sign in sign up
<<
Home , Antiviral drug, Bictegravir, Doravirine, E1 (HCV), Gp41, HIV integration

© National HIV Curriculum PDF created October 7, 2021, 3:18 am

Antiretroviral and Initial

This is a PDF version of the following document: Module 3: Antiretroviral Therapy Lesson 1: Antiretroviral Medications and Initial Therapy

You can always find the most up to date version of this document at https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all.

Background

The availability of highly effective antiretroviral therapy in the mid-1990s transformed HIV from a fatal to a manageable, chronic disease. Persons with HIV who take modern combination antiretroviral therapy significantly reduce their morbidity and mortality associated with HIV infection,[1,2,3] as well as lower their risk of transmitting HIV to others.[4,5,6] The United States Food and Administration (FDA) has approved medications in five different classes to treat HIV infection: entry inhibitors, inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNTRIs), strand transfer inhibitors (INSTIs), and inhibitors (PIs) (Figure 1).[7,8] This Topic Review will summarize the mechanism of action of antiretroviral medications, indications for antiretroviral therapy, and recommended antiretroviral regimens for treatment-naïve individuals. Separate Topic Reviews will address issues related to antiretroviral therapy, including adverse effects, drug interactions, simplification or switching therapy, assessment of drug resistance, and management of virologic failure. In addition, detailed information for each antiretroviral and for all fixed-dose combinations is available in the Antiretroviral Medication section of this web site.

Page 1/83 HIV Cycle and Antiretroviral Drug Targets

Understanding the basic HIV life cycle is the foundation for understanding the mechanism of action of the different classes of antiretroviral medications. The following discussion will focus on key HIV and relevant steps in the HIV life cycle related to HIV antiretroviral therapy. The Howard Hughes Medical Institute has produced an excellent HIV Life Cycle video (below) that summarizes the key steps in the HIV life cycle.

HIV Entry and Entry Inhibitors

HIV Envelope

The initial step in the HIV life cycle involves a complex interaction between HIV envelope spikes and surface . The HIV envelope consists of two structural components: surface envelope (gp120) and transmembrane envelope glycoprotein () (Figure 2).[9] The surface of HIV is studded with approximately 14 envelope spikes, with each spike consisting of a trimer of three gp120 and gp41 subunits (Figure 3).[10,11] Both gp120 and gp41 play an essential role in HIV entry into the host .

gp120: The gp120 subunit is the component of the envelope that interacts with the host receptors and coreceptors; these interactions involve the gp120 CD4 binding site on the outermost surface of gp120 and the more internal variable 3 (V3) region of gp120. The gp120 V3 region plays a major role in determining the coreceptor tropism of HIV. gp41: The gp41 subunit consists of three domains: ectodomain (in the extracellular region), the transmembrane domain (spans the HIV membrane), and the cytoplasmic tail (inside the HIV membrane).[12,13,14] The gp41 ectodomain has several functional components that include the N- terminal hydrophobic region (functions as the fusion ) and the N-terminal heptad repeat region 1 (HR1) and the heptad repeat region 2 (HR2). Prior to cell binding, the HIV gp41 exist in a conformation in which the gp41 is folded back on itself in an energy loaded state.

HIV Entry

The HIV entry process involves a sequential and coordinated interaction between the and the host cell that includes three key steps: (1) attachment of HIV gp120 with the host CD4 , (2) HIV gp120-host chemokine coreceptor binding, and (3) gp41-mediated fusion of HIV with the host surface membrane.[9,15]

Attachment: After initial nonspecific interactions between HIV and the host cell, the HIV gp120 attaches to the host CD4 receptor, with binding occurring at the CD4 binding pocket on HIV gp120 and the extracellular domain 1 (D1) of the CD4 receptor.[16] Coreceptor Binding: Following the initial gp120-CD4 receptor attachment, the HIV gp120 undergoes rearrangement, with formation of a bridging sheet and repositioning of the V3 loop. This rearrangement allows the HIV gp120 V3 loop to interact with a host chemokine coreceptor (CC)—either the CCR5 or CXCR4 coreceptor (Figure 4). The HIV coreceptor binding (CCR5 or CXCR4) depends on the HIV subtype (R5 or X4), which is determined primarily by the HIV gp120 V3 region. Fusion: The HIV gp120-coreceptor interaction is believed to activate the gp41 fusion machinery, which triggers the unfolding of the gp41, with the insertion of the distal end of gp41 (gp41 fusion peptide) into the host cell membrane.[9,16] Next, each of the three gp41 then undergo a hairpin-like fold, resulting in the formation of a six-bundle helix central coil in which the HR1 and HR2 domains mesh along a series of grooves. In the process of forming this hairpin-like coiled bundle, the HIV and host membranes are pulled toward each other, generating the necessary momentum for the formation of a fusion pore and HIV-host cell membrane fusion.[9,16]

HIV Entry Inhibitors

The FDA-approved HIV entry inhibitors includes three subclasses: (1) CD4 postattachment inhibitor, (2) CCR5

Page 2/83 coreceptor antagonists, and (3) fusion inhibitors; each one of these subclasses of entry inhibitors has one FDA- approved drug.[17,18]

Attachment Inhibitor: The early interaction of HIV and the host cell involves binding of the host CD4 receptor and the binding site of the HIV gp120 envelope . The attachment inhibitor is an oral prodrug that is hydrolyzed to the active form temsavir, which binds to the HIV gp120 envelope adjacent to the gp120-CD4 binding site.[19,20] The binding of temsavir prevents the gp120 conformational change required for normal attachment to the CD4 receptor (Figure 5).[19] Postattachment Inhibitor: The early interaction of HIV and the host cell involves binding of the host CD4 receptor and the HIV gp120 envelope. The initial attachment occurs with the domain 1 region of the host CD4 receptor and the HIV gp120 binding site. The humanized monoclonal binds to the domain 2 region of the host CD4 receptor and through steric hindrance it prevents the normal structural shifts that occur in gp120 that result in gp120-coreceptor binding (Figure 6); the net effect of ibalizumab is prevention of .[21,22] Ibalizumab does not block the initial attachment of CD4 domain 1 and HIV gp120. In addition, ibalizumab is not thought to interfere with CD4-mediated immune function since it does not interfere with CD4 binding of MCH class II molecules, which occurs at the CD4 domain 1 region. CCR5 Receptor Antagonists: The appropriate use of CCR5 antagonists depends on knowledge of the person’s HIV subtype. There are three HIV subtypes related to the host coreceptor binding: R5 HIV (binds only to the CCR5 coreceptor); X4 HIV (binds only to the CXCR4 coreceptor); dual-tropic HIV (binds to either the CCR5 or CXCR4 coreceptor).[23,24] Individuals with a mixture of R5 HIV and X4 HIV have mixed-tropic HIV. The CCR5 antagonists bind to the CCR5 coreceptor, causing a conformational change in the coreceptor that prevents HIV gp120 from binding to the CCR5 coreceptor (Figure 7).[23,25] The CCR5 antagonists do not effectively block the entry of X4, dual tropic, or mixed tropic HIV. The drug is the only FDA-approved CCR5 antagonist, and it is recommended for use in antiretroviral treatment-experienced individuals only if they have documented pure R5 HIV. Thus, prior to starting maraviroc, an HIV coreceptor tropism assay must be performed; these assays reports provide information on the presence of R5, X4, and dual/mixed (the reports do not differentiate dual and mixed isolates).[23,25,26]. Fusion Inhibitor: 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 fusion inhibitor is a 36-amino-acid synthetic peptide that corresponds to a 36-amino-acid segment in the HIV gp41 heptad repeat region 2 (Figure 8); the enfuvirtide peptide binds to the heptad repeat region 1 of gp41, thus preventing the normal interaction and folding of the gp41 heptad repeat regions 1 and 2.[24,27,28] Enfuvirtide is the only FDA-approved fusion inhibitor. Unique among the antiretroviral agents, the route of enfuvirtide delivery is subcutaneous injection.

Reverse and Reverse Transcriptase Inhibitors

HIV Reverse Transcriptase

The HIV reverse transcriptase is the enzyme involved in the critical HIV reverse transcription process. The HIV reverse transcriptase enzyme is a heterodimer consisting of the p66 and p51 subunits; the p66 and p51 subunit are 560 and 440 amino acids in length respectively, with the 440 amino acids of p51 overlapping with the first 440 amino acids of the p66 subunit (Figure 9).[29] The p66 subunit, which primarily has a catalytic role, consists of the and RNase H domains. Conceptually, the polymerase domain is structurally analogous to a human right hand, with specific regions corresponding to fingers, palm, and thumb. The p51 subunit functions have a structural role, and it is very closely related to, but not identical with, the polymerase domain of the p66 subunit. Each HIV-1 virion contains approximately 50 reverse transcriptase enzymes.[29]

Reverse Transcription

Page 3/83 The HIV reverse transcription process is a multistep process that results in a copy of linear, double-strand HIV DNA being generated from single strand HIV RNA. Each HIV-1 virion contains two copies of plus-stranded genomic RNA. Conceptually, the key steps in reverse transcription are the conversion of single strand HIV RNA to a single strand of HIV DNA, followed by digestion of the HIV RNA, and finishing with the formation of double-strand HIV DNA from the single strand of HIV DNA. The HIV reverse transcriptase enzyme plays a central role during reverse transcription and the enzymatic activities that occur involve the polymerase and RNase H active sites, which are both located in the p66 subunit. During this process, the HIV reverse transcriptase polymerase domain functions to add host to the expanding strand of DNA whereas the RNase H is digesting unwanted fragments of HIV RNA and HIV DNA. During this process of DNA synthesis, the HIV reverse transcriptase incorporates host nucleotides into the elongating primer strand, which is forming opposite to the HIV template strand (Figure 10).[29]

Reverse Transcriptase Inhibitors

The HIV reverse transcriptase inhibitors include two classes of antiretroviral medications: the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Mechanistically, the fundamental difference between these classes is that the NRTIs act as host decoys and cause termination of the elongating HIV DNA chain whereas the NNRTIs bind directly to the HIV reverse transcriptase enzyme and inhibit the function of the enzyme.

Nucleoside Reverse Transcriptase Inhibitors: The NRTIs require intracellular phosphorylation to obtain an active state. Once in a triphosphorylated state, the NRTIs mimic human nucleotides and can be interchangeably taken up by reverse transcriptase. Unlike the human nucleotides, the NRTI medications do not have a 3'-hydroxyl group and additional nucleotides cannot be added to the NRTI drug, hence the name chain terminator (Figure 11). Non-nucleoside Reverse Transcriptase Inhibitors: The NNRTIs bind to a hydrophobic pocket in the p66 subunit, which is close to the active polymerase site (Figure 12).[30,31] Binding of the NNRTI causes hyperextension of the reverse transcriptase thumb region, which causes a conformational change in this polymerase domain, thereby blocking the process of DNA polymerization, a critical step in HIV reverse transcription.[30,32] The NNRTI hydrophobic binding pocket region is predominantly lined by codons 98 to 108 and 179 to 190.[33]

HIV Integration and Integrase Strand Transfer Inhibitors

HIV Integrase

The HIV integrase enzyme is a 288 amino-acid protein that consists of three distinct structural domains: the amino (N)-terminal domain, the catalytic core domain, and the carboxy (C)-terminal domain; the catalytic core domain contains a trio of amino acids that coordinate binding with a divalent metal cofactor (either Mg2+ or Mn2+) and this region forms the active catalytic site (Figure 13).[34,35,36]. The HIV integrase enzyme can exist in the form of a monomer, dimer, tetramer, and possibly higher order forms, such as octamers. Each HIV-1 virion has an estimated 40 to 100 integrase enzymes.[36]

HIV Integration

For replications, must integrate the linear, double-stranded HIV DNA formed by reverse transcription into the host DNA. The integration of HIV DNA into host DNA is a multistep process and the HIV enzyme integrase performs two key catalytic reactions: 3’ processing of the HIV DNA and strand transfer of the HIV DNA into the host DNA.[35,36,37] Initially, the HIV integrase (most likely in the dimer form) binds to each end of the newly formed HIV DNA as part of an intracellular particle known as the preintegration complex (Figure 14).[35] The DNA-bound integrase removes two nucleotides on the 3’-ends of the DNA, forming sticky ends that are capable of inserting into the host DNA.[37] The preintegration complex then migrates into the nucleus of the host cell through a nuclear pore. Inside the nucleus, the host protein lens epithelium-derived growth factor (LEDGF)/p75 binds to the preintegration complex and the host DNA,

Page 4/83 serving as a tethering protein (or bridge) between the preintegration complex and the host DNA.[35,38] Next, the strand transfer reaction occurs when the integrase enzyme catalyzes the HIV DNA 3’-hydroxyl group attack on the host DNA and the HIV DNA is then inserted into the host DNA. In the final step, cellular enzymes perform DNA gap repair, which smooth over the HIV-host DNA junctions.[37]

Integrase Strand Transfer Inhibitors

Multiple potential sites of inhibition exist with the HIV integration process. Currently, available HIV integrase inhibitors utilize multiple mechanisms to block the integrase strand transfer step and are thus referred to as integrase strand transfer inhibitors (INSTIs) [39,40]. The INSTIs only bind to the integrase enzyme when the integrase enzyme is attached to the viral DNA.[41] The diketo acid group of the INSTIs binds to the magnesium ions in the of HIV integrase, thereby inhibiting the active site (Figure 15).[35] In addition, upon binding to the magnesium ions, the INSTIs displace the HIV DNA 3'-hydroxyl ends, which interrupts the integration process since the 3’-hydroxyl ends are the critical nucleophiles during the transfer of the strand of HIV DNA into the host DNA.[41] Further, binding of the INSTI to the integrase enzyme prevents the HIV complex from integrating into the host DNA. When the HIV integration process is blocked, the HIV DNA becomes a substrate for host repair enzymes that subsequently convert the HIV DNA complex into byproduct 2- (2-LTR) circles.[37]

HIV Protein Processing and HIV Protease inhibitors

HIV Protease

The HIV protease enzyme is a 99-amino-acid dimer made up of two identical subunits (Figure 16). This enzyme has a key role in post-transcriptional processing of the Gag (Pr55) and Gag-Pol (Pr160) polyproteins.[42] The HIV protease has three major conformational forms: open, semi-open, and closed (Figure 17). The protease enzyme has an active site near the center of the heterodimer and the active site includes two opposed aspartic acid (Asp) residues. Movement from the open to closed causes the flap ends to overlap and functionally act as a molecular scissor.

Polyprotein Processing and Maturation

The protease-related polyprotein processing occurs in a consistent sequential pattern. The Gag polyprotein contains four structural proteins: matrix (p17), (p24), nucleocapsid (p7), and p6 proteins. In addition, two spacer (p2 and p1) are part of Gag. During approximately 5 to 10% of the Gag events, a ribosomal frameshift occurs that results in translation of the Gag-Pol polyprotein.[43] The Gag-Pol polyprotein includes the same structural Gag proteins, with the addition of the Pol functional enzymes (protease, reverse transcriptase, and integrase). Each virion contains approximately 5,000 Gag polyproteins.[44] The HIV protease initially catalyzes its own release from the Gag-Pol polyprotein strand. Once the HIV protease is untethered, it processes both the Gag-Pol and the Gag polyproteins. The HIV protease polyprotein processing of the Gag protein occurs in a predictable sequential cascade (Figure 18).[43 ,45,46] The timing of the polyprotein processing occurs late in the HIV replication cycle, typically during and shortly after the virus release from the host cell. The processing of the Gag and Gag-Pol polyproteins results in release of the matrix, capsid, nucleocapsid, p6, protease, reverse transcriptase, and integrase proteins.[45] The HIV protease enzyme is not involved in the processing of the gp160 envelope protein, which is the precursor glycoprotein for the gp120 and gp41 envelope .

Protease Inhibitors

The HIV protease inhibitors are structurally complex molecules that bind to the active site of HIV protease and inhibit the protease enzyme activity (Figure 19).[42,43] The HIV protease inhibitors disrupt the normal Gag and Gag-Pol polyprotein processing, causing arrest of the normal maturation process, which thereby prevents infection of new cells. The protease inhibitors do not have an impact on cells already infected with HIV (those with proviral DNA integrated into the host DNA).

Page 5/83 Page 6/83 When to Initiate Antiretroviral Therapy

Recommendations for Initiation of Antiretroviral Therapy

The Adult and Adolescent ARV Guidelines recommend initiation of antiretroviral therapy for all persons with HIV to reduce morbidity and mortality associated with HIV infection and to prevent HIV to others [Table] Panel's Recommendations for Initiating Antiretroviral Therapy in Treatment-Naive Patients.[47] In addition, antiretroviral therapy should be started immediately, or as soon as possible, after the HIV diagnosis.[47]

Data for Clinical Benefit of Antiretroviral Therapy

The Adult and Adolescent ARV Guidelines recommendation to initiate antiretroviral therapy in all persons living with HIV to reduce morbidity and mortality is based on multiple cohort studies and clinical trials, as outlined below, that have shown a clear benefit of starting antiretroviral therapy earlier in the course of HIV disease progression.

ART Cohort Collaboration: The ART Cohort Collaboration (ART-CC) followed 12,574 treatment-naïve adults with HIV who started 3-drug antiretroviral therapy and investigators identified baseline CD4 cell count when starting antiretroviral therapy as the most important prognostic factor for new AIDS- defining illness or death (Figure 20).[48] Although the initial ART-CC used a CD4 count of 350 cells/mm3 or greater as the highest CD4 category, follow-up analysis with this cohort further stratified the data in the higher CD4 categories and reported a higher rate of progression to AIDS and/or death in patients who deferred therapy in the CD4 count range of 251-350 cells/mm3 compared with those who initiated therapy with a CD4 count between 351-500 cells/mm3.[49] CIPRA HT-001: In the CIPRA HT-001 conducted in Haiti, investigators randomized participants to start antiretroviral therapy at a CD4 count of 200-350 cells/mm3, or to defer treatment until either their CD4 count decreased to less than 200 cells/mm3 or they developed an AIDS-defining condition.[50] In an interim analysis of the study, participants who began antiretroviral therapy with CD4 counts of 200-350 cells/mm3 had a lower mortality rate and lower of tuberculosis than participants who deferred therapy (Figure 21).[50] Johns Hopkins Cohort: A study from Johns Hopkins found that among 1,173 adults with HIV treated with antiretroviral therapy, those with a baseline CD4 count less than 200 cells/mm3 had a more rapid 3-year disease progression than those who had a baseline of 201 to 350 cells/mm3, even when obtaining comparable durable virologic suppression (Figure 22).[51] NA-ACCORD: The North American AIDS Cohort Collaborative Collaboration on Research and Design (NA-ACCORD), an observational analysis including more than 17,000 patients, showed that adults with a CD4 count of 351 to 500 cells/mm3 who deferred antiretroviral therapy until the CD4 count declined to 350 cells/mm3 or lower had a 69% increased risk of death when compared with those who did not defer antiretroviral therapy.[2] In this same study, a parallel analysis involving adults with a CD4 count greater than 500 cells/mm3 found that deferral of therapy until the CD4 count declined to 500 cells/mm3 or lower was associated with a 94% increased risk of death when compared with earlier initiation of antiretroviral therapy.[2] SMART: The multinational Strategies for Management of Antiretroviral Therapy (SMART) trial randomized more than 5,400 participants with CD4 counts greater than 350 cells/mm3 to receive continuous antiretroviral therapy or to interrupt treatment until the CD4 count decreased to less than 250 cell/mm3. A subgroup analysis, which involved the 249 treatment-naïve participants at enrollment, found a trend of lower risk of serious AIDS- and non-AIDS-related events in the group who initiated therapy immediately when compared with those who deferred therapy until the CD4 count decreased to less than 250 cells/mm3.[52] START: The Strategic Timing of Antiretroviral Therapy (START) study was a multicenter international trial that examined the benefits and risks of initiating antiretroviral therapy in asymptomatic individuals with HIV who had a CD4 count greater than 350 cells/mm3.[1] Investigators randomized

Page 7/83 4,685 adults with HIV to one of two arms: 1) start antiretroviral therapy immediately (immediate- initiation group) or 2) defer antiretroviral therapy until the CD4 count decreased to 350 cells/mm3 or development of an AIDS-related condition (or another condition) that warranted the use of antiretroviral therapy (deferred-initiation group). Comparing the immediate-initiation group with the deferred-initiation group, the hazard ratio for a serious AIDS-related event was 0.28, for a serious non- AIDS event was 0.61, and 0.58 for death from any cause (Figure 23).[1] Swiss HIV Cohort Study: In the Swiss HIV Cohort Study, investigators compared early initiation of antiretroviral therapy (adults with CD4 counts greater than 350 cells/mm3) versus deferred therapy (adults monitored without therapy) and found an approximate 5-fold decrease in disease progression to AIDS in the subsequent 3-year period among those who initiated therapy (Figure 24).[53]

Data for Antiretroviral Therapy Reducing HIV Transmission

The Adult and Adolescent ARV Guidelines recommendation regarding use of antiretroviral therapy to prevent HIV transmission is based on multiple studies that indicate antiretroviral therapy dramatically lowers the risk of perinatal transmission of HIV and sexual transmission of HIV.

PACTG 076: In the Pediatric AIDS Clinical Trials Group study (PACTG) 076, given during pregnancy, labor, and to the infant for 6 weeks reduced mother-to-child transmission of HIV by nearly 70%.[54] This landmark trial established that perinatal HIV transmission could be markedly reduced with antiretroviral therapy. Multiple other studies have confirmed the overwhelming benefit of providing antiretroviral therapy to pregnant and breastfeeding women to prevent vertical transmission of HIV. HPTN 052: The most notable treatment-as-prevention trial, HPTN-052, enrolled 1,763 serodifferent (mostly heterosexual) couples from 9 countries and demonstrated that early initiation of antiretroviral therapy (prior to a decline in CD4 count or the onset of HIV-related symptoms) reduced rates of sexual transmission of HIV to the HIV-negative partner by 96% when compared with persons who deferred antiretroviral therapy. PARTNER-1 Study: In the first phase of the European PARTNER (Partners of People on ART—A New Evaluation of the Risks) study, investigators at 75 sites in 14 European countries evaluated the impact of antiretroviral therapy on HIV transmission risk in 888 HIV-serodifferent couples engaging in condomless sex, including 548 heterosexual couples and 340 gay male couples.[6] The eligibility for enrollment required the partner with HIV to be taking antiretroviral therapy and have an HIV RNA level less than 200 copies/mL.[6] Enrollment took place during September 2010 to May 2014 and during this time there were zero phylogenetically linked HIV transmissions that occurred in these couples, with an estimated 58,000 condomless sex acts (22,000 in gay male couples and 36,000 in heterosexual couples).[6] There were 11 new HIV during the study period, but none of these were phylogenetically linked. PARTNER-2 Study: In the second phase of the European PARTNER (Partners of People on ART—A New Evaluation of the Risks) study, investigators at the same 75 sites in 14 European countries continued the PARTNER study, but additional enrollment was open only for serodifferent gay men.[55] The extended enrollment included a total of 972 serodifferent gay male couples.[55] The design to include only serodifferent gay male couples was to make up for some of the imbalance of the predominantly heterosexual serodifferent couples enrolled in the PARTNER-1 trial. As with PARTNER-1, the eligibility for enrollment required the partner with HIV to be taking antiretroviral therapy and have an HIV RNA level less than 200 copies/mL. During the study, the serodifferent gay male couples reported condomless anal sex a total of 76,088 times and there were zero phylogenetically-linked transmissions.[55] There were, however, 15 new HIV infections during the study period, but none of these were phylogenetically linked.[55] Opposites Attract: The Opposites Attract trial was conducted from 2012-2016 and enrolled 358 HIV- serodifferent gay male couples in Thailand, Brazil, and Australia.[56] Of the 358 couples that enrolled, 343 had at least one follow-up visit and 75% (258 of 343) of the HIV-positive partners had an HIV RNA level less than 200 copies/mL.[56] There were zero phylogenetically-linked cases of HIV transmission from among 12,447 sex acts that involved (1) condomless anal intercourse, (2) the partner with HIV

Page 8/83 taking antiretroviral therapy and having an HIV RNA less than 200 copies/mL, and (3) the partner without HIV not taking preexposure prophylaxis.[56] There were three new HIV infections during the study period, but none were phylogenetically linked.[56]

Recommendations for Elite and Viremic Controllers

Definition of Elite and Viremic Controllers

A small percentage of persons naturally control their HIV without medications and are considered "elite controllers" of HIV. These individuals have a unique immunologic response to HIV that results in persistent control of plasma HIV RNA levels to levels consistently below the limit of quantitation. These individuals also usually maintain long-term control of CD4 cell count levels above 500 cells/mm3.[57] Similarly, a larger, but still small subset of individuals with HIV, referred to as "viremic controllers", have the ability to naturally maintain plasma HIV RNA at very low, but not undetectable, levels.[57] The viremic controllers also usually have high CD4 cell counts, but typically have less stable and lower CD4 cell counts than elite controllers.[58]

Management of Elite and Viremic Controllers

The optimal antiretroviral management of elite controllers and viremic controllers has generated controversy since, without antiretroviral therapy, these individuals naturally control HIV RNA levels and theoretically would pose minimal risk of transmitting HIV to others. These individuals, however, may still have increased risk of non-AIDS-related morbidity from immune activation and a significant proportion will eventually lose their immunologic control of HIV and have disease progression.[57,59,60] The Adult and Adolescent ARV Guidelines make the following key recommendations for "elite controllers":[47]

Antiretroviral therapy is clearly recommended for elite controllers if they have evidence of HIV disease progression. The clinical benefit of antiretroviral therapy in elite controllers who do not have HIV disease progression remains uncertain. Elite controllers have increased immune activation and markers for increased risk of atherosclerosis. There is a theoretical benefit of giving antiretroviral therapy to elite controllers to reduce immune activation and potential non-AIDS morbidity. If antiretroviral therapy is not given to elite controllers, close follow-up should occur since some of these individuals lose their natural control of HIV.

Page 9/83 Antiretroviral Regimens for Initial Therapy

The Adult and Adolescent ARV Guidelines stratify antiretroviral regimens for initial therapy as (1) Recommended for Most People with HIV, (2) Recommended in Certain Clinical Situations, and (3) Not Recommended as Initial Therapy.

Recommended Initial Regimens for Most People with HIV

The Adult and Adolescent ARV Guidelines regimens listed as Recommended Initial Regimens for Most People with HIV include an INSTI anchor drug in combination with at least one NRTI (Table 2).[61] The choice of the specific first-line antiretroviral regimen depends on multiple factors, including medical comorbidities, potential drug interactions, and patient preferences (pill burden, frequency of dosing, and food requirements. All of these regimens can be dosed once daily. Note that - should not be used as initial therapy in the following three situations: (1) the baseline HIV RNA level is greater than 500,000 copies/mL, (2) the persons undergoing treatment has chronic virus (HBV) or the HBV status is unknown, or (3) results from the HIV genotypic resistance testing are not available at the time antiretroviral therapy is planned to start.[61] Except for the HIV RNA level restriction for dolutegravir-lamivudine, all of these regimens can be used without regard to pretreatment HIV RNA level or CD4 cell count.

Recommended Initial Regimens in Certain Clinical Situations

Multiple antiretroviral regimens are available that are effective and tolerable, but are considered inferior to the regimens listed above. The Adult and Adolescent ARV Guidelines denotes this category as Recommended Initial Regimens in Certain Clinical Situations (Table 3).[61] This category also addresses regimens to consider when , , and tenofovir DF cannot be used or are not optimal to use, as well as addressing specific circumstances that apply to certain 2-drug regimens.[61,62,63,64]

Antiretroviral Regimens or Components Not Recommended

The Adult and Adolescent ARV Guidelines also includes a category for Antiretroviral Regimens or Components Not Recommended as Initial Therapy (Table 4).[61]

Special Considerations for Persons of Childbearing Potential

The Adult and Adolescent ARV Guidelines has specific recommendations for Individuals trying to conceive or who cannot use effective contraception.[65] Based on updated data, dolutegravir is now considered as a preferred in women of child-bearing age who are trying to conceive.[65] For women trying to conceive, the recommended antiretroviral regimens consist of an anchor drug (dolutegravir, , boosted with , or boosted with ritonavir) plus a dual NRTI backbone (abacavir-lamivudine, tenofovir DF-, or tenofovir DF plus lamivudine).[65]

Page 10/83 Choosing Specific Antiretroviral Regimen

Factors to Consider for Selecting Initial Regimen

In clinical practice, a number of specific clinical scenarios exist that may warrant consideration to avoid or using certain regimens. The following summarizes recommendations in the Adult and Adolescent ARV Guidelines.[66]

Pretreatment HIV RNA Level: The following regimens should not be used with pretreatment HIV RNA levels greater than 100,000 copies/mL due to higher rates of virologic failure: -based regimens, abacavir-lamivudine (when used with or ritonavir-boosted atazanavir), and raltegravir plus ritonavir-boosted darunavir. Dolutegravir-lamivudine should not be used when the pretreatment HIV RNA level is greater than 500,000 copies/mL based on limited data for the use of this regimen in persons with pretreatment HIV RNA levels greater than 500,000 copies/mL. Pretreatment CD4 Cell Count: Higher rates of virologic failure have occurred with rilpivirine-based regimens and raltegravir plus ritonavir-boosted darunavir when the pretreatment CD4 count is less than 200 cells/mm3. Accordingly, these regimens should not be used in persons who have a pretreatment CD4 count less than 200 cells/mm3. Treatment of HIV Before Drug Resistance Results Available: It is essential to use an antiretroviral regimen that has a high genetic barrier to resistance in the situation when treatment is initiated prior to availability of the HIV genotypic drug resistance test results. In general, NNRTI-based regimens should be avoided in this setting. The following regimens are recommended in this situation: -tenofovir alafenamide-emtricitabine Dolutegravir plus (tenofovir alafenamide or tenofovir DF) plus (emtricitabine or lamivudine) Darunavir (boosted with ritonavir or ) plus (tenofovir alafenamide or tenofovir DF) plus (emtricitabine or lamivudine) Food Requirements: The NRTI backbone combinations of abacavir-lamivudine, tenofovir DF- emtricitabine, and tenofovir alafenamide-emtricitabine can be taken with or without food. The INSTIs raltegravir and dolutegravir can be taken with or without food; the single-tablet regimens bictegravir- tenofovir alafenamide-emtricitabine, dolutegravir-abacavir-lamivudine, dolutegravir-lamivudine, and -tenofovir DF-lamivudine can also be taken with or without food. Efavirenz should be taken on an empty stomach. The following medications should be taken with food: rilpivirine, atazanavir boosted with either ritonavir or cobicistat, darunavir boosted with either ritonavir or cobicistat, -cobicistat-tenofovir DF-emtricitabine, and elvitegravir-cobicistat-tenofovir alafenamide- emtricitabine. Chronic Kidney Disease: For persons who have a pretreatment estimated glomerular filtration rate (eGFR) less than 60 mL/min, any regimen containing tenofovir DF should be avoided. If the eGFR is less than 30 mL/min, any regimen containing tenofovir alafenamide-emtricitabine should be avoided. Osteoporosis: In patients with known osteoporosis, tenofovir DF or any fixed-dose combination that contains tenofovir DF should be avoided. Psychiatric Illness: Efavirenz, and possibly rilpivirine, have been associated with worsening of psychiatric symptoms, and consideration should be given to avoiding these medications in persons with psychiatric illness. Hyperlipidemia: The INSTIs bictegravir, dolutegravir, and raltegravir are considered neutral. Tenofovir DF has a favorable impact on . The following medications often cause dyslipidemia: ritonavir-boosted PIs, cobicistat-containing regimens, and efavirenz. Concern for Excess Weight Gain: Use of INSTIs, particularly dolutegravir plus tenofovir alafenamide- emtricitabine and bictegravir-tenofovir alafenamide-emtricitabine have been associated with significant weight gain ins some individuals after starting antiretroviral therapy. Weight gain on these regimens has disproportionately impacted women and Black and Hispanic people. : Efavirenz should be avoided in persons with dementia. Cardiac QTc Interval Prolongation: Efavirenz and rilpivirine may prolong QTc interval; therefore these medications should be avoided in persons taking other medications that may prolong the QTc.

Page 11/83 Choosing the Anchor Drug in Regimen

The choice of the third drug, commonly referred to as the anchor drug, to combine with an NRTI backbone for an initial antiretroviral regimen depends on clinical, pharmacologic, and patient-level factors. In the Adult and Adolescent ARV Guidelines, the Recommended Initial Regimens for Most People with HIV utilize the INSTI bictegravir or dolutegravir as the anchor drug; the recommendation to use these two INSTIs as the anchor drug is based on high efficacy, high genetic barrier to resistance, low profile, and minimal drug interactions.[61] In previous years, the Adult and Adolescent ARV Guidelines included the INSTI elvitegravir, raltegravir, protease inhibitors, and NNRTIs as the anchor drug in the recommended regimen category, but certain limitations, such as poor tolerability, restrictions for use based on CD4 cell count and/or HIV RNA level, and lower genetic barrier to resistance have relegated these anchor to the alternative regimen category.

Choice of INSTI

In the Adult and Adolescent ARV Guidelines, two of the INSTIs (bictegravir and dolutegravir) are included as the anchor drug components of the Recommended Initial Regimens for Most People with HIV.[61] Note that bictegravir is available only as a fixed-dose combination. In the SPRING-2 study, once-daily dolutegravir was non-inferior to twice daily raltegravir in treatment-naïve patients with HIV infection.[67] In study 1490, initial therapy with bictegravir-tenofovir alafenamide-emtricitabine showed similar virologic responses as dolutegravir plus tenofovir alafenamide-emtricitabine.[68] Bictegravir and dolutegravir have emerged the most attractive INSTI-based options based on strong potency, high genetic barrier to resistance, and good tolerability.

Choice of PI

The Adult and Adolescent ARV Guidelines recommend two NRTIs plus either boosted darunavir or boosted atazanavir as the only protease inhibitor-based options in the category Recommended Initial Regimens in Certain Clinical Situations.[61] In the ARTEMIS trial, initial therapy with a ritonavir-boosted darunavir regimen was superior to a -ritonavir regimen, both in terms of virologic suppression and tolerability.[69] In the ACTG A5257 study, initial therapy with a ritonavir-boosted darunavir regimen had similar virologic efficacy to a ritonavir-boosted atazanavir regimen, but more patients discontinued the ritonavir-boosted atazanavir regimen due to adverse events (primarily hyperbilirubinemia).[70] Boosted darunavir and atazanavir can be dosed once daily (with food) and boosting can be achieved with either ritonavir or cobicistat. Coformulated boosted preparations are available as atazanavir-cobicistat and darunavir-cobicistat. Darunavir may cause rash in patients with a sulfa , but atazanavir often causes hyperbilirubinemia.

Choice of NNRTI

Multiple regimens that utilize an NNRTI as the anchor drug are available in the category of Recommended Initial Regimens in Certain Clinical Situations; in this category, the NNRTI anchor drugs include doravirine, efavirenz, and rilpivirine.[61] The ECHO and THRIVE studies, which compared efavirenz- and rilpivirine- based regimens, reported similar levels of undetectable HIV RNA levels at 48 weeks in the two regimens.[71,72,73] Rilpivirine should not be used in persons who have baseline HIV RNA level greater than or equal to 100,000 copies/mL or a CD4 count less than or equal to 200 cells/mm3. In addition, rilpivirine is contraindicated for individuals who are taking a proton pump inhibitor and must be taken with a meal of at least 500 calories.[61] For a person with uncontrolled or untreated depression, most experts would avoid the use of efavirenz, which has a high rate of central toxicities and an association with increased suicidality. Rilpivirine also causes central nervous system adverse effects in some patients, but to a lesser degree than efavirenz. Doravirine is better tolerated than efavirenz, it can be used in combination with proton pump inhibitors, and it can be taken with or without food. The NNRTI is approved only for use in antiretroviral treatment-experienced persons.

Page 12/83 Choosing NRTI Backbone in Regimen

The Adult and Adolescent ARV Guidelines include four different NRTI backbone combinations: abacavir- lamivudine, tenofovir alafenamide-emtricitabine, tenofovir DF-emtricitabine, and tenofovir DF-lamivudine.[61] Abacavir has been associated with increased cardiovascular risk, and although data is conflicting about this association, many experts would avoid abacavir in the setting of known cardiovascular disease risk factors. Tenofovir DF is linked to increased risk of renal dysfunction and loss of density; accordingly, tenofovir DF is not recommended for patients with renal disease or osteoporosis. Tenofovir alafenamide has a less favorable lipid profile than tenofovir DF.

Page 13/83 What Not to Use

The Adult and Adolescent ARV Guidelines provides a category for antiretroviral medications which, either alone or in combination, should not be offered for use at any time.[74] Regimens (or components of regimens) that are considered in the What Not to Use category include:

Antiretroviral Drugs Not Recommended

Delavirdine

Antiretroviral Regimens Not Recommended

Monotherapy with any antiretroviral medication Dual therapy with two NRTIs Triple therapy with three NRTIs

Antiretroviral Components Not Recommended

Atazanavir plus indinavir Cobicistat plus ritonavir as pharmacokinetic enhancers Didanosine plus stavudine Didanosine plus tenofovir DF Two NNRTIs in combination Emtricitabine plus lamivudine Etravirine plus an unboosted protease inhibitor Etravirine plus ritonavir-boosted Etravirine plus ritonavir-boosted in women with CD4 count above 250 cells/mm3 or in men with CD4 count above 400 cells/mm3 Unboosted darunavir, , or tipranavir Stavudine plus zidovudine, Tenofovir alafenamide plus tenofovir DF

Page 14/83 Monitoring Response to Antiretroviral Therapy

After initiating antiretroviral therapy, it is essential to monitor the virologic and immunologic response to therapy. The following outlines recommendations in the Adult and Adolescent ARV Guidelines for monitoring HIV RNA levels and CD4 cell counts in persons on antiretroviral therapy.[75,76] HIV RNA Monitoring

During the first 6 months after starting antiretroviral therapy most individuals will achieve a reduction in HIV RNA levels to less than 50 copies/mL. In some individuals, particularly those with extremely high baseline HIV RNA levels, the time to virologic suppression may extend past 6 months. The important parameter is whether the HIV RNA levels are continuing to decline. In general, INSTI-based regimens cause a more rapid reduction in HIV RNA levels than with NNRTI- or PI-based regimens.[77,78]

Baseline: All individuals initiating antiretroviral therapy should have a baseline HIV RNA level. After Initiating Therapy: After starting antiretroviral therapy, an HIV RNA level should be obtained preferably within 2 to 4 weeks and no later than 8 weeks. Subsequently, HIV RNA levels should be repeated thereafter every 4 to 8 weeks until the HIV RNA is suppressed. After Virologic Suppression: Once HIV RNA levels are suppressed, the frequency of HIV RNA monitoring should extend to every 3 to 4 months. With Long-Term Virologic Suppression: For adherent individuals who have consistently suppressed HIV RNA for at least 2 years (and stable immunologic status), HIV RNA monitoring can be extended to 6-month intervals. Virologic Breakthrough: In persons on antiretroviral therapy who have virologic breakthrough, monitoring of HIV RNA levels should be adjusted as needed. Change in Clinical Status: If an individual has a change in clinical status or has to initiate therapy with chronic or , the HIV RNA levels should be checked every 3 months.

CD4 Cell Count

Individuals who suppress HIV RNA levels on antiretroviral therapy typically have an increase in CD4 count of approximately 50 to 150 cells/mm3 after the first year, with subsequent average yearly increases of approximately 50 to 100 cells/mm3 until a steady state is attained.[79,80]

Baseline: All persons starting on antiretroviral therapy should have a baseline CD4 cell count. After Initiating Therapy: A repeat CD4 cell count value should be obtained at 3 months after starting therapy. During First 2 Years After Initiating Therapy: During the first 2 years on antiretroviral therapy the CD4 count should be monitored every 3 to 6 months. With Long-Term Stable Virologic Suppression: After 2 years on antiretroviral therapy, the frequency of CD4 cell count monitoring for adherent patients with consistently suppressed HIV RNA levels should be determined by immune status: If the CD4 count is less than 300 cells/mm3, monitoring should continue every 3 to 6 months. If the CD4 count is consistently in the 300 to 500 cells/mm3 range, monitoring can be extended to 12-month intervals. If the CD4 count is consistently greater than 500 cells/mm3, monitoring should then be considered optional. Change in Clinical Status: If an individual on antiretroviral therapy has a change in clinical status or has to initiate therapy with chronic corticosteroids or chemotherapy, the CD4 cell counts should be checked as clinically indicated.

Page 15/83 Poor CD4 Response to Antiretroviral Therapy

After starting antiretroviral therapy, the virologic response is the most important factor in predicting an overall successful treatment outcome. Typically, adults with HIV have a brisk increase in CD4 cells in the first 3 to 6 months after starting antiretroviral therapy, predominantly due to a release of memory CD4 cells trapped within lymphoid tissues.[81] In the second phase of CD4 recovery, there is a gradual increase in CD4 counts that continues for 3 to 6 years; this phase involves both naïve CD4 cells (from the thymus) and memory CD4 cells. In general, persons with lower nadir CD4 cell counts have lower likelihood of having a high or near normal CD4 count upon recovery following years of antiretroviral therapy (Figure 25).[82,83,84] Approximately 15% of persons with HIV and advanced immunosuppression fail to recover their CD4 count at a level greater than 200 cells/mm3 despite virologic suppression.[85] These “discordant” virologic-immunologic responses can generate concern, especially since persistent low CD4 is associated with increased AIDS- related and non-AIDS-related morbidity and mortality.[86,87]

Factors Associated with Poor CD4 Recovery

Investigators have identified multiple factors associated with a poor CD4 count response to antiretroviral therapy: older age, pretreatment CD4 count less than 200 cells/mm3, coinfection, HIV-2 coinfection, coexistence of other chronic medical conditions, and the use of antiretroviral regimens that contain certain medications, such as zidovudine or the combination of tenofovir DF and didanosine.[86,88] A meta-analysis of different antiretroviral regimens found that ritonavir-boosted protease inhibitor-based regimens produced better CD4 cell responses than either unboosted protease inhibitor regimens or non- nucleoside reverse transcriptase inhibitor-based regimens.[89] In addition, studies have shown greater CD4 count increases in raltegravir- and dolutegravir-based regimens than with efavirenz-based regimens.[78,90] Some medications, such as -alfa, peginterferon-alfa, or chemotherapeutic agents, can significantly reduce the CD4 count, with a gradual return to normal after the medication is discontinued; these types of medications generally do not impact the CD4 percentage nearly as much as the absolute CD4 cell count.

Recommendations for Patients with Persistently Low CD4 Counts

For persons with HIV who have a poor CD4 count recovery (CD4 count remains below 200 cells/mm3 despite having suppressed HIV RNA levels for at least 2 years), the Adult and Adolescent ARV Guidelines do not recommend intensifying or switching the antiretroviral regimen.[86] It is important to evaluate whether the individual is taking any medications (not used to treat HIV) that suppress the bone marrow or whether they have clinical manifestations (pancytopenia, systemic symptoms) that may suggest a bone marrow infiltrative process. In addition, individuals who have persistently low CD4 counts should receive appropriate prophylaxis for opportunistic infections, if indicated. Two large randomized trials (ESPRIT and SILCATT) showed interleukin-2 given to patients with suboptimal CD4 cell count responses causes a significant increase in CD4 cell counts, but the increase was not associated with any clinical benefit (Figure 26) and (Figure 27).[91] Thus, use of interleukin-2 to boost CD4 cell counts is not recommended.

Page 16/83 Discontinuation or Treatment Interruption

Discontinuation of antiretroviral therapy may be necessary at certain times due to acute side effects, illness, surgery that prohibits oral intake, or unavailability of the medications; aside from these factors, persons with HIV should not interrupt antiretroviral therapy. Planned treatment interruptions, often referred to as strategic treatment interruptions, at one time were thought to be potentially beneficial to limit long-term antiretroviral therapy toxicity. Subsequently, discontinuation of therapy was shown to be detrimental to overall outcomes, as it allows for viremia, which can cause acute symptoms and illness, and immune decline.

Data Related to Strategic Treatment Interruptions

In the Strategies for Management of Antiretroviral Therapy (SMART) trial, investigators randomly assigned patients with CD4 counts greater than 350 cells/mm3 to continuous versus episodic use of antiretroviral therapy (the episodic group waited until the CD4 count decreased to 250 cells/mm3 to start, then stopped when the count reached 350 cells/mm3, and reinitiated therapy if the CD4 count declined to less than 250 cells/mm3).[52] The investigators found that the episodic therapy group had a significantly increased risk of or death (from any cause), when compared with the continuous therapy group. Several other studies have shown that antiretroviral treatment interruption usually results in viral rebound, decreases in CD4 cell count, and eventually clinical progression.[92,93] Strategic treatment interruptions are not recommended.[94]

Recommendations

For patients who require a short-term, temporary discontinuation due to surgery or acute illness, or who make a planned interruption despite advice against interruption, the Adult and Adolescent ARV Guidelines provide specific recommendations for how to safely stop the medications, particularly for patients who are taking medications with significantly different half-.[94]

Page 17/83 Summary Points

Five classes of antiretroviral medications, which target specific points of intervention in the multi-step HIV life cycle, have been developed for clinical use: (1) entry inhibitors, (2) NRTIs, (3) NNRTIs, (4) INSTIs, and (5) PIs. The Adult and Adolescent ARV Guidelines recommend initiation of antiretroviral therapy for all persons with HIV to reduce disease progression and prevent transmission; this recommendation reflects evidence from clinical trials and cohort studies that have shown the benefits of starting antiretroviral therapy earlier in the course of HIV infection. In the Adult and Adolescent ARV Guidelines, the Recommended Initial Regimens for Most People with HIV consists of an INSTI anchor drug plus a 2-drug NRTI backbone. Other effective regimen options are available for use in certain clinical situations. The choice of the initial antiretroviral regimen depends on multiple patient factors, including medical and psychiatric comorbidities, patient preferences, and drug interactions. After the initiation of antiretroviral therapy, laboratory monitoring is important to measure the HIV RNA response to therapy, to follow the CD4 count, and to monitor for antiretroviral toxicity. Virologic response to antiretroviral therapy is the most important factor in predicting an overall successful treatment outcome, and most patients will achieve virologic suppression (HIV RNA below the lower level of detection of the assay, usually less than 20 to 75 copies/mL, depending on the assay used) within 24 weeks. Typically, individuals with HIV have a brisk increase in CD4 cells in the first 3 to 6 months after starting antiretroviral therapy, although a small proportion of patients fail to recover their CD4 count at a level greater than 200 cells/mm3 despite sustained virologic suppression. Scheduled antiretroviral treatment interruption is not recommended since this practice has been linked to an increased risk of opportunistic infection and death.

Page 18/83 Citations

1. INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373:795-807. [PubMed Abstract] -

2. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360:1815-26. [PubMed Abstract] -

3. Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated HIV- positive individuals in the United States and Canada. PLoS One. 2013;8:e81355. [PubMed Abstract] -

4. Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral Therapy for the Prevention of HIV-1 Transmission. N Engl J Med. 2016;375:830-9. [PubMed Abstract] -

5. McNairy ML, El-Sadr WM. Antiretroviral therapy for the prevention of HIV transmission: what will it take? Clin Infect Dis. 2014;58:1003-11. [PubMed Abstract] -

6. Rodger AJ, Cambiano V, Bruun T, et al. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. JAMA. 2016;316:171-81. [PubMed Abstract] -

7. Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med. 2012;2:a007161. [PubMed Abstract] -

8. Gandhi M, Gandhi RT. Single-pill combination regimens for treatment of HIV-1 infection. N Engl J Med. 2014;371:248-59. [PubMed Abstract] -

9. Wilen CB, Tilton JC, Doms RW. HIV: cell binding and entry. Cold Spring Harb Perspect Med. 2012;2:a006866. [PubMed Abstract] -

10. Schiller J, Chackerian B. Why HIV virions have low numbers of envelope spikes: implications for development. PLoS Pathog. 2014;10:e1004254. [PubMed Abstract] -

11. Zhu P, Liu J, Bess J Jr, et al. Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature. 2006;441:847-52. [PubMed Abstract] -

12. Yi HA, Fochtman BC, Rizzo RC, Jacobs A. Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41. Curr HIV Res. 2016;14:283-94. [PubMed Abstract] -

13. Chan DC, Fass D, Berger JM, Kim PS. Core structure of gp41 from the HIV envelope glycoprotein. Cell. 1997;89:263-73. [PubMed Abstract] -

Page 19/83 14. Montero M, van Houten NE, Wang X, Scott JK. The membrane-proximal external region of the human immunodeficiency virus type 1 envelope: dominant site of antibody neutralization and target for vaccine design. Microbiol Mol Biol Rev. 2008;72:54-84. [PubMed Abstract] -

15. Klasse PJ. The molecular basis of HIV entry. Cell Microbiol. 2012;14:1183-92. [PubMed Abstract] -

16. Pöhlmann S, Reeves JD. Cellular entry of HIV: Evaluation of therapeutic targets. Curr Pharm Des. 2006;12:1963-73. [PubMed Abstract] -

17. Haqqani AA, Tilton JC. Entry inhibitors and their use in the treatment of HIV-1 infection. Antiviral Res. 2013;98:158-70. [PubMed Abstract] -

18. Henrich TJ, Kuritzkes DR. HIV-1 entry inhibitors: recent development and clinical use. Curr Opin Virol. 2013;3:51-7. [PubMed Abstract] -

19. Cahn P, Fink V, Patterson P. Fostemsavir: a new CD4 attachment inhibitor. Curr Opin HIV AIDS. 2018;13:341-345. [PubMed Abstract] -

20. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2020;382:1232-43. [PubMed Abstract] -

21. Bettiker RL, Koren DE, Jacobson JM. Ibalizumab. Curr Opin HIV AIDS. 2018;13:354-8. [PubMed Abstract] -

22. Iacob SA, Iacob DG. Ibalizumab Targeting CD4 Receptors, An Emerging Molecule in HIV Therapy. Front Microbiol. 2017;8:2323. [PubMed Abstract] -

23. Esté JA, Telenti A. HIV entry inhibitors. Lancet. 2007;370:81-8. [PubMed Abstract] -

24. Kilby JM, Eron JJ. Novel based on mechanisms of HIV-1 cell entry. N Engl J Med. 2003;348:2228-38. [PubMed Abstract] -

25. Wilkin TJ, Gulick RM. CCR5 antagonism in HIV infection: current concepts and future opportunities. Annu Rev Med. 2012;63:81-93. [PubMed Abstract] -

26. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Laboratory testing: co-receptor tropism assays. October 25, 2018. [HIV.gov] -

27. Tilton JC, Doms RW. Entry inhibitors in the treatment of HIV-1 infection. Antiviral Res. 2010;85:91-100. [PubMed Abstract] -

Page 20/83 28. Cervia JS, Smith MA. Enfuvirtide (T-20): a novel human immunodeficiency virus type 1 fusion inhibitor. Clin Infect Dis. 2003;37:1102-6. [PubMed Abstract] -

29. Hu WS, Hughes SH. HIV-1 reverse transcription. Cold Spring Harb Perspect Med. 2012;2:a006882. [PubMed Abstract] -

30. Schauer G, Leuba S, Sluis-Cremer N. Biophysical Insights into the Inhibitory Mechanism of Non- Nucleoside HIV-1 Reverse Transcriptase Inhibitors. Biomolecules. 2013;3:889-904. [PubMed Abstract] -

31. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med. 2004;350:1023-35. [PubMed Abstract] -

32. Singh K, Marchand B, Kirby KA, Michailidis E, Sarafianos SG. Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase. . 2010;2:606-638. [PubMed Abstract] -

33. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med. 2001;344:472-80. [PubMed Abstract] -

34. Craigie R. HIV integrase, a brief overview from chemistry to therapeutics. J Biol Chem. 2001;276:23213-6. [PubMed Abstract] -

35. Engelman A, Cherepanov P. Retroviral Integrase Structure and DNA Recombination Mechanism. Microbiol Spectr. 2014;2(6). [PubMed Abstract] -

36. Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov. 2005;4:236-48. [PubMed Abstract] -

37. Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS. 2006;20:489-501. [PubMed Abstract] -

38. Vandegraaff N, Engelman A. Molecular mechanisms of HIV integration and therapeutic intervention. Expert Rev Mol Med. 2007;9:1-19. [PubMed Abstract] -

39. Grandgenett DP, Pandey KK, Bera S, Aihara H. Multifunctional facets of integrase. World J Biol Chem. 2015;6:83-94. [PubMed Abstract] -

40. Ingale KB, Bhatia MS. HIV-1 integrase inhibitors: a review of their chemical development. Antivir Chem Chemother. 2011;22:95-105. [PubMed Abstract] -

41. Hazuda DJ. HIV integrase as a target for antiretroviral therapy. Curr Opin HIV AIDS. 2012;7:383-9. [PubMed Abstract] -

Page 21/83 42. Flexner C. HIV-protease inhibitors. N Engl J Med. 1998;338:1281-92. [PubMed Abstract] -

43. Adamson CS. Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process. Mol Biol Int. 2012;2012:604261. [PubMed Abstract] -

44. Briggs JA, Simon MN, Gross I, et al. The stoichiometry of Gag protein in HIV-1. Nat Struct Mol Biol. 2004;11:672-5. [PubMed Abstract] -

45. Adamson CS, Jones IM. The molecular basis of HIV capsid assembly--five years of progress. Rev Med Virol. 2004;14:107-21. [PubMed Abstract] -

46. Freed EO. HIV-1 assembly, release and maturation. Nat Rev Microbiol. 2015;13:484-96. [PubMed Abstract] -

47. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Initiation of antiretroviral therapy. December 18, 2019. [HIV.gov] -

48. Egger M, May M, Chêne G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-29. [PubMed Abstract] -

49. Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373:1352-63. [PubMed Abstract] -

50. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010;363:257-65. [PubMed Abstract] -

51. Sterling TR, Chaisson RE, Keruly J, Moore RD. Improved outcomes with earlier initiation of highly active antiretroviral therapy among human immunodeficiency virus-infected patients who achieve durable virologic suppression: longer follow-up of an observational cohort study. J Infect Dis. 2003;188:1659-65. [PubMed Abstract] -

52. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-96. [PubMed Abstract] -

53. Opravil M, Ledergerber B, Furrer H, et al. Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count > 350 x 10(6)/l. AIDS. 2002;16:1371-81. [PubMed Abstract] -

54. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331:1173-80. [PubMed Abstract] -

Page 22/83 55. Rodger AJ, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019;393:2428-38. [PubMed Abstract] -

56. Bavinton BR, Pinto AN, Phanuphak N, et al. Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. Lancet HIV. 2018;5:e438-e447. [PubMed Abstract] -

57. Gonzalo-Gil E, Ikediobi U, Sutton RE. Mechanisms of Virologic Control and Clinical Characteristics of HIV+ Elite/Viremic Controllers. Yale J Biol Med. 2017;90:245-259. [PubMed Abstract] -

58. Okulicz JF, Marconi VC, Landrum ML, et al. Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV natural history study. J Infect Dis. 2009;200:1714-23. [PubMed Abstract] -

59. Grabar S, Selinger-Leneman H, Abgrall S, Pialoux G, Weiss L, Costagliola D. Loss of long-term non- progressor and HIV controller status over time in the French Hospital Database on HIV - ANRS CO4. PLoS One. 2017;12:e0184441. [PubMed Abstract] -

60. Pereyra F, Lo J, Triant VA, et al. Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AIDS. 2012;26:2409-12. [PubMed Abstract] -

61. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the antiretroviral-naive patient. June 3, 2021. [HIV.gov] -

62. Pulido F, Ribera E, Lagarde M, et al. Dual Therapy With Darunavir and Ritonavir Plus Lamivudine vs Triple Therapy With Darunavir and Ritonavir Plus Fumarate and Emtricitabine or Abacavir and Lamivudine for Maintenance of Human Immunodeficiency Virus Type 1 Viral Suppression: Randomized, Open-Label, Noninferiority DUAL-GESIDA 8014-RIS-EST45 Trial. Clin Infect Dis. 2017;65:2112-8. [PubMed Abstract] -

63. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir- emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. 2014;384:1942-51. [PubMed Abstract] -

64. Cahn P, Madero JS, Arribas JR, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393:143-55. [PubMed Abstract] -

65. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Considerations

Page 23/83 for antiretroviral use in special patient populations: Women with HIV. June 3, 2021. [HIV.gov] -

66. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: Table 7. Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical Scenarios. June 3, 2021. [HIV.gov] -

67. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381:735-43. [PubMed Abstract] -

68. Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390:2073-82. [PubMed Abstract] -

69. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med. 2013;14:49-59. [PubMed Abstract] -

70. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461-71. [PubMed Abstract] -

71. Cohen CJ, Andrade-Villanueva J, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378:229-37. [PubMed Abstract] -

72. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr. 2012;60:33-42. [PubMed Abstract] -

73. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active- controlled trial. Lancet. 2011;378:238-46. [PubMed Abstract] -

74. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What not to use. October 17, 2017. [HIV.gov] -

75. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Laboratory testing: plasma HIV-1 RNA () and CD4 count monitoring. May 1, 2014. [HIV.gov] -

Page 24/83 76. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Laboratory testing: laboratory testing for initial assessment and monitoring of patients with HIV receiving antiretroviral therapy. December 18, 2019. [HIV.gov] -

77. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383:2222-31. [PubMed Abstract] -

78. Lennox JL, Dejesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806. [PubMed Abstract] -

79. Kaufmann GR, Perrin L, Pantaleo G, et al. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. Arch Intern Med. 2003;163:2187-95. [PubMed Abstract] -

80. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44:441-6. [PubMed Abstract] -

81. Battegay M, Nüesch R, Hirschel B, Kaufmann GR. Immunological recovery and antiretroviral therapy in HIV-1 infection. Lancet Infect Dis. 2006;6:280-7. [PubMed Abstract] -

82. Gras L, Kesselring AM, Griffin JT, et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. J Acquir Immune Defic Syndr. 2007;45:183-92. [PubMed Abstract] -

83. Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, Crane HM, Willig J, Mugavero M, Saag M, Martin JN, Deeks SG. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48:787-94. [PubMed Abstract] -

84. Luz PM, Grinsztejn B, Velasque L, et al. Long-term CD4+ cell count in response to combination antiretroviral therapy. PLoS One. 2014;9:e93039. [PubMed Abstract] -

85. Egger M, Hirschel B, Francioli P, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Swiss HIV Cohort Study. BMJ. 1997;315:1194-9. [PubMed Abstract] -

86. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Management of the treatment-experienced patient: poor CD4 cell recovery and persistent inflammation despite viral suppression. June 3, 2021. [HIV.gov] -

Page 25/83 87. Zoufaly A, an der Heiden M, Kollan C, Bogner JR, et al. Clinical outcome of HIV-infected patients with discordant virological and immunological response to antiretroviral therapy. J Infect Dis. 2011;203:364-71. [PubMed Abstract] -

88. Karrer U, Ledergerber B, Furrer H, et al. Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir. AIDS. 2005;19:1987-94. [PubMed Abstract] -

89. Bartlett JA, Fath MJ, Demasi R, Hermes A, Quinn J, Mondou E, Rousseau F. An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults. AIDS. 2006;20:2051-64. [PubMed Abstract] -

90. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369:1807-18. [PubMed Abstract] -

91. INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee, Abrams D, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361:1548-59. [PubMed Abstract] -

92. Holkmann Olsen C, Mocroft A, Kirk O, et al. Interruption of combination antiretroviral therapy and risk of clinical disease progression to AIDS or death. HIV Med. 2007;8:96-104. [PubMed Abstract] -

93. Kousignian I, Abgrall S, Grabar S, et al. Maintaining antiretroviral therapy reduces the risk of AIDS- defining events in patients with uncontrolled and profound immunodeficiency. Clin Infect Dis. 2008;46:296-304. [PubMed Abstract] -

94. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Management of the treatment-experienced patient: discontinuation or interruption of antiretroviral therapy. April 8, 2015. [HIV.gov] -

References

Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:-34. [PubMed Abstract] -

Ali A, Bandaranayake RM, Cai Y, et al. Molecular Basis for Drug Resistance in HIV-1 Protease. Viruses. 2010;2:2509-35. [PubMed Abstract] -

Ambrose Z, Aiken C. HIV-1 uncoating: connection to nuclear entry and regulation by host proteins. . 2014;454-455:371-9. [PubMed Abstract] -

Page 26/83 Arribas JR, Girard PM, Landman R, et al. Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open- label, non-inferiority trial. Lancet Infect Dis. 2015;15:785-92. [PubMed Abstract] -

Attia S, Egger M, Müller M, Zwahlen M, Low N. Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS. 2009;23:1397-404. [PubMed Abstract] -

Balzarini J. Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1. Curr Top Med Chem. 2004;4:921-44. [PubMed Abstract] -

Bell NM, Lever AM. HIV Gag polyprotein: processing and early viral particle assembly. Trends Microbiol. 2013;21:136-44. [PubMed Abstract] -

Blumenthal R, Durell S, Viard M. HIV entry and envelope glycoprotein-mediated fusion. J Biol Chem. 2012;287:40841-9. [PubMed Abstract] -

Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis. 2014;14:572-80. [PubMed Abstract] -

Cahn P, Rolón MJ, Figueroa MI, Gun A, Patterson P, Sued O. Dolutegravir-lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study. J Int AIDS Soc. 2017;20:21678. [PubMed Abstract] -

Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378:229-37. [PubMed Abstract] -

Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-505. [PubMed Abstract] -

Cooper CL, van Heeswijk RP, Gallicano K, Cameron DW. A review of low-dose ritonavir in protease inhibitor combination therapy. Clin Infect Dis. 2003;36:1585-92. [PubMed Abstract] -

Cruciani M, Mengoli C, Serpelloni G, Parisi SG, Malena M, Bosco O. Abacavir-based triple nucleoside regimens for maintenance therapy in patients with HIV. Cochrane Database Syst Rev. 2013;:CD008270. [PubMed Abstract] -

Das K, Arnold E. HIV-1 reverse transcriptase and resistance. Part 1. Curr Opin Virol. 2013;3:111-8. [PubMed Abstract] -

Page 27/83 Das K, Arnold E. HIV-1 reverse transcriptase and antiviral drug resistance. Part 2. Curr Opin Virol. 2013;3:119-28. [PubMed Abstract] -

De Feo CJ, Weiss CD. Escape from human immunodeficiency virus type 1 (HIV-1) entry inhibitors. Viruses. 2012;4:3859-911. [PubMed Abstract] -

Eron JJ Jr. HIV-1 protease inhibitors. Clin Infect Dis. 2000;30 Suppl 2:S160-70. [PubMed Abstract] -

Fisher M, Pao D, Brown AE, et al. Determinants of HIV-1 transmission in men who have sex with men: a combined clinical, epidemiological and phylogenetic approach. AIDS. 2010;24:1739-47. [PubMed Abstract] -

Günthard HF, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2016;316:191-210. [PubMed Abstract] -

Jegede O, Babu J, Di Santo R, McColl DJ, Weber J, Quiñones-Mateu M. HIV type 1 integrase inhibitors: from basic research to clinical implications. AIDS Rev. 2008;10:172-89. [PubMed Abstract] -

Johnson EC, Malito E, Shen Y, Rich D, Tang WJ, Kent SB. Modular total chemical synthesis of a human immunodeficiency virus type 1 protease. J Am Chem Soc. 2007;129:11480-90. [PubMed Abstract] -

Kazanjian P, Wei W, Brown M, Gandhi T, Amin K. Viral load responses to HAART is an independent predictor of a new AIDS event in late stage HIV infected patients: prospective cohort study. J Transl Med. 2005;3:40. [PubMed Abstract] -

Lee PK, Kieffer TL, Siliciano RF, Nettles RE. HIV-1 viral load blips are of limited clinical significance. 2006;57:803-5. [PubMed Abstract] -

Li X, Krishnan L, Cherepanov P, Engelman A. Structural biology of retroviral DNA integration. Virology. 2011;411:194-205. [PubMed Abstract] -

Lok JJ, Bosch RJ, Benson CA, et al. Long-term increase in CD4+ T-cell counts during combination antiretroviral therapy for HIV-1 infection. AIDS. 2010;24:1867-76. [PubMed Abstract] -

Lucas GM, Ross MJ, Stock PG, et al. Clinical Practice Guideline for the Management of Chronic Kidney Disease in Patients Infected With HIV: 2014 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;59:e96-e138. [PubMed Abstract] -

Lundgren JD, Babiker AG, Gordin F, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373:795-807. [PubMed Abstract] -

Page 28/83 Lv Z, Chu Y, Wang Y. HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV AIDS (Auckl). 2015;7:95-104. [PubMed Abstract] -

Mocroft A, Phillips AN, Gatell J, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet. 2007;370:407-13. [PubMed Abstract] -

Mondi A, Fabbiani M, Ciccarelli N, et al. Efficacy and safety of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression: 144 week follow-up of the AtLaS pilot study. J Antimicrob Chemother. 2015;70:1843-9. [PubMed Abstract] -

Nettles RE, Kieffer TL, Kwon P, et al. Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA. 2005;293:817-29. [PubMed Abstract] -

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Considerations for antiretroviral use in patients with coinfections: hepatitis B (HBV)/HIV coinfection. October 17, 2017. [HIV.gov] -

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Considerations for antiretroviral use in patients with coinfections: hepatitis C (HCV)/HIV coinfection. December 18, 2019. [HIV.gov] -

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Considerations for antiretroviral use in patients with coinfections: Tuberculosis/HIV coinfection. June 3, 2021. [HIV.gov] -

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Considerations for antiretroviral use in special patient populations: acute and recent (early) HIV infection. December 18, 2019. [HIV.gov] -

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Drug-drug interactions: drug interactions between CCR5 antagonists and other drugs. June 3, 2021. [HIV.gov] -

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Drug-drug interactions: drug interactions between integrase inhibitors and non-nucleoside reverse transcriptase inhibitors or protease inhibitors. June 3, 2021. [HIV.gov] -

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Drug-drug

Page 29/83 interactions: drug interactions between integrase inhibitors and other drugs. June 3, 2021. [HIV.gov] -

Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1 infected compartments during combination therapy. Nature. 1997;387:188-91. [PubMed Abstract] -

Portilla J, Arazo P, Crusells J, et al. Dual therapy with darunavir/r plus etravirine is safe and effective as switching therapy in antiretroviral experienced HIV-patients. The BITER Study. J Int AIDS Soc. 2014;17:19803. [PubMed Abstract] -

Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr. 2010;55:49-57. [PubMed Abstract] -

Potempa M, Swanstrom R. Integrating the HIV-1 assembly/maturation pathway. Proc Natl Acad Sci U S A. 2013;110:8327-8. [PubMed Abstract] -

Ren J, Stammers DK. Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Virus Res. 2008;134:157-70. [PubMed Abstract] -

Sarafianos SG, Marchand B, Das K, et al. Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition. J Mol Biol. 2009;385:693-713. [PubMed Abstract] -

Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361:2230-40. [PubMed Abstract] -

Sax PE, Tierney C, Collier AC, et al. Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results. J Infect Dis. 2011;204:1191-201. [PubMed Abstract] -

Siegfried N, van der Merwe L, Brocklehurst P, Sint TT. Antiretrovirals for reducing the risk of mother-to- child transmission of HIV infection. Cochrane Database Syst Rev. 2011;:CD003510. [PubMed Abstract] -

Sluis-Cremer N, Tachedjian G. Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res. 2008;134:147-56. [PubMed Abstract] -

Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23:1547-56. [PubMed Abstract] -

Strategies for Management of Antiretroviral Therapy (SMART) Study Group, Emery S, Neuhaus JA, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008;197:1133-44.

Page 30/83 [PubMed Abstract] -

TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, et al. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med. 2015;373:808-22. [PubMed Abstract] -

Tronchet JM, Seman M. Nonnucleoside inhibitors of HIV-1 reverse transcriptase: from the biology of reverse transcription to molecular design. Curr Top Med Chem. 2003;3:1496-511. [PubMed Abstract] -

When To Start Consortium, Sterne JA, May M, et al. Timing of initiation of antiretroviral therapy in AIDS- free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373:1352-63. [PubMed Abstract] -

Wlodawer A, Erickson JW. Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem. 1993;62:543-85. [PubMed Abstract] -

Yamashita TE, Phair JP, Munoz A, et al. Immunologic and virologic response to highly active antiretroviral therapy in the Multicenter AIDS Cohort Study. AIDS. 2001;15:735-46. [PubMed Abstract] -

Zaccarelli M, Fabbiani M, Pinnetti C, et al. Switching to boosted protease inhibitor plus a second antiretroviral drug (dual therapy) for treatment simplification: a multicenter analysis. J Int AIDS Soc. 2014;17:19802. [PubMed Abstract] -

Zash R, Holmes L, Diseko M, et al. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med. 2019;381:827-40. [PubMed Abstract] -

Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med. 2018;379:979-81. [PubMed Abstract] -

Page 31/83 Figures

Figure 1 Reproductive Cycle of HIV-1 and Sites of Action of Major Classes of Antiretroviral Medications

Step 1 represents HIV-1 entry into the host cell, which involves the binding of the protein, glycoprotein 120 (gp120), to the CD4 molecule, followed by a conformational change in gp120 that allows binding to the chemokine host-cell receptor (e.g. CCR5 or CXCR4). Glycoprotein 41 (gp41), also part of the virus envelope, then mediates HIV-cell fusion to permit viral entry. The fusion inhibitor, enfuvirtide, blocks fusion between the virus (through gp41) and the CD4 molecule, and the CCR5 coreceptor antagonist, maraviroc, blocks viral binding (through gp120) to CCR5. Step 2 is reverse transcription, in which the single- stranded HIV-1 RNA is transcribed into double-stranded DNA by the HIV enzyme (polymerase) called reverse transcriptase. This step is the site of action of nucleoside and nucleotide reverse-transcriptase inhibitors (NRTIs) and non-nucleoside reverse-transcriptase inhibitors (NNRTIs). Step 3 is the migration of HIV DNA into the nucleus and its integration into the DNA of the host cell, a process catalyzed by the viral enzyme integrase. Integrase strand-transfer inhibitors (INSTIs) target this step. Step 4 is the transcription of the HIV-1 DNA into HIV messenger RNA (mRNA) and HIV genomic RNA. Step 5 is the transport of the HIV-1 RNA out of the nucleus and the translation of HIV-1 mRNA into viral polyproteins. To be functional, the transcribed proteins must be cleaved into smaller component proteins, a process that occurs in step 6 through the action of the HIV-1 enzyme protease. This is the site of action of protease inhibitors. Step 7 is the assembly of viral genomic RNA and viral enzymes (reverse transcriptase, integrase, and protease) into viral particles. Step 8 is the budding and maturation of new viral particles, which then go on to infect other host cells.

Source: Gandhi M, Gandhi RT. Single-pill combination regimens for treatment of HIV-1 infection. N Engl J Med. 2014;371:248-59. © 2014 Massachusetts Medical Society. Figure and Legend Reproduced with permission.

Page 32/83 Page 33/83 Figure 2 HIV Envelope Glycoprotein

Each HIV envelope spike is a trimeric structure, with each trimer comprised of gp120 subunits paired with gp41 subunits. The trimer of heterodimers is arranged in a tripod-like conformation. The gp120 is coated with an immunoprotective glycan shield that helps HIV evade the host .

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 34/83 Figure 3 HIV Envelope Surface Proteins

Each HIV has approximately 14 irregularly spaced envelope glycoprotein spikes on the surface of HIV.

Illustration by David Ehlert, Cognition Studio and David Spach, MD

Page 35/83 Figure 4 (Image Series) - HIV Tropism and Binding to Host Coreceptors (Image Series) - Figure 4 (Image Series) - HIV Tropism and Binding to Host Coreceptors Image 4A: R5-Tropic HIV

In this illustration, the R5-tropic HIV is represented by the blue envelope spikes; the R5 HIV binds to the host CCR5 coreceptor during the viral cell entry process.

Illustration by David Spach, MD

Page 36/83 Figure 4 (Image Series) - HIV Tropism and Binding to Host Coreceptors Image 4B: X4-Tropic HIV

In this illustration, the X4-tropic HIV is represented by the purple envelope spikes; the X4 HIV binds to the host CCR5 coreceptor during the viral cell entry process.

Illustration by David Spach, MD

Page 37/83 Figure 4 (Image Series) - HIV Tropism and Binding to Host Coreceptors Image 4C: Dual-Tropic HIV

In this illustration, the dual-tropic HIV is represented by both blue and purple envelope spikes; the dual-HIV can bind to the host CCR5 or CXCR4 coreceptors during the viral cell entry process.

Illustration by David Spach, MD

Page 38/83 Figure 4 (Image Series) - HIV Tropism and Binding to Host Coreceptors Image 4D: Mixed-Tropic HIV

In this illustration, the mixed-tropic HIV is represented by a mixture of R5-tropic HIV (blue envelope spikes) and X4-tropic HIV (purple envelope spikes); the R5 HIV binds to the CCR5 coreceptor and the X4 HIV binds to the CXCR4 coreceptor.

Illustration by David Spach, MD

Page 39/83 Figure 5 Mechanism of Action of Attachment Inhibitors

The attachment inhibitor fostemsavir is hydrolyzed to its active form temsavir, which binds to HV gp120 and prevents normal attachment of the host CD4 receptor with HIV gp120.

Illustration by David H. Spach, MD

Page 40/83 Figure 6 Mechanism of Action of CD4 Postattachment Inhibitors

The CD4 postattachment inhibitor ibalizumab is a humanized that binds to the domain 2 region of the human CD4 cell receptor. This binding does not prevent attachment of HIV gp120 with the host CD4 receptor, but, through steric hindrance it prevents normal postbinding conformational changes in gp120 that are required for gp120-coreceptor binding.

Illustration by David H. Spach, MD

Page 41/83 Figure 7 Mechanism of Action of CCR5 Antagonists

The CCR5 antagonist maraviroc binds to the host CCR5 coreceptor, rendering a conformational change in the coreceptor, which causes unfavorable binding of the V3 region of gp120 in the R5 strains of HIV.

Illustration by David H. Spach, MD

Page 42/83 Figure 8 Mechanism of Action of Fusion Inhibitor

The fusion inhibitor enfuvirtide is a 36-amino-acid peptide that represents a segment of the HIV gp41 HR2 domain. In the native gp41 configuration, a segment of gp41 folds back on itself and this involves tight coiling of the HR1 and HR2 segments. The drug enfuvirtide mimics the HR2 segment and binds to HR1, thus interfering with the normal HR1 and HR2 interaction.

Page 43/83 Figure 9 (Image Series) - Structure of HIV Reverse Transcriptase (Image Series) - Figure 9 (Image Series) - Structure of HIV Reverse Transcriptase Image 9A: HIV Reverse Transcriptase: p66 and p51 Subunits

Reverse transcriptase is a DNA polymerase heterodimer comprised of p66 and p51 subunits. The p66 and p51 subunits are 560 and 440 amino acids in length, respectively. These two subunits share the same first 440 amino acids.

Illustration by David Ehlert, Cognition Studio

Page 44/83 Figure 9 (Image Series) - Structure of HIV Reverse Transcriptase Image 9B: HIV Reverse Transcriptase: p66 Subunit

The p66 subunit is 560 amino acids in length comprised of the polymerase domain (N-terminal 440 amino acids) and the RNase H domain (C-terminal 120 amino acids).

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 45/83 Figure 9 (Image Series) - Structure of HIV Reverse Transcriptase Image 9C: HIV Reverse Transcriptase: Active Polymerase and RNase H Sites

The p66 subunit contains the active site for polymerase and RNase H. The polymerase active site is located in the palm subdomain of the polymerase domain and RNase H active site is in the RNase H domain.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 46/83 Figure 9 (Image Series) - Structure of HIV Reverse Transcriptase Image 9D: HIV Reverse Transcriptase: Polymerase Domain

The structure of the polymerase domain resembles a right hand and consists of four domains: fingers, palm, thumb, and connection.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 47/83 Figure 10 (Image Series) - HIV Reverse Transcription (Image Series) - Figure 10 (Image Series) - HIV Reverse Transcription Image 10A: HIV Reverse Transcription: Conversion of RNA to DNA

The key function of HIV reverse transcriptase is to convert HIV RNA to HIV DNA. The actual reverse transcriptase process is a multiple-step, highly complicated process that involves polymerase, RNase H, and an RNA-DNA intermediate hybrid.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 48/83 Figure 10 (Image Series) - HIV Reverse Transcription Image 10B: HIV Reverse Transcription and Incorporation of Nucleotides

The HIV reverse transcription process occurs by incorporating human nucleotides into the elongating strand of DNA. Thus, conceptually it is important to understand the nucleotide building blocks of the HIV RNA and DNA are human in origin.

Illustration by David H. Spach, MD

Page 49/83 Figure 10 (Image Series) - HIV Reverse Transcription Image 10C: Reverse Transcription: Primer and Template Strands

The reverse transcriptase, similar to other DNA polymerase enzymes, utilizes both a primer and a template. This simplified depiction shows the HIV RNA serving as the template and strand functioning as the primer where new nucleotides are added.

Illustration by David H. Spach, MD

Page 50/83 Figure 11 (Image Series) - Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action (Image Series) - Figure 11 (Image Series) - Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action Image 11A: Nucleoside Reverse Transcriptase Inhibitors

The nucleoside reverse transcriptase inhibitors, in their triphosphate form, mimic the host nucleotides that are incorporated into the elongating strand of DNA. The host cellular convert the nucleoside reverse transcriptase inhibitors to their active triphosphate form. In the active form, the nucleoside reverse transcriptase inhibitors compete with human nucleotides for a spot in the elongating DNA chain.

Illustration by David Spach, MD

Page 51/83 Figure 11 (Image Series) - Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action Image 11B: Incorporation of Nucleoside Reverse Transcriptase Inhibitors

After the nucleoside reverse transcriptase inhibitors become activated to a triphosphate form, they can compete with human nucleotides to be incorporated into the elongating DNA chain.

Illustration by David H. Spach, MD

Page 52/83 Figure 11 (Image Series) - Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action Image 11C: Primer Blocking

The incorporation of the nucleoside reverse transcriptase inhibitor into the elongating strand of DNA is referred to as primer blocking.

Illustration by David H. Spach, MD

Page 53/83 Figure 11 (Image Series) - Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action Image 11D: Chain Termination

All of the nucleoside reverse transcriptase inhibitors approved to treat HIV lack a 3'-hydroxyl component and thus additional nucleotides cannot be linked to the nucleoside reverse transcriptase inhibitor. The nucleoside reverse transcriptase inhibitors thus act as chain terminators when incorporated into the viral DNA by the HIV reverse transcriptase.

Illustration by David H. Spach, MD

Page 54/83 Figure 12 (Image Series) - Non-Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action (Image Series) - Figure 12 (Image Series) - Non-Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action Image 12A: Non-Nucleoside Reverse Transcriptase Inhibitor Binding Pocket

The non-nucleoside reverse transcriptase inhibitors work by directly binding to the non-nucleoside reverse transcriptase inhibitors binding pocket region, a region in the polymerase domain proximal to the polymerase active site. This binding directly impedes the function of the reverse transcriptase enzyme.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 55/83 Figure 12 (Image Series) - Non-Nucleoside Reverse Transcriptase Inhibitors: Mechanism of Action Image 12B: Non-Nucleoside Reverse Transcriptase Inhibitor-Induced Thumb Hyperextension of Reverse Transcriptase

The functional impact of non-nucleoside reverse transcriptase inhibitor binding to reverse transcriptase is likely multifactorial, and not entirely understood; one proposed mechanism suggests that is that non- nucleoside reverse transcriptase inhibitor binding results in a locked hyperextension of the polymerase thumb region (and possibly also the fingers region). This conformational change is believed to alter the polymerase binding site, impacting the functional role of the reverse transcriptase.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 56/83 Figure 13 (Image Series) - HIV Integrase (Image Series) - Figure 13 (Image Series) - HIV Integrase Image 13A: HIV Integrase

The HIV enzyme integrase plays a critical role in the process of integrating the HIV proviral DNA into the human DNA. Humans do not have an integrase enzyme. The HIV integrase enzyme is a 288 amino-acid protein that consists of three distinct structural domains: the carboxy (C)-terminal domain, the amino (N)-terminal domain, and the catalytic core domain. The catalytic core domain contains a trio of amino acids that coordinate binding with a divalent metal (either Mg2+ or Mn2+) and form an active catalytic site.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 57/83 Figure 13 (Image Series) - HIV Integrase Image 13B: HIV Integrase: Monomer, Dimer, and Tetrad Forms

The HIV integrase enzyme can exist in the form of a monomer, dimer, tetramer, and possibly higher order forms, such as octamers.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 58/83 Figure 14 (Image Series) - Integration of HIV DNA into Host DNA (Image Series) - Figure 14 (Image Series) - Integration of HIV DNA into Host DNA Image 14A: HIV Integrase: DNA Complex

The HIV integrase binds to HIV DNA (most likely in the dimer form); the integrase-HIV DNA complex is part of a particle known as the preintegration complex. This newly formed preintegration complex has to migrate inside the host nucleus for integration to occur.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 59/83 Figure 14 (Image Series) - Integration of HIV DNA into Host DNA Image 14B: HIV Integrase Strand Transfer

This strand transfer reaction is initiated as the HIV integrase catalyzes the HIV DNA 3-hydroxyl group attack on the host DNA. The attack by the viral DNA occurs on opposite strands of the host DNA in a staggered fashion, typically 4-6 base pairs apart.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 60/83 Figure 14 (Image Series) - Integration of HIV DNA into Host DNA Image 14C: Unfolding of Integrated HIV DNA

At this point, the newly joined viral-host DNA region unfolds. The insertion of the new HIV DNA induces a host cellular DNA damage response. This host response is critical in the final step of integration, known as gap repair.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 61/83 Figure 14 (Image Series) - Integration of HIV DNA into Host DNA Image 14D: Proviral HIV DNA

The HIV DNA that is incorporated into the host DNA is referred to as proviral DNA.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 62/83 Figure 15 Integrase Strand Transfer Inhibitor

With binding to the HIV integrase, the INSTIs have a multifaceted mechanism of action that includes sequestering the Mg2+ ions and blocking the binding site, displacing the 3'-hydroxyl ends of viral DNA that play a critical role in strand transfer, and prevention of host DNA substrate with the HIV complex.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 63/83 Figure 16 HIV Protease

HIV protease is a 99-amino-acid dimer made up of two identical subunits.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 64/83 Figure 17 HIV Protease and Configurations

This figure shows the HIV protease enzyme in three configurations: open, semi-closed, and closed.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 65/83 Figure 18 Sequential Steps in HIV Gag Protein Processing by HIV Protease

The HIV Gag protein processing occurs with sequential cleavages (steps 1 to 5) by HIV protease. The end result of this process is the separation of four proteins: matrix (MA), capsid (CA), nucleocapsid (NC), and p6. This cleavage process also separates out spacer peptide 1 (SP1) and spacer peptide 2 (SP2). Myristic acid moiety (myr) plays a key role in matrix binding to the phospholipid membrane.

Illustration: David H. Spach, MD

Page 66/83 Figure 19 HIV Protease Inhibitor

The HIV protease inhibitor (red pentagon) bind to the active site of HIV protease and prevent protease processing of the Gag and Gag-Pol polyproteins.

Illustration by David Ehlert, Cognition Studio and David H. Spach, MD

Page 67/83 Figure 20 ART Cohort Collaboration: Risk of Developing New AIDS-Defining Disease or Death After 3 Years Based on CD4 Cell Count and HIV RNA Level at the Time of

The analysis is based on 12,574 antiretroviral-naïve adult patients who started on antiretroviral therapy that consisted of a combination of at least 3 medications. An AIDS-defining illness was based on the 1993 CDC classification (except those persons who developed a CD4 count less than 200 cells/mm3 were not classified as having a new AIDS-defining illness).

Source: Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-29.

Page 68/83 Figure 21 CIPRA-HT-001: Survival in the Early-Treatment and Standard-Treatment Groups

In this open label trial conducted in Haiti, 816 adults with HIV and CD4 counts between 200 and 350 cells/mm3 were randomized to either early-treatment (immediate initiation of antiretroviral therapy) or standard-treatment (initiation of antiretroviral therapy when the CD4 count dropped to 200 cells/mm3 or less or when clinical AIDS developed). There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P = 0.001).

Source: Severe P, Juste MAJ, Ambroise A et al. Early versus Standard Antiretroviral Therapy for HIV-Infected Adults in Haiti. N Engl J Med. 2010;363:257-65. Reproduced with permission from the Massachusetts Medical Society, Inc. Copyright 2010 © Massachusetts Medical Society, Inc. All rights reserved.

Page 69/83 Figure 22 Disease Progression Related to Baseline CD4 Cell Count and Status of Virologic Suppression

In this study, 1,173 patients were followed on highly active antiretroviral therapy and data was analyzed according to the baseline CD4 cell count, durable virologic suppression, and evidence of disease progression. A durable virologic response was defined as having a greater number of undetectable (less than 400 copies/mL) viral loads than detectable viral loads after initiating therapy; disease progression was defined as a new AIDS-defining illness or death.

Source: Sterling TR, Chaisson RE, Keruly J, Moore RD. Improved outcomes with earlier initiation of highly active antiretroviral therapy among human immunodeficiency virus-infected patients who achieve durable virologic suppression: longer follow-up of an observational cohort study. J Infect Dis. 2003;188:1659-65.

Page 70/83 Figure 23 The START Trial: Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection

In the START trial, investigators randomized symptomatic individuals with HIV who had a CD4 count greater than 350 cells/mm3 to immediately start antiretroviral therapy or defer therapy. The number of serious AIDS- or non-AIDS-defining events occurred in fewer patients in the immediate therapy group versus those in the deferred therapy group (1.8% versus 4.1%).

Source: INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373:795-807.

Page 71/83 Figure 24 Swiss Cohort

In the Swiss HIV Cohort Study, investigators compared early initiation of antiretroviral therapy (patients with CD4 counts greater than 350 cells/mm3) versus deferred therapy (patients monitored without therapy).

Source: Opravil M, Ledergerber B, Furrer H, et al. Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count >350 x 10(6)/l. AIDS. 2002;16:1371-81.

Page 72/83 Figure 25 Median CD4 Cell Count Over Time After Starting Antiretroviral Therapy

In this study, 5,299 antiretroviral therapy-naïve patients were followed to observe CD4 cell count responses after 7 years of antiretroviral therapy. Groups were stratified by baseline CD4 count and although all groups had significant increases in CD4 counts, the recovery to near normal CD4 count levels was much more likely to occur in those with higher baseline CD4 counts.

Source: Gras L, Kesselring AM, Griffin JT, et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. J Acquir Immune Defic Syndr. 2007;45:183-92.

Page 73/83 Figure 26 Outcome of Patients in ESPRIT Trial

This graph shows the outcome of 4,111 patients with a CD4 count greater than 350 cells/mm3 who were randomized to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone.Abbreviations: OI = opportunistic infection

Source: INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee, Abrams D, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361:1548-59.

Page 74/83 Figure 27 Outcome of Patients in SILCATT Trial

This graph shows the outcome of 1,695 patients with a CD4 count less than 200 cells/mm3 who were randomized to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. Abbreviations: OI = opportunistic infection

Source: INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee, Abrams D, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361:1548-59.

Page 75/83 Table 1. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV

Panel's Recommendations for Initiating Antiretroviral Therapy in Treatment-Naive Patients

Antiretroviral therapy (ART) is recommended for all individuals with HIV to reduce morbidity and mortality (AI) and to prevent the transmission of HIV to others (AI). Initiate ART immediately (or as soon as possible) after HIV diagnosis in order to increase the uptake of ART and linkage to care, decrease the time to viral suppression for individual patients, and improve the rate of virologic suppression among persons with HIV (AII). When initiating ART, it is important to educate patients regarding the benefits of ART and to deploy strategies to optimize care engagement and treatment adherence (AIII). Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion Source:

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Initiation of antiretroviral therapy. December 18, 2019. [HIV.gov]

Page 76/83 Table 2. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV

Recommended Initial Regimens for Most People with HIV

Recommended regimens are those with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. Choice of antiretroviral therapy during pregnancy should be guided by recommendations from the Perinatal Guidelines. Integrase Strand Transfer Inhibitor + 2 Nucleoside Reverse Transcriptase Inhibitors: Note: For individuals of childbearing potential, see the table Considerations Before Initiating one of these regimens.

Bictegravir-tenofovir alafenamide-emtricitabine (AI)a Dolutegravir-abacavir-lamivudinea (AI)—if HLA-B*5701 negative Dolutegravir plus (tenofovir alafenamide or tenofovir DF)b plus (emtricitabine or lamivudine) (AI)

Integrase Strand Transfer Inhibitor + 1 Nucleoside Reverse Transcriptase Inhibitor

Dolutegravir-lamivudine (AI)—except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom antiretroviral therapy is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available aBecause of insufficient data, bictegravir should not be prescribed to people who are pregnant.

bTenofovir alafenamide and tenofovir DF are two forms of tenofovir approved by the FDA. Tenofovir alafenamide has fewer bone and kidney toxicities than tenofovir DF, whereas tenofovir DF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion Source:

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the antiretroviral-naive patient. June 3, 2021. [HIV.gov]

Page 77/83 Table 3. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV

Recommended Initial Regimens in Certain Clinical Situations

These regimens are effective and tolerable, but have some disadvantages when compared with the regimens listed in the Recommended Regimens for Most People with HIV, or they have less supporting data from randomized clinical trials. However, in certain clinical situations, one of these regimens may be preferred. Integrase Strand Transfer Inhibitors + 2 Nucleoside Reverse Transcriptase Inhibitors:

Elvitegravir-cobicistat-tenofovir alafenamideb-emtricitabine (BI)a Elvitegravir-cobicistat-tenofovir DFb-emtricitabine (BI)a Raltegravir plus tenofovir DFb-emtricitabine (BI) Raltegravir plus tenofovir alafenamideb-emtricitabine (BII) Boosted Protease Inhibitor plus 2 Nucleoside Reverse Transcriptase Inhibitors: (in general, boosted Darunavir is preferred over boosted Atazanavir):

Darunavir plus ritonavir plus (tenofovir alafenamide or tenofovir DF)b plus (emtricitabine or lamivudine) (AI) Darunavir-cobicistata plus (tenofovir alafenamide or tenofovir DF)b plus (emtricitabine or lamivudine) (AI) Atazanavir plus ritonavir plus (tenofovir alafenamide or tenofovir DF)b plus (emtricitabine or lamivudine) (BI) Atazanavir-cobicistata plus (tenofovir alafenamide or tenofovir DF)b plus (emtricitabine or lamivudine) (BI) Darunavir plus ritonavir plus abacavir-lamivudine—if HLA-B*5701 negative (BII) Darunavir-cobicistata plus abacavir-lamivudine—if HLA-B*5701 negative (BII) Non-Nucleoside Reverse Transcriptase Inhibitor + 2 Nucleoside Reverse Transcriptase Inhibitors:

Doravirine-tenofovir DFb-lamivudine (BI) Doravirine plus tenofovir alafenamideb-emtricitabine (BIII) Efavirenz (600 mg)-tenofovir DFb-emtricitabine (BI) Efavirenz (400 mg)-tenofovir DFb-emtricitabine (BI) Efavirenz (600 mg) plus tenofovir alafenamideb-emtricitabine (BII) Rilpivirine-tenofovir DFb-emtricitabine (BI)—if HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm3 Rilpivirine-tenofovir alafenamideb-emtricitabine (BI)—if HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm3 Regimens to Consider when Abacavir, Tenofovir alafenamide, and Tenofovir DF Cannot be Used or Are Not Optimal:

Dolutegravir-lamivudine (AI), except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom antiretroviral therapy is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available Darunavir plus ritonavir twice daily plus raltegravir twice daily (CI)—if HIV RNA <100,000 copies/mL and CD4 >200 cells/mm3 Darunavir plus ritonavir once daily plus lamivudine (CI) aBecause lower concentrations of cobicistat and its boosted drugs elvitegravir, darunavir, and atazanavir, have been observed during the second and third trimesters, it should be avoided during pregnancy. For women with viral suppression who become pregnant while on a cobicistat-containing regimen but wish to remain on this regimen after counseling regarding its lower-drug concentration, frequent viral load monitoring is recommended. For further information, refer to the Perinatal Guidelines.

Page 78/83 These regimens are effective and tolerable, but have some disadvantages when compared with the regimens listed in the Recommended Regimens for Most People with HIV, or they have less supporting data from randomized clinical trials. However, in certain clinical situations, one of these regimens may be preferred. bTenofovir alafenamide and tenofovir DF are two forms of tenofovir approved by the FDA. Tenofovir alafenamide has fewer bone and kidney toxicities than tenofovir DF, while tenofovir DF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion Source:

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the antiretroviral-naive patient. June 3, 2021. [HIV.gov]

Page 79/83 Table 4. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV

Antiretroviral Components or Regimens Not Recommended as Initial Therapy

Antiretroviral Components or Regimens Reasons for Not Recommending as Initial Therapy Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Abacavir-lamivudine-zidovudine Inferior virologic efficacy (coformulated) As triple NRTI combination regimen Abacavir-lamivudine-zidovudine plus tenofovir DF (as Inferior virologic efficacy quadruple-NRTI combination regimen) Stavudine plus lamivudine Significant toxicities (including lipoatrophy, peripheral neuropathy) and hyperlactatemia (including symptomatic and life-threatening lactic acidosis, hepatic steatosis, and pancreatitis) Didanosine plus lamivudine (or emtricitabine) Inferior virologic efficacy Limited clinical trial experience in antiretroviral-naïve patients Didanosine toxicities, such as pancreatitis and peripheral neuropathy Didanosine plus tenofovir DF High rate of early virologic failure Rapid selection of resistance Potential for immunologic nonresponse/CD4 cell decline Increased didanosine drug exposure and toxicities Zidovudine-lamivudine Greater toxicities (including bone marrow suppression, GI toxicities, myopathy, cardiomyopathy, and mitochondrial toxicities such as lipoatrophy, lactic acidosis, and hepatic steatosis) than recommended NRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Delavirdine Inferior virologic efficacy Inconvenient (three times daily) dosing Etravirine Insufficient data in antiretroviral-naïve patients Nevirapine Associated with serious and potentially fatal toxicity (hepatic events and severe rash, including Stevens Johnson Syndrome and toxic epidermal necrolysis) When compared to efavirenz, nevirapine did not meet noninferiority criteria Protease Inhibitors (PIs)

Atazanavir (unboosted) Less potent than boosted atazanavir Darunavir (unboosted) Use without ritonavir or cobicistat has not been studied

Page 80/83 Antiretroviral Components or Regimens Reasons for Not Recommending as Initial Therapy Fosamprenavir (unboosted) or Fosamprenavir plus Virologic failure with unboosted fosamprenavir- ritonavir based regimen may result in selection of mutations that confer resistance to fosamprenavir and darunavir Less clinical trial data for fosamprenavir plus ritonavir than for other ritonavir-boosted PIs Indinavir (unboosted) Inconvenient dosing (3 times daily with meal restrictions) Fluid requirement Indinavir toxicities, such as nephrolithiasis and crystalluria Indinavir plus ritonavir Fluid requirement Indinavir toxicities, such as nephrolithiasis and crystalluria Lopinavir-ritonavir Higher pill burden than other PI-based regimens Higher ritonavir dose than other PI-based regimens Gastrointestinal intolerance Nelfinavir Inferior virologic efficacy Diarrhea Ritonavir as sole PI High pill burden GI intolerance Metabolic toxicity Saquinavir (unboosted) Inadequate bioavailability Inferior virologic efficacy Saquinavir plus ritonavir High pill burden Can cause QT and PR prolongation; requires pretreatment and follow-up ECG Tipranavir plus ritonavir Inferior virologic efficacy Higher rate of adverse events than other ritonavir-boosted PIs Higher dose of ritonavir required for boosting than other ritonavir-boosted PIs Entry Inhibitors

Enfuvirtide (T-20) Only studied in patients with virologic failure Fusion Inhibitor Twice-daily subcutaneous injections High rate of injection site reactions Ibalizumab Only studied in a very small number of Postattachment inhibitor patients with virologic failure Requires intravenous therapy High cost Maraviroc Requires testing for CCR5 tropism before CCR5 Antagonist initiation of therapy No virologic benefit when compared with other recommended regimens Requires twice-daily dosing Source:

Page 81/83 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the antiretroviral-naive patient. June 3, 2021. [HIV.gov]

Page 82/83 Page 83/83

Powered by TCPDF (www.tcpdf.org)