Groups at increased risk for HIV infection

• Homsexuals
• IV drug adddicts
• Unscreened blood transfusions
• Hemophiliacs
• Heterosexuals with infected partner
• Children of mothers with HIV

Disease complex in AIDS patients

• Opportunistic infection
• Kaposi sarcoma
• B-cell non Hodgkins lymphoma
• Primary brain lymphoma
• Wasting syndrome
• Neurological impairment

Natural history of HIV infection

• Initial "retroviral syndrome"
• Asymtomatic phase (variable duration)
• Progressive development of impairment of cell mediated immunity
• Develop one or more of diseases related to AIDS

Pathophysiology

• Glycoprotein eenvelope of the virus has affinity for CD4 antigen
• Gains entry into cells containg CD4
• Reverse transcriptase mediated production of DNA provirus from RNA
• DNA provirus integrated into the host chromosome
• Activation of latent DNA provirus
• RNA genome assembled, and virus buds from the infected cell.

Immunodeficiency in AIDS

• T helper lymphocytes 
  • lysis
  • impaired production of lymphokines, interluken2 and interferon-y
• Cytotoxic lymphocytes do not kill effeectively virus infected cells or tumor cells
• Impaired B cell function

Opportunistic infections with defects in cellular immune function

• Protozoa
  • Pneumocystis
  • Toxoplasmosis
  • Cryptosporidium
• Fungal infections
  • Candida
  • Cryptococcus
  • Histoplasmosis
  • Coccidiomycoisis
• Bacterial
  • M. Tuberculosis
  • M. Avium intracellulare
  • Salmonella
• Viral
  • Herpes simplex
  • CMV
• Helminthic
  • Strongyloidiasis

What test(s) would you order to assess the stage of  HIV infection?

• CD4+ percentage of lymphocytes and total CD4+ cell counts.
•  In addition quantitative assessment of HIV RNA in plasma provides prognostic information at the time of presentation which adds to the information obtained with CD4+ cell count. 
• Independent of CD+ lymphocvte percentage or count, the greater the amount of HIV RNA the more rapidly the disease will progress.

What would you tell a patient about his future sexual experiences?

• He should avoid sexual activitv in which there is opportunity for exchange of body fluids. 
• That includes heterosexual intercourse, oral sex. and anal sex which is particularly risky.
•  If he is unable to abstain he should: 1. ALWAYS use a condom in situations in which body fluids might be exchanged and 2. Strive to establish mutually monogamous relationship.

1. HIV status is confirmed positive.
2. PPD now negative. He is probably anergic.
3. He has antibody to Hepatitis B surface antigen. He is immune and does not have chronic hepatitis B. He will derive no benefit from Hepatitis B Vaccine.
4. He is at risk for toxoplasmosis encephalitis in the future and may benefit from prophylaxis.
5. The CD4+ count is low but not in the AIDS range.
6. With a CD4 + count of 306 and viral load of 8400, he is in the second prognostic quartile with an 65% estimated likelihood of developing AIDS in 9 years. (See attached table at end of facilitator guide).

• Most experts would start combination therapy at this stage even though he has never been treated. 
• Combinations include zidovudine (ZDV) or stavudine (D4T) plus lamivudine (3TC) plus a protease inhibitor (indinavir or nelfinavir) or a non nucleoside reverse transcriptase inhibitor (nevirapine). 
• Other nucleosides, (didanosine. zalcitibine), NNRTI's (delavridine) and protease inhibitors (saquinavir, ritonavir) can be used either to substitute for intolerance or as part of salvage regimens. 
• Patients must be active participants in treatment decisions. Education of the patient about schedule, drug and food interactions and THE ABSOLUTE NECESSITY FOR COMPLIANCE is a requirement and ample time should be allotted.

Major toxicities only

• Zidovudine 
  • Bone marrow suppression neutropenia and anemia which is more severe in late stage HIV disease. Can monitor compliance with macrocytosis.
  • Myopathy - less common but seen in late stage disease and long term therapy.
  • Lactic acidosis associated with mitochondrial toxicity in the liver - RARE
  • Nuisance side effects: Nausea, vomiting and headache
• Didanosine 
  •  Pancreatitis - 5-9%
  • Peripheral neuropathv (burning or numbness in distal extremities) - 5-12%
  • Nuisance: Nausea, vomiting, diarrhea
• Lamivudine-Almost none! (nausea, diarrhea and abdominal pain)
• Zalcitibine - Neuropathy, pancreatitis, mouth or throat sores
• Stavudine - Neuropathy, nausea, headaches, diarrhea
• Saquinavir- Nausea. diarrhea, abdominal pain. headache
• Ritonavir - Nausea, vomiting, peripheral and circumoral neuropathy
• Indinavir - Diarrhea, Nephrolithiasis
• Nelfinavir- Diarrhea, rash

What is the likelihood that the infant acquired HIV infection from his mother?

• The risk of mother-to-child transmission of HIV ranges from about 15 to 35 percent.
•  The lowest rates are reported in Europe. the highest in Africa. 
• Transmission is influenced by multiple factors. 
• An important determinant may be viral load. 
• The presence of p24 antigenemia has consistently been associated with increased transmission. 
• Other factors associated with increased transmission include low maternal CD4 cell counts. advanced HIV disease and increased levels of beta., microglobulin. 
• Biologic and genetic variation of HIV mav also influence the risk of transmission. e.g., it has been suggested by some that syncytium-inducing virus, which is associated with advance clinical disease, may be more efficiently transmitted than non-syncytium-inducing virus. 
• High levels of maternal neutralizing- antibody have been shown to be associated with reduced transmission in some studies. 
• Other risk factors for mother-to-child transmission include chorioamnionitis and sexually transmitted diseases. 
• Mode of delivery, duration of labor, interval from time of membrane rupture to delivery and events during labor and delivery that can expose the infant to the mother's blood (e.g., episiotomy, severe lacerations) may also be important.

How is the virus transmitted from mother to infant?

• There is evidence from examinations of placental and fetal tissues that HIV infection can occur in utero. 
• Indirect evidence suggests that a substantial proportion of infants acquire the infection during the peripartum period. HIV is present in breast milk and infants may also acquire infection through breast feeding.

What is known about the pathogenesis of the infection in the fetus infant?

• The HIV infects the CD4+ subset of T lymphocvtes in addition to other cell types. 
• Infection of helper T cells causes abnormalities of lymphocyte function. syncytium formation and cell death.
•  Because the CD4+ lymphocyte plays a key role in many arms of the immune svstem. including B cell function and suppressor T cell function. the resultant helper T cell lymphopenia and lymphocyte dysfunction produce the many immunologic defects that form the basis for the clinical manifestations of AIDS.
• The infection of a cell begins with the attachment of the HIV envelope glycoprotein to the cell’s CD4 molecule, which serves as the HIV receptor. Co-receptors include the chemokine receptors and mediate attachment of monocytotropic (CCR5) and T-lymphocytotropic (CCXCR4) types of HIV. 
• The virus then fuses with the cell membrane, enters the cell, and becomes uncoated within the cytoplasm. 
• After transcription of the viral RNA into DNA by the reverse transcriptase enzyme of the virus, the DNA is circulated, and some of it is integrated into the host cell DNA in latent proviral form. 
• On activation, the proviral DNA is transcribed to RNA; then this RNA is translated so that the HIV proteins are synthesized. 
• The infection is characterized bv high level replication in lymphoid cells and low level replication or even latency in other lymphoid cells or macrophages. 
• Rate of progression is determined by both viral and host factors.

Abnormalities of the immune system: 

• Absolute lymphopenia is common in adults with AIDS but appears to be less common in children.
•  In HIV-infected children, defects in B cell function are usually apparent earlier than those of cell-mediated immunity, and recurrent or serious bacterial infections are the result. 
• Both B cell abnormalities and deficient helper T lymphocyte function contribute to defective humoral immunity.
•  Despite abnormal B cell function, elevated serum immunoglobulin levels are a hallmark of HIV infection in children. 
• Other abnormalities seen in children with HIV infection include diminished interferon and interleukin-2 production as well as abnormal natural killer cell activity.

• The diagnosis of HIV infection in infants born to HIV-infected mothers is made after the detection of the virus in culture, the HIV genome by the polymerase chain reaction, the viral antigen, or the persistence of HIV antibody beyond the age of 18 months.
•  The sensitivity of viral culture and PCR is only about 40% at birth. 
• However, after one month, the sensitivity of viral culture is about 90%, and the sensitivity of PCR is probably even higher. 
• The presence of HIV antibody before 18 months of age may represent HIV infection in the infant or just passive transfer of maternal antibody.

• In a randomized. placebo-controlled trial, investigators found that in pregnant women with CD4 counts greater than 200 per cubic millimeter and no previous antiretroviral drug treatment, a regimen of antepartum and intrapartum zidovudine for the mother and 6 weeks of zidovudine for the newborn reduced the risk of transmission by about two thirds from 25.5% to 8.3%. 
• Current trials employing combination antiretroviral therapy in pregnant women and their infants are ongoing. 
• Other approaches to reducing the transmission HIV from mother to child include avoidance of breast feeding and reduction in peripartum exposure (e.g., avoidance of intrapartum invasive procedures, vaginal disinfection, aggressive treatment of sexually transmitted diseases. ??cesarean section).

What are the long-term consequences of the infection in the infant?

• HIV-related symptoms and signs are rarely present at birth but develop over subsequent months or years.
•  In about a quarter of infected children, HIV infection progresses rapidly to AIDS or death in the first year.
•  In the remainder, it progresses more slowly, with some children surviving beyond childhood years. 
• The proportion of infected individuals who have rapid progression of disease is higher in children than adults. 
• This may be explained by the immaturity of the immune system at the time of HIV acquisition, the infecting dose of virus, and the route of infection.
• Pneumocystis carinii pneumonia has a peak incidence between 3 and 6 months of age and is associated with a high mortality rate. 
• Neurologic manifestations are common in children with rapidly progressive disease, typically with manifestations developing in the second six months of life. 
• Recurrent bacterial infections and lymphocytic intestitial pneumonitis are important manifestations in children.
•  Problems with growth and pubertal development are observed among children entering adolescence.