HIV Life Cycle
The HIV life cycle consists of multiple steps that involve a complex interaction with a cell (Figure 1).[,,] 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. Then 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 November 8, 2015, the United States FDA had approved 35 antiretroviral medications (Figure 3), including 12 fixed-drug combinations (Figure 4) for use in HIV-infected individuals. Among the 12 fixed-drug combinations, 5 of these are single tablet regimens. The antiretroviral medications in clinical use can be categorized into one of five classes: (1) entry inhibitors, (2) nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs), (3) non-nucleoside reverse transcriptase inhibitors (NNRTIs), (4) protease inhibitors (PIs), and (5) integrase strand transfer inhibitors (INSTIs). In addition, two medications, ritonavir (Norvir) and cobicistat (Tybost) are used as pharmacologic boosters as a component of some antiretroviral regimens.
Entry Inhibitors (EIs)
The entry inhibitor class now includes two subclasses: (1) CCR5 co-receptor antagonists and (2) fusion inhibitors, with one FDA-approved drug from each subclass (Figure 5). 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 coreceptor 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, an HIV Tropism Assay or envelope genotype should be performed to document that the patient has R5 (CCR5-tropic) HIV. 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 heptad repeat regions 1 and 2. Enfuvirtide is the only FDA-approved fusion inhibitor and it is indicated in antiretroviral treatment-experienced patients. The drug enfuvirtide is not active against HIV-2.
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 6): abacavir (Ziagen), didanosine (Videx and Videx EC), emtricitabine (Emtriva), lamivudine (Epivir), stavudine (Zerit), tenofovir disoproxil fumarate (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 disoproxil fumarate-emtricitabine (Truvada), zidovudine-lamivudine (Combivir), and zidovudine-lamivudine-abacavir (Trizivir).
Non-Nucleoside Reverse Transcriptase Inhibitors
The mechanism 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 7): delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), and Rilpivirine (Edurant). In addition, as noted above, the fixed-drug combination pills are tenofovir disoproxil fumarate-emtricitabine-efavirenz (Atripla) and tenofovir disoproxil fumarate-emtricitabine-rilpivirine (Complera). Efavirenz is not recommended for women with child bearing potential if they are 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.
Integrase Strand Transfer Inhibitors (INSTI)
The integrase strand transfer inhibitors interfere with the insertion of HIV DNA into host DNA. The integration of HIV into host DNA is a complex process 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. Three integrase strand transfer inhibitors are FDA approved: dolutegravir (Tivicay), elvitegravir (Vitekta), and raltegravir (Isentress) (Figure 8).
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 9): 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 other PIs. In the United States amprenavir (capsules and liquid) and saquinavir soft gel capsules (Fortovase) are no longer manufactured.
In an effort to optimize ease of medication administration and lower pill burden, single table regimens that required once daily dosing have been developed. As of February 2015, the FDA has approved five single tablet regimens (Figure 10): abacavir-lamivudine-dolutegravir (Triumeq), tenofovir disoproxil fumurate-emtricitabine-efavirenz (Atripla), tenofovir disoproxil fumarate-emtricitabine-elvitegravir-cobicistat (Stribild), tenofovir alafenamide-emtricitabine-elvitegravir-cobicistat (Genvoya), and tenofovir disoproxil fumarate-emtricitabine-rilpivirine (Complera).
HHS Recommended Regimens for Initial Therapy
The most recently updated HHS Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents were issued in April 2015. The Recommended Regimen Options for initial therapy consist of five regimens comprised of two NRTIs in combination with either an INSTI or a PI boosted with ritonavir (Figure 11): tenofovir disoproxil fumarate-emtricitabine plus ritonavir plus darunavir,[,,,] abacavir-lamivudine plus dolutegravir (if HLA-B*5701-negative),[,,,] tenofovir disoproxil fumarate-emtricitabine plus dolutegravir,[,,] tenofovir disoproxil fumarate-emtricitabine-elvitegravir-cobicistat,[,,,,,] and tenofovir disoproxil fumarate-emtricitabine plus raltegravir.[,,,] These five regimens are considered recommended based on excellent safety, efficacy, and durability data. The HHS guidelines also list six Alternative Regimen Options for initial therapy: two regimens recently classified as recommended (tenofovir disoproxil fumarate-emtritabine-efavirenz  and tenofovir disoproxil fumarate-emtricitabine plus ritonavir plus atazanavir[,] ), the single tablet regimen tenofovir disoproxil fumarate-emtricitabine-rilpivirine (for patients with a baseline CD4 count greater than 200 cells/mm3 and HIV RNA level less than 100,000 copies/ml), [,,,,] and three addition protease inhibitor regimens, including two that use cobicistat instead of ritonavir as the protease inhibitor booster (Figure 12). The guidelines also have the categories Other Regimen Options and Antiretroviral Components or Regimens Not Recommended as initial therapy.