HIV NOTES.presentation notes quick understanding pdf
- 1. 1 INFECTIOUS DISEASES HIV Infection HIV NOTES 1
- 2. HIV Infection • HIV causes acquired immunodeficiency syndrome(AIDS). • Clinical manifestations of AIDS result from consequences of a critically impaired immune system. • Almost 90% of deaths are caused by opportunistic infectio ns. Pathogenesis • HIV is retrovirus (family - retroviridae; subfamily -lentivirus ). • RNA virus which has enzyme reverse transcriptase and c onsists of a lipid bilayer membrane surrounding the capsid. • surface glycoprotein molecule(gp120) has strong affinity f or CD4 receptor protein on T –helper/inducer lymphocytes. • Monocytes and macrophages also express CD4 receptor. Siulapwa Rodney 2 HIV NOTES 2
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- 4. • HIV entry is a complex multistage process involving CD4 at tachment, binding to chemokine co – receptors such as CC R - 5 and CXCR - 4, and membrane fusion. • After penetrating the host cell, the virus sheds its outer coat and releases its genetic material (RNA). • Viral RNA is converted to viral DNA using nucleosides, by r everse transcriptase. • Viral DNA is integrated(inserted) into the host genome(DN A) by the enzyme integrase. • Viral DNA undergoes transcription and translation, producin g new viral proteins. • New virus particles are assembled and bud out of the host cell. • Maturation of new virus particles into infectious virions requ ire the action of protease enzyme. • Protease cleaves the precursor proteins into functional poly peptides. Siulapwa Rodney 4 HIV NOTES 4
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- 7. Clinical Manifestations • Sequelae of untreated HIV infection divided into five group s: 1. Opportunistic infections (infections that do not normally c ause disease in immunocompetent hosts) e.g. P. jiroveci p neumonia, CMV retinitis 2. Infections that can occur in immunocompetent patients b ut are more frequent, more severe and more atypical in HIV patients e.g. Salmonella, herpes simplex and Mycobacteriu m tuberculosis 3. Malignancies that occur rarely in immunocompetent patie nts e.g. Kaposi’s sarcoma, non – Hodgkin’s lymphoma. 4. Direct manifestations of HIV infection e.g. HIV encephal opathy, HIV myelopathy, HIV enteropathy 5.Consequences of chronic immune reactivation e.g. prema ture CVD death, neurocognitive dysfunction, loss of bone m ineral density Siulapwa Rodney 7 HIV NOTES 7
- 8. WHO clinical staging of HIV/AIDS Primary HIV Infection •Asymptomatic •Acute retroviral syndrome (fever, arthralgia, pharyngitis,rash a nd lymphadenopathy) Siulapwa Rodney 8 Stage Clinical presentation 1 • Asymptomatic • Persistent generalised lymphadenopathy HIV NOTES 8
- 9. Siulapwa Rodney 9 Clinical Stage Clinical presentation 2 a. Moderate unexplained weight loss (<10%) b. Recurrent respiratory infections(sinusitis, tonsillitis, otitis media and pharyngitis) c. Herpes zoster d. Angular cheilitis e. Recurrent oral ulceration f. Papular pruritic eruptions g. Seborrhoeic dermatitis h. Fungal nail infections 3 a. Unexplained severe weight loss( > 10%) b. Unexplained chronic diarrhoea (> 1 month) c. Unexplained persistent fever ( > 1month) d. Persistent oral candidiasis e. Oral hairly leukoplakia f. Pulmonary tuberculosis g. Severe bacterial infections (pneumonia, empyema, pyomyositis, bone/joint infection, meningitis) HIV NOTES 9
- 10. Siulapwa Rodney 10 Clinical Stage Clinical presentation 3 h. Acute necrotising ulcerative stomatitis, gingivitis i. unexplained anaemia (Hb < 8g/dL) j. Neutropenia ( < 500cells/µL) k.Chronic thrombocytopenia ( < 50,000cells/µL) 4 a. HIV wasting syndrome b. Pneumocystis jiroveci pneumonia c. Recurrent severe bacterial pneumonia d. Chronic herpes simplex infection e. Oesophageal/oropharyngeal candidiasis f. Extra pulmonary tuberculosis g. MAC/MAI h. Progressive multifocal encephalopathy i. Chronic cryptospridiosis j. Chronic isosporiasis k. Disseminated mycosis e.g. histoplasmosis HIV NOTES 10
- 11. (WHO, 2007) Siulapwa Rodney 11 Clinical stage Clinical presentation 4 • Lymphoma • cervical carcinoma • HIVAN • HIV associated cardiomyopathy HIV NOTES 11
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- 13. Investigations/ Monitoring Current and previous infections • Initial diagnosis of HIV infection made by detecting antibo dies (sero - conversion) against HIV within 3 – 4 weeks of i nfection. • Up to 3 months of ‘window period’ after exposure require d to exclude infection.(what does this mean???) • If HIV infection confirmed, patient should be tested for pot ential pathogens e.g. syphilis, hepatitis, CMV, varicella zost er, T. gondii. CD4 count • Measures the number of CD4 – positive T – lymphocytes i n a sample of peripheral blood. • Normal range is 500 – 1500 cells/mm3 • level of Immunosuppression can be estimated by monitori ng a patient’s CD4 count. Siulapwa Rodney 13 HIV NOTES 13
- 14. • CD4 count is used as a major indicator of when to conside r starting antiretroviral therapy. Viral load • Measures the number of HIV RNA in a sample of peripher al blood. • Estimates the amount of circulating virus in the blood. • Correlates with prognosis e.g. high viral load predicts fast er disease progression. • Reduction in viral load due to antiretroviral therapy is asso ciated with clinical benefit. • Clinical decisions such as when to start or change antiretr oviral therapies can be made based on viral load. Resistance testing • Genotypic HIV resistance test is recommended soon afte r diagnosis due to potential of transmitted (primary) resistan ce. Siulapwa Rodney 14 HIV NOTES 14
- 15. • Resistance testing allows selection of appropriate initial th erapy. • Further resistance tests should be performed at any subs equent virological failure to direct therapy choice. Tropism testing • Viruses may enter the cell using CCR5 co-receptor, CXC R4 co-receptor or both. • Viruses which only use one co-receptor are CCR5 – tropic or CXCR4 – tropic viruses. • Viruses which can use both co-receptor types are called d ual – tropic. • Mixed – tropic refers to a mixture of virus populations. • Tests should be performed in real time as viral tropism ch anges as the disease progresses. •If CCR5 inhibitors are to be used, it is essential to determin e that the virus is CCR5 - tropic (no significant use of CXC R4 receptor) Siulapwa Rodney 15 HIV NOTES 15
- 16. • If CCR5 inhibitors are to be used, it is essential to determi ne that the virus is CCR5 - tropic (no significant use of CXC R4 receptor) Siulapwa Rodney 16 HIV NOTES 16
- 17. Pharmacological management of HIV Infection Goals of drug therapy 1.Improve the quality and duration of life 2.Prevent deterioration of immune function and/or restore i mmune status 3.Treat and/or prevent opportunistic infections 4.Relieve symptoms Antiretroviral therapy •Currently one of the fastest evolving areas of medicine. •Specific details of treatment will continue to change as ne w drugs emerge. Siulapwa Rodney 17 HIV NOTES 17
- 18. General principles of antiretroviral therapy 1.A combination of three antiretroviral agents, selected on b asis of treatment history and resistance tests, should be pr escribed to increase efficacy and reduce development of dr ug-resistant virus. 2.A regimen should contain at least one drug that penetrate s the central nervous system and confers protection agains t HIV – related encephalopathy/ dementia. 3.Treatment strategies should be adopted that sequence dr ug combinations, taking potential cross-resistance and futur e therapy options into consideration. 4.Regimen adopted for a patient should be tailored to suit d aily lifestyle (high level of adherence is required) Siulapwa Rodney 18 HIV NOTES 18
- 19. Classes of antiretroviral drugs 1.Nucleoside and nucleotide analogue reverse transcriptas e inhibitors( NRTIs) 2.Non – nucleoside reverse transcriptase inhibitors(NNRTIs) 3.Protease inhibitors 4.Entry inhibitors 5.Integrase inhibitors 6.CCR-5 Co-receptor antagonist Siulapwa Rodney 19 HIV NOTES 19
- 20. Classes of antiretroviral drugs Siulapwa Rodney 20 HIV NOTES 20
- 21. Nucleoside and nucleotide analogue reverse tran scriptase inhibitors( NRTIs) Mechanism of action •NRTIs are phosphorylated intracellularly and then inhibit re verse transcriptase enzyme acting as a false substrate. •Nucleotide analogues only require two intracellular phosph orylations e.g. tenofovir •Activation of nucleoside analogues is a three – stage proc ess. Siulapwa Rodney 21 HIV NOTES 21
- 22. Examples of NRTIs…..LEADS TZ •Lamivudine (3TC, Epvir®) •Emtricitabine (FTC, Emtriva®) •Abacavir (ABC, Ziagen®) •Didanosine (ddI, Videx®) •Stavudine (d4T, Zerit® ) •Tenofovir (TDF, Viread®) •Zidovudine (AZT, Retrovir®) Combination formulations 1.Abacavir + lamivudine (Kivexa®) 2.Tenofovir + emtricitabine (Truvuda®) 3.Zidovudine + lamivudine ( combivir®) 4.Zidovudine + lamivudine + abacavir ( Trizivir®) Siulapwa Rodney 22 HIV NOTES 22
- 23. Formulation combining two NRTIs with an NNRTI: •Tenofovir + emtricitabine + efavirenz ( Atripla®) Combinations that should be avoided: •Zidovudine + stavudine ( intracellular competition resulting in antagonism) •Stavudine + didanosine (unacceptable toxicity i.e. lactic aci dosis, lipodystrophy) •Tenofovir + didanosine (unacceptable rates of virological fa ilure and potential CD4 count decline) Adverse effects of NRTIs •ABC – Usually well tolerated •Rash, headache, nausea and vomiting,diarrhoea, reduced appetite (common side effects) •Lactic acidosis, may increase risk of cardiovascular diseas e. Siulapwa Rodney 23 HIV NOTES 23
- 24. • ddI – nausea, bloating, diarrhoea • Pancreatitis, liver failure, peripheral neuropathy, hyperuricaemi a, lactic acidosis • FTC – Headache(most common), nausea, diarrhoea, dizzines s, lactic acidosis • 3TC – Generally well tolerated • GI disturbances, headache, anaemia, neutropenia • Lactic acidosis • d4T – peripheral neuropathy, pancreatitis, lactic acidosis, incre ased risk of lipoatrophy/lipodystrophy syndrome. • TDF – diarrhoea, nausea and vomiting, flatulence and headac he (most common) • Renal impairment and hypophosphataemia. • AZT – nausea, vomiting, headache, fatigue, muscle pain (common) Siulapwa Rodney 24 HIV NOTES 24
- 25. • AZT – haematological toxicities (neutropenia, anaemia), myop athy, lactic acidosis, increased risk of lipoatrophy/lipodystrophy syndrome. Non - nucleoside analogue reverse transcriptase inhibitor s( NNRTIs) Mechanism of action • NNRTIs inhibit the reverse transcriptase enzyme by binding to its active site. • They do not require prior phosphorylation and can act on cell – free virions as well as infected cells. Siulapwa Rodney 25 HIV NOTES 25
- 26. Examples of NNRTIs •Efavirenz (EFV, Sustiva®) •Nevirapine (NVP, Viramune®) •Etravirine (ETR, Intelence®) •Rilpivirine (RPV, Edurant®) •Resistance to NNRTIs occurs rapidly in incompletely suppressiv e regimens and it is therefore essential that they are prescribed with at least two NRTIs or a combination of NRTIs and PIs. •Cross resistance between NVP and EFV is high. •Etravirine has a different resistance profile( used as an alternati ve first – line NNRTI) •NNRTIs have much longer plasma half – lives than PIs and NR TIs Siulapwa Rodney 26 HIV NOTES 26
- 27. • When stopping NNRTI- based regimens, continue other agents for a period after cessation of NNRTI or switching to a boosted PI prior to regimen discontinuation. ..this is what we call coverin g the tail or tail cover of NNRTIs.7 days cover Adverse effects of NNRTIs • EFV – CNS disturbances (sedation, feeling stoned, dizzy, impai red concentration, vivid dreams, mood swings, hallucinations) • Rash • Raised LFTs • Hyperlipidaemia • lactic acidosis, may increase risk of cardiovascular disease • NVP – Rash, raised LFTs/hepatitis, • Nausea, headache, sedation, fatigue • Should not be started in women with CD4 count > 250cells/mm 3 or men with CD4 count > 400cells/mm3 : greater risk of rash – associated hepatic events. Siulapwa Rodney 27 HIV NOTES 27
- 28. • ETV – Rash, • nausea, • Diarrhoea, abdominal pain • Headache, pyrexia, fatigue • RPV – Headache, depression, insomnia, rash, raised LFT s, lipodystrophy • Less CNS disturbances than efavirenz and non – teratoge nic. Protease inhibitors (PIs) Mechanism of action • PIs bind to the active site of the HIV – 1 protease enz yme, preventing the maturation of newly produced virions so that they remain non – infectious Siulapwa Rodney 28 HIV NOTES 28
- 29. Examples of PIs •Atazanavir (ATV, Reyataz®) •Darunavir (DRV, Prezista®) •Fosamprenavir (FPV, Telzir®) •Indinavir (IDV, Crixavan®) •Lopinavir co – formulated with ritonavir (LPV/r, Kaletra®) (ritonavir does not add to antiviral activity - it is a pharmacokineti c enhancer) •Nelfinavir (NFV, Viracept®) •Ritonavir (RTV, Norvir®) •Saquinavir (SQV, Invirase®) •Tipranavir (TPV, Aptivus®) •RAINS LTDF Siulapwa Rodney 29 HIV NOTES 29
- 30. • Use of ritonavir – boosted PIs has superseded use of single PIs due to: 1.Better pharmacokinetic profiles( ↑ Cmax, ↑ t1/2 due to inhibitio n of cytochrome P450 enzymes) 2.Superior efficacy data 3.Reduced likelihood of resistance development • Newer PIs such as TPV and DRV are effective against ma ny viruses resistant to earlier PIs. • DRV is used in first – line PI therapy as once daily boosted a gent (800mg with 100mg of ritonavir). • Cobicistat is an alternative booster to ritonavir e.g. Siulapwa Rodney 30 HIV NOTES 30
- 31. Adverse effects of PIs •ATV –Nausea, diarrhoea, headache, rash, jaundice (most co mmon) •Hperbilirubinaemia •Raised LFTs •Does not appear to elevate lipids •ECG changes •lipodystrophy •DRV –Nausea, vomiting, diarrhoea, constipation, abdominal pain, rash Hyperlipidaemia(most common) • raised LFTs •Lipodystrophy •FPV - Nausea, vomiting, diarrhoea, rash, fatigue (most com mon) •Hyperlipidaemia, raised LFTs, Lipodystrophy Siulapwa Rodney 31 HIV NOTES 31
- 32. • NFV – diarrhoea and flatulence, nausea,(most common) • Hyperglycaemia • Lipodystrophy • SQV - Nausea, vomiting, diarrhoea, abdominal pain, anorexia, asthenia • Prolonged QT interval, raised LFTs, Lipodystrophy • TPV - Nausea, vomiting, diarrhoea, fatigue, raised LFTs, Lipo dystrophy Entry inhibitors • currently two types of entry inhibitors (fusion inhibitors and C CR5 inhibitors) are available. . Siulapwa Rodney 32 HIV NOTES 32
- 33. Fusion inhibitors Mechanism of action •Block the structural rearrangement of HIV – 1 gp41 thus stop t he fusion of the viral cell membrane with the target cell membr ane, preventing viral RNA from entering the cell. •Enfuvirtide (T – 20, Fuzeon®) is administered subcutaneously and largely used in heavily treatment experienced patients. •Main side effect is injection site reaction. Adverse effects •Insomnia, •headache, •lymphadenopathy, •eosinophilia •hypersensitivity reactions Siulapwa Rodney 33 HIV NOTES 33
- 34. CCR5 inhibitors Mechanism of action •Selectively bind to the human chemokine receptor CCR5, pre venting CCR5 – tropic HIV – 1 from entering cells. •Maraviroc (MVC, Celsentri®) is indicated for use in patients wit h only CCR5 – tropic virus, which is determined by tropism just prior to commencing treatment. •Usually used in patients with resistance to one or more other antiretroviral classes. Adverse effects •Nausea (most common) •Vomiting, abdominal pain, constipation, bloating •Dizziness, paraesthesia, somnolence, rash, insomnia, raised LFTs Siulapwa Rodney 34 HIV NOTES 34
- 35. Integrase inhibitors Mechanism of action •Bind to integrase enzyme, thus blocking the integration of viral DNA into host DNA. •Was initially used in patients with resistant virus •Increasingly used in first – line regimens or where tolerability with initial regimens is an issue. Examples include: •Raltegravir (RAL, Isentress®) •Elvitegravir (requires boosting with cobicistat) •Dolutegravir Adverse effects •Nausea and headache, dizziness, vertigo, abdominal pain, flat ulence, constipation, pruritus, arthralgia, fatigue, raised creatin e kinase, myopathy and rhabdomyolysis. Siulapwa Rodney 35 HIV NOTES 35
- 36. Toxicity of antiretroviral therapies Mitochondrial toxicity •Increasingly recognised in patients with prolonged exposur e to nucleoside analogue antiretrovirals e.g. d4T, ddI and to a lesser extent, AZT. •Explains such side effects as peripheral neuropathy, myop athy, pancreatitis, and lactic acidosis. •Side effects are managed by switching the likely offending agent, if possible. •NRTIs also function as substrates for other enzymes like D NA polymerase gamma (involved in the replication of mitoc hondrial DNA) •Disruption of DNA polymerase gamma is thought to result i n a wide variety of adverse effects ranging from lactic acidosis to hepatic steatosis Siulapwa Rodney 36 HIV NOTES 36
- 37. Rash and hepatitis •recognised as common side effects of NNRTIs. •Incidence and severity appear greatest with NVP in patients w ith higher CD4 count (>250cells/mm3 for women and > 400cell s/mm3 for men) •Management is either close observation (mild-to-moderate ca ses) or withdrawal of offending drug(severe cases). •ABC Hypersensitivity presents in the first 6 weeks of therapy a s a progressive illness with fevers, rash and flu-like symptoms. •Manage ABC – induced hypersensitivity by withdrawing ABC. Siulapwa Rodney 37 HIV NOTES 37
- 38. Lipodystrophy •Characterised by lipoatrophy ( fat loss from the face , upper li mbs and buttocks) and/ or lipohypertrophy (abnormal fat depos ition, affecting the abdomen and neck). •d4T and AZT are associated with lipoatrophy while PIs induce lipohypertrophy. •Management involves avoiding or switching away from offendi ng drugs and/or cosmetic approaches (fillers or liposuction). Metabolic disturbances •Hypercholesterolaemia and hypertriglyceridaemia are associa ted with PIs. •Incidence appears lower with ATV. •Managed by reducing modifiable risk factors, switch away fro m offending agent to a metabolically favourable agent or adjun ctive lipid - lowering therapy Siulapwa Rodney 38 HIV NOTES 38
- 39. • Renal impairment Renal impairment has been reported with TDF. • Creatinine clearance should be calculated and proteinuria qu antified prior to commencing therapy with TDF and should be monitored regularly. Cardiovascular disease • Increased risk of cardiovascular disease is associated with us e of some PIs ( LPV/r, IDV) and with NRTI, ABC. • Risk is independent of the effects on lipids and mechanism is yet to be determined. Siulapwa Rodney 39 HIV NOTES 39
- 40. Preferred 1st line cART and alternative regimens by specific populations •XTC is 3TC or FTC •EFV is the preferred NNRTI for first line cART initiation. •Consider using EFV at all times unless there are contraindications to it s use. •EFV is associated with central nervous system(CNS) side effects (e.g. d izziness, drowsiness, insomnia, abnormal dreams, and impaired concen tration) that generally occur with the first few doses and usually diminis h or disappear after 2-4 weeks. Special popul ations Description Preferred 1st line cA RT Alternative regimen Adults A once-daily fixe d-dose combinat ion is recommended TDF (TAF) + XTC +DT G TDF (TAF) + XTC + EFV ABC +3TC + DTG 40 HIV NOTES 40
- 41. Pregnancy/breastfeeding Special populati ons Description Preferred 1st line cA RT Alternative regime n Pregnant & Bre astfeeding Women A once-daily fixe d-dose combinat ion is recommended TDF + XTC + DTG TDF + XTC + EFV or ABC + 3TC + DTG 41 HIV NOTES 41
- 42. Children (0 -2weeks) •First-line regimen: AZT + 3TC + NVP •Alternative regimen: AZT + 3TC + RAL Children (2 weeks -5 years old) •Less than 20kg •First-line regimen: ABC + 3TC +LPVr •Alternative regimen: AZT +3TC + LPVr or AZT +3TC + RAL 42 HIV NOTES 42
- 43. Children (2 weeks -5 years old) •BETWEEN 20 -24.9KG •First-line regimen: ABC + 3TC + DTG •Alternative regimen: AZT +3TC + LPVr or ABC +3TC + LPVr •Equal or greater than 25KG •First-line regimen: TAF+ XTC + DTG 43 HIV NOTES 43
- 44. Elimination of Mother to child Transmi ssion (EMTCT) • CHILD BORN TO HIV POSTIVE MOTHER. 1.AT BIRTH Do HIV testing, if negative start : AZT + 3TC +NVP for 12 weeks 2. AFTER 6 WEEKS Test still negative , continue with AZT + 3TC +N VP 3. AFTER 10 WEEKS Test still negative , continue with AZT + 3TC +NV P 44 HIV NOTES 44
- 45. Elimination of Mother to child Transmi ssion (EMTCT) 4. AFTER 14 WEEKS Test still negative , continue with AZT + 3TC +N VP If mother virally suppressed stop AZT + 3TC +N VP 5. AFTER 6 MONTHS Test still negative , continue with AZT + 3TC +NV P If mother virally suppressed stop AZT + 3TC +NVP 45 HIV NOTES 45
- 46. FIRST LINE FOR HIV 2/ HIV 1 CO IN FECTION • 1. ADULTS TDF (TAF) +3TC + DTG • 2. CHILDREN ABC + 3TC + LPVr 46 HIV NOTES 46
- 47. SECOND LINE TREATMENT 1 . CHILDREN > 5 YEARS FIRST LINE: ABC + 3TC + LPVr SECOND LINE : AZT + 3TC + RAL or AZT + 3TC + DTG 2 CHILDREN 5 - 10 YEARS FIRST LINE: ABC + 3TC + EFV SECOND LINE : AZT + 3TC + LPV r or AZT + 3T C + DTG 3.ADULTS FIRST LINE: TDF + 3TC + DTG SECOND LINE : AZT + 3TC + LPVr 47 HIV NOTES 47
- 48. PRE EXPOSURE PROPHYLAXIS (P rEP) • The recommended treatment : TDF or TAF + XTC PrEP only becomes effective after 7days (21 day i n women) after starting the medications PrEP should be discontinued after 4 weeks of eli mination of risky exposure 48 HIV NOTES 48
- 49. Post Exposure Prophylaxis • Recommended treatment 1. medium risk: invasive injury, no blood visible on the needle Preferred treatment: TDF or TAF + XTC +DTG Alternative treatment : TDF or TAF + XTC + DRVr • 2. high risk: large volume of blood/fluids, known HIV patient, large bore needle, deep extensive inj ury Preferred treatment: TDF or TAF + XTC + LPVr Alternative treatment : TDF or TAF + XTC + ATVr 49 HIV NOTES 49
- 50. Post Exposure Prophylaxis 3. penetrative sexual abuse •AZT + 3TC + LPVr (children < 20kg) •AZT + 3TC + DTG (children equal or greater than 20kg) •TAF + FTC + DTG (children equal or greater than 25kg) 50 HIV NOTES 50