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Human immunodeficiency virus (HIV) infection

Human immunodeficiency virus (HIV) infection

 

HIV therapeutics is a specialised field so only those doctors with experience in HIV management should prescribe antiretroviral therapy.

Rather than acting as a detailed guide, this chapter aims to provide general information that will enable the practitioner or student to understand the principles of antiretroviral therapy, to recognise common adverse effects of the drugs, and to appreciate the importance of drug interactions with antiretrovirals. Prophylaxis and treatment of opportunistic infections in HIV-infected adults are also detailed.

 

Treatment with highly active combination antiretroviral therapy has led to substantial reductions in HIV infection-related morbidity and mortality. However, indications for initiation of antiretroviral treatment are now more conservative than they were in the past. This is because of i) difficulties with long-term adherence to many treatment regimens, ii) emerging information about toxicities of antiretroviral drugs, and iii) the potential for development of resistance to antiretroviral drugs (with subsequent narrowing of therapeutic options) if treatment does not completely suppress viral replication.

 

Indications for antiretroviral therapy

 

 

Treatment of established HIV infection

Indications for treatment according to current guidelines:

·            symptomatic patients including those with HIV-associated opportunistic infections, malignancies, central nervous system disease, thrombocytopenia

·            asymptomatic adults with CD4 cell counts <350/microlitre or HIV viral load >55 000 copies/mL (by reverse transcriptase polymerase chain reaction assay). [Note]

In seroconversion illness, treatment is appropriate on theoretical grounds but is of unproven clinical benefit based on current published evidence.

For further information refer to:

·            Australian antiretroviral guidelines [draft at time of writing], Australasian Society for HIV Medicine, 2001. www.ashm.org.au/index.php?PageCode=23.

For treatment of HIV-infected children, refer to US guidelines:

·            Guidelines for the use of antiretroviral agents in pediatric HIV infection; Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2001. www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=51.

 

Prevention of HIV infection

For prevention of maternal-fetal transmission by treating the mother prepartum and peripartum and treating the infant postpartum, refer to US guidelines:

·            Recommendations for the use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States, US Public Health Service Taskforce, 2002. www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=66.

For postexposure prophylaxis after significant exposure to a known HIV-infected source, refer to Postoccupational exposure prophylaxis (PEP) against blood borne viruses (BBV) and Postsexual assault prophylaxis.

 

Further reading

·            UK guidelines: British HIV Association (BHIVA) guidelines for the treatment of HIV disease with anti-retroviral therapy, 2001. www.aidsmap.com/about/bhiva/bhivagd.asp

·            US guidelines: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents [regularly updated]. Recommendations of the panel on clinical practices for treatment of HIV infection, 2002. www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=50.

Antiretroviral drugs

 

 

The 3 major classes of antiretrovirals are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors , see Table 1 (Antiretroviral drugs and oral dosing).

For initial antiretroviral therapy at least 3 drugs are used in combination [Note 1]

 

Two NRTIs: zidovudine plus lamivudine [Note 2], or zidovudine plus didanosine, or stavudine plus lamivudine

 

PLUS EITHER

1

a NNRTI: nevirapine or efavirenz

 

OR

1

a protease inhibitor: nelfinavir or indinavir

 

OR

1

a protease inhibitor in combination with low dose ritonavir [Note 3]: lopinavir+ritonavir [Note 2] or indinavir plus ritonavir or saquinavir plus ritonavir

 

OR if HIV viral load <100 000 copies/mL

2

abacavir.

 

Antiretroviral drugs and oral dosing (Table 1)

[For specific contraindications and neonatal doses, consult the product information. The drug name and not the abbreviation should be used when these drugs are prescribed.]

Antiretroviral

Usual adult doses

Paediatric doses

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTI)

abacavir

300 mg 12-hourly

>3 months: 8 mg/kg up to 300 mg 12-hourly

didanosine (ddI)

<60 kg: 250 mg daily

120 mg/m2 12-hourly (up to 150 mg/m2 in neurological disease)

>60 kg: 400 mg daily or 250mg if co-administered with tenofovir

  

lamivudine (3TC)

150 mg 12-hourly

4 mg/kg (up to 150 mg) 12-hourly

stavudine (d4T)

<60 kg: 30 mg 12-hourly

1 mg/kg (up to 30 mg) 12-hourly

>60 kg: 40 mg 12-hourly

  

tenofovir

300 mg daily

not available in paediatric formulation

zalcitabine (ddC)

0.75 mg 8-hourly

0.01 mg/kg 8-hourly

zidovudine (ZDV)

250 mg 12-hourly or 200 mg 8-hourly

160 mg/m2 (up to 200 mg) 8-hourly

zidovudine+lamivudine

300+150 mg 12-hourly

not available in paediatric formulation

zidovudine+lamivudine+abacavir

300+150+300 mg 12-hourly

not available in paediatric formulation

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

delavirdine

400 mg 8-hourly

not recommended under 12 years

efavirenz

600 mg daily

<40 kg: 200 to 400 mg daily, see product information

nevirapine

200 mg daily for 2 weeks, then 200 mg 12-hourly

see product information

Protease inhibitors (PI)

amprenavir

>50 kg: 1200 mg 12-hourly OR 600 mg 12-hourly when combined with low-dose ritonavir (100 mg 12-hourly)

<50 kg: 20 mg/kg 12-hourly

4 years or older, and <50 kg:

20 mg/kg 12-hourly (capsules)
OR 22.5 mg/kg 12-hourly (solution)

indinavir

800 mg 8-hourly OR 800 mg 12-hourly when combined with low-dose ritonavir (100 mg 12-hourly)

3 years or older: 500 mg/m2 (up to 800 mg) 8-hourly

lopinavir+ritonavir

400+100 mg 12-hourly

2 years or older: 230+57.5 mg/m2 12-hourly

nelfinavir

750 mg 8-hourly or 1250 mg 12-hourly

25 to 45 mg/kg 8-hourly

ritonavir

600 mg 12-hourly

(Poorly tolerated when used alone at this dose usually combined at low dose with another protease inhibitor.)

250 mg/m2 12-hourly, increase to 400 mg/m2 12-hourly over 5 days

saquinavir
soft gel capsules

 

1200 mg 8-hourly OR 1000 mg 12-hourly when combined with low-dose ritonavir (100 mg 12-hourly)

under study

saquinavir
hard gel capsules

1000 mg 12-hourly when combined with low-dose ritonavir (100 mg 12-hourly)

under study

Before starting antiretroviral therapy

 

 

Successful therapy is dependent upon a high level of adherence to the treatment regimen. Patients should be advised about strategies to improve adherence (for example, use of diaries, pill containers or alarms) and provided with detailed information about medication dosing and side effects.

Some antiretroviral drugs cause hyperlipidaemia and/or glucose intolerance. Cardiovascular risk factors should be assessed, and modified if possible.

 

 Monitoring antiretroviral therapy

 

 

Patients require close and regular (1- to 3-monthly) follow-up. The best indicator of antiretroviral activity is the HIV viral load, which should fall to below 50 copies/mL after 3 to 6 months in most patients not previously treated with antiretrovirals. The CD4 cell count generally increases when viral replication is suppressed. Monitoring of serum chemistries, blood lipids and haematology is also important.

Prophylaxis and treatment of opportunistic infections in HIV-infected adults (Table 2)

 

 

Pathogen

Primary treatment

Maintenance therapy
(secondary prophylaxis)
[Note 1]

Primary prophylaxis [Note 1]

Candida albicans (oropharyngeal)

 

  

fluconazole 50 mg orally daily for 10 to 14 days

OR

itraconazole 100 mg orally daily for 10 to 14 days

OR

miconazole 2% gel 3 mL orally 6-hourly for 10 to 14 days

OR

nystatin liquid 1 mL orally 6-hourly for 10 to 14 days

If frequent recurrences, fluconazole 50 mg orally daily or 150 mg weekly

- not established.

Candida albicans (oesophageal)

 

  

fluconazole 200 mg orally initially, then 100 mg daily for 14 days

OR

itraconazole 200 mg orally daily for 14 days

OR

ketoconazole 200 mg orally daily for 14 days

For repeated episodes

fluconazole 100 mg orally daily

OR

itraconazole 200 mg orally daily

OR

ketoconazole 200 mg orally daily

- not established.

Cryptococcus neoformans

 

  

amphotericin 0.75 mg/kg IV daily for 2 to 4 weeks

WITH OR WITHOUT

flucytosine 25 mg/kg IV/orally 6-hourly for 14 days [Note 2]

OR (mild disease) as a single drug,

fluconazole 800 mg orally/IV initially, then 400 mg daily

fluconazole 200 mg orally daily

- not indicated

- maintenance therapy for Candida with fluconazole would be effective prophylaxis for cryptococcosis

Cytomegalovirus

 

  

valganciclovir 900 mg orally 12-hourly for 14 to 21 days [Note 3]

OR

ganciclovir 5 mg/kg IV 12-hourly for 14 to 21 days

OR

foscarnet 90 mg/kg IV 12-hourly for 14 to 21 days

(actual dose based on creatinine clearance, see product information)

OR

cidofovir 5 mg/kg IV weekly for 2 weeks CO-ADMINISTER WITH probenecid (contraindicated if proteinuria >2+ or creatinine clearance <55 mL/minute)

valganciclovir 900 mg orally daily

OR

ganciclovir 10 mg/kg IV 3 times weekly or 5 mg/kg IV 5 times weekly

OR

foscarnet 90 to 120 mg/kg/day IV 5 times weekly (actual dose based on creatinine clearance, see product information)

OR

cidofovir 5 mg/kg IV every 2 weeks
CO-ADMINISTER WITH probenecid (contraindicated if proteinuria >2+ or creatinine clearance <55 mL/minute)

- not established.

Herpes simplexvirus

 

  

famciclovir 500 mg orally 12-hourly for 7 to 10 days

OR

valaciclovir 500 mg orally 12-hourly for 7 to 10 days

OR

aciclovir 200 mg orally 5 times daily for 7 to 10 days

For frequent, severe recurrences

famciclovir 500 mg orally 12-hourly

OR

valaciclovir 500 mg orally 12-hourly

OR

aciclovir 200 mg orally 8-hourly or 400 mg orally 12-hourly

- not established

Mycobacterium avium complex (MAC)

 

  

ethambutol 15 to 25 mg/kg orally daily

PLUS EITHER

clarithromycin 500 mg orally 12-hourly

OR

azithromycin 600 mg orally daily

WITH OR WITHOUT

rifabutin  300 mg orally daily [Note 4]

- as for primary treatment

- 2 to 3 drugs used according to tolerance and drug interactions

  

- commenced when CD4 cell count <75/microlitre

- azithromycin 1.2 g orally weekly or clarithromycin 500 mg orally 12-hourly or rifabutin 300 mg orally daily [Note 4]

Mycobacterium tuberculosis [Note 5]

 

  

- management only by specialists with HIV and TB expertise

- complex drug interactions between HIV and TB drugs usually preclude standard TB regimens

- not established

- if positive Mantoux test (>5mm in patient who has not had BCG) isoniazid 300 mg orally daily for 9 months

Pneumocystis carinii

 

  

trimethoprim+sulfamethoxazole 5+25 mg/kg orally/IV 6 to 8 hourly for 21 days

OR

pentamidine 4 mg/kg up to 300 mg IV daily for 21 days

OR (mild to moderate disease only)

dapsone 100 mg orally daily

PLUS

trimethoprim 5 to 7.5 mg/kg orally 12-hourly for 21 days

OR (mild to moderate disease only) as a single drug

atovaquone 750 mg orally 12-hourly for 21 days

trimethoprim+sulfamethoxazole 80+400 to 160+800 mg orally daily or 160+800 mg orally 3 or 4 times weekly or 12-hourly 2 times weekly

OR

pentamidine 300 mg IV/aerosolised every 2 to 4 weeks [Note 6]

OR

dapsone 100 mg orally 3 times weekly

- commenced when CD4 cell count <200/microlitre

- regimens as for maintenance therapy

Toxoplasma gondii

 

  

sulfadiazine 1 to 1.5 g orally/IV 6-hourly for 3 to 6 weeks

PLUS

pyrimethamine 50 to 100 mg orally initially, THEN 25 to 50 mg daily for 3 to 6 weeks [Note 7]

If hypersensitive to sulfadiazine, substitute

clindamycin 600 mg orally/IV 6-hourly for 3 to 6 weeks

sulfadiazine 500 mg orally 6-hourly or 1 g orally 12-hourly

PLUS

pyrimethamine 25 to 50 mg orally daily [Note 7 ]

If hypersensitive to sulfadiazine, substitute

clindamycin 600 mg orally 8-hourly

- prophylaxis for P. carinii with trimethoprim+sulfamethoxazole is effective prophylaxis for toxoplasmosis

Varicella-zostervirus

 

  

famciclovir 500 mg orally 8-hourly for 7 to 14 days

OR

valaciclovir 1 g orally 8-hourly for 7 to 14 days

OR

aciclovir 800 mg orally 5 times daily for 7 to 14 days

OR

aciclovir 10 mg/kg IV 8-hourly for 7 to 14 days

normally not necessary except after second episode of varicella-zostervirus

  

- not established.

Note 1:

For patients on highly active antiretroviral therapy, indications for cessation of either primary prophylaxis or maintenance therapy are:

·            CMV maintenance therapy: CD4 cell count >100–150/microlitre for 3 to 6 months with nondetectable or stable low HIV viral load

·            Cryptococcus neoformans maintenance therapy: CD4 cell count >100–200/microlitre for >=6 months with nondetectable or stable low HIV viral load

·            MAC: CD4 cell count >100/microlitre for 3 to 6 months with nondetectable or stable low HIV viral load (primary prophylaxis) or CD4 cell count >100/microlitre for >=6 months with nondetectable or stable low HIV viral load AND after 12 months of MAC treatment with no signs or symptoms of MAC (maintenance therapy)

·            Pneumocystis carinii: CD4 cell count >200/microlitre for 3 to 6 months with nondetectable or stable low HIV viral load

·            Toxoplasma gondii: as for Pneumocystis carinii.

Note 2:

Bone marrow suppression may occur with flucytosine; monitor levels (see Flucytosine monitoring).

Note 3:

At the time of publication, valganciclovir is available on the Section 100 Highly Specialised Drugs Program for cytomegalovirus retinitis only.

Note 4:

Significant drug interactions occur between protease inhibitors and rifabutin, see Interactions with antimicrobials.

Note 5:

Multidrug-resistant TB needs specialist advice, 5 to 6 drugs and longer duration of treatment, often 2 years.

Note 6:

Administer aerosolised pentamidine via a jet nebuliser producing a droplet size of 1 to 2 microns.

Note 7:

Calcium folinate 15 mg orally daily may reduce the incidence of neutropenia.

 

Reasons for changing antiretroviral therapy and recommended modifications (Table 3)

 

 

Reason

Regimen modification

Toxicity or intolerance of individual drugs in the regimen

          Use another drug from the same or different class

Antiretroviral failure (initial failure to decrease viral load, or viral load rebound after suppression):

 

a) due to poor adherence

          Review adherence, reinforce adherence strategies, consider regimen simplification.

          Monitoring of protease inhibitor and non-nucleoside reverse transcriptase inhibitor blood levels may be considered.

b) due to antiretroviral resistance

 

          Use at least 2 new drugs, preferably belonging to a different class or with a low probability of cross-resistance to drugs in the previous regimen.

          Use results of resistance testing if available.

c) due to altered pharmacokinetics (eg. drug-drug interaction, severe liver dysfunction, malabsorption)

          Review other medications and adjust accordingly.

          Monitoring of protease inhibitor and non-nucleoside reverse transcriptase inhibitor blood levels may be considered.

 

Some important adverse reactions of antiretroviral drugs (Table 3)

 

 

Antiretroviral

Adverse reactions

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTI)

class effects

hyperlactataemia, lactic acidosis, hepatic steatosis, lipodystrophy [Note 1]

abacavir

hypersensitivity reaction [Note 2] (fever, headache, myalgia, gastrointestinal symptoms, respiratory symptoms, with or without rash)

didanosine

pancreatitis, diarrhoea, nausea, peripheral neuropathy

lamivudine

abnormal liver function, anaemia and neutropenia (advanced disease), pancreatitis (rare)

stavudine

peripheral neuropathy, pancreatitis (rare)

tenofovir

asthenia, headache, diarrhoea, nausea, vomiting (class effects above less likely)

zalcitabine

peripheral neuropathy, mouth ulcers, pancreatitis (rare)

zidovudine

nausea, headaches (soon after starting), anaemia, neutropenia (advanced disease), myalgia, myopathy

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

delavirdine

rash, abnormal liver function, fever

efavirenz

rash, abnormal liver function, neuropsychological reactions (disturbed sleep, altered dreams, light headedness [on starting, usually resolves after days to weeks])

nevirapine

rash, hepatitis, fever

Protease inhibitors (PI)

class effects

lipodystrophy [Note 1], hyperglycaemia, hyperlipidaemia (most common with ritonavir), abnormal liver function

amprenavir

nausea, vomiting, diarrhoea, rash, perioral paraesthesia

indinavir

nephrolithiasis, nausea, hyperbilirubinaemia

lopinavir+ritonavir

nausea, vomiting, diarrhoea

nelfinavir

diarrhoea

ritonavir

nausea, vomiting, diarrhoea, perioral paraesthesia

saquinavir

diarrhoea, nausea, abdominal discomfort

Note 1: Abnormal fat accumulation (central obesity, breast enlargement, buffalo hump) or fat wasting in limbs and face (lipoatrophy); the relative contribution of PIs and NRTIs varies, but lipoatrophy is associated with use of thymidine analogues (stavudine, zidovudine)

Note 2: Rechallenge contraindicated in all patients, potentially fatal; presence of HLA-B57 highly predictive of hypersensitivity but reactions can occur in absence of HLA-B57.

 

Antiretroviral interactions

 

The protease inhibitors and non-nucleoside reverse transcriptase inhibitors inhibit or induce the cytochrome P450 enzymes and interact with many other drugs.

Some important contraindications are listed below (Table 2.10), see also Interactions with antimicrobials for more detail. Comprehensive, up-to-date information can be found at www.hiv-druginteractions.org/.

Prescribers should consult specialised up-to-date treatment guidelines, or drug information services if there is any doubt about the possibility of a significant interaction.

 

Some medications that are contraindicated with antiretroviral drugs (Table 5)

 

Protease inhibitors

NNRTI [Note]

amprenavir

indinavir

lopinavir+
ritonavir

nelfinavir

ritonavir

saquinavir

delavirdine

efavirenz

nevirapine

amiodarone

 

 

 

X

X

 

 

 

 

cisapride

X

X

X

X

X

X

X

X

 

diazepam

X

 

 

 

 

 

 

 

 

dihydroergotamine

X

X

X

X

X

X

X

X

 

ergotamine

X

X

X

X

X

X

X

X

 

flecainide

 

 

X

 

X

 

 

 

 

H2-receptor antagonists

 

 

 

 

 

 

X

 

 

ketoconazole

 

 

 

 

 

 

 

 

X

midazolam

X

X

X

X

X

X

X

X

 

pethidine

 

 

 

 

X

 

 

 

 

pimozide

X

X

X

X

X

X

 

 

 

proton pump inhibitors

 

 

 

 

 

 

X

 

 

quinidine

 

 

 

X

X

 

 

 

 

rifabutin

 

 

 

 

 

X

X

 

 

rifampicin

X

X

X

X

 

X

X

 

X

simvastatin

X

X

X

X

X

X

X

 

 

St John's wort

X

X

X

X

X

X

X

X

X

triazolam

X

X

X

X

X

X

X

X

 

X = contraindicated combination

Note: Non-nucleoside reverse transcriptase inhibitors

 

 

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