Management of Antiretroviral Treatment–Related Complications

Infect Dis Clin N Am

21 (2007) 103–132

Management of AntiretroviralTreatment–Related Complications

Risa M. Hoffman, MD, MPHa,*,Judith S. Currier, MDb

aUCLA Division of Infectious Diseases, Department of Medicine,

David Geffen School of Medicine at the University of California,

10833 Le Conte Avenue, 37-121 CHS, Los Angeles, CA 90095, USAbCenter for Clinical AIDS Research and Education, Division of Infectious Diseases,

Department of Medicine, David Geffen School of Medicine at the University of California,

9911 West Pico Boulevard, Suite 980, Los Angeles, CA 90035, USA

The year 2006 marks the 25th anniversary of the discovery of the firstreported case of acquired immunodeficiency syndrome (AIDS). With thislandmark comes celebration of tremendous advances in the understandingof pathogenesis and treatment of infection; however, the anniversary alsobrought the opportunity to analyze future challenges in HIV treatment.Although developing countries are now gaining access to basic antiretrovi-ral regimens (ARVs), only approximately 20% of 6 million individuals indeveloping countries needing treatment have access to ARVs [1]. Withthe success of these medications in restoring immune function and control-ling viral replication, HIV has been transformed into a chronic condition,requiring long-term therapy. Health care providers are increasingly con-fronted with complications of therapy, and expanded worldwide accessand ongoing treatment advances in developed countries have highlightedthe need for increased knowledge of adverse consequences and theirmanagement.

This article reviews six common complications of antiretroviral therapy(ART), including hyperlactatemia/lactic acidosis, hypersensitivity reactions,abnormal glucose metabolism, dyslipidemia, body composition changes,

Dr. Currier is supported by NIH Grants U01 A127660 and K24 AI56933.

* Corresponding author.

E-mail address: [email protected] (R.M. Hoffman).

0891-5520/07/$ - see front matter � 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.idc.2007.01.007 id.theclinics.com

mailto:[email protected]

104 HOFFMAN & CURRIER

and cardiovascular disease. Each section provides a brief discussion of riskfactors and clinical features, with primary emphasis on clinical managementand monitoring.

Hyperlactatemia/lactic acidosis

Risk factors and clinical features

Among patients undergoing nucleoside reverse transcriptase (NRTI)therapy, the incidence of lactic academia ranges from 8% to 21%. Stavudine(d4T, Zerit) is the most frequently implicated NRTI [2]. The proposedmechanism for lactic acid accumulation is inhibition of mitochondrial poly-merase-g. Poisoning of mitochondria pressures the cell to meet energy re-quirements through anaerobic metabolism, with generation of lactate.Affinity for polymerase-g is strongest for stavudine, but didanosine (ddI,Videx) and zidovudine (ZDV, AZT, Retrovir) follow in predilection forbinding the enzyme. Abacavir (ABC, Ziagen), tenofovir (TDF, Viread),and lamivudine (3TC, Epivir) are least implicated in symptomatic lactic ac-ademia, although case reports link both drugs to life-threatening episodes oflactate elevation [3,4]. A twofold increase in risk for symptomatic lactate el-evation has been noted for each NRTI added to a regimen, and the combi-nation of stavudine and didanosine is now discouraged by the United StatesPublic Health service because of a high risk for fatal lactic acidosis experi-enced with this combination, particularly in pregnant women [5].

NRTI-associated lactic academia can occur after months or years ontherapy. However, the overall incidence of this complication remains lowat less than 2% [6]. Demographic and genetic risk factors for the develop-ment of lactic academia are ill-defined. Possible predisposing conditionsinclude treatment for chronic hepatitis B or C coinfection, chronic muscledisorders, kidney disease, and combination therapy with metformin andNRTIs [7–11]. In the Swiss HIV Cohort Study, independent predictors forlactic academia included older age, severe immunodeficiency, liver dysfunc-tion, and stavudine-containing regimens. Increased waist-to-hip ratio wasalso found to be associated with development of severe hyperlactatemia[12]. Recent research from South Africa has described higher rates of symp-tomatic lactic academia than previously reported in developed countries,with highest risk in overweight women, and an overall mortality rate of29% [13]. All cases occurred in patients on South Africa’s first-line regimenof stavudine, lamivudine, and a non–nucleoside reverse transcriptase inhib-itor (NNRTI).

The clinical presentation of NRTI-associated lactic academia is variableand ranges from generalized weakness, myalgias, and paresthesias to non-specific abdominal symptoms. Physical findings can include weight loss,hepatomegaly, and fat redistribution. Laboratory evaluation reveals an ele-vated lactate with increased anion gap and acidemia on arterial blood gas

105ANTIRETROVIRAL TREATMENT COMPLICATIONS

testing. Other laboratory abnormalities may include elevated creatininekinase, lactate dehydrogenase, C-reactive protein, lipase, and amylase [14].Ultrasonography or CT may reveal an enlarged, fatty liver.

Diagnosis is achieved when lactate is elevated in the context of a compat-ible clinical syndrome. Lactate measurements should be drawn as venoussamples, without a tourniquet in place. Samples require storage on iceand processing within 4 hours. Recent exercise, dehydration, and blooddraw technique can falsely elevate lactate levels. Hyperlactatemia is definedas a lactate level from 2.5 to 5 mmol/L without acidosis. When lactate levelsexceed 5 mmol/L and are associated with bicarbonate less than 20 mmol/L,arterial pH less than 7.34, and anion gap more than 12, patients have lacticacidosis and are typically symptomatic. Mortality in excess of 60% has beendescribed for patients with a lactate level exceeding 15 mmol/L [15].

Management

The cornerstone of management is withdrawal of offending NRTIs andsupportive care. As a single intervention, drug cessation often leads toimprovement in clinical status and reversal of laboratory abnormalities.Supportive management of acidosis may include intravenous fluids, intuba-tion, and dialysis. Evidence for bicarbonate infusion is lacking, and data aremixed on the use of dichloroacetate, which acts on pyruvate dehydrogenaseto reduce the production of lactate [16]. Some authors recommend ‘‘mito-chondrial supportive care,’’ including the use of coenzyme Q10, L-carnitine,vitamin C, and riboflavin. Supplementation has been effective for patientswho have inherited mitochondrial disorders, but for NRTI-associated lacticacademia, data are limited to the case report or case series level [17–20].

Small studies have shown safety of switching to non–stavudine-contain-ing regimens in patients with mild lactate elevations [21,22]. For patientswho have a history of severe lactic acidosis, rechallenge with NRTI shouldbe performed with careful monitoring and attention to choice of drug, per-haps using tenofovir or abacavir given their lesser affinity for polymerase-g.Options also include use of an NRTI-sparing regimen, such as combinationprotease inhibitor and NNRTI. Risk for recurrent lactic acidosis must bebalanced against regimen potency.

Monitoring

Monitoring for lactate elevation is not generally recommended. Of onequarter of patients taking NRTIs who will have an elevated lactate duringtheir treatment course, 85% will be asymptomatic and have no clinical se-quelae [23]. Additionally, asymptomatic elevations do not predict episodesof severe lactic acidemia [24]. In the Swiss HIV Cohort Study, $11,268 wasspent to detect 42 episodes of severe hyperlactatemia. In this study, abnormalliver function tests were an independent predictor of severe


hyperlactatemia, and the authors propose that liver function monitoringmay be a more cost-effective approach [12]. Other reasonable strategies in-clude selective monitoring of serum lactate in presumed high-risk popula-tions, such as older individuals, those who have abnormal liver function,hepatitis B or C coinfection, and those being treated with stavudine- or di-danosine-containing regimens. The latter criterion would not be feasible indeveloping countries where stavudine is used in the first-line regimen, andhighlights the tremendous challenge of creating a safe and cost-effectiveapproach to hyperlactatemia in this setting.

Drug hypersensitivity


Non–nucleoside reverse transcriptase inhibitorsDrug reactions in association with antiretroviral therapy are common,

with manifestations of rash or transaminitis representing most syndromes.Risk factors for the development of a specific type of drug reaction are be-coming more elucidated. Drug class is one of the most important determi-nants, with NNRTIs posing the highest risk. Approximately 10% to 17%of patients taking NNRTIs will develop rash [25]. Maculopapular rash onthe trunk, face, and extremities occurs in 16% of patients on nevirapine(NVP, Viramune) during the first 6 weeks of therapy. Severe rash hasbeen seen in approximately 6.5% of patients on nevirapine and 4% on efa-virenz [26–28]. Female sex, CD4 cell counts less than 100 cells/mL, and ageolder than 40 years are independent risk factors for the development of cu-taneous reactions to NNRTIs [25]. Hepatotoxicity frequently accompaniesrash as part of a hypersensitivity reaction or can occur as a singularfinding.

Women have emerged as being at high risk for NNRTI hypersensitivity,with 3- to 12-fold risk for cutaneous reactions and increased likelihood ofnevirapine-associated severe skin rash and hepatotoxicity [29]. Other identi-fied risk factors include coexistent hepatitis B or C, obesity, pregnancy, andless-advanced stage of immunosuppression (CD4 cell count, O250 cells/mLin women and O400 cells/mL in men) [30,31]. In the United States, nevira-pine now carries a boxed warning regarding risks for severe hepatotoxicreactions in women and individuals with increased CD4 cell counts.

In the case of suspected drug reaction, the timing of symptoms in rela-tion to initiation of a drug, specific clinical features of the patient, andcomplete evaluation of medication history are important to note. Clinicallydistinguishing features for typical NNRTI reactions are (1) occurrencewithin the first 6 weeks of therapy (although manifestations remain com-mon through the first 12 to 18 weeks of therapy); (2) rash, ranging frommorbilliform to Stevens-Johnson syndrome, with severe involvement ofskin and mucous membranes; and (3) hypotoxicity, occurring along the


same timeline, and often asymptomatic and developing in association withrash. Of concern, individuals can develop fulminant liver failure withoutpreceding systemic hypersensitivity symptoms or other warning signs.

Abacavir

Abacavir hypersensitivity typically occurs within 6 weeks of drug initia-tion, with a mean of 12 to 14 days; however, reactions have been describedup to 12 months on therapy. In contrast to NNRTI hypersensitivity, rashwith abacavir is often mild and may be absent in up to 30% of cases [32].Abnormal laboratory studies can accompany systemic symptoms and in-clude leukopenia, anemia, thrombocytopenia, elevated blood urea nitrogen,creatinine, and lactate dehydrogenase. Eosinophilia is uncommon. The pres-ence of systemic symptoms such as fever, malaise, respiratory symptoms,and abdominal complaints, especially if they worsen with continued dosing,are highly suggestive of this diagnosis. Nonetheless, identification of thissyndrome is challenging because symptoms substantially overlap with othercommon processes, such as immune reconstitution, viral infections, andother drug reactions, and no single test can confirm or exonerate abacaviras causative.

The overall incidence of abacavir hypersensitivity ranges from 3% to 5%but is as high as 8% in Caucasians [33]. Two independent research groupshave shown a strong association with HLA-B*5701 and abacavir hypersen-sitivity [34,35], and in Australia, prospective screening for HLA-B*5701reduced the incidence of abacavir reactions from 8% to 2% [36]. The useful-ness and generalizability of this approach is now being tested in larger stud-ies. Because HLA-B*5701 is rare in certain African and Asian populations,ultimate cost-effectiveness of this approach varies according to geographicarea. The advent of abacavir patch testing may diminish cost and has shownstrong correlation with HLA-B*5701 positivity [37,38]. Testing for presenceof HLA type cannot be used to supersede clinical judgment, and presence orabsence of the allele should not be used as criteria for rechallenge with aba-cavir, but rather to guide therapy for treatment-naı̈ve subjects [33].

Management

Non–nucleoside reverse transcriptase inhibitorsIf patients develop mild to moderate rash during the first 2 weeks of

once-daily therapy, nevirapine can be continued but typical escalation totwice-daily regimen should be deferred until the rash has resolved. Useof prednisone and antihistamines (cetirizine) during the first few weeksof nevirapine has failed to show effectiveness in preventing hypersensitivityreactions [39,40]. Any patient presenting with rash should have testing ofliver function, a complete blood cell count with differential, and measure-ment of renal function. Treatment should be discontinued immediately for


severe skin reactions or when rash occurs with any of the following sys-temic symptoms: fever, urticaria, wheezing, clinical hepatitis, muscle orjoint aches, exfoliation, mucosal involvement or conjunctivitis, elevated al-anine aminotransferase or aspartate aminotransferase five times or morethe upper limit of normal (ULN), eosinophilia, granulocytopenia, or sig-nificant renal dysfunction. Patients who show evidence of these systemicsymptoms should undergo close observation and appropriate supportivecare. Limited data exist regarding the use of efavirenz in patients whohave a history of severe hypersensitivity reaction to nevirapine. Proteaseinhibitor (PI)–based therapy should be considered the safest alternativein these patients.

Abacavir

Treatment for suspected abacavir hypersensitivity is supportive andshould include immediate withdrawal of antiretroviral drugs. Symptomaticmanagement includes intravenous hydration, antiemetics, and analgesics.Corticosteroids are of no proven benefit. If abacavir is etiologic, improve-ment should occur within 1 to 2 days of drug cessation. Patients whohave a history of abacavir reactions should never be rechallenged withthis medication. Extremely high rates of anaphylactic reactions with cardio-vascular collapse and death have occurred in patients re-exposed to abacavirafter an initial reaction [32].

Monitoring

Non–nucleoside reverse transcriptase inhibitorsOptimal monitoring for NNRTIs has not been defined, but because of

high rates of severe skin reactions and hypotoxicity during the initial 3months of nevirapine, vigilance for skin changes and hepatotoxicity is war-ranted. Nevirapine (Boehringer Ingelheim, Germany) carries a manufac-turer’s recommendation for a dose escalation protocol to preventdevelopment of cutaneous reactions. This protocol includes initiation ofthe drug at a dose of 200 mg once daily for 2 weeks, followed by an increaseto twice-daily dosing if the patient is tolerating therapy. Before therapy, pa-tients should be screened for hepatitis B and C infection. Baseline liver func-tion should be obtained, with repeat testing 2 weeks after initiation and thenmonthly for the first 3 months. Coinfection with hepatitis B or C or under-lying liver disease is not a contraindication to NNRTI therapy, but morefrequent monitoring of liver function may be required. Transaminitis upto five times ULN is considered tolerable as long as close observation is con-tinued and associated systemic hypersensitivity is not present. Monitoringliver function does not always predict or prevent fulminant liver failure. Aproposed approach to nevirapine hypersensitivity is included in Fig. 1.


Abacavir

No monitoring laboratory tests are predictive of abacavir hypersensitiv-ity. Patient education at drug initiation is crucial and appropriate documen-tation after initial reaction is essential to prevent rechallenge in a patientwith prior abacavir reaction.

Abnormal glucose metabolism


An association between ART and abnormal glucose metabolism wasestablished in 1987 when the U.S. Food and Drug Administration (FDA)issued a public health advisory reporting 83 cases of new-onset hyperglyce-mia in patients taking PIs [41]. Since then, impaired glucose tolerance, insu-lin resistance, and diabetes mellitus have emerged as important clinicalsequelae of HIV therapy. Precise mechanisms are unknown, but HIV infec-tion seems to confer some increased risk for diabetes in the absence of ART.Retrospective data suggest that individuals infected with HIV have in-creased incidence and age-specific risk for diabetes [42] compared with thosewho are not. Other risk factors are similar to the general population and in-clude obesity, family history, nonwhite race, and older age. HIV-specific

*Baseline LFTs, *Hepatitis B and C Screen, CD4 <250 (women)

Or <400 (men):Initiate nevirapine 200 mg once daily

No adverse reaction and 2 week LFT

< 5 times ULN, proceed with dose

escalation to 200 mg twice daily

Rash within first 2 weeks. Check LFTS, CBC with

differential, and renal function, and evaluate for

mucositis and other systemic symptoms.

LFT > 5 times ULN, severe rash,

or rash with any of the following

systemic features: fever, clinical

hepatitis, muscle or joint aches,

urticaria, mucosal or

conjunctival involvement,

eosinophilia, granulocytopenia,

or significant renal dysfunction.

DISCONTINUE NEVIRAPINE

AND MONITOR

No features of Stevens-Johnson

(conjunctivital involvement, mucositis)

and LFTs < 5 times ULN: Continue

nevirapine at dose of 200 mg once daily

until symptoms resolve

Rash completely resolved and LFTs normal or stable, increase

dose to 200 mg twice daily and monitor with monthly LFTs.

If normal after 3 months, decrease frequency of monitoring

Routine Monitoring with

LFTs monthly through

first 3 months. If normal,

decrease frequency of

monitoring

When symptoms resolve, consider

initiation of PI-based regimen

*Baseline LFT abnormalities

and hepatitis co-infection is

not a contradiction to therapy but may warrant closer monitoring

CBC: Complete blood countLFT: Liver function tests ULN: Upper limit of normal

2 weeks

Fig. 1. Approach to nevirapine hypersensitivity.


factors include lipodystrophy, stavudine exposure, and hepatitis C coinfec-tion [43–45]. Gender-specific risk has been less well characterized, but a re-cent study showed increased rates of abnormal glucose metabolism amongmiddle-aged women on ART, although PI-use was not independently asso-ciated with insulin resistance [46]. Despite this finding, use of PIs remains thestrongest risk factor for abnormal glucose metabolism in HIV patients onART, with studies suggesting a prevalence of 8% to 46% for the spectrumof abnormalities, most commonly described as insulin resistance with im-paired glucose tolerance and normal fasting glucose [47,48]. The proportionof individuals with insulin resistance and impaired glucose tolerance thatwill progress to frank diabetes mellitus is unknown.

Diagnostic criteria for impaired glucose tolerance and diabetes in patientswho have HIV undergoing ART is based on fasting, random, or oral glu-cose tolerance testing (OGTT) (Box 1). Insulin measurements are problem-atic given variability among assays and lack of formalized normative values.

Management

Treatment options for diabetes reflect recommendations for the generalpopulation, with diet, exercise, and weight reduction of critical importance[49]. Additionally, medications (eg, corticosteroids, growth hormone, di-uretics, niacin) should be reviewed for contributions to abnormal glucosemetabolism. Pharmacologic management of hyperglycemia is largely extrap-olated from experience with type 2 diabetes in adults not infected with HIV,with careful attention to drug interactions and overlapping toxicities in pa-tients on ART. Metformin (Glucophage) is a biguanide that increases theaction of insulin, decreases hepatic glucose generation, and increases glucoseuptake by peripheral tissues. In populations infected with HIV, metforminhas been shown in small studies to improve insulin resistance and decrease

Box 1. Diagnosis of abnormal glucose metabolism

Impaired fasting glucose: 100–125 mg/dLImpaired glucose tolerance: 2-hour post-glucose 140–199 mg/dLDiabetes mellitus: fasting glucose >126 mg/dL or 2-hour

post-glucose >200 mg/dL. For a diagnosis of diabetes,patients must have symptoms (polyuria, polydipsia, weightloss) and a casual glucose >200 mg/dL OR fasting glucose>126 mg/dL OR a 2-hour post-glucose by OGTT >200 mg/dL

From the American Diabetes Association, Expert Committee on the Diagnosisand Classification of Diabetes Mellitus. Follow-up report on the diagnosis of dia-betes mellitus. Diabetes Care 2003;26:3160.


body weight after 3 months of therapy, particularly for patients who haveassociated lipodystrophy [21,50,51]. Metformin is a less attractive optionfor patients who have renal insufficiency or are taking NRTIs because ofthe risk for lactate elevations.

Thiazolidinediones bind to peroxisome proliferator-activated receptor-gamma (PPARs) and increase insulin sensitivity and glucose use, and de-crease glucose production. Because the two available drugs, rosiglitazone(Avandia) and pioglitazone (Actos), have slight differences in affinity forPPARs (gamma versus alpha), they therefore have theoretical and practicaldifferences in efficacy and toxicity. They have been shown to improve insulinsensitivity in patients who have HIV, but are associated with weight gainand fluid retention. Rosiglitazone has been associated with increases inlow-density lipoprotein (LDL), but a recent large study showed that piogli-tazone is less offensive in regard to lipid profile, and may even have a favor-able effect on triglyceride levels [52–54]. The entire class of medications hasbeen associated with hepatic dysfunction and should be used cautiously inpatients with preexisting liver disease. All patients taking thiazolidinedionesshould undergo close monitoring of transaminases, particularly in the firstyear of therapy. Sulfonylureas can stimulate insulin secretion and improveplasma glucose, but do not improve insulin resistance and may induce seri-ous hypoglycemia. Combination therapy for diabetes mellitus may be re-quired and has been shown to be effective in patients not infected withHIV [55]. When oral regimens fail to normalize glucose, insulin therapyshould be used to achieve adequate control of blood sugar.

Proper management of glucose abnormalities without frank diabetes isunclear. Preventive therapies are promising, with recent data showingthat rosiglitazone can reduce incident diabetes in adults not infected withHIV who have impaired fasting glucose or impaired glucose tolerance[56]. In the same study, ramipril (Altace) for individuals who have impairedfasting glucose levels or impaired glucose tolerance did not influence the in-cidence of diabetes but significantly increased regression to normoglycemia[57]. Whether longer duration of therapy with ramipril will decrease the in-cidence of diabetes is unclear, and although both drugs show promise, theyhave not been explored as preventive approaches to diabetes in patients in-fected with HIV who have impaired fasting glucose or impaired glucosetolerance.

For further management of abnormal glucose metabolism or frank dia-betes, consideration of substitution of PI for NNRTI is warranted in cer-tain cases, particularly when other metabolic abnormalities are present.Studies with amprenavir and atazanavir (ATV, Reyataz) have not beenlinked to the development of insulin resistance and may be feasible alterna-tives to class-switching [58–60]. Substituting PI for abacavir or NNRTI hasbeen shown to improve insulin resistance, but changes that offset toxicitymay compromise regimen potency and cause loss of viral suppression[61–63].


Monitoring

Before ART is initiated, patients should undergo risk assessment, includ-ing review of family history, body mass index, and medication list. A base-line evaluation for abnormal glucose metabolism should be considered withfasting glucose or, if high-risk, OGTT with 75 g of glucose. Once on ART,follow-up testing should be performed at 6 to 12 weeks and then once every3 months during the first year of therapy. If values are reassuring, monitor-ing can be performed once yearly for patients at low risk. Ongoing counsel-ing regarding diet, exercise, and other risk factor reduction is recommendedfor all patients, regardless of risk.

Lipid disorders


The characteristic lipid profile associated with chronic HIV infection in-cludes elevated triglycerides and decreased high-density lipoprotein (HDL)and LDL, associated with subtypes of LDL that are particularly proathero-genic. PI therapy has been closely linked with the development of hypertri-glyceridemia and increased LDL, with lipid changes occurring in 25% ofpatients at 1 year [64]. Ritonavir has induced similar lipid abnormalitiesin healthy volunteers after only 2 weeks of therapy, suggesting a strongrole for PIs as opposed to viral effect [65]. All PIs with the exception of ata-zanavir share this property. NNRTIs have also been linked to unfavorablelipid changes. Nevirapine increases LDL cholesterol, whereas efavirenz in-creases total cholesterol and has been associated with hypertriglyceridemiawith longer duration of exposure [66,67].

Genetic patterns may increase risk for lipid alterations in the setting ofART. Higher triglyceride levels have been linked to heterozygous or homo-zygous expression of the apolipoprotein E-2 genotype [68,69]. This findingunderlies the importance of obtaining family history and baseline fastinglipid panel before choosing an HIV regimen.

Management

Recommendations from the Infectious Disease Society of America(IDSA) and AIDS Clinical Trials Group (ACTG) have provided a frame-work for approaching dyslipidemia in individuals infected with HIV(Fig. 2) [70]. These guidelines call for management based on the NationalCholesterol Education Program (NCEP) Expert Panel on Detection, Evalu-ation, and Treatment of High Blood Cholesterol in Adults (Adult Treat-ment Panel III). Assessment of risk factors (Box 2) is used to guide choiceof therapy and treatment goals.When appropriate, Framingham calculationsare used to determine 10-year coronary heart disease risk. Non-HDL choles-terol can be used as a target in patients who are hypertriglyceridemic in


whomLDL is difficult to determine. Table 1 provides a suggested guideline fortiming of initiation and goals of treatment for dyslipidemia based on the afore-mentioned factors. This table considers data published after NCEP ATP III(Heart Protection Study, PROVE-IT), which supports choosing an LDL cho-lesterol goal of less than 70 mg/dL (non-HDL !100 mg/dL) in highest-risk

Baseline fasting lipid profile

Modifiable risk factor modification: diet,exercise, smoking cessation

LDL above threshold for risk category (or non-HDL above

threshold): STATIN

CHD Risk Assessment. If ≥ 2 risk factors,perform 10 year risk calculation.

Assess lipid goal based on risk factors andresults of lifestyle interventions (Table 1)

Serum triglycerides >500mg/dL: FIBRATE

Fig. 2. General approach to dyslipidemia and cardiovascular risk in patients infected with HIV

taking ART. (Adapted from Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation

and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults re-

ceiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infec-

tious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis

2003;37(5):613–27; with permission.)

Box 2. Major risk factors that modify low-density lipoproteingoals

Cigarette smokingHypertensionHDL cholesterol <40 mg/dLFamily history of premature coronary heart disease

(men <55 years; women <65 years)Age (men ‚45 years; women ‚55 years)Diabetes is a coronary heart disease risk equivalent.HDL level >60 mg/dL is protective and allows subtraction of one

of the above risk factors.

Adapted from the NCEP Expert Panel on Detection, Evaluation, and Treatmentof High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation2002;106:3143–21; with permission.


patients, such as those who have baseline LDL levels less than 100 mg/dL, re-cent acute coronary syndrome, andmultiple poorly controlled risk factors (ie,diabetes, smoking, metabolic syndrome) [71–73]. These data must be extrap-olated to theHIV-infectedpopulation carefully, because high-dose statin ther-apy or statin-fibrate combinationsmay be required to reach a goal of LDL lessthan 70 mg/dL. Patients undergoing ART may experience unacceptabletoxicity from this approach.

The NCEP ATP III gives special consideration to the metabolic syn-drome defined by three or more of the following: (1) triglyceride levels of150 mg/dL or more, (2) low HDL (women !50 mg/dL, men !40 mg/dL),(3) abdominal obesity, (4) hypertension, and (5) fasting glucose more than110 mg/dL. Whether the metabolic manifestations of HIV and ART repre-sent the same entity with equivalent risk has yet to be determined, but pend-ing further data, metabolic changes should be considered as a secondarytarget of therapy when addressing dyslipidemia.

Diet and exercise should be encouraged for all individuals (Box 3). Forelevated total cholesterol and LDL, HMG-CoA reductase inhibitors

Table 1

Low-density lipoprotein goals for risk categories

Risk category

(see Box 2

for risk factors) LDL goal

Initiate

therapeutic

lifestyle changes

Consider drug

therapy

High risk: CHD or

CHD risk

equivalenta

(10-year risk

O20%)

!100 mg/dL

Optional goal:

! 70 mg/dL

(if high

triglycerides,

non-HDL goal

!100 mg/dL)

R100 mg/dL R100 mg/dL (!100

mg/dL consider

pharmacotherapy

to reach goal

!70 mg/dL)

Moderately high

risk: 2þ risk

factors (10-year

risk 10%–20%)

!130 mg/dL

(non-HDL

!160 mg/dL)

R130 mg/dL R130 mg/dL

(100–129 mg/dL

consider drug

options)

Moderate risk:

2þ risk factors

(10-year risk

!10%)

!130 mg/dL

(non-HDL

!160 mg/dL)


Lower risk: 0–1 risk

factors

!160 mg/dL

(non-HDL

!190 mg/dL)


(160–189 mg/dL:

consider

pharmacotherapy)

a Diabetes, noncoronary atherosclerotic disease, or 2þ risk factors with 10-year risk O20%.

Adapted from the NCEP Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation 2002;106:3143–21 and

Grundy SM, et al. Implications of recent clinical trials for the National Cholesterol Education

Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44(5):1011–7.


(statins) have shown success among patients infected with HIV. The para-mount principle is avoiding statins that have substantial interaction with cy-tochrome p450 3A4. For patients taking PIs, simvastatin (Zocor) andlovastatin (Mevacor) should be avoided, but atorvastatin (Lipitor), fluvasta-tin (Lescol), and combination pravastatin (Pravachol) (with or without fe-nofibrate) have been used safely [74]. Pravastatin and fluvastatin are leastlikely to have drug interactions and are therefore considered safest in thestatin class.

Rosuvastatin (Crestor) is emerging as a new option for patients infectedwith HIV undergoing PI or NNRTI therapy. In one study, 16 patients un-dergoing PI-based regimens who were treated with rosuvastatin for 24 weeksexperienced significant decreases in total cholesterol, LDL, and triglyceridesand significant increase in HDL [75]. Rosuvastatin has outstanding potencyand is not dependent on cytochrome P450 for metabolism. Larger studiesare needed before this drug can be recommended broadly.

All statins should be initiated at low dose and titrated with careful mon-itoring of liver function, both before starting therapy and after 4 to 6 weekson therapy. Routine monitoring of muscle enzymes is not recommended,but patients should be educated about symptoms of myopathy so that clin-ically significant myositis or rhabdomyolysis can be identified early.

Ezetimibe (Zetia) is a new cholesterol absorption inhibitor that can besafely used with statins to decrease LDL, but studies have not been reportedin large numbers of patients infected with HIV. Bile acid sequestrants arenot recommended because of possible chelation of concurrent medicationsand tendency to cause hypertriglyceridemia. For PI-associated hypertrigly-ceridemia, particularly when levels exceed 500 mg/dL, fibric acid derivatives(gemfibrozil or fenofibrate) are effective. Alternatives for treatment includefish oil (3–6 g/d) and extended-release niacin. Fish oil can increase LDLlevels and niacin can worsen insulin resistance, so these risks must be

Box 3. Dietary interventions for dyslipidemia

Total fat: 25% to 35% of total caloric intakeSaturated fat: <7% of total caloriesPolyunsaturated fat: up to 10% of total caloriesMonounsaturated fat: up to 20% of total caloriesCholesterol: <200 mg/dayFiber: 20–30 grams/dayPlant sterols: 2 grams/day

Adapted from the NCEP Expert Panel on Detection, Evaluation, and Treatmentof High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation2002;106:3143–21; with permission.


balanced against benefits of treatment. In accordance with IDSA/ACTGguidelines, risk factor reduction is paramount. When pharmacotherapy isrequired, it should be prescribed with utmost attention to potential druginteractions and close observation for complications.

Although switching from any PI to atazanavir or class-switching to anNNRTI may be a reasonable option depending on a patient’s resistance pro-file, it has not been shown to be as effective as pharmacotherapy for man-aging dyslipidemia [76]. In recent studies, lipid abnormalities have beenprevented in naı̈ve patients initiated on atazanavir-based regimens. This ef-fect is somewhat attenuated by ritonavir boosting of atazanavir, but this ap-proach still offers lipid advantages over other PI-based regimens [77,78].Switching to nevirapine has been associated with rapid reversal of hypertri-glyceridemia without significant changes in total cholesterol [79,80]. Resultsfrom PI-to-efavirenz switches have yielded conflicting results [81–83].

Monitoring

Before starting ART, a fasting lipid panel should be obtained andfollowed at 3 to 6 monthly intervals during the first year. For patientswho have triglyceride levels greater than 400 mg/dL, calculated LDL isunreliable, and direct measurement should be obtained for further riskassessment and management decisions. Alternatively, non-HDL cholesterol(total cholesterol minus HDL cholesterol) can be monitored when directLDL measurement is not feasible. Lipids should be reassessed beforetherapy changes and once yearly for individuals undergoing stable HIVtreatment regimens. Ongoing lifestyle counseling and surveillance forsecondary causes of dyslipidemia should be integrated into routine visits(monitoring for thyroid disease, liver disease, renal disease, diabetes, anduse of exacerbating medications such as hormones and corticosteroids).

Body composition changes

Body fat abnormalities have been described in large numbers of patientsinfected with HIV, both on and off therapy. The term lipodystrophy has beenused to describe all forms of body fat redistribution and metabolic changes,and is not precise. Fat abnormalities fall into distinct categories of lipoatro-phy and lipohypertrophy, each syndrome with different risk factors, clinicalfeatures, and treatments.

Lipoatrophy: risk factors and clinical features

Lipoatrophy is defined as fat wasting of the face, extremities, and but-tocks. In fact, most patients with peripheral lipoatrophy have fat loss inthe subcutaneous tissue both centrally and peripherally [84]. Risk factorsfor the development of lipoatrophy include therapy with certain NRTIs


(eg, stavudine, didanosine, and zidovudine), older age, higher triglyceridesat the start of therapy, nadir CD4 count less than 200 cells/mL, and immunereconstitution/response to therapy. Additionally, lipoatrophy with or with-out other metabolic complications of ART seems to be a risk factor for car-diovascular disease [85,86]. HIV infection in the absence of therapy is a riskfactor for lipoatrophy, as shown in at least one study comparing limb fat inindividuals infected with HIV versus those who were uninfected [84]. Theprecise mechanism by which lipoatrophy occurs is unknown and is the sub-ject of ongoing studies. Mitochondrial toxicity, increased oxidative stress,and abnormal cytokine expression have been implicated in pathogenesis[87]. Fat biopsies in patients on stavudine and other thymidine analogshave shown severe mitochondrial depletion, and healthy volunteers havebeen noted to develop mitochondrial enzyme depletion after 2 weeks ofNRTI therapy with thymidine-containing drugs [3]. Diagnosing lipoatrophyis challenging, because formal criteria have not been developed. Objectivemeasurement of limb fat using dual energy x-ray absorptiometry (DEXA)scans is not generally recommended outside of the research setting. Carefulphysical examination and patient self-report may be adequate to monitorperipheral fat loss in clinical settings.

Lipoatrophy: management and monitoring

The decision to treat fat redistribution is frequently determined in thecontext of associated findings such as insulin resistance and hyperlipidemia.No consensus exists regarding whether treatment of body fat changes shouldbe undertaken in the absence of an associated metabolic syndrome. Thiazo-lidinediones have received significant attention as an investigational treat-ment of lipoatrophy because they stimulate PPAR-g and increaseadipogenesis in vitro. Most studies have shown minimal benefit, and showthat glitazone therapy for patients who remain on stavudine (a potent inhib-itor of PPAR-g) will have no impact on fat redistribution [53,88,89]. Twosmall studies have shown that uridine supplementation after 3 months oftherapy increases limb fat to a greater degree than seen in ARV switch stud-ies. In patients taking uridine, mitochondrial DNA levels did not changeand the mechanism of fat gain remains unclear [90,91]. In a single random-ized, placebo-controlled study of 33 men infected with HIV, 4 weeks of pra-vastatin significantly improved limb fat as assessed in baseline and follow-upDEXA measurement [92]. Larger studies are needed to confirm this unex-pected finding. Various plastic surgery techniques have emerged as treat-ment options for lipoatrophy, although only polylactic acid (Sculptra) hasbeen adequately tested in individuals infected with HIV and is FDA-approved for use [93]. Insurance coverage of polylactic acid is poor, becausethe procedure is usually designated as cosmetic. Autologous fat transfer andpolymethylmethacrylate have had mixed results and require larger studiesbefore widespread use can be recommended [94].


Changing ART may be appropriate for patients who have lipoatrophy,particularly among those currently receiving stavudine or zidovudinewhen tenofovir or abacavir are available therapeutic options. A recent studyshowed that after 48 weeks of therapy with either zidovudine or tenofovir,individuals taking zidovudine had clear limb fat losses, whereas those takingtenofovir had increased limb fat. Interpretation of the study is limited by thelack of baseline DEXA testing. Another study showed that switching froma thymidine-containing regimen (d4T or AZT) to either tenofovir or abaca-vir resulted in small but statistically significant gains in limb fat, with mostmarked improvement seen in patients switching from stavudine-containingregimens [95]. Fat losses from stavudine improved, but only approximately10% of fat recovery was seen at 1-year follow-up, and whether longer inter-vals would lead to substantial gains or whether these individuals would everreturn to pretreatment baseline is unclear [95–97].

Lipohypertrophy: risk factors and clinical features

Lipohypertrophy is defined by fat accumulation in the abdomen,breasts, and posterior neck (buffalo hump). Risk factors include PI use,older age, white race, more advanced degree of immunosuppression, andfemale gender [44,98,99]. The prevalence of PI-associated fat redistributionhas been reported to range from 2% to 84% [100–102]. The wide intervalreflects lack of consensus definition and diagnostic criteria. Patient andphysician report are most commonly used for diagnosis, but cross-sec-tional imaging techniques such as CT and MRI are the gold standardfor measuring body fat in the research setting. Routine use of these tech-niques is limited by expense and availability, and diagnosis can be madewith specific waist-to-hip ratio (O0.95 in men and O0.85 in women) orenlarged abdominal circumference (R102 cm in men and R88 cm inwomen) [103].

Management and monitoring

Lifestyle changes can be helpful in the management of lipohypertrophy,including dietary limitations of saturated fat, simple carbohydrates, andalcohol, and avoidance of rapid weight loss which can worsen lean tissueloss. Aerobic and resistance exercise can improve fat accumulation in indi-viduals infected with HIV, but excessive exercise has been shown to worsenlipoatrophy [104–106].

Recombinant human growth hormone (rhGH) has been found todecrease visceral fat, but also exacerbates insulin resistance and worsenslipoatrophy in clinical trials [48,107]. Benefits gained from rhGH seemto be reversed on cessation of the drug [108]. Growth hormone releasingfactor has been shown to decrease visceral fat and improve lipid profile,but until final results of phase 3 trials are available, cannot be


recommended. Testosterone may have some benefit in hypogonadal menby reducing visceral fat and improving insulin sensitivity, but also leadsto decreased limb fat and is not recommended for chronic treatment ofisolated lipohypertrophy [109,110]. Metformin has been shown to improveglucose tolerance, reduce weight and visceral fat, and decrease triglyceridelevels in randomized trials of individuals infected with HIV who have cen-tral fat accumulation and insulin resistance [50,51]. Benefits in reductionof visceral fat may be offset by worsening of preexisting lipoatrophy;therefore, metformin is not a recommended approach to lipohypertrophyin the absence of associated metabolic changes. Buffalo hump liposuctionhas been associated with surgical complications and high recurrence rate,and may not be covered by insurance. Unlike switch therapy for lipoatro-phy, switching off PI-based regimens has not been shown to improvelipohypertrophy [63,111].

Is cardiovascular risk increased?

Most observational and retrospective data support the association be-tween increased cardiovascular risk and ART, but studies not defined theextent of this risk. Although an early study from the Veterans Affairs system

Box 4. Monitoring for cardiovascular risk

ModifiableHypertensionObesityDietExerciseDyslipidemiaAbnormal glucoseMedications, including PIs*Cigarette smokingElevated homocysteineElevated lipoprotein(a)

NonmodifiableAdvancing ageFamily historyGenderChronic kidney diseaseMetabolism

* May be nonmodifiable if resistant virus.

Table 2

Summary of the major co

Monitoring

Hyperlactatemia/

lactic acidosis

s: If on

log,

nitor. If

lly or

regimen.

continue

resolved,

nalog,

e with

No established role for monitoring

asymptomatic individuals. Role for

selective monitoring of high-risk

patients unclear.

Nevirapine

hypersensitivity

less than

without

rapine

14 days,

oms

evens-

han five

tinue

gimen.

Baseline LFTs prior to starting

therapy, after 2 weeks of therapy,

and then monthly through the first 3

months. If patient develops skin rash

or gastrointestinal symptoms at any

point on therapy, check LFTs, CBC

with differential, and renal function.

120

HOFFMAN

&CURRIE

R

mplications of antiretroviral therapy

Risk factors Management

Definite or probable: stavudine,

didanosine, zidovudine, female

gender, higher body weight

Possible: chronic hepatitis or other liver

disease, NRTI plus metformin, older

age, advanced immunodeficiency.

Mild hyperlactatemia with symptom

stavudine or other thymidine ana

switch to non-thymidine and mo

on non-thymidine, observe carefu

consider switch to NRTI-sparing

Moderate-severe lactic acidosis: dis

all ARVs. Supportive care. When

if prior regimen was thymidine a

consider non-thymidine backbon

careful monitoring.

Definite or probable: female gender,

CD4 O 250 cells/mL for women and

O400 cells/mL for men (particularly

for hepatotoxicity), age O40 years,

hepatitis B or C coinfection, obesity,

pregnancy

Mild-moderate rash or transaminitis

five times upper limit of normal,

fever or mucositis: Continue nevi

and monitor. If develops in first

defer dose escalation until sympt

resolve.

Severe rash, systemic symptoms, St

Johnson, or transaminitis more t

times upper limit normal: Discon

nevirapine. Consider PI-based re

Abacavir

h

HLA-B*5701 Mild rash without systemic symptoms:

with careful monitoring.

with or without rash,

sening with additional

abacavir, document

future exposure to

No established monitoring or screening

currently recommended. HLA typing

for B*5701 is under study as possible

screening tool.

Ins

(

g

(

d

(

s: Diet and Exercise

rove IR and decrease

y if lipohypertrophy.

f potential for increased

improve IR, but

ight gain. Risk of

ect on IR, can cause

ed if oral therapy fails to

Before ART: Risk stratify with review

of family history, medication list, and

body mass index. Check fasting

glucose. Consider oral glucose

tolerance test for high-risk patients.

During ART: fasting glucose 6–12

weeks after starting therapy,

particularly for PI based regimens or

high-risk patients, then every 3

months during the first year of

therapy. Intensity of further

monitoring is based on individual

risk. PLUS Ongoing counseling

regarding diet and exercise,

regardless of risk.

(continued on next page)

121

ANTIR

ETROVIR

ALTREATMENTCOMPLIC

ATIO

NS

ypersensitivity continue abacavir

Systemic symptoms

particularly if wor

doses: Discontinue

allergy and avoid

abacavir.

ulin resistance

IR), impaired

lucose tolerance

IGT), and

iabetes mellitus

DM)

Definite or probable: HIV infection,

PIs, fat redistribution, stavudine,

hepatitis C coinfection, obesity,

family history, older age.

Possible: female gender

Lifestyle intervention

Metformin: may imp

weight, particularl

Caution because o

lactate.

Thiazolidinediones:

associated with we

hepatotoxicity.

Sulfonylureas: no eff

hypoglycemia

Insulin: should be us

control DM.

Table 2 (continued )

Risk fact Monitoring

Dyslipidemia Definite o

PIs exc

family

sedenta

gender,

medica

atification

and

with

atin, or

and

to reach

on use in

in or fish

and

in

ir or

Before ART: fasting lipid panel, family

history, cardiovascular risk

assessment.

During ART: fasting lipids at 3–6

monthly intervals during the first

year. Intensity of subsequent

monitoring should be based on risk,

but performed at least yearly. PLUS

Ongoing counseling regarding diet

and exercise and appropriate

monitoring for secondary causes of

dyslipidemia (diabetes, renal disease,

thyroid disease, liver disease, and

exacerbating medications).

122

HOFFMAN

&CURRIE

R

ors Management

r probable risk factors: HIV,

ept atazanavir, NNRTIs,

history, smoking, diabetes,

ry lifestyle, diet, age, male

chronic kidney disease,

tions (steroids, hormones)

Goals of therapy defined by risk str

based on NCEP ATP III.

Therapeutic lifestyle changes: Diet

Exercise

To reach LDL goals: statin therapy

pravastatin, fluvastatin, rosuvast

atorvastatin started at low dose

titrated. Ezetimibe can be added

LDL goals, although limited data

HIV patients on ART.

To reach triglyceride goals: fibrates

(fenofibrate or gemfibrozil). Niac

oil may also be used. Pravastatin

fenofibrate have been used safely

combination.

Switching ART: consider atazanav

switch to nevirapine for severe

dyslipidemia.

Lipoatrophy Definite or probable risk factors:

NRTIs (especially stavudine,

Presence of IR and dyslipidemia favors

decision to treat:

inimal

if

show

e

ns.

ing off

h

with

No monitoring beyond routine physical

examination and vigilance for

development of body fat

redistribution. Patients who

experience fat redistribution should

have screening for abnormal glucose

metabolism and dyslipidemia.

L rs

nd

visceral

s, but

benefit

:

y

R and

with

ching

No monitoring beyond routine physical

examination and vigilance for

development of body fat

redistribution. Patients with fat

redistribution should have screening

for abnormal glucose metabolism

and dyslipidemia.

(continued on next page)

123

ANTIR

ETROVIR

ALTREATMENTCOMPLIC

ATIO

NS

didanosine, and zidovudine) older

age, higher triglycerides at initiation

of therapy, nadir CD4 count !200

cells/mL, immune reconstitution.

Thiazolidinediones: investigational. M

benefit for lipoatrophy particularly

patient remains on stavudine.

Uridine: investigational. Small studies

limb fat increases greater than thos

achieved by switching ART regime

Plastic surgery: polylactic acid.

Switching ART: fat losses after switch

stavudine improve. Substitution wit

tenofovir or abacavir is associated

increase in limb fat.

ipohypertrophy Definite or probable risk factors: higher

body mass index before antiretroviral

therapy, PIs, older age, white race,

advanced immunosuppression,

female gender.

Presence of IR and dyslipidemia favo

decision to treat:

Lifestyle changes: limit saturated fat a

carbohydrates in diet; aerobic and

resistance exercise.

Metformin: investigational. Improves

fat and has other metabolic benefit

can worsen lipoatrophy.

Testosterone: investigational. Possible

in hypogonadal men, but worsens

lipoatrophy.

Recombinant human growth hormone

investigational. Results in temporar

decrease in visceral fat but worsens I

lipoatrophy.

Plastic surgery: liposuction associated

high recurrence rate.

Switching ART: No benefit from swit

off PI therapy.

Table 2 (continued )

Monitoring

Cardiovascular (CV)

disease

factors.

existing

irin,

tors, lipid

l of LDL

Before ART: obtain family history,

fasting lipids, fasting glucose. Assess

for hypertension, renal disease, and

other modifiable risk factors.

Counseling regarding risk reduction

of modifiable risk factors.

During ART: based on individual risk,

minimum yearly evaluation of blood

pressure, fasting lipid profile, fasting

glucose. Ongoing risk assessment and

counseling regarding diet, exercise,

smoking, and other modifiable risk

factors.

Abbreviations: A plete blood cell count; DM, diabetes mellitus; IR, insulin

resistance; LFT, live holesterol Education Program Adult Treatment Panel III;

NNRTI, non–nucleo inhibitor; PI, protease inhibitor.

124

HOFFMAN

&CURRIE

R

Risk factors Management

Definite or probable risk factors:

hypertension, diabetes, dyslipidemia,

family history, advanced age, male

gender, cigarette smoking, PIs.

Reduction of modifiable risk

Optimize management of

cardiovascular disease (asp

beta-blockers, ACE inhibi

therapy with optional goa

!70 mg/dL).

CE, angiotensin-converting enzyme; ART, antiretroviral therapy; CBC, com

r function test; LDL, low-density lipoprotein; NCEP ATP III, National C

side reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase


in patients infected with HIV who had limited PI exposure found a slightdecrease in cerebrovascular and cardiovascular events, other large studieshave shown small but significantly increased risk [112]. A French cohortstudy of patients undergoing PI-based therapy showed the incidence of myo-cardial infarction was increased threefold when therapy lasted longer than30 months [113]. The HIV Outpatient Study (HOPS) followed more than5500 patients and also found greater risk for myocardial infarction in pa-tients who used PIs, but an overall low event rate [114]. The French andHOPS data are supported by the findings of the Data Collection on AdverseEvents of Anti-HIV Drugs (D:A:D) study group. This study, the largest todate, prospectively followed more than 20,000 patients on ART representingmore than 35,000 person-years of follow-up, and showed a 26% relative in-crease in the rate of myocardial infarction per year of exposure during thefirst 4 to 6 years of use [115]. Predictors of myocardial infarction includeda history of cardiovascular disease, current or former smoking, anyARVs, age, and male gender. As of February 2005 the D:A:D study grouphad 94,469 person-years of follow-up and found that time on PI was asso-ciated with increased risk for myocardial infarction (16% per year of expo-sure), partially explained by dyslipidemia [116]. The absolute risk was low at0.4% per year of follow-up, and the absolute risk of events has been consis-tently low in subsequent studies. Any risk must be weighed against clearbenefits of HIV therapy.

Because the absolute cardiovascular event rate in HIV infection has re-mained low, use of validated surrogates has been increasingly used to studycardiovascular risk from HIV and ART. Impaired endothelium-dependentvasodilation is an indicator of atherosclerotic disease and has led to interestin surrogate markers such as carotid intima-media thickness (IMT), brachialartery flow-mediated dilation (FMD), and aortic pulse-wave velocity(PWV). Many of these studies have shown subclinical atherosclerosis in pa-tients undergoing ART, but the strongest predictors have been traditionalcardiovascular risk factors as opposed to specific antiretroviral regimensor features of HIV infection [117,118]. Additional risk factors describedinclude advanced degree of immunodeficiency [119], any ARVs [120], andPI-based therapy [121]. Pathogenesis of endothelial dysfunction in HIV isbeing actively explored, and validated surrogate markers may eventuallybe available to stratify and monitor high-risk patients [122–124].

Management of cardiovascular risk

Experience from research on cardiovascular disease highlights that tra-ditional cardiac risk factors may be more contributory than HIV-specificfactors. Thus, emphasis on changing these modifiable risks is of utmostimportance (Box 4). Before ART is initiated, patients should undergocardiovascular risk assessment with evaluation for hypertension, dyslipide-mia, and glucose abnormalities, and receive counseling on risk reduction


(eg, diet, exercise, smoking cessation). Patients undergoing on chronic ARTshould be intermittently monitored for diabetes and dyslipidemia, most in-tensively in the first year (approximately every 3 months) and then at leastyearly if no abnormalities are identified. Smoking is a critical modifiablerisk factor that should be addressed in the setting of HIV infection.

Summary

Successful treatment of HIV results in immune restoration, viral suppres-sion, prevention of opportunistic infections, and probable extension of aninfected individual’s lifespan to near-normal. These remarkable benefitsare accompanied by an array of treatment complications, with an impactthat has yet to be fully understood. A comprehensive approach to manage-ment of complications includes knowledge in three areas: (1) risk factors foradverse reactions, (2) clinical syndromes suggestive of an evolving complica-tion, and (3) informed treatment approaches to preventing and managingthese complications. Systematic evaluation has led to emerging informationabout risk factors for drug complications, such as gender, immune status,HLA subtypes, coinfections, and comorbidities. Knowledge of these riskscan inform choice of drug regimen and intensity of monitoring. An under-standing of clinical presentation of complications empowers the clinician forearly recognition of an adverse drug reaction, rapid response, and avoidanceof further morbidity. Fluency in options for preventing and treating compli-cations can provide maximal opportunity to balance treatment effects withquality of life (Table 2).

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Management of Antiretroviral Treatment–Related Complications