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HIV and AIDS, Diagnosis, Therapy, Pathogenesis and Prognosis






    Definition


    HIV is a virus that targets and alters the immune system, increasing the risk and impact of other infections and diseases. Without treatment, the infection might progress to an advanced disease stage called AIDS

    Pathogenesis


    The viral envelope protein, glycoprotein (GP)-120, binds to the CD4 molecule on dendritic cells. Interstitial dendritic cells are found in cervicovaginal epithelium as well as tonsillar and adenoidal tissue, which may serve as initial target cells in infection transmitted via genital-oral sex.
    Viral entry into these cells is mediated by different coreceptors. In order to enter macrophages, GP-120 must bind to the chemokine receptor CCR5 as well as CD4.
    HIV infected cells fuse with CD4+ T cells, leading to spread of the virus. Once virus enters the blood, there is widespread dissemination to organs such as the brain, spleen, and lymph nodes.
    Viremia was documented between 5 to 30 days after experimental intravaginal HIV exposure.
    At the time of initial infection with HIV, patients have a large number of susceptible CD4+ T cells and no HIV-specific immune response. Viral replication is therefore rapid.
    With the emergence of virus specific CD8+ cytotoxic T lymphocytes, plasma RNA levels fall precipitously by 2 to 3 logs, and symptoms of the acute retroviral syndrome resolve. In the absence of antiretroviral therapy, plasma HIV RNA levels will stabilize at an individual's given "set-point" within six months of infection.

    Risk Factors


    -      men who have sex with men (MSM)
    -      injection drug users.
    -      blood product recipients
    -      healthcare workers with a needle-stick exposure
    -      Transmission of HIV during early infection is correlated with unprotected anal intercourse, the number of sexual contacts, and high rates of acute sexually transmitted diseases in MSM.
    -      Patients with early HIV infection are highly contagious to others

    Clinical manifestation


    The most common symptoms of early HIV-Disease are (acute retroviral syndrome):
    -      Fever till 40°c, the most common symptom
    -      Lymphadenopathy starting from week 2, mild hepatosplenomegaly
    -      sore throat
    -      rash: 3 days after fever onset, persists till to 5-8 days: small (5 to 10 mm), well-circumscribed, oval or round, pink to deeply red colored macules or maculopapules
    -      myalgia/arthralgia
    -      headache: some patients may show signs of aseptic meningitis, or self-limited encephalopathy.
    -      night sweets
    -      mucocutaneous ulcers: shallow, sharply demarcated ulcers with white bases surrounded by a thin area of erythema, on the oral mucosa, anus, penis, or esophagus
    -      opportunistic infections: usually accompanied with late stage HIV: in early stage of the disease could occur:
    oral or esophageal candidiasis, CMV-proctitis, pneumocystis carinii, cryptosporidiosis
    certain features, such prolonged duration of symptoms and the presence of mucocutaneous ulcers, are suggestive of the diagnosis.


    Diagnosis


    screening immunoassay: which detects either IgG/IgM against HIV-Antigen or HIV-Antigen p24 (core antigen being positive days after RNA have been positive). 10-15 days till positivity
    Confirmatory test with western blot: 35-45 days till intermediate positivity and 45-60 till positivity.
    NOTE: when screening test is positive and confirmatory test is negative, that doesn’t mean that the test for HIV is negative.
    HIV virologic (viral load) test, PT-PCT: 10-15 days till positivity.


    HIV-Infection
    Immunoassay
    Western blot
    PT-PCR
    -  or repeat test in 2 weeks (when high suspect)
    -

    -
    Consider false positive and repeat test
    -
    -
    Positive but <10000 copies/ml
    Early infection
    -

    +
    Early infection
    +
    -/intermidiate
    +
    Established infection
    +
    +
    +

    Interpretation of different laboratory tests.


    STAGES OF HIV-1 INFECTION


    HIV-1 infection is divided into the following stages:
    Viral transmission:
    Sexual intercourse, exposure to contaminated blood, or perinatal transmission.
    1-   Primary HIV infection (also called acute HIV infection or acute seroconversion syndrome):
    Approximate six months following HIV acquisition with nonspecific symptoms.
    Seroconversion:
    Is to seroconvert to positive HIV serology. It occurs mostly within 4 to 10 weeks after exposure using newer diagnostic tests, and ≥95 percent seroconvert within six months 
    2-   Clinical latent period:
    It extends from seroconversion to six months following HIV transmission. During the period of asymptomatic infection, patients generally have no findings on physical examination except for possible lymphadenopathy: generalized, at least two noncontiguous groups but the inguinal LK.
    NOTE:
    The half-life of HIV in serum is approximately 1.2 days, about 24 hours intracellularly, and about 6 hours as extracellular virus. About 30 percent of the total body viral burden is turned over daily.
    6 to 7 percent of the total CD4 cells turnover each day, and the entire supply of CD4 cells turns over every 15 days.
    Viral load is the most important predictor of progressive disease in early stages of HIV infection while the CD4 count is an important prognosticator in late stage disease
    3-   Early symptomatic HIV infection (more recently referred to as Class B according to the 1993 CDC classification):
    The B conditions are not AIDS-indicator conditions. But they tend to be more frequent and difficult when associated with HIV:
    -      Thrush
    -      VZV (affect two dermatomes)
    -      Vaginal Candida
    -      Listeriosis
    -      Cervical Dysplasia or Carcinoma in situ
    -      ITP
    -      Hairy leukemia
    -      Fever/diarrhea (persist more than one month)

    4-   AIDS: At this stage the immune response will be too weaken and AIDS-defined conditions will occur.
    Conditions that define an AIDS diagnosis:
    -      P. carinii pneumonia: 42.6 percent
    -      Esophageal candidiasis: 15.0 percent
    -      Wasting: 10.7 percent
    -      Kaposi's sarcoma:10.7 percent
    -      Disseminated M. avium infection: 4.8 percent
    -      Tuberculosis: 4.5 percent
    -      Cytomegalovirus disease: 3.7 percent
    -      HIV-associated dementia: 3.6 percent
    -      Recurrent bacterial pneumonia: 3.0 percent
    -      Toxoplasmosis: 2.6 percent
    -      Immunoblastic lymphoma: 1.9 percent
    -      Chronic cryptosporidiosis: 1.5 percent
    -      Burkitt lymphoma: 1.5 percent
    -      Disseminated histoplasmosis: 1.0 percent
    -      Invasive cervical cancer: 0.9 percent
    -      Chronic Herpes simplex: 0.5 percent
    -       
    Also a CD4 cell count below 200/mm³ with or without symptoms will be classified as AIDS.

    5-   Advanced HIV infection:
    characterized by a CD4 cell count below 50/mm3

    LONG-TERM NONPROGRESSORS: are patients affected with HIV who satisfy following criteria: approximately 4-7% of all HIV-Patients:
    -      HIV infection for at least 10 years
    -      No antiretroviral agents
    -      Lack of symptoms
    -      CD4 count above 500/mm3
    ELITE CONTROLLERS: a small minority of HIV-Patients 0,3%: who have HIV-seropositivity, who have no evidence of viremia, as measured by standard assays (either <50 or <75 copies/mL), and maintain high CD4 cell counts

    AIDS surveillance case definitions: All patients in categories A3, B3, C1-C3 are reported as AIDS 


    Differential Diagnosis


    -      mononucleosis due to Epstein-Barr virus (EBV) or cytomegalovirus (CMV)
    -      toxoplasmosis
    -      rubella
    -      syphilis
    -      viral hepatitis
    -      disseminated gonococcal infection
    -      other viral infections

    Therapy


    When to initiate an antiretroviral Therapy (ART)?
    -      In patients with acute symptomatic HIV infection, Grad 2c.
    -      For patients with asymptomatic early HIV infection who are committed to lifelong therapy, Grad 2c.
    -      For those asymptomatic individuals who are not committed to taking therapy or who have significant barriers to adherence, a strategy of monitoring without HIV treatment is reasonable. Clinical evaluation, CD4 cell count, and viral load testing every three months should be done.
    How long should take the therapy?
    Once initiated, ART is continued indefinitely.
    treatment interruption strategy in patients with acute or early HIV infection is NOT recommended, Grad 1A
    Antiretroviral Therapy (ART):
    -      Regimens are described as having a "backbone" and a "base":
    -      The backbone typically consists of two nucleoside reverse transcriptase inhibitors (NRTIs).
    -      The base includes either a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) or Integrase inhibitor (INSTIs)
    -      Antiretroviral therapy (ART) regimens should have at least three active antiretroviral medications
    -      In general, regimens with four active drugs are not recommended since they are not more efficacious than three-drug regimens
    Drug classes used in treatment-naive patients:
    1- Nucleoside (and nucleotide) reverse transcriptase inhibitors (NRTIs). E.g.: Truvada (tenofovir+emtricitabine). Combivir (zidovudine+lamivudine).
    SE: Kidney problems
    2- Non-nucleoside reverse transcriptase inhibitors (NNRTIs): e.g.: Efavirenz
    SE: CNS toxicity for the first 1-3 weeks of the therapy, teratogenic, require only a single mutation to confer drug resistance
    3- Protease inhibitors (PIs): ritonavir -boosted atazanavir or darunavir 
    SE: GI-problems, increase of Triglyceride In blood. PPI reduces the absorption
    4- Integrase strand transfer inhibitors (INSTIs): e.g.:  Raltegravir
    Disadvantages: should be given twice a day 400 mg x2
    5- CCR5 antagonists: e.g.: Maraviroc

    Boosting in ART:
    that means to use Ritonavir which is a PI and can as side effect inhibit the hepatic microsomal enzyme CYP (450) 3A4.  his characteristic is used to "boost" the serum concentration of other protease inhibitors.
    While Ritonavir in therapeutic dosage (600mgx2/day) alone can’t be used at any ART regimen due to the side effects, is a boosting dosage (400 mg/day) can work as enhancer to other PIs.  

    Examples of some regimens:
    2 NRTIs + PIs (Ritonavir 100 mg (booster) + atazanavir 300 mg or darunavir 80 mg).
    2 NRTIs + NNRTI (efavirenz 600 mg/day)
    2 NRTIs + Integrase inhibitor (Raltegravir 400 mg x2 /day)
    The recommended NRTI coformulation is (tenofovir-emtricitabine 300/200 mg/Day) in all of above regimens

    GOALS OF THERAPY:
    Suppression of HIV viral load to less than 50 copies/mL
    Restoration of immune function (as indicated by the CD4 cell count)
    Prevention of HIV transmission
    Prevention of drug resistance
    Improvement in quality of life

    Prognosis


    The life expectancy of a person who carries the HIV virus is now approaching that of a person that tests negative for the virus, as long as they adhere to a combination of medications called antiretroviral therapy (ART)
    Kaiser Permanente study in 2016 suggested that between 1996 and 2016, the gap in life expectancy between people who are HIV positive and HIV negative closed from 44 years to 12 years.

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