Case 2: Discussion

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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 December 15, 2008, the United States FDA had approved 25 distinct antiretroviral medications (Figure 3) and 6 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 inhibitors (Figure 5).

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): 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 DF 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). The available fixed-drug combinations now include the three-drug combination consisting of tenofovir plus emtricitabine plus efavirenz (Atripla). This highly potent multiclass medication is taken as a single pill once daily.

Non-Nucleoside Reverse Transcriptase Inhibitors

The mechanims 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 four FDA-approved NNRTIs (Figure 5): delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), and nevirapine (Viramune). In addition, as noted above, the combination of tenofovir plus emtricitabine plus efavirenz is available as a fixed-drug combination pill (Atripla). Efavirenz is not recommended for use 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 has some activity against HIV-2, but the clinical significance of this activity remains unknown.

Protease Inhibitors

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): 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 (Figure 5) [3]. In the United States amprenavir (capsules and liquid) and saquinavir soft gel capsules (Fortovase) are no longer manufactured.

Entry Inhibitors

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) and it is indicated in antiretroviral treatment-experienced patients. The drug enfuvirtide is not active against HIV-2.

Integrase Inhibitors

The integrase 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 inhibitor and it is recommended for use in antiretroviral therapy experienced patients. This drug is in a subclass of integrase inhibitors known as strand transfer inhibitors.

DHHS Recommended Preferred and Alternative Regimens

The most recently updated DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents were issued in November 2008 [4]. These guidelines provide specific antiretroviral therapy recommendations for initial therapy, including preferred regimens and alternative regimens (Figure 6) [4], as well as regimens (Figure 7) or regimen components (Figure 8) that should be avoided. 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 2 NRTIs plus a NNRTI or 2 NRTIs plus a ritonavir-boosed PI. The preferred 2 drugs for the NRTI component are tenofovir-emtricitabine; lamivudine can substitute for emtricitibine. Efavirenz is the preferred NNRTI drug and the preferred PIs include four options: once daily atazanavir plus ritonavir, once daily darunavir plus ritonavir, twice daily fosamprenavir plus ritonavir, and once or twice daily lopinavir-ritonavir. The DHHS guidelines provide a number of regimens that can be used as alternatives to the preferred regimens (Figure 6).

DHHS Antiretroviral Regimens or Components Not Recommended

Certain antiretroviral regimens (Figure 7) 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 Recommended Components for Antiretroviral Therapy

In August 2008, the International AIDS Society-USA (IAS-USA) issued updated recommendations for the treatment of adult HIV infection [5]. Similar to the DHHS guidelines, the IAS-USA guidelines recommend using 2 NRTI plus efavirenz or 2 NRTI plus a ritonavir-boosted PI as preferred initial therapy (Figure 9) [6]. The preferred NRTIs consist of tenofovir-emtricitabine or abacavir-lamivudine. Efavirenz is the preferred NNRTI drug. The preferred PIs options consist of lopinavir-ritonavir, atazanavir plus ritonavir, fosamprenavir plus ritonavir, and saquinavir plus ritonavir. These guidelines differ slightly from the DHHS guidelines in that in the IAS-USA guidelines abacavir-lamivudine is included as a preferred 2-drug NRTI component and saquinavir plus ritonavir is included among the preferred ritonavir-boosted PI regimens.

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