, U&E, LFT, lipids, glucose.

  Tests for specific presentations:

  • PCP: CXR shows bilateral interstitial infiltrates.
  • Toxoplasma: contrast-enhancing lesions on CT/MRI brain.
  • Cryptococcal meningitis: cryptococcal antigen in CSF and serum.

  Monitoring:

  • 3 to 6 monthly: CD4 count, HIV quantitative RNA PCR ('viral load'), FBC.
  • Annual: U&E and LFTs, lipids, glucose.

• Management

  Lifestyle and preventative:

  • Counselling to prevent high-risk sexual behaviour. Lifelong condom use traditionally recommended, but good evidence that those with undetectable viral load cannot transmit even during condomless sex. Specific methods are available for reproduction in serodiscordant couples e.g. IUI with sperm washing, IVF with ICSI.
  • Assistance with partner notification and contact tracing.
  • Vaccines: hepatitis A and B, annual flu, pneumococcal vaccine, HPV. Avoid live vaccines if CD4 <200: VZV, MMR, BCG, oral and intranasal vaccines, yellow fever.

  Combination antiretroviral therapy (cART, aka highly-active ART [HAART]):

  • Triple therapy: {2 x NRTI} + {NNRTI or protease inhibitor or integrase inhibitor}.
  • When to start: the traditional thresholds were CD4 ≤350, AIDS-related illness, or pregnancy. However, research now suggests clear benefits of starting treatment as soon as the diagnosis is made.

  Treating co-infection:

  • Active TB: standard 4-drug regimen. Overlapping toxicities and drug interactions make TB-HIV co-treatment difficult, but if CD4 <350 (and especially <100), cART should be started as soon as practical e.g. within 1-2 months of starting TB treatment.
  • Latent TB: 6 months isoniazid and pyridoxine.
  • Hepatitis C: combination direct-acting antivirals (see viral hepatitis), paying attention to drug interactions.

  Prophylactic antibiotics:

  • Co-trimoxazole for PCP and toxoplasma if CD4 <200.
  • Azithromycin for MAC if CD4 <50.

  The following measures during pregnancy reduce the risk of vertical transmission to near zero:

  • cART, regardless of CD4.
  • Delivery: vaginal if virally supressed, C-section if viral load >50 copies/ml, plus intrapartum IV zidovudine infusion if viral load >1000 copies/ml.
  • No breastfeeding.
  • 4 weeks ART for baby: zidovudine if maternal viral load <50, cART if >50.

• Antiretroviral therapy (ART)

  Common side effects

  GI:

  • Diarrhoea and vomiting.
  • Hepatitis, especially nevirapine.

  Skin:

  • Mild rash.
  • In rare cases, hypersensitivity or SJS/TEN.

  Metabolic:

  • Lipodystrophy: fat reduction peripherally (head and limbs) but gain centrally. Seen with protease inhibitors and NRTIs.
  • Diabetes and dyslipidaemia. Especially with protease inhibitors, but possible with all.

  Common drug interactions

  • AEDs: phenytoin and carbamazepine should be avoided.
  • Sildenafil: use lower dose.
  • Lorazepam should be avoided.

  Nucleoside reverse transcriptase inhibitors (NRTI)

  Drugs:

  • Common combinations: emtricitabine/tenofovir, abacavir/lamivudine, lamivudine/zidovudine.
  • Others: didanosine, stavudine.

  Side effects:

  • Osteoporosis (tenofovir).
  • Myocardial infarction (abacavir).
  • Peripheral neuropathy.
  • Pancreatitis (didanosine, stavudine).
  • Lactic acidosis.
  • Zidovudine: myelosuppression, myopathy.

  Non-nucleoside reverse transcriptase inhibitors (NNRTI)

  • Drugs: nevirapine, efavirenz.
  • Side effects: psychosis and vivid dreams (efavirenz).
  • Interactions: warfarin.

  Protease inhibitors

  Drugs: indinavir, atazanavir, lopinavir, ritonavir (boosts others).

  Side effects:

  • Gallstones and ↑BR (atazanavir).
  • Kidney stones (indinavir).

  Interactions:

  • Rifampicin
  • Digoxin: use lower digoxin dose.
  • Oral contraception: use higher contraceptive dose.

  Others

  • Integrase inhibitors: dolutegravir, raltegravir.
  • Entry and fusion inhibitors: enfuvirtide, maraviroc (CCR5 antagonist).