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Case 2: Discussion

HIV Life Cycle

The HIV life cycle consists of multiple steps that involve a complex interaction with a host cell (Figure 1)[1,2]. The life cycle begins with viral entry, a multi-step interaction between the HIV envelope and the host target cell surface receptors. In the initial step of HIV entry, the HIV gp120 binds to the host target cell CD4 receptor, thereby anchoring HIV to the host cell. This interaction generates a conformational change in the HIV envelope V3 region that stimulates HIV binding with a host cell coreceptor; the main coreceptors used by HIV are CCR5 and CXCR4. Subsequently, the viral and host membranes fuse, the viral capsid enters the cell, and the HIV RNA is released. Once inside the cell, the HIV core dissolves, releasing the two copies of single-stranded HIV RNA. The next step, referred to as reverse transcription, involves the conversion of the single-stranded HIV RNA to double-stranded HIV DNA by the HIV enzyme reverse transcriptase. The reverse transcriptase uses the cellular nucleotides as the building blocks for synthesizing HIV DNA. Next the HIV DNA, which is complexed with other HIV proteins, migrates inside the host nucleus. The HIV integrase enzyme then catalyzes the integration of the HIV DNA into the host DNA. Once the HIV DNA has integrated into the host genome, it is referred to as proviral DNA. The HIV provirus remains part of the host DNA and is perceived by the cell as normal host cellular DNA. The cellular enzymes transcribe the proviral DNA into messenger RNA (mRNA) and genomic RNA. The control of the transcription of proviral DNA involves multiple factors, including the HIV Tat protein and cellular modulators. The viral mRNA then is exported out of the nucleus into the host cell cytoplasm where cellular enzymes translate the viral mRNA into viral proteins. The larger viral proteins require cleaving into smaller, functional proteins, a step performed by the HIV enzyme protease. The multiple components of the HIV are then assembled and as the HIV buds off from the cell, further processing occurs to complete the viral life cycle, with the final product consisting of a mature HIV virion capable of infecting other cells.

Classes of Antiretroviral Medications

Multiple potential points of intervention exist in the multi-step HIV life cycle (Figure 2). As of September 24, 2012, the United States FDA had approved 26 distinct individual antiretroviral medications (Figure 3) and 8 fixed-drug combinations for use in HIV-infected individuals (Figure 4). The antiretroviral medications in clinical use can be categorized into one of five classes: (1) nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs), (3) protease inhibitors (PIs), (4) entry inhibitors, and (5) integrase strand transfer inhibitors (Figure 5Nucleoside and Nucleotide Reverse Transcriptase InhibitorsNon-Nucleoside Reverse Transcriptase InhibitorsProtease InhibitorsEntry InhibitorsIntegrase InhibitorsSingle Tablet RegimensAcknowledgments).

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

The NRTIs and NtRTIs target the step of HIV reverse transcription. To reach their active form, the NRTIs must undergo three phosphorylation steps within the cell to reach the active triphosphorylated state; the NtRTIs require only two phosphorylation steps. After the NRTIs (or NtRTI) reach a triphosphorylated state they structurally resemble the cellular nucleotides and the HIV reverse transcriptase mistakenly incorporates the drug into the elongating strand of viral DNA. Once incorporated into viral DNA, the NRTI (or NtRTI) has a caboose-like effect by acting as a chain terminator, thus preventing further chain linkages in the elongating strand of viral DNA. There are eight FDA-approved drugs in this class (Figure 5, Image 1Nucleoside and Nucleotide Reverse Transcriptase InhibitorsNon-Nucleoside Reverse Transcriptase InhibitorsProtease InhibitorsEntry InhibitorsIntegrase InhibitorsSingle Tablet RegimensAcknowledgments): abacavir (Ziagen), didanosine (Videx and Videx EC), emtricitabine (Emtriva), lamivudine (Epivir), stavudine (Zerit), tenofovir (Viread), zalcitabine (Hivid), and zidovudine (Retrovir). The drug zalcitabine is no longer manufactured. The reverse transcriptase inhibitor tenofovir is classified as a NtRTI. In addition, there are four fixed-drug reverse transcriptase inhibitor formulations: abacavir-lamivudine (Epzicom), tenofovir-emtricitabine (Truvada), zidovudine-lamivudine (Combivir), and zidovudine-lamivudine-abacavir (Trizivir).

Non-Nucleoside Reverse Transcriptase Inhibitors

The mechanim of action of the NNRTIs is distinct from the NRTIs: the NNRTIs do not become incorporated into viral DNA, but instead directly bind to the hydrophobic pocket located close to the catalytic domain of the reverse transcriptase enzyme complex, thereby preventing the normal dynamic movement of the enzyme complex. In addition, unlike the NRTIs, drugs in the NNRTI class do not require phosphorylation to become activated. There are five FDA-approved NNRTIs (Figure 5, Image 2Nucleoside and Nucleotide Reverse Transcriptase InhibitorsNon-Nucleoside Reverse Transcriptase InhibitorsProtease InhibitorsEntry InhibitorsIntegrase InhibitorsSingle Tablet RegimensAcknowledgments): delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), and Rilpivirine (Edurant). In addition, as noted above, the fixed-drug combination pills are tenofovir-emtricitabine-efavirenz (Atripla) and tenofovir-emtricitabine-rilpivirine (Complera). Efavirenz is not recommended for use during the first trimester in pregnant women or in women with child bearing potential (women who want to conceive or those not using effective contraception). The NNRTIs delavirdine, efavirenz, and nevirapine are not active against HIV-2; etravirine and rilpivirine have limited activity against HIV-2.

Protease Inhibitors (PIs)

The HIV PIs selectively bind to and inhibit HIV protease, an enzyme that cleaves viral polyprotein precursors into individual functional proteins. The HIV protease normally cleaves proteins from the Gag-Pol polyprotein precursor, forming functional smaller proteins in the process. If the PI successfully blocks the HIV protease, deformed HIV particles are formed and these particles have diminished infectious capacity. There are 10 PIs that have been FDA-approved (Figure 5, Image 3Nucleoside and Nucleotide Reverse Transcriptase InhibitorsNon-Nucleoside Reverse Transcriptase InhibitorsProtease InhibitorsEntry InhibitorsIntegrase InhibitorsSingle Tablet RegimensAcknowledgments): amprenavir (Agenerase), atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir-ritonavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir), saquinavir hard gel capsule (Invirase) and saquinavir soft gel capsule (Fortovase), and tipranavir (Aptivus). Most PIs are now used in combination with low-dose ritonavir, with the ritonavir acting as a pharmacokinetic booster by inhibiting the metabolism of the other PI )[3]. In the United States amprenavir (capsules and liquid) and saquinavir soft gel capsules (Fortovase) are no longer manufactured.

Entry Inhibitors (EIs)

The entry inhibitor class now includes two subclasses: (1) CCR5 co-receptor antagonists and (2) fusion inhibitors. In the process of viral entry (after binding to the host CD4 receptor) HIV can potentially bind to either the host CCR5 or CXCR4 coreceptor. The HIV co-recepeptor binding depends on the HIV subtype: the HIV subtype known as R5 HIV (or CCR5-tropic HIV) preferentially binds to the CCR5 coreceptor whereas the X4 HIV (or subtype CXCR4-tropic HIV) binds to the CXCR4 coreceptor. Those strains of HIV that can enter via either the CCR5 or CXCR4 coreceptor are know as R5X4 HIV (or dual-tropic HIV). Patients with a detectable mixture of R5 and X4 HIV are considered to have mixed-tropic HIV. The CCR5 antagonists exert their mechanism of action by binding to the CCR5 coreceptor, causing a conformational change in the coreceptor that prevents the HIV gp120 from binding with the CCR5 coreceptor. The drug maraviroc (Selzentry) is the only FDA-approved CCR5 inhibitor and is recommended for use in antiretroviral treatment-experienced patients who have R5 HIV (CCR5-tropic HIV). Prior to starting a patient on maraviroc, a HIV Tropism Assay should be performed to document that the patient has R5 (CCR5-tropic) HIV[4]. The fusion inhibitor Enfuvirtide (Fuzeon) is a 36-amino acid synthetic peptide that corresponds with a segment in the HIV gp41 known as the heptad repeat region 2. In the normal fusion process, the HIV gp41 heptad repeat region 2 folds back on the heptad repeat region 1, in essence zipping up the gp41. This process pulls the HIV and host membranes together and results in the fusion of the viral and host membranes. The enfuvirtide peptide works by binding to the hepatad repeat region 1, thus preventing the normal interaction and folding of the gp41 hepatad repeat regions 1 and 2. Enfuvirtide is the only FDA-approved fusion inhibitor (Figure 5, Image 4Nucleoside and Nucleotide Reverse Transcriptase InhibitorsNon-Nucleoside Reverse Transcriptase InhibitorsProtease InhibitorsEntry InhibitorsIntegrase InhibitorsSingle Tablet RegimensAcknowledgments) and it is indicated in antiretroviral treatment-experienced patients. The drug enfuvirtide is not active against HIV-2.

Integrase Strand Transfer Inhibitors (INSTI)

The integrase strand transfer inhibitors interfere with the insertion of HIV DNA into host DNA[5]. The integration of HIV into host DNA is a complex preocess involving six major steps: (1) HIV integrase binds to the HIV DNA; (2) HIV integrase catalyzes the the 3' processing of the ends of the HIV DNA; (3) the HIV DNA, complexed with integrase and other HIV proteins, migrates inside of the host nucleus through the nuclear pores; (4) the HIV DNA-protein complex binds to the host DNA; (5) HIV integrase catalyzes the strand transfer of the HIV DNA into the host DNA; and (6) human enzymes repair the gaps left following the stand transfer process. The drug raltegravir (Isentress) is the only approved integrase strand transfer inhibitor (Figure 5, Image 5Nucleoside and Nucleotide Reverse Transcriptase InhibitorsNon-Nucleoside Reverse Transcriptase InhibitorsProtease InhibitorsEntry InhibitorsIntegrase InhibitorsSingle Tablet RegimensAcknowledgments) and it is recommended for use in both antiretroviral therapy naive and experienced patients.

Single-Tablet Regimens

In an effort to optimize ease of medication administration and lower pill burden, single table rgimens that required once daily dosing have been developed. As of September 2012, the FDA has approved three single table regimens (Figure 5, Image 6Nucleoside and Nucleotide Reverse Transcriptase InhibitorsNon-Nucleoside Reverse Transcriptase InhibitorsProtease InhibitorsEntry InhibitorsIntegrase InhibitorsSingle Tablet RegimensAcknowledgments): tenofovir-emtricitabine-efavirenz (Atripla), tenofovir-emtricitabine-rilpivirine (Complera), and elvitegravir-cobicistat-tenofovir-emtricitabine (Stribild).

HHS Recommended Preferred and Alternative Regimens

The most recently updated HHS Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents were issued in March 2012, with an addendum issued in September 2012[4]. These guidelines provide specific antiretroviral therapy recommendations for initial therapy, including recommended preferred regimens, alternative regimens, and regimens that are acceptable under certain circumstances (Figure 6Preferred RegimenAlternative RegimensAcceptable RegimensRegimens that may be Acceptable but Use with CautionRating SchemeAcknowledgments). The expert panel designated regimens as preferred if they were shown in clinical trials to have optimal efficacy and durability, as well as acceptable tolerability and ease of use. The preferred regimens consist of two NRTIs plus a NNRTI, two NRTIs plus a ritonavir-boosed PI, or two NRTIs plus an integrase strand transfer inhibitor. The preferred two drugs for the NRTI component are tenofovir-emtricitabine and four preferred options are recommended for use in combination with tenofovir-emtricitabine: efavirenz (NNRTI), atazanavir plus ritonavir (PI), darunavir (once daily) plus ritonavir (PI), and raltegravir (INSTI).

HHS Antiretroviral Regimens or Components Not Recommended

Certain antiretroviral regimens (Figure 7Regimens Not Recommended Rating Scheme Acknowledgments) and certain components of regimens (Figure 8) should not be offered at any time when initiating antiretroviral therapy[4]. Regimens that should not be offered at any time are monotherapy with NRTI or NNRTI, dual NRTI regimens, or triple NRTI regimens (except for abacavir plus zidovudine plus lamivudine or possibly tenofovir plus zidovudine plus lamivudine)[4]. Certain antiretroviral components are not recommended as part of the antiretroviral regimen for several reasons, including drug antagonism (zidovudine plus stavudine), additive toxicities (such as increased peripheral neuropathy with stavudine plus didanosine), toxicities that occur in specific patient populations (such as efavirenz in pregnancy), or a similar resistance profile with no likelihood of benefit (such as lamivudine plus emtricitabine).

IAS-USA Recommendations for Antiretroviral Therapy

In July 2012, the International Antiviral Society-USA (IAS-USA) issued updated recommendations for the treatment of adult HIV infection[6]. Similar to the HHS guidelines, the IAS-USA guidelines recommend using 2 NRTIs plus a third agent (efavirenz, a ritonavir-boosted PI, or raltegravir) as preferred initial therapy in treatment-naïve patients (Figure 9Recommended Initial Regimens Alternative Regimens CCR5-Based and NRTI-Sparing Regimens Rating Scale Acknowledgments). The preferred NRTIs are tenofovir-emtricitabine (with all regimens) and abacavir-lamivudine (with most regimens). Efavirenz is the preferred NNRTI drug and the preferred PIs consist of atazanavir plus ritonavir or darunavir plus ritonavir. Raltegravir is also considered a preferred 3rd agent. These guidelines also provide recommendations for alternative initial regimens, CCR5-based regimens, and NRTI-sparing regimens.

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    Figure 1. HIV Life Cycle

    This illustration shows the major steps in the HIV life cycle. The key steps shown are viral attachment, viral fusion with the host cell membrane, reverse transcription of HIV RNA to DNA, integration of HIV DNA with host DNA, transcription and translation of HIV RNA, and virus budding from host cell.


    Figure 1
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    Figure 2. Potential Points of Intervention in HIV Life Cycle

    Abbreviations: NRTIs = nucleoside reverse transcriptase inhibitors; NNRTIs = non-nucleoside reverse transcriptase inhibitors

    This illustration shows the major sites for potential intervention in the HIV life cycle.


    Figure 2
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    Figure 3. Timeline of FDA-Approval for Antiretroviral Medications in the United States

    As of September 2012, the FDA had approved 26 antiretroviral medications for use in the United States.


    Figure 3
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    Figure 4. Timeline for FDA Approval of Fixed Combination Antiretroviral Drugs in the United States

    As of September 2012, the FDA had approved 8 fixed-drug combination antiretroviral medications for use in the United States.


    Figure 4
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    Figure 5: Antiretroviral Medications. Image 1. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
    Figure 5 (series)
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    Figure 6: HHS Recommendations for Antiretroviral Regimens in Treatment-Naive Patients. Image 1. Preferred Regimens
    Figure 6 (series)
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    Figure 7: HHS Guidelines for the Use of Antiretroviral Agents Regimens Not Recommended in HIV-1 Infected Adults and Adolescents. Image 1. Antiretroviral Regimens Not Recommended
    Figure 7 (series)
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    Figure 8. DHHS Guidelines for the Use of Antiretrovira Agents in HIV-1 Infected Adults and Adolescents: Antiretroviral Components that Should Not Be Offered At Any Time
    Figure 8
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    Figure 9: 2012 Antiretroviral Therapy Recommendations of the International AIDS Society-USA Panel. Image 1. Recommended Initial Regimens
    Figure 9 (series)