Current HIV Treatment A different challenge every time. Sonali Sonecha Lead HIV Pharmacist 22 nd September 2016

Transcription

1 Current HIV Treatment A different challenge every time Sonali Sonecha Lead HIV Pharmacist 22 nd September 2016

2 Aims At the end of this session, delegates should be able to Apply the principles of antiretroviral treatment in current usage List side effects and other practical difficulties / problems associated with antiretroviral treatment Demonstrate comprehension of the reasons for / against treatment at various disease stages Apply the current UK treatment guidelines (BHIVA) to clinical practice

3 Session plan General introduction to antiretrovirals When to start treatment What to start Monitoring treatment Drug-drug interactions Switching therapy

4 Natural progression of HIV

5 When to start treatment

6 Guideline Start Consider Defer BHIVA (2016 interim update) All people living with HIV including those with PHI Only if necessary EACS (Oct 15) Symptomatic strongly recommended Asymptomatic and: CD4<350 strongly recommended CD4>350 - recommended Elite controllers with high and stable CD4 count if necessary USA-DHSS (Jul 16) All patients with HIV infection to reduce risk of disease progression & to prevent transmission of HIV - Case by case on basis of clinical or psychosocial factors WHO (Jun 16) All people living with HIV Priority: WHO disease stage 3 & 4 any CD4 & CD4<350 Only if necessary

7 Strategic Timing of ART (START) study Study to explore the benefits of starting asymptomatic HIV-positive patients on antiretroviral therapy who have a CD4 of >350 cells/mm 3 2 arms to this study: *or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy

8 Highlights of IAS 2015 clinicaloptions.com/hiv START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive Pts Study closed by DSMB following interim analysis HIV-positive, ART-naive adults with CD4+ cell count > 500 cells/mm 3 (N = 4685) Immediate ART ART initiated immediately following randomization (n = 2326) Deferred ART Deferred until CD4+ cell count 350 cells/mm 3, AIDS, or event requiring ART (n = 2359) INSIGHT START Study Group. N Engl J Med. 2015;[Epub ahead of print]. Lundgren J, et al. IAS Abstract MOSY0302.

9 Highlights of IAS 2015 clinicaloptions.com/hiv START: 57% Reduced Risk of Serious Events or Death With Immediate ART 4.1% vs 1.8% in deferred vs immediate arms experienced serious AIDS or non- AIDS related event or death (HR: 0.43; 95% CI: ; P <.001) Cumulative Percent With Event Mo Deferred ART Immediate ART INSIGHT START Group. N Engl J Med. 2015;[Epub ahead of print]. Lundgren J, et al. IAS Abstract MOSY0302. Reproduced with permission.

10 Highlights of IAS 2015 clinicaloptions.com/hiv START: Cancer Events With Immediate vs Deferred ART Cancer Event, n Immediate ART (n = 2326) Deferred ART (n = 2359) Total Kaposi s sarcoma 1 11 Lymphoma, NHL + HL 3 10 Prostate cancer 2 3 Lung cancer 2 2 Anal cancer 1 2 Cervical or testis cancer 1 2 Other types* 4 9 Cumulative % With Event Time to Cancer Event Rate/100 PY: immediate, 0.20; deferred, 0.56 (HR: 0.36; 95% CI: ; P =.001) Mo Deferred ART Immediate ART *Immediate ART: squamous cell carcinoma, plasma cell myeloma, bladder cancer, fibrosarcoma. Deferred ART: gastric adenocarcinoma, breast cancer, ureteric cancer, malignant melanoma, myeloid leukemia, thyroid cancer, leiomyosarcoma, liver cancer, squamous cell carcinoma of head and neck. INSIGHT START Group. N Engl J Med. 2015;[Epub ahead of print]. Lundgren J, et al. IAS Abstract MOSY0302. Reproduced with permission.

11 Date of preparation: August /UK/12-08/MMAR/1019 HPTN 052 Prevention of HIV with Early Antiretroviral Therapy Multicenter, international, randomized, NIH-funded Phase III study HIV serodiscordant adult couples ART-naïve, HIV-infected partner CD4 between N=1,763 couples HIV infected partner: 50% male Early Arm (n=886) Start ART when CD4 between Delayed Arm (n=877) Start ART when CD4 250 or AIDS diagnosis Primary Clinical Endpoint (in HIV-positive partner) Clinical Event: Pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death 41% relative risk reduction in clinical events with early vs. delayed treatment Primary Prevention Endpoint (in HIV-negative partner) Linked HIV transmission to HIV-1 negative partners DSMB recommended study be stopped early on 28 th April DSMB = Data and Safety Monitoring Board Adapted from Cohen MS, et al. N Engl J Med 2011;365:

12 HTPN052 transmission results 39 transmissions in study 35 delayed treatment arm of which 27 linked 4 in immediate treatment arm (p<0.001) of which 1 linked Immediate tx arm = 96% reduction linked HIV transmission In multivariate analysis associated with increased risk of linked transmission: higher baseline CD4+ cell count higher baseline HIV-1 RNA reduced condom use 12

13 HTPN052 clinical outcomes results This is the first RCT to examine benefits of ART initiated at CD4 count between compared to <250 There was a trend towards a shorter time to a primary clinical event (AIDS and non-aids defining) with delayed compared to immediate therapy (HR=1.4, p=0.07) Delayed therapy was associated with a significantly shorter time to AIDS events and TB Non-AIDS defining events were rare and similar between arms The overall incidence of clinical events was significantly lower in patients on immediate therapy (IRR=0.8, P=0.02) This difference was driven by clinical events directly related to HIV infection (e.g. TB, HSV, Zoster, Candida and skin conditions)

14 What to start: antiretroviral agents

15 Classes of ARV drugs Plus Cobicistat boosting agent for elvitegravir, darunavir or atazanavir

16 HIV lifecycle 1. Binding to CD4 cell 2. Reverse transcription of RNA to DNA 3. Integration 4. Transcription into nucleic DNA 5. Translation from mrna 6. Viral assembly 16

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19 Nucleoside/tide Reverse Transcriptase Inhibitors First drug available to treat HIV AZT (Zidovudine) in 1987 Often backbone of therapy Mimic natural purine and pyrimidine bases, competitive inhibition of reverse transcriptase enzyme Action Incorporated into DNA terminate the DNA chain incomplete parts of DNA Excretion: unchanged in urine so interactions minimal

20 Key Adverse effects: NRTIs Most occur within first 1/12 and are transient, class effects All drugs: nausea, vomiting, diarrhoea Abacavir hypersensitivity reaction (HLAB5701 positive) CV risk D.A.D. study D drugs: pancreatitis, lactic acidosis and peripheral neuropathy Stavudine & zidovudine: lipodystrophy Tenofovir DF an NtRTI Hypophosphotaemia: SPC recommends initial weekly monitoring Renal effects: Fanconi syndrome Reduced BMD

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22 Non-Nucleoside/tide Reverse Transcriptase Inhibitors Action Non-competitive, selectively binds to the enzyme inactivates catalytic site, preventing pro-viral DNA synthesis of HIV-1 Metabolised by CYP450 enzyme system Levels may be affected by other drugs Drug CYP iso-enzymes induced CYP iso-enzymes inhibited Efavirenz Potent 3A4, strong 2B6 Potent 3A4, moderate 2C9 & 2C19 Etravirine Weak 3A4 Weak 2C9, moderate 2C19 Nevirapin e Potent 3A4 & 2B6 - Rilpivirine Moderate 2C19, slight 1A2, 2B6, 3A4 -

23 Key Adverse Effects - NNRTIs Rash Most common with Nevirapine (black box warning) May be able to treat through Rare: Stephen s-johnson Syndrome CNS toxicity Most common with efavirenz Often resolves within few weeks Hepatotoxicity Most common with OD nevirapine (2NN study) LFT s checked every 2/52 for first month Caution in Hepatitis B and C patients Rare: fulminant hepatitis

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25 Lopinavir 3A4 & 2D6 lesser extent UGT, Possibly 1A2, 2C19, 2C9 Protease Inhibitors Act directly on the protease enzyme to stop the final stage of the HIV lifecycle Action: Stop maturation of the viral particle by enzyme cleavage of proteins Metabolised by 3A4 levels may be affected by other drugs Boosted PI: Low dose ritonavir is utilised as CYP3A4 inhibitor decrease dose or frequency Drug Ritonavir CYP iso-enzyme inhibited Potent (in order) 3A>2D6>2C9, 2C19>> 2A6,2E1 UGT enzymes CYP iso-enzyme induced Other 1A2, 2B6, 2C9, 2C19 Induces glucoronidation Inhibits P-gp, OATP1B1/1B3 & MATE1 Atazanavir 3A4, UGT1A1, weak 2C8 - Boosted induces glucoronidation Darunavir 3A4 - -

26 Key Adverse effects - PIs All PIs Fatigue, nausea, diarrhoea short-term Lipid, hepatic & metabolic effects Ritonavir Metallic taste, bloating Atazanavir Hyperbilirubinaemia, jaundice & renal stones Darunavir Sulfonamide allergy, rash Kaletra GI effects, dyslipidaemia & high triglycerides

27 Cobicistat Licensed pharmacokinetic enhancer but no antiviral activity Used as an alternative to ritonavir boosting with PI s and with elvitegravir in Stribild or Genvoya Strong inhibitor of CYP3A4 enzyme but less so of other CYP agents, different interaction profile to RTV Impairs renal tubular secretion of creatinine resulting in small increase in serum Cr, but does not affect gfr

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30 Integrase Inhibitors Prevent integration of viral DNA into host genome DDI: PPIs and antacids / chelation Raltegravir First licensed Integrase. Requires BD dosing Elvitegravir (as Stribild) Requires boosting with Cobicistat, CYP3A4 inhibitor Do not start if baseline CrCl<70mls / min Dolutegravir Once daily except in integrase resistance BD dose DDI UGT inhibitors or inducers will impact DTG 30

31 Key Adverse Effects - INIs Generally they are all well tolerated RAL Report of transient GI effects Rash DTG CNS toxicities insomnia mainly Rash / hypersensitivity EVG/COB Nausea and diarrhoea RTV like effects

32 Entry Inhibitors Fusion inhibitor: Enfuvirtide (T-20) Binds to HIV gp-41 and thus inteferes with entry to CD4 cells Administered by sub-cutaneous injection BD Rarely used Key side effects local injection site reactions CCR5 antagonist: Maraviroc Selective antagonist, blocks interaction between human CCR5 and HIV gp120 preventing cell entry Need tropism or geno-to-pheno CCR5 at baseline CYP3A4 substrate so dosing varies dependent on other ARVs Key side effects GI, cough, rash & hepatotoxicity 32

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34 What to start: guidelines

35 A brief history of HIV treatment 1987 Zidovudine available (monotherapy given) By TC, DDI and DDC licensed 1996 First PI saquinavir launched Delta study showed 2 drugs better than ACTG320 trial showed improved mortality and morbidity with 3 drugs vs CDC guidelines Hit early, hit hard New Millennium toxicity, liver morbidities, do not start tx until CD4<250 Since 2008 start CD4<350, better comparison between treatments 2012 Treatment as Prevention; availability of generics 2015 START: Treatment of all people living with HIV

36 PROGRESSION TO AIDS/DEATH 30 % of patients progressing No therapy Mono-therapy Dual-therapy 8 Triple therapy Months JAMA 1998 & CMAJ

37 How has Treatment Changed Since 1997 Atripla 2008 Combivir Nevirapine 2000 Stavudine Didanosine Indinavir 1997 In 1997 the medication patients took was not only larger and greater in number but also meant they had to plan all meals carefully! Breakfast Lunch Dinner 6am 12pm 6pm 12am

38 HAART / cart Highly Active Anti-Retroviral Therapy (combination therapy) Aims Extend life expectancy HIV now considered a chronic condition Higher quality of life Improve/strengthen the immune system s function Prevention of further transmission Actions Reduce HIV viral load to below detectable levels <40 copies/ml Increase CD4 counts

39 TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV Regimens containing ABC or Guideline Recommended Alternative Comments BHIVA (2015) EACS (Oct 15) TDF/FTC (Truvada) or TAF/ FTC RPV^ ATV/r DRV/r EVG/c RAL DTG TFV/FTC + RPV^ TFV/FTC + DRV/r TFV/FTC + RAL ABC/3TC + DTG (ANY VL) TFV/FTC + DTG TFV/FTC + EVG/c if CrCl> 70mls/min ABC*^/3TC (Kivexa) EFV ABC/3TC* + RAL TFV/FTC + EFV ABC/3TC* + EFV TFV/FTC or ABC/3TC* + ATZ/r TFV/FTC or ABC/3TC* + ATZ/c ABC/3TC* + DRV/r TFV/FTC or ABC/3TC* + DRV/c TFV/FTC + LPV/r Alternative combinations: DRV/r + RAL* LPV/r + 3TC *if HLAB5701 negative ^ if VL<100,000 copies/ml except when ABC/3TC with DTG Guidelines do not consider cost-effectiveness & thus there may be further national or local guidelines in place Generics only if do not break FDC *if HLAB5701 negative & caution if high CVD risk & VL>100K ^ if VL<100,000 copies/ml * If CD4>200 & VL<100K US-DHSS (Jul 16) DTG + ABC*/3TC DTG + TDF/FTC or TAF/FTC RAL + TDF/FTC or TAF/FTC EVG/c + TDF/FTC or TAF/FTC DRV/r + TDF/FTC + TAF/FTC DRV/r# + ABC*/3TC ATV/r# + TDF/FTC RAL + ABC*/3TC EFV + TDF/FTC RPV + TDF/FTC^ & CD4>200 Alternative combinations only recommended if both TDF & ABC are contra-indicated * if HLAB5701 negative ^ if VL<100,000 copies/ml # Cobicistat instead of ritonavir an option

40 BHIVA 2015: What to start with NRTI backbone Third Agent Preferred Tenofovir DF + emtricitabine (Truvada) Tenofovir AF + Emtricitibine (Descovy) Atazanavir/ritonavir Darunavir/ritonavir Dolutegravir Rilpivirine 2 Elvitegravir/cobicistat Raltegravir Alternative Abacavir 1,3 + lamivudine (2) (Kivexa) Efavirenz 1. Contraindicated if HLA B*5701 positive 2. Not recommended if baseline viral load greater than 100,000 copies/ml 3. Not recommended if high estimated cardiovascular risk (see Section 6.6 Cardiovascular disease) Churchill D et al BHIVA treatment guidelines

41 Naïve studies for ARVs EFV RPV RAL EVG/c DTG ATV/r DRV/r EFV ECHO THRIVE STARTMRK GILEAD 102 SINGLE ACTG5202 X RPV ECHO THRIVE X X X X X RAL STARTMRK X X SPRING-2 ACTG5257 ACTG5257 EVG/c GILEAD 102 X X X GILEAD 103 X DTG SINGLE X SPRING-2 X X FLAMINGO ATV/r ACTG5202 X ACTG5257 GILEAD 103 X ACTG5257 DRV/r X X ACTG5257 X FLAMINGO ACTG5257

42 What to Start With: 2NRTIs + NNRTI Recommended Rilpivirine VL<100K Alternative Efavirenz Studied extensively vs. NVP, RPV, RAL, DTG, EVG/c & ATV Recent studies have shown impact of side effect profile on outcome, hence this is now alternative Easier adherence But low resistance barrier Consider primary resistance 42

43 What to start with: 2NRTIs + INI Recommended: Raltegravir or Elvitegravir/ cobicistat or dolutegravir 50mg OD No direct head-head between all 3 DTG vs. RAL (Spring 2)

44 What to Start With: 2NRTIs + boosted PI Recommended: Boosted Atazanavir or Darunavir 800mg OD first line ATV/r versus DRV/r versus Raltegravir (ACTG5257) Less resistance at virological failure But - possible increased toxicity and drug interactions 44

45 NRTI backbone choice 3TC or FTC plus one of: Preferred -Tenofovir DF or Tenofovir AF Alternative - Abacavir if HLA b5701 negative & VL <100K (unless with DTG) Co-formulations Kivexa abacavir + 3TC OD Truvada tenofovir DF + FTC OD Descovy tenofoir AF + FTC OD 45

46 ACTG 5202 Study Design HIV-1 RNA 1000 c/ml Any CD4+ count > 16 years of age Arm A TDF/FTC QD ABC/3TC Placebo QD EFV QD Phase IIIb ART-naive 1857 enrolled Randomised 1:1:1:1 Stratified by screening HIV-1 RNA (< or 100,000 c/ml) B C ABC/3TC QD TDF/FTC Placebo QD TDF/FTC QD ABC/3TC Placebo QD EFV QD ATV/r QD Enrolled Followed through Sept 2009, 96 wks after last pt enrolled D ABC/3TC QD TDF/FTC Placebo QD ATV/r QD Daar, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB. 46

47 ACTG 5202 ABC/3TC vs TDF/FTC high viral load stratum ABC/3TC vs. TDF/FTC: primary virologic endpoint (High viral load stratum at DSMB action) ABC/3TC vs. TDF/FTC with Hazard Ratio EFV HR 2.46 (95% CI 1.20, 5.25) ATV/r HR 2.22 (95% CI, 1.19, 4.14) -4 Favors ABC/3TC 1 Favors TDF/FTC 5 Daar, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB. 47

48 ACTG 5202 ABC/3TC vs TDF/FTC low viral load stratum ABC/3TC vs. TDF/FTC: primary virologic endpoint (Low viral load stratum; n=1060) ABC/3TC vs. TDF/FTC with Hazard Ratio (whole study) EFV HR 1.23 (95% CI, 0.77,1.96) Probability VF free at Week 96: 87.4% vs 89.2% diff -1.8% (95% CI -7.5, 3.9) ATV/r HR 1.26 (95% CI, 0.76,2.05) Probability VF free at Week 96: 88.3% vs 90.3% diff -2.0% (95% CI -7.5, 3.4) -4 Favors ABC/3TC 1 Favors TDF/FTC 5 Daar, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB. 48

49 ACTG 5202 Atazanavir/r vs Efavirenz overall population Primary Efficacy Endpoint Time to Virologic Failure (ITT) Atazanavir/r vs Efavirenz overall population Hazard Ratio (whole study) Atazanavir/r vs. Efavirenz with ABC/3TC HR 1.13 (95% CI 0.82, 1.56) Probability VF free at Week 96: 83.4% vs 85.3% diff -1.9% (95% CI -6.8, 2.6) TDF/FTC HR 1.01 (95% CI 0.7, 1.46) Probability VF free at Week 96: 89% vs 89.8% diff -0.8% (95% CI -4.9, 3.3) 0 Favors ATV/r 1 Favors EFV 2 Daar, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB. 49

50 HIV/AIDS Update From Boston 2014 clinicaloptions.com/hiv ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART Stratified by HIV-1 RNA < or 100,000 c/ml, participation in metabolic substudy, CV risk Wk 96 after last patient enrolled ART-naive patients with HIV-1 RNA 1000 c/ml (N = 1809) ATV/RTV 300/100 mg QD + TDF/FTC (n = 605) RAL 400 mg BID + TDF/FTC (n = 603) DRV/RTV 800/100 mg QD + TDF/FTC Primary endpoints (n = 601) Virologic failure: time to HIV-1 RNA > 1000 c/ml (at Wk 16 or before Wk 24) or > 200 c/ml (at or after Wk 24) Tolerability failure: time to discontinuation of randomized component for toxicity Composite endpoint: the earlier occurrence of either VF or TF in a given participant Switch of regimens allowed for tolerability Landovitz R, et al. CROI Abstract 85.

51 HIV/AIDS Update From Boston 2014 clinicaloptions.com/hiv ACTG 5257: Primary Endpoint Analyses at Wk 96 Virologic Failure Tolerability Failure Composite Endpoint Regimens equivalent in time to VF Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV In part due to high proportion of pts with hyperbilirubinemia Considering both efficacy and tolerability, RAL superior to either boosted PI DRV/RTV superior to ATV/RTV ATV/RTV vs RAL 3.4% (-0.7 to 7.4) DRV/RTV vs RAL 5.6% ( ) ATV/RTV vs DRV/RTV -2.2% (-6.7 to 2.3) Favors RAL ATV/RTV vs RAL 13% ( ) DRV/RTV vs RAL 3.6% ( ) Favors DRV/RTV ATV/RTV vs DRV/RTV 9.2% ( ) Difference in 96-Wk Cumulative Incidence (97.5% CI) Landovitz R, et al. CROI Abstract 85. Reproduced with permission Favors RAL ATVRTV vs RAL 15% (10-20) Favors RAL DRV/RTV vs RAL 7.5% ( ) Favors DRV/RTV ATV/RTV vs DRV/RTV 7.5% ( )

52 HIV/AIDS Update From Boston 2014 clinicaloptions.com/hiv ACTG 5257: Virologic Efficacy In ITT analysis with ART changes allowed (per protocol), regimens similar in virologic efficacy at Wk 96 and through Wk 144 In ITT analysis when change = failure (Snapshot), RAL superior to both boosted PIs at Wk 96 and DRV/RTV superior to ATV/ RTV at Wks 96 and 144 Similar mean change in CD4+ count across arms ATV/RTV (+284); RAL (+288) DRV/RTV (+256) cells/mm 3 Proportion With HIV-1 RNA 50 c/ml ITT, Regardless of ART Change 94% 89% 88% ITT, NC = Failure (Snapshot) 80% 73% 63% RAL DRV/RTV ATV/RTV RAL DRV/RTV ATV/RTV Landovitz R, et al. CROI Abstract 85. Reproduced with permission Study Wk

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54 ARV Generics Already some ARV generics in UK Lamivudine & efavirenz most commonly used Key 1 st line agents soon going generic: Kivexa in Dec 2016 & tenofovir in July 2017 savings for NHS over next 5 years (Hill et al) Switch from single to multi-tablet regimens Engagement & education of patients and clinicians 54

55 Monitoring treatment BHIVA Guidelines 2016

56 Counselling patients starting treatment 2 way conversation, answer questions and address concerns Practical details on medication itself: What medication is called, details of administration, food requirements, dose timings How treatment works & will be monitored Understanding of disease, CD4 & VL, importance of adherence, drug resistance, treatment plan and goal of treatment Other points: Drug-drug interactions, travelling with medications What to do if missed/ late dose, vomits post-take Contact details for staff and clinics, OOH

57 ART initiation: Baseline Within 3 months before starting ART History: adherence, medication, drug & EtOH use, vaccination, knowledge & beliefs re: HIV, social hx Examination: weight, BP, BMI, waist circumference Assessment: CVD risk, fracture risk in over 50s Investigations FBC, U&E, LFT, lipid & bone profiles, urinalysis, UP:Cr CD4 & VL, VRT (not integrase unless indicated) HLAB*5701 / tropism if ABC / MVC considered HBV & HCV status

58 ART initiation: cont Re-assess patient within 2-4 weeks of starting treatment and repeat each visit first 6/12 History Side effects Adherence Investigations Renal and liver profile CD4 after 3/12 if <350 or repeat annually VL at 1, 3 & 6 months Should fall 10-fold within 1/12, otherwise repeat at 8/52 Should be undetectable within 6/12

59 Monitoring of undetectable ART History: medication hx & drug use, adherence, mood, adverse effects & patient concerns Examination: weight, BP, targeted physical exam, if new symptoms or signs Investigations: Cr, egfr, LFTs, glucose, bone profile, urinalysis, UP:Cr, VL every 6/12 patients Annual CVD risk & lipid profile if >40yrs, smoker or obese STI & Hepatitis status FBC, renal & liver profile Cervical cytology (women) Other assessments Fracture risk (FRAX score) in pts >50yrs every 3 yrs CD4 every year if >200; if >350 on 2 occasions >1yr apart only

60 Drug-drug interactions

61 Interactions Most likely to occur with NNRTIs and PI s as these go through and affect the Cytochrome P450 system in the liver Tenofovir also interacts with some ARV s AZT myelosuppressive use cautiously with similar agents Maraviroc substrate for CYP Raltegravir - glucoronidation Always check interaction status Consider following: Meds from other sources e.g. GP, dentist, OTC Herbal meds (e.g. St. John s Wort and PI s) Recreational / Party drugs (e.g. poppers, Chemsex) Contraception Impact of GI motility or acidity on drugs 61

62 To avoid problems Check for potential interactions (contact HIV pharmacist if necessary) If interaction is unavoidable what is the expected outcome? ie toxicity or failure of ARV or co-prescribed drug(s) Can you monitor for toxicity or adjust dose of coprescribed drug? eg reduce atorvastatin dose when prescribed with PI Therapeutic drug monitoring (TDM) of ARVs NNRTIs and PIs

63 Common interactions PPIs, antacids & rilpivirine rilpivirine to sub-optimal levels Steroid injections / inhalers & PI s levels corticosteroids Cushing s syndrome Simvastatin & PI s Simvastatin concentrations ~200% PI s and G potentially fatal increase in G levels 63

64 Drug interactions Prescribers of ARV need a good understanding of basic pharmacology principles to ensure effective and appropriate prescribing It is very important to consider potential drug interactions- this can not be over emphasised Places to look: - the bible! drugs_interact.html the lesser known bible - SPCs

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66 Switching treatment

67 Reasons for switch Toxicity Virological failure Co-morbidity Management of drug-drug interactions Treatment simplification Patient preference New clinical data Cost Locally ~8% switch treatment annually 1 1 Boyle et al Int Cong HIV Tx and Inf 2012,

68 Reasons for switching ARVs in cohort of patients at C&W Boyle et al, BHIVA 2012 oral abstract O28

69 Switching treatment: Key points Consider combinations being switched: Interactions between old and new agents? Patient counselling Old stocks of medications Patient VL status at time of switch Other co-morbidities or medications

70 Switching practicalities Switching one agent Usually for toxicity Review resistance profile pre-switch Switching due to virological failure Low level viraemia or blip repeat VL Check adherence & drug Hx Resistance test +/- tropism Where possible switch whole combination to 3 active drugs as soon as possible

71 Useful links

72 Questions