Human Immunodeficiency Virus (HIV) is the virus that causes AIDS. It is transmitted through bodily fluids and attacks CD4+ T cells of the immune system. The disease progresses through three stages as the number of CD4+ cells declines, resulting in opportunistic infections. Diagnosis involves antibody and viral load tests, while treatment is with antiretroviral drugs. Prevention strategies focus on safe sex practices, needle safety, and screening of pregnant women to prevent mother-to-child transmission.

1. Human Immunodeficiency Virus Eva L. Dizon,M.D. Pediatric Infectious Disease Microbiology Our Lady of Fatima University

2. OBJECTIVES General Goal: To know the characteristic of HIV, the development of AIDS , diagnostic test and its therapeutic management .

3. Specific Objectives: The student should be able to: 1. recite the most likely causes of HIV/AIDS and how this viral infection is usually acquired 2. describe how the virus attaches to human cells. Also know the human cell receptors that the virus attaches to (hint: M-tropic vs. T-tropic viruses). 3. describe the three different HIV/AIDS disease stages and what happens to the immune system during those disease stages. 4. describe the various means of diagnosing HIV/AIDS and when to use which test. 5. list the most common opportunistic infections that occur in HIV/AIDS patients. 6. describe the basic treatment regimen (HAART). 7. list ways of preventing HIV infections (hint: how do you prevent congenital infections?)

4. Etiology: Human immunodeficiency virus (HIV) types 1 and 2, human retroviruses, lentivirus subfamily. HIV is the causative agent of AIDS. The most common type is HIV-1 and is the infectious agent that has led to the worldwide AIDS epidemic. HIV-2 infection is less common and less virulent, but results in AIDS as well.

6. Epidemiology: HIV-1 (distributed worldwide) and HIV-2 (mainly endemic in west Africa) were first isolated and associated with the disease in 1982 and 1983. AIDS was first recognized in 1981, although retrospective studies suggest that cases occurred in Africa in the 1950's and in the U.S. by the 1970's.

10. Epidemiology Principal genetic groups of HIV-1: 1. Main 2. Outlier 3. N Genetic group M -is highly prevalent and is further classified into 10 established envelope subtypes, A through J. HIV-1 subtype B predominates in Europe and the Americas, whereas HIV-1 subtype C predominates sub-Saharan Africa. Mosaic forms, which combine the genetic material from two distinct subtypes, have also been identified.

12. The latest statistics of the global HIV and AIDS were published by UNAIDS in November 2009, and refer to the end of 2008. More than 25 million people have died of AIDS since 1981. Africa has over 14 million AIDS orphans. At the end of 2008, women accounted for 50% of all adults living with HIV worldwide In developing and transitional countries, 9.5 million people are in immediate need of life-saving AIDS drugs; of these, only 4 million (42%) are receiving the drugs. Estimate Range People living with HIV/AIDS in 2008 33.4 million 31.1-35.8 million Adults living with HIV/AIDS in 2008 31.3 million 29.2-33.7 million Women living with HIV/AIDS in 2008 15.7 million 14.2-17.2 million Children living with HIV/AIDS in 2008 2.1 million 1.2-2.9 million People newly infected with HIV in 2008 2.7 million 2.4-3.0 million Children newly infected with HIV in 2008 0.43 million 0.24-0.61 million AIDS deaths in 2008 2.0 million 1.7-2.4 million Child AIDS deaths in 2008 0.28 million 0.15-0.41 million

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16. Transmission: Modes of transmission: 1.sexual contact (heterosexual (most common means in the world) and homosexual) 2.blood or blood product transfusion (before routine testing) 3.transplanted tissue (before routine testing) 4.IV drug use with shared needles 5.transplacental ( in utero ) or by perinatal infection of neonates (breast milk).

17. DOH Reported Modes of Transmission HIV/AIDS Registry, January 1984-July 2007 (N=2,916) Reported Modes of Transmission Jan. 1984- July 2007 July 2007 Heterosexual Contact 1,781 10 Homosexual Contact 567 9 Bisexual Contact 200 9 Blood/blood product 19 0 Injecting drug use 7 0 Needle prick injuries 3 0 Perinatal 44 0 No exposure reported 295 3 TOTAL 2,916 31

23. Pathogenesis: 1.HIV can cross the epithelial barrier through a process known as transcytosis by M cells (these cells line the intestine). 2. HIV is picked up by antigen presenting cells (APCs), primarily dendritic cells (DCs). HIV directly infects CD4+ T lymphocytes in mucosal associated lymphoid tissue (MALT) 3.Establishes a fulminant local infection within a few days, and then spreads quickly throughout the body.

29. Symptoms of acute retroviremia in HIV-infected patients Myalgia lymphadenopathy fever fatigue pharyngitis rash (often on trunk) nausia diarrhea loss of weight night sweats mucocutaneous ulcers headache In blood: lymphopenia

32. Disease associated with various levels of CD4 cells during HIV infection HIV- Complications at CD4>500mm3 Infectious Acute retroviral syndrome Candida vaginitis Other Generalized LAD Guillain-Barre (very rare) Vague constitutional symptoms HIV- Complications at CD4 200-500mm3 Infectious Pneumococcal pneumonia TB Herpes zoster Kaposis sarcoma Oral hairy leukoplakia (OHL) Oropharyngeal candidiasis (thrush) Non-Infectious Cervical Carcinoma Lymphomas ITP (Immune thrombocytopenic purpura )

36. Stages of Disease Stage I- Acute Viral Infection (1-3 wks) Stage I ends with the production of high titers of anti-HIV antibodies at 2-3 months, postinfection. Anti-HIV antibodies are usually detectable by ELISA by 3-4 weeks. no symptoms, or any or all of the following "mononucleosis-like symptoms": fever , headache , malaise , myalgia, arthralgia lymphadenopathy hepatosplenomegaly meningitis, encephalitis rash - small pink papules or macules over much of the body

37. Stage II- Completely assymptomatic Lasts for 6 or more years in 65-85% of cases. Patients produce large amounts anti-HIV antibody HIV is detectable in blood, semen, and cervical secretions. New PCR procedures show that as many as 1 in 10 peripheral CD4+ cells are infected. HIV-antibody-complement complexes are trapped in lymph nodes, tonsils, spleen, etc. by follicular dendritic cells (FDC). CD4+ T cells disappear from the blood because they are sequestered in the lymph nodes (numbers are 5-10X higher than in the peripheral blood) Follicular Dendritic Cells (FDC) facilitate HIV transmission to uninfected T cells. When peripheral CD4+ cells number 500-200/µl, the FDC are dying and the internal structure of the lymph node is breaks down; HIV spills over into the blood.

38. Stage III- Overt Disease Severity is directly related to the decline of CD4+ T cells, which causes diminished function by TC, B cells (hypogammaglobinemia), macrophages and NK cells, and leads to opportunistic infections and spontaneous neoplasms.

40. Diagnosis Test ELISA Agglutination test Purpose Initial Screening test Western blot Immunofluorescence test Confirmatory test p24 antigen Virion RNA- RT PCR CD4 CD8 ratio Early marker of Infection Detection of a recent infection To confirm treatment efficacy Detection of recent infection Staging the disease and to confirm treatment efficacy Viral Isolation

41. Opportunistic Infections Skin. Among the earliest observed AIDS-related conditions occur as infectious or noninfectious skin eruptions. Fungal infections : Mucosal candidiasis and Thrush (white, non-adherent plaques and erythema) Intertriginous cutaneous candidiasis Paronychia Dermatophytosis - Tineas: pedis, cruris, corporis; due to Trichophyton rubrum ; Onychomycosis Disseminated fungal infections showing early skin lesions Cryptococcus neoformans - meningitis Histoplasma capsulatum - in endemic areas; pulmonary and renal failure Sporothrix schenckii -

42. Opportunistic infections Viral infections: Herpes simplex non-healing ulcers; genital, perioral, perianal; perform the Tzanck test Varicella zoster reactivation within the dorsal root ganglion Molluscum contagiosum (pox virus agent) - umbilicated, skin-colored papules on the face or trunk, confused with acne, sebaceous hyperplasia, disseminated cryptococcosis, and basal-cell carcinoma. Warts - pre-existing skin and genital warts become difficult to treat Oral hairy leukoplakia - whitish, corrugated or hairy, adherent plaques, lateral margins of the tongue Cytomegalovirus - nonhealing perianal or anal ulcers

43. Opportunistic infections Bacterial infections: Staphylococcus, Streptococcus, Haemophilus, Pseudomonas : folliculitis, impetigo, cellulitis Syphilis - rapidly progressing to tertiary syphilis; secondary syphilis may be seronegative; test individuals showing a papulosquamous rash with RPR and/or a silver stain of a skin biopsy Mycobacterium tuberculosis and avium-intracellulare skin lesions at the site of injections

44. Noninfectious inflammatory diseases: Seborrheic dermatitis - most common cutaneous manifestation; 3% of the general pop., 85% of the HIV+ pop.; often associated with Malassezia furfur Psoriasis - exacerbation of existing conditions Other inflammatory dermatitis - scabies, atopic dermatitis

45. Malignant neoplasms of the skin: Kaposi's sarcoma - pink to red to purple to brown, anywhere on skin; (1984) HHV8 also called Kaposi's sarcoma herpes virus (KSHV) has a causal role; treatment may not affect survival Lymphoma - Hodgkin's, non-Hodgkin's, Burkett, etc Invasive cervical cancer Other cutaneous manifestations: Epithelioid angiomatosis - violaceous papules and nodules resembling Kaposi's sarcoma Hair changes - greying, hairline recession Yellow nail syndrome Lungs: May have multiple infections. Pneumocystis carinii : pneumocystosis - damaged alveoli with cyst production.

46. Treatment HAART (Highly Active Antiretroviral Therapy)- available since 1995 HAART results in suppression of viral replication and halts damage to the immune system. It also partially restores the immune system leading to partial restoration of immune function. Clinical benefits accompanying these immunologic benefits include fewer opportunistic infections and longer life for the patients

47. Classes of Antiretroviral drugs 1. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI's) NRTIs inhibit HIV's reverse transcriptase and can be placed within the viral DNA. When the NRTI's are placed in the viral DNA by the reverse transcriptase transcription of the viral genes is inhibited. This prevents virus multiplication and subsequent spread of the viral infection.

48. Classes of antiretroviral drugs 2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI's) These drugs also inhibit reverse transcriptase which prevents virus multiplication and spread. They do it in a slightly different fashion than NRTI's. 3. Protease Inhibitors (PI's) The protease cleaves the viral proteins to the correct sizes so that a mature viral particle can be formed (viral assembly). The protease inhibitors inhibit the retroviral protease from cleaving the viral proteins. These drugs help to slow the spread of the virus to other uninfected cells. Do not use protease inhibitors in monotherapy. HIV quickly becomes resistant to the protease inhibitors .

49. Classes of antiretroviral drugs 4. Fusion inhibitors: A new class of drugs is currently approved for use in AIDS patients. The drug Enfuvirtide [T-20, pentafuside, Fuzeon (trade name)]

52. PREVENTION Safe sex, safe use of needles and more effective early screening. Treat HIV-1 infected pregnant women as indicated above to prevent infection of the fetus/infant. Vaccines: No vaccine is currently approved by FDA . Clinical trials are currently being conducted with a number of different vaccines.

54. Manifestations: High-risk patients with mononucleosis-like symptoms: fever malaise lymphadenopathy hepatosplenomegaly arthralgias rash Persistent generalized lymphadenopathy syndrome (PGL) multiple enlarged lymph nodes AIDS-related complex (ARC) fever - role for TNF, IL-1 fatigue diarrhea weight loss night sweats immunological abnormalities CNS disease (seen in long-term survivors) dementia spontaneous neoplasms

55. In resource-poor countries and communities, sometimes medical facilities and testing is unavailable, and it isn’t possible to decide the appropriate time to begin treatment on the basis of test results. The World Health Organization has developed a disease staging system for HIV infection which is not dependent on testing. WHO disease staging system for HIV Infection and Disease in Adults and Adolescents Clinical Stage I: Asymptomatic Generalized lymphadenopathy Performance scale 1: asymptomatic, normal activity Clinical Stage II: Weight loss, < 10% of body weight Minor mucocutaneous manifestations (seborrheic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations, angular cheilitis) Herpes zoster within the last five years