Hiv Aids

HIV Infection and AIDS David Kramer, M.D.

HIV Transmission Categories A. Risk Factors in Adults 1. Male sex with male (MSM) 42-45% 2. Injection drug use (IDU) 26-31% 3. Heterosexual 11% 4. Transfusion 1% a. Less than one in 700,000 units of blood is HIV infected because it is missed by routine screening 5. Hemophilia 1% 6. Undetermined 15% B. Risk factors in children (<13 years of age) 1. Perinatal 91% 2. Risk unidentified 5% a. Majority of pediatric cases are caused by perinatal transmission 3. Transfusion 3% 4. Hemophilia 1% II. Epidemiology A. Epidemiology of HIV Infection in Adolescents (13-19 years of age) 1. 15% of adult AIDS cases were acquired during adolescence 2. 25% of heterosexually acquired AIDS cases were infected as teens 3. Serious immune dysfunction at presentation is common a. Adolescents have a shorter survival time after HIV diagnosis than adults b. Severity of immune dysfunction suggests long-standing or advanced disease is usually present at diagnosis 4. Risk factors in adolescents vary by gender a. Higher proportion of females are infected in the adolescent age group than in any other age group b. Cause of Infection in Female Teens (1) Heterosexual contact (54-76%) (2) Intravenous drug use (16%) c. Cause of Infection in Male Teens (1) Received contaminated blood products (46%) (2) Male sexual contact (33%) B. Epidemiology of HIV Infection in Women 1. Increasing numbers and percentage of women 2. 20% of 1995 cases were women 3. Third leading cause of death in women of child-bearing age C. Epidemiology of HIV Infection in Children (<13 years of age) 1. The number of perinatally acquired AIDS cases reported to the CDC declined 27% between 1992 and 1995 2. The cause of the decline was probably more effective antiretroviral therapies and in part because of effect of perinatal ZDV therapy 3. More than 7,000 children have AIDS 4. >21,000 children have HIV infection D. Racial and ethnic minority populations 1. AIDS is disproportionately represented among women, children and adolescents with AIDS 2. Reported cases per 100,000 children a. African-American non-Hispanic - 6.4 b. Hispanic - 2.3 c. White non-Hispanic - 0.4 III. Perinatal Transmission I.

A. Risk factors in mothers giving birth to HIV-infected children 1. Increasing proportion were infected through heterosexual transmission; approximately 40% 2. 40% of women have unidentified risk. They probably were infected heterosexually by men unrecognized to be HIV-infected 3. Transmission because of intravenous drug use decreased to 20% 4. Transfusion-associated infection is extremely rare B. Timing of Transmission Perinatally Acquired HIV Infection 1. In Utero transmission accounts for 30-50% of perinatally acquired disease. Associated with more rapidly progressive disease. 2. Intrapartum transmission accounts for 50-70% of perinatally acquired disease. This period affords the best opportunity for interruption of transmission. C. Postpartum transmission (breast feeding) 1. The risk of transmission is14% 2. The risk of transmission from a mother who seroconverts while breast feeding is 29% 3. Women with HIV or at risk for HIV living in developed countries should not breast feed D. Interruption of Vertical Transmission. Administration of AZT therapy during pregnancy, labor and delivery, and to the infant for the first 6 weeks of life reduces the transmission rate from 25% to 8%. IV. Immunopathogenesis A. Constant high-level replication of the virus 1. Approximately one billion viral particles per day are replicated B. High steady-state level of virus in the blood C. Immune clearance of virus 1. Production of CD4 cells initially matches viral replication 2. Progressive depletion of CD4 cells occurs 3. Eventual profound immunologic dysfunction intercedes V. Characteristic Immunologic Disturbances in AIDS A. Laboratory T-cell abnormalities 1. Decreased number and function of CD4+ T cells 2. Impaired CD8 T-cell cytotoxicity 3. Impaired mitogen and antigen responses 4. Impaired cytokine production (IL-2, (IFN, etc) B. Clinical T-cell abnormalities 1. Impaired delayed-type hypersensitivity 2. Chronic active viral infections (VZV, CMV, EBV) 3. Opportunistic infections C. Laboratory B-cell abnormalities 1. Hypergammaglobulinemia 2. Impaired specific antibody responses a. Primary and secondary b. T-cell-dependent and independent antigens D. Clinical B-cell Abnormalities 1. Recurrent bacterial infections a. Encapsulated organisms most common (1) S. pneumoniae (2) H. influenzae VI. Measurements of Viral Load (VL) A. Assays Currently Available 1. RNA polymerase chain reaction (RNA-PCR) 2. Branched chain DNA (bDNA) 3. Nucleic acid amplification assay (NASBA)

B. In adults, viral load is predictive of disease progression, independent of CD4 count 1. >100,000 copies/ml--rapid deterioration 2. <10,000 copies/ml--stable course C. Predictors of Perinatal Transmission. Higher maternal viral loads are associated with increased transmission. However, even women with undetectable viral loads can transmit infection D. In children with perinatally-acquired disease, viral loads are much higher than adults (by 1-2 logs) 1. Peak at 1-2 months of age (up to 1,000,000 copies/ml) 2. Slow decline over time (50,000 - >200,000 by age 2 years) 3. Lower viral loads are present in slow progressors as compared to rapid progressors VII. CDC Classification System for HIV Infection in Children A. Classifies children on basis of symptoms/disease manifestations and level of immune suppression 1. Clinical categories a. Category N: not symptomatic b. Category A: mildly symptomatic c. Category B: moderately symptomatic (1) The only AIDS-defining illness in this category is lymphocytic interstitial pneumonitis (LIP) d. Category C: severely symptomatic (1) All other AIDS-defining illnesses 2. Immunologic categories (based on CD4 counts and percentage) a. Category 1: no evidence of suppression b. Category 2: moderate suppression c. Category 3: severe suppression B. Classification provides a comprehensive assessment of child's overall status C. Classification is used to define progressive disease or clinical endpoints in research trials VIII. Clinical Presentation of HIV Infection by Symptom Complex A. Common nonspecific findings (most in CDC category A) 1. In General, most common presenting findings 2. Oral thrush 3. Lymphadenopathy 4. Hepatosplenomegaly 5. Recurrent diarrhea 6. Poor growth B. Neurologic manifestations (CDC category C) 1. Developmental delay/loss of milestones 2. Progressive symmetrical motor deficits 3. Cerebral atrophy. Infection may present as acquired microcephaly 4. Basal ganglia calcifications 5. Chronic encephalopathy or dementia C. Lymphocytic interstitial pneumonitis (LIP) (CDC category B) 1. Most common chronic pulmonary process 2. Often associated with parotitis and digital clubbing 3. Insidious development of hypoxemia is common, which is usually reversible with corticosteroids 4. Probably associated with EBV infection D. Infectious complications 1. Chronic otitis media and sinusitis (CDC category A) a. Typical pathogens most common b. S. aureus, coagulase negative staph, and P. aeruginosa are detected in chronic draining ears 2. Recurrent and chronic herpesvirus infections (HSV, VZV). May require prophylaxis or chronic acyclovir therapy 3. Recurrent serious bacterial infections (CDC category C) a. Pneumonia. Multiple episodes may lead to bronchiectasis

b. Bacteremia 4. Opportunistic infections (CDC category C) a. Occur when CD4 count extremely low b. Pneumocystis carinii pneumonia c. Cryptosporidiosis d. Disseminated CMV e. Disseminated Mycobacterium Avium Complex (MAC) f. Disseminated fungal infections (Candida sp., Aspergillus sp., rarely Cryptococcus sp.) E. Neoplasms 1. B-cell lymphoma, CNS lymphoma 2. Kaposi's sarcoma (exceedingly rare) 3. Smooth muscle tumors F. Other conditions associated with HIV 1. Wasting syndrome 2. Cardiomyopathy 3. Nephropathy 4. Hematologic abnormalities a. Anemia, thrombocytopenia, neutropenia b. Absolute lymphopenia 5. Dermatologic diseases a. Disseminated molluscum contagiosum and flat warts b. Seborrheic dermatitis IX. Bimodal Presentation of Pediatric Disease A. Rapid progressors account for 30% of HIV-infected Patients 1. Onset of symptoms occur in first months of life a. Failure to thrive b. Opportunistic infections c. Encephalopathy 2. Death generally occurs within 3 years 3. High peak viral loads and low CD4 counts B. Slow progressors account for 70% of HIV-infected Patients 1. These patients are asymptomatic and without physical findings up to several years 2. Life expectancy is >5 years 3. Most common symptom complexes include generalized lymphadenopathy, lymphocytic interstitial pneumonia, and recurrent bacterial infections 4. Subtle presentations or maternal risk factors may be the only findings in asymptomatic cases 5. Children infected via transfusion or sexual transmission are more likely to have slowly progressive disease X. Diagnosis A. Assays for early diagnosis of perinatally-acquired disease 1. RNA PCR a. Using NASBA assay, 56% of 36 infected infants had positive test by 14 days of age vs. 33% using DNA PCR 2. HIV antibody is not definitive because of passive maternal transfer across the placenta B. Early Diagnostic Evaluation for Perinatally-acquired Disease 1. Perform PCR or culture at birth, 1 month and 3-4 months a. HIV diagnosis requires 2 positive results that must be at different time points (1) Definitive diagnosis is usually possible within first 1-3 months of life (a) Diagnosis is excluded if more than 2 negative results have been obtained, both performed greater than1 month of age (b) One performed >4 months of age

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2. ICD p24 antigen test a. If positive, the test may be used to confirm a positive PCR or HIV culture b. If negative, must repeat PCR or culture Diagnosis of children >18 months of age 1. HIV antibody by western blot 2. Positive results on >two different blood samples Antiretroviral Therapy Nucleoside Reverse Transcriptase Inhibitors 1. Zidovudine (AZT, ZDV) a. 120-180 mg/m2/dose po q6-8 hrs b. Adverse Effects. Anemia and granulocytopenia are the major toxicities. Elevated transaminases are less common c. Monotherapy results in 0.5 log decrease in viral load d. CSF:plasma ratio 60% 2. ddI (didanosine) a. 90 mg/m2/dose po q12 hrs b. Major toxicities include pancreatitis and peripheral neuropathy. c. Monotherapy results in 0.6 log decrease in viral load 3. ddC (zalcitabine) a. 0.01 mg/kg/dose po TID. Pharmacokinetics suggest this dose may be too low b. Same toxicities as ddI 4. d4T (stavudine) a. 1 mg/kg/dose q12 hr b. Peripheral neuropathy is the major (but rare) toxicity c. Penetrates CNS 5. 3TC (lamivudine) a. 4 mg/kg/dose q12 hr b. Peripheral neuropathy is the primary toxicity (rare) c. Concurrent use with AZT will suppress HIV resistance to AZT d. If used as monotherapy, resistance develops rapidly. Non-nucleoside Reverse Transcriptase Inhibitors 1. Nevirapine a. 120 mg/m2/dose BID b. Causes 1 log drop in viral load rapidly c. Penetrates CNS d. Resistance develops rapidly (especially as monotherapy) e. Rash is the major (but uncommon) toxicity; may progress to Stevens-Johnson syndrome 2. Delavirdine a. Similar efficacy as nevirapine b. Drug-drug interactions with protease inhibitors c. No published pediatric data Protease Inhibitors (PI's) 1. Overview a. Interrupts viral assembly and infectivity b. When combined with nucleosides, they produces a precipitous drop in viral load (1-2 logs) in adults c. Significant drug-drug interactions d. Entering clinical trials in children 2. Indinavir (Crixivan) a. Pediatric formulation is not available (only capsules) b. The major toxicity is nephrolithiasis (2-5%)

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XII. A. B. C.

3. Ritonavir (Norvir) a. First PI available in suspension formulation b. Side effects (1) Unpalatable and GI intolerance (2) Circumoral paraesthesias (3) Complete inhibition of p450 metabolic pathway leads to a significant increase in levels of drugs metabolized via this route (rifabutin) 4. Nelfinavir mesylate (Viracept) a. Available as a powder for suspension b. Diarrhea (rarely) 5. Saquinavir (Invirase) a. Pediatric formulation is not yet available b. Poor bioavailability limits serum drug levels. Last potent of all PI's c. When used in combination with ritonavir, the levels of saquinavir increase substantially Antiretroviral drug resistance 1. Rapid development of resistance occurs with monotherapy a. 89% of persons with late-stage disease have ZDV resistance after one year of monotherapy vs 31% with less advanced disease 2. High viral turnover promotes selection of drug-resistant mutants. Mutants have specific amino acid substitutions in reverse transcriptase or protease enzyme. Complete suppression of replication decreases selection of mutants. Goals of Combination Antiretroviral Therapy 1. Complementary drug interactions. Drugs act at different points in replication cycle 2. Reduction or delay in development of drug-resistant mutants a. Significantly decreasing viral load, fewer drug resistant mutants b. With multiple drugs, more mutations are necessary to develop resistance 3. Monotherapy is no longer recommended (except for prevention of vertical transmission) General Principles of Combination Therapy 1. Check for drug-drug interactions 2. Monitor laboratory values based on expected drug toxicities 3. Some examples of combination regimens in use a. 2 nucleosides (eg. ZDV + ddI, ddC or 3TC, d4T + 3TC) (1) ZDV and d4T are antagonistic in combination b. 1 nucleoside plus 1 non-nucleoside (eg. ZDV + nevirapine) c. 2 nucleosides + a protease inhibitor (eg. ZDV + 3TC + ritonavir) d. 1 nucleoside + a non-nucleoside + a protease inhibitor (eg. ZDV + nevirapine + ritonavir) Initiation of Antiretroviral Therapy 1. Consideration should be given to treating all infants/children at diagnosis 2. Current Recommendations for Antiretroviral Therapy: a. Significant symptoms b. Falling CD4 count c. No consensus on viral load "threshold" of 100,000 copies/ml d. Some favor highly aggressive therapy (3 drug) to prevent progressive disease ("hit early, hit hard") Outpatient Management of the HIV-infected child Monitor immunologic function and viral load regularly (Q3-6 Months) Nutritional Assessment every 3 Months Developmental and neuropsychological assessment q3-6 months 1. Physical/occupational therapy 2. Speech therapy 3. Play therapy

D. Provide immunizations with following exceptions: 1. Substitute inactivated enhanced polio vaccine (IPV) for live attenuated polio vaccine 2. Withhold MMR in CDC immunologic category 3 3. Add pneumococcal vaccine 4. Influenza vaccine yearly 5. Varicella vaccine under investigation in this population E. Prophylaxis against opportunistic infections XIII. Infection Control in Household Setting, Day Care or School A. Use "universal precautions" for handling all body fluids containing visible blood B. Immunize family members of HBsAg positive individuals C. Siblings of HIV-infected children should receive inactivated polio vaccine and varicella vaccine