HIV Infection 1. Definition Human immunodeficiency virus (HIV) infects human cells and causes gradual loss of immune system function. Acquired immunodeficiency syndrome (AIDS) is the latest and the most severe stage of HIV disease. It is characterized by signs and symptoms of severe immunodeficiency, when the body loses the ability to fight against infections. Weakness of the immune system predisposes the body to occurrence of opportunistic infections, neoplasms, and others (wasting and dementia). 2. Historical chronology of the disease AIDS was first recognized as a new and distinct clinical entity in 1981. The case reports were described in the USA, when previously healthy male homosexuals suffered from unusual diseases, such as Kaposi´s sarcoma and Pneumocystis carinii pneumonia. Soon, new categories of patients occurred: recipients of blood transfusions and blood products, adult people from central Africa, children born from probably infected mothers. This data pointed to infection etiology of these diseases. 3. Origin of the disease The date of the first occurrence of AIDS is unknown, but the first period started probably in the 1950´s as a result of decolonization of developing countries, changing of customs, developing of worldwide traveling and liberalization of sexual behavior. The HIV is related to a SIV (Simian Immunodeficiency Virus) of African monkeys and was at this time brought out of jungle. The HIV virus was identified as the etiologic agents responsible for AIDS in 1983 in two laboratories independently: In French Pasteur´s Institute (L.Montagnier) and was named LAV (Lymphadenopathy Virus) and in American National Cancer Institute (R.Gallo) and was named HTLV III (Human T-lymphocyte Virus III). It was found they both are equal and named HIV 1 (Human Immunodeficiency Virus). Later in 1986, similar virus was identified in France and Sweden, originally named LAV II and later renamed as HIV 2. It is less virulent and causes milder infections in the West Africa. 4. Etiology HIV is an enveloped RNA virus and belongs to the genus Lentivirus and family Retroviridae. Two types (HIV 1 and HIV 2) have been classified, and 9 subtypes of HIV 1: A,B,C,D,E,F,G,H,I forming group M (major) and group O (outlier). In Central Europe the subtype B is the most common (85%). Viral morphology HIV virus has an external envelope consisting of the phospholipidic membrane, surface glycoprotein gp 120 and transmembranic glycoprotein gp 41, internal membrane and conic nucleocapside (core) made from p 24 protein. There are two equal RNA fibres and some enzymes inside the nucleocapside (reverse transcriptase, protease, integrase, ribonuclease). 5. Morbidity and mortality According to the World Health Organization (WHO) approx. 55 million of people became infected all over the world between 1981 and 1999, 90% of them in developing countries in Africa and Asia. It has been found that 16 000 people is infected every day, it means one person every 5 second. Already 18.8 million people have died of AIDS, 3.8 million of them were children. The geographic distribution varies: the majority of HIV/AIDS cases appear in sub- Saharan Africa. There are more than half million persons living with HIV/AIDS in Europe. In the Czech Republic, 859 HIV+ people were reported by the end of 2003, 197 of them are foreigners. 6. Epidemiology HIV is transmitted through 3 primary routes: by sexual contact with infected person, by significant exposure to infected blood or blood products and from infected mother to child. Modes of HIV transmission: 1) Horizontal: a) Sexual route (homosexual or heterosexual intercourses (including in vitro fertilization). The highest risk of sexual transmission is associated with unprotected anal receptive intercourse (0.1-0.3%). b) Parenteral route. Use of contamined injection equipment (by drug users, by sportsmen using injectable anabolic steroid, by blood transfusion and blood product recipients, by haemophiliacs). Risk of transmission by blood transfusion is low now, but exists. This is because of a window period of about 20 days between infection and seroconversion. Accidental exposure to HIV infected blood is dangerous, mucosal exposure is less risky. No risk has been identified in cutaneous contact (with intact skin) and exposure to saliva, urine etc. 2)Vertical (mother-to-child route). During pregnancy, during delivery (intra partum), breast feeding. Risk of HIV infection from mother-to-child is approximately 25% in European and North American countries, and it is higher in Africa. The treatment during pregnancy decreases the risk of transmission to 8%. Delivery method (Cesarean section) should be used to reduce risk as well. Since breast feeding increases risk by 10%, it should be avoided. Routine screening of all pregnant women is recommended in many countries including CR. 7. Pathogenesis The HIV virus needs for its incoming to the host cell bonding to the specific host cell receptor. The receptor is an CD4 antigen in the membrane of T helpers (Th) lymphocytes, less in monocytes, macrophages, dendritics cells and cells of the glia cells. Own viral genome is connected with a protein p24 for increasing its stability. With the protein p24, connection of the virus and the host’s CD4 membrane antigen is realized. The virus invades a cell through pinocytosis. Viral RNA is by viral reverse transcriptase transcribed to the host DNA and by viral integrase integrated to the host cell genome and leads to constant production of viral copies. A pharmacological inactivation some of viral enzymes (reverse transcriptase, integrase and protease) blocks the viral replication and is substance of antiretroviral therapy. When the cell is activated by an antigenic impulse, viral protease finishes the process of releasing the virus. These new virions immediately attack next CD4+ cells and leads to their destruction. The immune system is exhausted by acceleration of the CD4+ production and destruction, and soon the destruction predominates. In patients´laboratory exam the decreasing of absolute and relative CD4+ count appears. The deep CD4+ count decreasing (under 200/mm3) is strongly associated with the risk of development of opportunistic infections. There are three forms of relations between virus and infected host cell: 1) Infected host cell metabolizes normally, has normal functions and divides (splits) itself. This situation is named LATENT CELL INFECTION. 2) Infected host cell from time to time produces structural units of new virions ( viral RNA, enzymes, proteins, glykoproteins...). These units are at the host cell surface completed into new virions. They are released from the cell surface out, and infect new host cells. At the same time, formerly infected host cell survives and metabolizes. This situation is named CHRONIC CELL INFECTION. 3) The latent or chronic cell infection is changed into ACUTE CELL INFECTION as result of stimulation by external stimuli (chemical, physical, infectious, stress). The host cell metabolism is completely submitted to HIV virus and the cell is destroyed. 8. Virological diagnosis Direct and indirect methods can be used. Direct methods detect either virus, its nuclear acid (viral RNA=genome) or its p24antigen. We use them for diagnosis of vertical mother-to-child infection at children, for early diagnosis in the "window period" before seroconversion and for monitoring of illness developing and therapeutic effect. Direct detection by cultivation is dangerous for staff and is used only experimentally. Detection by identification of the genome is used routinely with a help of PCR method (polymerase chain reaction). This test quantifies viral load, i.e. count of copies in 1 ml of periferic blood. Detection by identification of p24 antigen is also widely used. It serves for early diagnosis in suspected early disease. Antigen p24 than disappears and can be detected again at the beginning of full-blown AIDS. Indirect methods detect specific antibodies of IgG, IgM, IgA classes. For the purpose of the first screening, total IgG antibodies are detected with highly sensitive EIA (enzyme-immunoassay) method. A positive result must be confirmed by the less sensitive, but more specific WB (western blot) method. The antibodies are detectable with one to three months delay after acquiring the HIV infection and persist during the whole patient’s life. The term seroconversion means appearance of the antibodies in the serum. Alternatively, for epidemiological studies, secretoric IgA antibodies detection from the saliva is possible. What situations and findings are suspicious from HIV infection? - In persons with risky behaving ( intravenous drugs users, changing sexual partners, homosexuals...) and suffering from infectious mononucleosis syndrome, rash, neurological symptoms and leucopenia. - In patients with prolonged nonspecific complaints (diarrhea, loss of weight, lymphadenopathy, fever of unknown origin, extent herpes zooster in younger people, repeated or progressive mucocutaneous candidiosis) - In patients with unclear leucopenia, lymphopenia,anemia, trombocytopenia, mild aminotranspherase elevation. How to make a serology diagnosis? A total antiHIV antibodies detection made from a blood serum (5-7 ml of coagulable blood). Every anti HIV examination needs a patient’s agreement in the Czech Republic. The positive result must be referred in National Reference Laboratory for AIDS. The patient is dispensarised in the AIDS center. What are the measures with unknown needle injury? Detection of antibodies against VHA, VHB, VHC, HIV. Antiretroviral prophylaxis, if necessary. The second day in the case of serologic negativity antiVHA and antiVHB vaccine is applied. Application of non specific immunoglobuline antiVHA . 9. Incubation and clinical manifestation Incubation is from 4 to 12 weeks. Clinical staging is following: 1st phase - Primary HIV infection (acute retroviral syndrome). It lasts 1-3 weeks. The patient has a mononucleosis-like syndrome or influenza syndrome (fever, lymphadenopathy, pharyngitis, malaise, fatigue, myalgias, artralgias, headache, rash). The rash may consist of macular, papular or acne-like lesions located on the upper chest and back, which are not painful or itchy. In laboratory examination, we can find transient depletion of the CD4 count. The p24 antigen appears 14th day after exposure. HIV antibodies appear 20th day and persist all patient’s life. At the end of this period, clinical signs disappear, the CD4 count normalizes and p24 antigen is no more detectable. 2nd phase- Asymptomatic or latent. It lasts from 18 months to 15 years, about 8 years in average. It depends on the number of infection stimuli in this period. The patient feels well, has no complaints, his susceptibility to infections is normal. A mild lymphadenopathy can persist (PGL, persisting generalized lymphadenopathy). However, in laboratory we can find slow declination of CD4 count (more than 500- 300/mm3), mild lymphopenia and anemia in blood count. 3rd phase - Early symptomatic. It lasts several years. The clinical signs of immunodeficiency are found. Patients suffer from the "small opportunistic infections", as herpes zooster, oral candidiosis, hairy leukoplakia of the tongue etc., and some immunopatological signs as peripheral neuropathy, thrombocytopenia etc. A depletion of CD4 is aggravating (500-300/mm3). 4th phase - Late symptomatic, AIDS. It can take several years, or less. Severe opportunistic infections appear, such as Pneumocystis pneumonia, cerebral toxoplasmosis, chronic cryptosporidiosis, candidiasis oesophageal, tracheal, bronchial and pulmonary and many other (separated or in combination). HIV encephalopathy and tumors appear. CD4 less than 200/mm3. 5th phase- Advanced (full-blown) AIDS. Severe opportunistic infections appear, especially of CMV disease (retinitis, generalized infection) and disseminated mycobacteriosis. The wasting syndrome occurs. 10. Classification of HIV infection The latest classification according to the Centers for Disease Control (CDC) in Atlanta from 1993 has two points of view, laboratory and clinical. It is useful not only for clinical purposes, but also for obtaining epidemiological data. Laboratory categories: 1. more than 500 CD4+ lympho in mm3 2. from 200 to 500 CD4+ lympho in mm3 3. less than 200 CD4+ lympho in mm3 Clinical categories: A. Asymptomatic HIV infection, or Persisting generalized lymphadenopathy (PGL), or Primary (acute) HIV illness (mononucleosis-like syndrome and rash). B. Non-specific signs: temperature of 38,5 C during 1 month or more, diarrhea 1 month or more) and "small" opportunistic infections (OI-oropharyngeal and vulvovaginal candidiosis, herpes zooster, oral hairy EBV leukoplakia, listeriosis, bacillary angiomatosis, thrombocytopenic purpura... C.=AIDS - “big" opportunistic infections (Pneumocystis carinii pneumonia, cerebral toxoplasmosis, candidiasis oesophageal, tracheal, bronchial or pulmonary, CMV retinitis or generalized CMV infection especially in liver and GIT, recurrent Salmonella bacteriaemia, chronic intestinal cryptosporidiosis or isosporiasis, tuberculosis, recurrent pneumonia, extrapulmonary cryptococosis or histoplasmosis, progressive multifocal leukoencephalopathy (PML). - HIV encephalopathy, wasting syndrome. - tumors: Kaposi´s sarcoma, lymphomas (Burkitt´s, primary in brain...), invasive cervical cancer in women. 11. Therapy The management pf HIV-positive patients includes four main components: A) Antiretroviral drugs (high-active antiretroviral therapy, HAART)- 15 drugs B) Prophylaxis against opportunistic pathogens C) Treatment of opportunistic infections (OIs) D) Symptomatic therapy of all internal disorders (anemia, dehydratation...), surgical care, dental care, psychological care. Dietary interventions and nutritional supplement. Ad A) Antiretroviral drugs The drugs are unable to eradicate virus from the body. They can minimize viral replication, restore immunological function, improve quality of life and reduce morbidity and mortality. They inhibit one of two key viral enzymes required by HIV for replication. Agents, that inhibit the enzyme reverse transcriptase, are called reverse transcriptase inhibitors (RTIs). They are divided into two groups depending on their chemical structure: nucleoside RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs). Agents, that inhibit the function of protease, are called protease inhibitors (PIs). The entry inhibitors (EIs) are the newest agents using in a clinical practice from 2003: they inhibit the fusion of virus with the human lymphocytes. NRTIs: zidovudin = azidothymidin - RETROVIR, AZITIDIN didanosin - VIDEX zalcitabin- HIVID stavudin -ZERIT lamivudin- EPIVIR abacavir -ZIAGEN tenofovir - VIREAD zidovudin + lamivudin - COMBIVIR NNRTIs: nevirapin- VIRAMUNE delavirdin - RESCRIPTOR efavirenz - STOCRIN, SUSTIVA IPs: saquinavir - INVIRASE, FORTOVASE ritonavir - NORVIR indinavir - CRIXIVAN nelfinavir - VIRACEPT amprenavir - AGENERASE atazanavir -REYATAZ lopinavir + ritonavir - KALETRA EIs: enfuvirtid - FUZEON Monotherapy is not the recommended treatment, although it plays an important role in prevention of mother-to-child HIV transmission. Combined therapy can delay drug- resistance of viruses and improve pharmacokinetics (additive or synergic effect of drugs combination, enabling drugs to reach different cellular and body compartments). Combination of 3 antiretroviral drugs of different groups together is usually used. The combination consists of 2 NRTIs and 1 IP or NNRTI. The first NRTI is always zidovudine or stavudine and the second NRTI is either lamivudine or didanosine or zalcitabine. Since some patients do not succeed with their initial therapy, they need a second, third and fourth line regimen (alternative, switch, salvage therapy). Combined therapy is very expensive, available for only 10% infected people in the world. For example in CR, triple therapy for one patient costs about CZK 400 000 a year. As we have 859 patients, it is about CZK 343 000 000 per year. When to start the AR therapy? According to last consensus of American Medical Association AR therapy is started in every patient with HIV infection: -regardless of clinical symptomatology -with any CD4+ count -with viral load more than 5 000 - 10 000 copies/ml. Beside, some special reasons exist for initiation of AR therapy: 1. Primary HIV infection 2. Pregnancy of HIV+ woman (from the 2nd trimester) 3. Newborn of HIV+ mother (for 6 weeks of life) 4. Exposure to HIV-inficated biological material ( needle injury..) It should be started optimally in 2 hours, maximally in 72 hours after exposure. We use zidovudine 3x200 mg/d+ lamivudine 2x150mg/d+ indinavir 3x800 mg/d for 4 weeks. Risk of the HIV infection is in this case 0,3-0,5 %. Ad B) Prophylactics against opportunistic pathogens An OI prophylactics is primary and secondary. The first one serves as protection against the first attack of the OI. The second represents a chronic suppressive therapy after the first episode of OI. In the prophylaxis, we usually use lower doses of the same drugs, which are used therapeutically. 12. Opportunistic infections and other complication due to HIV infection There are three groups of complications: A) Opportunistic infections- bacterial, viral, protozoal, mycotic B) Tumors C) Pathological states evoked (provoked) directly by presence of HIV virus in the body. The most frequent opportunistic infection agents and drugs used for their elimination are: 1) Protozoal: Toxoplasma gondii (pyrimethamine, sulphadiazine) Cryptosporidium parvum (paramomycine, azalides) 2) Mycotic: Candida sp. (ketokonazole, fluconazole, itraconazole, amphotericine) Pneumocystis carinii (pentamidine,,dapson, cotrimoxazole) Cryptococcus neoformans (amphotericine, fluconazole) 4) Viral: Herpetic viruses – HSV 1,2, CMV, EBV ( aciclovir, foscarnet, famciclovir, ganciclovir) . Papovaviruses. 5) Bacterial: Mycobacterium tuberculosis (antituberculotics), Atypical Mycobacterias (antituberculotics with macrolides, azalides, quinolones) Non-typhoid Salmonella (antibiotics) We can presuppose an appearance of some of them according to decreasing of CD4 count: CD4 + lymphocytes 500/ul Bacterial infections (pneumonia, pyodermia, otitis, sepsis), herpes simplex labialis, h.zooster. 300/ul Candidosis oropharyngeal, Mycobacteriosis pulmonary et extrapulmonary, Kaposi´s sarcoma 200/ul Pneumocystis carinii pneumonia, primary cerebral lymphoma, HIV encephalopathy, herpes simplex genitalis, progressive multifocal leucoencephalopathy 150/ul Toxoplasmic encephalitis, intestinal kryptosporidiosis, wasting syndrome. 100/ul Candidosis esophageal, Cryptococcal meningitis, 50/ul Mycobacteriosis disseminated, Cytomegalovirus retinitis, encephalitis Ad B) Tumors Kaposi´s sarcoma This is a typical tumor of HIV/AIDS patients, especially at homosexuals. Etiologic agent is probably sexually transmitted 8th human herpetic virus (HHV-8). The most common clinical manifestation is the mucocutaneous one, with livid maculas or noduli in the skin of the face, trunk and extremities and in the mouth, and lymphadenopathy. Gastrointestinal and pulmonary manifestation also exist. Therapy consists of chemotherapy, radiotherapy, local surgical therapy. Mostly Kaposi´s sarcoma is not fatal. Primary cerebral lymphoma This is the most frequent cerebral tumor at HIV/AIDS patients, especially at children. Clinical manifestation is similar to cerebral toxoplasmosis manifestation. The only therapeutical possibility is actinotherapy. Systemic non-Hodgkin lymphoma This tumor from B-lymphocytes attacks gastrointestinal system, liver, bone marrow and menings. Clinical symptoms are not specific, fever and cachexia are usual. Diagnosis is histologic, from biopsy of affected organ. Chemotherapy. Ad C) Pathologic states evoked directly by presence of HIV virus HIV encephalopathy (formerly called AIDS dementia complex). This disorder is a result of the HIV virus invasion to the brain. Clinical manifestation is progressive dementia without focal neurological finding, diffuse cerebral atrophy on CT and NMR. Highly dosed zidovudin in therapy. Peripheral neuropathies. Distal sensitive polyneuropathy (DSPN) and chronic inflammatory demyelinisational neuropathy (CIDP) are the most frequent of them. HIV enteropathy. The disease leads to chronic diarrhea with all consequences. Wasting syndrome. It is characterized by unwanted loss of body weight of more than 10% and 30 days´ fever or diarrhea, having no other cause (OI, tumor etc.) Wasting syndrome is usual in late symptomatic and especially in advanced (full- blown) stage of HIV infection. At this time, patient is always loosing his weight and becomes cachectic. The cachectisation can be fatal by itself, even without presence of other complications such as tumors or opportunistic infections. From the chronic loss of weight, we can estimate surviving time: when body weight is 71% of normal body weight, the death is coming in about 100 days. Therapy with nutrition support, transfusions, drugs stimulating appetite, anabolic steroids, recombinant human growth hormone is used. 13. AIDS at infants and children About 3% of HIV infected people in the world are children. The dominating mode of HIV transmission in children is vertical, from infected mother (80% of infected children). The risk of transmission is 20-30% in Europe and it can be reduced to 5-8%, when: - treatment with zidovudine in pregnancy is started, -Caesarean section as delivery method is used, and - breastfeeding is avoided. Diagnosis of infection in neonates remains problematic. All newborns of HIV+ mothers carry maternal HIV antibodies, sometimes for several months, and only 50% of infected children have virus detectable by test at birth. The children should be followed until the age of 18 months to exclude HIV infection. At about 80% of infected children, infection symptoms occur in the first year of age. Diagnosis of HIV infection at vertically infected children is made by presence one of three criteria: 1) Clinical signs of AIDS 2) Direct HIV detection 3) AntiHIV antibodies persisting over 18 months of age Progression of the disease is faster in children. Development of HIV infection in children: There are two possibilities of development of HIV infection at children. The first one is faster, resembling to an adult disease. It has similar laboratory findings and tends to opportunistic infections. It is probably result of transplacentally acquired infection. Surviving time is shorter, several years. The second possibility is characterized by recidiving (repeated) bacterial infections and by lymphocytic interstitial pneumonitis. The child is probably infected in perinatal period. Surviving time is longer, it takes many years. Clinical manifestation The occurrence of repeated pneumonias, gastroenteritis and skin infection is common presentation of childhood AIDS. At infants up to 1 year of age, we can find early non-specific signs as non-prosperity, lymphadenopathy, hepatomegaly and splenomegaly. Also HIV hepatitis and diarrhea are typical in this age. Some complications, typical in adults, are rare in children ( cerebral toxoplasmosis, cryptococcal meningitis, Kaposi´s sarcoma). The vaccination scheme is modified. Passive immunization is possible. When the live attenuated vaccine is used, we must compare risk and benefit. 14. Supervising strategy in the CR. All data are registered in one center in CR, in National Reference Laboratory for AIDS of National Institute of Public Health, Prague. The first HIV positivity finding at any patient must be referred there. The patient is obliged to undertake an examination and treatment and to announce his virus carrying before taking any medical care. The patient is dispensarised in one of the AIDS center in CR, informed about new life conditions and way of living (sexual behaving, daily regimen, nutrition and rest, traveling, limited contact with animals ...). He should not become donor of blood, organ or sperm. On the contrary, he cannot be professionally or socially limited by his virus carrying, only by his actual health state. Prevention strategy for population 1) Education, safe sex (condom use). 2) Screening of blood products. 3) Needle exchange scheme in IDU´s. 4) Antenatal screening. 5) Voluntary testing of persons in high-risk categories 15. Prognosis. The average time for untreated persons from acquiring of infection to appearance of severe complications is about 10 years. About 5% of infected are "long term non- processors". Surviving time with developed AIDS in adults is 1-2 years maximum up to 5 years.