Options for the treatment of HIV: A review

Abstract

CDC has estimated that approximately 1.2 million people in the United States were living with HIV infection at the end of 2011 (the most recent year for which data are available).1www.cdc.gov/hivGoogle Scholar Of those 1.2 million people, around 1 in 7—close to 170,000—were unaware of their infection status.1www.cdc.gov/hivGoogle Scholar For pharmacists who do not regularly dispense medications for the treatment of HIV, understanding treatment complexities for these patients can be intimidating.Regimen selectionA good place to start when attempting to understand the nuances of HIV treatment is the HIV life cycle itself. The replication of HIV is a multistage process, with each stage crucial for successful replication.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg Because each stage is critical, each is a potential target for antiretroviral therapy.The goal of highly active antiretroviral therapy (HAART) is to attack the virus at various points throughout the life cycle, leading to inhibition of the replication process.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf In general, HAART uses at least three different antiviral drugs from at least two different classes.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf The classes of medications available for the treatment of HIV are shown in Figure 1.The ideal initial regimen for patients who have not been previously treated typically contains two nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) in combination with either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) boosted with ritonavir (Norvir—AbbVie), or an integrase strand transfer inhibitor (INSTI).5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfRegimen selection varies widely and depends on a multitude of factors.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf A full review of available treatment options is available in the guidelines developed by the Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfLet's briefly review the stages of the HIV life cycle and the medication classes that inhibit each (Figure 2) .5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfFigure 2HIV life cycle 3,4View Large Image Figure ViewerDownload (PPT)HIV life cycleFirst stage. The first stage is binding, fusion, and subsequent entry of the virus into a single host CD4 cell.2-4 Infection of the host cell requires the presence of the CD4 receptor and coreceptors (i.e., CCR5, CXCR4) on the host cell membrane.4 Glycoproteins on the surface of the HIV cell attach to the CD4 receptor.4 Coreceptor attachment then occurs, leading to a conformational change in HIV glycoproteins.4The coreceptors then draw the two cell membranes together, and fusion eventually occurs.4www.youtube.com/watch?v=PdzFvxfDGbg The viral capsid enters the CD4 cell and releases two viral RNA strands and the three essential replication enzymes: reverse transcriptase, integrase, and protease.4www.youtube.com/watch?v=PdzFvxfDGbgSecond and third stages. In the second stage, reverse transcriptase converts viral RNA into a DNA double helix through reverse transcription.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg Following reverse transcription, the integrase enzyme cleaves portions of the newly created DNA double helix in the third stage of the life cycle, creating two sticky ends.4www.youtube.com/watch?v=PdzFvxfDGbg This allows for transfer and integration of the viral DNA into the host cell genome within the nucleus of the CD4 cell.4www.youtube.com/watch?v=PdzFvxfDGbgFourth through sixth stages. The CD4 cell becomes activated, and transcription of proviral DNA into messenger RNA (mRNA) occurs.4www.youtube.com/watch?v=PdzFvxfDGbg The mRNA then migrates into the cytoplasm, where building blocks for a new virus are synthesized.4www.youtube.com/watch?v=PdzFvxfDGbgLarge proteins are then cleaved into smaller core proteins by viral proteases.4www.youtube.com/watch?v=PdzFvxfDGbg Two viral RNA strands and the replication enzymes come together, and the core proteins assemble around them, forming a capsid for a new HIV-1 molecule.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg The virus is then released from the CD4 cell in the budding stage.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg The virus matures and becomes ready to infect other host CD4 cells.4www.youtube.com/watch?v=PdzFvxfDGbgThis process happens billions of times per day and leads to ultimate destruction of the host immune system.4www.youtube.com/watch?v=PdzFvxfDGbgHIV life cycle inhibitorsFigure 2, in addition to displaying the various stages of the HIV life cycle, also shows the stage of the life cycle in which various drug classes exhibit their effect.The entry and fusion inhibitors inhibit the first stage.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google Scholar, 7Fuzeon [package insert]. Genentech;. 2014; Google Scholar Maraviroc (Selzentry—Pfizer), the only entry inhibitor approved by FDA for the treatment of HIV, is a coreceptor antagonist.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google Scholar This agent selectively binds to the CCR5 coreceptor on the CD4 membrane, preventing the entry of HIV into the host cell.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google ScholarEnfuvirtide (Fuzeon—Roche), the only FDA-approved fusion inhibitor, binds to HIV glycoproteins and prevents conformational changes required for fusion of the HIV and CD4 cell membranes.7Fuzeon [package insert]. Genentech;. 2014; Google ScholarNRTIs and NNRTIs both inhibit the second stage of the HIV life cycle through distinct mechanisms.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google Scholar NRTIs act as analogs of the DNA building blocks (guanine, adenine, thymine, and cytosine).8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google Scholar When reverse transcriptase encounters these analogs, chain elongation is terminated.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google ScholarIn contrast, NNRTIs bind directly to the reverse transcription enzyme, eliciting a conformational change and leading to the subsequent inability of reverse transcriptase to perform its essential enzymatic function of transcribing viral RNA into double- stranded DNA.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google ScholarIntegration of viral DNA into the host cell genome can be blocked with INSTIs, and cleavage of viral proteins into smaller core proteins can be prevented with protease inhibitors.9http://journal.frontiersin.org/Journal/10.3389/fgene.2012.00328/fullGoogle Scholar, 10https://youtu.be/MK2r8J7SCSgGoogle Scholar Currently available therapies do not include agents that act at the fifth or sixth stages of the HIV life cycle.As stated on the previous page, the ideal regimen for treatment-naive patients typically includes two NRTIs in combination with either an NNRTI, a PI boosted with ritonavir, or an INSTI.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf However, resistance mutations, often resulting from suboptimal patient adherence, can contribute to greater regimen complexity.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfA regimen falling outside of these parameters should not, therefore, be immediately dismissed as inappropriate. Consultation with the pre- scriber may result in identifying the factors contributing to, and justifying, regimen selection.Pharmacists can play a valuable role in the management of patients with HIV through regimen assessment, pre- scriber engagement, adverse event and adherence counseling, and encouragement of active patient participation in care. CDC has estimated that approximately 1.2 million people in the United States were living with HIV infection at the end of 2011 (the most recent year for which data are available).1www.cdc.gov/hivGoogle Scholar Of those 1.2 million people, around 1 in 7—close to 170,000—were unaware of their infection status.1www.cdc.gov/hivGoogle Scholar For pharmacists who do not regularly dispense medications for the treatment of HIV, understanding treatment complexities for these patients can be intimidating. Regimen selectionA good place to start when attempting to understand the nuances of HIV treatment is the HIV life cycle itself. The replication of HIV is a multistage process, with each stage crucial for successful replication.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg Because each stage is critical, each is a potential target for antiretroviral therapy.The goal of highly active antiretroviral therapy (HAART) is to attack the virus at various points throughout the life cycle, leading to inhibition of the replication process.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf In general, HAART uses at least three different antiviral drugs from at least two different classes.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf The classes of medications available for the treatment of HIV are shown in Figure 1.The ideal initial regimen for patients who have not been previously treated typically contains two nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) in combination with either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) boosted with ritonavir (Norvir—AbbVie), or an integrase strand transfer inhibitor (INSTI).5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfRegimen selection varies widely and depends on a multitude of factors.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf A full review of available treatment options is available in the guidelines developed by the Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfLet's briefly review the stages of the HIV life cycle and the medication classes that inhibit each (Figure 2) .5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf A good place to start when attempting to understand the nuances of HIV treatment is the HIV life cycle itself. The replication of HIV is a multistage process, with each stage crucial for successful replication.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg Because each stage is critical, each is a potential target for antiretroviral therapy. www.youtube.com/watch?v=PdzFvxfDGbg The goal of highly active antiretroviral therapy (HAART) is to attack the virus at various points throughout the life cycle, leading to inhibition of the replication process.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf In general, HAART uses at least three different antiviral drugs from at least two different classes.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf The classes of medications available for the treatment of HIV are shown in Figure 1. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf The ideal initial regimen for patients who have not been previously treated typically contains two nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) in combination with either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) boosted with ritonavir (Norvir—AbbVie), or an integrase strand transfer inhibitor (INSTI).5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf Regimen selection varies widely and depends on a multitude of factors.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf A full review of available treatment options is available in the guidelines developed by the Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf Let's briefly review the stages of the HIV life cycle and the medication classes that inhibit each (Figure 2) .5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf HIV life cycleFirst stage. The first stage is binding, fusion, and subsequent entry of the virus into a single host CD4 cell.2-4 Infection of the host cell requires the presence of the CD4 receptor and coreceptors (i.e., CCR5, CXCR4) on the host cell membrane.4 Glycoproteins on the surface of the HIV cell attach to the CD4 receptor.4 Coreceptor attachment then occurs, leading to a conformational change in HIV glycoproteins.4The coreceptors then draw the two cell membranes together, and fusion eventually occurs.4www.youtube.com/watch?v=PdzFvxfDGbg The viral capsid enters the CD4 cell and releases two viral RNA strands and the three essential replication enzymes: reverse transcriptase, integrase, and protease.4www.youtube.com/watch?v=PdzFvxfDGbgSecond and third stages. In the second stage, reverse transcriptase converts viral RNA into a DNA double helix through reverse transcription.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg Following reverse transcription, the integrase enzyme cleaves portions of the newly created DNA double helix in the third stage of the life cycle, creating two sticky ends.4www.youtube.com/watch?v=PdzFvxfDGbg This allows for transfer and integration of the viral DNA into the host cell genome within the nucleus of the CD4 cell.4www.youtube.com/watch?v=PdzFvxfDGbgFourth through sixth stages. The CD4 cell becomes activated, and transcription of proviral DNA into messenger RNA (mRNA) occurs.4www.youtube.com/watch?v=PdzFvxfDGbg The mRNA then migrates into the cytoplasm, where building blocks for a new virus are synthesized.4www.youtube.com/watch?v=PdzFvxfDGbgLarge proteins are then cleaved into smaller core proteins by viral proteases.4www.youtube.com/watch?v=PdzFvxfDGbg Two viral RNA strands and the replication enzymes come together, and the core proteins assemble around them, forming a capsid for a new HIV-1 molecule.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg The virus is then released from the CD4 cell in the budding stage.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg The virus matures and becomes ready to infect other host CD4 cells.4www.youtube.com/watch?v=PdzFvxfDGbgThis process happens billions of times per day and leads to ultimate destruction of the host immune system.4www.youtube.com/watch?v=PdzFvxfDGbg First stage. The first stage is binding, fusion, and subsequent entry of the virus into a single host CD4 cell.2-4 Infection of the host cell requires the presence of the CD4 receptor and coreceptors (i.e., CCR5, CXCR4) on the host cell membrane.4 Glycoproteins on the surface of the HIV cell attach to the CD4 receptor.4 Coreceptor attachment then occurs, leading to a conformational change in HIV glycoproteins.4 The coreceptors then draw the two cell membranes together, and fusion eventually occurs.4www.youtube.com/watch?v=PdzFvxfDGbg The viral capsid enters the CD4 cell and releases two viral RNA strands and the three essential replication enzymes: reverse transcriptase, integrase, and protease.4www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg Second and third stages. In the second stage, reverse transcriptase converts viral RNA into a DNA double helix through reverse transcription.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg Following reverse transcription, the integrase enzyme cleaves portions of the newly created DNA double helix in the third stage of the life cycle, creating two sticky ends.4www.youtube.com/watch?v=PdzFvxfDGbg This allows for transfer and integration of the viral DNA into the host cell genome within the nucleus of the CD4 cell.4www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg Fourth through sixth stages. The CD4 cell becomes activated, and transcription of proviral DNA into messenger RNA (mRNA) occurs.4www.youtube.com/watch?v=PdzFvxfDGbg The mRNA then migrates into the cytoplasm, where building blocks for a new virus are synthesized.4www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg Large proteins are then cleaved into smaller core proteins by viral proteases.4www.youtube.com/watch?v=PdzFvxfDGbg Two viral RNA strands and the replication enzymes come together, and the core proteins assemble around them, forming a capsid for a new HIV-1 molecule.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg The virus is then released from the CD4 cell in the budding stage.2http://aidsinfo.nih.gov/education-materialsGoogle Scholar, 3www.aids.gov/hiv-aids-basics/justdiagnosed-with-hiv-aids/hiv-in-your-body/hiv-lifecycle/Google Scholar, 4www.youtube.com/watch?v=PdzFvxfDGbg The virus matures and becomes ready to infect other host CD4 cells.4www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg This process happens billions of times per day and leads to ultimate destruction of the host immune system.4www.youtube.com/watch?v=PdzFvxfDGbg www.youtube.com/watch?v=PdzFvxfDGbg HIV life cycle inhibitorsFigure 2, in addition to displaying the various stages of the HIV life cycle, also shows the stage of the life cycle in which various drug classes exhibit their effect.The entry and fusion inhibitors inhibit the first stage.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google Scholar, 7Fuzeon [package insert]. Genentech;. 2014; Google Scholar Maraviroc (Selzentry—Pfizer), the only entry inhibitor approved by FDA for the treatment of HIV, is a coreceptor antagonist.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google Scholar This agent selectively binds to the CCR5 coreceptor on the CD4 membrane, preventing the entry of HIV into the host cell.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google ScholarEnfuvirtide (Fuzeon—Roche), the only FDA-approved fusion inhibitor, binds to HIV glycoproteins and prevents conformational changes required for fusion of the HIV and CD4 cell membranes.7Fuzeon [package insert]. Genentech;. 2014; Google ScholarNRTIs and NNRTIs both inhibit the second stage of the HIV life cycle through distinct mechanisms.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google Scholar NRTIs act as analogs of the DNA building blocks (guanine, adenine, thymine, and cytosine).8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google Scholar When reverse transcriptase encounters these analogs, chain elongation is terminated.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google ScholarIn contrast, NNRTIs bind directly to the reverse transcription enzyme, eliciting a conformational change and leading to the subsequent inability of reverse transcriptase to perform its essential enzymatic function of transcribing viral RNA into double- stranded DNA.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google ScholarIntegration of viral DNA into the host cell genome can be blocked with INSTIs, and cleavage of viral proteins into smaller core proteins can be prevented with protease inhibitors.9http://journal.frontiersin.org/Journal/10.3389/fgene.2012.00328/fullGoogle Scholar, 10https://youtu.be/MK2r8J7SCSgGoogle Scholar Currently available therapies do not include agents that act at the fifth or sixth stages of the HIV life cycle.As stated on the previous page, the ideal regimen for treatment-naive patients typically includes two NRTIs in combination with either an NNRTI, a PI boosted with ritonavir, or an INSTI.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf However, resistance mutations, often resulting from suboptimal patient adherence, can contribute to greater regimen complexity.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfA regimen falling outside of these parameters should not, therefore, be immediately dismissed as inappropriate. Consultation with the pre- scriber may result in identifying the factors contributing to, and justifying, regimen selection.Pharmacists can play a valuable role in the management of patients with HIV through regimen assessment, pre- scriber engagement, adverse event and adherence counseling, and encouragement of active patient participation in care. Figure 2, in addition to displaying the various stages of the HIV life cycle, also shows the stage of the life cycle in which various drug classes exhibit their effect. The entry and fusion inhibitors inhibit the first stage.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google Scholar, 7Fuzeon [package insert]. Genentech;. 2014; Google Scholar Maraviroc (Selzentry—Pfizer), the only entry inhibitor approved by FDA for the treatment of HIV, is a coreceptor antagonist.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google Scholar This agent selectively binds to the CCR5 coreceptor on the CD4 membrane, preventing the entry of HIV into the host cell.6Selzentry [package insert]. ViiV Healthcare;. 2014; Google Scholar Enfuvirtide (Fuzeon—Roche), the only FDA-approved fusion inhibitor, binds to HIV glycoproteins and prevents conformational changes required for fusion of the HIV and CD4 cell membranes.7Fuzeon [package insert]. Genentech;. 2014; Google Scholar NRTIs and NNRTIs both inhibit the second stage of the HIV life cycle through distinct mechanisms.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google Scholar NRTIs act as analogs of the DNA building blocks (guanine, adenine, thymine, and cytosine).8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google Scholar When reverse transcriptase encounters these analogs, chain elongation is terminated.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google Scholar In contrast, NNRTIs bind directly to the reverse transcription enzyme, eliciting a conformational change and leading to the subsequent inability of reverse transcriptase to perform its essential enzymatic function of transcribing viral RNA into double- stranded DNA.8NEJM. 2004; 350: 1023-1025Crossref PubMed Scopus (638) Google Scholar Integration of viral DNA into the host cell genome can be blocked with INSTIs, and cleavage of viral proteins into smaller core proteins can be prevented with protease inhibitors.9http://journal.frontiersin.org/Journal/10.3389/fgene.2012.00328/fullGoogle Scholar, 10https://youtu.be/MK2r8J7SCSgGoogle Scholar Currently available therapies do not include agents that act at the fifth or sixth stages of the HIV life cycle. As stated on the previous page, the ideal regimen for treatment-naive patients typically includes two NRTIs in combination with either an NNRTI, a PI boosted with ritonavir, or an INSTI.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf However, resistance mutations, often resulting from suboptimal patient adherence, can contribute to greater regimen complexity.5http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf A regimen falling outside of these parameters should not, therefore, be immediately dismissed as inappropriate. Consultation with the pre- scriber may result in identifying the factors contributing to, and justifying, regimen selection. Pharmacists can play a valuable role in the management of patients with HIV through regimen assessment, pre- scriber engagement, adverse event and adherence counseling, and encouragement of active patient participation in care. www.youtube.com/watch?v=PdzFvxfDGbg http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf