Challenges in Pediatric

1. Challenges in Pediatric/Adolescent HIVCase Studies Ana Puga, M.D. Pat Emmanuel, M.D.

2. Case 1 5 month old admitted to hospital with respiratory distress, failure to thrive and oral thrush PMH: Mother HIV tested in early pregnancy and was negative. Hospitalized for preterm labor, chorioamnionitis at 33 weeks and delivered no testing done at time. Infant had several prior hospitalizations for pneumonia, RAD, poor feeding and FTT.

3. Case 1 After intubation, infant was diagnosed with PCP pneumonia, HIV DNA PCR positive. Maternal testing at that time also positive. Initial CD4: 36%, 239 Initial RNA: 680,000 What medications would you start?

4. Learning points case 1 Opportunities to prevent MTCT of HIV Presentation of HIV infancy When to start ART in children What medications to use

5. Maternal to Child Transmission of HIV 6,000-7,000 HIV infected women gave birth in 2000

7. HIV Testing in Pregnancy MUST counsel & offer testing to those who appear at delivery with NO record of an HIV test during pregnancy! Florida Administrative Code-Ch64D-3.019 Discuss reasons for refusal/offer testing at subsequent visits If a woman declines HIV testing, a signed objection MUST be attempted! Florida Statute-s.384.31 Opt out testing and rapid testing in L and D being implemented throughout Florida EVERYONE GETS TESTED (tell patient) If in an area of high prevalence, as anyone in Florida is! During the time of new HIV infection, the viral load skyrockets!, therefore, increasing the risk of baby being +. EVERYONE GETS TESTED (tell patient) If in an area of high prevalence, as anyone in Florida is! During the time of new HIV infection, the viral load skyrockets!, therefore, increasing the risk of baby being +.

8. Rationale for rapid testing for HIV in Labor and Delivery

9. Natural history of Perinatal HIV Symptoms develop over months to years 25% rapidly progress to AIDS 75% experience slow progression 25% mortality by age five (European data) Annual rate of disease progression, 6-8%

10. Symptomatic HIV in the First Year Failure to thrive 50% will have Wt & Ht < 5% Developmental Delay 30% will have HC < 5% 20% will have cortical atrophy on CT 40% will have abnormal motor function Opportunistic infections PCP, Candidiasis

12. Goals of Antiretroviral Therapy Preserve Immune Function Delay/prevent disease progression Suppress viral replication Reduce development of viral resistance Prevent developmental delays and promote normal growth Increase survival

13. ARV Therapy for Infants <12 Months Initiate treatment for any infant with clinical or immunologic symptoms Consider treatment for infants who are asymptomatic with normal immune function Because of the high risk for rapid progression of HIV disease, many experts would treat all HIV-infected infants <12 months old, regardless of clinical, immunologic, or virologic parameters. Other experts would treat all infected infants <6 months old, and use clinical and immunologic parameters and assessment of adherence issues for decisions regarding initiation of therapy in infants 6 to 12 months of age. Some intriguing data suggest that the risk of disease progression during the first 2 years of life may be related to maternal clinical, immunologic, and virologic HIV disease status during pregnancy, with more rapid progression in infants born to women with more advanced HIV disease [84]. Because of the high risk for rapid progression of HIV disease, many experts would treat all HIV-infected infants <12 months old, regardless of clinical, immunologic, or virologic parameters. Other experts would treat all infected infants <6 months old, and use clinical and immunologic parameters and assessment of adherence issues for decisions regarding initiation of therapy in infants 6 to 12 months of age. Some intriguing data suggest that the risk of disease progression during the first 2 years of life may be related to maternal clinical, immunologic, and virologic HIV disease status during pregnancy, with more rapid progression in infants born to women with more advanced HIV disease [84].

14. HIV RNA and Children:Clinical Considerations Children >12 months with HIV RNA >100,000 copies/mL are at higher risk for disease progression and death Predictive value of HIV RNA in infants <12 months old less than older children In infants, HIV RNA levels are much higher and overlap with rapid and non-rapid progressors CD4+ counts/percentages may be more useful in evaluating risk in infants <12 months than HIV RNA; in older children both parameters are useful Some data indicate that high HIV RNA levels (i.e., >299,000 copies/mL) in infants aged <12 months may be correlated with disease progression and death; however, RNA levels in infants who have rapid disease progression and those who do not have overlapped considerably (23, 36). High RNA levels (i.e., levels of >100,000 copies/mL) in infants also have been associated with high risk for disease progression and mortality, particularly if CD4+ T cell percentage is <15% (38). Similar findings have been reported in analysis of data from PACTG protocol 152 correlating baseline virologic data with risk for disease progression or death during study follow-up (Table 4 in the Guidelines) (39). In this study, the relative risk for disease progression was reduced by 54% for each 1 log10 decrease in baseline HIV RNA level. Some data indicate that high HIV RNA levels (i.e., >299,000 copies/mL) in infants aged <12 months may be correlated with disease progression and death; however, RNA levels in infants who have rapid disease progression and those who do not have overlapped considerably (23, 36). High RNA levels (i.e., levels of >100,000 copies/mL) in infants also have been associated with high risk for disease progression and mortality, particularly if CD4+ T cell percentage is <15% (38). Similar findings have been reported in analysis of data from PACTG protocol 152 correlating baseline virologic data with risk for disease progression or death during study follow-up (Table 4 in the Guidelines) (39). In this study, the relative risk for disease progression was reduced by 54% for each 1 log10 decrease in baseline HIV RNA level.

15. Likelihood of Developing AIDS Within 12 MonthsBy Age and HIV-1 RNA Log10 Copy Number in Children Receiving No Therapy or ZDV Monotherapy The most robust dataset available to elucidate the predictive value of plasma RNA for disease progression in children was assembled in the individual patient meta-analysis discussed earlier, the HIV Pediatric Prognostic Markers Collaborative Study (see section on �Immunologic Parameters in Children� in the Guidelines.) (38). Analyses were performed for age-associated risk in the context of plasma RNA levels. Similar to data from previous studies (50, 51), the risk of clinical progression to AIDS or death dramatically increases when HIV RNA exceeds 100,000 copies (5.0 log10 copies)/mL; at lower values, only older children show much variation in risk. The relationship between plasma virus and risk approached a more linear association than for CD4+ percentage, resulting in more difficulty in assigning risk thresholds. At any given level of HIV RNA, infants under age 1 year were at higher risk of progression than older children, although these differences were less striking than observed for the CD4+ percentage data. Despite data indicating that high RNA levels are associated with disease progression, the predictive value of specific HIV RNA levels for disease progression and death for an individual child is moderate (50, 83). HIV RNA levels may be difficult to interpret during the first year of life because levels are high and there is marked overlap in levels between children who have and those who do not have rapid disease progression (27, 47). Additional data indicate that CD4+ T cell percentage and HIV RNA copy number at baseline and changes in these parameters over time assist in determining the mortality risk in infected children, and the use of the two markers together may more accurately define prognosis (50, 51). The most robust dataset available to elucidate the predictive value of plasma RNA for disease progression in children was assembled in the individual patient meta-analysis discussed earlier, the HIV Pediatric Prognostic Markers Collaborative Study (see section on �Immunologic Parameters in Children� in the Guidelines.) (38). Analyses were performed for age-associated risk in the context of plasma RNA levels. Similar to data from previous studies (50, 51), the risk of clinical progression to AIDS or death dramatically increases when HIV RNA exceeds 100,000 copies (5.0 log10 copies)/mL; at lower values, only older children show much variation in risk. The relationship between plasma virus and risk approached a more linear association than for CD4+ percentage, resulting in more difficulty in assigning risk thresholds. At any given level of HIV RNA, infants under age 1 year were at higher risk of progression than older children, although these differences were less striking than observed for the CD4+ percentage data. Despite data indicating that high RNA levels are associated with disease progression, the predictive value of specific HIV RNA levels for disease progression and death for an individual child is moderate (50, 83). HIV RNA levels may be difficult to interpret during the first year of life because levels are high and there is marked overlap in levels between children who have and those who do not have rapid disease progression (27, 47). Additional data indicate that CD4+ T cell percentage and HIV RNA copy number at baseline and changes in these parameters over time assist in determining the mortality risk in infected children, and the use of the two markers together may more accurately define prognosis (50, 51).

16. WHAT DRUGS TO USE ALWAYS use combination therapy If treating an infant, consider what mother has been on and what she is resistant to Use 2 NRTIs and either a PI or an NNRTI Plan for the future, what you give now will affect what options available for later The best ARV regimen is the one that your patient will take

17. Medication decisions Potency Formulations and data in infants Adherence (Food restrictions, # of pills, frequency, side effects) Drug interactions Future regimens Hepatitis Renal dysfunction

18. Types of ARV Regimens for Children PI-based (2 NRTIs + PI) NNRTI-based (2 NRTIs + NNRTI) NRTI-based (3 NRTIs) Each class-based regimen has advantages and disadvantages. Protease inhibitor-based regimens, while highly potent, have a high pill burden and palatability challenges in children (Table 11). NNRTI-based regimens are palatable and effective, but a low genetic barrier to resistance leads to rapid development of drug resistance mutations when therapy does not fully suppress viral replication, and there is cross-resistance among members of this drug class (Table 10). Triple NRTI-based regimens, while sparing of other drug classes, may have lower potency than other regimens (Table 9). Within each drug class, some drugs may be preferred over other drugs for treatment of children, based on: the extent of pediatric experience; drug formulation, including taste and volume of syrups and pill size and number; storage and food requirements; and short- and long-term toxicity. Each class-based regimen has advantages and disadvantages. Protease inhibitor-based regimens, while highly potent, have a high pill burden and palatability challenges in children (Table 11). NNRTI-based regimens are palatable and effective, but a low genetic barrier to resistance leads to rapid development of drug resistance mutations when therapy does not fully suppress viral replication, and there is cross-resistance among members of this drug class (Table 10). Triple NRTI-based regimens, while sparing of other drug classes, may have lower potency than other regimens (Table 9). Within each drug class, some drugs may be preferred over other drugs for treatment of children, based on: the extent of pediatric experience; drug formulation, including taste and volume of syrups and pill size and number; storage and food requirements; and short- and long-term toxicity.

19. PI-Based Regimens Advantages Potent NNRTI-sparing Targets HIV at 2 steps Resistance requires multiple mutations Disadvantages High pill burden Multiple drug interactions Metabolic complications Poor palatability Few pediatric formulations

20. Initial ARV Therapy:Recommended (PI-Based) �1 Dual NRTI combination recommendations: Strongly recommended choices: Zidovudine plus didanosine or lamivudine; or stavudine plus lamivudine. Alternative choices: Abacavir plus zidovudine or lamivudine; or didanosine plus lamivudine. Use in special circumstances: Stavudine plus didanosine; or zalcitabine plus zidovudine. Insufficient Data: Tenofovir- or emtricitabine-containing regimens. Not Recommended: Zalcitabine plus didanosine, stavudine, or lamivudine; or zidovudine plus stavudine �2 Amprenavir should not be administered to children under age 4 years due to the propylene glycol and vitamin E content of the oral liquid preparation and lack of pharmacokinetic data in this age group ��1 Dual NRTI combination recommendations: Strongly recommended choices: Zidovudine plus didanosine or lamivudine; or stavudine plus lamivudine. Alternative choices: Abacavir plus zidovudine or lamivudine; or didanosine plus lamivudine. Use in special circumstances: Stavudine plus didanosine; or zalcitabine plus zidovudine. Insufficient Data: Tenofovir- or emtricitabine-containing regimens. Not Recommended: Zalcitabine plus didanosine, stavudine, or lamivudine; or zidovudine plus stavudine �2 Amprenavir should not be administered to children under age 4 years due to the propylene glycol and vitamin E content of the oral liquid preparation and lack of pharmacokinetic data in this age group �

21. NNRTI-Based Regimens Advantages Effective Palatable Less dyslipidemia/fat maldistribution PI-sparing Lower pill burden Disadvantages Cross resistance among NNRTIs Rare, but serious life-threatening skin rashes Hepatic toxicity Multiple drug interactions See Table 10 in the Guidelines.See Table 10 in the Guidelines.

22. Initial ARV Therapy:Recommended (NNRTI-Based) �1 Dual NRTI combination recommendations: Strongly recommended choices: Zidovudine plus didanosine or lamivudine; or stavudine plus lamivudine. Alternative choices: Abacavir plus zidovudine or lamivudine; or didanosine plus lamivudine. Use in special circumstances: Stavudine plus didanosine; or zalcitabine plus zidovudine. Insufficient Data: Tenofovir- or emtricitabine-containing regimens. Not Recommended: Zalcitabine plus didanosine, stavudine, or lamivudine; or zidovudine plus stavudine 2 Amprenavir should not be administered to children under age 4 years due to the propylene glycol and vitamin E content of the oral liquid preparation and lack of pharmacokinetic data in this age group 3 Efavirenz is currently available only in capsule form, although a liquid formulation is currently under study to determine appropriate dosage in HIV-infected children under age 3 years; nevirapine would be the preferred NNRTI for children under age 3 years or who require a liquid formulation. 4 Except for zidovudine chemoprophylaxis administered to HIV-exposed infants during the first 6 weeks of life to prevent perinatal HIV transmission; if an infant is confirmed as HIV-infected while receiving zidovudine prophylaxis, therapy should either be discontinued or changed to a combination antiretroviral drug regimen. 5 With the exception of lopinavir/ritonavir, data on the pharmacokinetics and safety of dual protease inhibitor combinations (e.g., low dose ritonavir pharmacologic boosting of saquinavir, indinavir, or nelfinavir) are limited, use of dual protease inhibitors as a component of initial therapy is not recommended, although such regimens may have utility as secondary treatment regimens for children who have failed initial therapy. Saquinavir soft and hard gel capsule require low dose ritonavir boosting to achieve adequate levels in children, but pharmacokinetic data on appropriate dosing are not yet available. 6 With the exception of efavirenz plus nelfinavir plus 1 or 2 NRTIs, which has been studied in HIV-infected children and shown to have virologic and immunologic efficacy in a clinical trial�1 Dual NRTI combination recommendations: Strongly recommended choices: Zidovudine plus didanosine or lamivudine; or stavudine plus lamivudine. Alternative choices: Abacavir plus zidovudine or lamivudine; or didanosine plus lamivudine. Use in special circumstances: Stavudine plus didanosine; or zalcitabine plus zidovudine. Insufficient Data: Tenofovir- or emtricitabine-containing regimens. Not Recommended: Zalcitabine plus didanosine, stavudine, or lamivudine; or zidovudine plus stavudine 2 Amprenavir should not be administered to children under age 4 years due to the propylene glycol and vitamin E content of the oral liquid preparation and lack of pharmacokinetic data in this age group 3 Efavirenz is currently available only in capsule form, although a liquid formulation is currently under study to determine appropriate dosage in HIV-infected children under age 3 years; nevirapine would be the preferred NNRTI for children under age 3 years or who require a liquid formulation. 4 Except for zidovudine chemoprophylaxis administered to HIV-exposed infants during the first 6 weeks of life to prevent perinatal HIV transmission; if an infant is confirmed as HIV-infected while receiving zidovudine prophylaxis, therapy should either be discontinued or changed to a combination antiretroviral drug regimen. 5 With the exception of lopinavir/ritonavir, data on the pharmacokinetics and safety of dual protease inhibitor combinations (e.g., low dose ritonavir pharmacologic boosting of saquinavir, indinavir, or nelfinavir) are limited, use of dual protease inhibitors as a component of initial therapy is not recommended, although such regimens may have utility as secondary treatment regimens for children who have failed initial therapy. Saquinavir soft and hard gel capsule require low dose ritonavir boosting to achieve adequate levels in children, but pharmacokinetic data on appropriate dosing are not yet available. 6 With the exception of efavirenz plus nelfinavir plus 1 or 2 NRTIs, which has been studied in HIV-infected children and shown to have virologic and immunologic efficacy in a clinical trial

23. Initial ARV Therapy:Recommended (NRTI-Based) USE IN SPECIAL CIRCUMSTANCES FOR INITIAL THERAPY OF CHILDREN Dual NRTI therapy alone is recommended for initial therapy only in Special Circumstances. Use of a regimen consisting of 2 NRTIs alone may be considered when the health care provider or guardian/patient has concerns regarding the feasibility of adherence to a more complex drug regimen. It is important to note that drug regimens that do not result in sustained viral suppression, such as a dual NRTI regimen, may result in the development of viral resistance to the drugs being used and cross-resistance to other drugs within the same drug class. Thus, a dual NRTI regimen would be chosen for initial therapy only under very limited circumstances. �1 Dual NRTI combination recommendations: Strongly recommended choices: Zidovudine plus didanosine or lamivudine; or stavudine plus lamivudine. Alternative choices: Abacavir plus zidovudine or lamivudine; or didanosine plus lamivudine. Use in special circumstances: Stavudine plus didanosine; or zalcitabine plus zidovudine. Insufficient Data: Tenofovir- or emtricitabine-containing regimens. Not Recommended: Zalcitabine plus didanosine, stavudine, or lamivudine; or zidovudine plus stavudine USE IN SPECIAL CIRCUMSTANCES FOR INITIAL THERAPY OF CHILDREN Dual NRTI therapy alone is recommended for initial therapy only in Special Circumstances. Use of a regimen consisting of 2 NRTIs alone may be considered when the health care provider or guardian/patient has concerns regarding the feasibility of adherence to a more complex drug regimen. It is important to note that drug regimens that do not result in sustained viral suppression, such as a dual NRTI regimen, may result in the development of viral resistance to the drugs being used and cross-resistance to other drugs within the same drug class. Thus, a dual NRTI regimen would be chosen for initial therapy only under very limited circumstances. �1 Dual NRTI combination recommendations: Strongly recommended choices: Zidovudine plus didanosine or lamivudine; or stavudine plus lamivudine. Alternative choices: Abacavir plus zidovudine or lamivudine; or didanosine plus lamivudine. Use in special circumstances: Stavudine plus didanosine; or zalcitabine plus zidovudine. Insufficient Data: Tenofovir- or emtricitabine-containing regimens. Not Recommended: Zalcitabine plus didanosine, stavudine, or lamivudine; or zidovudine plus stavudine

24. Initiation of Therapy for Children ? 1 year of age AIDS or <15% CD4+ with any Viral Load Treat Mild- moderate symptoms or 15-25% CD4+ with VL > 100,000 copies/mL Consider Treatment Asymptomatic & >25% CD4+ & VL <100,000 copies/mL ? Defer & monitor

25. Case 2 19 y/o Black male diagnosed October 2003. Negative HIV Ab in May 2003. Infected by MSM behavior Co-infected with Hepatitis B On history, recalls �a bad cold� at end of April 2003. On physical exam, no significant findings. At initial visit, baseline lab work done Immunized for Hep A and Pneumovax

26. What tests would you do at baseline?

27. Resistance Test

28. RESISTANCE: This decade�s challenge in Pediatric HIV treatment When to test for resistance? Which test to use? Are there any sensitive drugs left? Which medications to recycle? Do we keep them on a failing regimen? Which drugs do we keep on? Where are the new drugs for kids?

29. CDC Survey: Drug-Resistant HIV Among Recently Diagnosed Patients Slide #8: CDC Survey: Drug-Resistant HIV Among Recently Diagnosed Patients A CDC survey retrospectively evaluated the prevalence of mutations associated with drug resistance (MAR) among recently diagnosed untreated patients with HIV.1 A total of 1078 patients enrolled between 1998 and 2000. 74% were male, 26.7% were non-Hispanic whites, 46.2% were African American, and 22.4% were Hispanic. HIV exposure risk: 44.0% were men who have sex with men, 10.2% were heterosexual injection drug users, and 45.5% reported heterosexual exposure. Overall prevalence of MAR was 9.1%.1 The slide shows prevalence data from 5 cities that participated in all 3 years of the survey.1 There was a nonsignificant increase in prevalence of MAR overall and for NRTI, NNRTI, PI, and >2 drug classes. Authors concluded:1 Transmission of MAR-resistant strains may increase as treatment becomes more common. Prevalence may vary depending on treatment outcomes and success of reduction measures. Reference Bennett D, Zaidi I, Heneine W, et al. Prevalence of mutations associated with antiretroviral drug resistance among recently diagnosed persons with HIV, 1998-2000. Program and Abstracts of the 9th Conference on Retroviruses and Opportunistic Infections. February 24-28, 2002. Seattle, WA. Abstract 372-M. Slide #8: CDC Survey: Drug-Resistant HIV Among Recently Diagnosed Patients A CDC survey retrospectively evaluated the prevalence of mutations associated with drug resistance (MAR) among recently diagnosed untreated patients with HIV.1 A total of 1078 patients enrolled between 1998 and 2000. 74% were male, 26.7% were non-Hispanic whites, 46.2% were African American, and 22.4% were Hispanic. HIV exposure risk: 44.0% were men who have sex with men, 10.2% were heterosexual injection drug users, and 45.5% reported heterosexual exposure. Overall prevalence of MAR was 9.1%.1 The slide shows prevalence data from 5 cities that participated in all 3 years of the survey.1 There was a nonsignificant increase in prevalence of MAR overall and for NRTI, NNRTI, PI, and >2 drug classes. Authors concluded:1 Transmission of MAR-resistant strains may increase as treatment becomes more common. Prevalence may vary depending on treatment outcomes and success of reduction measures. Reference Bennett D, Zaidi I, Heneine W, et al. Prevalence of mutations associated with antiretroviral drug resistance among recently diagnosed persons with HIV, 1998-2000. Program and Abstracts of the 9th Conference on Retroviruses and Opportunistic Infections. February 24-28, 2002. Seattle, WA. Abstract 372-M.

30. Evidence for transmitted resistance in ARV-na�ve adolescents and young adults Recently infected ARV-na�ve adolescents 16�24 years (mean age 19.7 years) Sample from 15 US cities Overall rate of resistance: (genotype; phenotype) 18%; 22% NNRTIs: 15%; 18% PIs: 4%; 6% NRTIs: 4%; 4% Background/ Objective Recent studies of prevalence of primary HIV drug resistance in the US have been in predominantly white male adults. This study was designed to look at minority youth Methods Multicenter study cohort of newly diagnosed youths aged 12�24 yrs All enrolled subjects had a serologic detuned ELISA to identify recent infection (within 180 days) Genotypes and phenotypes done in those with recent infection (Monogram assay) HIV drug-resistance mutations as defined by the IAS-USA Drug Resistance Mutations Group Results 55 subjects identified with recent infection: 35% female (mean age 18.6 [16�23]) 65% male (mean age 19.7 [16�24]) (p=0.06) Major resistance mutations present in 10 patients (18%): NNRTI (n=8): K103N alone (5), K103N+Y181C (1), Y181C alone (1), V108I (1) NRTI (n=2): M41L, L74V, + T215F (1) and M184V (1) PI (n=2): L90M (1), M36I + M46L (1) Phenotypic resistance in 12 patients (22%): NNRTI � 10 (18%) NRTI � 2 (4%) PI � 3 (5.5%) 2 patients had NNRTI and 1 patient had PI phenotypic resistance without genotypic resistance 1 patient had resistance to both NNRTI and PI 1 patient had genotypic and phenotypic resistance to ART in all 3 classes Conclusion Supports extending recommendation of testing newly infected adults to adolescentsBackground/ Objective Recent studies of prevalence of primary HIV drug resistance in the US have been in predominantly white male adults. This study was designed to look at minority youth Methods Multicenter study cohort of newly diagnosed youths aged 12�24 yrs All enrolled subjects had a serologic detuned ELISA to identify recent infection (within 180 days) Genotypes and phenotypes done in those with recent infection (Monogram assay) HIV drug-resistance mutations as defined by the IAS-USA Drug Resistance Mutations Group Results 55 subjects identified with recent infection: 35% female (mean age 18.6 [16�23]) 65% male (mean age 19.7 [16�24]) (p=0.06) Major resistance mutations present in 10 patients (18%): NNRTI (n=8): K103N alone (5), K103N+Y181C (1), Y181C alone (1), V108I (1) NRTI (n=2): M41L, L74V, + T215F (1) and M184V (1) PI (n=2): L90M (1), M36I + M46L (1) Phenotypic resistance in 12 patients (22%): NNRTI � 10 (18%) NRTI � 2 (4%) PI � 3 (5.5%) 2 patients had NNRTI and 1 patient had PI phenotypic resistance without genotypic resistance 1 patient had resistance to both NNRTI and PI 1 patient had genotypic and phenotypic resistance to ART in all 3 classes Conclusion Supports extending recommendation of testing newly infected adults to adolescents

31. Resistance testing An in vitro method to measure resistance of HIV to antiretroviral agents. Can identify drugs that should be avoided. Testing should be done in the presence of antiretroviral agents, discontinuation of therapy often results in proliferation of wild type virus. A viral load >1,000 is required

32. Genotypic Assays Available commercially Amplify reverse transcriptase gene Generate amplicons, sequence DNA Mutations reported as letter-number-letter indicating amino acid at specific codon that is substituted Specific mutations assoc. with specific drugs

33. Gene Chart (by Academy of Continuing Education Program)

34. Phenotypic Assays Comparable to microbiologic susceptibility RT and Pr genes inserted into molecular HIV clone and grown in presence of drug Results reported as concentration needed to inhibit 50%, 90% or 95% of test strains >4 fold in IC50 compared to wild type is considered resistant

35. CHARACTERISTICS OF HIV + YOUTH More typical of Female Youth 20 years of age or less with 2 + children History of sexual trauma � molestation/rape Clinical levels of depression with no intervention Poor relationships with opposite sex Constantly seeking acceptance from men Sex is means of emotional connection

36. Initiation & Goal of Therapy for Adults & Adolescents Initiation: CD 4+ : <350 cells to >200 cells Viral Load : >55,000 copies/mL exceptions: Symptomatic infection, pediatrics, pregnancy & acute antiretroviral syndrome Goal: < 50 copies/ml HIV � �undetectable� Elevation/ Stability of CD4+ cells

37. Treatment Guidelines Tanner staging: Tanner I and II should be dosed following Pediatric Guidelines Tanner V dosing according to adult guidelines During Tanner III and IV dose according to , status of growth spurt: Pediatric dosing prior to growth spurt and adult dosing post-spurt, monitor closely.

38. When to Change ARV Therapy Clinical Disease Progression Virologic or Immunologic considerations Toxicity or Intolerance - Neuropathy - Pancreatitis - Persistent nausea, vomiting, diarrhea

39. Causes of Treatment Failure Inadequate potency Sub-therapeutic plasma drug levels Nonadherence Inter-patient variability (pharmacokinetics) Drug-drug interactions Bioavailability Imperfect adherence Tolerability Pill burden Fatigue Resistance/cross-resistance Advanced HIV disease Slide #12: Causes of Treatment Failure In select clinical trials, successful viral suppression by combination antiretroviral therapy is achieved in up to 90% of patients. However, in clinical practice, these rates are less.1 There are a number of factors that contribute to treatment failure, including inadequate potency, sub-therapeutic plasma drug levels, imperfect adherence, resistance/cross-resistance, and advanced HIV disease. Imperfect adherence can occur as a result of an inability to tolerate antiretroviral therapy, pill burden, and fatigue. Reference Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA. 2000;283:229-234. Slide #12: Causes of Treatment Failure In select clinical trials, successful viral suppression by combination antiretroviral therapy is achieved in up to 90% of patients. However, in clinical practice, these rates are less.1 There are a number of factors that contribute to treatment failure, including inadequate potency, sub-therapeutic plasma drug levels, imperfect adherence, resistance/cross-resistance, and advanced HIV disease. Imperfect adherence can occur as a result of an inability to tolerate antiretroviral therapy, pill burden, and fatigue. Reference Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA. 2000;283:229-234.

42. BARRIERS TO CARE Social/Emotional Barriers Denial of Diagnosis Depression Domestic Violence Mistrust Fear of medical condition Fear of Disclosure and rejection Lack of information Low literacy Environmental and Physical Barriers Too ill to attend visit Clinic Hours Wait time Transportation Childcare Perceived lack of sensitivity Clinics aimed to child/adult care

43. BARRIERS TO CARE Financial Barriers Not aware of resources Cannot afford medical care Cannot afford child care Type of jobs held are insensitive to medical needs Believe they cannot receive care without parental consent Cultural Barriers Cultural beliefs regarding medication/treatment Ethnic beliefs towards medical providers Non-Citizenship or immigration problems creates fear about receiving services Chaotic lifestyle of youth

44. Adherence Associated With Optimal Therapeutic Response Slide #15: Adherence Associated With Optimal Therapeutic Response Paterson and colleagues1 assessed the effects of different levels of adherence to PI therapy on virologic, immunologic, and clinical outcomes. 81 HIV-infected patients, mixture of treatment-na�ve (n=8) and experienced (n=73), prospectively followed for 6 months. Veterans Affairs and university medical center settings. Microelectronic monitoring system. PIs prescribed Indinavir (n=23). Nelfinavir (n=33). Ritonavir (n=3). Saquinavir (n=3). Ritonavir and saquinavir (n=17). Amprenavir (n=2). The level of adherence was significantly correlated with virologic success (ie, viral load of <400 copies/mL) (P<0.001). Adherence of >95% Associated with the highest incidence of virologic success. Greatest mean increase in CD4 cell counts (83 vs 6 cells/mm3; P=0.045) and less days hospitalized (2.6 vs 12.9; P<0.001) compared with <95% adherence to PIs. Reference Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21-30. Slide #15: Adherence Associated With Optimal Therapeutic Response Paterson and colleagues1 assessed the effects of different levels of adherence to PI therapy on virologic, immunologic, and clinical outcomes. 81 HIV-infected patients, mixture of treatment-na�ve (n=8) and experienced (n=73), prospectively followed for 6 months. Veterans Affairs and university medical center settings. Microelectronic monitoring system. PIs prescribed Indinavir (n=23). Nelfinavir (n=33). Ritonavir (n=3). Saquinavir (n=3). Ritonavir and saquinavir (n=17). Amprenavir (n=2). The level of adherence was significantly correlated with virologic success (ie, viral load of <400 copies/mL) (P<0.001). Adherence of >95% Associated with the highest incidence of virologic success. Greatest mean increase in CD4 cell counts (83 vs 6 cells/mm3; P=0.045) and less days hospitalized (2.6 vs 12.9; P<0.001) compared with <95% adherence to PIs. Reference Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21-30.

45. Adherence Forgetting Denial Lack of planning Number of pills Dosing requirements Confidentiality concerns Other priorities

46. Medication Adherence Adherence is difficult Teaching about adherence must be an ongoing process and addressed at every clinic visit by the whole team May depend on caregivers Children/youth must be able to take the medication TOOLS: Pill boxes Daily phone calls Beepers/watches Nursing visits G-tubes Intensive education

47. Case #3 BP: 16 y.o black female, CDC class C3 Perinatal; diagnosed <1yr of age PMH: LIP, encephalopathy w/ developmental delay, recurrent zoster & HSV, recurrent pneumonia, RAD, bronchiectasis, chronic sinusitis, recurrent parotitis & otitis, chronic folliculitis, flat warts Adherence issues

48. Case #3 continued Antiretroviral History 8/90-2/95: AZT 2/95-12/95: DDI 1/96-4/98: Norvir 3/96: AZT, DDI added 4/98-8/99: Nelfinavir, Epivir, Zerit 6/99-8/99: IL-2 added 8/99-3/01: HU, Videx, Zerit, Sustiva 7/00: stopped HU 3/01-7/02: Kaletra, Combivir, Ziagen 8/02-7/03: Kaletra, Trizivir, Videx

49. Case #3 continued 7/03-11/05: Kaletra, SQV, Zerit, Epivir, Viread On each regimen VL remained high CD4 count fell to less than 100 Genotype and phenotype obtained. Mutations:L10V, V32I, L33F, M36I, I47V, F53L, I54V, L63P, A71V, V82A, L90M, M41L, E44D, D67N, K70R, K103,M184V, T215Y, K291Q Need to review NIH records�we only have #�s from � to presentNeed to review NIH records�we only have #�s from � to present

51. What to do? Adherence, Adherence, Adherence! Look for drug interactions Monitor drug levels Find new regimen ? What is available

52. Case #3 cont�d 11/05 hospitalized for med change, DOT, and intensive teaching and support Fuzeon, Tipranavir, Norvir, Zerit, Emtriva Mom took over responsibility for meds CD4/VL prior to change 8%, 73 275,000

54. Salvage options in perinatal HIVIssues Many children treated with suboptimal regimens for many years Accumulation of multiple resistance mutations which can remain archived Several year delay in FDA approval for children Often no pharmacokenetic data or formulations for children Adherance complicated by age, caregiver, knowledge of disease, disclosure

55. Up until 1995, there were only 4 drugs approved for the treatment of HIV infection. Since that time, 12 new drugs have entered the marke, with introductions of new classes of agents that interfere with different viral targets. Today,combination therapy that uses several drugs with complementary mechanisms of action have produced the most effective means of controlling HIV replication, thereby slowing disease progression. Up until 1995, there were only 4 drugs approved for the treatment of HIV infection. Since that time, 12 new drugs have entered the marke, with introductions of new classes of agents that interfere with different viral targets. Today,combination therapy that uses several drugs with complementary mechanisms of action have produced the most effective means of controlling HIV replication, thereby slowing disease progression.

57. HIV Entry Mechanism

58. Enfuvirtide (T-20) -- Overview FDA-approved fusion inhibitor; 36 AA peptide HIV IC50 1.7 ng/ml Dose: 90 mg sq bid side effects: injection site rxn (common); hypersensitivity reactions (uncommon); eosinophilia (10% >700; 2% >1400); ?increased risk of pneumonia on phase III studies resistance: changes in gp41 (positions 36-43) Approved for children >6 years

59. New Antiretrovirals-Tipranivir Aptivus approved 6/05 500mg Tipranivir/200mg Ritonivir Similar SE: lipids, GI intolerance, liver toxicity, rash and drug interactions Sulfa drug/cross reactivity with allergies Decreased response with major PI mutations. Better response with Enfuvirtide

60. New Antiretrovirals- TMC114 (darunavir) Protease inhibitor in phase III trials and expanded access. 600 mg with 100 mg Ritonivir BID Has shown efficacy in PI experienced patients (>1 PI mutation):40-50% demonstrated VL<50 copies at 24 weeks. SE: GI intolerance, HA, rash and increased lipids.

61. New Antiretrovirals-Entry Inhibitors UK-427,857 (maraviroc) SCH-D (vicriviroc) GSK-873,140 (aplaviroc) halted due to liver toxicity

62. Maximizing protease inhibitors-use of therapeutic drug monitoring Variable phamacokenetics in children, issues around adherence and drug interactions complicate treatment. Measuring drug levels can be helpful Inhibitory quotient: relationship of drug exposure to drug susceptibility IQ = Cmin (plasma trough) IC50 (fold change X 0.07)

64. Case # 4 JF: 23 y.o. Hispanic female, CDC A3 Acquired via abuse as small child; diagnosed at age 10 years of age. PMH: 1996 uveitis, Herpes zoster Multiple social issues; moved from relative to relative Major adherence issues

65. Case #4 continued Antiretroviral History 5/96-10/96: Zerit, Videx 10/96-10/97: AZT, Epivir 10/97-4/99: Zerit, Viramune, Nelfinavir 4/99-8/00: Combivir, Sustiva, Crixivan 8/00-12/03: Kaletra, Epivir, Zerit 12/03-2/06: on/off meds (mostly off)

66. Case #4 continued Pregnant 7/05-miscarriage before meds started, then she moved out of state Late January 2006-pregnant again, due 6/06, just moved back to area, on no meds 1/06 CD4 215, VL 14,431 Genotype 12/99 showed multiple mutations and resistance to all med classes Phenotype 4/00 showed resistance to all meds

68. Case #4 continued Dilemma!!! What antiretrovirals do we give her? Will she take them? When do we start?