Anti-retroviral Medications PDF

Anti-retroviral Medications Wayne Parker, PharmD 1.Classify anti-HIV drugs based upon their site of inhibition in the viral replication cycle. 2. Learn and Explain the mechanisms of action of each class of anti-HIV drugs. 3. Choose a combination therapy of ART in an HIV-infected individual. 4. Compa...

Anti-retroviral Medications Wayne Parker, PharmD 1.Classify anti-HIV drugs based upon their site of inhibition in the viral replication cycle. 2. Learn and Explain the mechanisms of action of each class of anti-HIV drugs. 3. Choose a combination therapy of ART in an HIV-infected individual. 4. Compare pharmacokinetic properties of each class of anti-HIV drugs. 5. Learn major side effects of each class of anti-HIV drugs. 6. Describe major drug interactions of anti-HIV drugs. 7.Describe the various drug combinations used for the treatment of HIV infections (99% of the time, it’s a 3 drug regimen) 8. Learn facts about cobicistat and ritonavir as “boosters” 9. Learn when to use PrEP and PEP therapy and the regimen prescribed. § Human Immunodeficiency Virus (HIV) is a RNA retrovirus that attacks the immune system § Mainly CD4 T cells § Causing a progressive decrease in the CD4 T cell count § Once CD4 count falls below a critical level § Person becomes more susceptible to opportunistic infections due to the loss of cell mediated immunity § CD4 counts are commonly used to assess the severity of disease § HIV viral loads can also be measured § Used to assess disease progression and possible drug resistance § Antiretroviral therapy (ART) § 3 drug regimen is preferred 2 NRTI – backbone of therapy § Movement to INSTI being preferred 3rd agent in regimen (guideline based) § § Newer guidelines have indicated one, 2 drug regimen as a choice for treatment (lamivudine + dolutegravir; pt must meet certain criteria – see notes section) § Treatment guidelines are quickly changing yearly with the addition of long-acting agents and long-acting formulations and better resistance and safety studies Transmission: 1. Spread through infected blood 2. Semen and vaginal secretions 3. Vertical transmission may also occur, either during pregnancy, at birth, or through breastfeeding Unprotected intercourse and sharing needles with HIV positive individuals are the two most common means of HIV transmission. § Condoms § Monogamous relationship with HIV – negative individual (recently tested) § Last HIV testing that is negative after 6 months from their sexual encounter with another individual Nucleoside Reverse Transcriptase Inhibitors (NRTI) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI) Protease Inhibitor (PI) Abacavir Lamivudine Tenofovir Zidovudine Emtricitabine Didanosine Stavudine Efavirenz Nevirapine Delavirdine Relpivirine AtazaNAVIR Enfuvirtide maraviroc ritoNAVIR ampreNAVIR indiNAVIR lopiNAVIR nelfiNAVIR saquiNAVIR Etravirine End in “NAVIR” FosampreNAVIR DaruNAVIR TipraNAVIR Fusion Inhibitor CCR5 Integrase Receptor Strand Antagonist Transfer Inhibitors (INSTI) End in “GRAVIR” Raltegravir Dolutegravir Bictegravir Elvitegravir Cabotegravir TENOFOVIR EMTRICITABINE § ****Most common time you will see only 2 antiretrovirals used (all other instances – at least 3 used) § Pre-exposure prophylaxis, or PrEP, is a way for people who do not have HIV (must be HIV negative before starting) but who are at substantial risk of getting it to prevent HIV infection by taking a pill every day. § When someone is exposed to HIV through sex or injection drug use, these medicines can work to keep the virus from establishing a permanent infection. § When taken consistently, PrEP has been shown to reduce the risk of HIV infection in people who are at high risk by up to 99%. (74% protection in persons who inject drugs) § People who use PrEP must commit to taking the drug every day and seeing their health care provider for follow-up every 3 months. § Once PrEP is initiated DAILY, follow up visits are needed every 2-3 months recommending § HIV Test and pregnancy test § Every other visit: check SCr and for bacterial STDs § The decision to initiate depends on the person’s risk of acquiring HIV § PrEP can reduce the risk of HIV transmission by > 99% § Populations where PrEP has shown a reduction in HIV transmission (candidates for PrEP): Any person who has a sexual partner with HIV and a detectable viral load 2. Men who have sex with men (MSM) and transgender women who do not use protection during sex and/or had a documented sexually transmitted infection 3. Heterosexual active persons who have sex with partners who are at high risk (high HIV prevalence areas and partners who inject drugs) 4. Persons who inject drugs 1. § Undetectable = Untransmissible § People living with HIV who achieve and maintain an undetectable viral load by taking and adhering to ART cannot sexually transmit the virus to others § HPTN 052 and PARTNER and Opposites Attract clinical studies § What does this mean? ART therapy as a prevention measure 2. If your partner has HIV and has undetectable viral load on ART therapy, then they are not considered high risk and PrEP is not needed 1. § Truvada ® § Emtricitabine & tenofovir disoproxil fumarate § Most recommended and preferred, most studied in diverse populations § Once daily § Can not use in pts with < 60 GFR § Descovy ® § Emtricitabine & tenofovir alafenamide § Once daily or “on demand” (before and after sex) § Use “2-1-1” method of dosing § Can not use in pts with < 30 GFR § Apreptude ® § Long-acting IM cabotegravir § IM injection every 2 months § May be used regardless of renal fxn § Main ADRs associated with PrEP: § Mild, mostly N/V § Severe: Bone toxicity (tenofovir) has been associated with long term use § Highly suggest reading pages 7-14 of the following link if you would like a little more clinical reinforcement of PrEP § https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-provider-supplement- 2021.pdf § PrEP does not have to continue indefinitely § Continue as long as risk of infection with their main or nonmain partner persists § May d/c once partner with HIV has initiated ART and has achieved a stable suppressed viral load (typically 6 months) § This is only for main partner § Continue PrEP is still having condomless sex with other partners or if there is a risk of virologic failure with partner (noncompliance) § If decision to d/c oral PrEP, continue for 2 days to 1 month after last sexual encounter § Depends on certain populations § If you’re HIV-negative or don’t know your HIV status, and in the last 72 hours you § think you may have been exposed to HIV during sex (for example, if the condom broke), § shared needles and works to prepare drugs (healthcare workers) or § were sexually assaulted § Begin within 72 hours for maximum effectiveness (goal is 1-2 hours) § Take daily for 28 days § Treatment § Regimen of choice à tenofovir with emtricitabine PLUS (bictegravir or dolutegravir) § INSTI based § May use either formulation of tenofovir bc the short duration of therapy § Alternative regimen tenofovir with emtricitabine plus [darunavir with ritonavir] § PI based § D/C if testing shows the source pt is HIV negative § With continuous antiretroviral therapy (ART) and viral suppression, most people with HIV achieve a life expectancy close to that of people without HIV § However, mortality gap primarily due to CV disease and cancer § REPRIEVE trial: showed people with HIV aged 40 – 75 taking ART on pitavastatin showed 35% reduction in major CV events following a 5 year period § Recommendation: Age 40 – 75 yo on ART therapy § Moderate – high intensity statin therapy § You do not need to know for exam or boards § Lenacapavir approved December 2022 § MOA: First-in-class HIV capsid inhibitor § Use: in combination with other ARV drugs for the treatment of heavily treatment-experienced adults with multidrugresistant HIV-1 injection § You do not need to know for exam or boards § New discussions regarding d/c or interruption of long-acting antiretrovirals drugs including ibalizumab and IM formulations of cabotegravir and rilpivirine § Recommendations regarding concomitant use of fostemsavir or long acting cabotegravir plus rilpivirine with different hepatitis C treatment regimens § Prior guidelines have pushed raltegravir because of ADRs of dolutegravir but current clinical trials have demonstrated better safety with dolutegravir so dolutegravir is now preferred over raltegravir § December 20, 2021 – FDA approved extended release cabotegravir, a long- acting injectable option for HIV pre-exposure prophylaxis § Do not need to know for test or boards § Long-acting cabotegravir and rilpivirine regimen in persons with HIV § First long-acting injectable (IM) regimen approved; once monthly § Cabotegravir – INSTI § Rilpivirine - NNRTI § Can be used as an optimization strategy for people with HIV currently on oral antiretroviral therapy (ART) with documented viral suppression for at least 3 months § Should receive oral cabotegravir and oral rilpivirine for 28 days as an oral lead-in period to asses tolerance to the drugs § Treatment as prevention (TasP) – The strategy used when ART is used to prevent HIV transmission. ART, when used appropriately, can consistently suppress plasma HIV RNA levels to < 200 copies/mL. This prevents transmission of HIV to sexual partners. Commonly known as undetectable = untransmittable (U = U) § New section to help providers integrate TasP into their clinical practice § Providers should inform persons with HIV that maintaining HIV RNA levels < 200 copies/mL with ART prevents HIV transmission to sexual partners § Persons starting ART should use another form of prevention with sexual partners for at least the first 6 months of treatment and until an HIV RNA level of < 200 copies/mL has been documented § Persons with HIV who rely on ART for prevention need to maintain high levels of ART adherence. Periods of poor adherence could result in transmission § HIV RNA level < 200 copies/mL does not prevent spreading or acquisition of other STDs § Dolutegravir and pregnancy § Dolutegravir may produce neural tube defects in infants born to women who received it § Old guidelines said to avoid; updated says to use with caution (risk vs benefit) § 2 drug-regimen (dolutegravir & lamivudine) added to recommended initial regimens for most people (except HIV RNA > 500, active Hep B coinf, without genotyping) § Shown by 2 large, randomized controlled trials showing this regimen non-inferior to DTG/tenofovir/embricitabine WHICH DRUGS DO WE CHOOSE? §Choose with care and tailor to individual §Important Factors in choosing a regimen §Potency §Susceptibility (Resistance) § Should be done at initiation of therapy or if treatment failure §Tolerability §Convenience § Pill burden (QDay, BID, TID, QID) §Optimization of adherence (pill burden) § Patient’s co-morbid conditions and degree of organ dysfunction § Liver disease, kidney disease, current medications (drug interactions) § Impact of factors related to regimen itself § Pill burden, pill size, potential for drug interactions, food/fasting requirements, side effects, drug resistance § Drug availability and cost § Plasma HIV RNA level (viral load) and CD4 cell count § Susceptibility of virus to antiretroviral therapy § If considering abacavir, testing for HLA-B*5701 § Individuals with this allele are at risk of developing severe hypersensitivity reaction § Pregnancy; Test for pregnancy upon initiation in all child bearing women YES! § Combination therapy with maximally potent agents will 1. reduce viral replication to the lowest possible level and 2. decrease likelihood of emergence of resistance § HIV drug resistance testing is recommended at entry into care to guide selection of initial ART § Standard of care is at least 3 antiretrovirals § Emphasis on monotherapy with any antiretroviral drug should not be used § Therapy is called Antiretroviral Therapy (ART) The Panel on Antiretroviral Guidelines for Adults and Adolescents recommends initiating ART immediately (on same day as diagnosis) (or as soon as possible) after HIV diagnosis in order to increase the uptake of ART and linkage to care, decrease the time to viral suppression for individual patients, and improve the rate of virologic suppression among persons with HIV (AII). § Primary goal: prevent HIV-associated morbidity and mortality and prolong the duration and quality of survivial § Suppress HIV multiplication § Goal is to have no detectable virus in the blood for as long as possible § Improve quality of life § Preserve future treatment options by using a regimen (decrease resistance) § Restore immune function § Goal to have T-cell count increase by 100 to 200 cells/microL during first few years and then remain high § The magnitude of CD4 recovery is directly correlated with CD4 count at ART initiation § Prevent HIV transmission to others § Treatment regimen that suppresses HIV but is also “patient friendly” in terms of tolerance and patient preference (# pills, pill size, frequency of admin) § Pregnancy § AIDs-defining conditions, including HIV-associated dementia (HAD) and AIDs- associated malignancies (Kaposi’s sarcoma, Hodgkin’s disease, non-Hodgkin’s lymphoma) § Acute opportunistic infections (OIs) § Cryptosporidiosis, PCP, MAC, TB, Toxoplasmosis, Candida inf § Caution: immune reconstitution syndrome (IRIS) may occur § Lower CD4 counts ( 200 cells/microL § Higher rates of failure have been seen in pts with viral load > 100,000 copies/mL § Approved in 2021 as a long-term injectable with cabotegravir § Pharmacokinetics § Gastric acid and food are required for optimal absorption § Drugs that alter gastric pH (proton pump inhibitors) may impair absorption of relpivirine § Side effects § Neurologic and psychiatric side effects similar to efavirenz but less common PROTEASE INHIBITORS (PI) All end in “NAVIR” § All – metabolic ADRs (metabolic - similar to 2nd gen antipsychotics) § Hyperglycemia/Insulin Resistance § Lipodystrophy (fat redistribution) § GI intolerance § Dyslipidemia § Hepatitis § Immune Reconstitution Syndrome § CYP substrates and inhibitors § Atazanavir § PR interval prolongation, hyperbilirubinemia, rash, nephrolithiasis § Ritonavir is a potent inhibitor of CYP3A4 (“booster”) § Altered taste, PR prolongation, N/V/D § Will see a protease inhibitor “boosted” by ritonavir written like this: § Darunavir/r (darunavir is “boosted” with ritonavir) 59 PROTEASE INHIBITORS (PI) § Mechanism of Action § Prevent cleavage of precursor molecules associated with structural proteins of mature virion core (one of last steps in HIV replication) § Protease Inhibitors bind to aspartate protease – a viral enzyme that cleaves precursor polypeptides in HIV buds § Results in production of immature, noninfectious viral particles § Resistance is common à monotherapy is contraindicated § Indication § Component of ART in treatment of HIV infection PROTEASE INHIBITORS (PI) § Common Drug Interactions § All protease inhibitors are substrates of CYP3A4 § Some protease inhibitors are CYP3A4 inhibitors § Amprenavir, indinavir, lopinavir, ritonavir § Decrease clearance of other drugs § Do not give these with drugs that are heavily metabolized by CYP3A4 § Ritonavir § Low, subtherapeutic doses can still cause CYP3A4 inhibition § Used in combination with other PI to act as “PI booster” § This increases efficacy, reduces number of daily doses, and increases compliance § Rules § Take with food! § Give with ritonavir or cobicistat § Advantage over other PI § Better GI tolerance § Not associated with development of insulin resistance § Disadvantages § Need for gastric acid and food for optimal absorption § Avoid concomitant use with medications that alter gastric pH (ex. Proton pump inhibitors, H2 antags, antacids) § Space out before or after § Drug interaction § When given with omeprazole, absorption of atazanavir is decreased by 76% (contraindicated together) § Atazanavir is CYP3A4 inhibitor and CYP2C9 inhibitor § Do not administer with tenofovir and efavirenz (unless ritonavir is given concomitantly) § Side Effects § Peripheral neuropathy, rash, N,V,D,HA, abdominal pain § Atazanavir inhibits hepatic (UGT1A1) glucuronidation enzyme à indirect hyperbilirubinemia with over jaundice in 8% of patients § NOT associated with dyslipidemia, fat redistribution, metabolic syndrome § May cause PR prolongation and concentration dependent increase in QT § Especially if taken with CYP3A4 inhibitor like clarithromycin § Pharmacokinetics § Once daily dosing § Take with light meal to enhance bioavailability (requires acid pH for absorption) § Separate from any medication that reduces acid secretion by 12 hours § Indication Co-administer with ritonavir or cobicistat Appears to be best tolerated PI § Side Effects § D,N,HA,skin rash, dyslipidemia, liver toxicity, § Discontinue if develop a rash associated with fever, transaminase elevations, eosinophilia, and severe skin reactions (SJS/TEN) § Contraindications § Patients allergic to sulfa § Has a sulfonamide side group § Do not use in § Patients with severe liver disease § Pharmacokinetics § Metabolized and inhibitor of CYP3A § Drug Interactions § CYP3A4 inhibitors § Indication § It is a Protease Inhibitor but full dose as a PI causes significant adverse effects § Instead, a low dose or sub-therapeutic dose is given as a “booster” § Subtherapeutic doses of ritonavir inhibit CYP3A4 metabolism of other NAVIR drugs (protease inhibitors) à increased concentration of NAVIR drugs § Combination provides potent viral suppression and prevents emergence of resistance § Combination improves patient compliance by decreasing pill burden by lowering dose of parent drug à pharmacokinetic boosting § Improve trough serum drug concentrations, increase drug half lives, and boost C Max § Side Effects § D,N,abdominal pain, asthenia § Pharmacokinetics § Lopinavir is metabolized by CYP3A § Drug Interactions § CYP3A4 inducers will decrease levels of lopinavir (St. John’s wort, phenytoin, phenobarbital, rifampin, dexamethasone, carbemazepine § Black Box Warning § Contraindicated in children < 4 years old & pregnancy (excipient propylene glycol) § Side Effects § Perioral paresthesias, depression, rash (3%) § Pharmacokinetics § Rapid GI absorption § High fat meals may decrease absorption and should be avoided § Substrate and inhibitor of CYP3A4 § Fosamprenavir is hydrolyzed in GI tract to amprenavir – (prefer due to lower pill burden) § Drug Interactions § Contains propylene glycol – contraindicated with metronidazole and disulfuram § Other CYP3A4 inducers § Contraindications § Hepatic insufficiency § Side Effects § Not soluble in urine à crystallization of drug in urine à kidney stones (3-15%) à renal failure & indirect hyperbilirubinemia § Nephrolithiasis § Pharmacokinetics § Empty stomach for maximal absorption § Highest CSF penetration of all PI (76% of serum levels) § Dosage adjustment necessary in hepatic insufficiency § Substrate and inhibitor or CYP3A4 § Drug Interactions § Indinavir is a substrate and inhibitor of CYP3A4 § Indinavir levels decrease with rifampin, fluconazole, St, John’s wort § Indinavir levels increase with delaviridine, ketoconazole, itraconazole à decrease dose when give together § Rules for administration § Take with at least 48 ounces of water daily § Side Effect § Diarrhea & flatulence § Pharmacokinetics § Absorption is increased 2 to 3 fold when taken with food § Metabolized by CYP3A and inhibitor of CYP3A § Drug Interactions § CYP3A inhibitors (same classwide) § Black Box Warning § Cardiac Arrhythmia risk when combined with ritonavir (prolong PR and QT interval, Torsade de pointes) § Pharmacokinetics § Taken within 2 hours of a fatty meal to enhance absorption § Extensive first pass metabolism by CYP3A4 § CYP3A4 substrate and inhibitor § Combination with ritonavir has increased efficacy and decreased GI side effects § Drug Interactions § Other CYP3A4 inducers and metabolizers (avoid with statins, rifampin, St. John’s wort) § Co-administration with ritonavir (risk versus benefit) § Cardiac arrhythmia risk versus higher and more efficacious levels achieved § Co-administration with nelfinavir à decrease dose of saquinavir § Co-administration with dalavirdine or rifampin à monitor liver function tests § Co-administration has been adopted by most clinicians à reduction in daily dose and frequency of administration INTEGRASE STRAND TRANSFER INHIBITOR (INSTI) all end in “GRAVIR” § N/V/D § Insomnia § Muscle weakness and rhabdomyolysis (increase creatine kinase) § Rash § Note: the relative less severity compared to other antiretrovirals and less drug interactions = generally preferred first choice 3rd agent § Note: elvitegravir requires “boosting” with cobicistat (think of cobicistat (not a statin) similar to ritonavir but it has no inherent antiviral activity) § Mechanism of Action § Binds integrase (viral enzyme essential for replication of both HIV-1 and HIV-2) preventing integration of viral genome in host cell DNA 73 § Indication § Treat HIV patients resistant to multiple other drugs § Pharmacokinetics § Metabolized by glucuronidation (no cyp drug interactions) § Side Effects § N,D,HA, increase in creatinine phosphokinase § Drug Interactions § Rifampin co-administration can reduce levels of raltegravir (inhib gluc) § Antacid and medications with cations (Ca, Mg,Fe) can interfere with absorption § Notes § Resistance only requires a single point mutation § Does not require “boosting” § Fewer significant drug interactions § Unlikely to develop drug-resistant virus § Caution in pregnancy § Used as long-acting injectable (along with rilpivirine) § IM once monthly § Not to be used in ART naïve patients § Only to be used as a replacement for stable oral therapy in patients with viral suppression § ADRS: § Insomnia, psychiatric/mental disorders, weight gain § Requires “boosting” with cobicistat FUSION INHIBITOR & CCR5 ANTAGONISTS Fusion inhibitors - enfuvirtide CCR5 antagonist - maraviroc § Mechanism of Action § Blocks entry of virus into cells (outside of cell mechanism) by binding to gp41 subunit of viral envelope glycoprotein § Prevents conformational changes required for fusion of viral and cellular membranes § Indications § Treatment-experienced patients with persistent HIV-1 replication despite ongoing therapy § Side Effects § Injection site reactions, hypersensitivity, eosinophilia § Pharmacokinetics § Administered subQ (tide) in combination therapy § Mechanism of Action § Binds selectively to CCR5 co-receptor necessary for HIV entrance (outside of cell mechanism) into CD4+ cells § Indication § Combination with other meds for treatment –experienced adult patients infected with CCr50tropic_HIV-1 § Must undergo screening test (trofile) to determine if HIV is CCR5-tropic disease § Pharmacokinetics § CYP3A4 substrate and requires dosage adjustment with drugs that interact with CYP3A4 § Black Box Warning § Hepatotoxicity § Side Effects § Cough, RTI, muscle pain, diarrhea, rash (including SJS) § Notes § Treatment not established in treatment-naïve adult patients and pediatric patients TREATMENT GUIDELINES IN PREGNANCY § Pregnancy test to all individuals starting ART therapy § Multiple factors must be considered when choosing an antiretroviral (ART) drug regimen for a pregnant woman, including comorbidities, convenience, adverse effects, drug interactions, resistance testing results, pharmacokinetics (PK), and experience with use in pregnancy. § In general, the same regimens as recommended for treatment of non-pregnant adults should be used in pregnant women if appropriate drug exposure is achieved in pregnancy, unless there are known adverse effects for women, fetuses, or infants that outweigh benefits. § In most cases, women who present for obstetric care on fully suppressive ART regimens should continue their current regimens. TREATMENT GUIDELINES IN PREGNANCY DURING LABOR AND DELIVERY § Most transmissions occur during labor & delivery § Continue antepartum combination antiretroviral therapy (ART) drug regimen on schedule as much as possible during labor and before scheduled cesarean delivery § ADD Intravenous (IV) zidovudine to HIV-infected women with HIV RNA >1,000 copies/mL (or unknown HIV RNA) near delivery § Scheduled cesarean delivery at 38 weeks’ gestation is recommended for women who have HIV RNA >1,000 copies/mL § Newborn should take liquid zidovudine every 6 hours for 4-6 weeks after birth § Begin within 6 to 12 hours after birth § It has inherent antiretroviral activity § Used as a smaller dose as a “boosting” agent for only the protease inhibitor antiretroviral drugs § How you will see it written § Example: darunavavir/r § This means darunavir is “boosted” with ritonavir. Ritonavir is inhibiting darunavir’s metabolism so there will be higher concentrations of darunavir in the body. § A component (as a pk enhancer) of a recommended initial regimen in ART- naïve patients § Mechanism of action – without inherent antiretroviral activity § Pharmacokinetic Enhancers (CYP3A Inhibitors) § Indication § As a pharmacokinetic enhancer of atazanavir or darunavir (once daily dosing regimen), in combination with other antiretroviral agents in the treatment of HIV-1 infection § Approved 9/24/14 § Similar to ritonavir but no antiviral activity § Side effects § Modest increase in serum creatinine (renal function) by inhibiting tubular secretion of creatinine § Significant drug interactions § Used to “Boost” PI and elvitegravir AIDSinfo: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf The Move Toward Lower Pill Burdens Regimen Dosing 1996 Zerit/Epivir/Crixivan 10 pills, Q8H 1998 Retrovir/Epivir/Sustiva 5 pills, BID 2002 Combivir (AZT/3TC)/EFV 3 pills, BID 2003 Viread/ Emtriva/Sustiva 3 pills, QD 2004 Truvada/Sustiva 2 pills, QD Daily pill burden DO NOT MEMORIZE! Zidovudine Didanosine Zalcitabine Stavudine lamvudine -Hematotoxicity (major) -Headache -Asthenia -Myalgia -Myopathy -Peripheral neuropathy -peripheral neuropathy (major) -GI distress -pancreatitis -neutropenia -rash -peripheral neuropathy (major) -myelosupression -least toxic -GI side effects -neutropenia -active in hepatitis B -Pancreatitis(major) -Pripheral neuropathy -Hyperuricemia -Liver dysfunction Drug Class Advantage Disadvantage NNRTI -long half lives -greater risk of resistance at time of treatment failure than with PI -potential for cross resistance -skin rash -potential for CYP450 drug interactions -transmitted resistance more common than with PI PI -higher genetic barrier to resistance than NNRTI and RAL -PI resistance at the time of treatment failure uncommon with ritonavir boosted PIs -metabolic complications such as dyslipidemia, insulin resistance, and hepatotoxicity -GI adverse effects -CYP3A4 inhibitors and substrates; potential for drug interactions (more pronounced with ritonavir-based regimens) Integrase inhibitors Virologic response noninferior to EFV; superior at 4–5 years Fewer drug-related adverse events and lipid changes than with EFV No food effect Fewer drug-drug interactions than with EVG/COBI/TDF/FTC-, PI-, NNRTI-, or MVC-based regimens Virologic response noninferior to EFV; superior at 4–5 years Fewer drug-related adverse events and lipid changes than with EFV No food effect Fewer drug-drug interactions than with EVG/COBI/TDF/FTC-, PI-, NNRTI-, or MVC-based Regimens CCR5 antagonist Virologic response noninferior to EFV in post hoc analysis of MERIT study (see text) Fewer adverse effects than EFV Requires viral tropism testing before initiation of therapy, which results in additional cost and possible delay in initiation of therapy In the MERIT study, more MVC-treated than EFV-treated patients discontinued therapy due to lack of efficacy Less long-term experience in ART-naive patients than Cytokine (interleukin) Secreted by Th1 CD4 cell Stimulates CD8 cytotoxic T lymphocytes Increases proliferation and maturation of CD4 cells §Indication §Produced by recombinant DNA technology §Treatment for metastatic renal cell cancer §Investigational Use with antiretroviral medications §Given subQ §Potential to halt progression of HIV disease by maintaining and individual’s CD4+ T cell count in normal range for prolonged periods of time § 12/31/2012 Approval of Fulyzaq (crofelemer) to relieve symptoms of diarrhea in HIV/AIDS patients taking antiretroviral therapy § 07/23/2012 More than 150 antiretroviral drugs available through PEPFAR for worldwide HIV/AIDS relief § 07/16/2012 Truvada approved to reduce the risk of sexually transmitted HIV in people who are not infected with the virus § 07/03/2012 Approval of first In-Home rapid HIV antibody test kit § First generic medication § PRO – Cheaper save $4,000 a year savings per patient § USA - $920 million on its annual drugs bill § CON – higher pill burden 3 X daily versus once a day § Labelling Changes -9 § New Formulations – 2 § New Combinations – 9 § New rules – 2 § New Guidance for Industry Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment § FDA announces Public Meeting on HIV Patient-Focused Drug Development and HIV Cure Research § New drugs – Tivicay (dolutegravir), a new drug to treat HIV-1 infection approved § 08/08/2013 First rapid diagnostic test to detect both HIV-1 antigen and HIV-1/2 antibodies approved §Following this review, and taking into account the recommendations of advisory committees to the U.S. Department of Health and Human Services (HHS) and the FDA, the agency will take the necessary steps to recommend a change to the blood donor deferral period for men who have sex with men from indefinite deferral to one year since the last sexual contact. §More combination products ! §FDA is posting a Snapshot of six new molecular entities (NMEs) that were approved by FDA between May and June 2014. §Revised HHS Adult and Adolescent Antiretroviral Treatment Guidelines available §Drug labelling changes §New Drug interactions §Atazanavir pediatric dosage form §More combination products ! § We changed recommendation of when to begin ART therapy § We now begin ART therapy for all patients at diagnosis instead of waiting until CD4 count is < 500 § We began PrEP and PEP therapy § We changed medication regimen of PEP therapy § We changed when and in whom to initiate PrEP therapy § Changes in treatment during pregnancy § Dolutegravir not indicated in women who are pregnant or of childbearing age § Bectegravir now recommended therapy § CD4 directed post-attachment HIV-1 inhibitor approved (ibalizumab) § More and more brand names are becoming generic which eases the cost for patients = increase compliance