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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Alejandro Lemor, M.D. [2]

Overview

The primary goal of antiretroviral therapy (ART) is to reduce HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication, as defined by achieving and maintaining plasma HIV RNA (viral load) below levels detectable by commercially available assays. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Based on emerging evidence, additional benefits of ART include a reduction in HIV-associated inflammation and its associated complications.

Medical Therapy

Anti-HIV medications (also called antiretrovirals) are grouped into six drug classes according to their mechanism of action. The six classes are as follows:

  1. Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
  2. Nucleoside reverse transcriptase inhibitors (NRTIs).
  3. Protease inhibitors (PIs).
  4. Fusion inhibitors.
  5. CCR5 antagonists.
  6. Integrase inhibitors.

Multidrug regimen has proved to be very beneficial because of reduction in progression to AIDS, opportunistic infections, rate of hospitalizations and deaths. [1]

Goals of Therapy

  • Durable suppression of HIV viral load ( to <50 cells/mL ).
  • Restoration of normal CD4 cell count.
  • Prevention of transmission of the disease.
  • Prevention of building of drug resistance.
  • Improvement in quality of life of the patient.

Uncontrolled viremia causes inflammation and immune activation, which has an overall effect on cardiovascular, renal and hepatic systems. Controlling viremia also controls these effects.

Anti Retroviral Therapy (ART)

  • Current optimal HAART options consist of drug combinations consisting of at least three drugs belonging to at least two classes of antiretroviral agents.
  • Typical regimens consist of:
  • In treatment-naive patients, four drug regimen is not found to be more efficacious than three-drug regimens and is associated with more adverse events.[2][3]

Anti Retroviral Regimens

WHO Recommendations in Adults

▸ Click on the following categories to expand treatment regimens.

ARV Regimens

  ▸  First-Line Regimens

  ▸  Second-Line Regimens

First-line Regimen
Preferred Regimen
Emtricitabine (FTC)
OR
Lamivudine (3TC)
PLUS
Tenofovir (TDF)
PLUS
Efavirenz (EFV)
Alternative Regimen 1
(If preferred regimen is contraindicated or not available)
Zidovudine (AZT)
PLUS
Lamivudine (3TC)
PLUS
Efavirenz (EFV)
OR
Nevirapine (NVP)
Alternative Regimen 2
(If preferred regimen is contraindicated or not available)
Tenofovir (TDF)
PLUS
Emtricitabine (FTC)
OR
Lamivudine (3TC)
PLUS
Nevirapine (NVP)
Adapted from WHO 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection [4]
Second-line Regimen
If TDF + 3TC based regimen failed
Zidovudine (ZDV)
PLUS
Lamivudine (3TC)
PLUS
Ritonavir-boosted Atazanavir (ATV/r)
OR
Ritonavir-boosted Lopinavir (LPV/r)
If ZDV + 3TC based regimen failed
Tenofovir (TDF)
PLUS
Lamivudine (3TC)
PLUS
Ritonavir-boosted Atazanavir (ATV/r)
OR
Ritonavir-boosted Lopinavir (LPV/r)

National Institute of Health (NIH) Recommendations

▸ Click on the following categories to expand treatment regimens.

Recommended Regimens

  ▸  NNRTI-Based Regimen

  ▸  PI-Based Regimen

  ▸  INSTI-Based Regimen

Alternative Regimens

  ▸  PI-Based Regimen

  ▸  INSTI-Based Regimen

Recommended Regimen
NNRTI-Based Regimen
Efavirenz/Tenofovir/Emtricitabine
NNRTI-based regimen for patients with < 100,000 copies/mL
Efavirenz
PLUS
Abacavir/Lamivudine (only for HLA-B*5701 negative patients)
OR
Rilpivirine/Tenofovir/Emtricitabine (only for patients with CD4 < 200 cells/mm³)
Emtricitabine may be substituted for lamivudine or vice versa
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [5]
Recommended Regimen
PI-Based Regimen
Atazanavir/Ritonavir(low dose)
PLUS
Tenofovir/Emtricitabine
OR
Darunavir/Ritonavir(low dose)
PLUS
Tenofovir/Emtricitabine
PI-based regimen for patients with < 100,000 copies/mL
OR
Atazanavir/Ritonavir(low dose)
PLUS
Abacavir/Lamivudine (only for HLA-B*5701 negative patients)
Emtricitabine may be substituted for lamivudine or vice versa
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [5]
Recommended Regimen
INSTI-Based Regimen
Dolutegravir
PLUS
Abacavir/Lamivudine (only for HLA-B*5701 negative patients)
OR
Dolutegravir
PLUS
Tenofovir/Emtricitabine
OR
Elvitegravir/Cobicistat/Tenofovir/Emtricitabine(contraindicated in patients with CrCl <70mL/min)
OR
Raltegravir
PLUS
Tenofovir/Emtricitabine
Emtricitabine may be substituted for lamivudine or vice versa
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.[5]
Alternative Regimen
PI-Based Regimens
Darunavir/Ritonavir(low dose)
PLUS
Abacavir/Lamivudine (only for HLA-B*5701 negative patients)
OR
Lopinavir/Ritonavir(low dose)
PLUS
Abacavir/Lamivudine (only for HLA-B*5701 negative patients)
OR
Lopinavir/Ritonavir(low dose)
PLUS
Tenofovir/Emtricitabine
Emtricitabine may be substituted for lamivudine or vice versa
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [5]
Alternative Regimen
INSTI-Based Regimens
Raltegravir
PLUS
Abacavir/Lamivudine (only for HLA-B*5701 negative patients)
Emtricitabine may be substituted for lamivudine or vice versa
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [5]

Anti Retroviral Drug Classes

Drug Name Dose Adverse Events
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
300 mg BID or 600 mg once daily Fever, rash, nausea, vomiting, diarrhea, abdominal pain, malaise, fatigue, sore throat, cough, shortness of breath.
400 mg once daily
In combination with TDF: 200 mg once daily
Pancreatitis, nausea, vomiting, peripheral neuropathy, retinal changes, optic neuritis, lactic acidosis with hepatic steatosis.
200 mg once daily Hyperpigmentation, skin discoloration
250-300 mg BID Macrocytic anemia, neutropenia, nausea, vomiting, headache, insomnia, asthenia, nail pigmentation, lactic acidosis, severe hepatomegaly with hepatic steatosis (rare), hyperlipidemia, insulin resistance/diabetes mellitus, lipoatrophy, myopathy.
150 mg BID or 300 mg once daily Minimal toxicity, severe acute exacerbation of hepatitis may occur in HBV coinfected patients who discontinue 3TC.
>60 kg: 40 mg BID
<60 kg: 250 mg BID
Peripheral neuropathy, lipoatrophy, pancreatitis, lactic acidosis, severe hepatomegaly with hepatic steatosis (rare), hyperlipidemia, insulin resistance/diabetes mellitus, rapidly progressive ascending neuromuscular weakness (rare).
300 mg once daily Renal insufficiency, Fanconi syndrome, osteomalacia, decrease in bone mineral density, severe acute exacerbation of hepatitis may occur in HBV coinfected patients who discontinue TDF, asthenia, headache, diarrhea, nausea, vomiting, and flatulence.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
600 mg once daily Rash, increased transaminase levels, hyperlipidemia, dizziness, somnolence, insomnia, depression, suicidality, confusion, abnormal thinking, impaired concentration, amnesia, agitation, depersonalization, hallucinations, and euphoria
200 mg BID Rash, Stevens-Johnson syndrome, nausea
200 mg once daily for 14 days, then 200 mg BID or 400 mg once daily Rash, Stevens-Johnson syndrome, nausea, hepatitis
25 mg once daily Rash, depression, insomnia, headache, hepatotoxicity
Protease Inhibitors (PIs)
400 mg once daily
In combination with TDF: 300 mg + RTV 100 mg once daily
In combination with EFV: 400 mg + RTV 100 mg once daily
Indirect hyperbilirubinemia, PR interval prolongation, hyperglycemia, fat maldistribution, cholelithiasis, nephrolithiasis, renal insufficiency, increase in transaminase levels, hyperlipidemia, skin rash
800 mg once daily Skin rash, Stevens-Johnson syndrome, hepatotoxicity, diarrhea, nausea, headache, hyperlipidemia, fat maldistribution, hyperglycemia.
1400 mg BID or
700 mg + RTV 100 mg BID
In combination with EFV: 700 mg + RTV 100 mg BID or 1400 mg + RTV 300 mg once daily
Skin rash, diarrhea, nausea, vomiting, headache, hyperlipidemia, hyperglycemia, increase in transaminase levels, nephrolithiasis, fat maldistribution.
800 mg q8h Nephrolithiasis, nausea, hepatitis, indirect hyperbilirubinemia, hyperlipidemia, headache, asthenia, blurred vision, dizziness, rash, metallic taste, thrombocytopenia, alopecia, hemolytic anemia, hyperglycemia, fat maldistribution.
400 mg/100 mg BID or 800 mg/200 mg once daily Diarrhea, nausea, vomiting, pancreatitis, asthenia, hyperlipidemia, hyperglycemia, fat maldistribution, increase in transaminase levels, PR interval prolongation, insulin resistance/diabetes mellitus.
1250 md BID or 750 mg TID Diarrhea, hyperlipidemia, hyperglycemia, fat maldistribution, increase in transaminase levels.
100-400 mg/d q12-24h Diarrhea, nausea, vomiting, paresthesia, hyperlipidemia, hepatitis, asthenia, taste perversion, hyperglycemia, fat maldistribution.
1000 mg BID Diarrhea, nausea, vomiting, headache, hyperlipidemia, hyperglycemia, fat maldistribution, PR interval prolongation, insulin resistance/diabetes mellitus.
500 mg BID Hepatotoxicity, skin rash, hyperlipidemia, hyperglycemia, fat maldistribution.
Integrase Inhibitors
50 mg q12-24h Rash, insomnia, headache.
150 mg once daily Nausea, diarrhea, decrease bone density, severe acute exacerbation of hepatitis may occur in HBV coinfected patients.
400 mg BID Rash, Steven-Johnson syndrome, toxic epidermal necrolysis, nausea, headache, diarrhea, pyrexia, CPK elevation.
Fusion Inhibitor
90 mg SQ BID Local injection reactions, increased incidence of bacterial pneumonia, rash, fever, nausea.
CCR5 Antagonist
150-600 mg BID Abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper respiratory tract infections, hepatotoxicity.
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [5]
CDC Grading of Recommendations and Levels of Evidence
Strength of recommendation Level of evidence
A. Strong I. One or more randomized trials with clinical outcomes and/or validated laboratory endpoint
B. Moderate II. One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes
C. Optional III. Expert opinion based on evaluation of other evidence

Recommendations for Initiating Antiretroviral Therapy

  • Antiretroviral therapy (ART) is recommended for all HIV-infected individuals. The strength of this recommendation varies on the basis of pretreatment CD4 cell count:
    • CD4 count <350 cells/mm3 (AI)
    • CD4 count 350 to 500 cells/mm3 (AII)
    • CD4 count >500 cells/mm3 (BIII)
  • Regardless of CD4 count, initiation of ART is strongly recommended for individuals with the following conditions:
  • Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner; therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners (AI [heterosexuals] or AIII [other transmission risk groups].
  • Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case by case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

Treatment Failure

Definitions of Treatment Failure
Clinical Failure
  • New or recurrent WHO stage 4 condition
CD4 Cell Failure
  • Fall of CD4 count to pre-therapy baseline (or below), OR
  • 50% fall from the on-treatment peak value (if known), OR
  • Persistent CD4 levels below 100 cells/mm3
Virological Failure
  • Plasma viral load > 1 000 copies/ml
Table adapted from WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection[4]
Treatment Failure Criteria Stage 1 Stage 2 Stage 3 Stage 4
CD4 cell failure Not recommended to switch regimen. Repeat CD4 count in 3 months Not recommended to switch regimen. Repeat CD4 count in 3 months Consider switching to second-line regimen Recommend to switch to second-line regimen
CD4 cell failure and viral load failure Consider second-line regimen Consider second-line regimen Recommended to switch to second-line regimen Recommended to switch to second-line regimen
Switching should not be done until the first regimen has been given sufficient time to succeed (at least 6 months).
Table adapted from WHO GUIDELINES ON ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN ADULTS AND ADOLESCENTS [6]

Special Considerations

  • HAART allows the stabilization of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped.[7][8]
  • It would take more than the lifetime of an individual to be cleared of HIV infection using HAART.[9]
  • Many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality.[10][11][12]

HIV in Children

Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations are more aggressive for children than for adults.[13]

Treatment Adherence

Adherence is taking the correct dose of each anti-HIV medication at the correct time and exactly as prescribed. Adherence is very important for successful HIV treatment. The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues, along with side effects that create intentional non-adherence, also has a weighty impact.[14][15][16]

Difficulty in Adherence

There are several reasons why adhering to an HIV treatment regimen can be diicult. Most treatment regimens involve taking several pills every day with or without food, or before or after other medications. Other factors that can make treatment adherence difficult include:

  • Difficulty taking medications (such as trouble swallowing pills).
  • Side effects from medications (for example, fatigue or diarrhea).
  • Daily schedule issues (including a busy schedule, shift work, or travel away from home) .
  • Being sick or depressed .
  • Alcohol or drug abuse.

Importance of Adherence

Adherence effects the success of HIV treatment in two ways:

  • Good adherence to an HIV treatment regimen helps anti-HIV medications work effectively to reduce the viral load. Skipping medications, even occasionally, gives HIV to multiply rapidly. Preventing the virus from multiplying is the best way to stay healthy.
  • Good adherence to an HIV treatment regimen also helps prevent drug resistance. One or more anti-HIV medications in a treatment regimen can become ineffective as a result of drug resistance.

Skipping medications makes it easier for drug resistance to develop. HIV can develop resistance to the anti-HIV medications in a person’s current regimen or to other, similar anti-HIV medications not yet taken, limiting options for successful HIV treatment. And drug-resistant strains of HIV can be transmitted to others, too. Although there are many different anti-HIV medications and treatment regimens, studies show that a person’s first regimen offers the best chance for long-term treatment success. Adhering to the regimen from the start will help ensure that the HIV treatment is successful.

Virologic Response

The most reliable indicator of response to ART is plasma HIV RNA and should be measured in all patients at baseline and regularly during therapy.[17][18] It is thus useful in predicting clinical progression.

Viral load reduction may be more rapid in following patients:[19]

  • Having high CD4 cell count.
  • Having lower levels of baseline viremia.
  • In treatment-naive patients.
Time Expected decrease in Viral load
1 week Decrease by 0.75 to 1 log10 copies/mL
1 month Decrease by 1.5 to 2 log10 copies/mL to <5000 copies/mL .
2 to 4 months. <500 copies/mL
4 to 6 months. < 50 copies/mL.

Transient increase in the viral load can be present in acute illness and vaccinations.

Virologic Failure

It is defined either as primary failure to achieve a viral load <50 copies/mL or any sustained recurrence of viremia to >50 copies/mL after initial viral suppression.[20]

Two main causes of the failure are:

  1. Drug resistance.
  2. Failure of the drugs to reach the target site.

Viral Blips

It refer to an isolated low-level of detectable HIV RNA (>50 to 500 copies/mL) that occurs during long-term monitoring on a stable ART regimen.[21]

Department of Health and Human Services (DHHS) have suggested that viral blips do not require intervention with a new regimen unless the viral load is sustained at >200 copies/mL.

Monitoring CD4 and Viral Load

Scenario CD4 Monitoring Viral Load Monitoring
Before receiving ART Yes Yes
While receiving ART 3 month after initiation of ART 2-4 weeks after initiation of ART, then every 4-8 weeks
ART regimen is modified due to drug toxicity Will depend on previous CD4 counts 4-8 weeks after modification of regimen
ART regimen is modified due to virologic failure Every 3-6 months 2-4 weeks after initiation of ART, then every 4-8 weeks
During the first 2 years of ART Every 3-6 months Every 3-4 months
While on ART with detectable viremia (>200 copies/mL) Every 3-6 months Every 3 months
Change in clinical status
(new HIV clinical symptom or initiation of interferon, chronic systemic corticosteroids, or antineoplastic therapy)
Will depend on the clinical scenario Every 3 months
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [5]

Other Laboratory Monitoring

Time-point Laboratory Tests
At HIV diagnosis

  • Hepatitis B Serology
  • Hepatitis C Serology
  • Serum Na, K, HCO3, Cl, BUN, creatinine
  • ALT, AST, Bilirubin

  • CBC with differential
  • Lipid Profile
  • HbA1c or fasting glucose
  • Urinalysis
  • Resistant testing

At initiation of ART

  • Hepatitis B serology
  • Serum Na, K, HCO3, Cl, BUN, creatinine
  • ALT, AST, Bilirubin
  • CBC with differential
  • Lipid Profile

  • HbA1c or fasting glucose
  • Urinalysis
  • Pregnancy test
  • Resistant testing
  • HLA-B*5701 testing (if considering ABC in regimen)

After 2-8 weeks after ART initiation

  • Serum Na, K, HCO3, Cl, BUN, creatinine
  • ALT, AST, Bilirubin

  • CBC with differential
  • Lipid Profile

Every 3-6 months

  • Serum Na, K, HCO3, Cl, BUN, creatinine
  • ALT, AST, Bilirubin

  • CBC with differential
  • HbA1c or fasting glucose (if abnormal previously)

Every 6-12 months
  • Lipid profile
  • Urinalysis (if taking TDF)
  • HbA1c or fasting glucose (if abnormal previously)
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [5]

References

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  6. WHO GUIDELINES ON ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN ADULTS AND ADOLESCENTS.
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