Common Adverse Effects of Antiretroviral

Therapy for HIV Disease

CARIN E. REUST, MD, MSPH, University of Missouri School of Medicine, Columbia, Missouri

Family physicians are treating patients infected with human immunodeficiency virus in their practices more often.
Long-term complications of this disease are multifactorial and can be related to the virus itself or to adverse effects
of antiretroviral therapy. Each drug class has side effects: nucleoside/nucleotide reverse transcriptase inhibitors are
associated with lactic acidosis, lipodystrophy, and hyperlipidemia; non-nucleoside reverse transcriptase inhibitors are
associated with neuropsychiatric symptoms, rash, liver toxicity, and lipid abnormalities; and protease inhibitors are
associated with gastrointestinal intolerance and glucose and lipid abnormalities. The entry inhibitor maraviroc and the
integrase inhibitor raltegravir have been approved for treatment-naive and treatment-experienced patients. Maraviroc
is associated with bronchitis, nasopharyngitis, and esophageal candidiasis. Adverse effects of raltegravir are comparable to those experienced with placebo, with the exception of increased risk of myopathy and rhabdomyolysis. Information about drug interactions for both of these medications is limited. Non-nucleoside reverse transcriptase inhibitors
and protease inhibitors are primarily metabolized through the cytochrome P450 system, and as a result have numerous
drug-drug interactions. Monitoring for adverse effects of antiretroviral therapy includes a complete blood count and
comprehensive metabolic profile every three to six months. A lipid profile and urinalysis for proteinuria should be performed annually. Dual energy x-ray absorptiometry should be considered in patients older than 50 years. Long-term
morbidity related to antiretroviral therapy includes liver, renal, glucose, and lipid abnormalities, and cardiovascular
and bone disease. With some exceptions for lipid management, these morbidities can be managed as in the general
population. (Am Fam Physician. 2011;83(12):1443-1451. Copyright 2011 American Academy of Family Physicians.)

Patient information:
A handout on side effects
of antiretroviral therapy,
written by the author of
this article, is provided on
page 1456.

urvival rates in patients with human

immunodeficiency virus (HIV) infection are improved with early treatment;
therefore, current recommendations
are to begin antiretroviral therapy (ART) in
patients with a CD4 cell count of 500 per mm3
(0.50 109 per L) or less1-4 (Table 11,4). Because
of this new threshold, family physicians can
expect to see patients with HIV infection
who have been taking ART for longer lengths
of time. Pill counts and frequency of dosing
have decreased to one to three pills per day
for usual starting regimens. Despite this, ART
regimens continue to have significant adverse
effects that require monitoring for drug interactions and long-term morbidity related to
cardiovascular, bone, and kidney disease.
General Principles of ART
The basic configuration of antiretroviral
regimens is unchanged. The most common
initial regimens are a non-nucleoside reverse
transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) with two nucleoside/
nucleotide reverse transcriptase inhibitors

(NRTIs). Figure 1 shows the current preferred initial regimens.1 Common toxicities
of ART can make adherence to therapy difficult. However, adherence is important to
prevent the development of drug resistance.
Unlike therapy for other diseases, a strategy
of decreasing the dose or switching to a different drug to minimize toxicity and maximize adherence may not be possible with
ART; the benefit of suppressing HIV may
override other considerations. Identification
and awareness of ART toxicity are necessary
to facilitate patient adherence and determine
when a change in therapy may be needed.
Routine monitoring in patients receiving ART includes a complete blood count
and a comprehensive metabolic panel every
three to six months. A lipid profile and urinalysis for proteinuria should be performed
annually. When ART is changed, a complete
blood count, metabolic panel, and lipid profile should be performed two to eight weeks
afterward. Abnormal results should prompt
more frequent testing based on clinical
assessment.1,4,5

Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2011 American Academy of Family Physicians. For the private, noncommer-

June 15, cial

2011
83, Number
www.aafp.org/afp

American
Physician
use ofVolume
one individual
user of the12
Web site. All other rights reserved.
Contact [email protected]
for copyright questions
and/orFamily
permission
requests. 1443

Adverse Effects of Antiretroviral Therapy for HIV

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
rating

References

Antiretroviral therapy is recommended in patients with CD4 cell counts of 500 per mm (0.50 10 per L) or less.

1-4

Patients taking antiretroviral therapy should be screened for cardiac risk factors (e.g., dyslipidemia, diabetes
mellitus) annually or after a change in therapy, or more frequently if clinically indicated.

1, 5, 8, 16

Dual energy x-ray absorptiometry should be considered in men and women 50 years and older who are taking
tenofovir (Viread) or didanosine (Videx). Vitamin D levels should be monitored if clinically indicated.

5, 8

Annual screening for renal disease should include glomerular filtration rate and screening for proteinuria.
Black patients; those with CD4 cell counts less than 200 per mm3 (0.20 109 per L); those with viral loads
greater than 4,000 copies per mL; and those with diabetes, hypertension, or co-occurring hepatitis C
should be screened every six months.

5, 39

Clinical recommendations
3

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented
evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

There are several drug-drug interactions between

ART and other medications. NNRTIs, PIs, and the entry
inhibitor maraviroc (Selzentry) have the most interactions because they are metabolized through the cytochrome P450 (CYP450) system. A comprehensive list
of interactions is available at http://aidsinfo.nih.gov/
contentfiles/AA_Tables.pdf, Tables 13 and 15a through
15e. Common interactions are listed in Table 2.1,5,6 Physicians should check for drug interactions when a new
medication is initiated and check current medications
when a change is made in ART.

Table 1. Initiating Antiretroviral Therapy

in Treatment-Naive Patients
Recommendations of the Panel on Antiretroviral
Guidelines for Adults and Adolescents1
Initiate therapy for patients with:
CD4 cell count < 350 per mm3 (0.35 109 per L)*
Hepatitis B virus coinfection when treatment is indicated
History of AIDS-defining illness
HIV-associated nephropathy
Pregnancy
Recommendations of the International AIDS Society USA
Panel4
Initiate therapy for patients with:
Symptomatic HIV disease
Asymptomatic HIV disease and CD4 cell count 500 per mm3
(0.50 109 per L)
Asymptomatic HIV disease with:
Active hepatitis B or C coinfection
Age > 60 years
Cardiovascular disease or high risk of cardiovascular disease
High risk of HIV transmission
HIV-associated nephropathy
Pregnancy
Rapid decline in CD4 cell count (> 100 per mm3 [0.10 109
per L] per year)
Viral load > 100,000 copies per mL
HIV = human immunodeficiency virus.
*Approximately 55 percent of this panel strongly recommends
starting antiretroviral therapy in patients with a CD4 cell count of 350
to 500 per mm3. One-half of the panel favors starting antiretroviral
therapy in patients with a CD4 cell count greater than 500 per mm3.
Information from references 1 and 4.

1444 American Family Physician

Drug Classes
NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE
INHIBITORS

NRTIs, the backbone of ART, are associated with lactic acidosis and lipodystrophy (Table 3).1,7 Symptoms
of lactic acidosis include fatigue, nausea and vomiting, abdominal pain, diarrhea, and an increase in liver
function markers because of hepatic steatosis. A serum
venous lactate level can be used to screen for this complication, but should be confirmed by arterial blood gas
testing. If venous or arterial lactate levels are more than
45.05 mg per dL (5.00 mmol per L), the NRTI should
be cautiously changed to a nonthymidine NRTI.5,8 Lipodystrophy includes lipoatrophy (i.e., loss of subcutaneous fat in the face and extremities) and lipohypertrophy
(i.e., dorsocervical fat pad and central abdominal fat
accumulation). Polylactic acid and calcium hydroxylapatite injections can provide short-term benefit for facial
lipoatrophy5,8 ; and liposuction and administration of
recombinant growth hormone may provide short-term
benefit for lipohypertrophy.5,8 Diet changes, including a
decrease in polyunsaturated fat intake and an increase

www.aafp.org/afp

Volume 83, Number 12

June 15, 2011

Preferred and Alternative Regimens for First-Line HIV Therapy

Preferred regimens*
NNRTI-based regimen
Efavirenz

Key

Tenofovir

Integrase strand transfer inhibitor (InSTI)

Non-nucleoside reverse transcriptase inhibitor (NNRTI)
Nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)
Protease inhibitor (PI)

Emtricitabine

PI-based regimens
Atazanavir

Darunavir

Ritonavir
Ritonavir

Emtricitabine

Emtricitabine

Tenofovir
Tenofovir

InSTI-based regimen
Raltegravir

Emtricitabine

Tenofovir

Alternative regimens
NNRTI-based regimens
Efavirenz

Abacavir or zidovudine

Nevaripine

Zidovudine

Lamivudine

Lamivudine

PI-based regimens
+

Atazanavir
Fosamprenavir
+

Lopinavir

Ritonavir
+

Ritonavir

Ritonavir

Abacavir or zidovudine
+

Lamivudine

(Abacavir or zidovudine) + Lamivudine

(Abacavir or zidovudine) + Lamivudine

or

or

Emtricitabine + Tenofovir

Emtricitabine + Tenofovir

*Preferred regimens for nonpregnant patients are arranged in order of approval by the U.S. Food and Drug Administration for components other
than nucleosides (thus, by duration of clinical experience) and alphabetically within each class.
Regimens with potential disadvantages compared with preferred regimens; may be preferred for some patients.

Figure 1. Preferred and alternative initial regimens for antiretroviral therapy in patients with human immunodeficiency
virus (HIV) infection.
Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. Rockville, Md.: U.S. Department of Health and Human Services; 2011. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Accessed April 9, 2011.

in fiber intake, as well as the use of metformin (Glucophage), may decrease lipohypertrophy.8
The most commonly used NRTIs are zidovudine (Retrovir), lamivudine (Epivir), emtricitabine (Emtriva),
and tenofovir (Viread). Adverse effects associated with
zidovudine include bone marrow suppression, nausea
and vomiting, fatigue, and headache. Lamivudine and
emtricitabine are well tolerated. However, in patients with
co-occurring HIV and hepatitis B infections, discontinuing these medications can cause a flare of hepatitis B.
Tenofovir is a common NRTI in initial regimens and
is taken with lamivudine or emtricitabine. Tenofovir
combined with emtricitabine (Truvada) allows oncedaily dosing. Tenofovir has been associated with renal
abnormalities such as glycosuria, hypophosphatemia,
and increased creatinine levels, and the potential for
acute tubular necrosis. However, there is uncertainty
about the role of tenofovir in renal dysfunction. The
June 15, 2011

Volume 83, Number 12

risk of acute renal failure in patients taking tenofovir

is estimated to be 1 percent; this risk may be increased
in those with advanced HIV disease, greater treatment
experience, or preexisting renal disease.9 Cumulative
tenofovir exposure may increase the risk of chronic
kidney disease, but the increase is similar to the risk
associated with cumulative atazanavir (Reyataz) and
lopinavir/ritonavir (Kaletra) use.10
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

NNRTIs are associated with rash and lipid disorders

(Table 4).1,7,11 The rash may require stopping the medication and using a different drug class for ART. Lipid
disorders associated with NNRTIs can be managed with
statins, niacin, fibrates, and omega-3 fatty acids.1,12
Nevirapine (Viramune) and efavirenz (Sustiva) are
first-generation NNRTIs in common use. However,
nevirapine is limited by its association with severe

www.aafp.org/afp

American Family Physician 1445

Adverse Effects of Antiretroviral Therapy for HIV

Table 2. Common Drug Interactions with ART

Medications

Considerations

Anticonvulsants

Anticonvulsants such as carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin) should not be used
with ART unless no other option is available

Cardiac
medications

Dihydropyridine calcium channel blockers and diltiazem should be used cautiously with PIs if alternatives are not
available; digoxin and warfarin (Coumadin) can be used with ART, but digoxin dosing may need to be decreased
with PIs, and warfarin dosing will be affected by NNRTIs

Contraceptives

All methods are acceptable, including intrauterine devices and injectable medroxyprogesterone acetate (DepoProvera) 5,6; for women taking NNRTI-based regimens, no adjustment in combined oral contraceptive dose is
recommended; for women taking PI-based regimens that include ritonavir (Norvir), oral contraceptives should
contain at least 35 mcg of ethinyl estradiol; for women taking PI-based regimens that do not include ritonavir,
oral contraceptives should contain 25 to 30 mcg of ethinyl estradiol

Gastrointestinal
medications

Common antiemetic and antidiarrheal agents can be used without modification to treat vomiting and diarrhea
associated with ART; histamine H2 receptor blockers, proton pump inhibitors, and antacids should be used with
caution in patients taking PI-based regimens because many PIs require acid for metabolism

Herbal medications

Herbal medications and interactions with ART are not well-studied, with the exception of St. Johns wort, which is
not recommended

Hormone therapy

Hormone therapy has not been well-studied in women with human immunodeficiency virus infection, but can be
considered for treatment of severe menopausal symptoms; the associations between hormone therapy and ART
with cardiac disease suggest cautious and short-term use

Phosphodiesterase
type 5 inhibitors

Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) levels are increased by ART; lower dosing is required

Psychiatric
medications

Most psychiatric medications are compatible with ART; however, lorazepam (Ativan), oxazepam, and temazepam
(Restoril) should not be used

ART = antiretroviral therapy; NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor.
Information from references 1, 5, and 6.

hepatotoxicity and liver failure in women with a

baseline CD4 cell count of more than 250 per mm3
(0.25 109 per L) and in men with a baseline count of
more than 400 per mm3 (0.40 109 per L). Efavirenz is
the most commonly used NNRTI, and is combined in a
once-daily pill with emtricitabine and tenofovir (Atripla).
Efavirenz can cause adverse effects of the central nervous
system (e.g., sleep, cognitive, and mood disorders) in
50 percent of patients during the first month of treatment; this prevalence decreases to 23 percent at three
months, and is similar to baseline by six months.1,13,14
Efavirenz also can cause hyperlipidemia and liver toxicity, and is not recommended for use during pregnancy.
Etravirine (Intelence) is the first second-generation
NNRTI.15 It has been studied primarily in treatmentexperienced patients. Resistance, including intra-class
resistance, has developed to first-generation NNRTIs
with a single mutation (K103N). Multiple mutations
are required before resistance to etravirine develops,
and it can be used in patients with resistance to other
NNRTIs caused by K103N mutation. The most common
adverse effects are rash and nausea. The liver, lipid, and
1446 American Family Physician

neuropsychiatric effects common with first-generation

NNRTIs have not been reported with etravirine.
Development of a rash (19.5 percent of patients) is an
indication for stopping the medication and not rechallenging; severe and possibly fatal Stevens-Johnson
syndrome, toxic epidermal necrolysis, and erythema
multiforme occur in 1.3 percent of patients taking etravirine.15 Women may be at higher risk of rash than men
(30 versus 18 percent).15 Etravirine is metabolized by the
CYP450 system, so drug interactions will be significant
as they are identified.
PROTEASE INHIBITORS

Several PIs are currently in use (Table 5).1,7,16 Boosting

refers to the use of a small dose of ritonavir (Norvir) in
combination with another PI. Most ART regimens are
boosted, although some patients cannot tolerate the
adverse gastrointestinal effects of ritonavir. PIs are metabolized by the CYP450 system and are associated with the
most drug-drug interactions. Common adverse effects of
PIs include gastrointestinal effects, lipohypertrophy, glucose intolerance or diabetes mellitus, and lipid disorders.

www.aafp.org/afp

Volume 83, Number 12

June 15, 2011

Adverse Effects of Antiretroviral Therapy for HIV

Table 3. Adverse Effects of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Drug

Food restrictions

Renal or hepatic
modification*

Abacavir
(Ziagen)

None

Hepatic

Screen for HLA-B*5701 before use; do not use if positive; potentially fatal
hypersensitivity reaction (rash and systemic symptoms) can occur in
negative patients; observational cohort found association between abacavir
plus didanosine and myocardial infarction, but randomized studies have not
confirmed

Didanosine
(Videx)

Take on empty
stomach

Renal

Peripheral neuropathy, pancreatitis, gastrointestinal effects, retinal changes,

optic neuritis, increased risk of complications when used in combination
with stavudine, noncirrhotic portal hypertension

Emtricitabine
(Emtriva)

None

Renal

Minimal adverse effects; hyperpigmentation of palms and soles, risk of hepatitis B

flare when stopped (also effective for treatment of hepatitis B)

Lamivudine
(Epivir)

None

Renal

Risk of hepatitis B flare when stopped (also effective for treatment of

hepatitis B)

Stavudine
(Zerit)

None

Renal

Potentially fatal lactic acidosis and pancreatitis, especially when

combined with didanosine; peripheral sensory neuropathy; lipoatrophy;
hyperlipidemia; glucose intolerance; diabetes mellitus

Tenofovir
(Viread)

None

Renal

Asthenia, headache, diarrhea, nausea, vomiting, flatulence, renal toxicity,

proteinuria, renal failure, decreased bone mineral density, risk of hepatitis B
flare when stopped (also effective for treatment of hepatitis B)

Zidovudine
(Retrovir)

None (may be
better tolerated
with food)

Renal

Anemia, neutropenia, nausea, vomiting, headache, fatigue, myopathy,

hepatitis, hyperpigmentation of oral mucosa and nail beds

Adverse effects

Class adverse effects include mitochondrial toxicity (e.g., lactic acidosis, steatosis), lipoatrophy (especially when combined with efavirenz
[Sustiva]), lipohypertrophy, and hyperlipidemia (especially stavudine and zidovudine).
NOTE:

*Renal or hepatic modification requires decreased dosing based on the severity of underlying disease. Some drugs may be contraindicated. Check
prescribing information for up-to-date recommendations.
Information from references 1 and 7.

Approximately 60 percent of patients taking PIs have

elevated total cholesterol levels (greater than 240 mg
per dL [6.22 mmol per L]), and 75 percent have triglyceride levels greater than 500 mg per dL (5.65 mmol
per L).16 Unboosted atazanavir is considered the most
lipid-favorable PI; boosted darunavir (Prezista) and
boosted atazanavir are the next best choices if baseline
hyperlipidemia is significant.1 PIs are associated with
glucose intolerance; however this condition is present in
15 to 20 percent of patients with HIV infection, and diabetes develops in up to 6 percent, regardless of PI use.1,5
All medications for diabetes can be used without dosage adjustment in patients with HIV infection.1 Insulinsensitizing agents, including metformin and thiazolidinediones, are recommended.8
Because PIs are metabolized by the CYP450 system,
the choice of statins is important in patients with lipid
June 15, 2011

Volume 83, Number 12

disorders who are also taking ART (Table 6).5,8,16 Pravastatin (Pravachol) can generally be used without dosage
adjustment, but the lowest possible dosage should be
used in patients who are also taking darunavir. Rosuvastatin (Crestor) and atorvastatin (Lipitor) are alternative
medications. Simvastatin (Zocor) and lovastatin (Mevacor) should not be used with PIs; niacin, fibrates, and
omega-3 fatty acids can be used.12
ENTRY AND FUSION INHIBITORS

HIV enters the CD4 cell by fusing with the cell membrane
and attaching to chemokine receptors. Entry and fusion
inhibitors block these receptors, preventing the virus from
entering the cells. Enfuvirtide (Fuzeon), a fusion inhibitor, is used primarily in treatment-experienced patients
with limited therapeutic options. However, it is a painful subcutaneous injection, and is not commonly used.

www.aafp.org/afp

American Family Physician 1447

Adverse Effects of Antiretroviral Therapy for HIV

Table 4. Adverse Effects of Non-Nucleoside Reverse Transcriptase Inhibitors
Renal or hepatic
modification

Drug*

Food restrictions

Adverse effects

Efavirenz
(Sustiva)

Take on empty
stomach at
bedtime

Renal

Dizziness, insomnia, headache, inability to concentrate, abnormal dreams,

lipoatrophy when used with stavudine (Zerit) or zidovudine (Retrovir), potential
teratogenicity, false-positive cannabinoid and benzodiazepine screening assays

Etravirine
(Intelence)

Take with food

None

Nausea, peripheral neuropathy, hypertension, hypersensitivity reaction; increased

liver function, increased cholesterol and triglyceride levels

Nevirapine
(Viramune)

None

Hepatic

Severe hepatotoxicity, liver failure, and death; women with baseline CD4 cell
count > 250 per mm3 (0.25 109 per L) and men with baseline CD4 > 400 per
mm3 (0.40 109 per L) are at highest risk

Class adverse effects include hyperlipidemia and rash, which can progress to Stevens-Johnson syndrome, toxic epidermal necrosis, or erythema
multiforme.
NOTE:

*Another non-nucleoside reverse transcriptase inhibitor, Rilpivirine (Endurant), was approved by the U.S. Food and Drug Administration on May
20, 2011, for use in treatment-naive patients.
Renal or hepatic modification requires decreased dosing based on the severity of underlying disease. Some drugs may be contraindicated. Check
prescribing information for up-to-date recommendations.
Information from references 1, 7, and 11.

Table 5. Adverse Effects of Protease Inhibitors

Drug

Food restrictions

Renal or hepatic
modification*

Atazanavir
(Reyataz)

Take with food

Hepatic

Adverse effects
Asymptomatic indirect hyperbilirubinemia, rash (20% of patients;
does not require discontinuation), PR prolongation, kidney stones
Use with caution in patients with underlying cardiac conduction
abnormalities; requires acid in stomach for absorption; see
prescribing information for dosing with antacids, histamine H2
blockers, and proton pump inhibitors

Darunavir (Prezista)

Take with food

None

Rash (10% of patients; may be severe and require discontinuation)

Use with caution in patients with sulfonamide allergy

Fosamprenavir
(Lexiva)

None

Hepatic

Perioral paresthesia, rash (19% of patients; may be severe)

Indinavir (Crixivan)

Take 1 hour before or 2

hours after meal; drink 50
oz (1.5 L) of water per day

Hepatic

Indirect hyperbilirubinemia, kidney stones, renal insufficiency,

alopecia, dry skin and mucous membranes, paronychia,
ingrown toenails, gallstones

Lopinavir/ritonavir
(Kaletra)

None (may be better

tolerated with food)

None

Potentially fatal pancreatitis, increased risk of myocardial

infarction with long-term use, PR and QT prolongation

Nelfinavir (Viracept)

Take with food

None

Diarrhea

Ritonavir (Norvir)

Take with food

Hepatic

Altered taste, circumoral and peripheral paresthesia

Saquinavir (Invirase)

Take within 2 hours of a

meal

Hepatic

Rash, prolonged QT interval, hyperprolactinemia (rare)

Tipranavir (Aptivus)

None

Hepatic

Severe hepatitis; intracranial hemorrhage

Use with caution in patients with sulfonamide allergy

Use with caution in patients with sulfonamide allergy

NOTE: Class

adverse effects include gastrointestinal effects (e.g., diarrhea, nausea, vomiting), hyperglycemia and insulin resistance (may not be classspecific), hyperlipidemia, bleeding in patients with hemophilia, peripheral lipoatrophy and central fat accumulation, hepatotoxicity (especially with
tipranavir), and multiple drug interactions.
*Renal or hepatic modification requires decreased dosing based on the severity of underlying disease. Some drugs may be contraindicated. Check
prescribing information for up-to-date recommendations.
Used in boosted regimens; dosage should be decreased when combined with other protease inhibitors.
Information from references 1, 7, and 16.

Adverse Effects of Antiretroviral Therapy for HIV

Table 6. Treatment of Dyslipidemia in Patients with Human Immunodeficiency Virus Infection

Lifestyle and dietary changes

Medications

Dietary cholesterol intake < 200 mg per day

Fibrate for patients with triglyceride levels 500 mg per dL (5.65 mmol per L)

Exercise (> 200 kcal per day)

Saturated fat intake < 7% of total daily calories

Statin for patients with triglyceride levels > 200 to 499 mg per dL (2.26 to 5.64 mmol
per L)

Smoking cessation

LDL cholesterol goals and thresholds for therapy

Weight loss

Cardiovascular risk factors*

LDL goal (mg per

dL [mmol per L])

LDL threshold to initiate drug

therapy (mg per dL [mmol per L])

Non-HDL threshold to initiate drug therapy

(mg per dL [mmol per L])

0 or 1 risk factor

< 160 (4.14)

190 (4.92)

210 (5.44)

10-year risk 10 to 20%

< 130 (3.37)

130 (3.37)

160 (4.14)

10-year risk < 10%

< 130 (3.37)

160 (4.14)

190 (4.92)

< 100 (2.59)

130 (3.37)

160 (4.14)

2 or more risk factors

Coronary artery disease or

diabetes mellitus

HDL = high-density lipoprotein; LDL = low-density lipoprotein.

*Risk factors include tobacco use, hypertension (blood pressure > 140/90 mm Hg), HDL < 40 mg per dL (1.04 mmol per L), age > 45 years (men)
or > 55 years (women), family history (first-degree relative with coronary artery disease before 55 [men] or 65 years of age [women]).
Non-HDL: total cholesterol minus HDL.
Information from references 5, 8, and 16.

Common adverse effects include neutropenia and an

increased risk of pneumonia (Table 7).1,7,17
C-C chemokine receptors on CD4 cells include CCR5
(R5) and CXCR4 (X4). Maraviroc, an entry inhibitor, is
the only available CCR5 antagonist. It is approved for
use in both treatment-naive and treatment-experienced
patients.18,19 Maraviroc works only on R5 cells; therefore,

an R5 tropism test should be performed before initiating

therapy with maraviroc.1 Maraviroc is as effective as efavirenz when each drug is combined with lamivudine/
zidovudine (Combivir). However, maraviroc is better
tolerated; 13.6 percent of patients discontinued therapy
with efavirenz because of adverse effects, whereas only
4.2 percent discontinued maraviroc.20 Compared with

Table 7. Adverse Effects of Fusion, Entry, and Integrase Inhibitors

Food
restrictions

Renal or hepatic
modification*

Entry inhibitor:
maraviroc (Selzentry)

None

None

Cough, fever, upper respiratory symptoms, rash, abdominal pain, orthostatic

hypotension, musculoskeletal symptoms; hepatotoxicity may be associated
with rash and eosinophilia; increased risk of myocardial infarction (1.3%)
compared with placebo in 24-week study17

Fusion inhibitor:
enfuvirtide (Fuzeon)

None

None

Injection site reactions, eosinophilic hypersensitivity reactions (less than 1%)

and neutropenia; may increase risk of bacterial pneumonia

Integrase strand
transfer inhibitor:
raltegravir (Isentress)

None

None

Diarrhea, nausea, headache, increased creatine kinase levels, myopathy,

rhabdomyolysis

Drug

Adverse effects

*Renal or hepatic modification requires decreased dosing based on the severity of underlying disease. Some drugs may be contraindicated. Check
prescribing information for up-to-date recommendations.
Information from references 1, 7, and 17.

June 15, 2011

Volume 83, Number 12

www.aafp.org/afp

American Family Physician 1449

Adverse Effects of Antiretroviral Therapy for HIV

patients taking efavirenz, those receiving maraviroc have

more cases of bronchitis and nasopharyngitis. Patients
taking maraviroc also report more fever and esophageal
candidiasis, but fewer headache symptoms than those
receiving placebo.18 Lipid profiles in patients receiving
maraviroc are also better compared with those receiving
efavirenz. Studies of interactions with other medications
are limited.
INTEGRASE STRAND TRANSFER INHIBITORS

Integrase strand transfer inhibitors prevent viral DNA

from integrating into host DNA by inhibiting the integrase enzyme involved in strand transfer.21-24 Raltegravir
(Isentress) is the first drug in this class to be approved for
use in both treatment-naive and treatment-experienced
patients.21-24 It is taken orally twice per day. Resistance to
raltegravir develops easily, which may limit its long-term
effectiveness. Myopathy and rhabdomyolysis have been
reported in patients receiving raltegravir23,24 ; however,
adverse effects are similar to those with placebo. Compared with patients receiving efavirenz, those receiving
raltegravir have fewer central nervous system and neuropsychiatric problems.23,24 Studies of interactions with
other medications are limited.
Treatment Considerations
The role of ART in the development of cardiac, bone, and
kidney disease in patients with HIV infection is unclear
because HIV itself contributes to these long-term complications. Increased screening for these complications is
recommended.4,5
Cardiovascular disease accounts for 10 percent of
deaths in patients with HIV infection.1 ART that includes
indinavir (Crixivan), lopinavir/ritonavir, didanosine
(Videx), or abacavir (Ziagen) increases the risk of heart
disease.25,26 Multiple studieswith conflicting results
suggest that lower CD4 cell counts, higher viral load,
and cumulative exposure to ART are associated with
increased cardiovascular risk.1,25,27 Heavy alcohol use (at
least 14 drinks per week in men) may increase the risk of
cardiovascular disease independently of CD4 cell count,
ART, or traditional cardiac risk factors.28 Patients should
be screened for traditional cardiac risk factors (e.g.,
hypertension, diabetes, dyslipidemia, tobacco use, family history) annually or after a change in therapy, or more
frequently if clinically indicated, and treated according
to guidelines for the general population.1,5,8,16
Vitamin D deficiency, osteopenia, and osteoporosis
are more common in patients with HIV infection5,8,29-34 ;
osteopenia occurs in 52 percent of patients and osteoporosis in 15 percent.35 Tenofovir or didanosine use is
1450 American Family Physician

associated with lower bone mineral density in men and

women.29 Vitamin D deficiency is associated with the use
of NNRTIs32 ; screening should be considered in patients
receiving these drugs. Osteoporosis screening should
begin after 50 years of age in patients receiving tenofovir or didanosine, and is recommended in all patients
older than 50 years who have HIV infection if other risk
factors are present (other than female sex and menopause).5,8 Bisphosphonates, calcium, and vitamin D can
be used for treatment of osteoporosis.36-38
It is estimated that 30 percent of patients with HIV
infection have abnormal kidney function.5,39 Many HIV
medications require dosage adjustment in patients with
glomerular filtration rates less than 50 mL per minute per
1.73 m2 ; however, NNRTIs and PIs do not.39 Renal insufficiency is related to ART (tenofovir, indinavir, atazanavir,
lopinavir/ritonavir) but also to HIV-associated nephropathy. Patients should be screened at least annually by calculation of glomerular filtration rate and urinalysis for
proteinuria. Black patients; those with CD4 cell counts
of less than 200 per mm3 (0.20 109 per L) or viral loads
of more than 4,000 copies per mL; and those with cooccurring diabetes, hypertension, or hepatitis C should
be screened every six months.5,39 Patients with 1+ proteinuria or a glomerular filtration rate of less than 60 mL
per minute per 173 m2 should have renal ultrasonography
and 24-hour urine collection for protein analysis, and
renal biopsy should be considered.39 Treatment includes
angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, ART for patients with HIVassociated nephropathy, and steroids for adults with
HIV-associated nephropathy.39 Protein restriction has
not been proven beneficial.39
The Author
CARIN E. REUST, MD, MSPH, FAAFP, is an associate professor of clinical
family and community medicine at the University of Missouri School of
Medicine, Columbia. She has served on the board of directors of the AIDS
Project of the Ozarks, and has served as medical director for the Regional
AIDS Interfaith Network.
Address correspondence to Carin E. Reust, MD, MSPH, FAAFP, University of Missouri School of Medicine, MA 303 HSC, Columbia, MO 65212
(e-mail: [email protected]). Reprints are not available from
the author.
Author disclosure: No relevant financial affiliations to disclose.
REFERENCES
1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. Rockville, Md.: U.S. Department of Health and Human
Services; 2011. http://www.aidsinfo.nih.gov/ContentFiles/Adultand
AdolescentGL.pdf. Accessed April 9, 2011.

www.aafp.org/afp

Volume 83, Number 12

June 15, 2011

Adverse Effects of Antiretroviral Therapy for HIV

2. Gallant JE. When to start antiretroviral therapy: a swinging pendulum?

Top HIV Med. 2008;16(2):82-88.
3. Kitahata MM, Gange SJ, Abraham AG, et al.; NA-ACCORD Investigators. Effect of early versus deferred antiretroviral therapy for HIV on
survival. N Engl J Med. 2009;360(18):1815-1826.

23. Lennox JL, DeJesus E, Lazzarin A, et al.; STARTMRK investigators.

Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection:
a multicentre, double-blind randomised controlled trial. Lancet.
2009;374(9692):796-806.

4. Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of

adult HIV infection: 2010 recommendations of the International AIDS
Society-USA panel. JAMA. 2010;304(3):321-333.

24. Steigbigel RT, Cooper DA, Kumar PN, et al.; BENCHMRK Study Teams.
Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359(4):339-354.

5. Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the
management of persons infected with human immunodeficiency virus:
2009 update by the HIV Medicine Association of the Infectious Diseases
Society of America. Clin Infect Dis. 2009;49(5):651-681.

25. Friis-Mller N, Reiss P, Sabin CA, et al.; DAD Study Group. Class of
antiretroviral drugs and the risk of myocardial infarction. N Engl J Med.
2007;356(17):1723-1735.

6. Castao PM. Use of intrauterine devices and systems by HIV-infected

women. Contraception. 2007;75(6 suppl):S51-S54.
7. Drugs for HIV infection. Treat Guidel Med Lett. 2009;7(78):11-22.
8. New York State Department of Health. Long-term complications of
antiretroviral therapy. http://hivguidelines.org/GuidelineDocuments/
a-longterm.pdf. Accessed May 29, 2010.
9. Szczech LA. Renal dysfunction and tenofovir toxicity in HIV-infected
patients. Top HIV Med. 2008;16(4):122-126.
10. Kirk O, Mocroft A, Reiss P, et al. Chronic kidney disease and exposure
to ART in a large cohort with long-term follow-up: the EuroSIDA Study.
Paper # 107LB. 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010, San Francisco, Calif. http://retroconference.
org/2010/Abstracts/39775.htm. Accessed March 15, 2011.
11. Etravirine (Intelence) for HIV infection. Med Lett Drugs Ther. 2008;
50(1288):47-48.
12. Gerber JG, Kitch DW, Fichtenbaum CJ, et al. Fish oil and fenofibrate for
the treatment of hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: results of ACTG A5186 [published correction appears
in J Acquir Immune Defic Syndr. 2009;50(3):343]. J Acquir Immune
Defic Syndr. 2008;47(4):459-466.

26. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in

patients with HIV infection exposed to specific individual antiretroviral
drugs from the 3 major drug classes: the data collection on adverse events
of anti-HIV drugs (D:A:D) study. J Infect Dis. 2010;201(3):318-330.
27. Molina JM, Andrade-Villanueva J, Echevarria J, et al.; CASTLE Study
Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/
ritonavir, each in combination with tenofovir and emtricitabine,
for management of antiretroviral-naive HIV-1-infected patients: 48
week efficacy and safety results of the CASTLE study. Lancet. 2008;
372(9639):646-655.
28. Freiberg MS, McGinnis KA, Kraemer K, et al.; VACS Project Team. The
association between alcohol consumption and prevalent cardiovascular diseases among HIV-infected and HIV-uninfected men. J Acquir
Immune Defic Syndr. 2010;53(2):247-253.
29. Jacobson DL, Spiegelman D, Knox TK, Wilson IB. Evolution and predictors of change in total bone mineral density over time in HIV-infected
men and women in the nutrition for healthy living study. J Acquir
Immune Defic Syndr. 2008;49(3):298-308.
30. Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da Silva
BA. Loss of bone mineral density after antiretroviral therapy initiation,
independent of antiretroviral regimen. J Acquir Immune Defic Syndr.
2009;51(5):554-561.

13. Hawkins T, Geist C, Young B, et al. Comparison of neuropsychiatric side

effects in an observational cohort of efavirenz- and protease inhibitortreated patients. HIV Clin Trials. 2005;6(4):187-196.

31. Grund B, Peng G, Gibert CL, et al.; INSIGHT SMART Body Composition
Substudy Group. Continuous antiretroviral therapy decreases bone mineral density. AIDS. 2009;23(12):1519-1529.

14. Lochet P, Peyrire H, Lotth A, Mauboussin JM, Delmas B, Reynes J.

Long-term assessment of neuropsychiatric adverse reactions associated
with efavirenz. HIV Med. 2003;4(1):62-66.

32. Mueller NJ, Fux CA, Ledergerber B, et al.; Swiss HIV Cohort Study.
High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. AIDS.
2010;24(8):1127-1134.

15. Elsayed RK, Caldwell DJ. Etravirine: a novel nonnucleoside reverse transcriptase inhibitor for managing human immunodeficiency virus infection. Am J Health Syst Pharm. 2010;67(3):193-205.
16. Dub MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and
management of dyslipidemia in human immunodeficiency virus (HIV)infected adults receiving antiretroviral therapy: recommendations
of the HIV Medical Association of the Infectious Disease Society of
America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003;
37(5):613-627.
17. Two new drugs for HIV infection. Med Lett Drugs Ther. 2008;50
(1277):2-4.
18. Gulick RM, Lalezari J, Goodrich J, et al.; MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl
J Med. 2008;359(14):1429-1441.

33. Cazanave C, Dupon M, Lavignolle-Aurillac V, et al.; Groupe

dEpidmiologie Clinique du SIDA en Aquitaine. Reduced bone mineral
density in HIV-infected patients: prevalence and associated factors.
AIDS. 2008;22(3):395-402.
34. Yin M, Dobkin J, Brudney K, et al. Bone mass and mineral metabolism in
HIV+ postmenopausal women. Osteoporos Int. 2005;16(11):1345-1352.
35. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence
of osteopenia and osteoporosis: a meta-analytic review. AIDS.
2006;20(17):2165-2174.
36. Mondy K, Powderly WG, Claxton SA, et al. Alendronate, vitamin D, and
calcium for the treatment of osteopenia/osteoporosis associated with
HIV infection. J Acquir Immune Defic Syndr. 2005;38(4):426-431.

19. Dolin R. A new class of anti-HIV therapy and new challenges. N Engl
J Med. 2008;359(14):1509-1511.

37. McComsey GA, Kendall MA, Tebas P, et al. Alendronate with calcium
and vitamin D supplementation is safe and effective for the treatment of
decreased bone mineral density in HIV. AIDS. 2007;21(18):2473-2482.

20. Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both
in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis.
2010;201(6):803-813.

38. Huang J, Meixner L, Fernandez S, McCutchan JA. A double-blinded,

randomized controlled trial of zoledronate therapy for HIV-associated
osteopenia and osteoporosis. AIDS. 2009;23(1):51-57.

21. Havlir DV. HIV integrase inhibitorsout of the pipeline and into the
clinic. N Engl J Med. 2008;359(4):416-418.
22. Cooper DA, Steigbigel RT, Gatell JM, et al.; BENCHMRK Study Teams.
Subgroup and resistance analyses of raltegravir for resistant HIV-1
infection. N Engl J Med. 2008;359(4):355-365.

June 15, 2011

Volume 83, Number 12

39. Gupta SK, Eustace JA, Winston JA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society
of America. Clin Infect Dis. 2005;40(11):1559-1585.

www.aafp.org/afp

American Family Physician 1451