This document discusses integrase inhibitors for the treatment of HIV. It summarizes clinical trials comparing the integrase inhibitors raltegravir, elvitegravir, and dolutegravir to efavirenz and atazanavir/ritonavir in treatment-naive patients. The studies found integrase inhibitors were as effective as or better than comparators in suppressing HIV, with fewer side effects. Raltegravir given once daily was inferior to twice daily dosing. Elvitegravir/cobicistat was found to be noninferior to efavirenz and atazanavir/ritonavir through 144 weeks.
This document discusses immunomodulators, which are drugs that either suppress (immunosuppressants) or enhance (immunostimulants) the immune system. It describes several classes of immunosuppressants including calcineurin inhibitors like cyclosporine and tacrolimus, antiproliferative agents like azathioprine, mTOR inhibitors like sirolimus, glucocorticoids like prednisolone, and biologics like infliximab. Their mechanisms of action, uses, and adverse effects are summarized. Immunostimulants discussed include levamisole, thalidomide, BCG vaccine, and interferons.
Vinca Alkaloids as Anticancer Agents (Looking back and peering ahead)Mohammad Abrar Khan
This document discusses Vinca alkaloids, which are anti-cancer agents originally isolated from the Madagascar periwinkle plant. It covers the structure, mechanism of action, applications, and total synthesis of major Vinca alkaloids like vinblastine and vincristine. The document also summarizes emerging vinblastine-related compounds through modifications to the catharanthine and vindoline nuclei. Finally, it discusses drug targeting approaches for Vinca alkaloids like conjugating vinblastine to folic acid to selectively target cancer cells overexpressing folate receptors.
The document provides information about urinary tract infections (UTIs). It discusses the epidemiology, etiology, signs and symptoms, pathogenesis, classification, and treatment of UTIs. It notes that UTIs are commonly caused by bacteria like E. coli and can affect the kidneys (pyelonephritis), bladder (cystitis), or urethra (urethritis). Common signs include pain or burning during urination. Treatment involves antibiotics like sulfonamides, nitrofurantoin, fluoroquinolones, and cephalosporins which can be bacteriostatic or bactericidal.
This document discusses two classes of protein synthesis inhibitors - tetracyclines and chloramphenicol. It provides details on their mechanisms of action, classifications, spectra of activity, pharmacokinetics, clinical uses, resistance, side effects and interactions. Tetracyclines are classified based on source and duration of action. They inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit. Chloramphenicol also inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. Both classes have broad-spectrum activity and are associated with various side effects.
classification of antiviral agents,replication of HIV virus and replication of virus.targets of virus,classification of antiviral agents with structure and mechanism action of antiviral agents
Amoebiasis is an infection with Entamoeba histolytica produced by the ingestion of cysts of this organism. Amoebiasis can be asymptomatic or can lead to severe, life-threatening dysentery. The organism exists in two forms, the motile trophozoite form or the dormant cyst form.
In the intestine, the cysts develop into trophozoites that adhere to colonic epithelial cells by means of lectin on the parasitic membrane, which has similarity to the host adherence proteins.
The trophozoite then lyses the host cell (hence histolytica) and invades the submucosa, where it may secrete a factor that inhibits IFNY- activated macrophages, which would otherwise kill it. These processes may result in dysentery
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
This document discusses immunomodulators, which are drugs that either suppress (immunosuppressants) or enhance (immunostimulants) the immune system. It describes several classes of immunosuppressants including calcineurin inhibitors like cyclosporine and tacrolimus, antiproliferative agents like azathioprine, mTOR inhibitors like sirolimus, glucocorticoids like prednisolone, and biologics like infliximab. Their mechanisms of action, uses, and adverse effects are summarized. Immunostimulants discussed include levamisole, thalidomide, BCG vaccine, and interferons.
Vinca Alkaloids as Anticancer Agents (Looking back and peering ahead)Mohammad Abrar Khan
This document discusses Vinca alkaloids, which are anti-cancer agents originally isolated from the Madagascar periwinkle plant. It covers the structure, mechanism of action, applications, and total synthesis of major Vinca alkaloids like vinblastine and vincristine. The document also summarizes emerging vinblastine-related compounds through modifications to the catharanthine and vindoline nuclei. Finally, it discusses drug targeting approaches for Vinca alkaloids like conjugating vinblastine to folic acid to selectively target cancer cells overexpressing folate receptors.
The document provides information about urinary tract infections (UTIs). It discusses the epidemiology, etiology, signs and symptoms, pathogenesis, classification, and treatment of UTIs. It notes that UTIs are commonly caused by bacteria like E. coli and can affect the kidneys (pyelonephritis), bladder (cystitis), or urethra (urethritis). Common signs include pain or burning during urination. Treatment involves antibiotics like sulfonamides, nitrofurantoin, fluoroquinolones, and cephalosporins which can be bacteriostatic or bactericidal.
This document discusses two classes of protein synthesis inhibitors - tetracyclines and chloramphenicol. It provides details on their mechanisms of action, classifications, spectra of activity, pharmacokinetics, clinical uses, resistance, side effects and interactions. Tetracyclines are classified based on source and duration of action. They inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit. Chloramphenicol also inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. Both classes have broad-spectrum activity and are associated with various side effects.
classification of antiviral agents,replication of HIV virus and replication of virus.targets of virus,classification of antiviral agents with structure and mechanism action of antiviral agents
Amoebiasis is an infection with Entamoeba histolytica produced by the ingestion of cysts of this organism. Amoebiasis can be asymptomatic or can lead to severe, life-threatening dysentery. The organism exists in two forms, the motile trophozoite form or the dormant cyst form.
In the intestine, the cysts develop into trophozoites that adhere to colonic epithelial cells by means of lectin on the parasitic membrane, which has similarity to the host adherence proteins.
The trophozoite then lyses the host cell (hence histolytica) and invades the submucosa, where it may secrete a factor that inhibits IFNY- activated macrophages, which would otherwise kill it. These processes may result in dysentery
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
A loading dose is an initial higher dose of a drug given at the beginning of treatment to more rapidly reach steady state plasma concentrations. Drugs with long half-lives benefit from a loading dose to quickly achieve therapeutic drug levels. The loading dose should approximate the amount of drug in the body at steady state. The main importance of a loading dose is to attain the average plasma concentration at steady state as quickly as possible to provide quick therapeutic effects in some cases.
Herb drug and herb food interaction ppt by nitesh kumarNITESH KUMAR
HERB DRUG AND HERB FOOD INTERACTION IS AN IMPORTANT CHAPTER IN HERBLA DRUG TECHNOLOGY IN THE SYLLABUS OF B.PHARMACY 6TH SEM. IT GIVES A BETTER UNDERTANDING OF HERB FOOD INTERACTION AND RELATED DRUGS.
The document discusses drugs used to treat sexually transmitted infections. It begins by defining key terms like venereal disease, sexually transmitted disease, and sexually transmitted infection. It then covers the etiological classification of STIs, listing the causative organisms for various conditions. The majority of the document discusses treatment for specific STIs, including drugs, doses, and regimens used to treat infections like syphilis, gonorrhea, chlamydia, herpes, and HIV/AIDS. It also covers the syndromic approach for STI treatment, which classifies infections according to clinical manifestations and recommends therapy using clinical algorithms.
Vincristine is an antitumor alkaloid isolated from Vinca rosea that is used to treat various cancers. It works by inhibiting cell division through interaction with tubulin, which arrests mitosis. Common side effects include neuropathy, infection risk, and hair loss. Vincristine is administered intravenously and distributed widely through the body, where it remains tightly bound, before being metabolized in the liver and excreted primarily in feces.
This document discusses anti-amoebic drugs used to treat amoebiasis, an infection caused by Entamoeba histolytica. It classifies anti-amoebic drugs according to where they act - luminal, systemic, or mixed. Metronidazole is discussed as a common broad-spectrum antibiotic effective against both luminal and systemic amoebiasis. It is absorbed and metabolized in the liver, with potential adverse effects like nausea. Nurses monitor for drug interactions and side effects. Paromomycin is a luminal-only antibiotic that acts against E. histolytica in the intestines.
This document summarizes HIV infection and treatment. It describes how HIV was identified in the 1980s as the cause of AIDS. HIV can be transmitted through bodily fluids. Left untreated, HIV weakens the immune system and allows opportunistic infections. Treatment aims to suppress the virus and restore immune function. Highly Active Antiretroviral Therapy (HAART) uses a combination of three antiretroviral drugs from two classes to control the virus. Guidelines recommend starting treatment based on CD4 count. The goals of treatment are to improve quality of life and prevent disease progression.
This document discusses chemotherapy for tuberculosis, including first-line and second-line antitubercular drugs. It describes the classification, mechanisms of action, pharmacokinetics, and adverse effects of isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin as first-line drugs. It also mentions that the goals of antitubercular chemotherapy are to kill dividing bacilli, kill persisting bacilli, and prevent emergence of drug resistance. The document assigns discussing the mechanisms, adverse effects, and uses of second-line drugs including kanamycin, amikacin, capreomycin, fluoroquinolones, and ethionamide.
Cyclophosphamide is an alkylating agent used to treat white blood cell cancers and lymphoma. It works by being metabolized into phosphoramide mustard, which adds alkyl groups to DNA, forming crosslinks between and within DNA strands. This leads to DNA damage and ultimately cell death. The expression of genes coding for enzymes involved in cyclophosphamide metabolism, such as cytochrome P450 and ALDH, can affect how sensitive cancer cells are to the drug.
This document discusses various classes of antiviral drugs, including their mechanisms of action, pharmacokinetics, therapeutic uses, and adverse effects. It describes DNA and RNA polymerase inhibitors such as acyclovir, ganciclovir, and ribavirin which work by inhibiting viral replication. It also covers adamantane derivatives amantadine and rimantidine which inhibit influenza virus uncoating, as well as neuraminidase inhibitors oseltamivir and zanamivir which prevent viral spread. Immunomodulators like interferons are also summarized, which activate the immune system against viruses.
This document summarizes several classes of antilipidemic drugs used to treat elevated blood lipids. It discusses bile-sequestering drugs like cholestyramine which bind to bile acids in the intestines. Fibric acid derivatives like fenofibrozate and gemfibrozil are used to reduce triglycerides and LDL. Statins like HMG-CoA reductase inhibitors block cholesterol production to lower LDL and increase HDL slightly. Ezetimibe inhibits cholesterol absorption from the intestines. Nicotinic acid lowers LDL and triglycerides while raising HDL but causes flushing as a side effect. All work in combination with lifestyle changes to reduce cardiovascular risks from high lipids.
Doxycycline is an antibiotic that can be used orally or intravenously to treat bacterial infections like pneumonia and acne, as well as protozoal infections including malaria. Common side effects include diarrhea, nausea, vomiting and a sunburn-like rash. Doxycycline is in the tetracycline antibiotic class and is effective against a variety of bacteria and protozoa, as well as helping to treat diseases caused by Wolbachia bacteria. Its use during pregnancy or in young children may permanently discolor teeth.
This document summarizes various anthelmintic drugs used to treat parasitic worm infections. It discusses the drug classes including benzimidazoles, quinolines, piperazine derivatives, vinyl pyrimidines, amides, natural products, and others. It provides details on specific drugs like albendazole, mebendazole, thiabendazole, oxamniquine, praziquantel, piperazine citrate, diethyl carbamazine, pyrantel pamoate, niclosamide, ivermectin, levamisole, metronidazole, and niridazole. It covers their mechanisms of action, structure-
Antiviral drugs are a class of medication used specifically for treating viral infections.Like antibiotics for bacteria, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic (also termed antibacterial), antifungal and antiparasitic drugs,or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Antivirals also can be found in essential oils of some herbs, such as eucalyptus oil and its constituents.
Nasal decongestants and Respiratory Stimulants.pdfShaikh Abusufyan
At the end of this e-learning session you are able to…
A. Discuss definition and therapeutic uses, limitation, classification and pharmacology of nasal decongestant.
B. Explain definition and uses, limitation, classification and pharmacology of respiratory stimulants.
I am happy to share lecture series on different topics of Pharmacology experiments, Pharmacy practice, Clinical pharmacy and Pharmacology. Wish you all happy learning.
For 30+ video lecture series on Pharmacology Experiment as per PCI B Pharm Syllabus refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1Ba6WSJjeBaK0HMF79hdad3g
For 2+ video lecture series on Pharmacoeconomics refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BY8U1TnlcHttsRB8hwpoJRL
For 5+ video lecture series on Pharmacoepidemiology refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BbqIaLoMmuF0Bf66SMFZtnb
For 5+ video lecture series on Drug discovery refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1Bbn9IE6c4MagVHZMNNinJov
For 5+ video lecture series on Drugs used in Special population use link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BZAed7zkXxyrgomJx2sSwHR
For 5+ video lecture series on Adverse Drug Reaction use link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BbWpd06N6RcV2q0K3JT29Wv
For 2+ video lecture series on Therapeutic drug monitoring refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BZQtOerZuDjx4yo0eOeTHIy
For 26+ video lecture series on Drugs act on central nervous system refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BY9xHaplYCYG26ALtIQp5aC
For 6+ video lecture series on drugs act on Gastrointestinal tract refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BYgHRHwuarKTt96bu_2L5WK
To support this channel you can through UPI ID: abushaikh07-yahoo.com@okhdfcbank
For More Such Learning You Can Subscribe to My YouTube Channel: https://www.youtube.com/channel/UC5o-WkzmDJaF7udyAP2jtgw/featured?sub_confirmation=1
Facebook Page: https://www.facebook.com/asacademylearningforever
Website Blog: https://itasacademy.blogspot.com/
Blood coagulation is a complex process involving coagulation factors that activate each other through the intrinsic and extrinsic pathways until a clot forms. Coagulants promote clotting while anticoagulants prevent clotting. Anticoagulants include heparin, warfarin and clopidogrel. Warfarin works by inhibiting vitamin K reductase and reducing coagulation factors. Clopidogrel is a prodrug that irreversibly inhibits the ADP receptor on platelets to prevent aggregation. Anticoagulants are used to treat and prevent conditions like thrombosis, pulmonary embolism and heart disease.
Tetracyclines are a class of broad-spectrum antibiotic drugs obtained from Streptomyces bacteria. They work by inhibiting protein synthesis in bacteria. Tetracyclines bind to the 30S subunit of bacterial ribosomes to prevent aminoacyl-tRNA from attaching, thereby terminating translation. They are effective against both gram-positive and gram-negative bacteria and are used to treat various infections. However, they can cause side effects like nausea, vomiting, diarrhea, and tooth discoloration.
The document discusses the pharmacotherapy of HIV/AIDS, including:
- Classification of antiretroviral drugs into NRTIs, NNRTIs, PIs, entry inhibitors, integrase inhibitors, and maturation inhibitors.
- Guidelines for starting antiretroviral therapy (ART) and recommendations for first and second line regimens.
- "Off label" uses of drugs like azithromycin, foscarnet, and hydroxyurea to treat opportunistic infections in HIV patients.
First and foremost choosing and using first line antiretroviral therapy.2013hivlifeinfo
DTG was noninferior to RAL through week 96 in the SPRING-2 trial. DTG was given once daily while RAL was given twice daily. There were few treatment failures and resistance mutations detected in both arms. DTG demonstrated durable efficacy comparable to RAL with more convenient once-daily dosing.
Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy- E...hivlifeinfo
The document discusses a debate between two HIV experts on whether integrase inhibitors should be the first choice for starting HIV therapy. It summarizes several key studies that have compared integrase inhibitors like raltegravir, elvitegravir, and dolutegravir to efavirenz or boosted protease inhibitors in treatment-naive patients. The studies showed integrase inhibitors were generally noninferior to alternatives in virologic suppression, and had fewer tolerability issues like gastrointestinal side effects.
A loading dose is an initial higher dose of a drug given at the beginning of treatment to more rapidly reach steady state plasma concentrations. Drugs with long half-lives benefit from a loading dose to quickly achieve therapeutic drug levels. The loading dose should approximate the amount of drug in the body at steady state. The main importance of a loading dose is to attain the average plasma concentration at steady state as quickly as possible to provide quick therapeutic effects in some cases.
Herb drug and herb food interaction ppt by nitesh kumarNITESH KUMAR
HERB DRUG AND HERB FOOD INTERACTION IS AN IMPORTANT CHAPTER IN HERBLA DRUG TECHNOLOGY IN THE SYLLABUS OF B.PHARMACY 6TH SEM. IT GIVES A BETTER UNDERTANDING OF HERB FOOD INTERACTION AND RELATED DRUGS.
The document discusses drugs used to treat sexually transmitted infections. It begins by defining key terms like venereal disease, sexually transmitted disease, and sexually transmitted infection. It then covers the etiological classification of STIs, listing the causative organisms for various conditions. The majority of the document discusses treatment for specific STIs, including drugs, doses, and regimens used to treat infections like syphilis, gonorrhea, chlamydia, herpes, and HIV/AIDS. It also covers the syndromic approach for STI treatment, which classifies infections according to clinical manifestations and recommends therapy using clinical algorithms.
Vincristine is an antitumor alkaloid isolated from Vinca rosea that is used to treat various cancers. It works by inhibiting cell division through interaction with tubulin, which arrests mitosis. Common side effects include neuropathy, infection risk, and hair loss. Vincristine is administered intravenously and distributed widely through the body, where it remains tightly bound, before being metabolized in the liver and excreted primarily in feces.
This document discusses anti-amoebic drugs used to treat amoebiasis, an infection caused by Entamoeba histolytica. It classifies anti-amoebic drugs according to where they act - luminal, systemic, or mixed. Metronidazole is discussed as a common broad-spectrum antibiotic effective against both luminal and systemic amoebiasis. It is absorbed and metabolized in the liver, with potential adverse effects like nausea. Nurses monitor for drug interactions and side effects. Paromomycin is a luminal-only antibiotic that acts against E. histolytica in the intestines.
This document summarizes HIV infection and treatment. It describes how HIV was identified in the 1980s as the cause of AIDS. HIV can be transmitted through bodily fluids. Left untreated, HIV weakens the immune system and allows opportunistic infections. Treatment aims to suppress the virus and restore immune function. Highly Active Antiretroviral Therapy (HAART) uses a combination of three antiretroviral drugs from two classes to control the virus. Guidelines recommend starting treatment based on CD4 count. The goals of treatment are to improve quality of life and prevent disease progression.
This document discusses chemotherapy for tuberculosis, including first-line and second-line antitubercular drugs. It describes the classification, mechanisms of action, pharmacokinetics, and adverse effects of isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin as first-line drugs. It also mentions that the goals of antitubercular chemotherapy are to kill dividing bacilli, kill persisting bacilli, and prevent emergence of drug resistance. The document assigns discussing the mechanisms, adverse effects, and uses of second-line drugs including kanamycin, amikacin, capreomycin, fluoroquinolones, and ethionamide.
Cyclophosphamide is an alkylating agent used to treat white blood cell cancers and lymphoma. It works by being metabolized into phosphoramide mustard, which adds alkyl groups to DNA, forming crosslinks between and within DNA strands. This leads to DNA damage and ultimately cell death. The expression of genes coding for enzymes involved in cyclophosphamide metabolism, such as cytochrome P450 and ALDH, can affect how sensitive cancer cells are to the drug.
This document discusses various classes of antiviral drugs, including their mechanisms of action, pharmacokinetics, therapeutic uses, and adverse effects. It describes DNA and RNA polymerase inhibitors such as acyclovir, ganciclovir, and ribavirin which work by inhibiting viral replication. It also covers adamantane derivatives amantadine and rimantidine which inhibit influenza virus uncoating, as well as neuraminidase inhibitors oseltamivir and zanamivir which prevent viral spread. Immunomodulators like interferons are also summarized, which activate the immune system against viruses.
This document summarizes several classes of antilipidemic drugs used to treat elevated blood lipids. It discusses bile-sequestering drugs like cholestyramine which bind to bile acids in the intestines. Fibric acid derivatives like fenofibrozate and gemfibrozil are used to reduce triglycerides and LDL. Statins like HMG-CoA reductase inhibitors block cholesterol production to lower LDL and increase HDL slightly. Ezetimibe inhibits cholesterol absorption from the intestines. Nicotinic acid lowers LDL and triglycerides while raising HDL but causes flushing as a side effect. All work in combination with lifestyle changes to reduce cardiovascular risks from high lipids.
Doxycycline is an antibiotic that can be used orally or intravenously to treat bacterial infections like pneumonia and acne, as well as protozoal infections including malaria. Common side effects include diarrhea, nausea, vomiting and a sunburn-like rash. Doxycycline is in the tetracycline antibiotic class and is effective against a variety of bacteria and protozoa, as well as helping to treat diseases caused by Wolbachia bacteria. Its use during pregnancy or in young children may permanently discolor teeth.
This document summarizes various anthelmintic drugs used to treat parasitic worm infections. It discusses the drug classes including benzimidazoles, quinolines, piperazine derivatives, vinyl pyrimidines, amides, natural products, and others. It provides details on specific drugs like albendazole, mebendazole, thiabendazole, oxamniquine, praziquantel, piperazine citrate, diethyl carbamazine, pyrantel pamoate, niclosamide, ivermectin, levamisole, metronidazole, and niridazole. It covers their mechanisms of action, structure-
Antiviral drugs are a class of medication used specifically for treating viral infections.Like antibiotics for bacteria, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic (also termed antibacterial), antifungal and antiparasitic drugs,or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Antivirals also can be found in essential oils of some herbs, such as eucalyptus oil and its constituents.
Nasal decongestants and Respiratory Stimulants.pdfShaikh Abusufyan
At the end of this e-learning session you are able to…
A. Discuss definition and therapeutic uses, limitation, classification and pharmacology of nasal decongestant.
B. Explain definition and uses, limitation, classification and pharmacology of respiratory stimulants.
I am happy to share lecture series on different topics of Pharmacology experiments, Pharmacy practice, Clinical pharmacy and Pharmacology. Wish you all happy learning.
For 30+ video lecture series on Pharmacology Experiment as per PCI B Pharm Syllabus refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1Ba6WSJjeBaK0HMF79hdad3g
For 2+ video lecture series on Pharmacoeconomics refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BY8U1TnlcHttsRB8hwpoJRL
For 5+ video lecture series on Pharmacoepidemiology refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BbqIaLoMmuF0Bf66SMFZtnb
For 5+ video lecture series on Drug discovery refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1Bbn9IE6c4MagVHZMNNinJov
For 5+ video lecture series on Drugs used in Special population use link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BZAed7zkXxyrgomJx2sSwHR
For 5+ video lecture series on Adverse Drug Reaction use link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BbWpd06N6RcV2q0K3JT29Wv
For 2+ video lecture series on Therapeutic drug monitoring refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BZQtOerZuDjx4yo0eOeTHIy
For 26+ video lecture series on Drugs act on central nervous system refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BY9xHaplYCYG26ALtIQp5aC
For 6+ video lecture series on drugs act on Gastrointestinal tract refer link given below: https://www.youtube.com/playlist?list=PLBVbJ9HCa1BYgHRHwuarKTt96bu_2L5WK
To support this channel you can through UPI ID: abushaikh07-yahoo.com@okhdfcbank
For More Such Learning You Can Subscribe to My YouTube Channel: https://www.youtube.com/channel/UC5o-WkzmDJaF7udyAP2jtgw/featured?sub_confirmation=1
Facebook Page: https://www.facebook.com/asacademylearningforever
Website Blog: https://itasacademy.blogspot.com/
Blood coagulation is a complex process involving coagulation factors that activate each other through the intrinsic and extrinsic pathways until a clot forms. Coagulants promote clotting while anticoagulants prevent clotting. Anticoagulants include heparin, warfarin and clopidogrel. Warfarin works by inhibiting vitamin K reductase and reducing coagulation factors. Clopidogrel is a prodrug that irreversibly inhibits the ADP receptor on platelets to prevent aggregation. Anticoagulants are used to treat and prevent conditions like thrombosis, pulmonary embolism and heart disease.
Tetracyclines are a class of broad-spectrum antibiotic drugs obtained from Streptomyces bacteria. They work by inhibiting protein synthesis in bacteria. Tetracyclines bind to the 30S subunit of bacterial ribosomes to prevent aminoacyl-tRNA from attaching, thereby terminating translation. They are effective against both gram-positive and gram-negative bacteria and are used to treat various infections. However, they can cause side effects like nausea, vomiting, diarrhea, and tooth discoloration.
The document discusses the pharmacotherapy of HIV/AIDS, including:
- Classification of antiretroviral drugs into NRTIs, NNRTIs, PIs, entry inhibitors, integrase inhibitors, and maturation inhibitors.
- Guidelines for starting antiretroviral therapy (ART) and recommendations for first and second line regimens.
- "Off label" uses of drugs like azithromycin, foscarnet, and hydroxyurea to treat opportunistic infections in HIV patients.
First and foremost choosing and using first line antiretroviral therapy.2013hivlifeinfo
DTG was noninferior to RAL through week 96 in the SPRING-2 trial. DTG was given once daily while RAL was given twice daily. There were few treatment failures and resistance mutations detected in both arms. DTG demonstrated durable efficacy comparable to RAL with more convenient once-daily dosing.
Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy- E...hivlifeinfo
The document discusses a debate between two HIV experts on whether integrase inhibitors should be the first choice for starting HIV therapy. It summarizes several key studies that have compared integrase inhibitors like raltegravir, elvitegravir, and dolutegravir to efavirenz or boosted protease inhibitors in treatment-naive patients. The studies showed integrase inhibitors were generally noninferior to alternatives in virologic suppression, and had fewer tolerability issues like gastrointestinal side effects.
This document provides an overview and summary of recent data on antiretroviral therapy (ART) for HIV. Key findings include:
- A study in Thailand found that daily oral tenofovir reduced HIV infection risk among injection drug users by 48.9%, leading to new guidelines recommending PrEP for high-risk drug users.
- US demonstration projects found high adherence to PrEP among at-risk populations, with tenofovir levels indicating protection.
- Multiple studies found dolutegravir to be superior to other regimens in treatment-naive patients, maintaining activity even at high viral loads.
- No transmissions occurred in a large study of serodiscordant couples where the
What’s New in Coformulated Antiretroviral Regimens.2014hivlifeinfo
This document discusses a presentation on new coformulated antiretroviral regimens given by Dr. Andrew Zolopa. It provides information on:
1) Currently available coformulated antiretroviral agents and regimens, including those containing cobicistat as a new boosting agent.
2) Clinical trial results showing noninferiority of elvitegravir/cobicistat/tenofovir/emtricitabine to efavirenz- and atazanavir/ritonavir-based regimens.
3) Ongoing studies of dolutegravir-containing regimens in treatment-naive patients.
Современное лечение ВИЧ: АРТ у пациентов с сопутствующими заболеваниями.Conte...hivlifeinfo
Современное лечение ВИЧ:АРТ у пациентов с сопутствующими заболеваниями.//Contemporary Management of HIV. Managing ART in HIV-Infected Patients With Common Comorbidities. 2016
In this downloadable slideset, David A. Wohl, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for managing ART in the context of common comorbidities.
Format: Microsoft PowerPoint (.ppt)
File size: 3.51 MB
Современное лечение ВИЧ: когда начинать, чем начинать. Contemporary Managemen...hivlifeinfo
.Contemporary Management of HIV. When to Start, What to Start.2016/Современное лечение ВИЧ: когда начинать, чем начинать.
In this downloadable slideset, Daniel R. Kuritzkes, MD, and Program Director Eric S. Daar, MD review key data and optimal approaches for first-line ART with contemporary HIV regimens.
Format: Microsoft PowerPoint (.ppt)
File size: 2.53 MB
Date posted: 2/9/2016
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Conte...hivlifeinfo
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Contemporary Management of HIV. Managing HIV in Viral Hepatitis Coinfection.2016
In this downloadable slideset, David L. Wyles, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for ART management in patients with HIV and viral hepatitis coinfection.
Format: Microsoft PowerPoint (.ppt)
File size: 1.85 MB
Новые данные с конференции по ВИЧ-инфекции CROI 2017/Clinical Impact of New D...hivlifeinfo
Clinical Impact of New Data From CROI 2017
Expert faculty members Joel E. Gallant, MD, MPH, and Charles B. Hicks, MD, summarize key studies from this important annual conference.
Format: Microsoft PowerPoint (.ppt)
File size: 1.25 MB
Date posted: 3/3/2017
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусной супрессией и ...hivlifeinfo
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусной супрессией и у пациентов с вирусологической неудачей. /Contemporary Management of HIV. Modifying Antiretroviral Therapy in Virologically Suppressed Patients and Those With Treatment Failure.2016
In this downloadable slideset, W. David Hardy, MD, and Program Director Eric S. Daar, MD review key data and optimal approaches for modifying ART in patients who are virologically suppressed or have experienced treatment failure.
Format: Microsoft PowerPoint (.ppt)
File size: 2.07 MB
Modern European Guidelines on HIV Treatment 2016. Key Updateshivlifeinfo
This document summarizes key points from modern European guidelines on HIV treatment. It discusses factors to consider when deciding when to start antiretroviral therapy (ART) and which first-line regimen to use. Major studies like START and FLAMINGO provided evidence that immediate ART improves health outcomes and that dolutegravir is as effective as protease inhibitor-based regimens. Guidelines now recommend starting all patients on ART due to its prevention of HIV-related diseases and transmission. Tenofovir alafenamide (TAF) shows improved bone and kidney outcomes compared to tenofovir DF (TDF) in switch studies.
Современное лечение ВИЧ : АРТ как профилактика.Contemporary Management of HIV...hivlifeinfo
Contemporary Management of HIV. Antiretroviral Therapy As Prevention.2016
In this downloadable slideset, Kenneth Mayer, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for pre- and post-exposure prophylaxis in patients at risk for HIV infection.
Format: Microsoft PowerPoint (.ppt)
File size: 2.13 MB
Highlights of AIDS 2014 .CCO Official Conference Coverage of the 20th Interna...Hivlife Info
The document summarizes highlights from the 20th International AIDS Conference held in Melbourne, Australia in July 2014. It includes results from several clinical trials presented at the conference evaluating new antiretroviral regimens for initial therapy and treatment switches in suppressed patients. One study found maraviroc plus darunavir/ritonavir was not non-inferior to tenofovir/emtricitabine plus darunavir/ritonavir for initial therapy. Another study found switching suppressed patients to a dual regimen of lopinavir/ritonavir plus lamivudine or emtricitabine was non-inferior to continuing a triple regimen. A sub-
First and foremost choosing and using first line antiretroviral therapy.2013Hivlife Info
This document discusses guidelines for initial antiretroviral therapy and recent clinical trials comparing different first-line regimens. The 2013 DHHS and 2012 IAS-USA guidelines recommend efavirenz (EFV) plus tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC) as preferred initial regimens. Recent trials found rilpivirine (RPV) to be noninferior to EFV through week 96, though with more virologic failures, especially in those with high baseline viral load. Elvitegravir/cobicistat/TDF/FTC was noninfer
Современное лечение и профилактика ВИЧ : передовые стратегии лечения у пациен...hivlifeinfo
Стратегии смены АРТ у пациентов с вирусной супрессией, включая смену АРТ при резистентности, рекомендации по инъекционным препаратам длительного действия , смена АРТ до или во время беременности
Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy- E...Hivlife Info
In this downloadable slideset, Joseph J. Eron, Jr., MD, and Daniel Kuritzkes, MD, review key data on the evolving use of INSTIs in patients beginning HIV therapy.
Format: Microsoft PowerPoint (.ppt)
File size: 2.29 MB
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусологической супре...hivlifeinfo
This document discusses modifying antiretroviral therapy (ART) in virologically suppressed patients with HIV. It describes two phase 3 trials, ATLAS and FLAIR, that evaluated switching to long-acting injectable cabotegravir plus rilpivirine (CAB/RPV) every 4 weeks in suppressed patients. Both trials found CAB/RPV to be noninferior to continued oral ART at 48 weeks. Common reasons to consider an ART switch include simplifying regimens or improving tolerability. Key factors that may increase risk of treatment failure with CAB/RPV include presence of rilpivirine resistance mutations at baseline and lower rilpivirine drug levels. The FDA
This 3-sentence summary provides the essential information from the document:
The document outlines a conference program from June 30 - July 3, 2013 in Kuala Lumpur, Malaysia called IAS 2013, which covered highlights and official coverage of HIV pathogenesis, treatment, and prevention. It includes slides on antiretroviral therapy guidelines, clinical trials of new drugs and regimens, and investigational long-acting antiretroviral agents. The
Оптимизация лечения ВИЧ в 2018 году / HIV Treatment Optimization: 2018hivlifeinfo
HIV Treatment Optimization: 2018
In this downloadable slideset, Eric S. Daar, MD, provides a comprehensive update on ART management.
Format: Microsoft PowerPoint (.ppt)
File Size: 723 KB
Released: April 26, 2018
Highlights of IAS 2013.CCO Official Conference Coverage of the 7th IAS Confer...Hivlife Info
The document summarizes highlights from the 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention held in Kuala Lumpur, Malaysia in June-July 2013. Key findings included the WHO updating treatment guidelines to recommend initiating ART at CD4 counts ≤500 cells/mm3 and preferring TDF+3TC(FTC)+EFV as the initial regimen. Studies found noninferiority of 400mg EFV and demonstrated the efficacy of second-line LPV/r-based ART and PrEP with TDF in specific populations. Adherence to treatment was an important factor in outcomes.
HIV Alert:Новые стратегии и агенты в лечении ВИЧ/Novel Strategies and Agents ...hivlifeinfo
HIV Alert-Новые стратегии и агенты в лечении ВИЧ/Novel Strategies and Agents for HIV Management.2017
In this downloadable slideset, Daniel R. Kuritzkes, MD, and Paul E. Sax, MD, review potential future HIV treatment strategies—including dual-therapy regimens, long-acting ART, and investigational agents—and discuss where these might fit into the current therapeutic landscape.
Format: Microsoft PowerPoint (.ppt)
File size: 570 KB
Date posted: 9/27/2017
Key Slides on ART for HIV : Evolving Concepts and Innovative Strategies.2020hivlifeinfo
Expert-authored slides on evolving ART concepts, including simplification to 2-drug therapy, ART safety during pregnancy, weight gain, and long-acting injectable ART.
File Size: 580 KB
Released: October 20, 2020
Современное лечение ВИЧ.Усилить или не усилить : преимущества и недостатки бу...hivlifeinfo
Современное лечение ВИЧ.Усилить или не усилить : преимущества и недостатки бустированных режимов АРТ / Contemporary Management of HIV.To Boost or Not to Boost-Advantages and Disadvantages of Boosted ART.2017
In this downloadable slideset, Eric S. Daar, MD, and Program Director Joseph J. Eron, Jr., MD, review advantages and disadvantages of boosted ART regimens for managing patients with HIV.
Format: Microsoft PowerPoint (.ppt)
File size: 514 KB
Date posted: 6/16/2017
New Data on Resistance to DAAs and Implications for Therapy.2015hivlifeinfo
This document provides an overview of a presentation on new data regarding resistance to direct-acting antivirals (DAAs) and implications for HCV therapy. It includes the faculty list and their disclosures, as well as slides summarizing recent studies on DAA resistance variants, their impact on treatment outcomes, and persistence after treatment failure. Key findings discussed are the role of NS3 Q80K testing prior to simeprevir + sofosbuvir in genotype 1a patients, effectiveness of DAA regimens against prior protease inhibitor resistance, and durability of NS5A resistance variants.
Fall 2014 HIV Update.Clinical Impact of New Data From ICAAC 2014, IDWeek 2014...Hivlife Info
In this downloadable slideset, Joseph J. Eron, Jr., MD and Jürgen K. Rockstroh, MD, review key HIV studies presented at the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy, 2014 IDWeek, and 2014 HIV Drug Therapy Glasgow.
Format: Microsoft PowerPoint (.ppt)
File size: 1.70 MB
Fall 2014 HIV Update.Clinical Impact of New Data From ICAAC 2014, IDWeek 2014...hivlifeinfo
In this downloadable slideset, Joseph J. Eron, Jr., MD and Jürgen K. Rockstroh, MD, review key HIV studies presented at the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy, 2014 IDWeek, and 2014 HIV Drug Therapy Glasgow.
Format: Microsoft PowerPoint (.ppt)
File size: 1.70 MB
This document discusses contemporary management of HIV with a focus on individualizing first-line antiretroviral therapy (ART). It provides an overview of recommended first-line ART regimens including integrase strand transfer inhibitors (INSTIs), discusses clinical trial data comparing different INSTI and protease inhibitor options, and considers factors in choosing among available single-tablet regimen options. It also addresses the potential roles of newer non-nucleoside reverse transcriptase inhibitors and tenofovir alafenamide versus tenofovir disoproxil fumarate in first-line ART.
Топ достижений лечения ВИЧ в 2017 г / Top Advances in ART for 2017hivlifeinfo
Top Advances in ART for 2017
In this downloadable slideset, Joel E. Gallant, MD, MPH, provides a comprehensive update on ART management.
Format: Microsoft PowerPoint (.ppt)
File size: 579 KB
Date posted: 3/29/2017
Highlights of AIDS 2014 .CCO Official Conference Coverage of the 20th Interna...hivlifeinfo
This document summarizes highlights from the 20th International AIDS Conference held in Melbourne, Australia from July 20-25, 2014. It provides an overview of several studies presented at the conference related to antiretroviral therapy, including studies showing that switching to simpler dual-drug regimens was noninferior to triple therapy in suppressed patients, and that dolutegravir maintained activity against HIV even in the presence of NRTI resistance. A sub-analysis found that lower levels of pre-existing NRTI resistance were associated with increased risk of virologic failure on a second-line regimen.
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients...Hivlife Info
Доктор David A. Wohl при участии группы экспертов, рассматривает основные исследования о том, когда и как, при каких условиях переводить пациентов со стабильной супрессией ВИЧ на новые методы лечения .
Join expert faculty members Joseph J. Eron, Jr., MD, and Kimberly Y. Smith, MD, MPH, for a review of the HIV highlights of this important annual conference.
Similar to The role of integrase inhibitors in first line and later antiretroviral therapy.2013 (20)
Дискуссии о здоровом старении с ВИЧ /Key Slides on Healthy Aging With HIV.2022hivlifeinfo
Дискуссии о здоровом старении с ВИЧ
Узнайте о медицинских и немедицинских проблемах, с которыми сталкиваются стареющие пациенты с ВИЧ, включая дополнительные проблемы, с которыми сталкиваются пожилые женщины и пожилые люди, живущие в условиях ограниченных ресурсов.
Основы ведения АРТ у многократно леченных пациентов 2022 / Foundations of ART...hivlifeinfo
Основы ведения АРТ у многократно леченных пациентов (2022)
Тактики ведения пациентов с большим опытом лечения, включая анализ резистентности, последние рекомендации и данные по новым схемам АРТ
Ключевые слайды по индивидуальному выбору АРТ / Key Slides on Individualized ...hivlifeinfo
Слайды с последними данные и рекомендациями по выбору АРТ, как для пациентов, ранее не получавших лечения, так и пациентов с вирусологической супрессией. Оценки разных вариантов лечения, индивидуализация АРТ для женщин детородного возраста и во время беременности, пациентов с опортунистическими инфекциями и новые данные об исследовательских стратегиях АРТ.
Современное лечение ВИЧ: новые парадигмы в АРТ / Contemporary Management of H...hivlifeinfo
Набор слайдов c рассмотрением важных вопросов об АРТ первого ряда, арв-препаратами пролонгированного действия и схемами АРТ с двумя препаратами, акцент в публикации на роль новых стратегий.
Современное лечение ВИЧ: лечение многократно леченных пациентов с резистентно...hivlifeinfo
This document discusses management of HIV in heavily treatment-experienced patients with multiclass resistance and limited treatment options. It provides an overview of the problem, including that some older patients were treated early in the HIV epidemic with less potent regimens, resulting in resistance. Younger patients may have congenital HIV and been treated long-term. Assessment of virologic failure and resistance testing are important to select an effective new regimen. Current options for active drugs in these patients include maraviroc, ibalizumab, fostemsavir, and enfuvirtide, which have novel mechanisms of action. Adherence assessment is also critical to determine if the current regimen may still be effective if taken as prescribed.
Современное лечение ВИЧ: новые подходы к оптимизации АРТ/Contemporary Managem...hivlifeinfo
Вопросы, связанные с АРТ первого ряда, смена арв-стратегии для пациентов с вирусной супрессией, акцентом на возрастающую роль новыхантиретровирусных стратегий.
Clinical Impact of New Data From AIDS 2020hivlifeinfo
current ART in principal populations, including older patients and women who become pregnant; metabolic outcomes during ART; HIV and COVID-19; investigational ART strategies; and HIV prevention.
Слайдсет о новом в лечении ВИЧ.Key Slides on What’s Hot in HIV Treatment.2020 hivlifeinfo
Expert-authored slides on the latest issues relating to HIV care, featuring patient cases and considerations for optimal treatment approaches. Topics include integrating newer ARVs, individualizing ART for women of childbearing potential and during pregnancy, adverse events during ART, and anticipated roles of emerging ART strategies.
Гиперлипопротеидемия(а) как опасное генетически обусловленное нарушение липид...hivlifeinfo
Гиперлипопротеидемия(а) как опасное генетически обусловленное нарушение липидного обмена и фактор риска атеротромбоза и сердечно-сосудистых заболеваний
Липопротеид(а) [Лп(а)] представляет собой сложный надмолекулярный комплекс, принадлежащий к апоВ100 содержащим липопротеидам. Лп(а) состоит из ЛНП-подобной частицы, в которой молекула апобелка В100 ковалентно связана дисульфидной связью с уникальной полиморфной молекулой апобелка(а). Концентрация Лп(а) генетически контролируется, при этом варьирует в очень широком диапазоне. Повышенный уровень Лп(а) является независимым фактором риска атеросклероза коронарных, сонных и периферических артерий, ИБС и стеноза аортального клапана, сопутствующих сердечно-сосудистых осложнений, а также осложнений после операций реваскуляризации миокарда. Несмотря на это, уровень Лп(а) по-прежнему не учитывается в стратификации риска сердечно-сосудистых заболеваний. Отчасти, это может быть связано с тем, что ни современная лекарственная терапия, ни новые поколения биологических гиполипидемических препаратовтерапия практически не влияют на концентрацию Лп(а), за исключением 20-30% снижения Лп(а) никотиновой кислотой и ингибиторами пропротеиновой конвертазы субтилизин-кексин 9 типа (PCSK9).
Лекция освящает современные представления о Лп(а), как факторе риска сердечно-сосудистых заболеваний, возможности и целесообразности его определения, а также посвящена современным возможностям коррекции гиперлипопротеидемии(а).
Физическая активность и физические тренировки как метод профилактики сердечно...hivlifeinfo
Чушкин М.И., Мандрыкин С.Ю., Карпина Н.Л., Попова Л.А. Физическая активность и физические тренировки как метод профилактики сердечно-сосудистых заболеваний. Кардиология. 2018;58(9S):10-18
Большое число данных свидетельствует, что функциональные возможности кардиореспираторной системы являются не менее важным фактором прогноза летальности, чем курение, артериальная гипертензия, ожирение, гиперхолестеринемия, СД. Пациенты с большей физической активностью имеют значительно меньший риск ССЗ, чем пациенты, ведущие неактивный образ жизни. В данном обзоре авторы показали возможности оценки физической активности и основные положения назначения физических тренировок для сохранения и повышения функциональных возможностей кардиореспираторной системы.
Key Slides on Individualizing ART Management Based on Treatment Safety and To...hivlifeinfo
Обзор последних рекомендаций DHHS , индивидуализация лечения в отдельных группах пациентов, минимизация побочных эффектов и межлекарственных взаимодействий
Современное лечение ВИЧ.Обобщённые данные с конференции CROI 2020 / Contempor...hivlifeinfo
This document summarizes data presented at CROI 2020 on current and investigational antiretroviral therapies (ART) for HIV. Key findings include:
- A pooled analysis found the 3-drug regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) was effective and well-tolerated in people over age 50 similar to younger patients.
- The switch to BIC/FTC/TAF was noninferior to remaining on baseline regimens even in people with baseline nucleoside reverse transcriptase inhibitor resistance.
- Through week 96, dolutegravir plus lamivudine was similarly effective
Incorporating New ART Options Into First-line and Switch Strategies for HIV C...hivlifeinfo
This document discusses several new HIV treatment regimens approved between 2017-2019, including three-drug fixed-dose combinations of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF), and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/COBI/FTC/TAF). Clinical trials showed BIC/FTC/TAF and DOR/3TC/TDF were
This document summarizes an expert panel discussion on innovative antiretroviral therapy (ART) paradigms. The panel discussed whether positive results from two-drug and long-acting injectable regimens in clinical trials will translate to long-term efficacy and safety. They also considered the potential risks of resistance emerging with two-drug regimens and the impact of missed doses with long-acting injectables. The panel agreed that maintaining cold storage requirements for long-acting injectables may pose challenges for implementation in low- and middle-income countries but that qualitative research found patients highly satisfied with the convenience of long-acting ART.
Свобода интернета 2018: делегирование репрессий.Доклад Международной Агорыhivlifeinfo
«Настоящий доклад посвящен обзору вмешательства в свободу интернета в России в 2018 году и основан на данных постоянного мониторинга ситуации, который мы ведем более 10 лет.
Как обычно, доклад состоит из двух основных разделов, первый из которых посвящен описанию результатов мониторинга с приведением наиболее показательных примеров, а второй – авторской оценке состояния свободы интернета. В приложении даны сводные результаты мониторинга в виде таблицы со ссылкой на дату, источник, регион и вид ограничения по каждому известному эпизоду, а также карта нарушений, на которой цветом обозначен уровень относительной свободы интернета в отдельных субъектах Федерации.»
https://guides.files.bbci.co.uk/bbc-russian/AGORA_Freedom-of-the-Internet-2018.pdf
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Kat...rightmanforbloodline
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
• Equipping health professionals to address questions, concerns and health misinformation
• Assessing risk and mitigating harm from adverse health narratives in communities, health workforce and health system
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
The role of integrase inhibitors in first line and later antiretroviral therapy.2013
1. Joseph J. Eron Jr., MD
Professor of Medicine
University of North Carolina School of
Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
The Evolving Role of Integrase
Inhibitors in HIV Therapy
This program is supported by an educational grant from
2. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
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3. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Program Director and Content Planning
Faculty
Joseph J. Eron Jr., MD
Professor of Medicine
University of North Carolina School
of Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
Paul E. Sax, MD
Clinical Director
HIV Program and Division of
Infectious Diseases
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Kimberly Y. Smith, MD
Associate Professor of Medicine
Division of Infectious Diseases
Rush University Medical Center
Chicago, Illinois
4. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Disclosures
Joseph J. Eron, Jr., MD, has disclosed that he has served as a
consultant for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline/ViiV,
Gilead Sciences, Merck, Tibotec/Janssen, and Tobira; has received
funds for research support from Bristol-Myers Squibb and
GlaxoSmithKline/ViiV; and has served on the data and safety monitoring
board for Vertex.
Paul E. Sax, MD, has disclosed that he has received consulting fees
from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV,
Janssen, and Merck and funds for research support from Bristol-Myers
Squibb, Gilead Sciences, and GlaxoSmithKline/ViiV.
Kimberly Y. Smith, MD, MPH, has disclosed that she has received
consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Janssen, Merck, and ViiV.
7. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
HIV Viral Life Cycle
Attachment
fusion
Budding
Reverse
transcription
Maturation
Integration
Uncoating
Transcription,
translation
Assembly
8. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
HIV Viral Life Cycle
Currently available integrase inhibitors
Raltegravir (approved 10/07)
Elvitegravir* (approved 8/12)
Dolutegravir (approved 8/13)
Budding
Reverse
transcription
Maturation
Transcription,
translation
Assembly
*Currently available only as part of a coformulated single-tablet regimen.
Attachment
fusion
Uncoating
Integrase
inhibitors
9. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Integrase Inhibitors in DHHS Guidelines
All 3 integrase inhibitors are now part of preferred first-line
regimens
DHHS Guidelines. February 2013. DHHS Recommendation on INSTIs. October 2013.
Preferred Regimens Alternative Regimens
NNRTI EFV/TDF/FTC
EFV + ABC/3TC
RPV/TDF/FTC or RPV + ABC/3TC
Boosted PI
ATV/RTV + TDF/FTC
DRV/RTV + TDF/FTC
ATV/RTV + ABC/3TC
DRV/RTV + ABC/3TC
FPV/RTV + (TDF/FTC or ABC/3TC)
LPV/RTV + (TDF/FTC or ABC/3TC)
INSTI
RAL + TDF/FTC
EVG/COBI/TDF/FTC
DTG + ABC/3TC
DTG + TDF/FTC
RAL + ABC/3TC
11. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
STARTMRK: Raltegravir vs Efavirenz in
Treatment-Naive Patients
Randomized, double-blind (through 5 yrs), placebo-controlled, phase III trial
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
HIV-infected, treatment-naive
patients with HIV-1 RNA
> 5000 copies/mL and
no resistance to EFV,
TDF, or FTC
(N = 563)
Efavirenz 600 mg QHS + TDF/FTC
(n = 282)
Raltegravir 400 mg BID + TDF/FTC
(n = 281)
Lennox J, et al. Lancet. 2009;374:796-806.
Stratified by HIV-1 RNA (> vs ≤ 50,000 copies/mL)
and viral hepatitis status
12. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
STARTMRK: RAL vs EFV in Treatment-
Naive Patients: 5-Yr Final Report
RAL noninferior to EFV in HIV-1 RNA < 50 c/mL at Wk 48
(primary endpoint; ITT, NC = F analysis); superior from Wk 192
Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85.
281
282
100
80
60
40
20
0
HIV-1RNA<50c/mL(%)
0 48 72 96 120 144
Wks
RAL
EFV
Pts at Risk, n
281
282
276
282
280
281
281
282
277
281
280
281
86
82
81
79
75
69
281
282
192
76
67
∆: +9.5% (95% CI: 1.7% to 17.3%;
noninferiority P < .001)
24012 216
71
61
277
282
279
279
24
279
282
168
281
282
13. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
STARTMRK: RAL vs EFV in Treatment-
Naive Patients: 5-Yr Final Report
Efficacy as good as or better
than EFV in all baseline
subgroups tested
CD4+ cell count at Wk 240:
+374 (RAL) vs +312 (EFV)
RAL associated with
– Fewer CNS adverse events
(39.1% vs 64.2%; P < .001)
– Fewer drug-related clinical
adverse events (52.0% vs
80.1%; P < .001)
– Fewer discontinuations due to
adverse events (5% vs 9%)
Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85 plus Supplemental Digital Content.
VF and Resistance at Wk 240
RAL
(n = 281)
EFV
(n = 282)
VF, n (%) 55 (19.6) 59 (20.9)
Resistance data
available, n 23 20
INSTI or NNRTI
mutations only, n 1 7
NRTI mutations only, n 3 2
NRTI + (RAL or EFV)
resistance mutations, n 3 3
14. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
QDMRK: RAL QD Inferior to RAL BID at
Wk 48 in Treatment-Naive Patients
Randomized, noninferiority phase III
trial of RAL 800 mg QD (n = 382) vs
RAL 400 mg BID (n = 389), both with
TDF/FTC[1]
RAL QD inferior to RAL BID at Wk 48 in
ITT (NC = F) analysis
Lower RAL trough levels associated
with higher risk of failure in QD arm but
not in BID arm
More resistance at failure in QD arm
PK studies of 2 new RAL formulations
administered as 1200-mg once daily
showed promise in healthy patients[2]
1. Eron J, et al. Lancet Infect Dis. 2011;11:907-915. 2. Krishna R, et al. EACS 2013, Abstract PE10/17.
HIV-1RNA<50c/mL
(NC=F)
*Failure included both failure to suppress and rebounders.
Most patients with VF and RAL resistance had
≥ 2 mutations associated with resistance to RAL.
Parameter, n RAL QD
(n = 382)
RAL BID
(n = 388)
Pts with VF* and
HIV-1 RNA > 400 c/mL
30 16
Resistance data available 27 11
FTC resistance only 11 2
Integrase inhibitor and FTC
resistance
9 2
No evidence of resistance 7 7
83
89
0
20
40
60
80
100
RAL 800 mg
QD (n = 382)
RAL 400 mg
BID (n = 389)
318/
382
343/
389
∆: -5.7
(95% CI: -10.7 to -0.83;
P for noninferiority = .044)
Wk 48
15. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Elvitegravir/Cobicistat vs EFV or ATV/RTV
+ TDF/FTC in Treatment-Naive Pts
Randomized, double-blind, active-controlled phase III studies
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438.
Treatment naive;
HIV-1 RNA ≥ 5000 copies/mL;
any CD4+ cell count;
susceptible to TDF, FTC, and EFV, or ATV;
eGFR ≥ 70 mL/min
Study 102[1]
(N = 700)
Study 103[2]
(N = 708)
EVG/COBI/TDF/FTC QD
(n = 348)
EFV/FTC/TDF QD
(n = 352)
EVG/COBI/TDF/FTC QD
(n = 353)
ATV/RTV + TDF/FTC QD
(n = 355)
16. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
EVG/COBI/TDF/FTC Noninferior to
EFV/TDF/FTC Through Wk 144
EVG/COBI arm noninferior to EFV
arm at Wk 48 primary endpoint[1]
and
through Wk 144[2,3]
– Results consistent across
subgroups: BL HIV-1 RNA,
CD4+ cell count, age, sex, race
– Treatment-related study d/c: 6% in
EVG/COBI arm vs 7% in EFV arm
at Wk 144
VF: 7% in EVG/COBI arm and 10%
in EFV arm at Wk 144
Similar CD4+ cell count increase at
Wk 144:
– +321 cells/mm3
(EVG/COBI) vs
+300 cells/mm3
(EFV)
1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-
100. 3. Wohl D, et al. ICAAC 2013. Abstract H-672a.
Wk 48 Wk 144
EVG/COBI/TDF/FTC
(n = 348)
EFV/TDF/FTC
(n = 352)
80
75
0
20
40
60
80
100
88 84
Δ: 3.6%
(-1.6 to 8.8)
Δ: 4.9%
(1.3 to 11.1)
84
82
Wk 96
Δ: 2.7%
(-2.9 to 8.3)
17. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
EVG/COBI/TDF/FTC Noninferior to
ATV/RTV + TDF/FTC Through Wk 144
EVG/COBI arm noninferior to
ATV/RTV arm at Wk 48 primary
endpoint[1]
and through Wk 144[2,3]
– Results consistent across subgroups:
BL HIV-1 RNA, CD4+ count,
adherence, age, sex, race
Treatment-related study d/c:
6% in EVG/COBI arm vs
9% in ATV/RTV arm at Wk 144
VF: 8% in EVG/COBI arm vs
7% in ATV/RTV arm at Wk 144
Similar CD4+ cell count increase at
Wk 144: +280 cells/mm3
(EVG/COBI)
vs +293 cells/mm3
(ATV/RTV)
1. De Jesus E, et al. Lancet. 2012;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr.
2013;62:483-486. 3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2.
EVG/COBI/TDF/FTC
(n = 353)
ATV/RTV + TDF/FTC
(n = 355)
Δ: 3.0%
(-1.9 to 7.8)
Δ: 1.1%
(-4.5 to 6.7)
Wk 48 Wk 144
78
75
0
20
40
60
80
100
90 87
Δ: 3.1%
(-3.2 to 9.4)
83
82
Wk 96
18. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
EVG/COBI/TDF/FTC Adverse Events
Summary
EVG/COBI vs EFV: fewer CNS, rash events; smaller
increase in TC, HDL-C, and LDL-C (but similar increase in
TC:HDL ratio), similar TG increase; more nausea[1]
EVG/COBI vs ATV/RTV: less jaundice; similar increase in
TC, HDL-C, and LDL-C; smaller TG increase[2]
Small, rapid increase in serum creatinine related to
inhibition of tubular secretion of creatinine by COBI
– 0.14 ± 0.13 mg/dL at Wk 48; most change occurs by Wk 2[3]
4 pts (0.6% of total) developed tubulopathy, likely from
TDF[3]
1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-
2438. 3. TDF/FTC/EVG/COBI [package insert].
19. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
EVG/COBI/TDF/FTC Resistance Summary
EVG/COBI vs EFV through
Wk 144[1-3]
EVG/COBI vs ATV/RTV
through Wk 144[4-6]
1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr.
2013;63:96-100. 3. Wohl D, et al. ICAAC 2013. Abstract H-672a. 4. De Jesus E, et al. Lancet.
2012;379:2429-2438. 5. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486.
6. Clumeck N, et al. EACS 2013. Abstract LBPS7/2
EVG/COBI
(n = 348)
EFV
(n = 352)
Wk 48 96 144 48 96 144
Resistance
at VF, n 8 +2 +0 8 +2 +4
INSTI
RAMs, n 7 +2 +0
NNRTI
RAMs, n 8 +2 +4
NRTI
RAMs, n 8 +2 +0 2 +1 +1
EVG/COBI
(n = 353)
ATV/RTV
(n = 355)
Wk 48 96 144 48 96 144
Resistance
at VF, n 5 +1 +2 0 +0 +2
INSTI
RAMS, n 4 0 +1
PI RAMs, n 0 +0 +0
NRTI
RAMs, n 3 +1 +2 0 0 +2
21. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
SPRING-2: DTG vs RAL + 2 NRTIs in Naive
Patients
DTG noninferior to RAL at both
Wk 48 primary endpoint[1]
and
Wk 96[2]
Treatment-related study d/c:
2% in each arm at Wk 96
VF atWk 96[2]
: 5% (22/411) in
DTG arm and 7% (29/411) in
RAL arm
Similar CD4+ cell count
increase at Wk 96:
– +276 cells/mm3
(DTG) vs
+264 cells/mm3
(RAL)
HIV-1RNA<50copies/mL(%)
88 85
DTG 50 mg QD
(n = 411)
RAL 400 mg BID
(n = 411)
0
20
40
60
80
100
81
76
Wk 48 Wk 96
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17.
361/
411
351/
411
333/
411
314/
411
Δ: 4.4%
(-1.1% to 10.0%)
Δ: 2.5%
(-2.2% to 7.1%)
22. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC
in Naive Patients at Wk 48
DTG superior to EFV at Wk 48
primary efficacy endpoint
Treatment-related study d/c:
2% in DTG arm vs 10% in EFV
arm
VF at Wk 48: 4% (18/414) in
DTG arm and 4% (17/419) in
EFV arm
CD4+ cell count increase at
Wk 48 greater with DTG:
– +267 cells/mm3
(DTG) vs +208
cells/mm3
(EFV)
(P < .001)
HIV-1RNA<50c/mLatWk48(%)
88
81
Δ +7.4%
(95% CI +2.5% to +12.3%; P = .003)
Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
DTG 50 mg +
ABC/3TC QD
EFV/TDF/
FTC QD
0
20
40
60
80
100
364/
414
340/
419
23. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in
Naive Patients at Wk 48
DTG superior to DRV/RTV at
Wk 48 primary efficacy
endpoint
– Treatment-related study d/c:
2% in DTG arm vs 4% in
DRV/RTV arm
VF at Wk 48: < 1% (n = 2) in
each arm
Similar CD4+ cell count
increase at Wk 48:
– +210 cells/mm³ in each arm
HIV-1RNA<50c/mLatWk48(%)
90
83
Δ +7.1%
(95% CI: +0.9% to +13.2%; P = .025)
Feinberg J, et al. ICAAC 2013. Abstract H1464a.
DTG 50 mg
QD + NRTIs
DRV/RTV
800/100 mg QD
+ NRTIs
217/
242
200/
242
0
20
40
60
80
100
24. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Virologic Suppression at Wk 48 by
Baseline HIV-1 RNA
1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. DeJesus E, et al. Lancet.
2012;379:2429-2438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract H1464a.
≤ 100,000 c/mL
> 100,000 c/mL
SPRING-2[4]
3020100-20 -10
Difference, % (DTG-RAL) and 95% CI
In favor of RAL In favor of DTG
≤ 100,000 c/mL
> 100,000 c/mL
SINGLE[4]
3020100-20 -10
Difference, % (DTG-EFV) and 95% CI
In favor of DTGIn favor of EFV
Study 102[2]
FLAMINGO[5]
≤ 100,000 c/mL
> 100,000 c/mL
3020100-20 -10
Difference , % (DTG-DRV/RTV) and 95% CI
In favor of DTGIn favor of DRV/RTV
40
≤ 100,000 c/mL
> 100,000 c/mL
Difference, % (EVG/COBI-EFV) and 95% CI
In favor of EFV In favor of EVG/COBI
Study 103[3]
-15 -10 -5 5 10 150
≤ 100,000 c/mL
> 100,000 c/mL
Difference, % (EVG/COBI-ATV/RTV) and 95% CI
In favor of ATV/RTV In favor of EVG/COBI
≤ 100,000 c/mL
> 100,000 c/mL
STARTMRK[1]
3020100-20 -10
Difference, % (RAL-EFV) and 95% CI
In favor of EFV In favor of RAL
-15 -10 -5 5 10 150
25. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Similar Efficacy of INSTIs (RAL or DTG) +
ABC/3TC or TDF/FTC, Even for High BL VL
In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or
DTG, including with high BL HIV-1 RNA*
Eron J, et al. Glasgow 2012. Abstract P204.
< 100k 100K - < 250K 250K - 500K > 500K
0
20
40
60
80
100
HIV-1RNA<50c/mLatWk48by
FDASnapshotAnalysis(%)
86
n/
N =
88
225/
257
91
306/
335
36/
42
82
72/
88
81
13/
16
76
29/
38
72
13/
18
64
18/
28
Baseline HIV-1 RNA (c/mL)
TDF/FTC
ABC/3TC
*Pooled data from both INSTIs.
26. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Dolutegravir: Adverse Events Summary
DTG vs RAL[1,2]
– Adverse events similar between
arms
DTG vs EFV[3]
– CNS events and rash more
common with EFV; insomnia
more frequent with DTG
DTG vs DRV/RTV[4]
– More diarrhea with DRV/RTV;
more headache with DTG
DTG associated with small,
rapid increase in serum
creatinine in first 4 wks of tx that
remained stable through Wk 48
(mean change from baseline:
+0.11 mg/dL; range: -0.60 to
0.62 mg/dL)[5]
– Rise in creatinine related to
inhibition of tubular secretion of
creatinine by DTG
– No drug-related
discontinuations due to renal
adverse events
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17.
3. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 4. Feinberg J, et al. ICAAC 2013. Abstract
H1464a. 5. Dolutegravir [package insert].
27. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Resistance Summary
DTG vs RAL[1,2]
– 0 pts with resistance in DTG arm
– 1 pt with INSTI-R and 4 pts with NRTI-R with RAL at Wk 48;
no additional resistance by Wk 96
DTG vs EFV[3]
– 0 pts with resistance in DTG arm
– 1 pt with NRTI and 4 with NNRTI resistance in EFV arm
DTG vs DRV/RTV[4]
– No pts with resistance in either arm
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17. 3. Walmsley
S, et al. N Engl J Med. 2013;369:1807-1818. 4. Feinberg J, et al. ICAAC 2013. Abstract H1464a.
28. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Integrase Inhibitors for Initial Therapy:
Conclusions
While there are many options for initial therapy, regimens
that include an integrase inhibitor have many favorable
characteristics
– All are potent, well tolerated, favorable metabolic profile
– Rates of transmitted (baseline) drug resistance to INSTIs
presumed to be low
– Few drug–drug interactions (RAL, DTG)
– Resistance rarely reported with DTG
– Available as single-pill regimen (EVG)
Integrase inhibitor–based regimens may be appropriate for
many (if not most) treatment-naive patients
30. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Switching Virologically Suppressed
Patients to RAL
SWITCHMRK-1 and -2[1]
– Switching to RAL inferior to remaining on LPV/RTV-based regimen in pts with
HIV-1 RNA < 50 c/mL for > 3 mos, particularly among those with previous VF
– TC, non–HDL-C, and TG improved in switch pts
SPIRAL[2]
– Switching from to RAL noninferior to remaining on boosted PI-based regimens
through Wk 48 in pts with HIV-1 RNA < 50 c/mL for ≥ 6 mos
Switching to RAL significantly improved lipids and TC:HDL-C ratio
EASIER/ANRS 138[3]
– Switch from ENF to RAL regimens maintained virologic suppression through Wk 48
in patients with multidrug resistance and HIV-1 RNA < 400 c/mL for ≥ 3 mos
1. Eron J, et al. Lancet. 2010;375:396-407. 2. Martinez E, et al. AIDS. 2010;24:1697-1707.
3. Gallien S, et al. J Antimicrob Chemother. 2011;66:2099-2106.
31. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Study 123: Switch From RAL + TDF/FTC to
EVG/COBI/TDF/FTC
Open-label, multicenter, 48-wk pilot study of switch from RAL + TDF/FTC to
EVG/COBI/TDF/FTC in pts with HIV-1 RNA < 50 c/mL for 6 mos (N = 48)
Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 12 postswitch
Secondary endpoints: Safety and tolerability by Wk 24 and Wk 48
HIV-1 RNA < 50 c/mL at Wk 24 and Wk 48 postswitch
All subjects maintained virologic
suppression at Wks 12 and 24
– 38/38 subjects who reached
Wk 48 at time of report also
suppressed
TC and LDL-C improved;
no renal AEs
Crofoot G, et al. IAS 2013. Abstract TUPE283.
HIV-1RNA<50c/mL(%)
100
80
60
40
20
0
Wk 12
48/48 48/48 38/38*
Wk 24 Wk 48
32. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Examples of Ongoing INSTI Switch
Studies in Suppressed Pts
Raltegravir (primarily switches for tolerability)
– TDF-based NRTI + boosted PI → RAL + boosted PI in pts with low BMD
– Boosted PI → RAL in HIV/HCV-coinfected pts to assess effect on fibrosis
progression
– NNRTI or boosted PI → RAL to assess effect on lipids
– LPV/RTV → RAL to assess endothelial recovery
– NRTIs + boosted PI → RAL + boosted PI to assess safety and efficacy of
NRTI-sparing regimen
Elvitegravir (primarily switches for simplicity)
– Phase IIIb open-label pilot study: RAL + TDF/FTC → EVG/COBI/TDF/FTC
– Phase IIIb open-label study: NNRTI + TDF/FTC → EVG/COBI/TDF/FTC
– Phase IIIb open-label study: Boosted PI + TDF/FTC → EVG/COBI/TDF/FTC
ClinicalTrials.gov.
34. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
TRIO Study (ANRS 139): RAL + ETR +
DRV/RTV in Treatment-Experienced Pts
Multicenter phase II study of DRV/RTV + ETR + RAL (N = 103); addition of
NRTIs, ENF at discretion of physician
– Inclusion criteria: susceptibility to DRV and ETR based on ≤ 3 DRV and
≤ 3 ETR RAMs, respectively
– 59% of pts had < 1 active agent in OBR, as assessed by GSS
86% of pts reached HIV-1 RNA < 50 c/mL at Wk 48 (95% CI: 79% to 93%)[1]
Of 100 pts entering extension trial through Wk 96, 88% achieved HIV-1 RNA
< 50 c/mL (95% CI: 82% to 94%)[2]
Median CD4+ cell count change: +150 cells/mm3
4 tx-related grade 3/4 AEs reported before Wk 48: recurrent epidermal
necrolysis (n = 1) (study d/c); nephrolithiasis (n = 1); lipodystrophia (n = 1);
muscle spasm (n = 1)
No further events between Wks 48 and 96
1. Yazdanpanah Y, et al Clin Infect Dis. 2009;49:1441-1449.
2. Fagard C, et al. Acquir Immune Defic Syndr. 2012;59:489-493.
35. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Study 145: Elvitegravir vs Raltegravir in
Treatment-Experienced Patients
Randomized, placebo-controlled phase III study
Molina J, et al. Lancet Infect Dis. 2012;12:27-35.
HIV-infected pts,
HIV-1 RNA ≥ 1000
copies/mL,
resistance or 6 mos of
exposure to ≥ 2
antiretroviral classes
(N = 702)
Wk 96
*EVG currently unavailable as single agent.
†
EVG dose reduced to 85 mg QD for pts receiving ATV/RTV or LPV/RTV as part of background regimen.
‡
Background regimen to include fully active RTV-boosted PI, selected using resistance testing.
§
Selected from ENF, ETR, MVC, or NRTI. Option of also adding FTC or 3TC for pts with M184V/I.
Wk 48
Elvitegravir 150 mg (or 85 mg) QD*
+
Boosted PI‡
+ Third Agent§
(n = 351)
Raltegravir 400 mg BID +
Boosted PI‡
+ Third Agent§
(n = 351)
36. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Study 145: EVG Noninferior to RAL at Wks
48 and 96
Similar incidence of
resistance at VF with EVG vs
RAL
– Integrase resistance: 6.6%
vs 7.4%
– OBR resistance: 7.4% vs
7.1%
Both regimens well tolerated
– Higher rates of diarrhea with
EVG at Wks 48 and 96
– Discontinuations: 3% vs 4%
Elion R, et al. J Acquir Immune Defic Syndr. 2013;63:494-497.
100
80
60
40
20
0
Subjects(%)
Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96
Virologic
Response
Virologic
Failure*
Other
59 58
EVG (n = 351)
RAL (n = 351)
48 45
26 29 26 26
22 23 19 19
*VF includes never suppressed, rebound, switch of BR, and
d/c due to lack of efficacy.
Others include death, discontinuation due to AE,
investigator’s discretion, lost to follow-up, pregnancy, protocol
violation, subject noncompliance, withdrawal of consent.
37. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
SAILING: Dolutegravir vs Raltegravir in
ART-Exp’d, Integrase Inhibitor–Naive Pts
Randomized, double-blind, noninferiority, phase III study
Treatment-experienced,
integrase inhibitor–naive
patients with HIV-1 RNA
> 400 copies/mL and
≥ 2 class resistance
(N = 715)
Dolutegravir 50 mg QD
+ Raltegravir placebo + OBR*
(n = 354)
Raltegravir 400 mg BID
+ Dolutegravir placebo + OBR*
(n = 361)
Stratified by number of fully active background
agents, use of DRV, screening HIV-1 RNA
(≤ vs > 50,000 copies/mL) Wk 48
*OBR comprising at least 1 and no more than 2 active agents.
Cahn P, et al. Lancet. 2013;382:700-708.
38. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
SAILING: Superior Rate of Virologic
Suppression With DTG vs RAL at Wk 48
Lower incidence of resistance
at VF with DTG vs RAL
– Integrase resistance: 1%
(4/354) vs 5% (17/361);
P = .003
– OBR resistance: 1% (4/354) vs
3% (12/361)
Both regimens well tolerated
with similar AE profiles
– Grades 2-4: 8% vs 9%
– Discontinuations: 3% vs 4%
No difference in outcome between
study arms when combined with
fully active DRV/RTV
Cahn P, et al. Lancet. 2013;382:700-708.
100
80
60
40
20
0
Subjects(%)
Virologic
Success
Virologic
Nonresponse
No Wk
48 Data
DTG + OBR (n = 354)
RAL + OBR (n = 361)
71
64
20
28
9 9
Δ: 7.4% (95% CI: 0.7-14.2;
P = .03)
39. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
VIKING-3: Dolutegravir After Failure of
Integrase Inhibitor–Based Regimen
Phase III single-arm trial
Mean HIV-1 RNA change from baseline to Day 8
– Overall: -1.4 log10 copies/mL (P < .001)
– No primary integrase resistance mutations at BL: -1.6 log10 copies/mL
– Q148 + ≤ 1 secondary integrase resistance mutation: -1.1 log10 copies/mL
– Q148 + ≥ 2 secondary integrase resistance mutations: -1.0 log10 copies/mL
Nichols G, et al. Glasgow 2012. Abstract O232.
Pts with HIV-1 RNA
≥ 500 c/mL, RAL and/or
EVG resistance, and
resistance to ≥ 2 other
antiretroviral classes*
(N = 183)
Dolutegravir 50
mg BID +
Continue Failing
Regimen
Dolutegravir 50 mg BID +
Optimized Background Regimen With
Overall Susceptibility Score ≥ 1
(ie, ≥ 1 active drug)
Day 8 Wk 24 Wk 48
*Detected at screening or based on historical evidence.
Functional
Monotherapy
Optimized Therapy
40. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
VIKING-3: Efficacy of DTG in
INSTI-Experienced Pts at Wk 48
24-wk data on full cohort
(N = 183) and 48-wk data on
first 114 pts
Response rates affected
by baseline INSTI resistance
but not overall susceptibility
score of background regimen
HIV-1 RNA < 50 c/mL at Wk 24
by INSTI Mutation(s), n/N (%)
Overall Susceptibility Score
0 1 ≥ 2 Total
No Q148 4/4 (100) 35/40 (83) 57/70 (76) 96/114 (79)
Q148 + 1 2/2 (100) 8/12 (67) 10/17 (59) 20/31 (65)
Q148 + ≥ 2 1/2 (50) 2/11 (18) 1/3 (33) 4/16 (25)
Outcome, n (%) Wk 24
(n = 183)
Wk 48
(n = 114)
HIV-1 RNA < 50 c/mL at
Wk 24 (snapshot, ITT-E) 126 (69) 64 (56)
Virologic nonresponse 50 (27) 44 (39)
d/c due to AE or death 5 (3) 5 (4)
Nichols G, et al. IAS 2013. Abstract TULBPE19.
41. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Drug–Drug Interactions With Integrase
Inhibitors and Key Drugs
RAL[1,2]
EVG/COBI[1]
DTG[3]
Rifampin
Antacids
containing
polyvalent cations
(Ca++, Mg++)
Antacids
Benzodiazepines
Beta blockers
Calcium channel
blockers
Erectile dysfunction
drugs
Inhaled/injectable
corticosteroids
MVC
OCPs (norgestimate)
Rifampin
Statins
EFV
ETR
FPV/RTV
Medications containing
polyvalent cations (Ca++,
Mg++), including
laxatives, antacids
Metformin
Rifampin
TPV/RTV
1. DHHS Adult Guidelines. February 2013. 2. Raltegravir [package insert]. 3. Dolutegravir [package insert].
*May be a class effect
42. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Integrase Inhibitors for Treatment-
Experienced Patients: Conclusions
INSTIs appropriate for many treatment-experienced pts
– For INSTI-naive pts, all INSTIs should be active
– DTG superior to RAL, EVG noninferior to RAL
– For INSTI-experienced pts, DTG superior to RAL
– Cross-resistance between EVG and RAL
Difficult to use EVG due to current FDC-only regimen, lack of data
combining FDC with other ARVs
Much clinical experience with RAL as component of new regimens for
pts with NRTI, NNRTI, PI experience
DTG represents a new option for INSTI-experienced pts
– BID dosing recommended for those with INSTI resistance
43. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Raltegravir Summary:
Advantages and Disadvantages
Advantages Disadvantages
INSTI with longest track record of
safety and efficacy—approved in
2007
Noninferior to EFV in initial therapy
at Wk 48 (superior from Wk 192
through Yr 5 final analysis)
Fewer CNS adverse effects, less
rash, and better lipids than EFV
Few drug–drug interactions
No food effect
Conflicting data on efficacy in switch
strategies
Integral part of many regimens in
treatment-experienced pts
Twice-daily dosing
No FDC available or planned
Rare CNS, cutaneous, and muscle-
related adverse effects
Inferior to DTG in treatment-
experienced patients
Risk of resistance at VF, especially in
treatment-experienced pts
When VF failure occurs with
resistance, 2-class resistance is
common
44. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Elvitegravir Summary:
Advantages and Disadvantages
Advantages Disadvantages
Only INSTI currently available as a
1-pill once-daily regimen
Noninferior to EFV and ATV/RTV in
initial therapy
Maintains antiviral activity as well as
comparators across HIV-1 RNA and
CD4+ cell count strata
Fewer CNS adverse effects, less
rash, and better lipids than EFV
Less jaundice than ATV/RTV
Appears to be effective switch
regimen for patients on first-line RAL
Noninferior to RAL in treatment-
experienced patients
Not recommended for patients with
eGFR < 70 mL/min
Must be taken with food
Cobicistat inhibits tubular secretion of
creatinine, increasing Cr levels
More nausea than EFV
Risk of resistance at VF, especially in
treatment-experienced patients
When VF occurs with resistance,
2-class resistance is common
Many COBI-related drug–drug
interactions
Currently only available in FDC,
limiting regimen flexibility
45. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Dolutegravir Summary:
Advantages and Disadvantages
Advantages Disadvantages
Once-daily administration
Small mg dose and tablet size
Noninferior to RAL and superior to
EFV and DRV/RTV
Maintains comparable or better
virologic activity to EFV, RAL,
DRV/RTV across low and high HIV-
1 RNA
Fewer CNS and rash events vs EFV
When VF occurs, no integrase
resistance mutations as yet detected
in treatment-naive patients
Few drug–drug interactions
Can be taken with or without food
Not yet available as part of FDC
Inhibits tubular secretion of
creatinine, increasing Cr levels
Relatively little clinical experience
compared with RAL (especially) and
EVG
46. Go Online for More Educational
Content on Integrase Inhibitors!
Interactive Virtual Presentation with faculty commentary and case
studies illustrating the use of integrase inhibitors across the treatment
spectrum
clinicaloptions.com/Integrase2013
Editor's Notes
Hello, my name is Dr. Joseph Eron. I am a Professor of Medicine and Director of the AIDS Clinical Trials Unit at the University of North Carolina in Chapel Hill. I would like to welcome you to this CME-certified program about the Evolving Role of Integrase Inhibitors in HIV Therapy.
You are invited to use these slides for personal study or in your own noncommercial presentations.
I was the Program Director for this activity and worked with Paul E. Sax, MD, and Kimberly Y. Smith, MD, MPH, to pull together the comprehensive content in this program.
These are the disclosures for faculty members.
Let’s move on to our program: The evolving role of integrase inhibitors in HIV therapy.
We will first discuss the viral life cycle and mechanisms of action of the various HIV medications.
As HIV infects cells, it must go through multiple steps: it first has to attach and fuse to the cell. The next step is reverse transcription of the viral RNA to DNA; there are many inhibitors that block that step. The next critical step is the integration of the reverse transcribed viral DNA into the host DNA. This step is critical: If viral DNA is not integrated into host DNA, the virus cannot replicate.
This integration is catalyzed by an HIV-encoded enzyme called integrase. Since this is a viral enzyme, not a human enzyme, integrase has been a target for drug development for quite a while. After the virus has integrated it is transcribed along with the host DNA; and then comes translation and assembly of host and viral proteins. Protease inhibitors work during the assembly process; mature viral particles that are infectious are not possible without active proteases.
There are now 3 integrase inhibitors available in the United States. Raltegravir has been available for 6 years. Elvitegravir was approved in 2012 but in the United States is currently available only in a fixed-dose, coformulated single-tablet regimen. Dolutegravir was most recently approved—in August 2013. This program will address all 3 of these drugs.
How do these integrase inhibitors currently fit into our guidelines? Since October 2013, all three are now components of preferred first-line regimens.
Raltegravir combined with tenofovir disoproxil fumarate (DF)/emtricitabine is a preferred regimen in both the US Department of Health and Human Services (DHHS) and International Antiviral Society (IAS)–USA guidelines. Raltegravir in combination with abacavir/lamivudine is an alternative regimen. In October 2013, the US Department of Health and Human Services issued a recommendation specifically about integrase inhibitors in which it upgraded the elvitegravir/cobicistat fixed-dose regimen to preferred status and also added dolutegravir plus either tenofovir/emtricitabine or abacavir/lamivudine to the preferred category.
The elvitegravir/cobicistat fixed-dose regimen must be given with food and should be given only to patients with estimated CrCl ≥ 70 mL/min. The other 2 integrase inhibitors can be given without regard to food. Regimens that contain abacavir/lamivudine should be given only to patients who are HLA-B*5701 negative.
Let’s discuss studies of integrase inhibitors in treatment-naive patients.
BID, twice daily; EFV, efavirenz; FTC, emtricitabine; QHS, dosed at bedtime; TDF, tenofovir.
The STARTMRK study compared raltegravir head to head with efavirenz in treatment-naive patients. This was a randomized double-blinded study through 5 years. Both drugs were paired with the fixed-dose combination tenofovir DF/emtricitabine.
EFV, efavirenz; ITT, intent to treat; NC = F, noncompleter equals failure; RAL, raltegravir.
At the 48-week primary endpoint analysis, raltegravir was noninferior to efavirenz with respect to the percentage of patients with HIV-1 RNA &lt; 50 copies/mL. Over the rest of the study, however, there was a gradual separation between the efficacy seen in the 2 arms. By the fourth year, the efficacy result in the raltegravir arm was actually superior to that seen in patients treated with efavirenz. At the final time point the difference was 10%; this met the criteria for noninferiority and superiority, favoring raltegravir. Over the course of the study, both therapies were very effective; the subtle difference that occurred over time was predominantly driven by tolerability.
CNS, central nervous system; EFV, efavirenz; INSTI, integrase strand transfer inhibitor; RAL, raltegravir; VF, virologic failure.
We generally describe both raltegravir and efavirenz as having a low barrier to resistance. In one sense, that’s true: If there is virologic rebound with these drugs, mutations almost always develop. However, this slide shows that virologic rebound and resistance with these drugs is actually quite uncommon, even over a 5-year study. The table demonstrates that there were 55 patients in the raltegravir arm and 59 patients in the efavirenz arm that had protocol-defined virologic failure and were available for resistance testing. The number of patients in the raltegravir arm that developed integrase resistance was actually quite smalla total of 4and 6 developed NRTI resistance. For efavirenz, you see a similar result: NNRTI resistance was slightly more commonthere were 10 patients that had NNRTI resistance. NRTI resistance was numerically slightly less: Only 5 patients developed NRTI resistance.
CD4+ cell count responses were very good in both arms. As we’ve seen before, the CD4+ cell count increase was greater with raltegravir than efavirenzwhether that’s statistically significant is unclear. There were fewer central nervous system (CNS) adverse events, fewer drug-related adverse events, and fewer discontinuations with raltegravir vs efavirenz.
BID, twice daily; BL, baseline; FTC, emtricitabine; ITT, intent to treat; NC = F, noncompleter equals failure; QD, once daily; RAL, raltegravir; TDF, tenofovir; VF, virologic failure.
A problem often cited with raltegravir is the need for twice-daily administration. The QDMRK study compared once-daily raltegravir with twice-daily raltegravir, both with tenofovir DF/emtricitabine, in treatment-naive patients. After 48 weeks, 83% of those on the once-daily regimen had HIV-1 RNA &lt; 50 copies/mL vs 89% on the twice-daily regimen. Upon statistical analysis, the response with the once-daily regimen was inferior to that seen with the twice-daily regimen.
When the results were examined more fully, it was evident that there were nearly twice as many patients30 vs 16with virologic failure in the once-daily arm. Not surprisingly, there were also more patients with resistance—20 patients had evidence of resistance on once-daily raltegravir compared with 4 on the twice-daily schedule. Many interpret this as solid evidence that in treatment-naive patients starting therapy, raltegravir should be administered as a twice-daily medication.
A more recent study of 2 new formulations of raltegravir administered as 1200 mg once daily showed that these agents had favorable pharmacokinetics in the fed or fasted state in healthy patients. They are being studied for potential development.
ATV, atazanavir; COBI, cobicistat; EFV, efavirenz; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; RTV, ritonavir; TDF, tenofovir.
Let’s now address the elvitegravir combination regimen. In order for elvitegravir to be active and have adequate pharmacokinetics, it must be administered with a pharmacologic booster, such as cobicistat or ritonavir. There were 2 large, randomized phase III trials of elvitegravir/cobicistat, one comparing it with efavirenz and the other comparing it with atazanavir/ritonavir. The partner NRTIs in both of these trials were tenofovir DF and emtricitabine. As we noted above, elvitegravir, cobicistat, tenofovir DF, and emtricitabine are all combined in a single tablet.
The studies are randomized, double-blind, active-controlled, phase III studies; the study designs appear on this slide.
BL, baseline; COBI, cobicistat; d/c, discontinuation; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; TDF, tenofovir; VF, virologic failure.
This slide illustrates the comparison of the single-tablet elvitegravir/cobicistat regimen with the single-tablet efavirenz regimen; this study has now reported data through 144 weeks. What can be seen consistently over time is that both regimens are very effective. At Week 48, the proportion with HIV-1 RNA &lt; 50 copies/mL with the integrase inhibitor regimen was 88%. If we go back and compare that with the results of raltegravir in STARTMRK at 48 weeks (86% with HIV-1 RNA &lt; 50 copies/mL), the results are very similar.
Efficacy with the elvitegravir/cobicistat regimen was numerically better than with the efavirenz regimen at all 3 time points—48, 96, and 144 weeks—and statistically meet the criteria for noninferiority. The results are consistent across multiple demographic and disease subgroups. Treatment-related discontinuations are similar between treatment arms; the rate of virologic failure at 144 weeks was 3% higher in the efavirenz arm than in the elvitegravir/cobicistat arm. CD4+ cell count increases were also similar; so overall, this trial demonstrates very similar effects of elvitegravir/cobicistat in a fixed-dose combination compared with efavirenz in a fixed-dose combination, both with tenofovir/emtricitabine.
ATV, atazanavir; BL, baseline; COBI, cobicistat; d/c, discontinuation; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir; VF, virologic failure.
This slide illustrates the comparison between the elvitegravir/cobicistat fixed-dose combination and atazanavir/ritonavir plus a separate tablet of tenofovir/emtricitabine over 144 weeks. Again, please notice the efficacy of the integrase strand transfer inhibitor (INSTI) regimen: 90% of patients reached HIV-1 RNA &lt; 50 copies/mL at 48 weeks. As well, there was very little difference between the 2 treatment arms in this trial; elvitegravir/cobicistat attained the criteria for noninferiority to the boosted PI regimen. The results in this trial were consistent across the various demographic and disease subgroups that were studied such as baseline viral load, baseline CD4+ cell count, adherence, age, race, sex, and so on.
Treatment discontinuations were slightly fewer with elvitegravir/cobicistat compared with atazanavir/ritonavir, and the number of virologic failures was similar. CD4+ cell count increases were also similar, so it’s quite clear that the overall efficacy and tolerability of these regimens were very similar.
ATV, atazanavir; CNS, central nervous system; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; HDL-C, high density lipoprotein-cholesterol; LDL-C, low density lipoprotein-cholesterol; RTV, ritonavir; TC, total cholesterol; TDF, tenofovir; TG, triglycerides.
When one compares elvitegravir/cobicistat with efavirenz, there are clearly fewer CNS toxicities, fewer rash events, and smaller increases in total cholesterol, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol, but it’s important to note that the total cholesterol/HDL cholesterol ratio actually did not increase among efavirenz patients. There were similar changes in triglycerides; so while the rash and the CNS effects probably have clinical importance, the cholesterol and triglyceride effects probably have limited, if any, clinical significance. There was more nausea with elvitegravir/cobicistat, although the nausea seen with this regimen tends to be quite short-lived.
In the comparison between elvitegravir/cobicistat with atazanavir/ritonavir, there was less jaundice with elvitegravir/cobicistat. Regarding lipids, increases in the cholesterol fractions were all similar, but with elvitegravir/cobicistat there was a smaller triglyceride increase that that seen with the boosted PI regimen.
It’s important to remember that with any cobicistat-including regimen, a small but rapid increase in serum creatinine of approximately 0.14 or 0.15 mg/dL will occur. It usually occurs quickly, by Week 2. This is not an effect on renal function; the effect is due to a decrease in creatinine excretion in the proximal tubule.
On the other hand, we do know that tenofovir causes tubulopathy. There were actually 4 cases of tubulopathy very early, in the first 24-48 weeks of Study 102. The good news is that over the rest of the 144 weeks there were no more cases of tubulopathy with elvitegravir/cobicistat; and in the 103 study, compared with atazanavir/ritonavir, there were no cases of tubulopathy that developed in the elvitegravir/cobicistat arm.
ATV, atazanavir; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; PI, protease inhibitor; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; VF, virologic failure.
If we review the resistance data from these studies, one of the main points is that even though elvitegravir is boosted by cobicistat, the resistance patterns are not those of a boosted protease inhibitor. The resistance patterns one sees with elvitegravir/cobicistat are similar to those seen with raltegravir.
In Study 102, over 144 weeks, a total of 10 patients developed resistance, a similar number to what we saw in the STARTMRK trial. For efavirenz, the number is slightly higher—14 patients. With elvitegravir/cobicistat, we are more likely to see integrase resistance and NRTI resistance at similar rates, whereas with efavirenz one sees NNRTI resistance in nearly every patient with resistance and fewer with NRTI resistance.
If we look at Study 103, there are very similar data for elvitegravir/cobicistat: 8 patients developed resistance over 144 weeks. With atazanavir/ritonavir we see a pattern evident in many trials of first-line therapy with boosted PIs, that is, no resistance to either boosted PIs or NRTIs at virologic failure over the first 96 weeks; between 96 weeks and 144 weeks, 2 patients developed NRTI resistance.
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BID, twice daily; CrCL, creatinine clearance; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; QD, once daily; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; VL, viral load.
Dolutegravir is the newest antiretroviral drug and also the newest INSTI. The phase III clinical trial program compared dolutegravir in 3 separate trials with drugs in the preferred regimens in each of the three classes. The SPRING-2 study was a double-blinded head-to-head comparison of dolutegravir with raltegravir with a choice of NRTIs, either tenofovir DF/emtricitabine or abacavir/lamivudine. The SINGLE study was a head-to-head double-blind study vs efavirenz; in this case, dolutegravir was always paired with abacavir/lamivudine and efavirenz was given as the single-tablet coformulated regimen, efavirenz/tenofovir DF/emtricitabine. The FLAMINGO study was an open-label head-to-head comparison with darunavir/ritonavir, with a choice of NRTIs by investigator.
BID, twice daily; d/c, discontinuation; DTG, dolutegravir; QD, once daily; RAL, raltegravir; VF, virologic failure.
In the SPRING-2 study—the comparison of dolutegravir with raltegravir—approximately two thirds of patients were also treated with tenofovir/emtricitabine, the rest with abacavir/lamivudine. At 48 weeks, 88% of patients treated with dolutegravir had HIV-1 RNA &lt; 50 copies/mL. Again, this is very similar to other first-line studies of INSTIs. The response to raltegravir is slightly lower, with dolutegravir clearly meeting the criteria for noninferiority. At 96 weeks, 81% vs 76% had HIV-1 RNA, respectively—slightly more than a 4% difference favoring dolutegravir and maintaining the criteria for noninferiority.
Treatment-related study drug discontinuation was very low: 2% in each arm at 96 weeks. Virologic failures were 5% in the dolutegravir arm and 7% in the raltegravir arm; the CD4+ cell count increases were the same in each arm.
3TC, lamivudine; ABC, abacavir; d/c, discontinuation; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; QD, once daily; TDF, tenofovir; VF, virologic failure.
The SINGLE study compared dolutegravir plus abacavir/lamivudine with efavirenz as part of the fixed-dose combination with tenofovir DF/emtricitabine. The 48-week data showed that 88% of those treated with the INSTI dolutegravir reached HIV-1 RNA &lt; 50 copies/mL, but only 81% of those treated with efavirenz reached this endpoint; this difference of 7.5% meets the criterion for statistical superiority. This is the first example of a regimen attaining superiority to fixed-dose efavirenz/tenofovir DF/emtricitabine at the 48-week primary endpoint. It was clear that this difference was primarily driven by treatment-related study discontinuation: 2% with dolutegravir vs 10% with efavirenz. Virologic failure was 4% in both arms.
There is a difference in CD4+ cell count response—the difference is 60 cells/mm³, which is statistically significant. We’ve seen this lower CD4+ cell count response with efavirenz in many studies but it is unclear whether this difference is clinically relevant.
d/c, discontinuation; DRV, darunavir; DTG, dolutegravir; QD, once daily; RTV, ritonavir; TDF, tenofovir; VF, virologic failure.
The FLAMINGO trial is an open-label head-to-head comparison of dolutegravir vs darunavir/ritonavir; as in SPRING-2, the investigators could select between tenofovir DF/emtricitabine and abacavir/lamivudine. Approximately 60% chose tenofovir DF/emtricitabine and 40% chose abacavir/lamivudine. With the INSTI dolutegravir, 90% reached HIV-1 RNA &lt; 50 copies/mL vs 83% with darunavir/ritonavir. This 7% difference and the 95% confidence interval meets the criteria both for noninferiority and superiority of dolutegravir vs darunavir/ritonavir. Treatment-related discontinuations favored dolutegravir by 2%. Virologic failures were very low in both arms. However, there were numerically more administrative failures—patients that dropped off the study—in the darunavir/ritonavir arm and when this was added to the difference in treatment discontinuation, the superiority threshold was reached. CD4+ cell count responses were 210 cells/mm³ in each arm.
ATV, atazanavir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir.
If we look at virologic suppression at 48 weeks across all the INSTI studies that we’ve discussed and how this endpoint is affected by viral load, we can see some interesting patterns. In STARTMRK, raltegravir was noninferior to efavirenz at 48 weeks. We see similar responses at both high versus low baseline viral loads with perhaps a slightly better response with raltegravir in the lower viral load stratum. In Study 102, elvitegravir/cobicistat is slightly favored in both low and high baseline viral load groups. In Study 103, again, elvitegravir/cobicistat is slightly favored, but not significantly in the comparison.
In the SPRING-2 study, the dolutegravir arm is similar to raltegravir in the baseline low viral load stratum, with a possible difference in those with high baseline viral loads. In SINGLE, dolutegravir is slightly favored over efavirenz in both of the viral load subgroups. And finally, in the FLAMINGO study comparing dolutegravir with darunavir/ritonavir, responses in the stratum below 100,000 copies were quite comparable; however, among those with baseline viral loads &gt; 100,000 copies/mL, responses numerically and statistically favored dolutegravir.
It will be very important that we determine the reasons for this apparent superiority. When these studies are published, we’ll want to assess virologic failures, toxicity failures, and administrative failures before concluding whether or not this represents a difference in potency, since multiple factors are reflected in the overall combined endpoint used in the US Food and Drug Administration snapshot analysis.
3TC, lamivudine; ABC, abacavir; BL, baseline; DTG, dolutegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; RAL, raltegravir; TDF, tenofovir; VL, viral load.
What about partner drugs for the integrase inhibitors? Are they different? The SPRING-2 study compared dolutegravir with raltegravir, each paired with abacavir/lamivudine or tenofovir DF/emtricitabine. We know from ACTG 5202 that abacavir/lamivudine was not as effective as tenofovir DF/emtricitabine at high baseline viral loads when partnered with efavirenz or atazanavir/ritonavir. But when we look at the SPRING-2 study, even at higher viral loads abacavir/lamivudine appears to be performing just as well if not numerically better than tenofovir DF/emtricitabine. When my group presented this study last year, we also looked at the endpoint of time to virologic failure and this was also not different between abacavir/lamivudine and tenofovir DF/emtricitabine—regardless of the partner INSTI—when comparing patients with low and high baseline viral load.
CNS, central nervous system; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; RAL, raltegravir; RTV, ritonavir; tx, treatment.
Let’s review adverse events with dolutegravir. We saw in the SPRING-2 study of dolutegravir and raltegravir that they are both very tolerable with few adverse events. In the SINGLE study of dolutegravir vs efavirenz, remember that overall efficacy results were driven by tolerability. There were more treatment-related discontinuations with efavirenz, predominantly due to CNS events and rash. In the FLAMINGO study of dolutegravir vs darunavir/ritonavir, more diarrhea was documented with darunavir/ritonavir and more headache with dolutegravir. Side effects in both arms were relatively mild.
It is important to remember that dolutegravir, like cobicistat, is associated with a rise in serum creatinine of about 0.1-0.2 mg/dL. This happens within the first 2-4 weeks and tends to be stable over time. It is also due to inhibition of tubular secretion of creatinine by dolutegravir, although dolutegravir inhibits a different transporter than cobicistat. The overall effect is, however, similar.
DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; INSTI, integrase strand transfer inhibitor; R, resistance; RAL, raltegravir; RTV, ritonavir.
When we consider resistance, there is a clear difference between dolutegravir and raltegravir. In the head-to-head comparison of dolutegravir and raltegravir—the SPRING-2 study—no patients developed resistance either to INSTIs or NRTIs in the dolutegravir arm. There was only 1 patient in the raltegravir arm who developed integrase resistance, but there were 4 who developed NRTI resistance.
In the comparison of dolutegravir vs efavirenz—–the SINGLE study—once again, no patients in the dolutegravir arm developed integrase or NRTI resistance, whereas 1 patient on efavirenz developed NRTI resistance and 4 patients developed NNRTI resistance. And finally, in FLAMINGO, the head-to-head comparison of dolutegravir with darunavir/ritonavir, no patients in either arm developed resistance to protease inhibitors, integrase inhibitors, or NRTIs. In addition, there were only 2 patients with virologic failures in each arm.
DTG, dolutegravir; EVG, elvitegravir; INSTI, integrase strand transfer inhibitor; RAL, raltegravir.
There are now several INSTIs available for initial therapy of HIV-infected persons. All are potent and well tolerated, with favorable metabolic profiles. We believe that transmitted resistance to integrase inhibitors is currently low. Raltegravir and dolutegravir have relatively few drug-drug interactions. Resistance seems to be less common with dolutegravir. Currently, there is 1 single-tablet regimen containing an INSTI (elvitegravir/cobicistat/tenofovir DF/emtricitabine). I believe it’s a reasonable conclusion that INSTI-based regimens may be appropriate for many of your patients that are treatment naive.
ENF, enfuvirtide; HDL-C, high density lipoprotein-cholesterol; LPV/RTV, lopinavir/ritonavir; PI, protease inhibitor; RAL, raltegravir; TC, total cholesterol; TG, triglycerides; VF, virologic failure.
There have been several switch studies with raltegravir; in SWITCHMRK 1 and 2, a lopinavir/ritonavir-based regimen was switched to a raltegravir-based regimen, but in this study the switch did not meet noninferiority. This was a blinded and relatively complicated study.
Another study, SPIRAL, had a very similar design. It was an open-label switch from any boosted PI regimen to a raltegravir regimen; in this case, the switch to raltegravir was noninferior when considering the proportion with HIV-1 RNA &lt; 50 copies at 48 weeks after the switch. Switching to raltegravir in both studies—both SWITCHMRK and SPIRAL—improved lipids and the total cholesterol-to-HDL ratio. There’s also evidence in the SPIRAL study that some inflammatory markers improved by switching to raltegravir.
In the EASIER study, switching from enfuvirtide to raltegravir was effective, and patients were able to maintain virologic suppression.
AE, adverse event; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; LDL-C, low density lipoprotein-cholesterol; RAL, raltegravir; TC, total cholesterol; TDF, tenofovir.
Study 123 assessed the switch from raltegravir and tenofovir DF/emtricitabine as separate agents, to the fixed-dosed combination elvitegravir/cobicistat/tenofovir DF/emtricitabine. This is a small study with 48 patients but so far all those patients that have switched and have reached 48 weeks after the switch have maintained a suppressed viral load. When one considers this switch, it is important to realize that a trade-off is being made: the simplicity of a single-tablet regimen but with the potential for more drug‑drug interactions and a low level of nausea at the time of the switch.
BMD, bone mineral density; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; HCV, hepatitis C virus; LPV/RTV, lopinavir/ritonavir; PI, protease inhibitor; RAL, raltegravir; TDF, tenofovir DF.
This slide lists many of the ongoing studies of switches to INSTIs. There are many phase III switch studies ongoing, from a variety of regimens to raltegravir and to elvitegravir/cobicistat/tenofovir DF/emtricitabine.
Let’s review studies of integrase inhibitors in treatment-experienced patients.
AE, adverse event; d/c, discontinuation; DRV, darunavir; ENF, enfuvirtide; ETR, etravirine; GSS, genotypic susceptibility score; OBR, optimized background regimen; RAL, raltegravir; RAM, resistance associated mutation; RTV, ritonavir; tx, treatment.
The TRIO study included highly treatment-experienced patients who were naive to integrase inhibitors. This study was undertaken when 3 new drugs had become available: raltegravir, etravirine, and darunavir/ritonavir. Giving 3 active potent drugs to patients as a new regimen should provide a very potent regimen. In this study, 88% of 100 patients had HIV-1 RNA &lt; 50 copies/mLat 96 weeks.
3TC, lamivudine; ATV/RTV, atazanavir/ritonavir; BID, twice daily; ENF, enfuvirtide; ETR, etravirine; EVG, elvitegravir; FTC, emtricitabine; LPV/RTV, lopinavir/ritonavir; MVC, maraviroc; PI, protease inhibitor; QD, once daily; RAL, raltegravir.
Study 145 compared elvitegravir with raltegravir in treatment-experienced patients, each paired with a boosted PI plus a third agent (a regimen that at this time, is unavailable in the United States). The boosted PI and the third agent were chosen before the random assignment to the INSTI. These were treatment-experienced, integrase-naive patients and they had to have resistance or exposure to 2 or more antiretroviral classes.
AE, adverse event; BR background regimen; d/c, discontinuation; EVG, elvitegravir; OBR, optimized background regimen; RAL, raltegravir; VF, virologic failure.
At 48 weeks and 96 weeks, response rates were very similar between elvitegravir and raltegravir: 58% and 59%, respectively, achieved HIV-1 RNA &lt; 50 copies/mL at 48 weeks, and 48% and 45% achieved the same endpoint at 96 weeks. Virologic failure was slightly more common with raltegravir, and nonvirologic failure (tolerability or loss to follow up) was very similar between the 2 groups. This suggests that when paired with a boosted PI, the tolerability of elvitegravir and raltegravir were very similar. Integrase resistance occurred in roughly 7% of the virologic failures, slightly higher than but not significantly different from raltegravir. Discontinuations were similar between the 2 groups.
ART, antiretroviral therapy; BID, twice daily; DRV, darunavir; OBR, optimized background regimen; QD, once daily.
The SAILING study was recently published. This was a randomized double study comparing dolutegravir with raltegravir in antiretroviral therapy–experienced, but integrase-naive patients. This study did not require pairing the drugs with a boosted PI, because there is no boosting requirement for either dolutegravir or raltegravir. The patients were treatment experienced, with at least 2-class resistance, and they had to be susceptible to an optimized background compromising at least 1 but no more than 2 fully active agents.
AE, adverse event; DTG, dolutegravir; DRV, darunavir; OBR, optimized background regimen; RAL, raltegravir; RTV, ritonavir; VF, virologic failure.
At 48 weeks, the dolutegravir arm was actually superior to the raltegravir arm with 71% vs 64% reaching HIV-1 RNA &lt; 50 copies/mL at 48 weeks. In this case, the difference is driven by virologic nonresponse. Both regimens are quite well tolerated, so the discontinuation rate was low and similar between the 2 arms. Integrase resistance was only seen in 1% (4 patients) in the dolutegravir arm compared with 5% (17 patients) on raltegravir but this difference was statistically significant. Resistance to background agents was also low among those on dolutegravir—1%—compared with 3% with raltegravir. So it appears that the patterns with resistance to dolutegravir seen in the studies of treatment-naive patients were seen once again in this more experienced population.
BID, twice daily; BL, baseline; EVG, elvitegravir; RAL, raltegravir.
The VIKING study assessed treatment-experienced patients with integrase inhibitor resistance. All patients in this study had a history of integrase resistance; they were not required to have integrase resistance at baseline. The 183 individuals that entered the trial received dolutegravir functional monotherapy for an 8-day period to test the activity of dolutegravir in these patients, and then at Day 8, their regimen was optimized. They were required to be susceptible to 1 fully active drug in the background regimen and were given that along with dolutegravir. In this study, dolutegravir was given at a dose of 50 mg twice daily.
Over the 8-day monotherapy period, it was clearly seen that dolutegravir demonstrated activity against viruses that have INSTI resistance. The best result was seen in those with a history of integrase resistance but no integrase resistance mutations at baseline. These patients had a decrease in HIV-1 RNA of 1.5 log10 copies/mL. Those that had 1 integrase mutation with Q148 still had a good response, but slightly less than those with no mutations. However, if Q148 was paired with ≥ 2 integrase mutations, there was a diminution of effect.
AE, adverse event; BL, baseline; d/c, discontinuation; DTG, dolutegravir; INSTI, integrase strand transfer inhibitor; ITT-E, intent-to-treat, exposed.
At Weeks 24 and 48, the proportion of patients with HIV-1 RNA &lt; 50 copies/mL was 69% and 56% overall. Most of the treatment failure was virologic nonresponse; very little was due to discontinuation due to adverse event. As shown in in the lower table, among patients with no mutation at locus 148 (so among patients with no mutations or mutations at loci 143 or 155), nearly 80% had a virologic response at Week 24. On the other hand, in those with mutations at locus 148 plus ≥ 2 mutations, the response rate was substantially lower. The number of patients with this many mutations is fairly small but response to dolutegravir will be attenuated.
COBI, cobicistat; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; EVG, elvitegravir; FPV, fosamprenavir; MVC, maraviroc; OCPs, oral contraceptive pills; RAL, raltegravir; RTV, ritonavir; TPV, tipranavir.
This slide summarizes some of the key drug-drug interactions with integrase inhibitors. It is important to realize that one will see many of the same interactions with cobicistat as with ritonavir. Rifampin affects all of the INSTIs; rifampin can be used with raltegravir or dolutegravir, but there is a recommendation for dose adjustment.
Dolutegravir and raltegravir should not be dosed at the same time as antacids or laxatives that contain calcium or magnesium (this may be a class effect, but is mentioned in the prescribing information for these 2 drugs). There also is a theoretic interaction with metformin of which one should be aware.
ARV, antiretroviral; BID, twice daily; DTG, dolutegravir; EVG, elvitegravir; FDC, fixed-dose combination; INSTI, integrase strand transfer inhibitor; PI, protease inhibitor; RAL, raltegravir.
So, let’s summarize: integrase inhibitors are clearly appropriate as a component of antiretroviral regimens for many treatment-experienced patients. Dolutegravir seems to be the best choice for most treatment-experienced patients who are integrase naive. With integrase inhibitor–experienced patients, dolutegravir is the only choice, and it should be dosed at 50 mg twice daily.
CNS, central nervous system; DTG, dolutegravir; EFV, efavirenz; FDC, fixed-dose combination; INSTI, integrase strand transfer inhibitor; VF, virologic failure.
Let’s summarize some advantages and disadvantages of raltegravir. We have the most experience with this drug; it is 6 years since its approval. There are few drug-drug interactions and no substantial food effect. Although the switch data were conflicting, in the right setting switches to raltegravir-based regimens are safe and effective. Raltegravir’s disadvantages include twice-daily dosing; and there are no fixed-dose combinations available with raltegravir.
ATV, atazanavir; CNS, central nervous system; COBI, cobicistat; Cr, creatinine; EFV, efavirenz; eGFR, estimated glomerular filtration rate; FDC, fixed-dose combination; INSTI, integrase strand transfer inhibitor; RAL, raltegravir; RTV, ritonavir; VF, virologic failure.
Elvitegravir has the advantage of currently being included in the only INSTI single-tablet regimen. Longer-term data are accumulating and there is much interest in this elvitegravir/cobicistat/tenofovir DF/emtricitabine combination regimen as part of a switch strategy. There are disadvantages: It is not recommended for patients with an estimated glomerular filtration rate 70 mL/min, and there is a food requirement for this drug. With cobicistat, there are many drug–drug interactions plus a benign increase in creatinine that needs to be taken into account when monitoring patients. For the time being, elvitegravir is only available as part of this fixed-dose combination, so there are limited possibilities for its use.
Al, aluminum; Ca, calcium; CNS, central nervous system; Cr, creatinine; DRV/RTV, darunavir/ritonavir; EFV, efavirenz; EVG, elvitegravir; FDC, fixed-dose combination; Fe, iron; Mg, magnesium; RAL, raltegravir; VF, virologic failure.
Finally, dolutegravir is the only INSTI that is dosed once daily and does not require a pharmacologic booster. It’s been already compared with 3 of the preferred regimens in the US treatment guidelines for treatment-naive patients and has compared favorably to all 3. As yet, in treatment-naive patients, we have not seen emergence of resistance at virologic failure. There appear to be few drug–drug interactions, and it can be taken with and without food. Some disadvantages: It’s not yet available as part of a fixed-dose combination, and there is a creatinine effect with its use that one should monitor.