HIV and AIDS An update

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1 HIV and AIDS An update Barnet branch 24 th February 2009 Neal Marshall Specialist pharmacist HIV services Royal Free Hampstead NHS Trust

2 Objectives To gain an insight into the epidemiology of HIV To gain a basic understanding of the treatment of HIV disease To be aware of the complexities of treatment

3 What does it stand for? HIV Human Immunodeficiency Virus Causes a gradual decline in immune function by destroying CD4 immune helper cells AIDS Acquired Immunodeficiency Syndrome Diagnosed when the patient suffers one a list of AIDS-defining illness

4 First reports: MMWR 1981 Pneumocyctis Pneumonia Los Angeles Gottlieb MS et al. MMWR 1981;30:250-2 Kaposis s and Pneumocystis Pneumonia among homosexual men -New York and California Friedman-Kein A et al MMWR 1981;30:305-8

5 Early History of AIDS Jan 82: July 82: July 82: Dec 82: Syndrome termed GRID Infections noted in haemophilliacs, Haitians CDC defines AIDS 4 cases of unexplained immune deficiency in infants reported (MMWR)

6 The 4 H club Homosexuals Haemophiliacs Heroin addicts (IVDU) Haitians Hookers

7 Early History of AIDS Jan 83: First screening of high risk blood doners May 83: Pasteur institute report Lymphadenopathy Virus (LAV) April 84: Discovery of AIDS virus (HTLV-III) by Robert Gallo announced in USA Aug 84: First commercial AIDS test May 86: Virus remained HIV

8 Evolving therapy management : Treatment of opportunistic diseases and symptoms only 1987: First antiretroviral (ZDV) licensed : Availability of other NRTIs (ddc, ddi) : Dual combination therapy (2 NRTIs) 1995: Quantification of HIV load by PCR

9 Evolving therapy management 1995: First HIV protease inhibitor (PI) and introduction of HAART 1996: Non-nucleoside RT inhibitors (NNRTIs) 1998: Resistance testing 2000: PI boosting 2001: Therapeutic drug monitoring

10 Adults and children estimated to be living with HIV, 2007 North America 1.2 million [ million] Caribbean [ ] Latin America 1.7 million [ million] Western & Central Europe [ million] Middle East & North Africa [ ] Sub-Saharan Africa 22.0 million [ million] Eastern Europe & Central Asia 1.5 million [ million] East Asia [ million] South & South-East Asia 4.2 million [ million] Oceania [ ] Total: 33 million (30 36 million) Royal Free Hampstead NHS Trust

11 Estimated number of adults and children newly infected with HIV, 2007 North America [ ] Caribbean [ ] Latin America [ ] Western & Central Europe [ ] Middle East & North Africa [ ] Sub-Saharan Africa 1.9 million [ million] Eastern Europe & Central Asia [ ] East Asia [ ] South & South-East Asia [ ] Oceania [ ] Total: 2.7 million ( million) Royal Free Hampstead NHS Trust

12 Estimated adult and child deaths from AIDS, 2007 North America [ ] Caribbean [ ] Latin America [ ] Western & Central Europe 8000 [ ] Middle East & North Africa [ ] Sub-Saharan Africa 1.5 million [ million] Eastern Europe & Central Asia [ ] East Asia [ ] South & South-East Asia [ ] Oceania 1000 [< ] Total: 2.0 million ( million) Royal Free Hampstead NHS Trust

13 New HIV diagnoses Adjusted number of new HIV diagnoses by prevention group, UK 5,000 4,500 MSM Blood product recipients Mother-to-child transmission Heterosexual contact IDU 4,000 3,500 3,000 2,500 2,000 1,500 1, Proportional adjustment for missing information applied HIV and AIDS New Diagnoses and Deaths

14 New HIV diagnoses Adjusted numbers of new HIV diagnoses by probable risk group and country of infection, UK 4,500 MSM UK 1 MSM abroad 1 Heterosexual UK 2 Heterosexual abroad 2 4,000 3,500 3,000 2,500 2,000 1,500 1, Proportional adjustment applied for missing information (both probable risk and country of infection) 2 Additional proportional adjustment applied to the UK acquired group for persons with evidence of sexual contact both in the UK and a country abroad where national HIV prevalence is estimated to be <1% HIV and AIDS New Diagnoses and Deaths

15 Late diagnosis Health Protection Agency: A complex picture; HIV and other STIs in the UK:

16 Estimated number of persons living with HIV Estimated number of adults (15 to 59 years) living with HIV (both diagnosed and undiagnosed) in the UK: ,000 22,950 Diagnosed Undiagnosed Total 73,300 (68,800 78,500) 20,000 15,000 13,250 7,850 10,000 5,000 6,300 2,650 3,650 3,750 2,850 4,600 2, , MSM Heterosexual men born in Africa Heterosexual women born in Africa Heterosexual men born elsewhere including UK Heterosexual women born elsewhere including UK IDU men IDU women MPES

17 Transmission 4 main routes of transmission: 1. Sex (vaginal or anal) 2. Transfusions 3. Sharing needles (IVDUs) 4. Vertical transmission from mother to child

18 CD4 and viral load HIV/PNP/07/31366/1

19 CD4 count CD4 is a receptor on white blood cells HIV uses the CD4 receptor to infect cells CD4 count used as a marker of immune function The lower the CD4 the less efficient the immune system Low CD4 (<200 cells/mm 3 ) puts pts at risk of opportunistic infections

20 CD4 count (cells/mm 3 ) CD4 and infection Oral candida Herpes zoster Anaemia, weight loss Tuberculosis* Pneumocyctis jiroveci pneumonia Oesophageal candida Recurrent HSV / VZV infection Toxoplasmosis Cryptococcal meningitis Kaposi s sarcoma* PML NHL* Cryptosporidiosis Disseminated CMV MAI Time * Can occur at higher CD4 counts

21 Viral load (VL) The amount of virus in 1 millilitre of blood Without treatment VL from 5,000 5 million copies/ml Aim of treatment to become undetectable (VL < 50 cps/ml) An undetectable VL reduces amount of replication of virus, and reduces chance of resistance to antiretroviral drugs

22 Testing for HIV ELISA based test antibody based test 4 th generation antibody/antigen test 3 month window till positive Same day testing now available Walk in clinic Finger prick test Result available in 15 minutes

23 How does HIV enter the cell? HIV virus CD4 CCR5 RNA RT DNA Integrase Protease HIV virus

24 Where could drugs work HIV virus Fusion inhibitors CD4 CCR5 antagonists CCR5 RNA RT NRTI / NNRTI DNA Integrase Protease inhibitors Protease HIV virus

25 Available antiretrovirals Raltegravir Delavirdine Etravirine DDC d4t 3TC Efavirenz Combivir Trizivir FTC Maraviroc Kivexa AZT DDI Nevirapine Abacavir Tenofovir Truvada NRTI Saquinavir HG Fosamprenavir NNRTI Ritonavir Saquinavir SG Atazanavir PI CCR5 antagonist Indinavir Amprenavir Saquinavir 500 Kaletra tabs Entry inhibitor Nelfinavir Kaletra SGC Fuzeon Darunavir Integrase inhibitor

26 CD4 count (cells/mm 3 ) When to treat: CD4 guided? Immunocompetent Start here and the patient may become ill Start here and the patient may suffer more long term side effects of the drugs Treatment window Open to opportunistic infections Time

27 When to treat-bhiva Guidelines HIV disease stage CD4 count (cells/mm 3 ) Recommendation Early (primary) infection) Any CD4 level Treatment in clinical trial; or neurological involvement; AIDS-defining illness; or CD4<200cells/mm3 >3/12. Established (chronic) infection without symptoms CD4 > 500 CD4 between CD4 between Consider enrolling into a when to treat study Treat if high risk (AIDS diagnosis, HBV needing Tx, low CD4 %, high risk of CV events) Start treatment ASAP when patient ready CD4 < 200 Start treatment Established (chronic) infection with symptoms Any CD4 level Start treatment (except TB when CD4>350)

28 What do we treat HIV with? Anti-retroviral drugs Triple therapy Highly Active Anti-retroviral Therapy (HAART) 6 classes of licensed ARV NRTIs Nucleoside reverse transcriptase inhibitors NNRTIs Non-nucleoside reverse transcriptase inhibitors PIs Protease inhibitors Fusion inhibitors (enfuvirtide, aka T20) Integrase inhibitors (raltegravir) CCR5 receptor antagonists (maraviroc)

29 Choosing the right regimen Resistance Co-morbidities Interactions Toxicities Short & long term Prescriber and patient preference Perceived adherence

30 Patients with Virologic Failure, % Adherence affects clinical outcome 95% adherence is required to achieve undetectable viral loads in 80% of patients > <70 Adherence, % 99 patients prescribed PI based regimens Adherence calculate as % of doses prescribed over median 6 month period (range 3-15). Adherence >95% had fewer days in hospital (2.6 vs 12.9 /1000days P=0.001). Doctors incorrectly predicted adherence in 41% of patients Paterson DL, Swindells S, Mohr J et al. Ann Intern Med. 2000;133(1):21-30

31 Highly active antiretroviral therapy (HAART) Most evidence for either: BHIVA guidelines NRTIs + NNRTI (regimen of choice) 2 NRTIs + PI NRTIs NNRTIs PIs tenofovir, abacavir, lamivudine (3TC), emtricitabine (FTC), Zidovudine (AZT) Efavirenz, nevirapine, etravirine(tmc125) Kaletra, atazanavir, saquinavir, darunavir

32 NRTIs Nucleoside reverse transcriptase inhibitors 7 drugs licensed Most often used class of ARV Lamivudine (3TC) Abacavir Emtricitabine (FTC) Tenofovir (TDF) Zidovudine (AZT) Stavudine (D4T) Didanosine (DDI)

33 Choosing the NRTI backbone Limit choice to: Truvada (Tenofovir / emtricitabine) 1 tab OD Kivexa (abacavir / lamivudine) 1 tab OD Combivir (zidovudine / lamivudine) 1 tab BD Factors to consider Efficacy Toxicity Convenience (OD vs BD) Hepatitis B co-infection (use Truvada) Pregnancy (pref. for zidovudine/lamivudine)

34 Toxicity Zidovudine Anaemia (esp with combivir as AZT 300mg bd) More limb fat loss vs. Tenofovir (Gilead 934) Tenofovir Concerns over renal safety Concerns over osteopaenia Abacavir Hypersensitivity (5-7%) risk of MI?

35 NRTI toxicity?

36 NNRTIs 1st generation: Efavirenz 600mg nocte Nevirapine 200mg OD 2/52 then 200mg BD 2 nd generation: Etravirine (TMC125) 200mg BD Commonly used 1 st line 2 NRTIs + 1 NNRTI

37 Efavirenz or Nevirapine? Nevirapine Hepatoxicity CD4 cut off for prescribing, don t Rx if: > 250 cells/mm 3 > 400 cells/mm 3 Rash (inc. SJS / TEN) Efavirenz CNS disturbances (concern if Hx of depression) Not advised if considering pregnancy Lipids compared to nevirapine Preferred NNRTI according to BHIVA guidelines

38 Atripla Tenofovir 300mg Emtricitabine 200mg Efavirenz 600mg One pill once a day 2 drug companies working together

39 PIs: Protease inhibitors 6 in regular use Atazanavir Fosamprenavir Lopinavir (kaletra) Saquinavir Darunavir Tipranavir Most require ritonavir boosting for best pharmacokinetic effect

40 Licensed dosed of Protease inhibitors within EU Once-daily am Twice-daily pm Atazanavir + ritonavir Fosamprenavir + ritonavir Lopinavir/r (Kaletra ) Saquinavir + ritonavir Darunavir + ritonavir Please note images are not to scale Reyataz SmPC Month 2008; Telzir SmPC February 2008; Kaletra SmPC November 2007; Invirase SmPC November 2007; Prezista SmPC January 2008.

41 But in practice Once-daily am Twice-daily pm Atazanavir + ritonavir Fosamprenavir + ritonavir +/- Lopinavir/r (Kaletra ) Saquinavir + ritonavir Darunavir + ritonavir Please note images are not to scale

42 Side effects Diarrhoea Kaletra = fosamp > saq > darunavir > Ataz Triglycerides & TC Kaletra = fosamp > saq = darunavir = Ataz Hyperbilirubinamia Atazanavir 4% jaundiced

43 Polypharmacy HIV Truvada + efavirenz (2) Truvada + kaletra (5) Truvada + Ataz + rit (3) Recurrent HSV Aciclovir 400mg bd (2) Valacilcovir 500mg od (1) TC & TG Atorva 20mg od (1) Omacor 2 cap bd (4) fenofibrate 267mcg od (2) BP / protein urea Losarten 100mg od (2)

44 Review: First line HAART 2 NRTI + NNRTI 2 NRTI + boosted PI Which NRTI backbone? Truvada or Kivexa? HBV co-infection? CVD? Pregnancy - AZT Which NNRTI? Efavirenz recommended Considering pregnancy? NNRTI or PI? Check baseline resistance Better outcomes with NNRTI but fail with more resistance Increased CV risk with PIs? Which PI? Any? Cheapest? Darunavir? Most data on once daily?

45 New drugs, new classes Fusion Inhibitor Stops fusion of virus to CD4 cell Enfuvirtide (aka T20) CCR5 receptor antagonists Block HIV entry into cell Maraviroc Integrase inhibitors Inhibit HIV integration into cellular DNA Raltegravir

46 Patients with Highly Resistant virus Drug choice depends on resistance pattern Viral load <50 now achievable for most patients

47 Can I stop once I ve started? Conflicting evidence Depends on CD4 cut offs Stopping between cells/mm 3 Increased non-aids defining events (CV & cancers) Stopping between cells/mm 3 No overall sig. diff in events, but less CV events

48 Cytochrome P450 Induction/inhibition of CYP450 can influence drug metabolism NNRTI/rifampicin induce CYP450 Ritonavir inhibits CYP450

49 Drug interactions Multiple, varied and complex! Resources Liverpool website: Toronto clinic: Drug data sheet ( PPI interactions (e.g. omeprazole) Atazanavir levels (avoid PPI, caution with H 2 A) 2x Saquinavir levels ( levels well tolerate) Raltegravir levels (integrase inhibitor) -? significance

50 Statins Drug (metabolism) NNRTIs Protease inhibitors (boosted) Simvastatin (CYP3A4, 2D6, 2C9) 60% AUC simva Advice: AVOID!!! 600 x AUC simva Advice: AVOID!!! Fluvastatin (CYP2C9>>3A4) Pravastatin (50% CYP3A, 50% renal metab) Atorvastatin (CYP3A4) No sig. interaction Rx as normal 40% AUC prava. Rx as normal and titrate 40% atorva levels. Start at 20mg and titrate. No sig interaction. Rx as normal, but may see more s/e at max dose Variable depending on PI. Advice: Start 20mg and titrate 4 6 x atorva levels Advice: Start with 10mg od and titrate. Usual max 20mg od Rosuvastatin (10% 3A4, 2C9) No data.? Slight AUC rosuva Limited data suggest 2 x AUC rosuva. Advice: Start 5mg od & titrate Royal Free Hampstead NHS Trust

51 Flixotide/Seretide inhalers or flixonase nasal spray Beclomethasone appears not to be affected Royal Free Hampstead NHS Trust

52 Cost 1st line therapy: 500/month 2 nd /3 rd line: /month Resistant patients: /month

53 HIV & pregnancy Not a contraindication and not discouraged National Antenatal screening HIV pregnancy register Actions: Initiate HAART weeks C-section if VL>50cps/ml (SVD if VL<50) Neonate given 4/52 PEP Bottle feed (no breast feeding)

54 Estimated proportion of HIV-infected pregnant women diagnosed before delivery 1 and of exposed infants becoming infected with HIV 2, England & Scotland Proportion of exposed infants who become infected Unlinked anonymous prevalence monitoring 1 Includes previously diagnosed and those diagnosed through antenatal testing 2 Assumes vertical transmission rate of 26.5% in undiagnosed women and 2.2% in diagnosed women 3 These data contain reports received by the end of June 2008, data for recent years is subject to reporting delay Proportion of HIV-infected women who are diagnosed before delivery 18% 100% 16% 14% Antenatal HIV screening introduced 90% 80% 12% 10% 8% 6% 4% 2% 0% Estimated proportion of infants exposed who become infected with HIV HIV infected pregnant women diagnosed before delivery % 60% 50% 40% 30% 20% 10% 0%

55 Roles of the specialist pharmacy Dispense and check prescriptions Drug interactions Support patients to adhere to regimens Prepare treatment guidelines Prescribe medicines Monitor costs Therapeutic Drug Monitoring (TDM) Submissions for Drug and Therapeutics committees

56 Role of the community pharmacist Recurrent/unusual infections Oral candida Recurrent HSV Flu like illness / rash Refer to GP Warts

57 Take home points Remarkable advances in treatment since AIDS first described HIV now a chronic life long condition HAART therapy needed to treat HIV Excellent Adherence required to maintain undetectable viral load Drug interactions and polypharmacy major issues Pharmacists play a vital role in managing this disease

58 Further Information General info: Drug interactions: Guidelines: Drug SPC Specialists

59 HIV and AIDS An overview Neal Marshall Specialist pharmacist HIV services Royal Free Hampstead NHS Trust

60 Pneumocyctis Pneumonia (PCP) Pneumocystis jirovecii Most common AIDS defining presenting disease Tx Septrin 120mg/kg/day Steroids if destaurating

61 Cerebral Toxoplasmosis Toxoplasmosis gondii Tx Lumbar puncture Suphadiazine Pyrimethamine

PHCP 403 by L. K. Sarki

PHCP 403 by L. K. Sarki objectives To gain insight into the epidemiology of HIV To gain basic understanding of the etiology of HIV disease To know the clinical manifestations of the disease To gain a basic