Human Immunodeficiency Virus Acquired Immunodeficiency syndrome first described in 1981 HIV-1 isolated in 1984, and HIV-2 in 1986 Belong to the lentiv

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1 Global HIV/AIDS Manju Gaglani, M. D. Pediatric Infectious Diseases Scott & White Clinic

2 Human Immunodeficiency Virus Acquired Immunodeficiency syndrome first described in 1981 HIV-1 isolated in 1984, and HIV-2 in 1986 Belong to the lentivirus subfamily of the retroviridae Enveloped RNA virus, 120nm in diameter HIV-2 shares 40% nucleotide homology with HIV-1 Genome consists of 9200 nucleotides (HIV-1): gag core proteins - p15, p17 and p24 pol - p16 (protease), p31 (integrase/endonuclease) env - gp160 (gp120:outer membrane part, gp41: transmembrane part) Other regulatory genes ie. tat, rev, vif, nef, vpr and vpu

3 HIV particles

4 HIV Genome

5 Replication The first step of infection is the binding of gp120 to the CD4 receptor of the cell, which is followed by penetration and uncoating. The RNA genome is then reverse transcribed into a DNA provirus which is integrated into the cell genome. This is followed by the synthesis and maturation of virus progeny.

6 Schematic of HIV Replication

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8 HIV-1 Genotypes There are 3 HIV-1 genotypes; M (Main), O (Outlayer), and N (New) M group comprises of a large number subtypes and recombinant forms Subtypes - (A, A2, B, C, D, F1, F2, G, H, J and K) Recombinant forms - AE, AG, AB, DF, BC, CD O and N group subtypes not clearly defined, especially since there are so few N group isolates. As yet, different HIV-1 genotypes are not associated with different courses of disease nor response to antiviral therapy. However, certain subgroups may be difficult to detect by certain commercial assays.

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10 Natural History of HIV Infection without Antiretroviral Therapy Fauci A, Pantaleo D, Stanley S, Weismann D. Annals of Internal Medicine 124: , 1996.

11 HIV infection and AIDS Human Immunodeficiency virus infection at this time essentially is an uncontrolled global epidemic spreading mainly by heterosexual contact Acquired immunodeficiency syndrome is the last symptomatic stage of HIV infection after a latent stage, lasting months to several years

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13 Adults and children estimated to be living with HIV, 2007 Western & Eastern Europe Central Europe & Central Asia North America 1.6 million [ million] [ million] 1.3 million [ million] Middle East & North Africa Caribbean [ ] Sub-Saharan Africa 1.6 million [ million] [ ] [ ] Latin America East Asia 22.5 million [ million] South & South-East Asia 4.0 million [ million] Oceania [ ] 000] Total: 33.2 ( ) million

14 Over 6800 new HIV infections a day in 2007 More than 96% are in low and middle income countries About 1200 are in children under 15 years of age About 5800 are in adults aged 15 years and older of whom: almost 50% are among women about 40% are among young people (15-24)

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27 HIV Transmission Mother to Baby During Pregnancy or Birth Through Breast Feeding

28 Of 100 Babies Born to HIV HIV--infected Mothers infected during breast feeding 17 infected during birth 67 not infected* 5 infected in utero *Without treatment for parents, most will be orphaned

29 Timing of MotherMother-to to--child HIV Transmission with Breastfeeding and No ARV Early Postpartum (0-6 months) Early Antenatal (<36 wks) Late Postpartum (6-24 months) Labor and Delivery Late Antenatal (36 wks to labor) 0% 20% 40% Proportion of Infections 60% 80% 100%

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34 Transmission of HIV inutero, during labor labor,, or via breastmilk Counseling and Voluntary testing of all pregnant women at early prenatal visit Assess HIVHIV-positive women for HAART and mode of delivery (Perinatal Guidelines) For Prevention of Perinatal Transmission PACTG 076 based: AZT to mother if asymptomatic, after 14 weeks, and also AZT infusion during labor, AZT to newborn to start immediately and give for 44-6 weeks Other alternatives available for special circumstances Look for maternal coinfections including TB, syphilis, toxoplasmosis, hepatitis B or C, cytomegalovirus, and herpes simplex virus

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38 Management of HIV Exposed Infant H&P, look for coinfections e.g. Hep B/C, syphilis, TB, CMV, toxoplasma, HSV AZT (with or without 3TC or NVP) for 6 weeks HIV DNA Qualitative PCR (or RNA Quantitative at or 2-3 wks, 1-2 m and 4-6 mons testing (24 (24 hr if mother had high virus load, 4 weeks And 4 months) For nonnon-breastfeeding infants - Two neg PCRs at or after 2 weeks and 4 weeks, one neg PCR at or after 8 weeks and 1 neg HIV 1&2 AB EIA at or after 6 m needed for presumptive exclusion of HIV For nonnon-breastfeeding infants - definitive exclusion 2 neg PCR at or after 1 month and 4 months or 2 neg HIV1 HIV1&2 AB EIA after 6 months of age No Breastfeeding For breast feeding infants, similar testing using date after breastfeeding completely ceased instead of DOB CBC at 24 hrs, 4 wks, 8 wks FU if anemia Start PCP prophylaxis at 4-6 weeks and d/c when 4 mos testing is neg Confirm absence of HIV 1&2 AB at months 2 neg tests 1 month apart Immunization If not severely immunosuppressed, Ok to give live viral vaccines

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42 Clinical Manifestations of HIV infection and AIDS in Children Multi-organ system involvement and MultiOpportunistic Infections For Clinical Classification System Refer 2006 AAP Redbook N, A, B, C (Asymptomatic, mild, moderate, and severe; and Immune Supression categories 1, 2, 3. eg N1, C3.

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45 Pneumocystis jirovecii pneumonia

46 Lymphoid interstitial pneumonitis / pulmonary lymphoid hyperplasia (LIP/PLH)

47 LIP/PLH - parotid gland enlargement

48 Herpes simplex virus

49 Pseudomembranous candidiasis

50 Severe tinea corporis

51 Severe encephalopathy

52 Generalized brain atrophy

53 Cardiomegaly

54 Severe HIV wasting

55 Abdominal lymphoma

56 ELISA for HIV 1&2 antibody Microplate ELISA for HIV antibody: coloured wells indicate reactivity

57 Western blot for HIV 1 or 2 antibody There are different criteria for the interpretation of HIV Western blot results e.g. CDC, WHO, American Red Cross. The most important antibodies are those against the envelope glycoproteins gp120, gp160, and gp41 p24 antibody is usually present but may be absent in the later stages of HIV infection

58 Four FDAFDA-approved Rapid HIV Tests Sensitivity (95% C.I.) Specificity (95% C.I.) OraQuick Advance - whole blood - oral fluid - plasma 99.6 ( ) 99.3 ( ) 99.6 ( ) 100 (99.7 ( ) 99.8 ( ) 99.9 ( ) Uni Uni--Gold Recombigen - whole blood - serum/plasma 100 ( ) 100 ( ) 99.7 ( ) 99.8 ( )

59 Four FDAFDA-approved Rapid HIV Tests Sensitivity (95% C.I.) Specificity (95% C.I.) Reveal G2 - serum - plasma 99.8 ( ) 99.8 ( ) 99.1 ( ) 98.6 ( ) Multispot - serum/plasma - HIV HIV ( ) 100 ( ) 99.9 ( )

60 OraQuick Advance HIVHIV-1/2 CLIA-waived for finger CLIAstick, whole blood, oral fluid; moderate complexity with plasma Store at room temperature Screens for HIVHIV-1 and 2

61 Reactive Control Positive HIV-1/2 Positive Negative Read results in minutes

62 Goals of Antiretroviral therapy Suppress HIV replication as much as possible, for as long as possible Prevent immune destruction Delay or prevent viral resistance - a major contributor to treatment failure - by the use of highly active antiretroviral therapy Achieve normal survival

63 Targets for Antiretrovirals

64 Important Terms ART ARVs HAART Triple Therapy Anti ntir Retroviral Treatment Anti ntir RetroV etrovirals Highly Active Anti ntir Retroviral Treatment Three Antiretrovirals Basically it all means the same thing!

65 Triple Therapy Now we understand why triple therapy works. Two drugs can keep HIV from multiplying, even if it has mutated BUT, three drugs can work even better! Unfortunately, triple therapy is NOT able to cure HIV HIV is a very tricky virus. While most of it is getting killed by triple therapy, a few viruses find places to hide where they are safe from triple therapy

66 Managing Complications from HIV infection Opportunistic Infections: prevention and treatment eg: TMPTMP-SMX for PCP Other Complications: LIP, Apthous Stomatitis, Malignancies Nutrition, Immunizations Neuropsychological complications Palliative Care and pain management

67 Elements of Comprehensive Care and Support Human rights and legal support Socioeconomic support People, children, and families affected by AIDS Medical and Psychological nursing care support

68 Multidisciplinary (Team) Effort Administrator ART Care Model Social worker or Counsellor Physician Patient Nursing Nutritionist Laboratory SWs & MAs Community worker Pharmacist Minimum team members: RN, MD, Nutritionist, Pharmacist

69 Care of a child/adolescent with HIV infection or AIDS A team of dedicated professionals from multiple disciplines with a good understanding of the complexity of issues involved Patient education and counseling regarding hygiene, behavior, adherence Scrupulous use of standard precautions Respect for patient confidentiality

70 Why is HIV so Hard to Treat? 10 billion copies of the virus are made every day! Challenge of adherence Problem of resistance Difficulty of side effects

71 What Is Resistance? HIV reproduces very quickly, making billions of new viruses every day Because the virus often makes errors while copying itself, each new generation of viruses differs slightly from the one before Some changes to the structure of the virus can improve its ability to reproduce despite high levels of antianti-hiv drugs being present These new changes to the structure of the virus make it able to reproduce even in the presence of ARVs and thus, are said to be resistant to those drugs

72 Reducing Resistance The BEST way to reduce the development of resistance is to ensure maximum viral suppression using three drugs, taken as the correct dose, dose, at the correct time,, in the correct time way

73 % patients with viral suppression <400 copies/ml What Rate of Adherence Is Needed in ARV Therapy? % 70-80% 80-90% 90-95% >95% Percent adherence to therapy Source: Paterson D et al, 6th Conf ROI 1999 abstr #92

74 What does Adherence Look Like? * Twice a day regimen * Morning Dose 8 AM 8 PM Threshold of Therapeutic Viral Suppression Drug Level Drug concentration Evening Dose Higher toxicity (side effects) 8 AM Source: David Pantalone, Dept of Psychology, UW

75 and NonNon-Adherence? Drug resistant virus Drug resistant virus * Twice a day regimen * 8 AM 8 PM 8 AM Threshold of Viral Suppression Drug concentration Therapeutic Drug Level Achieved Source: David Pantalone, Dept of Psychology, UW

76 Effectiveness of Highly Active Antiretroviral Therapy (HAART) Before HAART On HAART

77 ABCs to Prevent HIV/STDs A = Abstinence B = Be Faithful C = Condom use

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