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Home , Bictegravir, Doravirine, Fostemsavir, Islatravir, Lenacapavir

Overview of Antiretrovirals for HIV Treatment

Margaret Fikrig, MD July 20, 2020

133 AN AIDS TIMELINE: The 1st Decade RONALD REAGAN 1981-1989 GEORGE H.W. BUSH 1989-1993

’82 ’85 ’87 AZT approved “AIDS” First HIV test

SCIENCE/CLINICAL ’83 Virus isolated INTERNATIONAL

1981 1985 1986 1987 1988 1989 1990

134 AN AIDS TIMELINE: The 2nd Decade

GEORGE H.W. BUSH 1989-1993 WILLIAMWILLIAM CLINTON CLINTON 1993 1993-2000-2000

92’ ddl/ddC 93’ d4t Dual NRTI’s HAART ’97: NEL, DLV, Combivir

’95: ’96: NVP, IDV, RIT

’92 AIDS ’96 HIV -’94 leading cause viral load ACTG SCIENCE/CLINICAL of death approved adults 25-44 076 for yrs old PMCT AIDS Deaths Red down 40% Ribbon due to Tony HAART Awards INTERNATIONAL

1991 1992 1993 1994 1995 1996 1997 1998 1999

135 An AIDS Timeline: The 3rd Decade

GEORGE W. BUSH 2001-2008 BARACK H. OBAMA 2009 - Present

’00 ’01 ’03 ‘04 ’05 ‘06 ’07 ’08 ’11 ’12 ’13 Trizivir, Tenofovir Fuzeon Truvada TPV MVC ETV RPV Stribild DRV Complera Kaletra Atripla SCIENCE/CLINICAL

’00 ’04 ’10 ’12 International 13th National PEPFAR: AIDS Int’l HIV/AIDS $15B for Conference AIDS Strategy Conf. HIV/AIDS Washington, over a in ACA passed DC Durban period of 5 South years Africa INTERNATIONAL 25 30 years years

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

136 An AIDS Timeline: The 3rd Decade

BARACK H. OBAMA 2009 - 2017 DONALD J TRUMP 2017-PRESENT

’11 ’13 ‘14 ’15 ’12 ’16 ’17 ’18 ’19 Care RPV Stribild Dolutegravir Odefsey Continuum Triumeq START Descovy Juluca USPSTF Complera Delstrigo Hope Act approved study recs PrEP, Dovato SCIENCE/CLINICAL Biktarvy Symtuza ’12 International AIDS Conference Washington, DC INTERNATIONAL 30 40 years years

2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021

137

139 Chain Termination with NRTIs

If was the last nucleoside to be added, then the RT enzyme can no longer add new nucleosides

(1) Thymidine added, chain (2) Zidovudine added, chain elongation can continue termination occurs

THY ZDV

OH N3 YES NO X

P P P P P P

OH RT enzyme OH RT enzyme NNRTIs Mechanisms of Action

• Non-nucleoside reverse transcriptase inhibitors

• Structurally diverse, hydrophobic molecules

• Inhibit HIV-1 replication (not HIV-2) by binding to RT in a pocket adjacent to the catalytic site; results in the distortion of the key catalytic aspartic acid residues.

• (EFV), (NVP), (ETR), (RPV) and Doravirine

141 Protease is an aspartic protease.

Most PIs are synthetic 53 53 peptide like compounds 54 54 designed to mimic a natural 46 46 dipeptide cleavage site

82 82 84 84 20 20 63 63 10 24 2410 90 90 71 71

142 Integrase Strand Transfer Inhibitors (INSTI’s)

a Linear PIC Viral DNA PIC

Integrase enzyme HO-3-AC CA-3-OH INSTIs TG GT CD4+ T cell cytoplasm LTRs

Nucleus

1 & 2 2-LTRs LTRs Integration

Gap repair

Lataillade & Kozal: AIDS Patient care & STDs, 2006 Entry Inhibitors

• Fusion Inhibitors (FI): T20 - Fuzeon

• Inhibits HIV-1 attachment/fusion by binding to and thus prevents HIV binding to T cell

• CCR5 Inhibitor:

• Inhibits HIV-1 entry through the CCR5 receptor R5 Viruses Dual Viruses X4 Viruses •Utilize the CCR5 co-receptor only •Can utilize both •Utilize the CXCR4 •Prevalent in early disease co-receptors co-receptor only

•Emerge in later disease •Associated with accelerated CD4 T-cell decline

CD4

T cell surface CXCR4 CCR5

145 Berger EA et al, Nature 1998;391:240 HIV-1

gp41

gp120

CD4

CCR5

T cell surface 146 HIV-1

HIV-1 RNA

HIV-1 nucleocapsid

T cell 147 How CCR5 antagonists binds to CCR5 causing a conformational change

CD4

CCR5

CCR5 antagonist

T cell surface 148 DHHS HIV Treatment Guidelines

• Last updated December 18, 2019 • https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandad olescentgl.pdf

149 Goals of Treatment

• Reduce HIV-related morbidity; prolong duration and quality of survival • Restore and/or preserve immunologic function • Maximally and durably suppress HIV viral load • Prevent HIV transmission

15 0 When to Start ART

• Current recommendation: ART for all HIV infected patients is based on START study • START Study opened in March 2011, included 215 sites in 35 countries, enrolled 4685 patients with CD4 over 500. Half started ART immediately and half started when CD4<350. • Measured outcomes of AIDS events, non-AIDS events such as CVD, and death. • The trial was stopped early in March 2015 when analysis showed reduction of 53% in risk for serious illness or death and 70% risk reduction for

AIDs defining illnesses. 15 1 15 2 153 New rec for screening for DM

•2.3 In conditions associated with an altered relationship between A1C and glycemia, such as sickle cell disease, pregnancy (second and third trimesters and the postpartum period), glucose-6- phosphate dehydrogenase deficiency, HIV, hemodialysis, recent blood loss or transfusion, or erythropoietin therapy, only plasma blood glucose criteria should be used to diagnose diabetes. B

Prior guidelines used A1c q 3-6 mos if abnormal, and q12 mos if normal.

154 155 Initial Treatment: Choosing Regimens

• Recommended regimens have comparable efficacies, but vary in pill burden, drug side effects, drug interactions, and propensity to select for resistance if adherence is suboptimal.

• Regimens are tailored for the individual based on: – Pretreatment HIV RNA level – Pretreatment CD4 count – HIV genotypic drug resistance testing – HLA-B 5701 status – Anticipated adherence – Patient comorbidities • CVD, hyperlipidemia, renal disease, osteopenia, psychiatric illness • Pregnancy or its potential • Coinfection with Hep B, Hep C, tuberculosis, cryptococcus – Regimen-Specific Considerations • Regimen’s barrier to resistance • Potential adverse drug effects • Potential drug interactions • Convenience- pill burden, dosing frequency, food requirements 15 6 DHHS Guidelines last updated December, 2019 aidsinfo.nih.gov DHHS Guidelines: Preferred Initial ART

157 DHHS Guidelines – First line ART

INSTI Integrase Inhibitors +

Nucleoside Reverse Transcriptase OR Boosted Inhibitors 2 NRTI PI/r Protease + Inhibitors

OR + Non Nucleoside NNRTI Reverse Transcriptase Inhibitors

158 DHHS Guidelines last updated December,2019 aidsinfo.nih.gov First Line Approved STR

Triumeq Biktarvy

DTG/ABC/3TC BIC/TAF/FTC

• If patient is HBV co-infected  Use TDF/FTC or TAF/FTC • Check HLA B*5701 before the use of • Dolutegravir should not be used in first trimester of pregnancy (Risk for Neural Tubal Defect 0.3%vs. 0.1%) 159 DHHS Guidelines last updated December,2019 aidsinfo.nih.gov DOVATO: ART of 2

• If patient is HBV co-infectedDovato  Need to Use TDF/FTC or TAF/FTC • 3TC/DTG should not be3TC/DTG used for HIV VL >500, 000 copies, if starting before GT or HBV testing is back • Dolutegravir should not be used in first trimester of pregnancy 160 DHHS Guidelines last updated December,2019 aidsinfo.nih.gov DHHS Guidelines last updated December, 2019 aidsinfo.nih.gov DHHS Guidelines: Preferred Initial ART

161 Backbone Drugs (2NRTI’s)

• Abacavir/- ABC/3TC- Epzicom – Pro: Less renal and bone toxicity than TDF/FTC – Con: -- Requires HLA B5701 testing due to hypersensitivity reaction – Has been linked with increased cardiovascular events in some studies – Less effective than TDF/FTC when initial VL>100,000 (not true with dolutegravir) – Not used when CrCl<50 as 3TC must be dose adjusted – Cannot be used in patients with Hep B co- • Tenofovir/- TDF/FTC- Truvada – Pro: -Effective in HBV co-infected patients. -More favorable lipid effects than ABC or TAF

– Con: -Renal toxicity including proximal tubulopathy and AKI -Decreases BMD Not used with CrCl<50 as FTC must be dose adjusted

• /FTC- Descovy – Pro- Effective in HBV co-infected patients - Less renal and bone toxicity than TDF -Can be used with CrCl down to 30

Con- LDL, HDL and TG increase more than with TDF - Associated with weight gain when switched from TDF

162 Integrase Strand Transfer Inhibitors (INSTI’s) • Raltegravir – RAL- (Isentress) – Pro: - Longest experience (2007). – No food requirement – No CYP3A4 interactions

– Con: - Twice daily dosing of 400mg tablet, 400mg – or two 600mg tablets daily » ( FDA approved May 2017) – Lower genetic barrier to resistance than DTG – Increased CK, myopathy and rhabdomyolosis reported * – Absorption reduced by cation containing substances (Al, Ca, Fe, Mg, Zn) * – Rare depression and SI in patients with pre-existing issues* – Insomnia * – Increased weight gain when used with TAF than with other antiretrovirals*

163 INSTI’s

• Dolutegravir- DTG (Tivicay) – Pro: - Once daily – Higher barrier to resistance than EVG or RAL – Comes coformulated with ABC/3TC (Triumeq) – Comes coformulated with RPV (Juluca) – No food requirement – No CYP3A4 interactions.

– Con: - Inhibits renal tubular secretion of Cr and can increase serum Cr without affecting GFR -Increases metformin levels two fold. -Increased risk of neural tube defect

164 INSTI’S CONTINUED

• – Pro: - Once daily – Comes co-formulated with TAF/FTC – Higher barrier to resistance than EVG,RAL, similar to DTG

Con: -diarrhea, headache, fatigue, weight gain

165 166 167 168 169 12/2019 DHHS guidelines: Alternate Regimens in certain clinical situations

170 Genvoya

• TAF/FTC//

• Cons: – Cobi is a strong cytochrome P (CYP) 3A4 inhibitor so it has more drug interactions – ELV has a lower barrier to resistance than dolutegravir or bictegravir – Cobi inhibits tubular secretion of Cr and can increase serum Cr without affecting GFR – Should be taken with food

STRIBILD- TDF/FTC/Elvitegravir/cobi

171 12/2019 DHHS guidelines: Alternate Regimens in certain clinical situations

172 Alternative ART Combinations

INSTI Integrase Inhibitors +

Nucleoside Reverse Transcriptase OR Boosted Inhibitors 2 NRTI PI/r Protease + Inhibitors

OR + Non Nucleoside NNRTI Reverse Transcriptase Inhibitors

173 Boosted PI (DRV/r)

• –DRV- (Prezista) – Pro: - Once-daily dosing – Higher barrier to resistance than NNRTI’s, EVG or RAL

– Con: - 2 pills with boosting with , not coformulated – Skin rash (mild to mod and self-limited) – Food requirement – GI adverse effects – CYP3A4 inhibitor and substrate – DRV has a sulfonamide moiety and should be used with caution in patients with severe sulfa allergies.

174 Alternative Boosted PI’s cont’d

• Darunavir/cobicistat- DRV/c- Prezcobix – Pro: - Once daily dosing and coformulated tablet – Higher barrier to resistance than NNRTI’s, EVG, RAL – PI resistance at time of treatment failure uncommon. – Con: - Skin rash (mild to mod and self-limited) – Food requirement – GI adverse effects – CYP3A4 inhibitor and substrate – DRV has a sulfonamide moiety and should be used with caution in patients with severe sulfa allergies. – Cobi inhibits secretion of CR and can increase CrCl without affecting GFR – Coadministration with TDF not recommended when CrCl<70 – No study comparing actual efficacy of DRV/c to DRV/r

175 PI-Based STR

Symtuza TAF/FTC/DRV/c

176 Symtuza • On July 17, 2018, FDA approved Symtuza: 800mg Darunavir, 150mg cobicistat, 200mg emtricitabine and 10mg tenofovir alafenamide. • Can be used down to Creatinine Clearance of 30mL/min. • Take with food. • Not recommended for pregnant patients. (Must take 600mg DRV, boosted with ritonavir, twice daily. • Not recommended for patients with severe liver impairment (Child-Pugh class C) • Main adverse reactions are diarrhea, rash, nausea, abdominal discomfort and flatulence. • In the EMERALD trial, of 763 Symtuza patients, 53 had archived M184 mutation and all had VL<50 and week 48.

177 Alternative Boosted PI’s • /Ritonavir- ATV/r- (Reyataz/Norvir) – Pro: - Once daily dosing, though 2 pills – Higher barrier to resistance than NNRTI’s, EVG and RAL – PI resistance at time of treatment failure uncommon – Con: -Causes indirect hyperbilirubinemia – Food requirement – Absorption depends on low gastric pH, so must time H2 antagonists, antacids, and PPI’s appropriately – Causes nephrolithiasis, cholelithiasis and nephrotoxicity – Adverse GI effects – CYP3A4 inhibitor and substrate • Atazanavir/Cobi- (Evotaz) – Pro: same as above, plus Coformulated tablet – Con: -same as above, plus cobi increases serum Cr, no decrease in GFR – Coadministration with TDF not recommended if CrCl<70 – Cobi is potent CYP3A4 inhibitor

178 Alternative PI’s

• /ritonavir- LPV/r- Kaletra – Pro: Only RTV-coformulated PI • No food requirement – Con: high rate of GI complaints and diarrhea • requires 200mg/d of RTV • Requires twice daily dosing unless have fewer than 3 lopinavir mutations, then qd (2pills bid) • Possible higher risk of MI than other PI’s • PR and QT prolongation • Nephrotoxicity • CYP3A4 inhibitor and substrate, so drug interactions • - FPV- Lexiva – Pro: DOC contract – Con: Rash • 2 pills twice daily or 2 pills plus ritonavir once daily • Diarrhea • Hepatotoxicity

179 12/2019 DHHS guidelines: Alternate Regimens in certain clinical situations

180 NNRT Based STR

Atripla Complera Odefsey Delstrigo

EFV/TDF/FTC RVP/TDF/FTC RVP/TAF/FTC TAF/3TC/DOR

• If patient is HBV co-infected  Use Truvada or Descovy • Efavirenz should not be used in first trimester of pregnancy • Rilpivirine should not be co-administered with PPI • Rilpivirine should not be used if HIV VL >100,000 copies

181 Non-Nucleoside Reverse Transcriptase Inhibitors • Efavirenz • Rilpivirine • Etravirine • Nevirapine • Doravirine – All have low barrier for resistance, and resistance to all in the class (except ETR and DOR) may occur with a single mutation. A resistance mutation to DOR may confer resistance to other NNRTI’s except ETR. – All are less well tolerated than the Recommended regimens

182 NNRTI’s • Efavirenz- EFV- Sustiva

– Pro: - Once daily dosing – Coformulated with TDF/FTC (Atripla) – Documented efficacy in patients with high HIV VL

– Con: - Transmitted resistance more common than with PI’s and INSTI’s single mutation (K103) -Neuropsychiatric side effects with abnormal dreams, dizziness, depression and suicidality -Teratogenic in nonhuman primates with neural tube defects. Avoid in woman of child bearing age. A suppressed woman who becomes pregnant can continue on it, and it can be started after first trimester. -Decreases AUC of oral contraceptives -Dyslipidemia with elevation in LDL and TG -Skin rash -Potential for CYP450 drug interactions -Should be taken on an empty stomach (food increases absorption and toxicities)

183 NNRTI’s • Rilpivirine- RPV- Edurant – Pro: - Once daily dosing – Coformulated with TDF/FTC (Complera) and TAF/FTC (Odefsey) – Coformulated with DTG (Juluca) – Odefsey and Juluca are smaller than other single pill therapies – Compared to EFV: fewer discontinuations for CNS adverse events, fewer lipid effects, fewer rashes.

– Con: -Not recommended for HIV VL >100,000 or CD4<200 because higher rate of failure • Transmitted resistance more common than with PI’s and INSTI’s • Potential for CYP450 drug interactions • Meal requirement >390Kcal • Requires acid for absorption- so contraindicated with PPI’s, use H2 antagonists or antacids with caution • Depression and suicidality, but less than EFV

184 NNRTI’s • Doravirine – Pro: • available as an STR with DOR/TDF/3TC called Delstrigo • Can be taken with or without food • Generally well tolerated with few adverse effects • Compared in DRIVE-FORWARD study with DRV/r regimen and DOR had superior virologic suppression and less diarrhea, with lower rate of discontinuation. DOR also had lower rise in LDL and TG than DRV/r group.

– Con: • DOR is metabolized by CYP3A4 so should not be coadministered with strong CYP3A4 inducers and its levels may increase in presence of a CYP3A4 inhibitor. It is not a CYP3A4 inducer/inhibitor, like efavirenz is. • Low barrier to resistance and Y188 mutations confers resistance to other NNRTI’s except ETR. • DOR has not been compared directly to INSTI based regimens in trials

185 Characteristics of non-preferred NNRTIs

• Etravirine - ETR- Intelence – Twice per day – Dyslipidemia and lipodystrophy – Rash – Peripheral neuropathy – Hepatotoxicity – CYP450 metabolized, so drug interactions • Nevirapine- NVP- Viramune – High rate of rash. – Hepatotoxicity (may be severe and life-threatening; risk higher in patients with higher CD4 counts at the time they start NVP( >250F, >400M) – Inferior to EFV in studies – CYP450 metabolized, so drug interactions

18 6 12/2019 DHHS guidelines: Alternate Regimens in certain clinical situations

187 188 189 Considerations for Persons of Childbearing Age Updated results have shown that the prevalence of NTDs in infants who were exposed to DTG at the time of conception is lower (0.3%) than reported in the preliminary data, but still higher than in infants who were exposed to ART that did not contain DTG (0.1%).6,7

It is not yet known whether use of other INSTIs around the time of conception also poses a risk of NTDs

Thus far, based on data collected from the Antiretroviral Pregnancy Registry on Raltegravir, no case of NTD has been reported. Among those receiving RAL during pregnancy, the rate of fetal malformations is within the expected range for pregnancy outcomes in the United States.

To enable individuals of childbearing potential to make informed decisions, providers should discuss the benefits and risks of using DTG around the time of conception, including the low risk of NTDs and the relative lack of information on the safety of using other commonly prescribed ARV drugs, including other INSTIs, around the time of conception

For individuals who are trying to conceive, the Panel recommends initiating one of the following regimens, which are designated as Preferred regimens during pregnancy in the Perinatal Guidelines: RAL, ATV/r or DRV/r plus TDF/FTC, TDF/3TC, or ABC/3TC.

For individuals who are not planning to conceive but who are sexually active and not using contraception, consider a regimen’s effectiveness and tolerability, the available data on potential teratogenicity, and the person’s preferences (e.g., low pill burden) when choosing among regimens recommended for initial therapy

For individuals who are using effective contraception, a DTG-based regimen is one of the recommended options; however, clinicians should discuss the risks and benefits of using DTG with patients to allow them to make an informed decision (AIII). • An approach similar to that outlined for DTG should be considered for BIC-containing ART (AIII). • EVG/c should not be used during pregnancy because of inadequate drug concentrations in the second and third190 trimesters (AII). 191 • Pill box • Key chain canister • Set phone alarm for patient Ways to • Clinic pharmacist • Smart phone app improve • adherence service • APNH- uses Pharm Blue to provide meds in adherence Blister packs and delivers to patient with periodic check-ins

192 193 MARAVIROC (Selzentry, 2007)

+ CCR5 antagonist- must do trofile test prior to use to determine if patient’s virus uses CXCR4

+ Dosed twice daily

+ It is a CYP 3A4 substrate, so dose must be adjusted when used with CYP3A4 inducers (rifampin, carbamazepine, phenytoin) or inhibitors (fluconazole, cobicistat)

+ Side effects include diarrhea, nausea, depression, elevated liver enzymes

194 How CCR5 antagonists binds to CCR5 causing a conformational change

CD4

CCR5

CCR5 antagonist

T cell surface 195 Ibalizumab (Trogarzo)

FDA approved in March 2019 to be used in combination with other antiretrovirals in adults with multidrug resistant HIV-1 infection. There is no cross-resistance with other ART classes.

A monoclonal antibody directed against CD-4 domain 2 and acts as a post-attachment HIV-1 inhibitor by interfering with steps required for the HIV to enter host cells. It is effective in CCR5 and CXCR4 tropic strains

By binding to domain 2, it does not cause immunosuppression, as the domain 1 is still available for CD4 binding of MHC molecules and therefore doesn’t interfere with CD4- mediated immune functions.

Administered IV every 2 weeks after an initial loading dose.

Adverse effects include diarrhea, nausea, dizziness and fatigue

As a monoclonal Ab, it has no drug interactions.

196 197 (Rukobia) On July 2, 2020, the FDA approved 600mg fostemsavir tablets for treatment of people living with HIV who have failed other ART therapies due to multi-drug resistance or intolerance.

It is a gp 120 attachment inhibitor- by attaching to the gp 120 protein on the outer surface of HIV, it blocks HIV from attaching to the CD4 receptor on host cells.

It is a prodrug hydrolyzed to active drug called temsavir.

Of patients who had fostemsavir added to their failing ART regimen, 53% achieved viral suppression at 24 weeks, and 60% at 96 weeks.

Nausea was most common adverse effect

Cannot be used with many oral contraceptives or with P450 CYP 3A inducers such as carbamazepine, phenytoin, and rifampin.

198 On the Horizon

• (ISL) is first in class Nucleoside reverse transcriptase translocation inhibitor (NRTTI) in development for treatment and prevention of HIV-1 infection. Data looks promising for it being used with Doravirine as 2 drug maintenance therapy.

• is first in class selective HIV-1 capsid inhibitor in clinical development as part of long-acting ART, oral and SC formulations.

199 200 201 202 203 204 205 https://hivdb.stanford.edu/hivdb/by-mutations/ 206 Case 1

• Ms. B. 32 year old woman who presents for her annual visit • She offers no complaints • She is sexually active with men only and is currently in a monogamous relationship for 1 year • She is on oral contraception and not using condoms • She denies substance use except alcohol on weekend • She works as a school teacher • No history of STI • Her physical exam is normal except dry skin Baseline Laboratory Tests

• HIV Viral Load • Hepatitis A serology • CD4 count • Hepatitis B serology • HIV Genotyping • HCV screening • CBC • STI screening/Syphilis • CMP • PPD or Quantiferon • HLA B*5701 • Toxoplasmosis IgG Case 1

• Ms. B. 32 year old woman newly diagnosed HIV • She is on oral contraception • She is ready to start ART and wants single tablet regimen (STR)

• Her HIV Viral load was 285, 000 copies, no resistance mutations detected • Her CD4 count was 540 cell/dl • She has normal CBC and renal function • She is HLA B5701 negative • She is Hepatitis B immune • She is not planning to get pregnant in the next year

• What would you treat her with? First Line Approved STR

Triumeq Biktarvy Dovato

DTG/ABC/3TC BIC/TAF/FTC 3TC/DTG

DHHS Guidelines last updated December,2019 aidsinfo.nih.gov Case Study 2

• 59 yo man newly diagnosed with HIV, MSM risk factor • Initial CD4= 18, VL=2 million • Smoker, HTN on lisinopril, hyperlipidemia on atorvastatin, depression on Prozac First Line Approved STR

Triumeq Biktarvy Dovato

DTG/ABC/3TC BIC/TAF/FTC 3TC/DTG

DHHS Guidelines last updated December,2019 aidsinfo.nih.gov Case Study #3

• 32 yo man diagnosed in 2009, K103 mutation on initial GT. PMH only positive for h/o syphilis. Transfers to NSC on Truvada/Atazanavir/r with CD4=507, VL UD • Asks for single pill therapy • What would you switch him to? Case 3 cont’d

• He is seen twice in the ED with severe chest pain due to Triumeq being “stuck” in his chest. He is afraid to swallow any big pill now. • What would you switch him to? Case 3 cont’d

• Biktarvy is smaller • www.hivclinic.ca Information on crushing and liquid drug formulations. The end

216