AM1HIV-AIDS

Objectives

I.             HIV Infection/AIDS

               1.      Identify qualitative  and quantitative  defects of the CD4 cell population as the primary cause of the immunodeficiency seen in HIV infection.

sg Noble p. 272, Martini pp. 771-790.  Updated 4 Mar

Qualitative effects would affect function.  The function of CD4 cells includes secretion of cytokines that stimulate cell-mediated and antibody mediated immunity and activation of sensitized B cells.  HIV infected CD4 cells don’t proliferate normally, and can’t secrete their normal repertoire of cytokines which act to “orchestrate other arms” of the immune system.

Quantitative effects would include decreased cell numbers in the CD4 population, due to direct lysis after HIV infection and the indirect effect of decreased proliferation.

The Immune Response:

Recall that the immune response consists of Cell Mediated Immunity (CMI) (primarily T cell) and Humoral Mediated (B cell) Immunity (HMI).  CD (cluster of differentiation) markers are cell membrane proteins of T cells. There are over 50 CD proteins, but CD4 is specific to T helper (T_H) cells, i.e. CD4+Tcells.

Primary target cell for HIV is the CD4 cell.  HIV is a retro (RNA) virus that gains entrance into the immune by binding to CD4, thus entering CD4 cells and ultimately destroying them after replicating and shedding virus.  Because T helper cells play a central role in both cell mediated, and antibody mediated response to viruses, the ultimate destruction of CD4 T cells shuts down the immune system.  

HIV also infects monocytes, macrophages, and B lymphocytes.  Interestingly, Ts (suppressor, or CD8+) cells don’t appear to be infected by HIV. Activated Ts cells produce inhibitory cytokines that suppress the function of both T and B lymphocytes.  Normally, this suppression acts to limit over-response of the immune system to a single stimulus.  In the setting of HIV, this suppression taken alone is another strike against already disabled CD4 and plasma cell activity.

CD4 T cells normally activate by exposure to Class II MHC proteins found only on antigen presenting cells (APCs) such as phagocytes of the mono/mac lineage and lymphocytes.  Normal CD4 T cell activation results in cell division producing T helper and memory T_H cells.

T_H cells secrete cytokines that coordinate specific and non-specific immunity, as well as CMI and HMI.  These cytokines affect T_H cells, cytotoxic T cells, NK cells and promote B cell division, plasma cell maturation and Ab production.  

In summary, without CD4 cell activity, both Antigen Presenting Cells and lymphocytes are impaired, thus impacting both cell mediated and humoral mediated immune response.  This weakens the body’s defense not only against HIV, but against other opportunistic pathogens, as manifest by the wide ranging infections that AIDs patients succumb to.  Reduced immune surveillance also allows for development of cancers.

Anonymous Noble 272-272

There is a drastic drop with intitial infection, then levels go to very low, increasing with development of Antibodies (but not back to baseline). The host (early on) can replace CD4 cells as they are destroyed, but over time most Pts. experience progressive decline to profound immunodeficiency. Besides rapid replication, there is a high rate of mutation of cells, with the end result of a great quantity of mult. Virus strains (quasivirus). CD4 is HIV's primary target - the quant/qual. defects effect over-all T-helper cell function

Anonymous Gorroll, p.68

Once the virus enters the body, it attaches to the surface of CD4+ T lymphocytes.  These helper T lymphocytes are the target of HIV-1, by virtue of the affinity of the virus for receptors on their surface.  Once attached, the virus enters the lymphocyte and uncoats.  Its RNA is transcribed to DNA by reverse transcriptase.  The DNA may remain in the cytoplasm or become integrated in to the host cell genome, where it can remain latent until some stimulus triggers replication of virus.  This is considered the qualitative defect of the CD4 cell.  Ten billion viral particles are produced in an infected person each day.  Most of these viral particles are produced by activated CD4+ lymphocytes, which are killed when the virus enters the lytic stage of infection.  These cells are central to maintaining immunocompetence.  With damage to the CD4-cell population, patients are at increased risk for clinical manifestations directly associated with the disease, including HIV encephalopathy and HIV-1 wasting.  

Anonymous Nobel 271

CD4 count predicts long term clinical outcomes

↑ viral load = ↓ CD4 count

Qualitative and quantitative CD4 cell defects impair overall T helper cell function.

CD4 cells do not proliferate normally when stimulated.

CD4 cells do not elaborate the proper complement of cytokines necessary to generate appropriate

responses from other arms of the immune system.

CD4 counts drop transiently during primary “initial” HIV infection, occasionally to very low levels.  

As antiviral antibodies from CD4 levels rise although not completely to baseline.

Primary infection =  immediately after infection

•        viremia in plasma

•        50-70% pts. exhibit fever, chills, malaise, diffuse lymph node swelling, diarrhea, rash, HA, sore throat (general flu like s/s).

•        lasting 1-3 weeks

•        viremia in plasma follows

               2.      Recognize that HIV also affects macrophages and the humoral immune response and contribute to clinical disease.

Anonymous Noble pg 272

CD4s do not proliferate normally when stimulated or elaborate proper complement of cytopkines necessary to generate appropriate responses from other areas of immune system. Macrophage/monocytes lineage becomes dysfunctional in antigen presentation. Humoral response is impaired and progressively worsens with advancing disease.

Anonymous Noble, p. 272

The primary target cell for HIV is the CD4 cell, which has a pivotal role in orchestration of the immune response; not surprisingly, virtually all arms of the immune system are damaged during progressive infection.  Qualitative and quantitative CD4 cell defects induced by the virus impair overall T-helper cell function.  CD4 cells do not proliferate normally when stimulated, nor do they elaborate the proper complement of cytokines necessary to generate appropriate responses from other arms of the immune system.  Cells of the macrophage/monocyte lineage become dysfunctional in antigen presentation.  The humoral immune response is impaired and worsens with advancing disease.  As a result, exposed to neoantigens.  All these immune system defects ultimately lead to the host becoming susceptible to a large group of opportunistic pathogens that are common to other cellular immunodeficiency states.  Abnormalities in immune surveillance of neoplastic clonal expansion may be one important mechanism by which HIV-infected patients develop neoplasms such as non-Hodgkin’s lymphoma.

sg Martini p. 786, Noble p. 272, CMDT p.1275

HIV can infect macrophages and B lymphocytes in addition to CD4+Tcells.  

Macrophages are phagocytic Antigen Presenting Cells which active T cell defenses against foreign bacteria, cells and proteins.  Macs ingest foreign antigens, process these antigens, then present them to CD4 (T helper) or CD8 (suppressor and cytotoxic T cells).  Macs also secrete cytokines, e.g. the interleukins (ILs) and interferons (IFNs).  HIV infected macrophages serve as a viral reservoir which helps the virus spread to other organ systems (CNS).  HIV infected macrophages also cause neuropathology by releasing neurotoxins and cytokines where they shouldn’t be released, resulting in neurotransmitter dysfunction and general neurologic dysfunction.

B cell defects are mainly due to disordered CD4 lymphocyte function (indirect effect). B cell response to new antigenic challenge can be impaired, because available B cells are impaired, destroyed, or are captivated making antibodies against HIV.  

Anonymous Nobel 272

Macrophage/monocytes become dysfunctional in antigen presentation.

Humoral immune response is impaired and worsens with advancing ds.

Pts. develop inadequate antibody response when exposed to neoantigens

(ie. Susceptibility to opportunistic pathogens)

               3.      Identify the most common ways in which HIV is transmitted in the United States.

Anonymous Noble pg 276

In men: men having sex with men
in women: women having heterosexual sex with persons who have past or current Hx of injectable drug use. (Used to be IV drug use was the direct cause)

Anonymous Noble, p.272-274

Although HIV has been isolated from a variety of body fluids, the only fluids recognized to transmit disease are blood and blood products, semen, vaginal fluid, and breast milk.  Any body fluid can be rendered infectious if contaminated with blood.  The major means of HIV transmission worldwide is by heterosexual intercourse.  Other recognized modes of transmission include anal-receptive intercourse among gay men, sharing of contaminated needles among injection drug users (IDU’s), transfusion of infected blood products, and vertical transmission (in utero, the intrapartum, or breast-feeding).

sg  CMDT p. 1274

It appears that in the US, HIV is spread via sexual contact, with highest rate of transmission amongst homosexual males involved in unprotected, receptive anal intercourse.

Transmission is similar to Hep B. In the US, current estimates put 700,000 Americans infected with HIV.  In 2000, 315,000 Americans had AIDs.  Breakdown of these as follows: gay/bisexual men 51%, heterosexual IV drug users 28%; 18% heterosexual non-drug users.  Women accounted for 24%.  

Transmission modes, estimated infection risks:

•        Sexual contact, receptive anal risk 1:100, receptive vaginal 1:1000

•        Insertive anal intercourse 1:1000, insertive vaginal intercourse 1:10,000.

•        Needlestick with infected blood 1:300.

•        Sharing of drug needles from infected source 1:150.  Vertical transmission via infected mothers (to babies) 13-40%.

Anonymous Nobel 272-276

U.S. male = anal receptive intercourse among gay men

U.S. female = heterosexual intercourse

Worldwide = male and female = heterosexual intercourse followed by anal receptive intercourse among gay men, sharing contaminated needles among IDU’s, transfusion of infected blood products, vertical transmission (in utero, intrapartum, breastfeeding).

Transmission mediums: blood, blood products, semen, vaginal fluid, breast milk

               4.      Describe the natural history and clinical course of HIV infection, identifying typical complications seen as the CD4 count drops.

Anonymous Noble 271-275, Chart on 274, Goroll pg. 59-60

Immediately s/p initial infection = rapid viral replication w/ high viremia measurable in plasma. 50-70% of Pts. develops symptoms: fever, chills, malaise, diffuse node swelling, diarrhea, skin rash, HA and sore throat. This resolves in 1-3 weeks. Initial immune response is brisk and aggressive.
-CD4 begins to drop: Pt. initially asymptomatic (CD4 >500) or possibly has persistent generalized lymphadenopathy.
-CD4 200-500: "Constitutional" symptoms including: fatigue, intermittent unexplained fevers, and diarrhea, night sweats occur. Pt. "feels" ill. Thrush, oral hairy leukoplakia, Kaposi's sarcoma,

Herpes Zoster, (ITP) immune thrombocytopenia purpura develops.
-CD4 100-200:  P. carinii, neuro. conditions develop
-CD4 <200:  onset of opportunistic infections, AIDS dementia, CNS lymphoma, death.

Anonymous

Immediately after infection with HIV, rapid viral replication occurs. High levels of viremia can be measured early in the plasma. During this period an estimated 50-70% of patients develop symptomatic illness (primary HIV infection). Symptoms often include fever, chills, malaise, diffuse lymph node swelling, rash, headache, and sore throat. This syndrome usually lasts 1 to 3 weeks and then resolves.

After primary HIV infection, during which a transient fall occurs in the CD4 count, patients typically become asymptomatic. Immune thrombocytopenia, herpes zoster (shingles), and persistent generalized lymphadenopathy (PGL) are among the earliest manifestations. During this “asymptomatic” period the CD4 count remains at or near the normal range (500 cells/mm³ or higher).

With further CD4 count decline (between 200 to 500 CD4 count), various constitutional symptoms begin to appear, including fatigue, intermittent unexplained fevers, diarrhea, and night sweats. For the first time patients feel ill.

At CD4 count of about 200 cells/mm³, patients are at risk for developing Pneumocystis carinii pneumonia (PCP). With a CD4 count of 100 to 200 cells/min³, other conditions may include early peripheral and central nervous system complications of infection. Once the CD4 count has dropped below 50 to 100 cells/mm³, patients become susceptible to the remaining AIDS-related conditions, including cryptococcal meningitis, Cytomegalovirus retinitis, toxoplasmic encephalitis, disseminated Mycobacterium avium complex infection, AIDS wasting syndrome, primary CNS lymphoma, and AIDS dementia complex.

Anonymous Noble, 274-75.

After primary HIV infection, during which a transient fall occurs in the CD4 count, patients typically become asymptomatic.  Immune thrombocyotpenia, herpes zoster (shingles), and persistent generalized lymphadenopathy (PGL) are among the earliest manifestations.  Herpes zoster can be recurrent and involve more than one dermatome during a single outbreak.  With PGL, lymph nodes in multiple location, especially the occipital, posterior cervical and axillary regions, become enlarged, firm, nontender, and unattached to the underlying tissue.  Although some patients report a waxing and waning of lymph node size the adenopathy generally persists for many months or longer.  During this “asymptomatic” period the CD4 count remains at or near the normal range (500 cells/mm or higher).  With further CD4 count decline, various constitutional symptoms begin to appear, including fatigue, intermittent unexplained fevers, diarrhea, and night sweats.  For the first time, patients feel ill.  By now the CD4 count has typically dropped to between 200 and 500 cell/mm.  Pulmonary tuberculosis and bacterial pneumonia can occur during this early stage of HIV infection, as can lymphoma and Kaposi’s sarcoma, although all these conditions occur more often with lower CD4 counts.  At a CD4 count of about 200cells/mm, patients are at a risk for developing Pneumocystis carinii pneumonia (PCP), which, until the widespread use of prophylaxis, was the most common opportunistic infection seen in patients with AIDS in the developed world.  With a CD4 count of 100-200cells/mm, other conditions may include the early peripheral and central nervous system complications of infection.  Once the CD4 count has dropped below 50-100 cells/mm, patients become susceptible to the remaining AIDS-related conditions, including cryptococcal meningitis, cytomegalovirus retinitis, toxoplasmic encephalitis, disseminated Mycobacterium avium complex infection, AIDS wasting syndrome, primary CNS lymphoma, and AIDS dementia complex.

sg Noble pp. 274-275

Natural History of HIV/AIDS:

(are these studies of people that were treated or untreated? Not sure)

Studies have looked at time course in selected populations as follows:
Gay Males:

•        2% developed AIDS within 2 years of seroconversion

•        10 years required before 50% developed HIV
Hemophiliacs:

•        less rapid progression than gay men

•        27%progressed to AIDS w/i 7 years from time of seroconversion

•        Rate of progression inversely correlated with age, younger took longer   to convert

Transfusion pts:

•        Most rapid progression

•        50% developed AIDS by 7 years

•        IV Drug Users: limited history but thought to be similar to that of gay            men

HIV infection, Clinical Course: from Noble p. 274, Fig. 32-3

*PGL, Persistent generalized lymphadenopathy

*ITP, immune thrombocytopenia purpura

Anonymous Nobel 274

Natural history:  approx. figures known at this time:

2% develop AIDS within 2 years of seroconversion

50+% develop AIDS within 10 years of seroconversion

<5% remain s/s free with normal CD4 levels for 15+ years

Hemophiliacs progress more slowly than gay men.

Progression to AIDS relates inversely with age:

                        Younger than 17 slower than 35 yrs. +

                        Non hemophiliac transfusion recipients progress more rapidly than gay men or hemophiliacs

                        (50% by 7 yrs.).

               5.      Describe the usage of the ELISA antibody tests for screening for HIV infection, the role of Western blot assay as the specific confirmatory test, and the absolute CD4 lymphocyte count for prognosis and therapy* decisions.

Anonymous Noble pg. 282

ELISA (enzyme-linked immunosorbent assay) a "very sensitive" test if positive, then:
Western blot analysis is done for confirmation.
Accuracy is extremely high. False negative results uncommon, usually occurring during the window period between infection and seroconversion with a max. Duration of 6 mths.

Prognosis parallels CD4 count:
CD4 of >500 remain otherwise healthy for years as the CD4 drops, symptoms increase (see question #4) prognosis worsens
CD4 <200 = diagnosis of AIDS and survival of 1-3 years.

Therapy decisions:  Before prescribing meds. Prognosis (as predicted by CD4 ct. and plasma HIV RNA levels should be factored into the decision. This is based on MACS (Multicentered AIDS Cohort Study) data, which demonstrates correlation between risk of progression to AIDS defining
illness and plasma viral load/CD4 ct. Higher viral load and lower CD4 ct. = faster decline, progression of worsening symptoms, more rapid path to death. See fig.32.2  pg. 273

Anonymous

Enzyme-linked immunosorbent assay (ELISA), screening test for HIV infection. 50% of ELISA tests are positive within 22 days after HIV transmission; 95% are positive within 6 weeks after transmission. Sensitivity > 99.9%; to avoid false-positive results, repeatedly reactive results must be confirmed with Western blot.

Western blot confirmatory test for HIV. Specificity when combined with ELISA >99.9%. Indeterminate results with early HIV infection, HIV-2 infection, autoimmune disease, pregnancy, and recent tetanus toxoid administration.

Absolute CD4 lymphocyte Count most widely used predictor of HIV progression. Risk of progression to an AIDS opportunistic infection or malignancy is high with CD4 <200 cells/uL. Before prescribing medications, the physician should factor the patient’s prognosis, as predicted by the CD4 counts and plasma HIV RNA levels, into the decision. Those patients with less than 500 CD4 cells/mm³ or plasma HIV RNA levels exceeding 10,000 copies/ml (bDNA assay) or 20,000 copies/ml (RT-PCR assay) should be offered therapy.

The goals of therapy are (1) suppress viral load completely for prolonged period duration, (2) restore or at least maintain immunologic function, (3) minimize HIV-related morbidity and mortality, and (4) improve quality of life.  

Anonymous Noble,  p. 279-80

The criteria for a positive HIV test are a repeatedly positive enzyme-linked immunosorbent assay (ELISA) followed by a positive Western Blot.  The accuracy of testing is extremely high.  False-negative results are uncommon and usually occur during the window period between infection and seroconversion, a period with a maximum duration of 6 months.  False-negative results also have been described in patients infected with subtype O and those with late-stage HIV infection whole serostatus paradoxically becomes negative in the face of very advanced infection.  

The CD4 count, CD4 percentage, and HIVmRNA (viral load) are measured during the initial evaluation of a newly HIV-infected individual.  The CD4 count and percentage provide the best available clinical data on the relative health of the immune system.  The CD4 count is used 1) staging HIV infection; 2) determining the need for antiretroviral  therapy and for prophylaxis of opportunistic infection; 3) assessing the risk of specific HIV-related conditions, and 4) making and reporting the diagnosis of AIDS.  (total CD4 counts of 200-500mm generally correspond to CD4 percentages of 14% and 29%, respectively.

sg CMDT p. 1285

Lab Findings in HIV Infection:

ELISA:  HIV enzyme linked immunosorbent assay: tests that detect Antibody concentration in a person’s serum via binding and subsequent measurement of lab labeled antibodies, usually via colorimetric techniques. They can be quantitative)

• Screening test for HIV infection:

• Sensitivity >99.9%

• Confirm with Western Blot (a lab test that directly detects protein)

• 50% Elisa test positive within 22 days after HIV transmission

• 95% positive within 6 weeks after transmission

Western Blot*:

• Considered confirmatory test when used with Elisa, with greater than 99.9% specificity

Absolute CD4 lymphocyte count:

• Most widely used predictor of HIV progression

• Progression to AIDS high with CD4 counts <200 cells / microliter.

FYI* What’s a Western? (biology.arizona.edu)

               Whereas ELISA measures antibody to whole virus and gives a "positive," "negative" or indeterminate test result, western blotting is a more specific test. It allows one to visualize antibodies directed against each viral protein. For this reason, it is a confirmatory test for a positive HIV ELISA. In an HIV Western blotting, proteins are electrophoresed into a gel. As the proteins migrate through the gel they are separated based upon size and charge. Characteristically, smaller proteins migrate through the gel faster than larger proteins.  The proteins are then transferred to a membrane and detected by with antibody labeling.

Anonymous Nobel 279 and CMDT 1285

The criteria for a positive HIV test are a repeatedly positive enzyme-linked immunosorbent assay

(ELISA) followed by a positive Western blot.

There is a lot more to be said here, but the books differ somewhat and the (*) above indicates

we’ll learn about this through lecture.  The CMDT 1285 chart seems helpful but I’m not sure it is

up to date.

               6.      Describe the history, physical examination, and lab tests* that should be obtained in the initial evaluation of a patient with newly diagnosed HIV infection.

                        (*Note: since this chapter was written, lab tests to quantitate viral load have  been developed.  Our lecturer will provide the latest guidelines on the use of  viral load tests in practice.)

Kevin; CMDT; 1272

HISTORY

o       Sexual contact with an infected person

o       Parenteral exposure to infected blood by transfusion or needle exchange

o       Perinatal exposure

PHYSICAL EXAMINATION

• “Evaluation of HIV infected patients should be carried out with the same priority based logical approach used for all emergency department patients, with attention to concerns particular to this population.” Taken from TINTINALLI 954  History and PE should focus on identifying the clinical stage of disease in order to direct attention to the most likely complications.  

LAB TESTS:

Anonymous Noble, p.279-80

*(Lecturer will provide latest guidelines on the use of viral load tests in practice.)

Past medical Hx including any type of infections, malignancies, STDs, chickenpox, hepatitis, gynecologic problems (abnl paps), vaccinations, TB (exposure and testing), current medical symptoms such as fevers, night sweats, weight loss, diarrhea, cough, skin rashes or lesions, oral thrush or mouth ulcerations, headache, changes in neurologic function.

Complete PE with special focus of lymph nodes, funduscopic exam, oropharynx and skin, abdominal exam for enlarged spleen and/or liver, genital exam, neuropsychologic screening to evaluate cognitive function.

Labs include a repeat HIV test (in some cases), CBC, Chem panel, CD4 count, UA, fasting lipid panel, VDRL (test for syphilis), PPD, HBsAg, HBcAb, HBsAb, Hep C antibody, varicella titer, (if no hx of chixpox), CMV.  Women: pap, GC and CC cultures.

Anonymous Noble, p. 279-280.  *since this chapter was written, lab tests to quantitate viral load have been developed.  Our lecturer will provide the latest guidelines on the use of viral load tests in practice.

The physician should ascertain when the patient was likely infected, by what means, and when the patient was diagnosed.  Patients should be question about their past medical history, including HIV-related opportunistic infections and malignancies, STDs, chickenpox, hepatitis, gynecologic problems (particularly PAP testing). Vaccinations, and tuberculosis, both tuberculin skin testing and possible close contacts with individuals with active tuberculosis.  Additional questions should focus on common HIV-related symptoms, including fevers, night sweats, weight loss, diarrhea, cough, skin rashes or lesion, oral thrush or ulcerations, headache, and changes in neurologic function or mental status.  

A complete physical examination should be performed with special attention to the evaluation of lymph nodes, funduscopic examination, oropharnyx and skin, abdominal examination to detect enlargement of the liver or spleen, genital examination, and neuropsychological screening to evaluate cognitive function and detect early dementia.  Patients who are cachectic or who report significant weight loss require medical evaluation to look for reversible causes.

Lab tests:  confirmation of HIV seropositivity; CD4 count and CD4 percent; HIV mRNA (viral load); CBC, differential, & chemistries (electrolytes, renal, and liver profiles, fasting lipids); urinalysis, chest radiograph, toxoplasma and cytomegalovirus serologies (IgG); Syphilis screen (RPR or VDRL); Hepatitis screen (Hep. A antibody, HBsAG, HbsAb, HbcAb, hep. C antibody).

Anonymous Nobel

Hx

PE

Confirmation of HIB seropositivity

CD4 count and CD4 percent

HIV mRNA (viral load)

CBC, differential, and chemistries (electrolytes, renal and liver profiles, fasting lipids)

Urinalysis

Chest radiograph

Toxoplasma and CMV serologies (IgG)

Syphilis screen (RPR or VDRL)

Hepatitis screen (hepatitis A antibody, HbsAg, HbsAb, HbcAb, Hepatitis C antibody)

Tuberculin skin test (PPD) and exposure history

Pap test and screening for chlamydia and gonorrhea

G6PD screen

Vaccinations (pneumococcal, influenza, hepatitis A & B)

Nobel:  Follow up Evaluations

Hx

PE

Chemistries, repeated periodically (e.g., liver profile, lipid panel)

CD4 count and percent (every 3-6 months)

Viral load (every 3-4 month; also 3-4 weeks after any change in antiviral regimen)

Tuberculin skin test (PPD) & Syphilis screen (annually)

Pap test (at least annually)

Vaccinations (influenza yearly; pneumococcal at 5 years)

               7.      Describe an approach to health care maintenance of HIV-infected individuals, including vaccinations and prophylaxis for opportunistic infections.

KEVIN Taken from TINTINALLI 954

APPROACH/PROPHYLAXIS

• Antiretroviral therapy:  

o       General guidelines include initiation of antiviral threrapy in persons with CED4 cell counts of less than 500 cells/microliter.  Therapy must be tailored to individuals patients with attention to suppression of viral replication, preservation of immune function, drug side effects, drug interactions, and the pt’s preference.  

o       AZT-delays progression of AIDS

Anonymous Noble, p.280-81

Varicella (if not immune), Hep A, Pneumococcal (Pneumovax) q 5 yrs, Flu q yr, Hep B (?)

Anonymous Noble, p. 281

With the complexity of current antiretroviral therapy and the urgent need to keep up with the general health maintenance of this patient group, most physicians prefer to track information in a paper or computed flowsheet.  A detailed record of the antiretroviral history is essential, including start and stop dates of medications, reasons for medication and dose changes, and some subjective estimate of patient adherence.  Chronologic listing of CD4 counts, CD4 percentages, and HIV viral load measurements should be kept.  Ideally these data should be recorded to allow easy comparisons between the antiretroviral regimen and the viral load and CD4 response to facilitate future decisions regarding medication changes.  The flowsheet should also contain a record of initial screening results and annual screenings for HIV-related preventative care.  The standard adult preventative care plan should be similar to the standard plan of age-matched, non-HIV-infected patients (screening for CV risk factors, mammograms, etc.).  Vaccination status must be continually updated, as discussed.  Advancing HIV infection impairs the host’s ability to form specific antibodies with infection or immunization.  Therefore vaccinations must be given as early in the course of HIV infection as possible.  Patients should undergo annual PPD screening and testing for syphilis with a VDRL or RPR.  For women, Pap smears need to be performed at the least yearly.  The CD4 count must be closely watched to determine the need for opportunistic infection prophylaxis.  For patients with a CD4 count less the 100-150 cells/mm, an ophthalmologist should perform a yearly retinal examination to screen for CM retinitis.  For patient with Hep. Band C coinfection, liver enzymes should be periodically rechecked.  Similarly, given the lipid profile abnormalities assoc. with some antiretroviral agents, repeat lipid studies should also be performed.

Anonymous CMDT 1287

CD4 counts every 3-6 mo.

Viral load tests every 3-6 months and 1 month following a change in therapy

PPD

INH with positive PPD and normal chest x-ray

RPR or VDRL

Toxoplasma IgG serology

Pneumococcal vaccine

Influenza vaccine in season

Hepatitis B vaccine for those who are HbsAb-negative

Haemophilus influenzae b vaccination

Papanicolaou smears every 6 months for women

Consider anal swabs for cytologic evaluation yearly for men with hx of receptive anal intercourse

CD4 < 500 = Antiretroviral therapy

CD4 < 200 = P carinii prophylaxis

CD4 < 75 = M avium complex prophylaxis

CD4 < 50 = CMV prophylaxis

               8.      Describe the role of plasma HIV-1 RNA levels in the management of HIV infection

KEVIN

Initial Plasma HIV-1 RNA Levels and Progression to AIDS in Women and Men

Timothy R. Sterling, M.D., David Vlahov, Ph.D., Jacquie Astemborski, M.H.S., Donald R. Hoover, Ph.D., M.P.H., Joseph B. Margolick, M.D., Ph.D., and Thomas C. Quinn, M.D.

ABSTRACT

Background It is unclear whether there are differences between men and women with human immunodeficiency virus type 1 (HIV-1) infection in the plasma level of viral RNA (the viral load). In men, the initial viral load after seroconversion predicts the likelihood of progression to the acquired immunodeficiency syndrome (AIDS), but the relation between the two has not been assessed in women. Currently, the guidelines for initiating antiretroviral therapy are applied uniformly to women and men

Anonymous Goroll, p. 38, 68; Care and Management of Patients with HIV Infection

After a short period of localized infection, there is a high-grade viremia as documented by the plasma HIV RNA levels or quantitative culture of plasma.   During viremia, HIV disseminates throughout the lymphoid tissue and begins to establish a substantial reservoir of chronically infected cells.  This period may be accompanied by sx of acute infectious mono in 50 % of patients.  HIV antibody testing is not useful during this phase as it may take several months to develop antibodies.  The initial period of viremia may represent a dangerous phase of increased infectivity through sexual or blood-blood contact.  I think this may be the theory behind immediate anti-viral treatment if exposure is suspected. (Needle sticks, etc.)  I did not find this in any of our standard texts, so if this is not what we are looking for, maybe the lectures will make it clearer.  Early treatment may control viral replication.

Anonymous Noble, p.286 & Gorroll, p.74

The impact of effective antiretroviral therapy can be detected quickly.  Results of therapy are evaluated primarily with plasma HIV-mRNA levels (viral load).  At a minimum the HIV mRNA level is expected to decrease by 10-fold (1 log) at 8 weeks and to no detectable virus (less than 50 copies/ml) at 4-6 months after initiation of treatment.  More than 90% of patients who eventually achieve undetectable viral loads accomplish this within 12 weeks of therapy.  Significant increases of HIV1-RNA concentration or drops in CD4-cell count should precipitate the initiation of antiretroviral therapy.

               9.      Recognize or describe the following selected complications and sequelae of HIV-related infections and neoplasms:

                                 Pneumocystis carinii pneumonia (PCP)

                                 Tuberculosis and atypical mycobacteria infection

                                 CNS disease (toxoplasmosis, cryptococcal meningitis, AIDS dementia complex, etc.)

                                 oral hairy leukoplakia and oral candidiasis

                                 GI manifestations (esophagitis and AIDS-associated diarrhea)

                                 anemia and neoplastic complications (KS, non-Hodgkin's lymphoma, and invasive cervical cancer)

                                 skin manifestations (infections, psoriasis, and seborrheic dermatitis)

                                 CMV retinitis

                                 GYN manifestations (recurrent or severe Candida vaginitis, severe genital HSV-2 infection, cervical dysplasia and neoplasia, etc.)

KEVIN; CMDT 1485

PLEASE LOOK AT CHART ON PAGE 1290 OF TINTINALLI  

• Pneumocystis carinii pneumonia (PCP)

o       Fever, Dyspnea, Nonproductive cough

o       Tachypnea

o       SOB

o       Weight Loss

o       Fatigue

KEVIN; CMDT 257

•        Tuberculosis and atypical mycobacteria infection

Needle Biopsy shows granulomatous inflammation in approx 60% of patients

•        CNS disease (toxoplasmosis, cryptococcal meningitis, AIDS dementia complex, etc.)

CMDT 1279

•        toxoplasmosis:  most common space occupying lesion; HA, focal neuro deficits, seizures or altered mental status.

•        Cryptococcal meningitis- TINTINALLI 958

o Fever, HA, nausea, altered mentation, focal neuro defiocits

•        oral hairy leukoplakia and oral candidiasis

•        AIDS dementia complex:

Difficulty with cognitive tasks and exhibit diminished motor speed.  May first notice deteriorating in hand writing.  Periods of lucidity and confusion.

TINTINALLI 1281

•        GI manifestations (esophagitis and AIDS-associated diarrhea)

Candidal esophogitis:  common, empirical antifungal treatment is begun with fluconazole.  

Enterocolitis:  many organisms, do a stool culture to deter organism

Diarrhea is the most frequent GI complaint and is estimated to occur in 50-90% of AIDS painets.  TINTINALLI 958

TINTINALLI 1283-84

•        anemia and neoplastic complications (KS, non-Hodgkin's lymphoma, and invasive cervical cancer)

KS (Kaposi’s sarcoma most common HIV related malignancy.  Examin the eyelids, conjuntiva, pinnae, palate, and toe webs.  Usually appears purlish, nonblanching lesions that can be popular or nodular in dark skinned lesions may appear more brown.

Invasive cervical cancer:  Incidence is 40% More aggressive withi HIV women.  Frequent GYN exams for HIV + women are necessary.  

                           NON HODGKINS LYMPHOMA:

Aggressive, usually B-cell in origin, diffuse large cell tumors.   

                           skin manifestations (infections, psoriasis, and seborrheic dermatitis)

Grouped as viral, bacterial, fungal, neoplastic, and nonspecific edermatides

                                 CMV retinitis-Tintinalli 165

Enlarging progressivbely yellowish white patches of retinal opacifications which are accompanied by retinal hemorrhages.

                                 GYN manifestations (recurrent or severe Candida vaginitis, severe genital HSV-2 infection, cervical dysplasia and neoplasia, etc.)CMDT 1481

Acute vulvar puritus, burning vaginal discharge, and dyspareunia/

Anonymous Pulmonary Complications

Pneumocystis carinii pneumonia (PCP) – CD4 count < 200; insidious onset, progressive sx: fever, dyspnea, nonproductive cough, chest tightness with inspiration, fatigue and wt loss; CXR shows bilateral, interstitial or alveolar infiltrates or focal infiltrates, consolidation, cavitary or cystic lesions, nodular densities, or nothing at all (normal cxr).  Bronchoscopy almost always indicated if induced sputum does not yield dx.  (Noble, p. 288)

Tuberculosis –  reactivation as high as7%; one of earliest complicating infections in HIV; moderate immunologic impairment, relatively high CD4 counts; MDR-TB highly lethal; presenting sx – pulmonary sx, fever, wt loss, cough usually productive and occ streaked with blood, chest pain; higher incidence of extrapulmonary TB; CXR shows lower lobe infiltrates, upper lobe involvement, cavitation; sputum culture necessary to treat individual’s isolate to make sure the right bug is being treated!  (MDR-TB)

Atypical mycobacteria infection (Mycobacterium avium complex and Mycobacterium kansasii)

MAC – CD4 count< 50-100; presenting sx include fever, night sweats, fatigue wt loss, abdominal pain, diarrhea.  PE may reveal lymphadenopathy, hepatosplenomegaly.  Labs may chow anemia, elevated ALK PHOS; dx made by culturing the organism from blood, bone marrow, or another sterile body site. (Care and Management of Patients with HIV Infection)

Mycobacterium kansasii – serious pulmonary disease; clinical manifestations similar to pulmonary TB; CXR shows diffuse interstitial or apical infiltrates and thin-walled cavities.

CNS disease (Care and Management of Patients with HIV Infection)

Toxoplasmosis – CD4 count < 100; hx – gradual onset;  headache, confusion, fever, lethargy, seizures; PE – abnl level of consciousness, focal neurologic signs such as hemiparesis, ataxia, or cranial nerve palsies; dx – typical ring-enhancing lesions on CT scan or MRI in the presence of serum antibodies to Toxoplasma gondii (neg in 5-10 %).

Cryptococcal meningitis – CD4 count < 100; hx – insidious onset, 2-4 wks fever, malaise, headache, sometimes associated with N/V. Only 25-30% have meningeal signs such as neck stiffness or photophobia,; dx – lumbar puncture showing positive cryptococcal antigen, mild pleocytosis, positive India ink smear demonstrating the capsule of cryptococcus.

AIDS dementia complex – late complication of AIDS that is characterized by progressive impairment of intellectual ability associated with decreased motor function and behavioral changes; CD4 counts < 200; hx – gradual onset (wks to months); classic triad – (1) cognitive changes; (2) motor impairment; (3) behavioral changes.

Oral Complications  Noble, p. 294

Oral hairy leukoplakia – causative agent – EBV; PE – asymptomatic verrucous white patches that cannot be scraped off.

Oral candidiasis – predictive of the progression to AIDS; PE – removable white plaques on the oral mucosa or with red patches on the palate, buccal mucosa, or tongue.

GI manifestations

Esophagitis – CD4 count < 200; causative agent – usually candidiasis;  Sx – odynophagia, dysphagia.  (Noble, p. 297)

AIDS-associated diarrhea – three or more liquid stools per day persisting for longer than 1 month; small bowel diarrhea – malabsorption, voluminous stools, dehydration, wt loss, and periumbilical pain;  large bowel diarrhea – small-volume stools, intact absorption, lower quadrant pain, WBCs in stool.  Several methods can be used to dx but most cost effective is stool cultures, aggressive endoscopy and biopsy

Anemia and neoplastic complications

KS – bluish-red cutaneous malignancy; typically affects oral cavity, nasal mucosa, genitalia, trunk, and feet; early lesions are macular areas of discoloration that enlarge to form reddish-purple papules, nodules, and large plaques; dx – skin biopsy; rarely fatal in AIDS patients.  (Care and Management of Patients with HIV Infection)

Non-Hodgkin’s lymphoma – B-cell tumors with high or intermediate grade of malignancy;  Cd4 count < 200; sx – fevers, chills, night sweats, wt loss, lymph node enlargement; CNS, GI, bone marrow, and liver involvement occurs in 68% -98%. Dx – lymph node biopsy. (Care and Management of Patients with HIV Infection)

Invasive cervical cancer – HIV has been associated with the development of cervical CA with nearly half of HIV-infected women demonstrating  cervical intraepithelial neoplasia (CIN) on routine colposcopy with the majority coinfected with HPV; sx – abnormal vaginal discharge, bleeding, or pelvic pain; PE -  cervix may have an erosion or ulcer or may be partially replaced by a fungating tumor; bimanual and rectovaginal exams should be performed to assess the local extent of spread into the parametria and uterosacral ligaments. Noble, p.377-80

Skin manifestations

Infections – I think this evident, most immunocompromised people are more prone to infections. In this case, I would think of boils, folliculitis, herpes simplex, herpes zoster, molluscum contagiosum, scabies.  The presentation of this conditions may be atypical in HIV patients and treatment would probably be more aggressive.

Psoriasis – the incidence of this may increase with HIV infection but I couldn’t find any specifics.

Seborrheic dermatitis – may be marker for HIV; possible cause – overgrowth of yeast; typical signs -  patches of erythema with scaling on the sides of nose, central forehead, and hair-bearing areas of the scalp and beard region; sx – minimal; dx – inspection, biopsy. (Noble, p. 296)

CMV retinitis – affects 30%-40% of patients with AIDS; CD4 count < 50; retinal detachment 25%-40%; asymptomatic or floaters, blurry vision or decreased acuity, scotomas may occur; PE – stellate-shaped keratic precipitates may be seen on the cornea, vitreous is hazy and contains inflammatory cells, may see patchy areas of retinal whitening with surrounding areas of hemorrage;  tx – immediate referral to ophthalmologist. Noble, p. 1659

GYN manifestations

Recurrent or severe Candida vaginitis – occurs earlier in HIV; common problem.

Severe genital HSV-2 infections – exudative, painful bilateral vulvovaginitis is seen; enlarged, firm, tender lymph nodes, cervicitis develops in ¾  of women, can be contracted at birth, cervical CA strongly associated with HSV-2; tx - immunocompromised may need IV acyclovir. Goroll, p. 1050-52)

Cervical dysplasia and neoplasia – I think this has already been covered above.  

Anonymous Noble, p. 288-305

•        Pneumocystis carinii pneumonia (PCP)-antiretroviral therapy and pneumocystis prophylaxis have reduced mortality and morbidity from PCP; it is still one of the most common opportunistic infections in AIDS patients.  Disease most likely results from reactivation of latent infection acquired through the respiratory route early in life.

•        Tuberculosis infection-the HIV epidemic has resulted in a worldwide rise in the incidence of tuberculosis (TB).  Because M. tuberculosis is more virulent than many other HIV-associated opportunistic pathogens, it often causes disease at an earlier stage of HIV infection and is frequently the initial manifestation, particularly in the developing world.

•        atypical mycobacteria –mycobacterium kansasii is a cause of serious pulmonary disease in patients with advanced HIV disease.   Although only disseminated M. kansasii infection is an AIDS-indicator condition, pulmonary disease appears to be the most common.

•        CNS disease:

•        Toxoplasmosis-encephalitis caused by the obligate intracellular parasite Toxoplasma gondii is the most common mass lesion of the CNS in adult patients with AIDS (with CD4 cell counts <100cells/mm).

•        Cryptococcal meningitis-most common CNS infection in patients with AIDS.  C. neoformans is an encapsulated yeast with global distribution.  Infection occurs through the respiratory route, but meningitis is the most frequent clinical presentation.

•        AIDS dementia complex-subcortical dementia caused by HIV, or AIDS dementia complex (ADC) refers to a constellation of disturbances believed to result from HIV infection of the brain.  This AIDS-indicator condition is usually found in patients with late-stage infection.  Cognitive impairment, altered motor performance, and abnormal behavior define the clinical triad of ADC.

•        Oral hairy leukoplakia-caused by EBV involves the lateral aspects of tongue.  Asymptomatic verrucous white patches that cannot be scraped off are the typical presentation.

•        Oropharyngeal Candidiasis (thrush)- a common manifestation is a common manifestation of HIV infection.  It usually occurs before the development of other opportunistic infections and is predictive of progression to AIDS, independent of the CD4 lymphocyte count.

•        Esophagitis- odynophagia and dysphagia are the primary symptoms related to esophageal involvement in HIV-infected patients.  Esophageal candidiasis, which requires a much greater degree of immunosuppression that oropharyngeal candidiasis, is an AIDS-indicator condition according to the CDC case definition.

•        AIDS-associated diarrhea- Intestinal disease is one of the most common HIV-related manifestations, with 30-80% of patients experiencing some form of diarrhea during their illness.  The CDC defines AIDS-associated diarrhea three or more liquid stools per day persisting for longer than 1 month.   

•        Kaposi’s Sarcoma- has been related to a novel herpesvirus (HHV-8), consistent with the epidemiology of an STD.  Affects the oral cavity, nasal mucosa, genitalia, and feet in addition to the trunk.

•        Non-Hodgkin’s lymphoma-has been the AIDS-defining condition in 3% of U.S. cases and occurs in all risk groups.  About 25% of all cases occur in patients with HIV infection.

•        Invasive cervical cancer-it is recommended that a Pap smear be performed semiannually because women with HIV are at an increased risk.

•        Anemia-myelosuppressive drugs, direct suppression by HIV, bone marrow infiltration by infections and neoplasms and nutritional disorders.  Anemia occurs in more than 60% of AIDS patients.  The usual pattern of normochromic and normocytic anemia, with increased iron stores, that worsens over time.

•        Cutaneous complications-occurs in almost all patients with HIV.  Examination of the entire skin surface and mucous membranes is essential to making an accurate diagnosis.

•        Psoriasis- pending lecture???????

•        Seborrheic dermatitis-HIV-associated seborrheic dermatitis often precedes other signs of HIV infection and can be considered a possible marker of HIV infection.  

•        CMV retinitis-reaction of latent virus is one of the most common AIDS-related opportunistic infections in patients with a CD4 count lower than 100/mm.  Pts. complain of seeing spots or floaters or visual field defects and usually develops unilaterally.

•        Misc - Candida vaginitis, severe genital HSV-2 infection, cervical dysplasia and neoplasia- nearly one-third of women have an active gynecologic problem at their first HIV clinic visit, most often 1) recurrent vaginal candidiasis, 2) severe genital HSV-2 infection, 3) cervical dysplasia and neoplasia, and 4) recurrent or severe pelvic inflammatory disease.  Recurrent vaginal candidiasis is the most common initial manifestation of HIV, as well as one of the most frequent opportunistic infections during HIV infection in women, which may not be recognized as HIV related.

               10.    Identify other special issues in the management of HIV-infected patients (see Noble, pp. 960-1).

KEVIN; TINTINALLI 961

• Ethical Considerations in testing and treatment of HIV infected pt’s.  

• Confidentiality

• Resuscitation of patients with advanced AIDS

• Precautions to Healthcare workers

Anonymous Goroll, p.281-82

Healthcare providers need to be aware of:

1)  community resources available to assist pts dealing with drug abuse, mental illness, homelessness, child care, lack of medical insurance, poverty.

2)  experimental protocols and make them available to their patients when appropriate

3)  their role in encouraging or assisting with the disclosure of the patient’s HIV status

4)  their role in reporting HIV infections

5)  their role in counseling to prevent transmission

6)  their role in maintaining up-to-date information and training

7)  the importance of non-traditional families and support networks and the legalities involved

Anonymous Nobel 281

v     Avoidance of transmission

v     Disclosure laws

v     More immediate concerns like substance abuse, mental illness, homelessness, child care, lack of medical insurance, and poverty.

v     Housing and employment discrimination

v     Rejection by family and friends (i.e. support system)

v     Maintaining up to date knowledge

v     Unproved and experimental/alternative treatments   

v     Community alternative treatment trends

v     Nontraditional family dynamics

v     Durable power of attorney for health care

               11.    Since antiretroviral therapy recommendations are changing rapidly, we will not have specific objectives or test questions on these drugs.  The material in Noble on pp. 933-7 is good for the time it was written, and well worth reading, but we will try to provide something more current just prior to the lecture.

Zen Seeker Noble 219 http://home.mdconsult.com/das/book/body/0/959/158.html#P0219 and 282 http://home.mdconsult.com/das/book/body/0/959/190.html#top

No new stuff!

Many antiviral drugs are now available to treat HIV infection. When used in combination regimens referred to as highly active antiretroviral therapy (HAART), these drugs can have a dramatic clinical effect on morbidity and mortality ( Table 28-6; see Chapter 32 ).

More tables on page 282