Antiretroviral Therapy for HIV Infection

Updated: Sep 12, 2018
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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An estimated 36.7 million people are infected with HIV worldwide. [1] In the United States, more than 1.1 million people have HIV infection, and almost 1 in 7 (14%) are unaware of their infection. The estimated incidence of HIV in the United States has declined by 18% between 2008 and 2014, and is now at about 40,000 new infections occurring each year. [2]

Significant advances in antiretroviral therapy have been made since the introduction of zidovudine (AZT) in 1987.

With the advent of highly active antiretroviral therapy (HAART), HIV-1 infection is now manageable as a chronic disease in patients who have access to medication and who achieve durable virologic suppression. [3]

Excess mortality among patients with AIDS was nearly halved in the HAART era (see the image below) but remains approximately 5 times higher in patients with AIDS than in HIV-infected patients without AIDS. Risk factors for excess mortality include a viral load greater than 400 copies/mL, CD4 count less than 200 cells/mL, and cytomegalovirus retinitis. [4]  Despite reductions in mortality with antiretroviral therapy, overall mortality remains 6 times higher in persons with HIV than the general population. [5]

Changes in survival of people infected with HIV. A Changes in survival of people infected with HIV. As therapies have become more aggressive, they have been more effective, although survival with HIV infection is not yet equivalent to that in uninfected people. Modified from an original published by Lohse et al (2007), "Survival of persons with and without HIV infection in Denmark, 1995-2005."

HAART provides effective treatment options for treatment-naive and treatment-experienced patients. Pharmacologic drug classes include:

  • Nucleoside reverse transcriptase inhibitors (NRTIs)

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

  • Protease inhibitors (PIs)

  • Integrase inhibitors (INSTIs)

  • Fusion inhibitors (FIs)

  • Chemokine receptor antagonists (CCR5 antagonists)

  • Entry inhibitors (CD4-directed post-attachment inhibitors)

Each class targets a different step in the viral life cycle as the virus infects a CD4 T lymphocyte or other target cell. The use of these agents in clinical practice is largely dictated by their ease or complexity of use, side-effect profile, efficacy based on clinical evidence, practice guidelines, and clinician preference.

Resistance, adverse effects, pregnancy, and coinfection with hepatitis B virus, or hepatitis C virus present important challenges to clinicians when selecting and maintaining therapy.

This article reviews the mechanism of action, resistance, pharmacokinetics, and adverse effects of each of these classes, as well as current treatment guidelines for their use in adults and adolescents with HIV infection. Also discussed are the important challenges involved in selecting and maintaining antiretroviral therapy for pregnant women and patients with acute HIV infection, hepatitis B or C coinfection, or Mycobacterium tuberculosis coinfection.

For additional information on HIV disease, see the following Medscape Reference articles HIV Infection and AIDS and Pediatric HIV Infection.


FDA-Approved Antivirals and Regimens

Individual antiretroviral drugs are described below. Dosing guides assume an absence of drug-drug interactions (except ritonavir) and normal renal and hepatic function.

Nucleoside reverse transcriptase inhibitors (NRTIs)

Abacavir (Ziagen):

  • Dosage form: 300-mg tablet; 20-mg/mL oral solution
  • Adult dose: 600 mg PO qd or 300 mg PO bid
  • Comments: Take without regard to meal
  • Adverse events: Hypersensitivity reaction (may include fever, rash, nausea, vomiting, diarrhea, malaise, shortness of breath, cough, pharyngitis); patients positive for HLA-B*5701 are at highest risk for hypersensitivity (perform HLA screening before initiating)

Didanosine (Videx, Videx EC) (dosage adjustment with renal impairment required):

  • Dosage forms: 125-mg, 200-mg, 250-mg, 400-mg delayed-released capsule; 10-mg/mL powder for solution
  • Adult dose: >60 kg, 400 mg PO qd; < 60 kg, 250 mg PO qd
  • Comments: Take 30 min ac or 2 hr pc; for oral solution, divide daily dose bid
  • Adverse events: Peripheral neuropathy, pancreatitis, nausea, lactic acidosis

Emtricitabine (Emtriva) (dosage adjustment with renal impairment required):

  • Dosage form: 200-mg capsule; 10-mg/mL oral solution
  • Adult dose: 200 mg PO qd (capsule) or 240 mg (24 mL) oral solution PO qd
  • Comments: Take without regard to meals
  • Adverse events: Minimal toxicity, hyperpigmentation, severe acute exacerbation of hepatitis may occur with HBV-coinfection upon discontinuation

Lamivudine (Epivir) (dosage adjustment with renal impairment required):

  • Dosage forms: 150-mg, 300-mg tablet; 10-mg/mL oral solution
  • Adult dose: 300 mg PO qd or 150 mg PO bid
  • Comments: Take without regard to meals
  • Adverse events: Minimal toxicity, severe acute exacerbation of hepatitis may occur with HBV-coinfection upon discontinuation

Stavudine (Zerit) (dosage adjustment with renal impairment required):

  • Dosage forms: 15-mg, 20-mg, 30-mg, 40-mg capsule; 1-mg/mL oral solution
  • Adult dose: >60 kg, 40 mg PO bid; < 60 kg, 30 mg PO bid
  • Comments: Take without regard to meals
  • Adverse events: Peripheral neuropathy, pancreatitis, lactic acidosis, lipoatrophy, hyperlipidemia

Tenofovir disoproxil fumarate (DF) (Viread) (dosage adjustment with renal impairment required):

  • Dosage forms: 150-mg, 200-mg, 250-mg, 300-mg tablets; 40-mg/g oral powder
  • Adult dose: 300 mg PO qd
  • Comments: Take without regard to meals
  • Adverse events: Nausea, vomiting, diarrhea, headache, asthenia, renal insufficiency [6] , bone mineral density loss

Tenofovir alafenamide AF (various):

  • Dosage forms: available as part of multiple coformulations
  • Adult dose: 25 mg PO qd; 10 mg PO qd (concomitant administration with ritonavir or cobicistat)
  • Comments: Take without regard to meals
  • Adverse events: Nausea, abdominal pain, fatigue, headache, back pain, cough

Zidovudine (Retrovir) (dosage adjustment with renal impairment required):

  • Dosage forms: 300-mg tablet; 100-mg capsule; 10-mg/mL oral solution; 10-mg/mL intravenous solution
  • Adult dose: 300 mg PO bid or 200 mg PO tid
  • Comments: Take without regard to meals
  • Adverse events: Nausea, vomiting, headache, asthenia, anemia, neutropenia

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine (Rescriptor) (Note: Discontinued in the U.S. with estimated availability for 100-mg tablets until October 2018 and for 200-mg tablets until February 2020):

  • Dosage forms: 100-mg, 200-mg tablets
  • Adult dose: 400 mg PO tid
  • Adverse events: Rash, headache

Efavirenz (Sustiva):

  • Dosage forms: 600-mg tablet; 50-mg, 200-mg capsule
  • Adult dose: 400-600 mg PO qd
  • Comments: Take on empty stomach to decrease adverse effects
  • Adverse events: Rash, CNS (e.g., somnolence, vivid dreams, confusion, visual hallucinations), hyperlipidemia

Etravirine (Intelence) (approved only for antiretroviral treatment–experienced patients with drug resistance):

  • Dosage forms: 25-mg, 100-mg, 200-mg tablets
  • Adult dose: 200 mg PO bid following a meal
  • Adverse events: Rash, nausea

Nevirapine (Viramune, Viramune XR):

  • Dosage forms: 200-mg tablet; 400-mg XR tablet; 10-mg/mL suspension
  • Adult dose: 200 mg PO bid (administer 200 mg qd for 2 weeks, then increase to 200 mg bid); XR, 400 mg PO qd
  • Comments: Take without regard to meals
  • Adverse events: Rash, hepatitis

Rilpivirine (Edurant):

  • Dosage forms: 25-mg tablet
  • Adult dose: 25 mg PO qd with a meal
  • Adverse events: Depressive disorders, insomnia, headache, rash

Doravirine (Pifeltro):

  • Dosage forms: 100-mg tablet
  • Adult dose: 100 mg PO qd
  • Comments: Take with or without food; coadministration with strong CYP3A inducers may decrease systemic exposure and lead to loss of therapeutic effect and possible HIV resistance
  • Adverse events: Immune reconstitution syndrome

Protease inhibitors (PIs)

Atazanavir (Reyataz):

  • Dosage forms: 100-mg, 150-mg, 200-mg, 300-mg capsules; 50-mg single packet oral powder
  • Adult dose: 400 mg PO qd or 300 mg + ritonavir 100 mg PO qd or cobicistat 150 mg PO qd
  • Comments: Take with food
  • Adverse events: Indirect hyperbilirubinemia, prolonged PR interval, hyperglycemia, skin rash (20%), hyperlipidemia

Darunavir (Prezista):

  • Dosage forms: 75-mg, 150-mg, 300-mg, 400-mg, 600-mg tablets
  • Adult dose: 800 mg qd + ritonavir 100 mg PO qd or cobicistat 150 mg PO qd (approved only for antiretroviral treatment–naïve patients or  treatment-experienced patients without darunavir-resistance mutations); 600 mg bid + ritonavir 100 mg PO bid (treatment-experienced patients)
  • Comments: Take with food
  • Adverse events: Rash, nausea, diarrhea, hyperlipidemia, hyperglycemia

Fosamprenavir (Lexiva):

  • Dosage forms: 700-mg tablet; 50-mg/mL oral suspension
  • Adult dose: 700 mg bid + ritonavir 100 mg PO bid or 1400 mg PO bid or 1400 mg + ritonavir 100-200 mg PO qd (approved only for antiretroviral treatment–naïve patients); 700 mg bid + ritonavir 100 mg PO bid (treatment-experienced patients)
  • Comments: Suspension, take without food; boosted with RTV, take with food
  • Adverse events: Rash, nausea, vomiting, diarrhea, hyperlipidemia, hyperglycemia

Indinavir (Crixivan):

  • Dosage forms: 100-mg, 200-mg, 400-mg capsules
  • Adult dose: 800 mg PO q8h (take 1 h ac or 2 h pc; may take with skim milk or low-fat meal); 800 mg PO bid + ritonavir 100-200 mg PO bid without regard for meals
  • Adverse events: Nephrolithiasis, nausea, indirect hyperbilirubinemia, hyperlipidemia, hyperglycemia

Lopinavir/ritonavir (Kaletra):

  • Dosage forms: 100-mg/25-mg, 200-mg/50-mg tablets; 80-mg/20-mg per mL oral solution
  • Adult dose: 400 mg/100 mg PO bid or 800 mg/200 mg PO qd (approved only for antiretroviral treatment–naïve patients or treatment-experienced patients without lopinavir-resistance mutations)
  • Comments: Tablet, take without regard to meals; oral solution: take with meals
  • Adverse events: Nausea, vomiting, diarrhea, asthenia, hyperlipidemia, hyperglycemia

Nelfinavir (Viracept):

  • Dosage forms: 250-mg, 625-mg tablets, 50 mg/g oral powder
  • Adult dose: 1250 mg PO bid or 750 mg PO tid
  • Comments: Nelfinavir cannot be boosted; take with food
  • Adverse events: Diarrhea, hyperlipidemia, hyperglycemia

Ritonavir (Norvir):

  • Dosage forms: 100-mg tablet; 100-mg soft gelatin capsule; 80-mg/mL oral solution
  • Adult dose: Boosting dose for other protease inhibitors, 100-400 mg/d (refer to other protease inhibitors for specific dose); nonboosting dose (ritonavir used as sole protease inhibitor), 600 mg bid (titrate dose over 14 days, beginning with 300 mg bid on days 1-2, 400 mg bid on days 3-5, and 500 mg bid on days 6-13)
  • Comments: Tablet, take with food; capsule or oral solution, food improves tolerability
  • Adverse events: Nausea, vomiting, diarrhea, asthenia, hyperlipidemia, oral paresthesias, hyperglycemia

Saquinavir (Invirase):

  • Dosage forms: 500-mg tablet; 200-mg hard gelatin capsule
  • Adult dose: 1000 mg + ritonavir 100 mg PO bid
  • Comments: Unboosted saquinavir is not recommended; take with food, or within 2 h pc
  • Adverse events: Nausea, diarrhea, headache, hyperlipidemia, hyperglycemia, PR and QT interval prolongation

Tipranavir (Aptivus) (approved only for antiretroviral treatment–experienced patients with drug resistance):

  • Dosage forms: 250-mg soft gelatin capsule; 100-mg/mL oral solution
  • Adult dose: 500 mg + ritonavir 200 mg PO bid without regard to meals
  • Comments: Unboosted tipranavir is not recommended
  • Adverse events: Hepatotoxicity, rash, hyperlipidemia, hyperglycemia, intracranial hemorrhage (rare cases reported)

Integrase inhibitors (INSTIs)

Raltegravir (Isentress, Isentress HD):

  • Dosage forms: 400-mg tablet, 600-mg tablet
  • Adult dose: Isentress, 400 mg PO bid; Isentress with rifampin,  800 mg PO bid; Isentress HD, 1200 mg PO once daily (for use in treatment-naïve or virologically suppressed on an initial regimen of 400 mg bid)
  • Comments: Take without regard to meals
  • Adverse events: Nausea, diarrhea, headache, CK elevations, myopathy/rhabdomyolysis (rare)

Dolutegravir (Tivicay):

  • Dosage forms: 50-mg tablet
  • Adult dose: 50 mg PO once daily; with UGT1A/CY3A inducers (e.g., efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, rifampin) or designated INSTI resistance mutations, 50 mg PO BID
  • Comments: Take without regard to meals
  • Adverse events: Cholesterol and TG elevations, CK elevations, liver enzyme elevations, hyperglycemia

Elvitegravir (Vitekta) (Note: Discontinued in the U.S. and Europe in 2016):

  • Dosage forms: 85-mg, 150-mg tablet
  • Adult dose: 85 mg PO once daily plus atazanavir or lopinavir plus ritonavir or 150 mg PO once daily plus darunavir or fosamprenavir or tipranavir plus ritonavir
  • Comments: Take with food
  • Adverse events: Immune reconstitution syndrome

Chemokine receptor antagonist (CCR5 antagonist)

Maraviroc (Selzentry):

  • Dosage forms: 150-mg, 300-mg tablets
  • Adult dose: 300 mg PO bid; 150 mg PO bid (CYP3A4 inhibitors ± inducers); 600 mg PO bid (CYP3A4 inducers)
  • Comments: Take without regard to meals
  • Adverse events: Constipation, dizziness, infection, rash, orthostatic hypotension

Fusion inhibitor (FI)

Enfuvirtide (Fuzeon) (approved only for antiretroviral treatment–experienced patients with drug resistance):

  • Dosage forms: 90-mg/mL powder for injection
  • Adult dose: 90 mg SC bid
  • Adverse events: Injection-site reactions (e.g., pain, erythema, induration, nodules)

Entry inhibitor

Ibalizumab (Trogarzo) (approved only for antiretroviral treatment–experienced patients with drug resistance):

  • Dosage forms: 150mg/mL(200mg/1.33mL single-dose vial)
  • Adult dose: First dose (single loading dose), 2000 mg IV infused over at least 30 min (begin maintenance doses 2 weeks after loading dose); maintenance doses, 800 mg IV q2Weeks infused over at least 15-30 min
  • Adverse events: Diarrhea, dizziness, nausea, and rash reported in 5-8% of patients; immune reconstitution syndrome reported in 1 patient

Complete Regimen Combination ARTs

ART Combination products approved as complete daily regimens, with brand name and generic names/dosages are as follows:

  • Stribild: Elvitegravir (150 mg) + cobicistat (150 mg) + emtricitabine (200 mg) + tenofovir DF (300 mg) qd
  • Genvoya: Elvitegravir (150 mg) + cobicistat (150 mg) + emtricitabine (200 mg) + tenofovir AF (10 mg) qd
  • Symtuza: Darunavir (800 mg) + cobicistat (150 mg) + emtricitabine (200 mg) + tenofovir AF (10 mg) qd
  • Odefsey: Rilpivirine (25 mg) + emtricitabine (200 mg) + tenofovir AF (25 mg) qd
  • Complera: Rilpivirine (25 mg) + emtricitabine (200 mg) + tenofovir DF (300 mg) qd
  • Biktarvy: Bictegravir (50 mg) + emtricitabine (200 mg) + tenofovir AF (25 mg) qd
  • Triumeq: Dolutegravir (50 mg) + abacavir (300 mg) + lamivudine (300 mg) qd
  • Juluca: Dolutegravir (50 mg) + rilpivirine (25 mg) qd (Note: this is a complete once-daily regimen in adults who are virologically suppressed [HIV-1 RNA < 50 copies/mL] on a stable ART regimen for ≥6 months with no history of treatment failure and no known substitutions associated with resistance.)
  • Atripla: Efavirenz (600 mg) + emtricitabine (200 mg) + tenofovir DF (300 mg) (Note: may be use alone as a complete regimen or in combination with other ARTs.)
  • Symfi: Efavirenz (600 mg) + lamivudine (300 mg) + tenofovir DF (300 mg) qd
  • Symfi Lo: Efavirenz (400 mg) + lamivudine (300 mg) + tenofovir DF (300 mg) qd
  • Delstrigo: Doravirine (100 mg) + lamivudine (300 mg) + tenofovir DF (300 mg) qd

Other Combination ARTs

Other ART combination products, with brand name and generic name/dosage, are as follows:

  • Descovy: Emtricitabine (200 mg) + tenofovir AF (25 mg) qd
  • Truvada: Emtricitabine (200 mg) + tenofovir DF (300 mg) qd
  • Epzicom: Abacavir (600 mg) + lamivudine (300 mg) qd
  • Cimduo: Lamivudine (300 mg) + tenofovir DF (300 mg) qd
  • Trizivir: Abacavir (300 mg) + lamivudine (150 mg) + zidovudine (300 mg) bid
  • Combivir: Zidovudine (300 mg) + lamivudine (150 mg) bid
  • Evotaz: Atazanavir (300 mg) + cobicistat (150 mg) qd
  • Prezcobix: Darunavir ethanolate (800 mg) + cobicistat (150 mg) qd

Nucleoside Reverse Transcriptase Inhibitors

The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) were the first agents available for the treatment of HIV Infection. Although less potent against HIV than non-nucleoside reverse transcriptase inhibitors (NNRTIs),  protease inhibitors (PIs), and integrase strand-transfer inhibitors (INSTIs), the NRTIs have had a central role in antiretroviral treatment and remain part of the current standard of care. [7, 8] They exhibit activity against HIV-1 and HIV-2. [9]

A total of 9 drugs make up the NRTI class; 8 are currently commercially available in the United States, as follows:

  • Abacavir (ABC, Ziagen)

  • Didanosine (ddI, Videx)

  • Emtricitabine (FTC, Emtriva)

  • Lamivudine (3TC, Epivir)

  • Stavudine (d4T, Zerit)

  • Tenofovir DF (TDF, Viread, part of the combination product Stribild and Complera)

  • Tenofovir AF (TAF, part of the combination product Genvoya, Odefsey, and Biktarvy)

  • Zalcitabine (ddC, Hivid; no longer available in the United States)

  • Zidovudine (ZDV, Retrovir; formerly azidothymidine [AZT])

Mechanism of action

NRTIs interrupt the HIV replication cycle via competitive inhibition of HIV reverse transcriptase and termination of the DNA chain. [10] Reverse transcriptase is an HIV-specific DNA polymerase that allows HIV RNA to be transcribed into single-strand and ultimately double-strand proviral DNA and incorporated into the host-cell genome. Proviral DNA chain elongation is necessary before genome incorporation can occur and is accomplished by the addition of purine and pyrimidine nucleosides to the 3’ end of the growing chain.

NRTIs are structurally similar to the DNA nucleoside bases and become incorporated into the proviral DNA chain, resulting in termination of proviral DNA formation. [11] Tenofovir, lamivudine, and emtricitabine exhibit activity against hepatitis B virus (HBV) in addition to HIV and are frequently incorporated into antiretroviral regimens for patients with HIV and HBV coinfection. [8]


Resistance to NRTIs occurs by one of two mechanisms: (1) impaired incorporation into the proviral DNA chain or (2) removal from the proviral DNA chain. [12] Mutations typically occur gradually, with accumulation of several mutations required before clinically significantly resistance develops. An exception is the M184V mutation, which confers high-level resistance to lamivudine and emtricitabine in a single step. Mutations that selectively impair incorporation into the proviral DNA chain include M184V, Q151M, and K65R.

Thymidine analog mutations (mutations associated with zidovudine resistance [M41L, D67N, K70R, L210W, T215Y, T215F, K219Q, K219E]) remove NRTIs from the DNA chain by fostering a conformational change in the reverse transcriptase domain that allows the addition of ATP or pyrophosphate to the end. This placement causes a break in the proviral DNA and NRTI bond, enabling continued elongation of the proviral DNA strand. [11, 12]


NRTIs are prodrugs and must undergo phosphorylation by intracellular kinases to exert their activity. Collectively, the oral bioavailability of NRTIs ranges from 25%-93%, with tenofovir and didanosine on the lower end of the spectrum. Food does not significantly affect absorption of any of the NRTIs except didanosine, which must be taken on an empty stomach to achieve optimal absorption and drug levels.

Although serum half-lives of NRTIs are relatively short, intracellular drug levels are the best indicator for drug activity and determine the dose administered for each NRTI. [13] Most NRTIs are renally eliminated and require dosage adjustments in patients with renal insufficiency; the exception is abacavir, which is given at the normal dose regardless of creatinine clearance.

NRTIs are not metabolized by the cytochrome P450 system; therefore, minimal drug-drug interactions occur. Interactions that have been found to be clinically significant involve didanosine. When given in combination with tenofovir, didanosine levels are higher than expected, and lower doses must be given to avoid potentially serious adverse effects. A similar scenario has been demonstrated when didanosine is combined with ribavirin in the treatment of patients with HIV and hepatitis C virus (HCV) coinfection. This combination should be avoided. [8]

Tenofovir alafenamide (AF) is a prodrug of tenofovir that has high antiviral efficacy similar at a dose less than one-tenth that of the original formulation of tenofovir prodrug (i.e., tenofovir disoproxil fumarate [DF]). Tenofovir AF provides lower blood levels but higher intracellular levels compared with tenofovir DF. [14, 15]  Tenofovir AF is a substrate for p-glycoprotein and can be given at a lower dose (10 mg) when coadministered with strong p-glycoprotein inhibitors (e.g., ritonavir, cobicistat). [16, 17]

Adverse events

Adverse effects of the NRTI class include mitochondrial toxicities (e.g., lactic acidosis, pancreatitis, peripheral neuropathy, hepatic steatosis, lipoatrophy). [8] Mitochondrial toxicities are due to NRTI binding to human mitochondrial DNA polymerase-γ enzyme, impairing cellular respiration. Under these conditions, normal aerobic metabolism shifts to an anaerobic process, resulting in the above manifestations.

Antiretroviral therapy reduces the risk of chronic kidney disease along with CD4 cell restoration and suppression of plasma viral load, despite an increased risk that is associated with initial treatment regimens that include tenofovir DF plus a ritonavir-boosted protease inhibitor. [18]

Binding affinity for mitochondrial DNA polymerase-γ by each NRTI is predictive of adverse-effect potential and varies as follows (in decreasing order of affinity): zalcitabine, didanosine, stavudine, lamivudine/emtricitabine, zidovudine, abacavir, and tenofovir. [19, 20]

Individual drug-specific adverse effects include bone marrow suppression, myopathy, and headache with zidovudine and a systemic hypersensitivity reaction with abacavir. [8] Abacavir and didanosine have been associated with an increased risk for adverse cardiovascular events. [21]

Initiation of ART is associated with increased bone turnover and bone loss from the spine and hip, with a number of subjects losing about 6% bone mass density within 1 year after starting treatment. [22] Adverse effects with the remaining NRTIs are outlined in greater detail in U.S. ART treatment guidelines. [8]

Although not recommended for patients with severe renal impairment, those with moderate renal impairment can take tenofovir AF. Tenofovir AF appears to be associated with less kidney toxicity and less decreases in bone density than previously approved tenofovir-containing regimens. [14, 23] Patients given elvitegravir/cobicistat/emtricitabine/tenofovir AF had significantly smaller mean serum creatinine increases than those given elvitegravir/cobicistat/emtricitabine/tenofovir DF (0.08 vs 0.12 mg/dL; P< 0.0001), significantly less proteinuria (median % change -3 vs 20; P< 0.0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; P< 0·0001) and hip (-.0·66 vs -2·95; P< 0.0001) at 48 weeks. [14]

In clinical trials, patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya) showed greater increases in serum lipids (total cholesterol and low-density lipoprotein) than those receiving other ART regimens, but the total cholesterol/high-density lipoprotein ratio was unchanged for both. [14]


Non-nucleoside Reverse Transcriptase Inhibitors

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) were introduced in 1996 with the approval of nevirapine. NNRTIs exhibit potent activity against HIV-1; efavirenz, in particular, confers the most significant inhibition of viral infectivity among the NNRTIs. [7]

First-generation NNRTIs include delavirdine (Rescriptor), efavirenz (Sustiva), and nevirapine (Viramune). Second-generation NNRTIs currently include etravirine (Intelence), approved for use in the United States in 2008, and rilpivirine (Edurant) [24] approved in 2011. In May 2017, it was announced that delavirdine has been discontinued in the U.S. with an estimated availability for the 100-mg tablets until October 2018 and for the 200-mg tablets until February 2020.

The highly specific NNRTI, doravirine, was approved by the FDA in 2018. Approval was based on the DRIVE-FORWARD clinical trial (n=766). Patients who were antiretroviral-naïve were randomly assigned to once-daily treatment with doravirine or darunavir 800 mg plus ritonavir 100 mg (DRV+r), each in combination with emtricitabine (FTC)/TDF or abacavir (ABC)/3TC. Treatment with doravirine led to sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferiority compared with DRV+r, each in combination with FTC/TDF or ABC/3TC. At week 48, 84% of the doravirine group and 80% of the DRV+r group had plasma HIV-1 RNA of less than 50 copies/mL. [25]

All NNRTIs exhibit the same mechanism of action. First-generation NNRTIs share similar resistance patterns, whereas etravirine and rilpivirine display a more unique resistance profile. [26] Their pharmacokinetic properties and adverse-effect profiles have important differences.

Mechanism of action

HIV reverse transcriptase is a heterodimer composed of 2 subunits (p66 and p51). [27] NNRTIs bind the p66 subunit at a hydrophobic pocket distant from the active site of the enzyme. This noncompetitive binding induces a conformational change in the enzyme that alters the active site and limits its activity. [27]

Etravirine differs from first-generation NNRTIs in its ability to bind at this site despite the presence of some mutations that limit the efficacy of first-generation agents. It is a highly flexible molecule that is able to rotate within the binding site to allow multiple binding conformations. [28]

All four NNRTIs exhibit activity against HIV-1 isolates. In vitro studies have shown that etravirine also has activity against HIV-2. [29]


Mutations within the reverse transcriptase gene domain alter the ability of the NNRTIs to bind the enzyme. First-generation NNRTIs have a low genetic barrier to resistance, whereby a single mutation in the binding site can decrease the ability of the drug to bind, significantly diminishing activity. [30] First-generation NNRTI resistance has been associated with mutations at multiple codons; however, the presence of either a K103N or Y181C mutation is sufficient to cause clinical failure of delavirdine, efavirenz, and nevirapine. [30]

Associated mutations include the following [30] :

  • Delavirdine - A98G, L100I, K101E, K103N, K103T, V179D, Y181C, Y188L, M230L, P236L, Y318F

  • Efavirenz - L100I, K101E, K103N, V108I, V179D, Y181C, Y188L, G190S, M230L

  • Nevirapine - A98G, L100I, K101E, K103N, V106A, V106I, V108I, Y181C, Y191I, Y188C, Y188H, G190A, P225H, M230L, P236L, Y318W

Etravirine has a higher genetic barrier to resistance than other currently available NNRTIs. A single mutation at 103 or 181 is insufficient to cause clinical failure of etravirine. [31] Clinical trials have identified 17 resistance mutations associated with decreased response to etravirine: V90I, A98G, L100I, K101E, K101H, K101P, V106I, E138A, V179D, V179F, V179T, Y181C, Y181I, Y181V, G190A, G190S, and M230L. [32]

A 2008 study found that different mutations affect viral susceptibility to etravirine to varying degrees. Each etravirine resistance-associated mutation was assigned a relative weight. The virologic response was found to be a function of the number and weight of resistance mutations. With a cumulative score of 0-2, a response rate of 74% was reported. With a score of 2.5-3.5 or 4 or more, response rates of 52% and 38%, respectively, were reported. [32]

The etravirine mutation weighting scheme is as follows [32] :

  • 3 - Y181I, Y181V

  • 2.5 - L100I, K101P, Y181C, M230L

  • 1.5 - V106I, E138A, V179F, G190S

  • 1 - V90I, A98G, K101E, K101H, V179D, V179T, G190A

Rilpivirine has a lower genetic barrier to resistance than etravirine.  While cross resistance with first-generation NNRTIs does not occur with the K103N mutation, decreased susceptibility to rilpivirine is predicted from in vitro and clinical studies with any of the following mutations: K101E/P, E138K/A/G/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C, M230I/L. [33]   Patients with baseline plasma HIV RNA greater than 100,000 copies/mL are also more likely to develop NRTI resistance mutations when used in combination with rilpivirine than with efavirenz. [34]


NNRTIs display considerable interindividual variability in their pharmacokinetic properties. All currently approved NNRTIs utilize the cytochrome P450 system for metabolism and exert varying induction and inhibition effects on specific isoenzymes (e.g., CYP3A4, CYP2C9). This results in a significant potential for drug-drug interactions (see Drug Interactions with Antiretroviral Therapy or DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents for additional information). [28, 35]

Delavirdine primarily uses the 3A4 isoenzyme for metabolism. Nevirapine is metabolized mainly by 3A4 with some secondary metabolism through 2B6. Efavirenz is primarily metabolized through 2B6 and secondarily through 3A4. Etravirine is a substrate of 3A4, 2C9, and 2C19. Rilpivirine is primarily metabolized by 3A4. [8]

With the exception of nevirapine, the NNRTIs are highly protein-bound (98-99%), primarily to albumin and alpha1 acid glycoprotein. The serum half-lives of the NNRTIs are fairly extended, ranging from 25-55 hours, except for delavirdine, which has a shorter half-life (2-11 h). [8, 28, 35]

Adverse events

Rash, which is the most common adverse effect associated with all NNRTIs, [8] usually develops within the first few weeks of therapy and resolves with continued treatment. [8, 28, 36] All NNRTIs except etravirine have the ability to cause some degree of hepatotoxicity. [28, 37] Delavirdine and efavirenz can increase transaminase levels, while nevirapine can cause severe toxicity, including hepatic necrosis in patients with CD4 counts that exceed 250 cells/µL. [8, 38]

Efavirenz causies CNS effects such as insomnia, vivid dreaming, dizziness, confusion, and hallucinations.  Rilpivirine is also associated with CNS effects such as insomnia, dizziness, vivid dreams, and headache but less commonly than efavirenz. [34]

Tolerance to efavirenz-related CNS adverse effects commonly occurs after several weeks of therapy. Bedtime administration and avoidance of food at the time of administration can minimize the intensity of adverse effects. CNS effects may persist in a small number of patients, requiring drug discontinuation. [8]

Gradual upward titration of efavirenz over 2 weeks can reduce neuropsychiatric symptoms and insomnia. In a randomized, double-blind, controlled trial of 114 patients, patients who received a full dose of 600 mg daily from day 1 had a higher incidence and severity of dizziness (66% vs 32.8%), hangover (45.8% vs 20.7%), impaired concentration (22.9% vs 8.9%), and hallucinations (6.1% vs 0%) during the first week, compared with patients who had gradual efavirenz titration to 600 mg daily by day 14. During week 2, the incidence of these aforementioned adverse events was similar in each group; however, severity was greater in the full-dose group. Virologic and immunologic efficacy was similar in both groups. [39]

A lower dose of efavirenz (400 mg) has also been evaluated as part of a fixed dose formulation with tenofovir DF and lamivudine and found to have comparable efficacy to efavirenz (600 mg)/tenofovir DF/emtricitabine after 96 weeks and fewer efavirenz-related adverse effects. [40]

Efavirenz use has been associated with an approximate two-fold higher risk for suicidality. This risk appears to be present with both early and chronic use. Increased risk for suicidality was observed in patients receiving psychoactive medications or with a psychiatric history, weighing less than 60 kg, and with injection drugs use. [41]


Protease Inhibitors

HIV protease inhibitors (PIs) were first introduced in 1995 and are an integral part of treatment of HIV infection. [8] A total of 8 compounds are approved for use, as follows:

Although all protease inhibitors exhibit the same mechanism of action, they have important differences in pharmacokinetics, efficacy, and adverse event profiles.

Mechanism of action

HIV protease is a 99-amino-acid, aspartic acid protein and is responsible for maturation of virus particles late in the viral life cycle. HIV protease systematically cleaves individual proteins from the gag and gag -pol polypeptide precursors into functional subunits for viral capsid formation during or shortly after viral budding from an infected cell.

HIV protease inhibitors function as competitive inhibitors that directly bind to HIV protease and prevent subsequent cleavage of polypeptides. [42] They exhibit activity against clinical isolates of both HIV-1 and HIV-2. [42]


Resistance to HIV protease inhibitors results from mutations both inside and outside the active protease domain. [43] Resistance typically occurs through the development of one or more major mutations, which produce conformational changes in the protease binding site, followed by secondary compensatory mutations that improve enzymatic activity and, in some cases, viral fitness. [43]

Resistance to first-generation protease inhibitors (indinavir, ritonavir, nelfinavir, saquinavir) occurs with the development of one or more of the following primary mutations [43] :

  • G48V, L90M (saquinavir)

  • M46I, V82A/L/F, I84V (indinavir)

  • V82A/L/F, I84V (ritonavir)

  • D30N, L90M (nelfinavir)

  • I50L, I84V, N88S (atazanavir)

  • I50V, I84V (fosamprenavir)

Multiple mutations are typically necessary to cause high-level resistance to boosted protease inhibitors (i.e., coadministered with cobicistat or low-dose ritonavir to decrease intestinal and hepatic 3A metabolism, thereby increasing protease inhibitor serum concentration levels), which exhibit a higher genetic threshold for resistance than unboosted protease inhibitors. [44] Cross-resistance to other protease inhibitors develops as the number of mutations increases.

The second-generation protease inhibitors lopinavir/ritonavir, darunavir, and tipranavir may retain activity in the presence of resistance to first-generation agents. Lopinavir/ritonavir requires the accumulation of 7 or more mutations before high-level resistance develops. [43] Darunavir and tipranavir typically retain activity against lopinavir/ritonavir and first-generation protease inhibitor–resistant strains. [43]

Eleven resistance mutations have been described for darunavir; accumulation of 3 or more is associated with virologic failure. Tipranavir also requires accumulation of multiple nonoverlapping mutations before high-level resistance develops. [43]

A review of 2725 HIV isolates for protease inhibitor susceptibility revealed that certain mutations could result in increased susceptibility to a particular drug, and that some effects on resistance had been underestimated. [45] The study concluded that cross-resistance between the various protease inhibitors now and in the future may be missed without systematic analysis of the effects of specific mutations.


Protease inhibitors exhibit substantial interpatient and intrapatient variability in pharmacokinetics. [46] Significant first-pass metabolism by CYP3A4 and 3A5 and intestinal efflux by p-glycoprotein is observed. [46] With the exception of indinavir, protease inhibitors are highly protein-bound (97-99%), primarily to albumin and alpha1 acid glycoprotein. [8] Distribution into the CNS is limited. Protease inhibitors have relatively short serum half-lives, ranging from 1.5-2 hours for indinavir and 7 hours for atazanavir. [8]

Reliance on metabolism through CYP3A4 results in significant potential for drug-drug interactions with other medications cleared through this pathway (see Drug Interactions with Antiretroviral Therapy or DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). Interactions with medications cleared through other CYP450 isoenzymes and phase II pathways (e.g., uridine glucuronosyltransferases [UGT]) are possible, depending on the individual protease inhibitor. [8]

Low-dose ritonavir (100-200 mg) is frequently coadministered with other protease inhibitors to block intestinal and hepatic 3A metabolism. The addition of low-dose ritonavir improves pharmacokinetic variability, resulting in more consistent serum concentrations throughout the dosing interval and improved treatment response. [46]  Cobicistat is a newer agent that also blocks CYP3A metabolism and is used to enhance the pharmacokinetic profile of protease inhibitors.

Adverse events

Common adverse events associated with protease inhibitors include gastrointestinal side effects (diarrhea, nausea, vomiting) and metabolic complications (dyslipidemia, insulin resistance, lipodystrophy).

Metabolic complications are common in patients receiving protease inhibitor therapy and represent an important consideration in selecting antiretroviral therapy. Dyslipidemia develops in up to 70% of patients receiving protease inhibitors and commonly requires institution of lipid-lowering therapy (i.e., statins, fibrates, omega3 fatty acids).

Drug interactions can preclude the use of some lipid-lowering agents (see Drug Interactions with Antiretroviral Therapy or DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). Lifestyle and genetic predisposition are important contributing factors to the type and severity of lipid abnormalities. [47]

In 1997, the FDA required that all protease inhibitors include labeling regarding the potential for hyperglycemia and diabetes mellitus with therapy; however, the different protease inhibitors have significantly different propensities for affecting glucose metabolism. Indinavir exhibits the greatest potential for altering glucose metabolism.

Modest effects have been observed with nelfinavir, lopinavir/ritonavir, fosamprenavir, and tipranavir. Atazanavir (boosted or unboosted), darunavir, and saquinavir appear to have limited effect on insulin sensitivity and glucose homeostasis. [48]

Altered fat distribution (fat redistribution) has been reported in 40-50% of patients receiving first-generation protease inhibitors in combination with nucleoside reverse transcriptase inhibitors (NRTIs). [49] Common manifestations include fat accumulation (lipohypertrophy; increased anterior cervical and dorsocervical fat, increased breast fat, centripetal obesity) or fat loss (lipoatrophy; sunken cheeks, wasted buttocks and extremities). Although both abnormalities may develop in the same patient, they are considered independent entities.

Fat accumulation has been primarily associated with protease inhibitor therapy; whereas, fat loss is more strongly attributed to concomitant treatment with thymidine analogue NRTIs (zidovudine, stavudine).  More recent data suggest that some second-generation protease inhibitors may be less likely to produce central fat accumulation. [50, 51, 52]

Numerous management strategies have been explored (e.g., metformin, recombinant human growth hormone, diet and exercise), with mixed results. Conversion from protease inhibitor–based therapy to a protease inhibitor–sparing regimen does not result in significant improvement and is not recommended. [53]

Adverse effects that occur with individual protease inhibitors need to be considered when selecting therapy for patients with other comorbidities.

Asymptomatic hyperbilirubinemia is common in patients who receive atazanavir and indinavir but does not require discontinuation of therapy in the absence of concomitant elevation in levels of liver transaminases. [8] Nephrolithiasis occurs with indinavir and, less commonly, atazanavir. [8]

Cardiac conduction abnormalities (atrioventricular block, bundle branch block) develop in 5% of patients receiving atazanavir and have been reported with other protease inhibitors (ritonavir, lopinavir/ritonavir, nelfinavir). [54]

Tipranavir may elevate levels of liver transaminases and should be avoided in patients with hepatitis B or hepatitis C coinfection. Intracranial bleeding events have been reported during tipranavir therapy. [8]


Integrase Strand-Transfer Inhibitors

The crystal structure of HIV integrase was first described in 1994 and led to the identification of novel inhibitors. [55] No homolog for HIV integrase exists in humans; therefore, identification of selective inhibitors is expected to result in a low frequency of adverse effects. [56, 57] The FDA approved raltegravir (Isentress) in 2007 as the first integrase strand-transfer inhibitor (INSTI) available for use. [58]

In 2017, a once daily dosage form of raltegravir (Isentress HD) was approved for adults and adolescents who weigh at least 40 kg. It is administered as a 1200 mg once-daily dose that is given as two 600-mg tablets in combination with other antiretroviral agents in patients who are either treatment-naïve or virologically suppressed on an initial regimen of raltegravir 400 mg BID. The ONCEMRK clinical trial found raltegravir 1200 mg once daily to be noninferior to 400 mg BID. [59]

Elvitegravir was initially approved in August 2012 as a component of the FDA-approved ‘quad’ pill, elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild). The 4-component tablet contains a complete once-daily regimen for treatment-naïve adults and includes the pharmacokinetic booster, cobicistat (a CYP3A4 inhibitor without antiviral activity), to augment the serum concentrations of elvitegravir. [60]

Approval of the ART fixed dose combination product was based on analyses of 48-week data from 2 randomized, double-blind, active-controlled trials in treatment-naïve, HIV-1 infected individuals (n=1408). Results showed a single tablet regimen of Stribild met its primary objective of noninferiority compared to (efavirenz/emtricitabine/tenofovir DF) fixed-dose combination (Atripla) and to a regimen containing ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF (Truvada). [61, 62]  

A newer fixed dose formulation as elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya) was approved by the FDA in November 2015 to improve the renal and bone safety profile of tenofovir.  Noninferiority was demonstrated in two phase III studies when compared with the elivitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild) formulation. [63]

Dolutegravir (Tivicay) was approved by the FDA in August 2013 for treatment of HIV-1 infection in combination with other antiretroviral agents in adults and children aged 12 years or older who weigh at least 40 kg.

A wide-ranging phase III trial program included 2 trials in treatment-naïve patients. The first trial included 822 HIV-infected, treatment-naïve patients randomized to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily) in combination with a fixed-dose dual-NRTI treatment. At week 48, virologic suppression was similar between the 2 groups; 88% for dolutegravir and 86% for raltegravir. [64]

The second trial also included treatment-naïve patients (n=833) and compared a once-daily dolutegravir regimen plus abacavir/lamivudine to once-daily efavirenz/emtricitabine/tenofovir DF (Atripla). A statistically significant improvement in virologic suppression was observed with dolutegravir (88%) compared with Atripla (81%). [65]

A third phase III trial studied 719 treatment-experienced patients who were failing on current therapy but had not previously been treated with an integrase inhibitor. Participants were randomized to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg. At week 24, 79% of patients on the regimen containing dolutegravir were virologically suppressed compared with 70% of patients on the regimen containing raltegravir. [66]

The VIKING-3 trial studied 183 treatment-experienced patients with resistance to multiple antiretroviral classes, including resistance to integrase inhibitors. Researchers evaluated the effectiveness of twice-daily dolutegravir on reducing viral loads in these patients and found the regimen improved virologic suppression at 24 weeks (63%). However, poor response was observed with INSTI-resistance involving Q148 plus 2 or more INSTI resistance substitutions. [67]

Approval of dolutegravir for the indication in children aged 12 years or older was based on data in integrase-naïve patients.

Bictegravir is an INSTI that was FDA approved as a once-daily, fixed dose combination tablet with emtricitabine/tenofovir AF in February 2018 (Biktarvy).  This combination is indicated for the treatment of antiretroviral-naïve patients or as a replacement for existing antiretroviral therapy in patients with viral suppression below 50 copies/mL for at least three months and no history of prior treatment failure or underlying resistance. 

FDA approval of bictegravir is based in part on two phase III, randomized, double-blind, non-inferiority studies comparing the fixed dose combination of bictegravir/emtricitabine/tenofovir AF with dolutegravir and lamivudine/abacavir either administered as separate components or as a coformulation in antiretroviral-naïve patients.  At 48 weeks, 89-92% and 93% of patients achieved viral suppression below 50 copies/mL in the bictegravir and dolutegravir treatment arms, respectively. [68, 69]

Two additional phase III, randomized studies examined switching patients with stable viral suppression below 50 copies/mL for at least three months from dolutegravir- or boosted protease inhibitor (atazanavir, darunavir)-based regimens to bictegravir/emtricitabine/tenofovir AF.  After 48 weeks, 92-94% in the bictegravir treatment arms maintained viral suppression compared with 95% and 89% in the dolutegravir and boosted protease inhibitor treatment arms, respectively, meeting the study definition for noninferiority. [70, 71]

Mechanism of action

HIV integrase is responsible for the transport and attachment of proviral DNA to host-cell chromosomes, allowing transcription of viral proteins and subsequent assembly of virus particles. [72] Proviral integration involves 2 catalytic reactions, as follows:

  • 3'-processing in the host-cell cytoplasm to prepare proviral strands for attachment

  • Strand transfer whereby proviral DNA is covalently linked to cellular DNA

These agents competitively inhibit the strand transfer reaction by binding metallic ions in the active site. [73, 74]


Resistance mutations in the integrase gene have been characterized for raltegravir and elvitegravir. [75, 76, 77] Two primary resistance pathways associated with raltegravir treatment failures in the BENCHMRK-1 and BENCHMRK-2 studies have been described, as follows [78] :

  • Q148K/R/H (25-fold decrease in susceptibility)

  • N155H (10-fold decrease in susceptibility)

The most common mutational sequence (Q148H/G140S) results in a greater than 100-fold decrease in susceptibility to raltegravir. [44] A third resistance pathway involving mutations at Y143C/H/R has also been described for raltegravir but is uncommon. [79] Secondary mutations (L74M/R, E92Q, T97A, E138A/K, G140S/A, V151I, G163R, H183P, Y226D/F/H, S230R, D232N) confer additional resistance. [79]

High-level resistance to elvitegravir is associated with mutations at E92Q in combination with E138K, Q148K/R/H, or N155H, leading to a 150-fold loss of susceptibility. Resistance patterns involving Q148H/G140S and Q148R/G140S demonstrate resistance to both elvitegravir and raltegravir, suggesting cross-resistance is likely. [80]

Dolutegravir exhibits a higher genetic barrier to resistance, attributed to its prolonged dissociation half-life from HIV-1 integrase-DNA complexes, and is considered a second-generation INSTI.  The presence of Q148R with two or more of the following INSTI mutations (L74I/M, E138K/A/D/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, G193E/R) is associated with a substantially lower response to dolutegravir. [81]   Treatment-emergent resistance is uncommon with dolutegravir but has been associated with the development of INSTI mutations at R236K, N155H, and S230R. [82]

Limited information presently exists regarding the resistance profile of bictegravir.  Similar to dolutegravir, bictegravir has an extended dissociation half-life from HIV-1 integrase-DNA complexes and exhibits a higher barrier to resistance than first-generation INSTIs (raltegravir, elvitegravir). [83]   In vitro, site-directed mutagenesis studies demonstrate that M50I, S153F, R236K, and M50I + R236K resulted in 1.3-, 1.9-, 2.2-, and 2.9-fold reductions in susceptibility to bictegravir. [84]


Raltegravir, dolutegravir, and bictegravir may be taken without regard for meals; whereas, elvitegravir should be taken with food to optimize its absorption.  All INSTIs are highly plasma protein bound (>98-99%) with the exception of raltegravir (83% bound to plasma proteins). [8]

Metabolism of raltegravir and dolutegravir occurs primarily through uridine diphosphate glucuronyl transferase 1A1 (UGT1A1). Bictegravir is metabolized equally through UGT1A1 and CYP3A4. Elvitegravir is primarily metabolized by CYP3A4 and secondarily through UGT1A1/UGT1A3. Elvitegravir is administered with cobicistat (150 mg) to reduce its first-pass metabolism and systemic clearance. [8, 84]

Dosage adjustment for INSTIs as individual components are not required in patients with renal or mild-to-moderate hepatic impairment; however, fixed dose combinations of INSTIs may not be recommended in some patients with renal insufficiency.  Use of dolutegravir/emtricitabine/abacavir (Triumeq) is not recommended in patients with creatinine clearances below 50 mL/min.  Initiation of elvitegravir in the fixed dose formulations elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild) and elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya) is not recommended in patients with creatinine clearances below 70 mL/min and 30 mL/min, respectively.  Bictegravir/emtricitabine/tenofovir AF (Biktarvy) is not recommended in patients with creatinine clearance below 30 mL/min. [8, 84]

Dolutegravir and bictegravir are inhibitors of organic cation transporter protein 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1). Dolutegravir also inhibits the breast cancer resistance protein (BCRP). Raltegravir and dolutegravir are substrates for p-glycoprotein. The pharmacokinetic booster, cobicistat, which is co-formulated with elvitegravir, is an inhibitor of p-glycoprotein, BCRP, MATE1, and organic anion transporters (OATP1B1, OATP1B35). [85, 84, 86, 87]

Raltegravir, dolutegravir, and bictegravir exhibit low potential to affect the metabolism of other drugs; however, other antiretroviral agents may alter the metabolism of these agents (see Drug Interactions with Antiretroviral Therapy or DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents).  Drug interactions between elvitegravir and other medications are more likely as a result of cobicistat coadministration.  Elvitegravir is also a modest inducer of CYP2C9, which may lead to drug-drug interactions with substrates (e.g., warfarin) of this isoenzyme. [88]

Antacids containing polyvalent cations and mineral supplements (e.g., iron) may decrease absorption of INSTIs by chelation reactions.  Raltegravir may be given with calcium carbonate antacids when administered twice daily (400 mg) but should not be coadministered when given once-daily (1200 mg) or with aluminum and magnesium hydroxide antacids. Elvitegravir- and bictegravir-containing regimens should be taken at least 2 hours before antacid administration.  Dolutegravir should be given at least 2 hours before or 6 hours after antacids with polyvalent cations.  When coadministration of mineral supplements is necessary, INSTIs should generally be given at least 2 hours before or 6 hours after the supplement.  Dolutegravir can be taken simultaneously with calcium and iron supplements if administered with food. No clinically significant decrease in INSTI absorption has been reported with gastric acid suppressants (proton pump inhibitors, H2 antagonists). [8]

Adverse events

As an antiretroviral class, INSTIs have a favorable safety and tolerability profile.  Common adverse effects include mild to moderate gastrointestinal effects (e.g., nausea, diarrhea) and headache. Drug-related insomnia may occur in up to 3.5% of patients receiving dolutegravir and 4% receiving raltegravir; hypersensitivity reactions, depression, and suicidal ideation may also occur in rare instances. [8, 85, 89]   

Elevations in creatine kinase levels (grade 2-4) were observed with raltegravir in phase III studies, along with rare cases of myopathy and rhabdomyolysis. [90, 85]  Raltegravir should be used with caution in patients receiving other medications that may increase the risk for myopathy and rhabdomyolysis. [85]

A relative risk of malignancy of 1.2 cases per 100 patient-years (95% CI, 0.4-4.1) has been reported in phase II and phase III clinical studies of raltegravir and requires continued surveillance. [90]  

Minor elevation in serum creatinine concentrations (0.1-0.2 mg/dL) is observed following initiation of dolutegravir, bictegravir, and elvitegravir regimens that contain cobicistat as a result of inhibition of renal transport proteins (OCT2, MATE1), leading to decreased clearance of creatinine by tubular secretion. [84, 87]


Fusion Inhibitors

Fusion inhibitors (FIs) were the first class of antiretroviral medications to target the HIV replication cycle extracellularly and received accelerated FDA approval in 2003. Their unique mechanism of action provides additional options for therapy in patients who are highly treatment resistant.

The use of fusion inhibitors has been limited, however, because of the production time and costs, limited coverage from insurance companies and HIV drug-assistance programs (HDAPs), inconvenient administration (subcutaneous injection), and adverse effect profile. The discovery of additional antiretroviral classes and medications with activity against highly resistant viral strains has further limited the utility of the fusion inhibitors. Currently, enfuvirtide (Fuzeon) is the only product marketed in this class.

Mechanism of action

Fusion inhibitors act extracellularly to prevent the fusion of HIV to the CD4 or other target cell. Enfuvirtide blocks the second step in the fusion pathway by binding to the HR1 region of glycoprotein 41 (gp41). This mechanism does not allow HR1 and HR2 to fold properly, thereby preventing the conformational change of gp41 required to complete the final step in the fusion process. [91, 92]


Resistance to enfuvirtide has been well described and occurs in the HR1 domain of gp41. Amino acid substitutions occur in the 36-45 regions and result in significant loss of enfuvirtide activity. [93]

The risk of resistance can be minimized by combining enfuvirtide with other antiretroviral agents that display genotypic or phenotypic activity, which is now more easily achieved with the availability of second-generation nonnucleoside reverse transcriptase inhibitors and protease inhibitors and new antiretroviral classes (e.g., integrase strand-transfer inhibitors and CCR5 inhibitors). [94, 95] Cross-resistance with other antiretroviral agents has not been demonstrated to date.


Enfuvirtide therapy requires twice-daily subcutaneous injection. It has not been shown to influence the metabolism of concomitant medications through the cytochrome P450 system.

Dose adjustments are not required in patients with renal insufficiency or mild-to-moderate hepatic insufficiency. Limited dosing data exist for patients with advanced liver disease; therefore, enfuvirtide should be used with caution in patients with hepatic decompensation. [8, 96]

Adverse events

Most patients receiving enfuvirtide experience injection-site reactions, increasing drug discontinuation rates. Manifestations include subcutaneous nodules, erythema, pruritus, pain, and ecchymoses. Other adverse effects that occur to a lesser extent include diarrhea, nausea, and fatigue. Hypersensitivity reactions have been described but are rare. Enfuvirtide has been associated with an increased risk for bacterial pneumonia, but causality has not been established. [94, 95]


Chemokine Receptor Antagonists

In August 2007, maraviroc (Selzentry) was approved by the FDA and was the first medication in a novel class of antiretroviral agents termed chemokine receptor 5 (CCR5) antagonists. It joins the fusion inhibitor, enfuvirtide, as another type of agent under the general antiretroviral treatment class of HIV-entry inhibitors.

Maraviroc is a selective chemokine receptor antagonist (CRA). It is imperative to test all patients for CCR5 tropism using a highly sensitive tropism assay before initiating the drug. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on maraviroc. It blocks viral entry via CCR5 co-receptor into host cells, reduces viral load, and increases T-cell counts in CCR5-tropic HIV-1 (i.e., R5 virus). This agent is indicated for combination treatment with optimized background therapy in treatment-experienced adults infected with only R5 virus who have evidence of viral replication and have HIV-1 strains resistant to multiple antiretroviral agents. It is approved for children as young as 2 years old.

Mechanism of action

The method by which HIV binds to CD4 cells and ultimately fuses with the host cell is a complex multistep process, which begins with binding of the gp120 HIV surface protein to the CD4 receptor. This binding induces a structural change that reveals the V3 loop of the protein. The V3 loop then binds with a chemokine coreceptor (principally either CCR5 or CXCR4), allowing gp41 to insert itself into the host cell and leading to fusion of the cell membranes.

Maraviroc is a small molecule that selectively and reversibly binds the CCR5 coreceptor, blocking the V3 loop interaction and inhibiting fusion of the cellular membranes. Maraviroc is active against HIV-1 CCR5 tropic viruses. It has no activity against CXCR4 tropic or dual/mixed tropic virus. [97]


Although experience with maraviroc is limited, treatment failure due to resistance has been observed. Resistance appears to occur via one of two mechanisms. The first mechanism is most likely through amino acid substitutions in the V3 loop of gp120. Although the specific mutations associated with resistance have not yet been described, they appear to allow HIV binding to the coreceptor despite the presence of maraviroc.

The second mechanism is not acquired resistance but rather the inability of phenotypic tropism assays to detect small quantities of CXCR4 virus that may be present, leading to overgrowth of CXCR4 virus in the presence of maraviroc and loss of viral control. The development of an enhanced tropism assay with higher sensitivity should minimize the frequency of this occurrence. [97, 98]

Genotypic assays can also be used to predict CCR5 and CXCR4 co-receptor tropism by sequencing the gp120 V3 loop. These assays have shown good-to-excellent concordance with phenotypic assays. [99, 100]


Maraviroc is approximately 75% protein-bound, primarily to albumin and alpha1 acid glycoprotein. Its terminal half-life is 15-30 hours. Maraviroc is metabolized through CYP3A4 and is a substrate for the efflux pump p-glycoprotein. Dosage adjustment is required when maraviroc is administered in combination with potent inhibitors or inducers of CYP3A4 (see Drug Interactions with Antiretroviral Therapy or DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). [97, 8]

Adverse events

Adverse events reported at a higher frequency than placebo in clinical studies include the following:

  • Cough

  • Pyrexia

  • Upper respiratory tract infections

  • Rash

  • Musculoskeletal symptoms

  • Abdominal pain

  • Dizziness

The rate of discontinuation due to adverse effects was similar to that found with placebo (4.9% and 5.3%, respectively). Postural hypotension is a dose-limiting effect that was discovered early in the development of maraviroc. In pooled analysis, postural hypotension occurred only in patients who received maraviroc at doses that exceeded 600 mg/day. The manufacturer warns that severe hepatotoxicity has been reported with maraviroc; caution should be used when maraviroc is administered to any patient predisposed to hepatic impairment. [97]


Post-attachment Inhibitors

The CD4-directed postattachment inhibitor, ibalizumab (Trogarzo), is the first medication approved for this class in March 2018. It is indicated HIV-1 infection in heavily treated adults with multidrug-resistant infection failing their current antiretroviral therapy regimen. It is used in combination with the patient’s current ART regimen.

Approval of ibalizumab was based on the MB-301 phase 3 trial. MB-301 was a single arm, 24-week study of ibalizumab plus optimized background regimen (OBR) in treatment-experienced patients infected with multidrug resistant HIV-1. The primary objective of the study was to demonstrate the antiviral activity of ibalizumab 7 days after the first dose of ibalizumab. Patients receiving their current failing ART, or no therapy, were monitored during a 7-day control period. Thereafter, a single loading dose of ibalizumab 2,000 mg IV was the only ART added to their regimen. The primary efficacy endpoint was the proportion of patients achieving a ≥0.5 log10 decrease in HIV-1 RNA 7 days after initiating ibalizumab therapy, day 14 of the study. Ibalizumab was continued at doses of 800 mg IV every 2 weeks through 24 weeks on study treatment. A total of 40 patients were enrolled in the study. After completion of treatment, patients were offered participation in the expanded access study (TMB-311). The expanded access study was also open for U.S. patients with limited options. [101]

The following study results were observed at 24 weeks: [101]

  • 43% of study participants achieved viral suppression < 50 copies/mm 3 and half < 200 copies/mm 3
  • While 60% of those with a baseline CD4 count of ≥ 50 cells/mm 3 achieved undetectable viral load, this fell to < 20% for those with lower CD4 counts
  • 55% of participants had at least a 1 log decrease and 48% had at least a 2 log decrease in HIV RNA; the average reduction from baseline was 1.6 log
  • The overall average CD4 cell gain was 48 cells/mm 3, but this differed according to baseline level: people who started with at least 50 cells/mm 3 saw a mean gain of about 75 cells/mm 3, while those with lower baseline levels gained an average of 9 cells/mm 3

Mechanism of action

Ibalizumab is a humanized monoclonal antibody (mAb) that binds to extracellular domain 2 of the CD4 receptor. The ibalizumab binding epitope is located at the interface between domains 1 and 2, opposite from the binding site for major histocompatibility complex class II molecules and gp120 attachment. Ibalizumab does not inhibit HIV gp120 attachment to CD4; however, its postbinding conformational effects block the gp120-CD4 complex from interacting with CCR5 or CXCR4 and thus prevents viral entry and fusion. [102]


Reduced ibalizumab susceptibility is associated with mutations that disrupt potential N-linked glycosolation sites (PNGS) in variable region 5 (V5) of HIV-1 envelope glycoproteins. Loss of glycan on the V5 N-terminus of gp120 is considered a major determinant of ibalizumab resistance. [102]


Ibalizumab maintenance therapy requires every 2 week IV infusions. The elimination half-life is approximately 3 days. It has not been shown to have any interactions. Dose modifications of ibalizumab are not required when administered with any other ARTs or any other drugs. [102, 103]

Adverse events

Diarrhea, dizziness, nausea, and rash reported in 5-8% of patients. Immune reconstitution syndrome reported in 1 patient. [103]


Pharmacokinetic Enhancers (Boosting Agents)

Cobicistat (Tybost) is a CYP3A inhibitor. As a single agent, it is indicated to increase systemic exposure of atazanavir or darunavir (once-daily dosing regimen) in combination with other antiretroviral agents. It is more commonly used in co-formulations with these protease inhibitors (darunavir/cobicistat [Prezcobix], atazanavir/cobicistat [Evotaz]) or as a component of several elvitegravir-containing fixed dose combinations (elvitegravir/cobicistat/emtricitabine/tenofovir DF [Stribild], elvitegravir/cobicistat/emtricitabine/tenofovir AF [Genvoya]).

Cobicistat may be used for treatment-naïve or experienced patients (without darunavir resistance-associated substitutions). The dosage is 150 mg PO once daily when used with atazanavir (300 mg PO once daily), darunavir (800 mg PO once daily) or elvitegravir (150 mg PO once daily).

Ritonavir is also a potent CYP3A4 inhibitor that is in many combination productions and included in many HIV treatment regimens to augment systemic exposure to other antiretroviral agents.


DHHS Treatment Guidelines

Goals of therapy

The U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents (DHHS ART Guidelines) issues recommendations for the administration of antiretroviral therapy. [8] Guidelines are based on results of clinical studies and expert opinion and are updated on an ongoing basis.

Separate guidelines address antiretroviral treatment for pregnant women, children, and individuals with potential occupational (e.g., health care industry) and nonoccupational (e.g., high-risk sexual encounters) exposure to HIV. Guidelines for antiretroviral treatment initiation in adults are also available from the International AIDS Society, the World Health Organization (WHO) and European AIDS Clinical Society. [104, 105, 106]

The discussion of antiretroviral treatment strategies in this article focuses on recommendations from the DHHS Panel.

The DHHS ART Guidelines present the following 4 overarching goals:

  • Reduce HIV infection–related morbidity and prolong duration and quality of life

  • Restore and preserve immunologic function

  • Maximally and durably suppress viral load (plasma HIV RNA)

  • Prevent HIV transmission

Suppression of viremia also has the potential to reduce cardiovascular, renal, and hepatic events thought to be related to ongoing inflammation and immune activation from uncontrolled viremia. The risk for both AIDS-related and non–AIDS-associated malignancy may also be reduced by improved immunity. [8]

Treatment-naive patients

Indications for initiating antiretroviral therapy

The DHHS ART Guidelines recommend that therapy should be initiated in all persons living with HIV irrespective of CD4 count and viral load to decrease the risk for HIV disease progression, non-HIV-related morbidity and mortality, and to prevent transmission of HIV infection.  The decision to begin antiretroviral therapy, as well as the selection of the individual antiretroviral components, should be tailored to each patient, taking into account patient-specific variables and preferences.  The patient’s readiness and commitment to lifelong therapy should similarly be evaluated. Data from the START and TEMPRANO randomized trials have shown compelling evidence regarding the benefit of initiating ART at higher CD4-cell counts (>500 cells/mL), rather than deferring treatment until CD4-cell counts decline. [107, 108] Findings from these studies showed a lower rate of death or severe HIV-related illness (e.g., tuberculosis, Kaposi sarcoma, malignant lymphomas) in those who were treated early with ART compared to those that deferred treatment until a lower CD4 cell count was observed.

Therapy options

Currently, 27 antiretroviral agents in 6 antiretroviral classes, including one monoclonal antibody and a myriad of fixed dose combination products, are approved for use in the U.S.. These agents vary in their antiviral potency and administration requirements. It is currently recommended that antiretroviral therapy be initiated with a combination of 3 active antiretrovirals.  The initial combination is generally composed of 2 NRTIs with an NNRTI, PI, or INSTI. [8]

In an attempt to simplify the selection of an initial regimen for treatment-naive patients, the DHHS ART Guidelines have broken down treatment options into 2 main categories:  i) regimens recommended for most people with HIV and ii) other regimens recommended in certain clinical situations.  All of the recommended regimens for most people include 2 NRTIs in combination with an INSTI. All of these recommended regimens have an evidence rating of AI (i.e., strong recommendation with data from randomized controlled trials). These recommendations are based on efficacy and safety of these combinations, as well as other factors, including ease of administration. [8]

Regimens for ART-naïve patients:

Table 1. Recommended Regimens for Most ART-Naive Patients (Open Table in a new window)

Integrase Component

Nucleoside Backbone


Tenofovir + Emtricitabine a,b





Abacavird + Lamivudine

a – lamivudine may be substituted for emtricitabine or vice versa

b – tenofovir component can be either tenofovir disoproxil fumarate (DF) or tenofovir alafenamide (AF) (both agents have an AI or AII rating)

c – raltegravir can be dosed 400 mg twice daily or 1200 mg once daily (utilizing the 600 mg formulation)

d – only for patients who are HLA-B*5701 negative


Table 2. Recommended Regimens for Certain Clinical Situations (Open Table in a new window)

Protease Inhibitor

Nucleoside Backbone

Darunavir/Ritonavir or Darunavir/Cobicistat


Atazanavir/Ritonavir or Atazanavir/Cobicistat

Tenofovir + Emtricitabinea,b


Abacavirc + Emtricitabinea

Non-Nucleoside Reverse Transcriptase Inhibitor





Tenofovir + Emtricitabinea,b

Integrase Strand-Transfer Inhibitore



Abacavirc + Emtricitabinea

a – lamivudine (3TC) may be substituted for emtricitabine (FTC) or vice versa

b – tenofovir component can be either tenofovir disoproxil fumarate (DF) or tenofovir alafenamide (AF) (both agent have an AI or AII rating)

c – only for patients who are HLA-B*5701 negative

d – only if HIV RNA < 100,000 copies/mL and CD4 >200 cells/mm3

e – only if HIV RNA < 100,000 copies/mL and HLA-B*5701 negative

f - raltegravir can be dosed 400 mg twice daily or 1200 mg once daily (utilizing the 600 mg formulation)


Fixed dose combinations available for use in recommended regimens:

Cimduo - tenofovir disoproxil fumarate (DF)/lamivudine — only for patients with pretreatment estimated CrCl ≥50 mL/min

Descovy - tenofovir alafenamide fumarate (AF)/emtricitabine — only for patients with pretreatment estimated CrCl ≥30 mL/min

Epzicom - abacavir/lamivudine — only for patients with pretreatment estimated CrCl ≥50 mL/min

Truvada - tenofovir DF/emtricitabine — only for patients with pretreatment estimated CrCl ≥30 mL/min

Prezcobix - darunavir/cobicistat

Evotaz - atazanavir/cobicistat

Atripla - efavirenz/tenofovir DF/emtricitabine — only for patients with pretreatment estimated CrCl ≥50 mL/min

Biktarvy - bictegravir/tenofovir AF/emtricitabine — only for patients with pretreatment estimated CrCl ≥30 mL/min

Complera - rilpivirine/tenofovir DF/emtricitabine — only for patients with pretreatment estimated CrCl ≥50 mL/min

Genvoya - elvitegravir/cobicistat/tenofovir AF/emtricitabine — only for patients with pretreatment estimated CrCl ≥30 mL/min

Odefsey - rilpivirine/tenofovir AF/emtricitabine — only for patients with pretreatment estimated CrCl ≥30 mL/min

Stribild - elvitegravir/cobicistat/tenofovir DF/emtricitabine — only for patients with pretreatment estimated CrCl ≥70 mL/min

Symfi - efavirenz/tenofovir DF/lamivudine — only for patients with pretreatment estimated CrCl ≥50 mL/min

Symfi-Lo - efavirenz (low dose)/tenofovir DF/lamivudine — only for patients with pretreatment estimated CrCl ≥50 mL/min

Triumeq - dolutegravir/abacavir/lamivudine — only for patients with pretreatment estimated CrCl ≥50 mL/min



Preexisting antiretroviral resistance can be detected in 6-16% of treatment-naive individuals. [8] Based on this possibility, DHHS guidelines recommend that resistance testing be performed in all patients with HIV infection at the onset of care.

Genotypes are generally the test of choice, as de novo resistance to NRTIs or NNRTIs is most commonly observed. Genotypes are also less costly and exhibit a shorter turnaround time. If the interval between entering care and beginning antiretroviral therapy is significant, it is generally recommended that the patient undergo testing with another genotype prior to therapy initiation to assess any resistance acquired in the interim. [8]

Therapy selection

The antiretroviral regimen selected should be based on patient-specific factors and preferences. Factors to consider include associated comorbidities, the adverse-effect profiles of the medications being considered, the potential for pregnancy, adherence barriers, regimen convenience, and potential drug-food and drug-drug interactions. Resistance testing findings should also be considered in the initial regimen selection.

Certain agents require consideration of other factors (e.g., HLA-B*5701 testing for abacavir hypersensitivity, pretreatment CD4 count for nevirapine, pretreatment viral load for rilpivirine) before their use. [8]

Treatment endpoints

Virologic suppression is the goal for all patients on antiretroviral therapy. Suppression is defined as an HIV-1 RNA level below the lower limit of detection of available assays. Different assays may have different lower limits of detection, generally ranging between 20 copies/mL and 75 copies/mL. For most patients, virologic suppression should be achieved 8 to 24 weeks after starting therapy. This may be prolonged in patients with very high baseline viral loads. The time to suppression may also vary based on the antiretroviral regimen selected. Historically, an interim measure of antiretroviral efficacy was a one log10 decline in HIV RNA by 2-8 weeks. If either of these endpoints is not met, the patient should be evaluated to determine whether nonadherence, drug intolerance, or resistance is a factor. Alteration of therapy may be necessary based on the specific circumstances. [8]

Treatment-experienced patients

Definition of virologic failure

Virologic failure, as defined in the DHHS ART Guidelines, is the failure to suppress and/or sustain a viral load < 200 copies/mL. [8] Although some controversy remains, a viral load of >200 copies/mL is used to define virologic failure based on data that supports ongoing viral evolution and resistance development at these levels.

There are conflicting data regarding patients with low-level viremia (viral loads between the lower limit of detection and 200 copies/mL). The risk of resistance developing at these lower viral loads is thought to be minimal; therefore, current guidelines recommend that these patients continue current therapy and be monitored every 3 months to assess the need for alteration.

In contrast, patients with persistent viral loads ≥200 copies/mL should be tested for resistance.  The ability of assays to detect resistance is greater with increasing viral load and may be difficult with viral loads between 200 and 500 copies/mL.  Below 500 copies/mL, changing antiretroviral therapy empirically should be done only on a case by case basis.

Table 3. Contributing Factors to Development of Virologic Failure [8] (Open Table in a new window)



Antiretroviral Regimen-Related

Comorbidities contributing to adherence

Presence of drug-resistance mutations (transmitted or acquired)

Pharmacokinetic properties

Social and psychosocial aspects

History of treatment failure

Virologic potency

Appointment attendance

Innate viral resistance (tropism/HIV-2)

Barrier to resistance

Consistent access to ART

HIV RNA level

Previous antiretroviral exposure


Administration requirements

Regimen burden

Drug-drug interactions

Prescription errors

Therapy selection

Antiretroviral activity and durability improves with the addition of fully active agents in a regimen.  Ideally, regimens should include at least 2 or, optimally, 3 fully active agents. The selection of individual agents should be based on the antiretroviral treatment history, genotypic and/or phenotypic resistance results, drug-drug interaction potential, and medication intolerance, with the goal of maximizing antiviral activity and adherence.

Divergence from the strategy of using 2 NRTIs with either an INSTI, NNRTI or a PI is typically necessary as the extent of drug resistance increases. It is not uncommon to include 4 to 6 antiretrovirals in a regimen for a patient with extensive drug resistance in order to increase the degree of activity. [8]

The introduction of new antiretroviral agents has broadened the number of active agents available for treatment of patients with infection due to resistant HIV and has improved the success rate of therapy. Limited information exists regarding optimal combinations of agents for treatment, as selection is often based on resistance testing results, prior treatment history, and intolerance. [8]

Enfuvirtide is highly effective in the treatment of antiretroviral therapy–experienced patients but requires subcutaneous injection twice daily and is associated with injection-site reactions.

Darunavir and tipranavir typically retain activity in the presence of multiple protease inhibitor mutations. However, the use of tipranavir has been hindered by the potential for interaction with other antiretroviral agents, hepatotoxicity, and reports of intracranial bleeding events.

Etravirine is considered a second-generation NNRTI and is most effective when combined with other active agents but may cause drug-drug interactions with other antiretroviral agents.

Dolutegravir and bictegravir can possibly be used in the setting of raltegravir and elvitegravir resistance, though administration may need to be increased to twice daily.

The role of maraviroc in patients with extensive drug resistance has been limited because of the high frequency of dual/mixed-tropic or CXCR4-tropic virus in patients with more longstanding HIV infection and the necessity for expensive tropism assay pretesting.

Goals of therapy

The goals of therapy in treatment-experienced patients are the same as in treatment-naive patients. [8] With the introduction of newer agents, suppression of viremia to below the limit of assay detection is now achievable in many patients who harbor drug-resistant viral strains.

Genotypic or phenotypic resistance testing should be used to assist with selection of appropriate therapy and should be obtained while patients remain on their previous therapy or within 4 weeks of discontinuation to improve the sensitivity of results. Phenotypic testing is generally added to genotypic testing when complex drug resistance mutation patterns, especially to protease inhibitors, are confirmed or suspected. [8]

Poor CD4 response and persistent inflammation despite viral suppression

Previous versions of the DHHS guidelines have included immunologic failure and disease progression as types of treatment failure. The failure to achieve or maintain CD4 cell recovery despite virologic suppression was considered immunologic failure; however, no standard definition of target values ever existed. The current guidelines address this as poor CD4 cell response and/or persistent inflammation despite viral suppression.

CD4 cell recovery generally continues for years in the setting of virologic suppression, with most patients achieving CD4 cell counts >500 cells/mm3. [8] There are some patients, however, that plateau at an unexpectedly low CD4 count and others that even experience a decline in count despite continuous viral suppression. Patient’s starting ART at very low baseline CD4 levels (< 200 cells/mm3) are more likely to experience a suboptimal CD4 recovery. [8] Early diagnosis and initiation of therapy is the best way to support maximal CD4 recovery.

Patients who experience suboptimal CD4 recovery or those with a declining CD4 count should be investigated to see if there are any underlying causes or contributing factors such as medications, co-infections, or malignancy. [8] Many times, no cause can be identified. Currently there are no recommended interventions to assist in CD4 recovery. Changing antiretroviral classes or adding additional agents to a suppressive regimen has shown no consistent benefit in increasing CD4 counts and is not recommended. Immune-based therapies (interleukin-2, growth hormone, interleukin-7) have been and continue to be investigated, but to date, none can be recommended. [8]

More recently, research has begun to focus on the heightened immune activation and inflammation produced secondary to HIV infection. This appears to be a factor related to morbidity and mortality independent of viral suppression and CD4 count. [8] Research is ongoing into the origin and contributing factors of this immune activation and inflammation and therapies to decrease it. At this time, routine monitoring of immune/inflammatory markers as well as any therapies to decrease ongoing activation cannot be recommended. [8]

Regimen switching in the setting of virologic suppression

With increased knowledge of resistance development and improvements in tolerability and potency of antiretroviral agents, altering therapy in patients with virologic suppression has become a more common practice. Some primary reasons for regimen change include [8] :

  • simplification to decrease pill burden or frequency of administration
  • tolerability/adverse effect profile
  • avoidance of drug-drug interaction
  • elimination of dosing requirements (food/fluid, timing)
  • pregnancy or future pregnancy planning
  • regimen cost

The over-arching goal when switching therapy is to maintain virologic suppression without endangering future options through resistance development. When considering therapy changes, a thorough patient history should be completed reviewing the patient’s previous antiretroviral exposure including response to therapy, tolerance, and previous resistance development. As previous resistance mutations may not show up on current testing, it is important to note all previous resistance testing and results. [8]

In general, switches can be made within antiretroviral classes or among classes. For most patients, maintaining a 3-drug regimen is advised; though in some select cases, patients may be maintained on a 2-drug regimen. [8] Currently, only dolutegravir plus rilpivirine or a boosted-PI plus emtricitabine or lamivudine combination are recommended for dual therapy regimens. Monotherapy regimens are not recommended for any patient at this time. Monitoring should be increased following an ART switch to assure tolerance and maintenance of viral suppression. The guidelines recommend patient contact within 1-2 weeks of switch to evaluate regimen adherence and tolerance, and laboratory monitoring 4-8 weeks following the switch for viral suppression and other lab concerns. [8]

Special populations


As mentioned earlier, the Department of Health and Human Services has a panel on treatment of pregnant women with HIV infection that also publishes treatment guidelines. [109]   Antiretroviral therapy is recommended in all pregnant women with HIV infection regardless of viral load or CD4 count. Independent of viral load, antiretroviral therapy has been shown to decrease the likelihood of mother-to-child transmission. The goal of therapy is to achieve maximal virologic suppression to minimize the transmission risk. It is recommended that all women initiating therapy for the first time or those receiving therapy who have a detectable viral load undergo genotypic resistance testing to guide therapy selection. [109]

Consistent with the adult treatment guidelines, antiretroviral therapy should consist of 3 active agents, with selection guided by resistance testing.  For treatment-naive patients, the current guidelines recommend 2 preferred NRTIs in combination with either a preferred PI or INSTI. [109]  

Preferred agents include the following [109] :

  • NRTI - Abacavir/lamivudine or tenofovir DF/emtricitabine or lamivudine

  • PI - Atazanavir/ritonavir or darunavir/ritonavir

  • INSTI - Raltegravir

Select other agents are recommended as alternative agents based on administration issues and/or adverse effect profile.  Zidovudine combined with lamivudine is the alternative NRTI backbone but is associated with more hematologic toxicity. Lopinavir/ritonavir is an alternative PI agent with established safety but exhibits higher gastrointestinal intolerance. Efavirenz and rilpivirine are alternative NNRTI options that can be considered. [109] Historically, efavirenz was not recommended in pregnancy due to birth defects seen in primate studies. These effects, however, have not been seen in human studies. A meta-analysis of 23 studies including 2000 live births and a French study of 13,124 live births found no increase in birth defects following first trimester efavirenz exposure. [110, 111]

There are currently insufficient data to recommend the use of tenofovir alafenamide in pregnancy. In addition, elvitegravir/cobicistat/emtricitabine/tenofovir DF should be avoided in pregnancy secondary to concerns of inadequate concentrations of both elvitegravir and cobicistat in the 2nd and 3rd trimester. [109]  In late May 2018, the DHHS guidelines added a warning regarding dolutegravir use in the first trimester of pregnancy secondary to data from a surveillance study in Botswana. [112] The National Institutes of Health-funded study reported neural tube defects in four infants born to 426 women who were on dolutegravir-based therapy at the time of conception.  The study is ongoing, and more data are expected, but based on this early report, it is recommended to avoid dolutegravir in women of child-bearing age who either desire to be pregnant or have a high potential for pregnancy. For women who are found to be pregnant and on dolutegravir, there appears to be no benefit to discontinuation after the first 8 weeks of pregnancy. [112, 113]

Nevirapine is no longer recommended for use in pregnancy due to potential for adverse events, such as hypersensitivity reactions, as well as complex initial dosing and low barrier to resistance. Based on toxicity, stavudine and didanosine are also not recommended. [109]   PI-based HAART is associated with increased preterm delivery (21.4% versus 11.8% with NRTI therapy) but not with increased infant hospitalizations or mortality [114]

The method of delivery and the use of intravenous zidovudine during delivery is based on the viral load at time of delivery. [109]  Women with viral loads >1000 copies/ml have increased risk of intrapartum transmission. Based on this, scheduled cesarean delivery at 38 weeks is recommended. In addition, intravenous zidovudine should be administered during labor. [109] The benefit of IV zidovudine in women with viral loads between 50 copies/ml and 999 copies/ml is not well known, and IV zidovudine could be considered. It is not recommended for women with viral loads < 50 copies/ml. [109] Regardless of all factors, the neonate should receive zidovudine for at least 4 weeks following deliver. Those infants with higher risk of perinatal transmission could also receive 2 or 3 drug therapy. [109]

More detailed information regarding treatment of pregnant women with HIV infection can be found in the guidelines referenced above. [109]  Providers are encouraged to report all cases of perinatal antiretroviral exposure to the Antiretroviral Pregnancy Registry.

Postexposure prophylaxis

Postexposure prophylaxis (PEP) has been demonstrated to reduce the risk of HIV infection when administered soon after exposure. Guidelines are available for occupational and nonoccupational exposures. [115, 116] Treatment recommendations are similar, however, due to an effort to reduce confusion and increase adherence by providing better tolerated antiretroviral regimens. In both situations, patients taking PEP should be counseled on the importance of adherence for the duration of treatment. 

If the source patient’s identify is known and able to be interviewed, providers should attempt to elicit current antiretroviral treatment, most recent HIV viral load, and history of resistance to avoid using potentially ineffective agents as part of the PEP regimen. However, soliciting this information should not delay the initiation of PEP; the regimen can be altered at a later time if needed.

Postexposure prophylaxis following occupational HIV exposure

PEP is recommended after a healthcare provider is exposed infectious materials from a source person who has or has reasonable suspicion of having HIV infection based on the definitions below:

  • Healthcare provider - all paid and unpaid persons working in healthcare settings
  • Exposure - percutaneous injury or contact of mucous membranes or nonintact skin without barrier protection
  • Infectious materials - blood, tissue, semen, vaginal secretions, cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, amniotic fluid, or visibly bloody body fluids

Treatment should be initiated as soon as possible (within hours) after an exposure has occurred. Efficacy of PEP initiated 72 hours after exposure has not been well described but can still be considered, even a week after exposure, in patients at high risk for transmission.

The preferred regimen is tenofovir DF/emtricitabine fixed dose combination (300/200 mg po daily) with raltegravir (400 mg po BID) for 28 days. Alternative options are available in the U.S. Public Health guidelines for occupational HIV exposure. [115]

Postexposure prophylaxis following nonoccupational HIV exposures

Nonoccupational exposure to HIV includes any exposure to potentially infectious bodily fluids and tissues not secondary to job duties. These exposures include but are not limited to sexual contact and the sharing of injection-drug equipment.

Data from animal studies, perinatal transmission studies, experience with occupational post-exposure prophylaxis, and observational studies support the premise that initiation of a brief course of antiretroviral therapy after nonoccupational exposure may decrease the likelihood of HIV transmission. [116]

It is recommended that patients who present 72 hours or sooner after a substantial-risk HIV exposure involving an HIV-infected source be offered postexposure prophylaxis consisting of 3 antiretroviral agents. The risk is based on the type of exposure. If the HIV status of the source is unknown, each case should be determined individually based on risk. [116]

Substantial risk criteria include the following:

  • Site of exposure - Vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact

  • Infectious material - Blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood

  • Source status - Known HIV infection in the source

Negligible risk criteria include the following:

  • Site of exposure - Vagina, rectum, eye, mouth, or other mucous membrane, intact or nonintact skin, or percutaneous contact

  • Infectious material - Urine, nasal secretions, saliva, sweat, or tears if not visibly contaminated with blood

  • Source status - Regardless of the known or suspected HIV status of the source

Postexposure prophylaxis is not recommended in patients who present more than 72 hours after exposure or who have exposures deemed to represent a negligible risk. If antiretroviral therapy is initiated, it should be continued for 28 days. [116]

The preferred regimens are as follows:

Table 4. Preferred Antiretroviral Agents for Nonoccupational Exposures  (Open Table in a new window)


NRTI backbone

3rd agent

Adults and adolescents > 13 years of age with estimated creatinine clearance > 60 mL/min

Tenofovir DF/emtricitabine fixed dose combination 300/200 mg po daily

Raltegravir 400 mg po BID


Dolutegravir 50 mg po daily

Pregnant women, women of childbearing age

Tenofovir DF/emtricitabine fixed dose combination 300/200 mg po daily

Raltegravir 400 mg po BID

Adults and adolescents > 13 years of age with estimated creatinine clearance < 60 mL/min

Zidovudine/lamivudine po BID; dose adjusted based on renal function

Raltegravir 400 mg po BID


Dolutegravir 50 mg po daily

Two additional considerations should be made for those requiring post-exposure prophylaxis. First, abacavir should never be used for PEP due to the necessity of HLA-B5701 testing used to detect hypersensitivity risk prior to administration. Second, as noted previously, recent data have identified a possible link between neural tube defects and dolutegravir use during conception through the first trimester of pregnancy. The use of dolutegravir should be avoided in women who are early in their pregnancy or not pregnant but at childbearing age. [115, 116]


Adolescents with HIV infection represent a heterogenous patient population. This population includes newly infected patients and long-term survivors who were infected perinatally or through blood products. Though adolescents were not included in the START or TEMPRANO studies, based on the findings from these studies, early ART is recommended in adolescents with HIV infection as well. [107, 108]  Regardless of the timing and mode of transmission (newly infected or perinatally acquired), utilizing the sexual maturity rating (SMR), also known as Tanner stage, is generally recommended when antiretroviral therapy is being considered. [8]  Adult treatment guidelines are usually appropriate in postpubertal adolescents (SMR IV or V), and pediatric guidelines are generally more appropriate for less sexually mature adolescents (SMR < III). [8] Close monitoring for efficacy and toxicity is imperative, regardless of the dosing schedule used to implement therapy. 

Studies have found high rates of transmitted drug resistance in younger patient populations infected through sexual transmission. [8] As such, baseline resistance testing in this patient population is imperative.

Adolescents often have a myriad of difficult psychosocial issues that affect their ability to adhere to antiretrovirals and other treatment recommendations. Employing a team based approach with extensive case management and potentially mental health providers may assist in achieving treatment goals. [8]

Patients with acute HIV infection

Limited data are available to define the role of treatment in patients with acute HIV infection. Though studies suggest potential immunologic and virologic benefits, initiating treatment during acute infection remain theoretical. Treating acute infection may decrease the severity of acute disease, lower the level of chronic viremia following symptom resolution, decrease viral mutation, preserve immune function, and reduce transmission. [8]

Based on these potential benefits, it is recommended that all patients with HIV-1 infection, including those with early or acute infection, be treated with antiretroviral therapy. [8]   Combination therapy should be initiated similar to that administered in patients with chronic infection. Though resistance testing is recommended, therapy may be initiated prior to resistance results being available. With this in mind, protease inhibitor–based regimens should be considered first-line owing to the lower incidence of resistance to these agents in treatment-naïve patients. [8] Boosted-darunavir based therapy in combination with an NRTI backbone (tenofovir DF or tenofovir AF with emtricitabine or lamivudine) is generally the regimen of choice. Based on this rationale, providers could also consider dolutegravir- or bictegravir-based therapy in combination with the same NRTI backbone though data are limited on transmitted integrase resistance and efficacy in early HIV infection. [8]


A significant amount of morbidity and mortality in persons with HIV infection results from coinfection with Mycobacterium tuberculosis (MTB), hepatitis B virus (HBV), or hepatitis C virus (HCV). Each of these infections is more difficult to manage in patients with HIV infection because of the accelerated rate of disease progression, drug-drug interactions, and additive toxicities that result from concomitant therapies.

The antiretroviral treatment sequencing strategy for each type of coinfection is challenging and must be tailored to individual patient-specific needs to provide the best possible outcome and to restore quality of life.


The overall rate of morbidity and mortality associated with MTB coinfection in patients with HIV infection is significant. Worldwide, an estimated 374,000 HIV positive people died from MTB infection in 2016; however, this statistic is difficult to fully elucidate due to the frequent classification of HIV as the cause of death regardless of other, possibly more contributory, comorbidities. [117]

Significant overlap exists in the patient populations who are exposed to MTB and are at risk for HIV infection. Disease progression rates of each are accelerated with coinfection and require swift and aggressive management strategies. Screening for MTB infection is recommended at HIV diagnosis in an attempt to capture the infection as quickly as possible to reduce morbidity and mortality. [118]

Current recommendations suggest that treatment for M tuberculosis infection and HIV infection be initiated separately because of additive adverse effects, overlapping toxicities, and risk for poor adherence with two multi-drug regimens. The ideal timeframe is dependent on the patient’s CD4 count. Treatment for MTB should be initiated first, followed by ART within 2 weeks for those with a CD4 count below 50 cells/mm3 and within 8 weeks for those with higher CD4 counts. Patients already on antiretroviral treatment should be initiated on MTB treatment immediately following an assessment of potential drug interactions and antiretroviral adjustments as needed. [118]  

Treatment selection for latent or active MTB infection is generally straightforward; however, significant drug-drug interactions are possible with antiretroviral medications when a rifamycin is included in the treatment plan because of their strong inductive effects on the cytochrome P450 system. [119]  Due to the potency of the rifamycins against MTB, however, this class should not be substituted. Rifabutin is usually selected over rifampin because of its less-potent metabolic induction when antiretroviral therapy is required, but dose adjustments are necessary when protease inhibitors and NNRTIs are administered concomitantly. [118]

For treatment-naïve patients (antiretroviral therapy initiation within the MTB infection treatment period), the preferred treatment is a 2 NRTI backbone with standard-dose efavirenz. This recommendation is based on the relatively extensive literature describing the low rates of adverse effects and pharmacokinetic stability leading to positive clinical outcomes. [118]

One alternative to the efavirenz component of the antiretroviral regimen is raltegravir at a standard (400 mg PO BID) or increased dose (800 mg PO BID). It should be noted that multi-class antiretroviral resistance has been noted with the concomitant use of raltegravir 800mg po BID (as part of triple-drug therapy for HIV) and the rifampin component of MTB treatment. [120] Raltegravir should be used cautiously and with close monitoring of HIV viral load.

Another alternative is ritonavir-boosted protease inhibitors. Rifabutin is preferred over rifampin when a PI is used; however, PIs can increase the concentration of rifabutin. Therefore, the dose of rifabutin should be reduced from 300 to 150 mg po daily or given as 300 mg three times per week during PI coadministration. [8]

Specific considerations by ARV class, applicable to treatment-naïve and treatment-experienced patients are listed below. [8]

  • NRTIs: Tenfofovir AF is contraindicated with rifamycins.
  • NNRTIs: Etravirine, rilpivirine, and nevirapine are contraindicated with rifampin.  Dose adjustments necessary when efavirenz and rilpivirine are used with rifabutin. Etravirine should not be used with a boosted PI and rifabutin.
  • PIs: Contraindicated with rifampin; use reduced-dose rifabutin instead.
  • INSTIs: When using rifampin, increase raltegravir to 800 mg BID and use cautiously. Increase dolutegravir to 50 mg BID. Elvitegravir/cobicistat and once daily raltegravir are contraindicated. Rifabutin may be safely used with standard doses of raltegravir and dolutegravir but is contraindicated with elvitegravir/cobicistat. The use of bictegravir with either rifampin or rifabutin is contraindicated. [84]
  • CCR5 antagonist: Dose adjustment required when maraviroc is used with rifampin. No change necessary when used with rifabutin.

Hepatitis B virus infection

Approximately 10% of individuals infected with HIV have HBV coinfection. [121] Treatment for each disease can be challenging because of accelerated disease progression and lower treatment response rates for HBV infection and increased rates of hepatotoxicity with antiretroviral therapy. Patients with HIV and HBV coinfection often have higher HBV DNA, lower HBeAg seroconversion rates, and an increased risk of liver-related mortality. [122, 123, 124, 125]

Additionally, acute hepatic flares due to antiretroviral therapy are more likely in the presence of HBV owing to the compromised state of the liver and immune reconstitution reactions that can occur with treatment initiation at low CD4 counts. [123] Nonetheless, overlapping therapies exist and are integrated into a treatment regimen that is optimal for both HIV infection and HBV infection.

The goals of therapy for HIV and HBV coinfection reflect those of HIV and HBV monoinfection. However, unlike those with HBV mono-infection, patients infected with both HIV and HBV should have treatment initiated for both infections as soon as possible rather than waiting for worsened clinical outcomes. Treatment should continue indefinitely. [118]

Most often, a combination of 3 antiretrovirals, including 2 with anti-HBV activity, is recommended in patients with HIV and HBV coinfection when treatment is indicated for either disease in order to prevent the development of antiretroviral drug resistance. Both HIV and HBV can acquire resistance to NRTIs, so therapy must be tailored to retain virologic control. [118]

An antiretroviral regimen for a patient infected with HIV and HBV should consist of tenofovir (either alafenamide or disoproxil fumarate) along with either emtricitabine or lamivudine; emtricitabine is coformulated with tenofovir in several fixed dose combination tablets, so this combination is used frequently. The decision to use tenofovir AF versus tenofovir DF should be based on renal function and potential risks of bone mineral density changes as tenofovir AF has proven non-inferior in HBV mono-infected patients. [126, 127]  Further, coinfected patients were able to maintain HBV and HIV suppression after switching from tenofovir DF-based antiretroviral regimens to tenofovir AF/emtricitabine/elvitegravir/cobicistat. [128]  Should a situation arise in which a patient cannot take either tenofovir AF or DF, entecavir may be initiated but should not be counted as one of the 3 antiretrovirals necessary to treat HIV. Neither lamivudine nor emtricitabine should be used as HBV monotherapy due to the potential for rapidly-developing resistance. [118]

If either virus acquires resistance, additional medications should be added to the current regimen rather than substituted in order to maintain virologic control of the remaining drug-susceptible virus. Due to limited data available on the use of either adefovir or telbivudine in coinfected patients, along with increased risk of toxicities, neither is not currently recommended in this population. [118]

Hepatitis C virus infection

Approximately 25% of persons with HIV infection are coinfected with HCV. [129]  HCV infection in the presence of HIV infection progresses to cirrhosis or end-stage liver disease twice as quickly as in HCV monoinfection. [130]  Although HIV disease progression has not been directly linked to HCV coinfection, it is significantly influenced by the lower rise in CD4 counts once antiretroviral therapy is initiated and the increased risk for hepatotoxicity with antiretroviral therapy. Historically, treatment outcomes, as measured by sustained virologic response 12 weeks after treatment completion (SVR12), were significantly lower in patients with HCV and HIV coinfection. [131, 132] However, with the approval and use of direct-acting antivirals, providers can expect similar SVR12 rates as those with HCV mono-infection. [133]

Because of its faster disease progression, HIV treatment is a greater priority than treatment for HCV; therefore, HIV suppression and antiretroviral regimen stability is achieved first. However, select patients may be unable to tolerate antiretrovirals and experience hepatic toxicity. In these cases, HCV is treated and then antiretrovirals can be initiated successfully.

Depending on the HCV genotype, presence of cirrhosis, and previous antiviral treatment, several highly effective regimens are available to treat HCV. Combination therapy is always used to target at least 2 of the 3 current drug targets: the NS5A, NS5B, and NS3/4A sites. In certain situations, ribavirin is still used; however, pegylated interferon has been phased out as a treatment option.

Drug interactions are now the greatest obstacle in treating HIV/HCV co-infected patients. In terms of safety outcomes, tenofovir DF used with ledipasvir or velpatasvir can lead to an increase in serum creatinine, particularly when combined with a pharmacokinetic booster. [134] The use of tenofovir DF should be avoided in these situations when the patient’s baseline estimated CrCL is under 60 mL/min; increased monitoring is sufficient when used in those with a CrCL > 60 mL/min. [133] Alternatively, tenofovir AF can be used without concern and can provide an easy switch option in these patients. The combination of protease inhibitors used to treat HIV (e.g., boosted darunavir and atazanavir) and NS3/4A protease inhibitors used to treat HCV (e.g. grazoprevir, pibrentasvir) can lead to increased risk of hepatic toxicity and should be avoided. Although ribavirin is generally avoided when possible due to increased toxicities and pill burden, situations arise which necessitate its use. Coadministration of zidovudine should be avoided due to increased hematologic toxicity risk. [133]

From an efficacy standpoint, the inductive effects of efavirenz and etravirine significantly reduce concentrations of elbasvir/grazoprevir, glecaprevir/pibrentasvir, and velpatasvir/sofosbuvir; therefore, these combinations should be avoided. [133] Numerous non-antiretroviral interactions are possible and must be considered when creating an HCV treatment plan as well.

In some situations, a patient may be unable to switch an antiretroviral regimen that has significant potential interactions with the recommended HCV treatment regimens. In such cases, daclatasvir combined with sofosbuvir is the preferred treatment. [133] Ribavirin may be added on, depending on the HCV genotype and presence of cirrhosis. Daclatasvir is a CYP3A4 substrate and will require dose adjustments when used with moderate 3A4 inducers (e.g., efavirenz, etravirine) and strong 3A4 inhibitors (e.g., atazanavir boosted with either ritonavir or cobicistat or elvitegravir boosted with cobicistat). Boosted darunavir and unboosted atazanavir are safe to use with standard dose daclatasvir. [135]

The duration of HCV treatment has decreased substantially with the updated direct-acting antivirals and ranges from 8 weeks to 12 weeks for the preferred regimens (elbasvir/grazoprevir, glecaprevir/pibrentasvir, ledipasvir/sofosbuvir, and velpatasvir/sofosbuvir) depending on the presence of cirrhosis. Mono-infected, non-black patients with a baseline HCVRNA under 6 million IU/mL qualify for an 8 week treatment duration; however, this regimen has not been studied in coinfected patients and, therefore, the treatment duration should remain 12 weeks. [133]

A final and significant consideration in HCV treatment is the potential for reactivation of HBV infection. A boxed warning was issued by the FDA in 2016 after reports of patients experiencing HBV reactivation leading to a liver transplant in one patient and death in two others. [136] No specific genotype, direct-acting antiviral, or patient characteristic has been identified as a risk factor for this complication. All patients should be tested for HBV prior to HCV treatment initiation and vaccinated when needed. Patients infected with HBV and HIV should already be on treatment for both infections; this should be continued throughout the duration of HCV treatment. [133]

Pre-exposure prophylaxis

Pre-exposure prophylaxis (PrEP) consisting of daily, oral tenofovir DF 300 mg and emtricitabine 200 mg is recommended for all adults and adolescents (≥35 kg) with substantial risk for acquiring HIV. [137]  This is not dependent upon transmission risk factor and is recommended for men who have sex with men (MSM), heterosexual men and women, and people who use intravenous drugs (PWID). [137] In the U.S., the FDA approved agent for PrEP is Truvada®, a fixed dose combination tablet of tenofovir DF 300 mg/emtricitabine 200 mg. [137]

Studies across these patient populations have shown a significant decrease in rates of new HIV infection with the use of PrEP therapy. The first published trial, a multinational study called the Pre-exposure Prophylaxis Initiative (iPrEx) trial, found that once-daily tenofovir DF/emtricitabine reduced the risk of acquiring HIV by 44% in a study population of high-risk, HIV-negative men or transgender women who have sex with men. [138]   The Partners PrEP trial, examining HIV transmission rates among discordant heterosexual couples in Uganda and Kenya, showed a combined efficacy rate of 75%. [139]  Among PWID, 2,413 people were included in the Bangkok Tenofovir Study. The study utilized only tenofovir DF therapy and was conducted at drug treatment clinics as part of a more comprehensive risk-reduction program. Tenofovir DF use was associated with a 48.9% reduction in HIV acquisition. [140]  Most recently, the Adolescent Medicine Trials Network for HIV/AIDS study 113 looked at safety and efficacy in a small patient population of 15 to 17 year olds. The study found that when used correctly, tenofovir DF/emtricitabine was effective at reducing HIV infection without significant increases in toxicity. The study also reported decreasing adherence over time, suggesting adolescents may need more intervention and monitoring while on PrEP therapy. [141]

Adherence is essential in efficacy. In studies, the level of protection varied widely depending on how consistently participants used PrEP. [137] In fact, some studies with very poor adherence showed no reduction in incidence with the use of tenofovir DF or tenofovir DF/emtricitabine. [142, 143]  Among those whose data indicate use on 90% or more days (based on self-reports, bottles dispensed, and pill counts), HIV risk was reduced by 73%. Among those whose adherence by the same measure was less than 90%, HIV risk was reduced by only 21%. [137] Comprehensive prevention services are also required (i.e., monthly HIV testing, condom provision, counseling, and management of other sexually transmitted infections).

Guidelines recommend limiting PrEP to a 90-day supply to allow for optimal follow-up and monitoring. At each visit, patients should be tested for HIV infection and monitored for signs and symptoms of acute infection. In addition, adverse effects, adherence, and risk-reduction behaviors should be discussed. Creatinine clearance monitoring and repeat sexually-transmitted infection testing should occur at least every 6 months but may be done every 3 months if warranted. [137]

HIV-discordant couples

A HIV serodiscordant couple is generally defined as two people in an ongoing sexual relationship where one person is living with HIV and the second person is not. In 2011, a Cochrane Database of Systematic Reviews analysis of 7 observational studies found that ART is very potent for the prevention of HIV in couples in which only one partner is infected with the virus. Results show that in serodiscordant couples, uninfected partners of infected individuals being treated with antiretroviral drugs have a 5-fold lower risk of contracting HIV compared to uninfected partners of infected individuals not receiving treatment. [144]

A multicontinent, randomized, controlled trial by the HIV Prevention Trials Network (HPTN 052) in 2011 evaluated early versus delayed antiretroviral therapy for HIV-infected patients with CD4 counts between 350 and 550/µL who were in stable sexual relationships with noninfected partners. Findings show that early initiation of antiretroviral therapy reduced transmission rates of the disease by 96%. Early therapy was also associated with a 41% reduction in the number of HIV-related clinical events. [145]

The PARTNER Study group looked at 888 serodiscordant couples (heterosexual and MSM) who reported condomless sex. Results reported no documented cases of within-couple HIV transmission if the HIV-positive partner was on suppressive ART. [146]  This finding was supported when  HPTN 052 follow-up data reported that among this cohort, partner linked infections (through phylogenetic and statistical methods) were not observed when virologic suppression was achieved with ART. [147]

Given these most recent data, the CDC released a Dear Colleague letter in September 2017 that stated “people who take ART daily as prescribed and achieve and maintain an undetectable viral load have effectively no risk of sexually transmitting the virus to an HIV-negative partner.” [148]