Hiv infection and aids
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The document covers HIV infection and AIDS, detailing its global and national prevalence, the virus's structure and replication, stages of infection, and diagnosis and treatment strategies. It emphasizes the importance of antiretroviral therapy (ART) and outlines various treatment regimens, opportunistic infections, and management of co-infections like tuberculosis. Additionally, it discusses preventive measures, including pre- and post-exposure prophylaxis.
Hiv infection and aids
- 1. HIV INFECTION AND AIDS Dr. Navin Adhikari IM Second Year Resident NAMS
- 2. EPIDEMOLOGY • AIDS was first recognized in the United States in 1981. • Globally, 38.0 million people were living with HIV in 2019, with 1.7 million newly infected in same year. 690000 people died from AIDS-related illnesses in 2019. 26 million people were accessing antiretroviral therapy as of the end of June 2020. • In Nepal 28,500 people were living with HIV in 2019 with 790 new infection. 19410 were under ART as of July, 2020.
- 3. ETIOLOGIC AGENT • HIV is the etiologic agent of AIDS, belongs to human retroviruses (Retroviridae) and the subfamily of lentiviruses. • HIV-1 and HIV-2 are strains. HIV-1 is the cause of the global HIV pandemic, while HIV-2, which causes a similar illness to HIV-1 but progresses more slowly and is less transmissible, is restricted mainly to western Africa. • HIV-2 has only 40% structural homology with HIV-1. • On the basis of DNA sequencing, HIV-1 is divided into three groups, which probably represent three zoonotic transfer from the chimpanzee: M (‘major’, worldwide distribution), O (‘outlier’) and N (‘non-major and non-outlier’).
- 4. MORPHOLOGY OF HIV • HIV virion is an icosahedral structure containing numerous external spikes formed by the two major envelope proteins, the external gp120 and the transmembrane gp41. • Two molecules of single stranded RNA within the nucleus. • The reverse transcriptase polymerase converts viral RNA into DNA (a characteristic of retroviruses). • The protease includes integrase (p32 and p10). • The p24 is core protein, its levels can be used to monitor HIV disease. • P17 is the matrix protein.
- 5. HIV GENOME • Genes that encode the structural proteins of the virus: Gag encodes the proteins that form the core of the virion (including p24 antigen) Pol encodes the enzymes responsible for protease processing of viral proteins, reverse transcription, and integration. Env encodes the envelope glycoproteins. • It also contains at least six other regulatory genes (tat, rev, nef, vif, vpr, and vpu) which code for proteins involved in the modification of the host cell to enhance virus growth and the regulation of viral gene expression.
- 6. HIV ENTRY AND REPLICATION • The HIV binds to host CD4 molecules via the envelope glycoprotein gp120. • Gp120 binding to secondary receptors (chemokine receptors, CXCR4, CCR5) and subsequent conformational change results infusion between gp41 and the cell membrane. • Entry of the viral capsid is followed by uncoating of RNA. • DNA copies are made from both RNA templates (reverse transcriptase). • In the nucleus the virally encoded DNA is inserted into the host genome (integration). • Regulatory proteins control transcription (a process in which an RNA molecule is synthesized from a DNA template). • The virus is reassembled in the cytoplasm and budded out from the host cell.
- 8. HIV INFECTION HIV infection can be divided into the following stages: 1. Viral transmission 2. Acute HIV infection (also called primary HIV infection or acute seroconversion syndrome) 3.Chronic HIV infection, is subdivided into : •Chronic infection, without AIDS •AIDS, characterized by a CD4 cell count <200 cells/microL •Advanced HIV infection, characterized by a CD4 cell count <50 cells/microL
- 9. VIRAL TRANSMISSION • HIV is transmitted by sexual contact, by exposure to blood and blood products. • Vertical transmission to infants of HIV-infected mothers (who may be infected in utero, perinatally or via breastfeeding). • The risk of contracting HIV after exposure to infected body fluid is dependent on the integrity of the exposed site, the type and volume of fluid, and the level of viraemia in the source person.
- 11. ACUTE HIV INFECTION • 50–70% of individuals with HIV infection experience an acute clinical syndrome within 3–6 weeks after primary infection. • Symptomatic acute HIV infection is characterized by fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, diarrhea, and headache (often described as a mononucleosis- like illness). • Symptoms usually persist for one to several weeks and gradually subside as an immune response to HIV develops and the levels of plasma viremia decrease • The differential diagnosis of primary HIV includes acute EBV, primary CMV infection, rubella, primary toxoplasmosis and secondary syphilis.
- 13. CHRONIC HIV INFECTION, WITHOUT AIDS • Chronic HIV infection is characterized by relative stability of the viral level and a progressive decline in the CD4 cell count. • In the absence of antiretroviral therapy (ART), the average time from HIV acquisition to a CD4 cell count <200 cells/microL is approximately 8 to 10 years. • Persons with HIV at this stage of disease can have generalized lymphadenopathy on physical examination. This is referred to as "persistent generalized lymphadenopathy" when the enlarged lymph nodes involve at least two noncontiguous sites other than inguinal nodes for more than three to six months without an alternative explanation. • Some patients experience generalized/nonspecific symptoms and signs such as fatigue, sweats, or weight loss.
- 14. EVENTS LEADING TO CHRONIC INFECTION
- 15. AIDS AND ADVANCED HIV INFECTION • AIDS is chronic HIV infection with CD4 cell count <200 cells/microL or the presence of any AIDS-defining condition regardless of the CD4 cell count. • The term advanced HIV infection is often used to refer to infection when the CD4 cell count is <50 cells/microL. • When patients achieve immune reconstitution (eg, increase in the CD4 cell count to >200 cells/microL) with antiretroviral therapy (ART) and have no AIDS-defining conditions, they are no longer considered to have AIDS.
- 16. AIDS-DEFINING CONDITIONS • AIDS-defining conditions are illnesses that occur more frequently or more severely because of immunosuppression. • These include mainly opportunistic infections but also certain malignancies as well as conditions without clear alternative etiology thought to be related to uncontrolled HIV infection itself. • The AIDS-defining conditions listed by the United States Centers for Disease Control and Prevention (used in high- income countries) and the World Health Organization criteria ( used in low- and middle-income countries) vary slightly.
- 18. PROGRESSION OF UNTREATED HIV INFECTION
- 19. Clinical Features Direct consequence of HIV infection 1. AIDS dementia complex (ADC), sensory polyneuropathy and aseptic meningitis. 2. Anaemia of chronic HIV infection is usually mild, normochromic and normocytic 3. HIV-associated nephropathy 4. Symptomatic HIV-associated cardiomyopathy 5. HIV wasting syndrome 6. HIV cholangiopathy
- 21. DIAGNOSIS • The detection of HIV infection depends on the presence of antibodies and virus component, which depends on the days since initial infection. • Eclipse period- This period refers to the period of about 7–10 days following HIV infection, during which currently available assays cannot detect any marker of HIV infection. • Window period. The period between HIV infection and the detection of HIV1/2 antibodies using immunological assays is the window period. • Recent infection. Any infection detected within six months of infection is considered recent infection.
- 22. Diagnostic tests 1. Detection of IgG antibody to envelope components - based on ELISA techniques, which may be confirmed with Western blot assays. 2. IgG antibody to p24 (anti-p24) 3. Genome detection assays- Nucleic acid-based assays that amplify and test for components of the HIV genome, aid diagnosis of HIV in the babies of HIV-infected mothers or in situations where serological tests may be inadequate, such as in early infection. 4. Viral p24 antigen (p24ag) 5. Fourth generation HIV test- detect both HIV antibody and HIV p24 antigen.
- 24. National HIV testing algorithm • A three-test HIV testing algorithm is adopted. • The first assay (A1) should be the most sensitive, and the second and third tests should have higher specificity.
- 26. TREATMENT OF HIV
- 27. ART INITIATION • National Centre for AIDS and STI Control (NCASC) has adopted the WHO “TREAT ALL” policy since the revision of the national HIV testing and treatment guidelines in 2017. • The goals of ART are to reduce the viral load to an undetectable level for as long as possible , improve the CD4 count to over 200 cells/mm3 so that severe HIV-related disease is unlikely, improve the quantity and quality of life without unacceptable drug toxicity and reduce HIV transmission. • ART should be initiated in all adults living with HIV, regardless of WHO clinical stage and at any CD4 cell count. • A comprehensive clinical assessment should be done as baseline status and to rule out OIs.
- 28. • In patients with major opportunistic infections, ART should generally be started within 2 weeks, with two important exceptions: in cryptococcal meningitis, ART should be deferred for 5 weeks, as earlier initiation increases the risk of death; and in tuberculosis, ART should be deferred until 8 weeks (except if the CD4 count is < 50 cells/mm3 ), as earlier initiation increases the risk of the immune reconstitution inflammatory syndrome.
- 31. ANTIRETROVIRAL REGIMEN • In 2018, WHO published interim guidelines recommending dolutegravir (DTG)- containing regimens as the preferred first- and second-line ART regimens for PLHIV. • In 2019 updated systematic review showed first-line regimen of DTG combined with two nucleoside reverse transcriptase inhibitors (NRTIs) leads to higher viral suppression and lower risk of discontinuing treatment and developing HIV drug resistance compared with efavirenz (EFV)-based regimens among treatment-naive adults. • DTG has other advantages over EFV, including lower potential for drug–drug interactions, more rapid viral suppression and a higher genetic barrier to developing HIV drug resistance (HIVDR). DTG is also active against HIV-2 infection, which is naturally resistant to EFV.
- 33. MONITORING • Follow up is required for opportunistic infections and/or immune reconstitution inflammatory syndrome (IRIS), as well as early adverse drug reactions (ADR), such as drug hypersensitivity and treatment treatment failure. • Treatment failure is defined as persistently detectable Viral Load (VL) exceeding 1000 copies/mL in two consecutive VL measurements within a 3-month interval with adherence support between measurements after 6 months of starting a new ART regimen. • The national programme recommends VL testing and CD4 count at 6 months and 12 months and only VL for stable patients every 12 months. CD4 testing is stopped in virally supressed patients
- 34. CD4 COUNT MONITORING • Long-term CD4 cell count monitoring adds little value in people who are stable on ART. • However, CD4 count is important for assessing the baseline risk of disease progression, particularly for individuals presenting with advanced disease, and decisions regarding starting and stopping prophylaxis for OIs. • CD4 cell count measurement may also be important for people who are failing ART and for unstable patients.
- 37. CLINICAL, IMMUNOLOGICAL AND VIROLOGICAL FAILURE • Clinical failure - New or recurrent clinical event indicating severe immunodeficiency (WHO clinical stage 4 condition) after 6 months of effective treatment. • Immunological failure - CD4 count at or below 250 cells/ mm³ following clinical failure b or Persistent CD4 levels below 100 cells/mm³. • Virological failure - Viral load above 1000 copies/mL based on two consecutive viral load measurements in 3 months, with adherence support following the first viral load test.
- 38. ARV TOXICITY • Lamivudine- Flare of hepatitis in HBVco-infected patients • Zidovudine- Anemia, granulocytopenia, myopathy, lactic acidosis, • Abacavir- Hypersensitivity reaction In HLA-B5701, ever, rash, nausea, vomiting, malaise or fatigue, and loss of appetite • Tenofovir- Renal toxicity, osteomalacia, flare of hepatitis in HBVco-infected patients • Nevirapine- Skin rash, hepatotoxicity • Etravirine- Rash, nausea, hypersensitivity reactions • Dolutegravir- Insomnia, headache, hypersensitivity reactions, hepatotoxicity • Efavirenz- Rash, dysphoria, elevated liver function tests, drowsiness
- 41. CHEMOPROPHYLAXIS Co-trimoxazole primary prophylaxis is started in 1. HIV-infected persons with a CD4 count < 350/mm3 2. all adults with severe and advanced HIV disease (WHO stage 3 or 4) 3. In settings where malaria and/or severe bacterial infections are highly prevalent regardless of CD4 cell count or WHO stage. 4. all HIV-infected patients with active TB disease regardless of CD4 cell count. • Co-trimoxazole prophylaxis may be discontinued in adults with HIV who are clinically stable on ART with evidence of immune recovery and viral suppression.
- 42. • A macrolide (azithromycin or clarithromycin) is recommended to prevent Mycobacterium avium complex ( MAC )in patients with a CD4 count below 50 cells/mm3 , which can be discontinued once the CD4 count has risen to over 100 cells/mm3 on ART. • Serum cryptococcal antigen test should be done in patients with a CD4 count below 100 cells/mm3 . If this is positive, pre-emptive therapy with fluconazole should be commenced.
- 43. HIV-TB COINFECTION • Tuberculosis is the most frequent life-threatening OI • PLHIV are around 20 times more likely to develop TB disease than those without HIV infection • TB preventive treatment (TPT) is an important intervention for preventing and reducing active TB among PLHIV. • Active TB must be excluded before beginning TB preventive treatment. • The 2020 update of WHO guidelines on TPT makes 9H, 6H, 4R, 3HP, 3HR, 1HP as options for use across all disease burden settings. • The national HIV programme currently recommends the 6- month isoniazid (6H) regimen for TPT.
- 45. TB management in PLHIV • All HIV-infected people with diagnosed active TB should be put on TB treatment immediately. • Antituberculosis treatment (ATT) should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment (2 weeks, if CD4 count < 50 cells/mm3). • IRIS may occur after initiation of ART. Both ART and TB treatment should be continued while managing IRIS. • DTG 50 mg BID (instead of 50 mg once daily) should be used for patients using rifampicin-based TB drugs. • In case a patient on a PI-based regimen needs to start ATT, the dose of PI should be doubled.
- 46. Immune reconstitution inflammatory syndrome (IRIS) • The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of antiretroviral therapy (ART) in HIV-infected individuals. • It occurs in 10–30% of patients initiating ART, usually within the first 4–8 weeks but can occur up to six months. • After a patient starts ART, IRIS may manifest as a worsening of previously diagnosed disease, termed paradoxical IRIS, or as the appearance of a previously undiagnosed disease, termed unmasking IRIS.
- 47. • IRIS should be considered only when the presentation cannot be explained by a new infection, expected course of a known infection or drug toxicity. • IRIS should be diagnosed by excluding: active OIs, treatment failure, side-effects of ARVs, ARV resistance • The most serious and life-threatening forms of paradoxical IRIS are for TB, cryptococcosis, Kaposi sarcoma and herpes zoster. • IRIS is generally self-limiting, and interruption of ART is rarely indicated. Glucocorticoids are often used for more severe IRIS manifestations.
- 48. Prevention of HIV • Pre-exposure prophylaxis- daily tenofovir plus emtricitabine has been shown to reduce the risk of HIV acquisition in people at ongoing high risk and is well tolerated. • Post-exposure prophylaxis- Start as soon as possible, preferably within 2 hours and maximum within 72 hours of exposure. The duration of treatment is 28 days. The choice of PEP drugs should be based on the country’s first-line ART regimen to treat HIV infection. Get a baseline HIV antibody test and monitor for seroconversion at 6 weeks, 3 months and 6 months after exposure.
- 50. References • Harrison's Principles of Internal Medicine, 20th Edition. • Davidson Principles and Practice of medicine 23rd Edition. • Kumar & Clark's Clinical Medicine, 7th Edition • Manson’s Tropical Disease, 23ed • National-HIV-Testing-Guidelines-May-10-2020, Nepal • Uptodate • https://www.unaids.org/en
- 51. THANK YOU