Haart

Author:Prof. Dr. med. Peter Altmeyer

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Last updated on: 01.01.2022

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Synonym(s)

Antiretroviral combination therapy; cART; Combined Anti-Retroviral Therapy; Highly active antiretroviral therapy; Highly Active Anti-Retroviral Therapy

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DefinitionThis section has been translated automatically.

Concept introduced in 1996 of combination therapies of various antiretroviral drugs for the treatment of HIV infection.

General definitionThis section has been translated automatically.

  • HAART is the acronym for Highly Active Anti-Retroviral Therapy.

  • Notice! Due to the complexity of the therapy, it should only be initiated, discontinued or changed in close consultation with a specialised centre.

  • By targeting the right combination of active ingredients at the right time, the measured viral load (detection by PCR) of sometimes 1.5 million copies/ml of blood can be pushed below the detection limit (this should not be confused with a cure). The life expectancy of HAART-treated patients gradually adjusts to normal life expectancy. A normal life is thus (almost) possible, although individual more aggressive forms of the disease and an increasing resistance problem should not be negated. It must therefore be stressed that there is no alternative to infection control (safer sex) as yet.
  • HAART consists of a combination of at least three antiretroviral drugs from at least two drug classes. Currently, several drug classes are available:

IndicationThis section has been translated automatically.

Undesirable effectsThis section has been translated automatically.

  • Frequently, dermatological side effects are seen under HAART, especially drug exanthema, lipodystrophy syndromes. Clinically significant is the immune reconstruction syndrome with the unmasking of latent infectious diseases or the new occurrence or reactivation of pre-existing diseases.
  • Antiretroviral therapy must be switched in up to 25% of all patients within the first year due to side effects.
  • Drug exanthema: Drug exanthema is triggered primarily by NNRTIs. In cases of mild, non-bullous reactions without general symptoms or mucosal involvement, HAART can be continued. The differential diagnostic differentiation from, for example, viral exanthema and syphilis can be difficult.
  • Hypersensitivity syndrome: The presence of a possibly life-threatening hypersensitivity reaction (HSR), which is sometimes also referred to as DRESS syndrome (= drug rush with eosinophilia and systemic symptoms), is indicated by the combined occurrence of usually 3-4 symptoms simultaneously (morbilliform to maculopapular exanthema, fever, nausea or vomiting) on average about 11 days after the start of treatment. In one third of the patients the hypersensitivity reaction proceeds without exanthema. Epicutaneous testing often demonstrates sensitization to abacavir. The allele HLA-B5701, which occurs in Caucasians, is positive in up to 90% of HSR and can be determined before starting therapy with abacavir. Re-exposure should be avoided after an HRS.
  • Immune reconstitution syndrome (IRIS): Especially patients with an advanced cellular immunodeficiency who start antiretroviral combination therapy are at risk of developing an aberrant, often pathogen-specific immune response. The skin, as a mirror of the immune system, is also frequently affected. In addition to infections (e.g. herpes zoster, herpes simplex, molluscum, HPV-associated changes), multifactorial (psoriasis, acne, eosinophilic folliculitis) and autoimmune-mediated skin changes occur. Antiretroviral therapy should be continued if possible and specific therapy initiated.
  • Lipodystrophy syndrome: Lipodystrophy syndrome is the term used to describe fat distribution disorders and metabolic changes in patients on HAART. Loss of subcutaneous adipose tissue is most apparent in the face, extremities, and gluteal. Lipohypertrophy is seen primarily visceral, less commonly nuchal. Associated metabolic changes include insulin resistance, glucose tolerance disorders, diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, and hyperlactatemia. Switching antiretroviral therapy should be considered, and drug treatment of metabolic disorders should take into account interactions with agents of antiretroviral therapy.
  • Mitochondrial toxicity: NRTIs in particular can competitively inhibit RNA-dependent DNA polymerase in mitochondria and thus their DNA replication. This results in impairment of mitochondrial enzymes. The thymidine analogues stavudine, and didanosine, in particular, and to a lesser extent zidovudine, are thought to be responsible for this.
  • Hyperpigmentation: Rarely, melanonychia striata medicamentosa occurs under zidovudine and emtricitabine.

Complication(s)This section has been translated automatically.

According to our own clinical experience, patients treated with antiretroviral combination therapy are more likely to develop bronchial carcinoma. The pathogenetic role underlying this is still unclear. Whether the disproportionately high number of smokers in this collective is the decisive factor is currently being discussed.

Note(s)This section has been translated automatically.

  • Interactions in HIV therapy are manifold and have so far only been rudimentarily investigated. NNRTIs and PIs are largely degraded by the cytochrome P450 system. Drug level measurements should be performed in cases of unclear interaction. Information on interactions with frequently used drugs can be found at www.ifi-interaktions-hotline.de.
  • Resistance analyses: Rule-based and data-based interpretation systems are available for the interpretation of genotypic and phenotypic resistance analyses.
    • Rule-based interpretation systems:
      • HIV-GRADE: http://www.hiv-grade.de/cms/grade/homepage.ht ml
      • Stanford database: http://hiv.net/link.php?id=24
      • HIV Genotypic Drug Resistance Interpretation - ANRS AC11: http://hiv.net/link.php?id=138
      • Los Alamos database: http://hiv.net/link.php?id=25
    • Data-based interpretation systems: geno2pheno: http://hiv.net/link.php?id=26.

LiteratureThis section has been translated automatically.

  1. Esser S, Helbig D, Hillen U, Dissemond J, Grabbe S (2007) HIV-therapy associated side effects. JDDG 5: 745-754
  2. May MT et al (2006) HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet 368: 451-458
  3. Salzberger B, Marcus U, Vielhaber B, Arasteh K, Golz J, Brockmeyer NH, Rockstroh J (2004) German-Austrian recommendations for the antiretroviral therapy of HIV infection (status May 2004). Eur J Med Res 9: 491-504

TablesThis section has been translated automatically.

Substance or group of substances

Trade name

Most important side effects

dietary regulation

Dosage form

Dose*

Nucleoside reverse transcriptase inhibitors (nucleoside analogues, NRTI)

Hepatic steatosis, rarely lactate acidosis, lipodystrophies syndrome§

Abacavir

Ziagen

hypersensitivity syndrome

Tablets of 300 mg, juice

2 times/day 300 mg p.o.

Didanosine

Videx

pancreatitis, neuropathy

take in soberly

Capsules of 400 mg, capsules of 250 mg, capsules of 125 mg, powder

> 60 kg KG: once/day 400 mg p.o.

< 60 kg bw: once/day 250 mg or twice/day 125 mg p.o.

Emtricitabine

Emtriva

Headaches, gastrointestinal complaints (diarrhoea, nausea)

125 milligram capsules,

Solution with 10 mg/ml

> 4 months and > 33 kg KG: once/day 200 mg p.o.

Lamivudine

Epivir

Headaches

Tablets of 300 mg, tablets of 150 mg, solution

once/day 300 mg or twice/day 150 mg p.o.

Stavudine

Zerit

neuropathy, pancreatitis

Capsules of 40 mg, capsules of 30 mg

> 60 kg KG: 2 times/day 40 mg p.o.

< 60 kg KG: 2 times/day 30 mg p.o.

Zidovudine

Retrovir

Neutropenia, anemia, myopathy

250 mg capsules, juice

2 times/day 250 mg p.o.

Combination preparation: lamivudine + zidovudine

Combivir

Headache, neutropenia, anaemia, myopathy

Tablets à (150 mg/300 mg)

2 times/day 150 mg/300 mg p.o.

Combination preparation: Lamivudine + Abacavir

Kivexa

Nausea, headache, gastrointestinal side effects such as vomiting and diarrhoea

Tablets à (300 mg/600 mg)

once/day 300 mg/600 mg p.o.

combined preparation: lamivudine + zidovudine + abacavir

Trizivir

Headache, neutropenia, anaemia, myopathy, hypersensitivity syndrome

Tablets à (150 mg/ 300 mg/300 mg)

2 times/day 150 mg/300 mg/300 mg p.o.

Nucleotidal reverse transcriptase inhibitors (nucleotide analogues, NtRTI)

Tenofovir

Viread

Gastrointestinal complaints (diarrhoea, nausea)

Tablets of 300 mg

once/day 300 mg p.o.

Combination preparation: Emtricitabine + Tenofovir

Truvada

Headaches, gastrointestinal complaints (diarrhoea, nausea)

Take with meal

Tablets à (200 mg/300 mg)

once/day 200 mg/300 mg p.o.

Non-nucleosidal reverse transcriptase inhibitors (NNRTI)

Drug reactions

Efavirenz*****

Sustiva, Stocrin

Psychotropic NW; drug exanthema

Capsules of 200 mg, capsules of 600 mg

once/day 600 mg p.o.

Nevirapine****

Viramune

drug exanthema, hepatotoxicity

Tablets of 100 mg

Initial: 100 mg once/day for 14 days, then dose adjustment to 200 mg p.o. twice/day or 400 mg p.o. once/day.

Etravirin

Intelence

diarrhea, headache, drug anthema, itching

Tablets of 100 mg

2 times/day 200 mg p.o.

Protease inhibitors (PI)**

Glucose intolerance, lipometabolic disorders, lipodystrophy syndrome§

Atazanavir

Reyataz

Diarrhea, headaches, hyperbilirubinemia (icterus)

Take with meal

Capsules of 100, 150, 200 mg

once/day 400 mg p.o.

Recommendation in combination with ritonavir: once/day 300 mg p.o. + ritonavir once/day 100 mg p.o.

Darunavir

Prezista

Nausea, diarrhoea, hyperlipidemia

Tablets of 400 mg

2 times/day 600 mg + ritonavir 2 times/day 100 mg p.o.

Fosamprenavir

Telzir

Diarrhoea

Film sheet 700 mg or suspension 50 mg/ml

2 times/day 1400 mg p.o.

Recommendation in combination with ritonavir: 2 times/day 700 mg p.o. + ritonavir: 2 times/day 100 mg p.o. Alternatively: 1 time / day 1400 mg p.o. + ritonavir: 1 time / day 200 mg p.o.

Indinavir

Crixivan

nephrolithiasis, hyperbilirubinaemia

Take on an empty stomach or on a low-fat diet

Capsules of 400 mg

As mono PI: 3 times/day 800 mg p.o.

Recommendation in combination with ritonavir: 2 times/day 400 mg indinavir + 2 times/day 100 mg ritonavir p.o.

Lopinavir + ritonavir

Kaletra

lipometabolic disorders, nausea, diarrhoea

Take with meal

Capsules à (133 mg/33 mg), solution

2 times/day 400 mg p.o. Lopinavir + 2 times/day 100 mg p.o. Ritonavir

Nelfinavir

Viracept

diarrhea, nausea

Not to be taken sober

250 mg tablets, powder

2 times/day 1250 mg p.o.

Ritonavir

Norvir

diarrhea, nausea, hypertriglyceridemia

Capsules of 100 mg, juice

2 times/day 600 mg p.o.; juice: 2 times/day 7,5 ml p.o.

Saquinavir

Invirase***

Diarrhoea, nausea (usually mild)

To be taken with protein- or fat-rich food

Filmbl. 500 mg

Recommendation in combination with ritonavir: 2 times/day 1000 mg saquinavir + 100 mg ritonavir p.o.

Fusion inhibitors/entry inhibitors

Local reactions at the injection site, flu-like symptoms

Enfuvirtide (T-20)

Fuzeon

Reactions at the injection site (erythema, urtica)

hypodermic injection

2 times/day 90 mg (1 ml) s.c.

* normal kidney function, body weight > 60 kg;

** all protease inhibitors are inhibitors of cytochrome P450; ritonavir is the most potent inhibitor, some isoenzymes are also induced by ritonavir

*** use only in combination with ritonavir;

**** Possibly increase the lopinavir/ritonavir dose in PI-pretreated patients to 533/133 mg 2 times/day in combination with efavirenz or nevirapin. In general, due to the mutual interactions when combining NNRTIs and PI, dose adjustments and, if necessary, drug monitoring must be considered;

***** different trade names in Germany and Austria;

§ the pathogenesis of lipodystrophies syndrome is still unclear. Both protease inhibitors and reverse transcriptase inhibitors appear to be involved in the development of the syndrome.

I

II

III

Graduation of therapy recommendations *

Based on at least one randomized study with clinical endpoints

On the basis of surrogate marker studies

According to experts

A

Clear recommendation

A I

A II

A III

B

Generally advisable

B I

B II

B III

C

Substitutable

C I

C II

C III

D

To be rejected in general

D I

D II

D III

E

Unambiguous rejection

E I

E II

E III

* Clinical endpoint studies will no longer be conducted due to the changed FDA and EMEA approval requirements for new substances

Substance or group of substances and preparations

Most important side effects

Dose*

Nucleoside reverse transcriptase inhibitors (nucleoside analogues, NRTI)

Hepatic steatosis, rarely lactate acidosis, lipodystrophies syndrome§

Abacavir (Ziagen)

hypersensitivity syndrome

2 times/day 300 mg p.o.

Didanosine (Videx)

pancreatitis, neuropathy

> 60 kg KG: once/day 400 mg p.o.

< 60 kg bw: once/day 250 mg or twice/day 125 mg p.o.

Emtricitabine (Emtriva)

Headaches, gastrointestinal complaints (diarrhoea, nausea)

> 4 months and > 33 kg KG: once/day 200 mg p.o.

Lamivudine (Epivir)

Headaches

once/day 300 mg or twice/day 150 mg p.o.

Stavudine (Zerit)

neuropathy, pancreatitis

> 60 kg KG: 2 times/day 40 mg p.o.

< 60 kg KG: 2 times/day 30 mg p.o.

Zalcitabine (Hivid)

Neuropathy, oral ulcers

3 times/day 0.75 mg p.o.

Zidovudine (retrovir)

Neutropenia, anemia, myopathy

2 times/day 250 mg p.o.

Combination preparation: lamivudine + zidovudine (Combivir)

Headache, neutropenia, anaemia, myopathy

2 times/day (150 mg + 300 mg) p.o.

Combination preparation: Lamivudine + Zidovudine + Abacavir (Trizivir)

Headache, neutropenia, anaemia, myopathy, hypersensitivity syndrome

2 times/day 150 mg + 2 times 300 mg + 2 times 300 mg p.o.

Nucleotidal reverse transcriptase inhibitors (nucleotide analogues, NtRTI)

Tenofovir (Viread)

Gastrointestinal complaints (diarrhoea, nausea)

once/day 300 mg p.o.

Non-nucleosidal reverse transcriptase inhibitors (NNRTI)

Drug reactions

Delavirdin (Rescriptor)

Drug exanthema

3 times/day 400 mg p.o.

Efavirenz (Sustiva, Stocrin) *****

Psychotropic NW; drug exanthema

once/day 600 mg p.o.

Nevirapine (Viramune) ****

drug exanthema, hepatotoxicity

Initial: 100 mg once/day for 14 days, then dose adjustment to 200 mg p.o. twice/day or 400 mg p.o. once/day.

Protease inhibitors (PI)**

Glucose intolerance, lipometabolic disorders, lipodystrophy syndrome§

Amprenavir (Agenerase)

diarrhea, headache, drug exanthema

2 times/day 1200 mg p.o.

Recommendation: Combination with ritonavir 2 times/day 600 mg amprenavir + 2 times/day 100 mg ritonavir p.o.

Atazanavir (Reyataz)

Diarrhea, headaches, hyperbilirubinemia (icterus)

once/day 400 mg p.o.

Recommendation in combination with ritonavir: once/day 300 mg p.o. + ritonavir once/day 100 mg p.o.

Fosamprenavir (Lexiva)

Diarrhoea

2 times/day 1400 mg p.o.

Recommended combination with ritonavir: fosamprenavir: once/day 1400 mg p.o. + ritonavir: once/day 200 mg p.o.

Alternative: Fosamprenavir: 2 times/day 700 mg p.o. + ritonavir: 2 times/day 100 mg p.o.

Indinavir (Crixivan)

nephrolithiasis, hyperbilirubinaemia

As mono PI: 3 times/day 800 mg p.o.

Recommendation in combination with ritonavir: 2 times/day 400 mg indinavir + 2 times/day 100 mg ritonavir p.o.

Lopinavir + ritonavir (Kaletra)

lipometabolic disorders, nausea, diarrhoea

2 times/day 400 mg p.o. Lopinavir + 2 times/day 100 mg p.o. Ritonavir

Nelfinavir (Viracept)

diarrhea, nausea

2 times/day 1250 mg p.o.

Ritonavir (Norvir)

diarrhea, nausea, hypertriglyceridemia

2 times/day 600 mg p.o.; juice: 2 times/day 7,5 ml p.o.

Saquinavir (Invirase***, Fortovase)

Diarrhoea, nausea (usually mild)

3 times/day 1200 mg p.o.

Recommendation in combination with ritonavir: 2 times/day 1000 mg saquinavir + 2 times/day 100 mg ritonavir p.o.

Fusion inhibitors/entry inhibitors

Local reactions at the injection site, flu-like symptoms

Enfuvirtide (Fuzeon)

reactions at the injection site (erythema, urtica)

2 times/day 90 mg (1 ml) s.c.

* normal kidney function, body weight > 60 kg;

** all protease inhibitors are inhibitors of cytochrome P450, ritonavir is the most potent inhibitor, some isoenzymes are also induced by ritonavir

*** use only in combination with ritonavir;

**** Possibly increase the lopinavir/ritonavir dose in PI-pretreated patients to 533/133 mg 2 times/day in combination with efavirenz or nevirapin. In general, due to the mutual interactions when combining NNRTIs and PI, dose adjustments and possibly drug monitoring must be considered;

***** different trade names in Germany and Austria;

§ the pathogenesis of lipodystrophies syndrome is still unclear. Both protease inhibitors and reverse transcriptase inhibitors appear to be involved in the development of the syndrome.

Combination partner 1

Degree of recommendation

Combination partner 2

Degree of recommendation

Nucleoside/nucleotide combinations

Recommended is the combination therapy of at least 2 NRTI/NtRTI (combination partner 1) with at least one NNRTI and/or PI (combination partner 2)

NNRTI

Tenofovir/emtricitabineI

AII

Efavirenz AII

AII

zidovudine/lamivudine

AI

nevirapine AII

AII

PI

lopinavir/ritonavir

AII

Fosamprenavir

AII

Combination partner 1

Degree of recommendation

Combination partner 2

Degree of recommendation

NRTI combinations of 2 NRTI

Recommended is the combination therapy of at least 2 NRTI (combination partner 1) with at least one NNRTI and/or PI (combination partner 2)

NNRTI

abacavir/lamivudine

BII

Nevirapine

BII

didanosin/lamivudine

BII

Emtricitabine

BII

PI

atazanir/ritonavir

BII

NRTI combinations of 3 NRTI

Atazanavir

BII

Abacavir/zidovudine/lamivudine *

BII

saquinavir/ritonavir

BII

nelfinavir/ritonavir

CII

indinavir/ritonavir

CII

Organ side effects

causative NRTIs

Neuromuscular NW

peripheral polyneuropathy

DDI, d4T

Myopathy

AZT

Cardiomyopathy

DDI, AZT

Hepatic and gastrointestinal NW

Steatosis

all NRTI (d4T >> other NRTI)

Pancreatitis

DDI, d4T

Haematological NW

Anemia, neutropenia

AZT

Nephrological NW

proximal tubule dysfunction, hypophosphatemia

TDF

Metabolic and adipocyte NW

Lipoatrophy

d4T > DDI > AZT > ABC > TDF > 3TC > FTC

hyperlactataemia, lactate acidosis

d4T > DDI > AZT > ABC > TDF > 3TC > FTC

Hyperlipidemia

d4T

Clinical

CD4+lymphocytes/µl

HIV RNA (copies/ml) (RT-PCR)

Therapy recommendation

HIV-associated symptoms and diseases (CDC: C, B)

All values

A I

Asymptomatic patients (CDC: A)

< 200

All values

A I

200-350

All values

B II

350-500

> 50,000-100,000 copies

B II

350-500

< 50,000 copies

C III

> 500

All values

C III

Acute retroviral syndrome

All values

All values

C II

Authors

Last updated on: 01.01.2022