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  1. 1. HIV/AIDS Dr Arina Odawa, MB,ChB (NBI), M.MED/STD,HIV,AIDS (SYDNEY), Chest Medicine (Tel Aviv & Japan) Consultant Physician STD/HIV/AIDS, Chest & Skin Medicine
  2. 2. Introduction AIDS was first recognized in the United States in the summer of 1981, when the U.S. Centers for Disease Control and Prevention (CDC) reported the unexplained occurrence of Pneumocystis carinii pneumonia in five previously healthy homosexual men in Los Angeles and of Kaposi’s sarcoma (KS) in 26 previously healthy homosexual men in New York and Los Angeles.
  3. 3. Introduction cont- Within months, the disease became recognized in male and female injection drug users (IDUs) and soon thereafter in recipients of blood transfusions and in hemophiliacs. As the epidemiologic pattern of the disease unfolded, it became clear that a microbe transmissible by sexual (homosexual and heterosexual) contact and blood or blood products was the most likely etiologic agent of the epidemic.
  4. 4. Introduction cont- In 1983, human immunodeficiency virus (HIV) was isolated from a patient with lymphadenopathy, and by 1984 it was demonstrated clearly to be the causative agent of AIDS. In 1985, a sensitive enzyme-linked immunosorbent assay (ELISA) was developed, which led to an appreciation of the scope and evolution of the HIV epidemic at first in the United States and other developed nations and ultimately among developing nations throughout the world (see below).
  5. 5. Definition With the identification of HIV in 1983 and its proof as the etiologic agent of AIDS in 1984, and with the availability of sensitive and specific diagnostic tests for HIV infection, the case definition of AIDS has undergone several revisions over the years. The current CDC classification system for HIV- infected adolescents and adults categorizes persons on the basis of clinical conditions associated with HIV infection and CD4 T lymphocyte counts.
  6. 6. Defn cont The system is based on three ranges of CD4 T lymphocyte counts and three clinical categories and is represented by a matrix of nine mutually exclusive categories A1, A2, A3, B1, B2, B3, C1, C2 and C3. Using this system, any HIV-infected individual with a CD4 T cell count of 200/L has AIDS by definition, regardless of the presence of symptoms or opportunistic diseases. Once individuals have had a clinical condition in category B, their disease cannot again be classified as category A, even if the condition resolves; the same holds true for category C in relation to category B.
  7. 7. AIDS surveillance case definition for Adults & Children Clinical Categories A B C CD4 cell categories Asymptomatic or PGL or Acute HIV infection Symptomatic AIDS indicator condition >500 >29% A1 B1 C1 200-499 14-28% A2 B2 C2 <200 <14% A3 B3 C3
  8. 8. Mode of Transmission HIV is transmitted by both homosexual and heterosexual contact; by blood and blood products; and by infected mothers to infants either intrapartum, perinatally, or via breast milk. After 20 years of scrutiny, there is no evidence that HIV is transmitted by casual contact or that the virus can be spread by insects, such as by a mosquito bite.
  9. 9. Sexual Transmission HIV infection is predominantly a sexually transmitted disease (STD) worldwide. Although in the United States 42% of new HIV infections are among men who have sex with men and 33% of new HIV infections are by heterosexual transmission, the most common mode of infection worldwide, particularly in developing countries, is clearly heterosexual transmission.
  10. 10. Transmission cont HIV has been demonstrated in seminal fluid both within infected mononuclear cells and in the cell- free state. The virus appears to concentrate in the seminal fluid, particularly in situations where there are increased numbers of lymphocytes and monocytes in the fluid, as in genital inflammatory states such as urethritis and epididymitis, conditions closely associated with other STDs. The virus has also been demonstrated in cervical smears and vaginal fluid.
  11. 11. Transmission cont There is a strong association of transmission of HIV with receptive anal intercourse, probably because only a thin, fragile rectal mucosal membrane separates the deposited semen from potentially susceptible cells in and beneath the mucosa and trauma may be associated with anal intercourse. Anal douching and sexual practices that traumatize the rectal mucosa also increase the likelihood of infection.
  12. 12. Transmission cont It is likely that anal intercourse provides at least two modalities of infection: (1) Direct inoculation into blood in cases of traumatic tears in the mucosa; and (2) infection of susceptible target cells, such as Langerhans cells, in the mucosal layer in the absence of trauma.
  13. 13. Transmission by blood & blood products HIV can be transmitted to individuals who receive HIV- tainted blood transfusions, blood products, or transplanted tissue as well as to IDUs who are exposed to HIV while sharing injection paraphernalia such as needles, syringes, the water in which drugs are mixed, or the cotton through which drugs are filtered. Parenteral transmission of HIV during injection drug use does not require intravenous puncture; subcutaneous (“skin popping”) or intramuscular (“muscling”) injections can transmit HIV as well, even though these behaviors are sometimes erroneously perceived as low-risk.
  14. 14. Transmission cont Among IDUs, the risk of HIV infection increases with the duration of injection drug use; the frequency of needle sharing; the number of partners with whom paraphernalia are shared, particularly in the setting of “shooting galleries” where drugs are sold and large numbers of IDUs may share a limited number of “works”. Comorbid psychiatric conditions such as antisocial personality disorder; the use of cocaine in injectable form or smoked as “crack”; and the use of injection drugs in a geographic location with a high prevalence of HIV infection also increase the risk of infection.
  15. 15. Transmission cont Transfusions of whole blood, packed red blood cells, platelets, leukocytes, and plasma are all capable of transmitting HIV infection. Currently, in most developed countries, the following measures have made the risk of transmission of HIV infection by transfused blood or blood products extremely small: (1) the screening of all blood for HIV nucleic acid, p24 antigen, and/or anti-HIV antibodies; (2) the self-deferral of donors on the basis of risk behavior; (3) the screening out of HIV-negative individuals with positive surrogate laboratory parameters of HIV infection, such as hepatitis B and C; (4) serologic testing for syphilis.
  16. 16. TRANSMISSION OF HIV: HEALTH CARE WORKERS AND LABORATORY WORKERS There is a small, but definite, occupational risk of HIV transmission to health care workers, laboratory personnel and others who work with HIV-containing materials, particularly when sharp objects are used.
  17. 17. MATERNAL-FETAL/INFANT TRANSMISSION HIV infection can be transmitted from an infected mother to her fetus during pregnancy, during delivery, or by breast- feeding. This is an extremely important form of transmission of HIV infection in developing countries, where the proportion of infected women to infected men is 1:1. Proportions of mother to-child transmissions is 23 to 30% before birth, 50 to 65% during birth, and 12 to 20% via breast-feeding.
  18. 18. In the absence of prophylactic antiretroviral therapy to the mother during pregnancy, labor, and delivery, and to the fetus following birth, the probability of transmission of HIV from mother to infant/fetus ranges from 15 to 25% in industrialized countries and from 25 to 35% in developing countries. These differences may relate to the adequacy of prenatal care as well as to the stage of HIV disease and the general health of the mother during pregnancy. Factor that is associated with higher rates of transmission is the presence of high maternal levels of plasma viremia. Low maternal CD4 T cell counts have also been associated with higher rates of transmission; since low CD4 T cell counts are often associated with high levels of plasma viremia. A prolonged interval between membrane rupture and delivery is another well-documented risk factor for transmission.
  19. 19. ARV treatment of HIV-infected pregnant women from the beginning of the second trimester through delivery and of the infant for 6 weeks following birth dramatically decreased the rate of intrapartum and perinatal transmission of HIV infection from 22.6% in the untreated group to 5%. The rate of mother-to-child transmission is approaching 1% or less in pregnant women who are receiving combination antiretroviral therapy for their HIV infection. Such treatment, combined with cesarean section delivery, has rendered mother-to- child transmission of HIV an unusual event in the United States and other developed nations. In developed countries, current recommendations to reduce perinatal transmission of HIV include universal voluntary HIV testing and counseling of pregnant women, antiretroviral prophylaxis with ARV drugs in cases in which the mother does not require therapy, combination therapy for women who do require therapy, obstetric management that attempts to minimize exposure of the infant to maternal blood and genital secretions, and avoidance of breast- feeding.
  20. 20. Breast-feeding is an important modality of transmission of HIV infection in developing countries, particularly where mothers continue to breast feed for prolonged periods. The risk factors for mother-to child transmission of HIV via breast- feeding are detectable levels of HIV in breast milk, the presence of mastitis, low maternal CD4 T cell counts, and maternal vitamin A deficiency. The risk of HIV infection via breast-feeding is highest in the early months of breast-feeding. In addition, exclusive breast-feeding has been reported to carry a lower risk of HIV transmission than mixed feeding. Certainly, in developed countries breast-feeding by an infected mother should be avoided. In certain developing countries, breast milk is the only source of adequate nutrition as well as immunity against potentially serious infections for the infant. Absolute breast feeding is practised with risk due to poverty.
  21. 21. TRANSMISSION BY OTHER BODY FLUIDS Although HIV can be isolated typically in low titers from saliva of a small proportion of infected individuals, there is no convincing evidence that saliva can transmit HIV infection, either through kissing or through other exposures, such as occupationally to health care workers. Saliva contains endogenous antiviral factors such as HIV-specific immunoglobulins of IgA, IgG, and IgM isotypes which are detected readily in salivary secretions of infected individuals. A number of soluble salivary factors also inhibit HIV to various degrees in vitro, probably by targeting host cell receptors rather than the virus itself. Secretory leukocyte protease inhibitor (SLPI), blocks HIV infection in several cell culture systems, and it is found in saliva at levels that approximate those required for inhibition of HIV, higher salivary levels of SLPI in breast-fed infants were associated with a decreased risk of HIV transmission through breast milk.
  22. 22. Although virus can be identified, if not isolated, from virtually any body fluid, there is no evidence that HIV transmission can occur as a result of exposure to tears, sweat, and urine. Natural History & Classification of HIV Infection 1 Viral transmission 2-3 weeks 2 Acute retroviral syndrome 2-3wks 3 Recovery + seroconversion 2-4wks 4 Asymptomatic chr HIV infection Avg 8yrs 5 Symptomatic HIVinfection/AIDS 1-3yrs
  23. 23. Initial Event Acute retroviral syndrome Fever 96%, Myalgias 54%, Hepatosplenomegaly 14%, Adenopathy 74%, Pharyngitis 70%, Rash 70%, Diarhoea 32%, Thrush 12% weight loss13%, Headache 32%, N/vomiting 27%, Neurologic symptoms 12%. Clinical recovery is accompanied by a reduction in plasma viraemia due to development of cytotoxic T cell response. CD4 decrease is due to HIV induced cell death. The rate of CD4 cell decline depend on the viral load. HIV RNA concentration in plasma show an initial burst increase during acute infection and then decline to a set point as a result of seroconversion and immune response. With continued infection, HIV RNA levels gradually increase. Late stage disease is characterised by a CD4 count of < 200cells/ml.
  24. 24. and the development of opportunistic infections and tumors, wasting and neurological complications. In untreated patient the median survival after CD4 has fallen 200cells/ml is 3.7yrs. The median survival after an AIDS defining illness is 1.3yrs. Correlation of complications with CD4 cell count CD4 cell count/ml Complications >500 Acute retroviral syndrome, candidal vaginitis 200-500 Pneumoccocal & other bacterial pneu- monia, PTB, H. zoster, thrush, Kaposi sarcoma <200 PCP, M/PTB, wasting, dementia, neuro- pathy, cardiomyopathy, lymphomas.
  25. 25. < 100 Disseminated herpes simplex, Toxoplasmosis Cryptococcosis, Cryptosporidiosis, candidal oesophagitis. < 50 Disseminated CMV, disseminated MAC Diagnosis of Primary HIV infection HIV RNA >10000 copies /ml + indeterminate or HIV negative serology or recent seroconversion. Diagnosis of Chronic HIV infection & AIDS Rapid tests – Unigold, Oraquick, Clearview, Reveal G2, Multispot Vitros, Determine, Colloidal, Orasure in saliva, Calypte test for urine. ELISA, Western blot, PCR and Viral load. CD4 count in serum.
  26. 26. Factors increasing the risk of acquisition of HIV Common to all transmission categories • High viral load • Lower CD4 cell count • AIDS • Seroconversion Vertical transmission • Older gestational age • Prolonged rupture of membranes • Chorioamnionitis • Fetal trauma (e.g. scalp electrodes) • Lower birth weight • Vaginal vs. elective caesarean delivery • No peripartum prophylaxis • First-born twin
  27. 27. Breastfeeding • Longer-duration feeding • Lower parity • Younger age • Mastitis Sexual transmission • STIs, especially genital ulcers • Cervical ectopy • Receptive vs. insertive anal sex • Rectal or vaginal trauma • Menstruation • Male–male vs.heterosexual sex • Non-circumcised • Increased number of partners
  28. 28. Injection drug use transmission • Sharing equipment • Frequency of use • Linked commercial sex • Lower income • Intravenous use • Cocaine use • Incarceration Occupational transmission • Deep injury • Visible blood on device
  29. 29. Virology and immunology HIV is a single-stranded RNA retrovirus from the Lentivirus family. After mucosal exposure, HIV is transported to the lymph nodes via dendritic, CD4 T lymphocytes or Langerhans cells, where infection becomes established. Dendritic cells express various receptors (e.g. DC–SIGN) that facilitate capture and transport of HIV-1. Free or cell associated virus is then disseminated widely through the blood with seeding of ‘sanctuary’ sites (e.g. central nervous system (CNS) and latent CD4 cell reservoirs. Each mature virion is spherical and has a lipid membrane lined by a matrix protein that is studded with glycoprotein (gp) 120 and gp41 spikes surrounding a cone-shaped protein core. This core houses two copies of the single-stranded RNA genome and viral enzymes.
  30. 30. The virus infects the CD4 cell in a complicated sequence of events beginning with engagement of the viral gp120 and the CD4 cell receptor (stage 1), which results in a conformational change in gp120. This permits interaction with one of two chemokine co-receptors (CXCR4 or CCR5: stage 2), which is followed by membrane fusion and cellular entry involving gp41 (stage 3). Monocyte macrophages,follicular dendritic cells and microglial cells in the central nervous system also express the CD4 cell receptor and are permissive to infection. After penetrating the cell and uncoating, a DNA copy is transcribed from the RNA genome by the reverse transcriptase (RT) enzyme (stage 4) that is carried by the infecting virion. Reverse transcription is an error-prone process and multiple mutations arise with ongoing replication (hence the rapid generation of viral resistance to drugs).
  31. 31. This DNA is transported into the nucleus and integrated randomly within the host cell genome via integrase enzyme (stage 5). Integrated virus is known as proviral DNA. On host-cell activation, this DNA copy is used as a template to transcribe new RNA copies (stage 6), which are processed and exported from the nucleus, viral mRNA then being translated into viral peptide chains (stage 7). The precursor polyproteins are then cleaved by the viral protease enzyme to form new viral structural proteins and viral enzymes such as the reverse transcriptase and protease (8). These then migrate to the cell surface and are assembled using the host cellular apparatus to produce infectious viral particles. These bud from the cell surface, incorporating the host cell membrane as their own lipid bilayer coat, and cell lysis occurs (stage 9).
  32. 32. Once maturation is complete, the new infectious virus (virion) is then available to infect uninfected cells and repeat the process. All of these processes are enabled by three viral genes (Gag, Pol and Env ), as well as the products of six regulatory genes (Vif, Vpr, Vpu, Nef, Tat and Rev ). Each day more than 1010 virions are produced and 109 CD4 cells destroyed. This represents a daily turnover of 30% of the total viral burden and 6–7% of the total body CD4 cells. A small percentage of T cells (< 0.01%) either produce small quantities of virus or enter a post-integration latent phase and represent the main reservoir of HIV. Together with virion-associated immune complexes bound to follicular dendritic cells, they refuel infection if host defences fail or HAART is discontinued.
  33. 33. There is ongoing low-level replication within these cells, even when plasma levels of HIV are below the level of detection as a result of antiretroviral treatment. They are important as sanctuary sites from antiviral therapy, as continuing sources of virus (including the generation of drug- resistant strains) and as eventual targets for eradication strategies. The half-life of the virus is 1–2 hours in plasma, 1.5 days in productively infected CD4 cells and over 12 months in latently infected CD4 cells. With time, there is gradual attrition of the CD4 cell population and, as CD4 cells are needed in initiating the immune response, any depletion renders the body susceptible to opportunistic infections and oncogenic virus-related tumours.
  34. 34. The predominant opportunistic infections seen in HIV disease are intracellular parasites (e.g. Mycobacterium tuberculosis) or pathogens susceptible to cell-mediated rather than antibody- mediated immune responses. The exact mechanism underlying the CD4 decline is not fully understood, but it is not restricted to virus-infected cells and is linked to the height of plasma viral load. Both are monitored closely in patients and used as measures of disease progression. Virus-specific CD8 cytotoxic T lymphocytes develop rapidly after infection and are crucial in recognising, binding and lysing infected CD4 cells, thus attempting to controlling HIV replication after infection and the subsequent rate of disease progression.
  35. 35. On the basis of DNA sequencing, HIV-1 can be subdivided into group M (‘major’, world-wide distribution), group O (‘outlier’, divergent from group M) and group N (‘non-major and non-outlier’, highly divergent) types. Groups O and N are restricted to West Africa and may screen weakly positive or negative on routine antibody testing. Group M can be subdivided further into subtypes; 9 are currently recognised (A–K), with numerous subsubtypes (e.g. A1–A4) and circulating recombinant forms (e.g. CRF01_AE). Globally, subtype C (Africa and India) accounts for half of strains. Subtype A (Africa, Asia and Eastern Europe) and subtype B (Western Europe, the Americas and Australia) are responsible for approximately 10% each, and in many countries, more than one subtype or recombinant exists, or is emerging in restricted groups (e.g. West Africa, South-east Asia, southern Europe, and Russia).
  36. 36. Increased HIV diversity has implications for diagnostic tests, treatments and vaccine development. It may also influence transmission (more frequent with subtype C), disease progression (faster with subtypes A and D), co- receptor usage (CXCR4 used early with subtype D) and emergent resistance patterns (subtype C). In Europe, the prevalence of non-B subtypes is increasing because of migrants (predominantly from Africa) and now accounts for a significant proportion of newly diagnosed infection. HIV-2 is an important but separate retrovirus which has at least five subtypes. The virus differs from HIV-1 in that patients have lower viral loads, slower CD4 decline, lower rates of vertical transmission and 12- fold lower progression to AIDS.
  37. 37. Antiretroviral Drugs Used in the Treatment of HIV Infection Drug Class, Names, Doses & Side effects I. Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTI) 1. Zidovudine (AZT, azidothymidine, Retrovir, 3'azido-3'-deoxythymidine) Dose: 200 mg q8h or 300 mg bid Side effects: Anemia, granulocytopenia, myopathy, lactic acidosis, hepatomegaly with steatosis, headache, nausea, nail pigmentation, lipid abnormalities, lipoatrophy, hyperglycemia 2. Didanosine (Videx, Videx EC, ddI, dideoxyinosine, 2',3'-dideoxyinosine Dose: Buffered: Requires 2 tablets to achieve adequate buffering of stomach acid; should be administered on an empty stomach 60 kg: 200 mg bid <60 kg: 125 mg bid Enteric coated: 60 kg: 400 mg qd < 60 kg: 250 mg qd Side effects: Pancreatitis, peripheral neuropathy, abnormalities on liver function tests, lactic acidosis, hepatomegaly with steatosis, optic neuritis, nausea, hyperglycemia
  38. 38. 3. Zalcitabine (ddC, HIVID, 2'3'-dideoxycytidine) Dose: 0.75 mg tid Side effects: Peripheral neuropathy, pancreatitis, lactic acidosis, hepatomegaly with steatosis, oral ulcers 4. Stavudine (d4T, Zerit, 2'3'-didehydro-3'-dideoxythymidine) Dose: >60 kg: 40 mg bid <60 kg: 30 mg bid Side effects: Peripheral neuropathy, pancreatitis, lactic acidosis, hepatomegaly with steatosis, ascending neuromuscular weakness, lipodystrophy, lipid abnormalities, hyperglycemia 5. Lamivudine (Epivir, 2'3'-dideoxy-3'-thiacytidine, 3TC) Dose: 150mg bd or 300mg od Side effects: Flare of hepatitis in HBV-coinfected patients who discontinue drug 6. Emtricitabine (FTC, Emtriva) Dose: 200mg od Side effects: Hepatotoxicity in HBV-coinfected patients who discontinue drug, skin discoloration
  39. 39. 7. Tenofovir (Viread) Dose: 300mg od Side effects: Renal osteomalacia, flare of hepatitis in HBV-coinfected patients who discontinue drug 8. Abacavir. II. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) 1. Delavirdine (Rescriptor) Dose: 400mg tid. Side effects: Skin rash, abnormalities in liver function tests 2. Nevirapine (Viramune) Dose: 200mg/day for 2 wks then 200mg bd or 400mg/day. Side effects: Skin rash, hepatotoxicity 3. Efavirenz (Sustiva) Dose: 600mg nocte Side effects: Rash, dysphoria, elevated liver function tests, drowsiness, abnormal dreams, depression, lipid abnormalities, potentially teratogenic 4. Etravirine Dose 200mg bd Side effects: Rash, nausea, hypersensitivity reactions 5. Rilpivirine Dose: 25mg od Side effects: Nausea, dizziness, somnolence, vertigo, less CNS toxicity and rash than Efavirenz
  40. 40. III Protease Inhibitors(PI) 1. Saquinavir mesylate (Invirase—hard-gel capsule) Dose: 1000 mg + 100 mg ritonavir bid Side effects: Diarrhea, nausea, headaches, hyperglycemia, fat redistribution, lipid abnormalities, PR and QT interval prolongation 2. Ritonavir (Norvir) Dose 600mg bd or 100mg as booster Side effects: Nausea, abdominal pain, hyperglycemia, fat redistribution, lipid abnormalities, may alter levels of many other drugs including saquinavir, paresthesias, hepatitis 3. Indinavir sulfate (Crixivan) Dose: 800 mg q8h or 800 mg + 100 mg ritonavir bid or 1000 mg q8h when used with efavirenz or nevirapine Side effects: Nephrolithiasis, indirect hyperbilirubinemia, hyperglycemia, fat redistribution, lipid abnormalities, nausea, transaminase elevations, headache.
  41. 41. 4. Nelfinavir mesylate (Viracept) Dose: 750 mg tid or 1250 mg bid Side effects: Diarrhea, loose stools, hyperglycemia, fat redistribution, lipid abnormalities, transaminase elevations 5. Amprenavir (Agenerase) Dose: Amprenavir 1200 mg bid or 600 mg + 100 mg ritonavir bid or 1200 mg + 200 mg ritonavir qd Side effects: Nausea, vomiting, diarrhea, rash, oral paresthesias, elevated liver function tests, hyperglycemia, fat redistribution, lipid abnormalities, headache, nephrolithiasis 6. Lopinavir/ritonavir (Kaletra, Aluvia) Dose 400/100mg Side effects: Diarrhea, hyperglycemia, fat redistribution, lipid abnormalities, nausea, pancreatitis, elevated liver function tests, PR and QT interval prolongations 7. Atazanavir (Reyataz) Dose: 400 mg qd or 300 mg qd + ritonavir 100 mg qd when given with efavirenz
  42. 42. Side effects: Hyperbilirubinemia, PR prolongation, nausea, vomiting, hyperglycemia, fat maldistribution, rash transaminase elevations. 8. Tipranavir (Aptivus) Dose: 500mg / 200mg retonavir bd Side effects: Diarrhea, nausea, fatigue, headache, skin rash, hepatotoxicity, intracranial hemorrhage, hyperglycemia, lipid abnormalities, fat redistribution. 9. Darunavir (Prezista) Dose 600mg/100mg retinavir bd with food Side effects: Diarrhea, nausea, headache, skin rash, hepatoxicity, hyperlipidemia, hyperglycemia. IV. Entry Inhibitors 1. Enfuvirtide (Fuzeon) Dose: 90 mg SC bid Side effects: Local injection reactions, hypersensitivity reactions, increased rate of bacterial pneumonia.
  43. 43. 2. Maraviroc (Selzentry) Dose: 150–600 mg bid depending on concomitant medications Side effects: Hepatotoxicity, nasopharyngitis, fever, cough, rash, abdominal pain, dizziness, musculoskeletal symptoms. V. Integrase Inhibitor 1. Raltegravir (Isentress) Dose: 400mg bd Side effects: Nausea, headache, diarrhea, CPK elevation, muscle weakness and rhabdomyolysis. 2. Elvitegravir Dose: 150 mg qd pharmacoenhancing agent. 3. Dolutegravir 4. Cabotecavir