Block_PBL_C4T1_The stages and natural history of HIV infection


The human immunodeficiency virus (HIV) pandemic has spread to every country in the world and has infected 59 million persons worldwide, including 20 million who have already died.

An estimated 1.1 million persons in the United States have been infected with HIV; at the end of 2003, c.a. 405,926 persons were living with AIDS. The number of reported cases in 2003 was essentially the same as the number in 1999. This trend follows a period of sharp decline in reported cases after the introduction of HAART.


Seroconversion – the development of detectable specific antibodies to microorganisms in the blood serum as a result of infection or immunization; often used in reference to blood testing for anti-HIV antibodies. In particular, "seroconverted" has been used to refer to the process of having "become HIV positive."

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Seroreversion – opposite of seroconversion, i.e. when the tests can no longer detect antibodies in a pt’s serum. Long-term nonprogressors – exhibit remarkable clinical stability and remain asymptomatic over many years without antiretroviral therapy; historically defined as HIV infection for at least 10 years, no antiretroviral agents, lack of symptoms, CD4 count above 500/mm3 The main correlate with delayed progression is low viral burden (eg, 1000 to 10,000 copies/mL) that probably reflects an effective immunologic response with HIV-specific CD4 T cells early in the course of infection [35].

Elite controllers – HIV-seropositive individuals who have no evidence of viremia, as measured by standard assays (either <50 or <75 copies/mL), and maintain high CD4 cell counts. These patients represent a small minority of HIV-infected individuals (1/300 patients) and the mechanisms that lead to spontaneous virologic control without treatment are unknown. Several factors may be responsible for spontaneous virologic control among individual elite controllers including infection with a defective HIV variant or host genetic polymorphisms

STAGES OF HIV-1 INFECTION HIV-1 infection is divided into the following stages:
1. 2. 3. 4. 5. 6. 7.

Viral transmission Primary HIV infection (also called acute HIV infection or acute seroconversion syndrome) Seroconversion Clinical latent period with or without persistent generalized lymphadenopathy (PGL) Early symptomatic HIV infection AIDS (AIDS indicator condition according to the 1987 CDC criteria and revised 1993 CDC criteria that include a CD4 cell count below 200/mm3 regardless of the presence or absence of symptoms) Advanced HIV infection characterized by a CD4 cell count below 50/mm3

_____________________________________________________________________________________________ 1. VIRAL TRANSMISSION

there were no cases of transmission among the 51 subjects with HIV RNA levels less than 1500 copies/mL.45 for seroconversion.254 compared with 38. Furthermore.Block_PBL_C4T1_The stages and natural history of HIV infection  Route for HIV transmission: acquired through sexual intercourse (vaginal sex. 1. 90 patients seroconverted (21.23. with a rate ratio of 2.7 percent).2 Sexually transmitted diseases  Presence of STD  increases the risk of HIV acquisition In a study of 174 monogamous Ugandan couples with discordant HIV serostatus.MBBS_H. lack of circumcision. Over a 30 month follow-up period. each log increment in viral load was asso.3 Sexual risk  In a study that enrolled 3257 MSM in six US cities from 1995 to 1997. 95% CI 1. Multiple other studies have confirmed these results. transfusion).N.1 Viral load  A dose response relationship of increased transmission with increased viral load was defined The influence of viral load in relation to other potential risk factors for heterosexual transmission of HIV was examined in a prospective study of 415 Ugandan couples with discordant HIV serostatus. nitrate inhalant use. The probability of transmission was approximately four times higher in patients with genital ulceration compared to those without. exposure to contaminated blood (injection drug use IDU.5 Genetic background  Similarity of HLA-class-I alleles between HIV discordant couples may affect the risk of transmission. and use of nitrate inhalants. presence of ulcerative sexually transmitted diseases. or perinatal transmission  Risk factors for HIV transmission: viral load.029 copies/mL). bl.4 Lack of circumcision  Associated with risk of HIV transmission in cohorts of heterosexual couples and MSM 1. PRIMARY HIV INFECTION  Symptoms and disease progression .52 to 3. The following findings were noted:  The efficiency of transmission was approximately the same for female to male as for male to female. by selecting for viral strains that are more likely to escape the immune containment of the seronegative partner  Sharing of HLA-B alleles was associated with accelerated intracouple transmission of HIV after controlling for other variables (hazard ratio 2. and host and genetic factors 1.26) 2. risk factors for HIV seroconversion: history of a large number of sexual partners.  There are few studies documenting oral transmission of HIV infection.  In multivariate analysis. sexual risk. unprotected receptive anal sex with a partner with an unknown HIV serostatus.  The mean viral load was significantly higher in those who transmitted HIV to their partner (90. this could reflect low titers of infectious virus in saliva. male-to-male sexual contact MSM). 1. 1.

of antiretroviral Tx After c. The lymph node architecture is disrupted and more HIV is released peripherally into the bloodstream as the disease progresses. intracellular and extracellular comp.  The lymphoid tissue serves as the major reservoir for HIV. Studies of the lymph nodes at this stage reveal high concentrations of extracellular HIV on the follicular dendritic cell processes within germinal centers and intracellular HIV predominantly in its latent form. The viral burden in peripheral blood mononuclear cells is relatively low at this time. lower early CD4 T cell counts. and ≥95 percent seroconvert within six months  Median time from exposure to positive serology in one study was 63 days 4. and symptomatic primary HIV infection predicted faster progression to death 3.MBBS_H. there is marked variability in disease progression.N. 24 hr. patients generally have no findings on physical examination except for possible lymphadenopathy  "Persistent generalized lymphadenopathy" (PGL) is defined as enlarged lymph nodes involving at least two noncontiguous sites other than inguinal nodes.  Viral dynamics  Asymptomatic HIV infection: high rates of HIV replication and destruction of an average of 10(9) CD4 cells daily with near balance of cell death and replacement  A relatively steady state of cell counts and viral load (e. **The persistence of detectable HIV RNA in plasma after primary HIV infection was associated with the development of AIDS and significant CD4 T cell count declines.f. The follicular dendritic cells in lymphoid tissue filter and trap free virus and infected CD4 T cells. ***Higher set point viremia.g. are approximately 1.Block_PBL_C4T1_The stages and natural history of HIV infection  Presence of symptoms and a prolonged illness (>14 days) appears to correlate with more rapid progression to AIDS  (78 versus 10 percent) than in those who were asymptomatic or had only mild symptoms  Level of viremia at seroconversion   Following HIV seroconversion.a. ↑ turnover rates of HIV (30% per day) and CD4 cells (6 – 7% per day)  The half-life of HIV in serum. in the abs. CLINICAL LATENT PERIOD   Period of early HIV disease: seroconversion to six months following HIV transmission During the period of asymptomatic infection. 6 m of infection  plasma viremia reaches a steady state level *CD8 Tc cells play a critical role in achieving equilibrium and preventing further decline in CD4 cell compartment. 6 hr respectively . stable HIV RNA levels) is achieved despite s.2 d. SEROCONVERSION  Most patients seroconvert to positive HIV serology within 4 to 10 weeks after exposure using newer diagnostic tests.

Peripheral neuropathy. frequent. 1000/mm3. Idiopathic thrombocytopenic purpura. Herpes zoster (involving two episodes or more than one dermatome).MBBS_H. Listeriosis  Also asso. w/ HIV infection However.   After 1y. Bacillary angiomatosis.Symptomatic (not A or C) C. the rate of CD4 cell decline averages about 50/mm3 per year. they are not AIDS-indicator conditions 6. Cervical carcinoma in situ. EARLY SYMPTOMATIC HIV INFECTION  Also called "Class B" according to the CDC 1993 classification system and was formerly called "AIDS-related complex".Block_PBL_C4T1_The stages and natural history of HIV infection  Implication of these observations is that "AIDS is primarily a consequence of continuous. leading to virus and immune-mediated killing of CD4 lymphocytes"  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  CD4 T cell dynamics   Considerable variation between patients in CD4 cell count and viral burden during this period Population-based studies of natural history of HIV infection in MSM show that the mean CD4 count prior to seroconversion is c.a. previously known as "AIDS-related complex" or ARC  Examples of B conditions in early symptomatic HIV infection: Thrush. with a range of 30 to 90/mm3 per year The rapid decline in CD4 cells in the early stages of HIV infection may reflect destruction of CD4 cells or a shift of CD4 cells from the peripheral blood to lymphatic tissue  A subset of patients has sustained high levels of CD4 cells. Pelvic inflammatory disease (esp if complicated by a tubo-ovarian abscess). PGL or acute HIV infection Clinical categories B*. The subsequent revised CDC classification has three ranges of CD4 cell counts and uses a matrix of nine mutually exclusive categories: CD4 cell categories A.  The 1987 definition of AIDS included conditions indicative of severe immunosuppression.AIDS indicator condition (1987) B1 B2 B3 C1 C2 C3 >500/mm3 (≥29 %) 200-499/mm3 (14-28%) <200/mm3 (<14%) A1 A2 A3 . Oral hairy leukoplakia. with many disorders. BUT more frequent and severe when asso. high-level replication of HIV-1.N.5°C or diarrhea for more than one month). AIDS  The definition of AIDS has evolved since the beginning of the epidemic. The count decreases to a mean of 780/mm3 at 6m post-seroconversion and to 670/mm3 at 1y. 5. The term "chronic nonprogressor" is sometimes used in reference to these patients.Asymptomatic. or difficult to manage). Cervical dysplasia. Constitutional symptoms (such as fever ~38. Vaginal candidiasis (that is persistent. especially defective cell-mediated immunity.

Immunoblastic lymphoma (1.  In advanced HIV infection. invasive cervical cancer.7%).  Humoral immunity generally improves dramatically after the initiation of antiretroviral therapy. and pulmonary tuberculosis. Wasting (10. 41:1.  The median time from the onset of severe immunosuppression (defined as a CD4 cell count below 200/mm3) to an AIDS-defining diagnosis (1987 criteria) is 12 to 18 months in persons not receiving antiretroviral treatment.Block_PBL_C4T1_The stages and natural history of HIV infection 1993 AIDS surveillance case definition for adolescents and adults.5%) 7. Recurrent bacterial pneumonia (3.7%). many of these antibodies are non-specific  may explain the paradox between high circulating levels of immunoglobulins and an ↑ risk of bacterial infections (eg. Toxoplasmosis (2.5%). Chronic Herpes simplex (0. B3.8%). carinii pneumonia (42. B cells exhibit increased expression of markers of activation and proliferation.6%). Examples of B conditions include (but are not limited to) those listed above. Their median survival is 12 to 18 months in the absence of antiretroviral therapy. * Symptomatic conditions not included in category C that (a) are attributed to HIV infection or indicate a defect in cell-mediated immunity or (b) are conditions considered to have a clinical course or to require management that is complicated by HIV infection.9%). ADVANCED HIV INFECTION Patients with advanced HIV infection have a CD4 cell count below 50/mm3.N. Burkitt lymphoma (1.5%). The following was the rank order of first AIDS-defining conditions in the CDC Adult/Adolescent Spectrum of HIV Disease Sentinel Surveillance Project: P.0%). humoral immunity wanes over time. Invasive cervical cancer (0. Kaposi's sarcoma (10. Disseminated M. Esophageal candidiasis (15%).  As with depletion of CD4 T cells.704 new cases in the 1997 fiscal year. All patients in categories A3. Tuberculosis (4.%). Cytomegalovirus disease (3. This may lead to a polyclonal hypergammaglobulinemia  However. recurrent pneumonia) that occurs in late-stage AIDS. B cells undergo terminal differentiation leading to increased immunoglobulin secretion. .9%). avium infection (4.6%). the CDC reported 71. Conditions that define an AIDS diagnosis Prior to the HAART era. Disseminated histoplasmosis (1. Chronic cryptosporidiosis (1.6%). C1-C3 are reported as AIDS based upon prior AIDS-indicator conditions and/or a CD4 cell count <200/mm3. Virtually all patients who die of HIV-related complications have CD4 cell counts in this range.5%).0%). Data from MMWR Morb Mortal Wkly Rep 1992.MBBS_H. The most substantive change in the classification was the inclusion of all patients with a CD4 cell count below 200/mm3 regardless of the presence or absence of symptoms.  The 1993 definition of AIDS includes all of the AIDS-indicator diseases in the 1987 version with three additions: recurrent bacterial pneumonia. HIV-associated dementia (3.

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