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Don’t Break My HAART: Breaking Away from Triple

Drug Therapies Among Virologically Suppressed HIV-1

Infected Patients

Pamela Ijeoma, Pharm.D.

PGY2 Ambulatory Care Resident

South Texas Veterans Health Care System

The University of Texas at Austin College of Pharmacy

UT Health San Antonio

Learning Objectives:

1. Identify management strategies to improve clinical outcomes in HIV-1 infection

2. Evaluate literature pertaining to the utility of dual antiretroviral maintenance therapy for HIV-1 infection

3. Identify appropriate patients in whom to consider a switch to dual therapy for the maintenance of virologic

suppression

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I) Human Immunodeficiency Virus (HIV)1-5

A) Genome

i) Retrovirus: Ribonucleic acid (RNA) genome

ii) Lentivirus characterized by long incubation periods capable of producing a wide range of pathologies

B) HIV-1 vs. HIV-2

i) Type 1

a) Increased virulence

b) Majority of HIV infections globally

ii) Type 2

a) Less infectious

b) Immunodeficiency develops slowly

c) Predominantly found in Sub-Saharan Africa

d) Increased incidence of HIV-associated wasting syndrome

e) Decreased response to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors

(PIs)

C) Viral structure

i) Lipid bilayer embedded with transmembrane and surface proteins

a) Transmembrane fusion peptide = glycoprotein 41 (Gp41)

b) Surface protein = glycoprotein 120 (Gp120)

ii) Nucleocapsid contains viral genome and three enzymes vital to HIV life cycle

a) Reverse transcriptase: Transcribes viral RNA genome into complementary deoxyribonucleic acid (DNA)

b) Integrase: Facilitates incorporation of pro-viral DNA into host cell genome

c) Protease: Cleaves viral polypeptide into individual functional enzymes

D) Host cell

i) CD4 T lymphocyte

a) Regulate immune response via activation of B-lymphocytes, cytotoxic T cells and macrophages

b) Mediate the host defense against the following pathogens: bacteria, fungi, and protozoa

Figure 1. HIV structure Available at: https://www.projectinform.org/wp-

content/uploads/2016/05/HIV-Genome-2-688x535.jpg

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E) Acquisition of HIV infection

i) Attachment and cell entry

a) HIV requires two binding events to enter the CD4 cell cytoplasm

• HIV utilizes Gp120 to attach to CD4 receptor

• Following attachment, Gp120 assumes a conformational change, allowing it to bind to chemokine

coreceptors on the CD4 cell membrane (CCR5 and/or CXCR4)

b) Binding of Gp120 to chemokine coreceptors enables fusion of viral and CD4 lipid membranes

ii) Transcription

a) Once within the cytoplasm, viral RNA genome is transcribed into pro-viral DNA

iii) Integration

a) Pro-viral DNA is transported from the cytoplasm into the host cell nucleus where it is incorporated into

the host genome in preparation for viral replication

• Viral integration requires: processing, joining, and post-integration repair

b) Stable integration of pro-viral DNA into the human genome is essential for completing the HIV life cycle

iv) CD4 count decline following infection

a) CD4 count and CD4% are both strong predictors of clinical disease progression

b) CD4 count declines by approximately 50-80 cells/µL annually without antiretroviral therapy (ART)

c) Degree of CD4 depletion correlates with development of opportunistic infection (OI)

d) Immune response significantly impaired when CD4 cell count falls < 200 cells/µL or CD4% < 14%

II) Phases of HIV Infection6

A) Acute HIV syndrome

i) Initial stage of HIV infection

a) Approximately 2-6 weeks after HIV infection

ii) Wide dissemination of HIV particles and a rapid decrease in CD4 cell count

iii) Seroconversion

a) Host may experience short, flu-like illness as the immune system begins to produce anti-HIV antibodies

Figure 2. HIV infection of CD4 cell Available at: https://microbewiki.kenyon.edu/

images /9/96/HIVlifecycle2.png

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B) Clinical latency

i) Asymptomatic stage of HIV infection

ii) Immune response post-infection

a) Anti-HIV antibodies are produced approximately 6-12 weeks after infection

b) CD8 cytotoxic lymphocytes target and destroy HIV-infected CD4 cells

c) Decrease in viral replication and CD4 cell turnover

d) Duration of clinical latency phase is highly variable

• Individuals may remain in clinical latency phase up to 10 years without ART

C) Acquired immune deficiency syndrome (AIDS)

i) Final stage of HIV infection

ii) Defined as: CD4 count < 200 cells/µL, CD4% < 14%, or development of an AIDS-defining condition (Table 1)

iii) Without ART, individuals with HIV eventually develop progressive immunodeficiency marked by CD4 cell

depletion and premature death

iv) Life expectancy is approximately 3 years without ART

Table 1: Common AIDS Defining Conditions6

Infection Organism Clinical Manifestation At Risk Population

Pneumocystis jirovecii pneumonia (PCP) Yeast Pneumonia CD4 < 200 cells/ µL

Kaposi's sarcoma Virus Skin cancer CD4 < 350 cells/ µL

Toxoplasmosis gondii encephalitis Protozoa Encephalitis CD4 < 100 cells/ µL

Mycobacterium avium complex (MAC) Bacteria Pulmonary manifestations Disseminated disease

CD4 < 50 cells/ µL

III) Historical Perspective of Antiretroviral Therapy (ART)4,7-15

A) HIV/AIDS epidemic within the United States (U.S.)

i) June 1981: 5 cases of immunodeficiency syndrome (biopsy confirmed PCP)

ii) July 1981: 26 cases of Kaposi's sarcoma

iii) August 1981: Centers for Disease Control and Prevention (CDC) begin tracking cases of Kaposi’s sarcoma and

PCP

a) Fall of 1981: 100 cases

b) February 1983: 1,000 cases

c) December 1983: 3,000 cases

d) October 1995: 500,000 cases

• AIDS becomes the leading cause of death among persons 25 to 44 years of age

B) Introduction of ART (Table 2)

Table 2: Food and Drug Administration (FDA) Approval of ART4

Year Outcome

1987 FDA approves the first antiretroviral agent, zidovudine

• Nucleoside monotherapy associated with virologic failure beyond 12 weeks

1992 FDA begins accelerated approval for HIV/AIDS related therapies

• Rapid access to multiple nucleosides

• Dual nucleoside therapy is introduced o Use associated with transient virologic suppression in HIV infected individuals with high

viral loads o HIV incidence and mortality rates continue to rise

1995 FDA approves the first PI, saquinavir

1996 FDA approves the first NNRTI, nevirapine

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C) Triple Therapy

i) Coined “highly active antiretroviral therapy” (HAART)

ii) Composed of 2 nucleoside reverse transcriptase inhibitors (NRTI) + 1 NNRTI or PI

iii) INCAS Study: Introduced in 1996 by Montaner et al. at the 11th annual International AIDS Conference

a) Triple therapy utilizing nevirapine + didanosine + zidovudine is associated with superior viral load

suppression compared to dual therapy with zidovudine + didanosine or zidovudine + nevirapine

b) HIV-1 RNA < 20 copies/mL at 52 weeks (51% vs. 12% vs. 0%; p < 0.001) respectively

iv) HAART is incorporated into clinical practice

a) HIV/AIDS-associated mortality declines for the first time since viral emergence

• 73% decline in AIDS related OI

• 70% decline in AIDS related death

b) Life expectancy post-HIV infection increased from 9 years in 1995 to 23.6 years in 2002

• With triple therapy resulting in longer lifespans, ageing patients with HIV experienced a reduction in

deaths from OIs but an increase in mortality associated with chronic comorbidities (Table 3)

Table 3: Mortality Associated with Chronic Comorbidities Among HIV-infected Persons in the U.S.15

Condition Mortality Rate

Cardiovascular disease 18%

Liver disease 18%

Pulmonary disease 16%

Renal disease 12%

GI disorders 11%

Infection 10%

Non-AIDS-related cancers 8%

Figure 3. Mortality decline post-triple therapy Available at: https://www.drugabuse.gov/publications/research-

reports/hivaids/how-does-drug-abuse-affect-hiv-epidemic

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IV) ART by Class4

Table 4: ART by Class4

Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTIs)

Drug Acronym Mechanism Side Effects

Abacavir ABC • Inhibit reverse transcriptase conversion of viral RNA to pro-viral DNA

• Nucleos(t)ide analogue is incorporated into growing viral DNA strand causing early strand termination

• Lactic acidosis

• Hepatic steatosis

Tenofovir disoproxil fumarate

TDF

Tenofovir alafenamide fumarate

TAF

Emtricitabine FTC

Lamivudine 3TC

Didanosine DDI

Zidovudine AZT

Stavudine D4T

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Drug Acronym Mechanism Side Effects

Rilpivirine RPV • Inhibit reverse transcriptase conversion of viral

RNA to pro-viral DNA

• Blocks allosteric site on reverse transcriptase

• Rash Efavirenz EFV

Nevirapine NVP

Etravirine ETR

Protease Inhibitors (PIs)

Drug Acronym Mechanism Side Effects

Atazanavir ATV • Inhibit formation of mature virion particle by

preventing proteolytic cleavage of viral

polyprotein into individual functional proteins

• Hyperlipidemia

• Hyperbilirubinemia

• Lipohypertrophy

• GI intolerance

Darunavir DRV

Lopinavir LPV

Ritonavir RTV

Tipranavir TPV

Indinavir IDV

Nelfinavir NFV

Fosamprenavir FPV

Saquinavir SQV

Figure 4. Antiretroviral therapy mechanism of action Adapted from: http://www.positivewomen.org.au/images/pill-chart-2015-01.jpg

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Integrase Strand Transfer Inhibitors (INSTI)

Drug Acronym Mechanism Side Effects

Dolutegravir DTG • Inhibit insertion of pro-viral DNA into host

genome

• Myopathy

• Insomnia

• Depression

• Suicidality

• Hepatotoxicity

Raltegravir RAL

Elvitegravir EVG

Cell Entry and Fusion Inhibitor

Drug Acronym Mechanism Side Effects

Maraviroc MCV • Binds to active site on CCR5 co-receptor,

inhibiting viral particles from entering CD4 cell

• Requires CCR5 tropism assay to determine

efficacy

• Hepatotoxicity

Enfuvirtide T-20 • Binds to Gp41, a glycoprotein on the surface of the HIV particle, and inhibits Gp41-mediated fusion of viral and CD4 cellular membranes

• Bacterial pneumonia

• Injection site reactions

Pharmacokinetic Enhancers/Boosters

Drug Acronym Mechanism

Cobicistat COBI • Potent CYP3A4 inhibitor

• Enhances systemic exposure of substrates

Ritonavir RTV • Potent CYP3A4 and P-glycoprotein inhibitor

• Enhances systemic exposure of substrates

V) Guideline Recommended Treatment Approach4, 18-25

A) Definition of adequate ART regimen

i) At least 2, but preferably 3, fully active agents from different antiretroviral classes

a) Regimens with less than 2 fully active agents are less likely to achieve virologic suppression and may

promote resistance

b) A fully active agent is one that is expected to have uncompromised antiviral activity based on patient’s

treatment history (Hx) as well as current/past drug-resistance testing

B) Goals of ART

i) Viral suppression

ii) Restore or preserve immunologic function

iii) Reduce HIV-associated morbidity/mortality

iv) Prevent HIV transmission

v) Improve quality of life

a) Minimize drug-related toxicities

b) Improve tolerability and convenience of ART

c) Manage drug-drug and/or drug-disease interactions

C) Guideline recommended initial regimens for the general population with HIV (Table 5)

i) Listed regimens have demonstrated high antiviral activity and favorable side effect profiles in clinical trials

ii) Each regimen consists of two NRTIs and one integrase strand transfer inhibitor (INSTI)

Table 5: Recommended Initial Regimens for the General Population with HIV4

NRTI NRTI INSTI Level of Recommendation

TAF or TDF FTC or 3TC DTG (AI)

TAF or TDF FTC EVG/COBI (AI)

TAF or TDF FTC or 3TC RAL (AI) for TDF; (AII) for TAF

ABC FTC or 3TC DTG (AI)—if HLA-B*5701 negative AI: Strong recommendation based on one or more randomized trials with clinical outcomes and/or validated laboratory endpoints AII: Strong recommendation based on one or more well-designed, non-randomized trials or observational cohort studies with long-term clinical outcomes

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D) Tenofovir/emtricitabine (TDF/FTC) remains the preferred dual NRTI backbone

i) Recommended in 3 of the 4 preferred regimens for treatment naïve individuals

a) Up to 80% of all treated patients living with HIV/AIDS are taking a tenofovir-containing regimen

ii) Benefits of tenofovir/emtricitabine combination

a) Potent antiviral activity

b) Well tolerated

c) Limited drug-drug interactions (DDIs)

d) Co-formulated as a once daily pill (Truvada®)

e) Anti-HBV activity

f) Improved lipid parameters (TDF)

iii) TDF warnings/precautions

a) TDF-induced tubular toxicity

• TDF is excreted in urine both by glomerular filtration and active tubular secretion

• Co-administration of TDF with other drugs also eliminated by active tubular secretion increase TDF

concentration via competitive inhibition

• Accumulation of TDF depletes mitochondrial DNA within tubular cells leading to oxidative

respiratory chain dysfunction and epithelial cell apoptosis

• Nephrotoxicity may result in one of the following:

(i) Slow progressive decline in creatinine clearance (CrCl) due to long term exposure

1. CrCl < 30 ml/min requires intermittent dosing

(ii) Drug-induced Fanconi Syndrome (rare)

1. Dysfunctional transport within the proximal tubules leads to urinary wasting of solutes

• See Appendix A for a summary of trials evaluating TDF-induced kidney injury

• See Appendix B for risk factors associated with TDF-induced kidney injury

b) TDF-induced decrease in bone mineral density (BMD)

• TDF-induced impairment of tubular function leads to decreased 1-α hydroxylation of vitamin D

(i) Net effect lowers tubular reabsorption of vitamin D–binding protein

• See Appendix C for a summary of trials evaluating TDF-induced bone density loss

iv) TDF vs. TAF: Impact on renal function and bone mineralization

a) TDF and TAF are both prodrugs of tenofovir diphosphate (TFV)

b) When compared to TDF, TAF has shown greater distribution into lymphoid tissues, reducing systemic

exposure of TFV by 86%

c) TAF was found to have smaller increases in serum creatinine, less proteinuria, and smaller BMD declines

when compared to TDF:

• Change in serum creatinine (+0.08 vs. +0.11 mg/dL; p < 0.001)

• Proteinuria (-3 vs. +20; p < 0.001)

• Lumbar spine BMD decline (-1.30 vs. -2.86; p < 0·0001)

• Total hip BMD decline (-0.66 vs. -2.95; p < 0·0001)

• TAF contraindicated in CrCl < 30 ml/min

E) INSTIs emerge as the preferred third agent

i) Recommended in all 4 guideline preferred regimens for treatment naïve individuals

a) High virologic efficacy

• Insertion of pro-viral DNA into the human genome is the final step in acquisition of persistent HIV

infection

• INSTIs associated with rapid and durable viral load suppression

(i) Hoenigl et al. demonstrated INSTI-based regimens significantly reduced the time to viral

suppression compared to boosted-PI based regimens (12 weeks vs. 24 weeks; p = 0.022)

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b) High genetic barrier to resistance

• First generation INSTIs, raltegravir and elvitegravir, share similar resistance profiles and a high

degree of cross-resistance

• Dolutegravir, a second generation INSTI, exhibits a high genetic barrier to resistance

(i) In integrase-naive subjects with a Hx of virologic failure, dolutegravir exhibited lower rates of

drug resistant mutations and higher rates of virologic suppression compared to raltegravir:

1. Resistant mutations (1% vs. 4.7%; 95% CI -6.1% – -1.2%)

2. Virologic suppression (71% vs. 64%; 95% CI 0.7 – 14.2)

c) Limited potential for DDIs

• Raltegravir and dolutegravir bypass CYP450 system

(i) metabolized via UDP-glucuronosyltransferase (UGT) pathway

• Elvitegravir/cobicistat has greater potential for DDIs due to cobicistat’s CYP450 inhibition

d) Limited effects on lipid concentrations

e) Utility in patients with renal impairment

ii) INSTI warnings/precautions

a) Increased risk of depression/suicidality

• Particularly in individuals with pre-existing psychiatric condition

b) Hepatotoxicity

c) Myopathy

VI) ART Considerations4, 26-29

A) HIV/hepatitis B virus (HBV) co-infection

i) Estimated at 5 - 10% of the HIV-infected population in the United States

ii) Persons with HIV/HBV coinfection and detectable viremia of both viruses are at increased risk of progression

to cirrhosis, decompensated liver disease, and the development of hepatocellular carcinoma (HCC)

iii) All patients should be assessed for HBV coinfection prior to ART initiation

a) HBV reactivation may occur upon initiation of ART lacking anti-HBV activity

b) Initial testing should include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs),

and total hepatitis B core antibody (anti-HBc)

c) HBV reactivation should be considered in HBsAg-positive and anti-HBs-positive patients who experience

elevated LFTs upon initiation of ART

iv) The following are recommended for HIV/HBV co-infection (HBsAg positive)

a) Quantitative serum HBV DNA testing to distinguish between active/inactive disease

v) HIV/HBV co-infected individuals should receive a fully suppressive ART regimen that includes 2 agents with

anti-HBV activity

a) TDF, TAF, FTC, and 3TC are the only agents with anti-HBV activity

• ART should include TDF or TAF in combination with FTC or 3TC

b) Entecavir should be used in addition to a fully suppressive ART regimen in those unable to tolerate TAF

or TDF

• Entecavir and 3TC share overlapping pathways to HBV resistance (rtM204 mutation), it is unknown

whether entecavir + 3TC or FTC will provide greater benefit than entecavir alone

• Avoid 3TC or FTC as the only HBV-active agent in ART as HBV mutations can emerge rapidly when

these drugs are used without a second drug active against HBV

vi) HBV reactivation may occur upon discontinuation of ART with anti-HBV activity

a) Discontinuation of ART active against HBV may cause hepatocellular damage and reactivation of HBV

b) HBV reactivation should be considered in individuals who experience elevated LFTs upon

discontinuation of ART

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B) HLA-B*5701 allele

i) Abacavir requires HLA-B*5701 genotype testing prior to initiation

a) Use is contraindicated in HLA-B*5701-positive individuals due to the risk of an immune mediated

hypersensitivity reaction

b) HLA-B*5701 allele occurs at approximately 5% frequency in European populations, 1% in Asian

populations, and less than 1% in African populations

c) Symptoms include: Rash, nausea/vomiting, respiratory distress, and/or death

C) Metabolic abnormalities

i) Compared to the general population, HIV infected adults are at increased risk of age-related chronic

diseases

a) HIV-infection stimulates a state of chronic inflammation, increasing the risks for the following:

atherosclerotic cardiovascular disease (ASCVD), chronic obstructive pulmonary disease (COPD), and

metabolic disorders

b) ART related toxicities further compound the risk of ASCVD

• Protease inhibitors, as a class, have been shown to adversely affect lipid and metabolic parameters

(i) Use associated with lipohypertrophy, body-fat redistribution, hyperlipidemia,

hypertriglyceridemia, insulin resistance, and an increased risk of MI

VII) Therapeutic Definitions30

A) Virologic suppression

i) Plasma RNA < 50 copies/mL

B) Virologic blip

i) A single, transient increase in viral load > 50 copies/mL, in a patient who was previously suppressed

ii) Does not necessitate an immediate change in ART

iii) Possible causes include either other infections (e.g., influenza, herpes, etc.) or recent vaccinations

C) Virologic failure

i) Two consecutive HIV RNA levels ≥ 200 copies/mL after 24 weeks on ART

ii) Follow-up viral load must be at least 2-3 months after initial viral load to be considered diagnostic

iii) Patients will require resistance testing followed by a change in ART regimen

D) Low-level viremia

i) HIV RNA < 200 copies/mL

ii) Risk of emerging resistance is believed to be relatively low

iii) Patients do not require a change in ART regimen

iv) Monitor HIV RNA every 3 months to assess the need for changes in ART in the future

E) Immune non-responders

i) Immune non-responders are patients whose CD4 counts fail to rise appropriately on therapy, despite a

suppressed viral load – “immunological discordance”

ii) Patients do not require a change in ART regimen

F) Latent HIV Reservoir

i) Despite effective ART, HIV often persists in a stable reservoir within resting CD4 cells

a) Latently infected CD4 cells do not actively produce viral particles

b) Latent HIV reservoirs can be found throughout the body (brain, lymph nodes, blood, and digestive tract)

c) The reservoir persists even in patients on long-term ART who have no detectable viremia

ii) Reservoir serves as a permanent archive for all wild-type and drug-resistant viruses that have circulated at

significant levels

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VIII) Clinical Question

A) Can maintenance of virologic suppression be achieved with dual therapy?

IX) Reasons to Consider Dual Therapy

A) Minimize drug-drug and/or drug-disease interactions

B) Improve tolerability of ART

C) Minimize cumulative drug exposure and reduce the risk of long-term drug toxicities

X) Goal of Dual Therapy31

A) Maintain virologic suppression without jeopardizing future treatment options

B) FDA advises a noninferiority margin of 4% for virologic failure analysis

XI) Literature Review

A) Previous literature evaluating dual therapy in virologically suppressed HIV-1 infected patients

Table 6: Dual Therapy in Virologically Suppressed HIV-1 Infected Patients32-36

Study Treatment Design Population Results

DUAL-GESIDA32

Darunavir/r + lamivudine vs. darunavir/r + 2 NRTIs

Open-label, randomized, multi-center, non-inferiority clinical trial • Non-inferiority margin = 12% • Required 128 participants per arm to achieve 80% power • Duration = 48 weeks

N = 249 • HIV RNA < 50 copies/mL ≥ 6 months (mean 23 months) • HBV negative • No Hx of ART failure or drug resistant mutations

DUAL-GESIDA met non-inferiority for the primary endpoint of HIV RNA < 50 copies/mL but was not powered to detect non-inferiority for the secondary endpoint of virologic failure:

• HIV RNA < 50 copies/mL darunavir/r + lamivudine vs. darunavir/r + 2 NRTI (88.9% vs. 92.7%; 95% CI -11.0 – 3.4)

• Virologic failure (3% vs. 2%) One patient allocated to the darunavir/r + 2 NRTI group developed non-signature PI resistance associated mutations (L10I, A71T, L76W) Darunavir/r + lamivudine associated with a significant increase in total and LDL cholesterol in patients receiving TDF at baseline:

• Total cholesterol (p< 0.001)

• LDL (p = 0.01)

ATLAS-M33 Atazanavir/r + lamivudine vs. atazanavir/r + 2 NRTIs

Open-label, randomized, multi-center, non-inferiority clinical trial • Non-inferiority margin = 12% • Duration = 96 weeks

N = 266 • HIV RNA < 50 copies/mL ≥ 6 months (mean 22 months) • HBV negative • No Hx of ART failure or drug resistant mutations

ATLAS-M met non-inferiority for the primary endpoint of HIV RNA < 50 copies/mL but was not powered to detect non-inferiority for the secondary endpoint of virologic failure:

• HIV RNA < 50 copies/mL at 48 weeks (90.6% vs. 83.9%; 95% CI -1.5 – 14.9; p = 0.113)

• HIV RNA < 50 copies/mL at 96 weeks (77.8% vs. 65.6%; 95% CI -2 – 23.2)

• Virologic failure (1.5% vs. 6.8%; p = 0.056)

Atazanavir/r + lamivudine increased the risk of hypertriglyceridemia and hyperbilirubinemia

• Hypertriglyceridemia (7.6% vs. 1.6%; p = 0.027)

• Hyperbilirubinemia (59.6% vs. 35.8%; p = 0.001)

Atazanavir/r + 2 NRTI was associated with a significant decline in GFR

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• Change in eGFR (5 vs. -3; p<0.001)

No participants developed drug resistant mutations

OLE34 Lopinavir/r + lamivudine vs. lopinavir/r + 2 NRTIs

Open-label, randomized, multi-center, non-inferiority clinical trial • Non-inferiority margin = 12% • Required 168 participants per arm with a response rate of 85% in both groups to achieve 80% power -OR- • Required 115 participants per arm with a response rate of 88% to achieve 80% power • Duration = 48 weeks

N = 239 • HIV RNA < 50 copies/mL ≥ 6 months • HBV negative • No Hx of ART failure or drug resistant mutations

OLE met non-inferiority for the primary endpoint of HIV RNA < 50 copies/mL but was not powered to detect non-inferiority for the secondary endpoint of virologic failure:

• HIV- RNA < 50 copies/mL lopinavir/r + lamivudine vs. lopinavir/r + 2 NRTI (87.8% vs. 86.6%; 95% CI -9.6 – 7.3; p=0.92)

• Virologic failure (5% vs. 5%) One participant allocated to the Lopinavir/r + lamivudine group developed NRTI drug resistant mutations (103Asn, 184Val): • Hx of non-adherence to antiretroviral treatment with tenofovir, lamivudine, and efavirenz before entering the study • Retrospective analysis of a saved sample showed 103Asn, 184Val, and 181Cys present at baseline Lopinavir/r + lamivudine was associated with a significant increase in total and LDL cholesterol

• Total cholesterol (p=0.019)

• LDL cholesterol (p=0.008) Lopinavir/r + lamivudine associated with a significant increase in eGFR when compared to triple therapy (p=0.003)

ARNS 167 LAMIDOL35

Dolutegravir + lamivudine

Open label, single arm, multi-center pilot • Duration = 48 weeks

N = 104 • HIV RNA < 50 copies/mL ≥ 24 months • HBV negative • No Hx of resistance or virologic failure

97% of participants remained virologically suppressed

HARNESS36 Atazanavir/r + raltegravir vs. Atazanavir/r + TDF/FTC

Open-label, randomized, multi-center, non-inferiority pilot • Duration = 48 weeks

N= 109 • HIV RNA < 50 copies/mL ≥ 3 months • HBV negative • No Hx of resistance or virologic failure

Atazanavir/r + raltegravir associated with higher rates of virologic failure and treatment discontinuation: • HIV- RNA < 50 copies/mL (69.4% vs. 86.5%) • Treatment discontinuation (77.8% vs. 86.5%) 2 participants allocated to the atazanavir/r + raltegravir arm developed resistant mutations • INSTI drug resistant mutations (Y143C, N155H) • PI and INSTI resistant mutations (L10V, G16Q, L33F, P39Q, M46L, G48V, Q58E, I62V, L63I/T, I64L, A71V, I72V, V77I, V82A, T91S, I93L) and (F121Y)

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B) Current literature evaluating dual therapy in virologically suppressed HIV-1 infected patients

SALT Trial37

SALT Trial: Simplification to dual therapy (atazanavir/ritonavir + lamivudine) versus standard triple therapy

Objective

Evaluate the efficacy of dual therapy with atazanavir/ritonavir plus lamivudine (ATV/r+3TC) vs. triple therapy with ATV/r plus 2 nucleos(t)ides for the maintenance of virologic suppression

Study Design

• Open-label, randomized, multi-center, non-inferiority clinical trial

Methods

• Participants randomized in a 1:1 fashion to receive ATV/r+3TC or ATV/r+ 2 nucleos(t)ides o Dual therapy arm:

▪ 30 days of triple therapy with ATV/ r + 2 nucleos(t)ides before switching to dual therapy with ATV/r

+ 3TC

▪ Transition phase designed to prevent induction of ATV/r by EFV or NVP

o Triple therapy arm: ▪ ATV/r + TDF/FTC ▪ ATV/r + ABC/3TC ▪ ATV/r + AZT/3TC

• Virologic failure: o Two consecutive (≥ 14 days but < 30 days apart) HIV-1-RNA ≥ 50 copies/mL o Missing patients and changes in any study drug were also considered failures

• Non-adherence: o Adherence < 90% determined utilizing pill counts and a medication adherence questionnaire

• Non-inferiority margin = 12%

• Duration 96 weeks

Inclusion Criteria Exclusion Criteria

• Age ≥ 18 years

• HIV RNA < 50 copies/mL ≥ 6 months

• Negative HBV surface antigen

• Switch in ART in previous 4 months before screening

• Hx of resistant mutations

• Previous Hx of ART failure

Primary Endpoint Secondary Endpoints

• HIV-1 RNA < 50 copies/mL at 48 weeks • HIV-1-RNA < 50 copies/mL at 96 weeks

• Virologic failure

• Viral load blip

• Change in CD4 T-cell count from baseline

Baseline Characteristics

ATV/r + 3TC N=140

ATV/r + 2NUCs N=141

Age, years (range) 45 (38–52) 42 (36–48)

Female sex 44 (31%) 32 (22%)

Previous AIDS-defining illness 37 (26%) 35 (24%)

Baseline CD4 count, cells/ μL (range) 579 (397–770) 614 (443–796)

Duration of ART prior to randomization, months (range) 39.4 (26.7–62.3) 40.5 (22.3–67.2)

Duration of viral load < 50 copies/mL pre-randomization, months (range) 27 (16–51) 29 (15–58)

Baseline NRTI Backbone

TDF/FTC 119 (83%) 116 (81%)

ABC/3TC 21 (15%) 25 (16%)

Baseline 3rd-agent class

NNRTI 47 (33%) 46 (32%)

Ritonavir-boosted PI 92 (64%) 94 (66%) Demographic and key baseline characteristics were well matched across treatment groups

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Results

ATV/r + 3TC N=133

ATV/r + 2NUCs1

N=134

Primary endpoint

HIV RNA < 50 copies/mL at 48 weeks 110 (83%) 104 (78%)

Secondary endpoints

HIV RNA < 50 copies/mL at 96 weeks 99 (74.4%) 99 (73.9%)

Viral load blip not leading to treatment interruption2 20 (15%) 23 (17%)

2 non-consecutive viral load blips not leading to treatment interruption 4 (3%) 5 (4%)

Virologic failure at 48 weeks 6 (4%) 4 (3%)

Virologic failure at 96 weeks 10 (7.5%) 7 (5.2%)

NRTI (M184V) and PI (L63P) resistant mutations 0 1 (<1%)

Change in CD4 count, cells/ μL + 19 + 18

Adherence to study drug 128 (96%) 125 (93%) 1 Post randomization triple therapy arm: TDF/FTC = 75.6%; ABC/3TC = 23.8%; AZT/3TC = <1% 2 A single, transient increase in VL > 50 copies/mL followed by a subsequent return < 50 copies/mL

Safety

Adverse Event (AE) ATV/r + 3TC N=140

ATV/r + 2NUCs N=141

Any adverse event 99 (70.7%) 99 (70.2%)

Mean change in triglyceride from baseline1 + 12.1% - 6.2% (p < 0.003)

Grade 3-4 AE2 99 (70.7%) 99 (70.2%)

Hyperbilirubinemia 91 (65%) 93 (65.9%)

Increased liver function tests (LFTs) 3 (2%) 1 (<1%)

Hypertriglyceridemia 3 (2%) 2 (1%)

Thrombocytopenia 2 (1%) 1 (<1%)

AEs leading to withdrawal from the study 7 (5%) 10(7.1%)

Death 1 (<1%) 0 1Denotes statistical significance 2Severe or life-threatening AE

Author’s Conclusion

Dual treatment with ritonavir-boosted atazanavir plus lamivudine is safe, effective, and well tolerated treatment strategy for patients with virologically suppressed HIV-1 infection. The long-term global efficacy was favorable and did not lead to the emergence of resistant mutations.

Reviewer’s Critique

Strengths

• 96-week follow-up: longer than the 48 weeks seen in similar trials

• Majority of participants allocated to triple therapy were on TDF/FTC based regimens pre-and post-randomization

• Objective measure to assess adherence: pill count

• 30-day run in to decrease DDIs and establish tolerability

Limitations

• Not powered to detect 4% non-inferiority for rate of virologic failure

• Open-label design

• Small sample size

Take Home

83% of participants allocated to the dual therapy arm maintained virologic suppression. This was enough to meet the pre-defined non-inferiority margin for the primary endpoint of virologic suppression. Rate of confirmed virologic failure was higher in the dual therapy arm. SALT was not powered to detect the more stringent noninferiority margin for virologic failure analysis. Dual therapy with atazanavir/ritonavir plus lamivudine was however, associated with a significant increase in triglycerides.

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SWORD Studies38

SWORD-1 and SWORD-2: Regimen switch to dolutegravir + rilpivirine from current antiretroviral regimen in HIV-1 infected and virologically suppressed adults

Objective

Evaluate the efficacy and safety of dual therapy with dolutegravir + rilpivirine (DTG + RPV) vs. triple therapy for maintenance of virologic suppression

Study Design

• Open label, randomized, multi-center, non-inferiority studies

Methods

• Participants randomized in a 1:1 fashion to receive DTG + RPV or continue with current ART

• Virologic failure o HIV-1-RNA ≥ 50 copies/mL and a second confirmatory VL ≥ 200 copies/mL

• Virologic success pre-defined non-inferiority margin of 8%

• Virologic failure complementary analysis pre-defined non-inferiority margin of 4% to maintain consistency with FDA guidelines

• Duration 48 weeks

Inclusion Criteria Exclusion Criteria

• Age ≥ 18 years

• HIV RNA < 50 copies/mL for ≥ 12 months

• No previous ART failure o Defined as HIV-1 RNA ≥ 400 copies/mL after

initial suppression < 50 copies/mL

• No more than one viral blip in the previous 12 months before screening

o Defined as HIV RNA > 50 copies/mL but < 200 copies/mL

• No switch in ART in previous 6 months pre-screening

• Negative HBV surface antigen

• Hx of PI, INSTI, NRTI, or NNRTI resistance-associated mutation

• Hx of INSTI R263K resistance - associated substitution

• Severe hepatic impairment (Child-Pugh C)

• Anticipated need to receive hepatitis c virus (HCV) treatment during the study period

• Substantial suicidality risk (determined by the site investigator)

• QT interval ≥ 450 msec Pregnancy or breastfeeding

Primary Endpoint Secondary Endpoints

• Participants with HIV-1 RNA <50 copies/mL at 48 weeks

• Virologic failure

• Change in CD4 T-cell count from baseline

Baseline Characteristics

DTG + RPV N=513

Current ART N=511

Age, years (range) 43 (21-79) 43 (22-76)

Age ≥ 50 years 147 (29%) 142 (28%)

Female Sex 120 (23%) 108 (21%)

Baseline CD4 count, cells/ μL (range) 611 (3-1774) 638 (9-1671)

≤ 500 cells/ μL 165 (32%) 149 (29%)

Baseline TDF use 374 (73%) 359 (70%)

Baseline 3rd-agent class

NNRTI1 275 (54%) 278 (54%)

Ritonavir-boosted PI2 133 (26%) 136 (27%)

INSTI3 105 (20%) 97 (19%)

Median duration of ART prior to randomization, months (range) 51 (8-221) 53 (9-270) 1The most commonly reported NNRTI at baseline was efavirenz 2The most commonly reported protease inhibitor at baseline was darunavir/r 3The most commonly reported INSTI at baseline was raltegravir Demographic and key baseline characteristics were well matched across treatment groups

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Results

DTG + RPV N=513

Current ART N=511

Primary endpoint

HIV RNA < 50 copies/mL 486 (95%) 485 (95%)

Secondary endpoints

Virologic failure 3 (<1%) 6 (1%)

NNRTI (K101K/E) resistant mutations1 1 (<1%) 0

Change in CD4 cell count from baseline, cells/μL +28 +22

Discontinued due to AE or death 17 (3%) 3 (<1%) 1 One participant on DTG + RPV with confirmed poor adherence developed an NNRTI resistance associated substitution (K101K/E) with no loss in rilpivirine susceptibility (1.2-fold change). Participant was able to achieve viral load < 50 copies/mL again after re-establishing adherence; No INSTI resistance–associated mutations were identified

Safety

Adverse Events DTG + RPV N=513

Current ART N=511

Any AE 395 (77%) 364 (71%)

Nasopharyngitis 49 (10%) 50 (10%)

Headache 41 (8%) 23 (5%)

Upper respiratory tract infection 24 (5%) 37 (7%)

Neuropsychiatric AEs 26 (5%) 2 (<1%)

AEs leading to withdrawal from the study 17 (3%) 3 (<1%)

CNS AEs leading to withdrawal 9 (2%) 1 (<1%)

Deaths1 1 (<1%) 1 (<1%) 1 Two deaths. Both unrelated to study drug. DTG+RPV Kaposi’s Sarcoma (N=1), current ART Lung cancer (N=1).

Authors Conclusion

Dual therapy with dolutegravir plus rilpivirine provides an efficacious alternative to guideline-preferred triple drug regimens in patients with virologically suppressed HIV-1 infection without histories of resistance.

Reviewer’s Critique

Strengths

• Largest study population for dual therapy

• Non-inferiority margins more stringent than the 12% used in previous trials: 10% for individual studies, 8% for pooled analysis, and 4% for virologic failure analysis

• Conducted midpoint futility analysis to ensure participants were not receiving suboptimal therapy

• High recruitment of commonly under-represented subpopulations (age ≥ 50 years, female sex)

• Strict reporting of adverse events: Volunteered by the participant, identified by investigator questioning participant, physical examination, or via laboratory analysis

• Robust follow up data collection

Limitations

• Open label design

• Subjective measure to assess adherence: Patient reported questionnaire

• Will require follow up studies to assess long-term efficacy beyond 48 weeks

• Baseline criteria did not assess the following: o Pre-ART CD4 count o Pre-ART viral load (VL) o Pre-randomization duration of VL < 50

copies/mL

Take Home

Dual therapy with dolutegravir + rilpivirine was non-inferior to triple therapy for the maintenance of virologic suppression. 95% of participants across both treatment groups maintained virologic suppression. Dolutegravir + rilpivirine was not associated with an increased risk of drug resistant mutations or metabolic effects. Dolutegravir + rilpivirine was associated with a non-significant increase in neuropsychiatric adverse events.

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XII) Summary of Evidence

A) Clinical trials excluded patients with a history of treatment failure, drug resistant mutations, or HIV/HBV co-

infection

B) Providers should have full access to patient’s ART history and any previous genotypic and phenotypic drug

resistance

i) Providers should use this information to determine drugs likely to have full vs. partial activity

C) If there is uncertainty about prior resistance, it would not be advisable to switch to dual therapy XIII) Recommendations

A) Dual therapy with dolutegravir + rilpivirine may be considered among virologically suppressed HIV-1 infected

individuals who require a change in ART due to toxicity. The following criteria must be met prior to switching to

dual therapy:

i) On stable ART

ii) HIV RNA < 50 copies/mL

iii) Unable to tolerate daily tenofovir administration

a) TDF: CrCl < 30ml/min or osteoporosis diagnosis

b) TAF: CrCl < 30ml/min

iv) Unable to tolerate abacavir-containing ART

a) HLA-B*5701 positive

v) HBV negative

a) Dolutegravir + rilpivirine has no activity against HBV

vi) No Hx of INSTI or NNRTI failure

vii) No Hx of INSTI or NNRTI resistance-associated mutation

viii) Stable mental health evaluation

B) Although dual therapy with boosted-PI based regimens met non-inferiority for virologic suppression, these trials

were not designed to detect the more stringent 4% noninferiority margin for virologic failure analysis

recommended by the FDA. Furthermore, boosted-PI regimens have been associated with an increased risk of

metabolic side effects making them a less favorable option than dolutegravir + rilpivirine

i) Dual therapy utilizing boosted-PI based regimens may be considered in the following patient population:

a) On stable boosted-PI regimen ≥ 6 months

b) HIV RNA < 50 copies/mL for ≥ 6 months

c) Unable to tolerate daily tenofovir administration

• TDF: CrCl < 30ml/min or osteoporosis diagnosis

• TAF: CrCl < 30ml/min

d) Unable to tolerate abacavir-containing ART

• HLA-B*5701 positive

e) HBV negative

f) No Hx of PI or NRTI failure

g) No Hx of PI or NRTI resistance-associated mutation

C) Suggested post-switch monitoring4

i) Patients should be evaluated more closely for several months following modification of ART before resuming

previous monitoring schedule

a) Adherence and tolerability

• Clinic visit or phone call 2 weeks post switch

• Dolutegravir + rilpivirine must be taken with a meal for full absorption

b) Efficacy and response to treatment

• HIV RNA 4-8 weeks post switch to assess efficacy

(i) Ensure HIV RNA remains < 50 copies/mL

c) Routine laboratory testing within 3 months

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XIV) Appendices

Appendix A: Trials evaluating TDF-induced Kidney Injury (Table 7)

Table 7: Summary of Trials Evaluating TDF-induced Kidney Injury39-41

Study Design Population Duration Results

Gallant JE et al.39

Prospective study evaluating TDF’s effect on creatinine clearance (CrCl)

N = 658 N = 344 with TDF exposure N = 314 controls

1 year TDF associated with significantly greater decline in CrCl (-13.3 ml/min vs. -7.5ml/min; p = 0.005)

Scherzer R et al.40

Retrospective study evaluating TDF’s effects on proteinuria, eGFR, and progression to chronic kidney disease (CKD)

N = 10,841

• N = 4,303 with TDF exposure

• N = 6,538 controls

5.5 years Each year of TDF-exposure increased the risk of proteinuria and CKD:

• Proteinuria (HR 1.3; 95% CI 1.22-1.37; p<0.0001)

• CKD (HR 1.33; 95% CI 1.18-1.51; p<0.0001)

Monteagudo-Chu MO et al.41

Retrospective study evaluating effect of TDF on progression to advanced stages of CKD in patients with and without baseline renal impairment

N = 230

• N = 111 with TDF exposure

• N = 119 controls

• 76% with normal renal function

• 24% with CKD-1

10 years TDF-exposure was associated with an increased risk of CKD progression:

• Progression from CKD-1 to CKD-2 (48.8% vs. 23.7%; p < 0.001)

• Progression from CKD-1 to CKD-3 (5.8% vs. 0.0%; p = 0.028)

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Appendix B: Risk factors for TDF-induced nephrotoxicity (Table 8)

Table 8: Risk Factors for TDF-Induced Nephrotoxicity 18, 19

Risk Factor Odds Ratio P value

Pre-existing renal dysfunction 17.4 p = 0.018

Concomitant use of nephrotoxic medications 2.40 p = 0.03

Advanced age 1.05 p = 0.02

Advanced HIV-infection 0.46 for each additional WHO stage P < 0.001 Appendix C: Trials evaluating TDF-induced decrease in BMD (Table 9)

Table 9: Summary of Trials Evaluating TDF-induced Bone Density Loss42, 43

Study Objective Population Duration Results

ASSERT Study42

Prospective trial evaluating the effects of TDF/FTC + EFV vs. ABC/3TC + EFV on BMD and markers of bone mineral turnover

N = 385 48 weeks Participants allocated to TDF/FTC + EFV experienced greater BMD declines at total hip and lumbar spine (LS):

• Total hip (-3.6% vs. -1.9%; p < 0.001)

• LS (-2.4% vs. -1.6%; p = 0.036)

• BMD loss ≥ 6% more common with TDF/FTC Hip = 13% vs. 3% Spine = 15% vs. 5%

• Decrease in LS BMD stabilized at 24 weeks

• Decrease in hip BMD ongoing through week 48

• Osteopenia or osteoporosis was not reported

START Bone Mineral Density Sub-study43

Retrospective trial evaluating effects of immediate vs. deferred ART initiation on BMD

N = 399 ▪ 83.7%

were on a TDF based regimen

2.2 years Immediate ART initiation resulted in greater BMD declines at femoral neck, total hip, and lumbar spine

• Femoral neck (–3% vs. –1.4%; 95% CI –2.6 to –0.8; p < 0.001)

• Total hip (–2.5% vs. –1.0%; 95% CI –2.2 to –0.8; p < 0.001)

• Lumbar spine (–1.9% vs. –0.4%; 95% CI –2.2 to –1.0; p < 0.001)

• BMD declines were greatest in the first year of ART

Appendix D: Recommended initial therapy based on specific clinical scenarios (Table 10)

Table 10: Recommended Initial Therapy Based on Specific Clinical Scenarios4

Clinical Scenario Avoid Recommended

CD4 cell count < 200 cells/µL

• RPV-based regimens

• DRV/r + DTG

HIV RNA > 100,000 copies/mL

• RPV-based regimens

• DRV/r + DTG

• ABC/3TC + EFV or ATV/r

CKD • TDF and ATV • ABC or TAF

Liver impairment • NVP, ATV, ABC, DRV, NFV, SQV, TPV, DTG, EVG

• FPV and IDV require dose adjustments

Osteoporosis • TDF • ABC or TAF

Psychiatric condition • EFV and RPV

• Monitor patients on INSTI based regimens

HIV-associated dementia • EFV • DTG or DRV

Cardiovascular disease • ABC and LPV • DTG, RAL, or RPV

Dyslipidemia • PIs, EFV, EVG, or TAF • DTG, RAL, RPV, or TDF

HIV/HBV co-infection • See section VIII of handout

TB treatment • TAF with any rifamycin containing regimen • EFV

• RAL requires dose adjustments