What test(s) would you order to assess the stage of his 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 him 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

• No.

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.

• Pneumocystis carinii is an organism of uncertain taxonomic position with ribosomal RNA sequences of fungi but DNA content, absent fungal protein elongation factor EF-3, and antimicrobial susceptibility characteristics all suggestive of protozoa.
• Its life cycle resembles sporozoa (protozoa).
•  Similar (?identical) organisms are found in lungs of lower animals.
•  It is a cause of serious pulmonary infections almost exclusively in immunocompromised humans.

• Study of epidemics suggest that person to person spread by airborne droplets occurs.
•  Most cases in the US including those in AIDS patients are thought to represent reactivation of latent infection.
•  Nursery outbreaks in post-WWII Europe and more recently in Southeast Asia as well as reports of increased numbers of secondary cases on oncology wards in the US suggest person to person spread still occurs.

• Pneumonia occurs in persons with suppressed T lymphocyte function as might be seen with starvation, corticosteroid administration or in HIV infection when CD4 T-lymphocyte count has dropped below 200/mM3.
• Virulence factors have not been identified. 
• Pneumonia is characterized by alveoli filled with desquamated alveolar cells, monocytes, organisms and fluid producing a distinctive foamy appearance.
• Type II pneumocytes are present. Round cells may be increased in the widened septa. 
• Healing is generally complete but some fibrosis and even residual thin-walled cavities may be left.

• Organisms can be identified morphologically in tissue biopsy or in pulmonary secretions.
• Induced sputum, bronchoalveolar lavage (obtained with bronchoscope) have reasonable yield.
•  Organisms can be stained with Geimsa (trophozoite) or Gomori methenamine silver (cyst).
• A fluorescent tagged anti-pneumocystis monoclonal antibody direct fluorescence test is very useful.

Seriously ill patients as indicated by a large a-A gradient benefit from systemic corticosteroids.

What alternative therapies are available? 

• Alternative treatments include pentamidine, trimetrexate, a dihydrofolate reductase inhibitor, atovaquone, a hydroxynapthoquinone, or the combination of primaquine and clindamycin can all be used.
• In patients with moderate to severe pneumonia, pentamidine should probably be the first alternative.

Can relapses of pneumonia due to Pneumocystis carinii be prevented? How?

Yes, prophylactic low dose T/S or dapsone or aerosolized pentamidine will reduce the frequency or prevent recurrences.

• Cryptosporidia are sporozoan protozoan parasites that infect the intestinal tract of a wide range of mammals including humans. Life Cycle.
• The fully mature, infective oocysts are excreted in the stool of the parasitized animal.
• Following ingestion by another animal,sporozoites are released from the oocyst and attach to the microvilli of the small bowel epithelial cells where they are transformed into trophozoites.
• They divide asexually by multiple fission (schizogony) to form schizonts containing eight daughter cells known as type 1 merozoites.
• Upon release from the schizont, each daughter cell attaches itself to another epithelial cell, where it repeats the schizogony cycle, producing another generation of type I merozoites.
• Eventually, schizonts containing four type 2 merozoites are seen.
• Incapable of continued asexual reproduction, these develop into male (microgamete) and female (macrogamete) sexual forms.
• Following fertilization, the resulting zygote develops into an oocyst that is shed into the lumen of the bowel.
•  The majority possess a thick protective cell wall that ensures their intact passage in the feces and survival in the external environment.
• Approximately 20% fail to develop the thick wall.
• The cell membrane ruptures releasing infective sporozoites into the intestinal lumen and initiating a new "autoinfective" cycle within the original host.
•  In the normal host, acquired immunity dampens both the cyclic production of type 1 merozoites and the formation of thin walled oocysts, halting further parasite multiplication and terminating the acute infection.
•  In the immunocompromised (AIDS) both processes continue resulting in chronic infection.

• Domestic animals are the major reservoir in this country.
• Transmission occurs by person to person, animal to person, and from the environment, particularly water.
• The principle route of transmission is by direct fecal-oral spread. 
• Waterborne outbreaks, including one in Milwaukee affecting 403,000 persons, have occurred.

How does cryptosporidia cause disease? 

• Organisms apear as spherical structures arranged in rows along the microvilli of epithelial cells.
• They are covered by a double membrane derived from reflection, fusion and attenuation of the microvilli and are thus considered intracellular.
• There may be villous atrophy and blunting, crypt hyperplasia and lengthening, and infiltration of the lamina propria with inflammatory cells.
• Mechanism of diarrhea is not known.
• Studies in AIDS patients have shown secretory mechanisms unaffected by fasting and malabsorptive mechanisms with positive D-xylose and decreased absorption of vitamin B12 as well as steatorrhea.

• There is no palliative or curative treatment for cryptosporidiosis.
• The disease is self-limited in the immunocompetent. 
• Currently paromomycin (a luminal antimicrobic) or azithromycin to treat infection or octreotide (a somatostatin analogue) to control the diarrhea are used in persons with AIDS.
•  Bovine transfer factor and hyperimmune bovine colostrum have been experimentally shown to ameliorate the symptoms.
•  Recent publications have documented clinical resolution of cryptosporidiosis in patients who responded to highly active antiretroviral therapy.

• Mycobacterium avium complex is a group of related acid-fast organisms that grow only slightly faster than M. tuberculosis and can be divided into a number of serotypes.
• Some cause disease in birds; others cause disease in mammals but not birds.
•  They are found in soil and water and in infected animals.

• Asymptomatic colonization after ingestion or inhalation precedes infection.
• Symptomatic localized infection can occur either in the lung or the G1 tract.
•  The GI tract is probably the most common portal of entry. 
• Focal pneumonias are uncommon in AIDS and dissemination usually ensues.
• Localized GI infection can occur from esophagus to rectum but the duodenum is most common.
•  Dissemination usually involves many organs-- most commonly the blood, bone marrow, liver, spleen. and lymph nodes; but the organism has been recovered from the eye, brain, meninges, CSF. skin, tongue. heart, lung, stomach, thyroid, breast, parathyroid, adrenals, kidney, pancreas, prostate, testis and urine.
•  Microscopically, tissues are filled with large numbers of distended histiocytes that on Ziehl-Neelson staining are packed with acid-fast bacilli.
• The histologic picture in disseminated MAC disease is similar to that seen in lepromatous leprosy and reflects an inability of the host to mount an efftective cell-mediated immune response which would be manifest as a granulomatous reaction.
• Phagocytosis by macrophages in patients with AIDS appears to be intact but intracellular killing does not occur.

• Fever and weight loss are characteristic with chronic diarrhea, abdominal pain and signs of extrahepatic biliary obstruction occurring less commonly.
•  Severe anemia is common. 
• Rarely reported are localized pneumonia, endobronchial lesions, arthritis, skin lesions and endophthalmitis.

• Diagnosis is established by recovery of the organism from a normally sterile site but blood, bone marrow, lymph node, and liver are most common.
• Blood cultures are set up in specialized liquid medium with radiometric detection systems developed specifically for mycobacteria.
• DNA probes are used to rapidly identify any growth of acid- fast- positive organisms.
• Tissue samples show infiltration with swollen macrophages containing large numbers of mycobacteria on acid-fast staining.

• Yes, initial antimicrobial treatment should be with clarithromycin (high dose) or azithromycin plus ethambutol.
•  Additional drugs may be used but recent results of clinical trials have shown that addition of clofazimine to a two drug regimen containing one of the macrolides plus ethambutol provided no benefit.
• Besides clofazimine, amikacin , rifampin, rifabutin ciprofloxacin can all be used. AT LEAST TWO DRUGS SHOULD BE USED TO PREVENT EMERGENCE OF RESISTANT MUTANTS.
• Clinical response may require 2 - 8 weeks and therapy should be continued for life. PREVENTIVE THERAPY in patients at high risk (T-cell counts <50 -100) with rifabutin or clarithromycin or azithromycin being recommended for lifelong prophylaxis.