11 Management of the Adverse Effects of Antiretroviral Therapy and Medication

S96

Management of the Adverse Effects of Antiretroviral Therapy and MedicationAdherence

Blake Max1,2 and Renslow Sherer1 From the 1CORE Center for Prevention, Care, and Research ofInfectious Disease (formerly the Cook County HIV Primary CareCenter), Division of Infectious Disease, Department of Medicine,

Cook County Hospital, and Rush Medical College, and 2Universityof Illinois College of Pharmacy, Chicago, Illinois

A commonly cited cause of poor adherence to highly active antiretroviral therapy (HAART)is adverse drug reactions. Short-term adverse effects are potential threats to successful intro-duction and maintenance of HAART. The long-term toxicities of HAART are still emergingand being defined, as evidenced by the recently described metabolic disorders (i.e., the syn-drome of maldistribution, hyperlipemia, glucose intolerance and insulin resistance). With 14licensed agents in 2000, other agents in common use, and numerous combinations of >3drugs, awareness and recognition of adverse effects are increasingly important for cliniciansand patients. The common adverse drug reactions encountered with HAART, including newagents and their impact on patient adherence, are reviewed. Current strategies to anticipateand mitigate adverse effects are summarized.

New evidence of reduced mortality and morbidity due toHIV disease was reported in 1998. Whitman and Murphy [1]reported a 65% decline in deaths due to AIDS in Chicago from1995 to 1997, which included a 35% decline among women, a57% decline among Hispanics, a 47% decline among African-Americans, and a 47% decline among persons with current orpast injection drug use. These data show broader populationswith significant mortality reductions than do national data [2]and suggest that a system of care and support that gives accessto potent antiretroviral therapy can benefit diverse populationsof people with HIV disease.

Nonetheless, there are numerous reasons for caution regard-ing the current state of treatment (as of 2000). In the best ofcircumstances, the goal of maximal virus suppression isachieved in only 50% of patients [3]. Highly active antiretroviraltherapy (HAART) regimens are often complex. Regimens caninclude numerous pills with frequent dosing and various, some-times conflicting, food requirements. Adverse events are com-mon and may lead to discontinuation of therapy, dose inter-ruption, and significant reductions in quality of life. Adherencemay be compromised because of adverse events, and adherenceis increasingly recognized as an important determinant of suc-cessful antiretroviral therapy [4].

This article will review the adverse effects of the currentlyapproved agents for the treatment of HIV disease and 2 un-approved agents in clinical use and management strategies to

Reprints or correspondence: Blake Max, Pharm.D., CORE Center forPrevention, Care, and Research of Infectious Disease, 2020 West HarrisonSt., Chicago, IL 60612 ([email protected])

Clinical Infectious Diseases 2000;30(Suppl 2):S96116q 2000 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2000/3006S2-0002$03.00

prevent or reduce adverse effects. Consideration will be givento new dosing strategies for existing drugs, new agents, newlyobserved adverse events associated with HAART (including theso-called metabolic disorders), and the implications of thesedata for current treatment strategies.

General Principles of HAART, Adverse Effects,and Adherence

Poor adherence has been strongly associated with virologicalfailure of potent antiretroviral therapy by several investigators.In a study of 143 patients in an urban HIV clinic, in whichviral load reductions of !500 copies/mL at 6 months wereachieved only for 47% of patients, Deeks [5] reported a 15-foldincrease in the likelihood of virological treatment failure in thepresence of poor adherence (as measured by patient self-reports). Surveys of people receiving HAART have shown that30% of patients missed doses within the previous 3 days, andadverse effects account for 10%15% or more of those discon-tinuations of treatment [6]. Because adverse events are commonwith all available antiretroviral agents, it is critical to anticipate,recognize, and manage them when providing primary care forHIV-infected patients. Because several recent studies and ini-tiatives address adherence [711], only the association betweenadherence and adverse events will be briefly considered here.

Adherence requires a reliable, trusting patient-physician re-lationship, and it results from a negotiation in which the patientis an active participant [12, 13]. With regard to adverse events,patients should be informed of potential side effects duringconsideration of the first regimen, options for subsequent reg-imens (i.e., sequencing), and possible management strategies incase of adverse events. Adverse events may influence the initialtreatment decision. For example, medications associated with

by guest on August 1, 2014

http://cid.oxfordjournals.org/D

ownloaded from

http://cid.oxfordjournals.org/

CID 2000;30 (Suppl 2) Management of Adverse Effects of Antiretroviral Therapy S97

Table 1. Possible strategies to improve adherence to antiretroviral therapy.

Medication-relatedInform, anticipate, and treat side effectsSimplify food requirementsAvoid adverse drug interactionsIf possible, reduce dose frequency and number of pills

Patient-relatedNegotiate a treatment plan that the patient understands and to which he or she commitsTake time and have multiple encounters to educate and explain goals of therapy and need for adherenceEstablish readiness to take medication before the first prescription is writtenRecruit family and friends to treatment plan and need for adherenceDevelop a concrete plan for the specific regimen, including relation to meals, daily schedule, and

possible side effectsConsider pill trials with jelly beansProvide written schedule of medications, daily or weekly pill boxes, alarm clocks, or other devicesDevelop adherence support groups or add adherence to regular agenda of support groupsDevelop linkages with CBOs around adherence with educational sessions and practical strategies

Physician-relatedEstablish trustServe as educator and source of information, ongoing support, and monitoringProvide access between visits for questions, problems via page numbers, and holiday coverageMonitor ongoing adherence and intensify management in periods of low adherence, such as more

frequent visits and recruitment of family, friends, and health care team membersUse health care team for difficult patients and patients with special needs, such as peer educators

for injection drug users or adolescentsConsider impact of new diagnoses on adherence, particularly depression, and drug use

Health teamrelatedUse nurses, pharmacists, peer educators, volunteers, and drug counselors to reinforce adherenceProvide training to support team related to adherenceAdd adherence interventions to job descriptions of support team members

NOTE. Data adapted from [16]. Adherence is defined as a measure of a patients ability to conform toa specific medication regimen and plan for care to which he or she has explicitly agreed. CBOs, community-based organizations.

a high risk of diarrhea may be less desirable for patients whoare experiencing diarrhea or HIV-related wasting. In view ofthe unforgiving nature of HIV infection, it is essential to es-tablish the patients readiness for HAART before the first pre-scription, including knowledge of and treatment for possibleadverse events [14]. Similarly, adherence is not a one-shotproblem; repeated monitoring, education, and intervention areneeded to ensure durable adherence, including close monitoringfor adverse events. Adherence requires an individualized ap-proach, since no single strategy will work for all patients. Ad-herence improves with recruitment of family, friends, or peersupport staff [15].

Potentially beneficial interventions to improve adherence aresummarized in table 1. In a recent study, an off-site clinicalpharmacist referral clinic was associated with improved virussuppression [17]. A similar strategy using an on-site clinicalpharmacist has been in place at the Cook County HIV PrimaryCare Center (now the CORE Center for Prevention, Care, andResearch of Infectious Disease, Chicago) for the past 2 years.The clinical pharmacist is available for patient education, sup-port for readiness before HAART, adherence follow-up andmonitoring, discussion of adverse events, pill and food strat-egies, and education of family and friends. In addition, theclinical pharmacist provides real-time consultation services tothe clinicians in the clinics. As noted in table 1, other membersof the health care team can provide additional support for this

consultative service, such as nurses, case managers, peer edu-cators, and community volunteers [18].

Antiretroviral Therapy and Common Adverse Effects

Guidelines for antiretroviral therapy that contain current op-tions for antiviral therapy and their common side effects haverecently been updated [3]. Although some adverse effects arecommon to the entire class, such as rash for the nonnucleosidereverse transcriptase inhibitors (NNRTIs), there are importantdistinctions for each drug within each class that require thephysician and health care team to review and monitor everydrug with the patient. Below, possible strategies for manage-ment and reduction of adverse effects are reviewed. Note thatin some cases, optimal management requires that treatment bediscontinued to eliminate or reduce the effect. In the text andtables in this article, data on the incidence of adverse effectsare taken from previously reported data from the pivotal ap-proval trials of each agent, as indicated in the package insert.

The patients medical diagnoses and treatments may influ-ence the management of adverse effects. In some cases, toxicitymay be intolerable in the presence of another drug with similartoxicity. For example, both zidovudine and ganciclovir maycause bone marrow suppression, and their concurrent use re-quires careful monitoring. This example illustrates that it is



ownloaded from


S98 Max and Sherer CID 2000;30 (Suppl 2)

Table 2. Common adverse effects of nucleoside reverse transcriptaseinhibitors (NRTIs).

NRTI, adverse effect % of patients affected

ZidovudineHeadache 1218Fatigue 27Neutropenia 231Nausea 426Anemia 17Insomnia 45Vomiting 38Myalgia 58Myopathy 618

DidanosinePancreatitis 59Diarrhea 1528Peripheral neuropathy 220Elevated AST and ALT levels 610

ZalcitabinePeripheral neuropathy 1030Stomatitis 217Rash 1020

StavudinePeripheral neuropathy, total 1324Gastrointestinal 46Headache 35Elevated AST and ALT levels 510

LamivudineNausea 4Headache 8Fatigue 4Insomnia 4

AbacavirNausea/vomiting 515Fever 57Dizziness 510Insomnia 27Rash 35Diarrhea 112Hypersensitivity reaction 35

NOTE. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 3. Dosage modifications of nucleoside reverse transcriptaseinhibitors (NRTIs) for patients with renal insufficiency.

NRTI, creatinineclearance, mL/min

Dosage per weight

Any !60 kg 160 kg

Zidovudine!25, hemodialysis 100 mg q8h

Didanosine (tablet)!10, hemodialysis 50 mg q24h 100 mg q24h

Zalcitabine1040 0.75 mg q12h!10, hemodialysis 0.75 mg q24h

Stavudine150 30 mg q12h 40 mg q12h2649 15 mg q12h 20 mg q12h!25, hemodialysis 15 mg q24h 20 mg q24h

Lamivudine2649 150 mg q24h1025 100 mg q24h!10, hemodialysis 2550 mg q24h

essential to take an individualized, case-by-case approach todrug regimen selection and assessment of adverse effects.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs have been a cornerstone of treatment for HIV infec-tion since zidovudine became available in 1986. With the recentapproval of abacavir in 1998 by the US Food and Drug Ad-ministration (FDA), there are now 6 NRTIs for the treatmentof HIV infection. NRTIs are nucleoside analogues (zidovudineand stavudine are thymidine analogues, lamivudine and zal-citabine are cytosine analogues, didanosine is an adenosine an-alogue, and abacavir is a guanosine analogue), and althoughthey all have the same mechanism of action, many adverseeffects of each agent are unique. NRTIs inhibit the HIV reversetranscriptase enzyme and terminate proviral DNA chain elon-gation. NRTIs must be phosphorylated intracellularly by spe-cific host cell enzymes to carry out their critical function. Un-fortunately, NRTIs inhibit not only viral reverse transcriptasebut also cellular DNA polymerases (particularly mitochondrial

polymerase g); mitochondrial toxicity may explain some oftheir long-term toxicity [1921].

Results of a recent clinical study of the combination of 3NRTIs (zidovudine, lamivudine, and abacavir) compared fa-vorably with the treatment standard of 2 NRTIs plus a proteaseinhibitor (PI) [22]. Although these data are promising, moredata are necessary on the durability of triple NRTI treatmentand the potency in patients with high viral loads (1100,000copies/mL). NRTI-based regimens also have a lower pill burdenthan PI-based regimens. The choice of NRTIs is based largelyon drug resistance, tolerability, and the individual patient. Al-though patients seldom inquire about drug resistance, drug ad-verse effects are often a focal point of patient concern. Clini-cians should be knowledgeable about the adverse effects ofantiretrovirals, so they can both keep the patient well informedand appropriately manage and monitor potential adverse ef-fects. With the selection of NRTIs available, if a patient issuffering from adverse effects of one NRTI, then it would beprudent to change it to another that would conceivably bebetter tolerated [23].

There are few adverse effects that characterize NRTIs as aclass. However, lactic acidosis with severe hepatomegaly withsteatosis, although uncommon, has caused deaths in patientsreceiving treatment with nucleoside analogues [2426]. Themechanism, which has yet to be completely elucidated, appearsto be mitochondrial toxicity [27]. Clinicians also need to beaware that many adverse effects of NRTIs are dose-related, anddose adjustments are often necessary for patients with organdysfunction. For example, the only NRTI that has data tosuggest a dose adjustment in hepatic failure is zidovudine (rec-ommended dose reduction of 50%) [28]. For patients with renaldysfunction, particularly those undergoing hemodialysis, dosereduction is required for all NRTIs except abacavir [29]. Com-mon adverse effects of NRTIs are noted in table 2, and dosagealterations of NRTIs for patients with renal insufficiency arenoted in table 3.



ownloaded from



Zidovudine. Over the years, there has been a decrease inthe recommended dose of zidovudine from 1500 mg/day to 600mg/day, which has improved tolerability. The most severe ad-verse effect is bone marrow suppression, which causes anemiaand/or neutropenia, but the most common adverse effects arenausea, malaise, myalgias, insomnia, and headache [3032].Bone marrow suppression appears to be more common in thosepatients with advanced disease and is related to the dose andthe duration of treatment. In patients with CD41 cell counts1100 cells/mL, hematologic effects occur in 2%14% of patients;however, the incidence is much greater among patients withCD41 cell counts !100 cells/mL [31]. Data from the AIDS Clin-ical Trials Group showed that the incidence of anemia andneutropenia associated with zidovudine ranged from 1% to31%, depending on the stage of disease and dose (in most ofthese early studies, the dosage was 12001500 mg/d) [32, 33].Nowadays the dose of zidovudine is much lower, thus zido-vudine-induced bone marrow suppression has become less fre-quent. Anemia can occur as soon as 1-2 months after zido-vudine is started but is more likely to develop after 2-4 monthsof therapy [30]. Zidovudine-induced anemia appears to resultfrom thymidine triphosphate deficiency leading to inhibition ofstem cell maturation [34]. Macrocytosis is also frequently ob-served in patients taking zidovudine, so much that elevatedmean corpuscular volume (MCV) increased 20% or more frompretreatment values in 96% of patients in one study [30]. Thisphenomenon of zidovudine-induced macrocytosis is not nec-essarily associated with anemia and not due to vitamin B12 orfolate deficiencies [35]. Some patients have developed throm-bocytosis while taking zidovudine, including patients who pre-viously were thrombocytopenic [31].

Although zidovudine has a multitude of CNS side effects,the 2 most common are headache and nausea (occurring in42% and 46%, respectively, of patients); however, these sideeffects have occurred in patients receiving 1500 mg/d [31], andthe incidence is lower when the dosage is 600 mg/d. Nausea isalso the most common gastrointestinal side effect and is morelikely to occur in patients with advanced disease. Myalgia hasbeen described in 8% of patients receiving zidovudine treat-ment [36]. Myopathy has also been reported and can be severe,comparable with a polymyositis syndrome [37]. Zidovudine-induced myopathy usually occurs after 612 months of therapyand is characterized by myalgias, muscle tenderness, weakness,and elevated serum concentrations of muscle enzymes (creatinekinase and lactate dehydrogenase). Symptoms usually resolveupon discontinuation of zidovudine treatment; however, reso-lution may take 12 months. Most cases are related to skeletalmuscle, but 1 study did suggest that zidovudine and otherNRTIs might cause cardiomyopathy [38]. Hyperpigmentationof fingernails and toenails is also associated with zidovudinetreatment [36, 39].

It is recommended that the daily dose of zidovudine be reducedby 50% for patients with creatinine clearances !25 mL/min [29].

Removal of zidovudine by dialysis is minimal; however, as forother NRTIs for which doses must be adjusted for hemodialysis,the dose should be administered after completion of dialysis.Although zidovudines primary metabolite (GZDV) accumulatesin the presence of renal dysfunction, this is not of clinical sig-nificance since GZDV is inactive and does not add to zidovu-dines toxicity.

The hemoglobin level and hematocrit should be monitoredclosely when zidovudine treatment is initiated, particularly inthose patients with advanced disease, those who have a historyof anemia, and those taking other myelosuppressive drugs (e.g.,ganciclovir, hydroxyurea, and pyrimethamine). Although zi-dovudines adverse effects are dose-related, patients who havedeveloped toxicity should not have their dose reduced to im-prove tolerability. This action could lead to subtherapeutic lev-els of zidovudine and potentially to HIV drug resistance. Gran-ulocyte colony-stimulating factor and erythropoietin have beenused to correct bone marrow suppression. Erythropoietin isrecommended for use if the serum erythropoietin level is !500IU/mL [40]. Granulocyte colony-stimulating factor has beenshown in a number of studies to resolve neutropenia caused byzidovudine [41]. If the patient is unable to tolerate adverseeffects of zidovudine, it may be more appropriate to switchtreatment to another NRTI, such as stavudine or abacavir.Headache and myalgias can be treated symptomatically withanalgesics, such as acetaminophen or nonsteroidal anti-inflam-matory drugs. Most of the adverse effects of zidovudine (e.g.,headache, malaise, nausea, and myalgia) are usually transientand diminish after the first few weeks of therapy [42]. It isimportant to educate patients about these adverse effects andtheir appropriate management.

Didanosine. Didanosine is the only NRTI for which foodhas a significant effect upon absorption. Because didanosine isextremely acid labile, each tablet is buffered with calcium car-bonate and magnesium hydroxide. Didanosine plasma concen-tration (area under the curve, AUC) decreased 55% when ad-ministered up to 2 hours after a meal [43]. Therefore, didanosineshould be administered before meals and on an empty stomach.The magnesium content may account for the gastrointestinaladverse effects, such as diarrhea, which occurs in 15%20% ofpatients.

Didanosine is partially metabolized in the liver, and one ofthe metabolites is uric acid. Approximately 60% of didanosineis eliminated via the kidneys as unchanged drug; therefore, itis recommended to administer one-quarter of the standard doseevery 24 h if patients are undergoing hemodialysis [29]. Becausehemodialysis removes 20% of total body stores of didanosine,the dose should be administered after dialysis, and no supple-mental doses are necessary. Dose reduction is necessary forpatients with renal impairment to prevent magnesium accu-mulation. The dose of didanosine is also based on body weight,and clinicians should ensure that the dose is adjustedaccordingly.



ownloaded from



Each dose of didanosine should contain at least 2 tablets toprovide the necessary buffering capacity. Didanosine is alsoavailable as a buffered powder for solution; however, a largerdose is required because the bioavailability of powder is20%25% less than that of the tablets. The buffered powderhas fallen out of favor because it is associated with more gas-trointestinal adverse effects than are the tablets. Didanosinehas an intracellular half-life of 843 h; therefore, once-dailydosing is frequently used in clinical practice and recently re-ceived FDA approval [44].

The most serious dose-limiting adverse effects associated withdidanosine are peripheral neuropathy and pancreatitis, whichhave occurred in 10%20% and 5%9%, respectively, of patientsin clinical trials [43]. Data from recent clinical trials have showna much lower incidence of peripheral neuropathy (2%3%) [45].

Like peripheral neuropathy, pancreatitis occurs more fre-quently in patients receiving treatment with higher doses ofdidanosine. Didanosine-associated pancreatitis may be mild,presenting as mild abdominal pain, but several cases of fatalpancreatitis have been reported [46, 64]. Patients at risk forpancreatitis are those with advanced disease, who have a historyof pancreatitis and/or alcohol abuse, who have hypertriglycer-idemia, who are being treated with high doses of didanosineand/or other pancreatotoxic medications, and/or who have re-nal impairment [47]. These patients should have pancreaticfunction monitored carefully. Many clinicians avoid treatingformer alcoholics with didanosine, although the available datasuggest that careful use with close monitoring allows didanosineto be administered in this setting. Pretreatment testing of am-ylase and lipase levels is of unproven value, but it is a reasonableprecaution to screen for subclinical chronic pancreatitis. Di-danosine treatment should be discontinued if signs and symp-toms of acute pancreatitis are evident. This may be particularlyimportant with combination therapy that includes a PI, whichhas been associated with metabolic abnormalities, includingelevated triglyceride levels. Symptoms usually resolve, and theserum amylase level returns to normal within 2 weeks afterdidanosine treatment is discontinued [48].

Diabetes mellitus occurred in patients receiving didanosinebefore the introduction of HAART [49]. Some patients whodeveloped hyperglycemia also had elevated serum amylase andlipase levels; therefore, patients who develop hyperglycemiaduring didanosine therapy should also be monitored closely forsigns of pancreatitis.

The most common adverse effects associated with didanosineare gastrointestinal; however, these symptoms should be treatedwith caution because some could be signs of evolving pancre-atitis. Diarrhea can be ameliorated with antidiarrheals, such asloperamide. Pancreatitis and peripheral neuropathy usually re-quire discontinuation of therapy, and patients with pancreatitisshould not be rechallenged with didanosine. Symptoms of pe-ripheral neuropathy could be treated with appropriate agents(see stavudine section). Of note, results from clinical trials on

the combination of stavudine and didanosine did not show thatthe incidence of peripheral neuropathy was higher in associa-tion than with either drug alone [50]. Once-daily dosing ofdidanosine also has not been associated with any increase ofadverse effects.

Zalcitabine. Zalcitabine is used less frequently because thedosing schedule is unfavorable, it has overlapping resistancewith other nucleotides, and it has significant toxicity: phase I/II studies showed that peripheral neuropathy was the mostsignificant dose-limiting toxicity that required discontinuationof treatment [51]. Studies have shown that neuropathy wasdose-dependent [52]; however, 23% of patients developed pe-ripheral neuropathy at the approved dosage of 2.25 mg/d.

Although no clear predictors of zalcitabine-induced periph-eral neuropathy have been identified, some studies have shownthat low CD41 cell counts (!50 cells/mL), pre-existing neuro-pathy, nutritional deficits, and high alcohol consumption in-crease the risk [52, 53, 63]. Clinicians must monitor patientsclosely to detect symptoms early and to modify treatment inorder to minimize its negative impact on quality of life. Otheradverse effects include ulcerative stomatitis, which was de-scribed in 3%17% of patients from various studies [54, 55] andunlike other NRTIs, zalcitabine is associated with a maclo-papular rash involving the trunk and extremities [56].

Zalcitabine is primarily eliminated via the kidneys, and doseadjustment is required for patients with diminished renal func-tion (see table 3).

Stavudine. Stavudine is structurally similar to zidovudinebut has a different adverse effect profile. The primary dose-limiting toxicity is sensory peripheral neuropathy with symp-toms similar to the neuropathy associated with didanosine andzalcitabine. The incidence of sensory peripheral neuropathy isdose-related; the highest frequency is associated with dosagesof 48 mg/kg/d, which are much higher than the recommendeddosage of 1 mg/kg/d [57]. One-year rates of peripheral neu-ropathy associated with dosages of 0.1, 0.5, and 2 mg/kg/d were6%, 17%, and 37%, respectively, whereas the cumulative dosewas not associated with development of peripheral neuropathy[58]; in 1 study, the incidence of stavudine-induced neuropathywas 55% [59]. Symptomatic patients typically have tingling,burning, and pain in the lower extremities, especially at night.Symptoms usually begin to diminish and/or resolve within 19weeks after stavudine therapy is discontinued. However, somepatients who developed peripheral neuropathy have persistentsymptoms, despite discontinuation of treatment. It is not clearwhether these symptoms are due to permanent toxicity fromstavudine or an entirely different etiology. It can be difficult todistinguish between HIV-induced peripheral neuropathy anddrug-induced peripheral neuropathy. The diagnosis is oftenmade on clinical grounds, and, if it is drug-induced peripheralneuropathy, the symptoms usually resolve when therapy isdiscontinued.

In a pivotal study on stavudine, 63% of patients had grade



ownloaded from



12 peripheral neuropathy that resolved after discontinuationwithin a median time of 17 days [60]. Patients and cliniciansshould be informed that symptoms may intensify for severalweeks before improving. Some patients may tolerate reintro-duction of stavudine therapy at a lower dose, but approximatelyone-half will have a recurrence of peripheral neuropathy. In aphase I study of patients who resumed stavudine treatment atone-half the dose, 60% were able to tolerate therapy for anaverage of 9 months [62]. However, what is not clear is if dosereduction still provides appropriate antiviral activity. Like zal-citabine, risk factors for peripheral neuropathy are a CD41 cellcount !100 cells/mL, history of peripheral neuropathy, use ofother neurotoxic agents, excessive alcohol intake, and vitaminB12 deficiency [53, 57]. Although these factors are not a con-traindication for prescribing stavudine, close monitoring is es-sential to prevent symptomatic progression.

Stavudine has little hematologic toxicity [57, 65]. However,macrocytosis has been observed in 68% of patients in phase Iand II trials with changes in MCV typically less than thoseobserved in zidovudine treated patients [57]. Other adverse ef-fects associated with stavudine that may or may not be dose-related are asthenia, headache, malaise, insomnia, abdominalpain, and modest increases in liver transaminase levels [61].

To reduce the incidence of adverse effects of stavudine, thedose requires adjustment based on weight and renal function(see table 3).

Treatment of stavudine-induced peripheral neuropathy is of-ten frustrating for both the patient and the clinician. Agentswith partial efficacy include analgesics and topical capsaicin,which may be helpful in a limited number of patients [66].Tricyclic antidepressants such as amitriptyline, desipramine, ornortriptyline are frequently used to treat peripheral neuropathyand in controlled studies have shown some efficacy for diabeticneuropathy [67]. Amitriptyline is commonly used at a startingdosage of 25 mg once a day at bedtime (maximum dose, 150mg). Tricyclic antidepressants have a number of unwanted an-ticholinergic side effects, such as sedation, dry mouth, and or-thostatic hypotension, which can be exacerbated if patients aretaking PIs due to inhibition of the metabolism of tricyclic an-tidepressants [68]. Anticonvulsants, such as carbamazepine andphenytoin, may also relieve symptomatic neuropathic pain.However, both of these agents must be used cautiously, if atall, in patients with HIV infection. Because of their enzyme-inducing properties, they are not recommended to be prescribedfor patients taking PIs or NNRTIs [3].

Gabapentin, another anticonvulsant, has received recent at-tention as therapy to relieve the symptoms of peripheral neu-ropathy [69]. If peripheral neuropathy is disabling, narcoticsmay be required to control pain. Other agents that are receivingattention include recombinant nerve growth factor, the anti-convulsant lamotrigine, and alternative therapies like acu-puncture [70]. The antiarrhythmic mexiletine has been shownto be no better than placebo for relieving symptoms of pe-

ripheral neuropathy [71]. The clinician should inform patientsin advance of the possibility of neuropathy and its symptomsand closely monitor the patient for those symptoms.

Lamivudine. Lamivudine has relatively few adverse effectsand is well tolerated. Unlike other nucleoside analogues, la-mivudine is not likely to be incorporated into mitochondrialDNA [72].

The most common adverse effects of lamivudine that werereported in dose-ranging clinical studies were diarrhea, malaise,fatigue, headache, and sleep disturbances [73, 74]. However,there are anecdotal reports of a variety of nonspecific CNSadverse effects that recur on rechallenge [75]. Lack of placebo-controlled safety data in most studies of lamivudine makesdetermination of the true incidence of adverse effects difficult.Hematologic toxicity and peripheral neuropathy are rarely as-sociated with lamivudine [76]. Studies evaluating lamivudinefor the treatment of hepatitis B have found that tolerabilitywas identical between treated and placebo groups (albeit at alower dose than that used for treatment of HIV infection) [77].In phase III clinical trials of lamivudine in combination withzidovudine, the incidence of adverse effects was no higher thanthat seen in the zidovudine monotherapy arm [78].

Lamivudine is primarily excreted via the kidneys; therefore,dose modification is required for patients with renal dysfunc-tion. It is not known whether lamivudine is removed by he-modialysis or by peritoneal dialysis, and data are lacking tomake dosing recommendations. In the absence of such data,the dosage should be based on the creatinine clearance withadministration of daily doses after dialysis (see table 3). La-mivudine (150 mg) has been combined with zidovudine (300mg) as a single tablet (Combivir; Glaxo Wellcome, ResearchTriangle Park, NC), which is a potent double nucleoside com-bination with convenient administration (1 pill twice daily).Lamivudine also has a long intracellular half-life (15 h), whichpermits once-daily investigational dosing strategies.

Abacavir. Abacavir is a novel guanine-based NRTI thatwas approved for use in October 1998. Abacavir has excellentpotency when part of a triple NRTI regimen, (compared witha regimen of 2 NRTIs and 1 PI) [22], is administered twicedaily, and has low selectivity for mammalian mitochondrialDNA synthesis. Abacavir is not metabolized by cytochromeP-450 isoenzymes; therefore, drug interactions are not expectedbetween abacavir and other agents metabolized by these en-zymes. Abacavir is not eliminated via the kidneys, and dosereduction is probably unnecessary for patients with renal dys-function. Abacavir is primarily metabolized by alcohol dehy-drogenase and glucuronyl transferase. Preliminary studies havenot shown a significant drug interaction between abacavir andalcohol [79].

Clinical trials have shown that the most commonly reportedadverse effects of abacavir are fatigue, asthenia, rash, headache,nausea, vomiting, and diarrhea [7981]. Because abacavir wasused in combination with other antiretrovirals in clinical trials,



ownloaded from



Table 4. Common adverse effects of nonnucleoside reverse transcrip-tase inhibitors (NNRTIs).

NNRTI, adverse effect % of patients affected

NevirapineRash, total 1724Rash, severe 48Stevens-Johnson syndrome 0.5Fever 510Elevated AST and ALT levels, and/or GGT 38Nausea 711Headache 710

DelavirdineRash, total 1018Diarrhea 4Fatigue 35Rash, severe 56Headache 311

EfavirenzCNS effects, total 52Rash, total 510Elevated ALT and AST levels 2CNS effects, severe 6Rash, severe 1


it is not clear whether these adverse effects are strictly due toabacavir or partially or wholly attributable to other antiretro-virals given concomitantly.

The most clinically significant adverse effect of abacavir is ahypersensitivity reaction characterized by flulike symptoms,which is a systemic reaction that typically involves multipleorgan systems. The most common symptoms are fever, rash,and gastrointestinal complaints and 85% of cases occur in thefirst 6 weeks [79]. Diagnosis requires 12 of the following symp-toms: fever, rash, malaise, nausea, vomiting, diarrhea, arthral-gias, abdominal pain, dyspnea, and/or paresthesias. Uncom-monly, respiratory complaints, such as cough and pharyngitishave been observed. Abacavir treatment is often started withother antiretroviral therapy that can also cause similar or iden-tical symptoms, which can complicate the diagnosis. If the pa-tient is believed to have developed the hypersensitivity reaction,abacavir treatment should be discontinued, and patients shouldnot be rechallenged. If abacavir is the cause of the symptoms,they usually resolve within 2448 h after discontinuation oftherapy. If a patient is rechallenged, severe symptoms can recurwithin hours, which may include life-threatening hypotension,anaphylaxis, and death [79, 82].

Approximately 5% of patients involved in clinical studies ofabacavir have developed the hypersensitivity reaction. Thesymptoms generally occur within the first 6 weeks after thestart of abacavir treatment, although symptoms may occur atany time during therapy. Physical findings often include lym-phadenopathy, mucus membrane lesions, and rash. It shouldbe noted that hypersensitivity reactions have occurred withoutrash, and rash has occurred without other symptoms of thereaction. It is extremely important for medical providers to beaware of this reaction, to diagnose it properly, and to informand/or educate patients about this reaction. Patient educationis critical but so is education of the medical community: forexample, emergency physicians will undoubtedly see patientswith the hypersensitivity reaction.

The hypersensitivity reaction requires discontinuation of aba-cavir treatment. After discontinuation of abacavir therapy, pa-tients can be treated with analgesics, antihistamines, anti-diarrheals, and/or fluids to relieve symptoms. Abnormal resultsof laboratory studies have included elevated transaminase lev-els, increased creatine phosphokinase or serum creatinine level,and lymphopenia; these are usually mild and self-limited. None-theless, careful monitoring is necessary for patients with un-derlying hepatic or renal dysfunction.

NonNucleoside Reverse Transcriptase Inhibitors(NNRTIs)

With approval of nevirapine in 1996 and delavirdine in 1998by the FDA and impressive results from clinical trials of efa-virenz [83], NNRTIs have gained a definitive place in the treat-ment of HIV infection. NNRTIs possess the same mechanism

of action as NRTIs, although they are quite different in mo-lecular structure. NNRTIs inhibit HIV replication by bindingto a specific nonsubstrate hydrophobic pocket of HIV type 1(HIV-1) reverse transcriptase [84]. This binding site is distinctfrom the NRTI binding site but also inhibits viral replication.The NNRTI binding site is located close to the reverse tran-scriptase catalytic site; allosteric binding inactivates HIV-1 re-verse transcriptase by altering its conformation.

The NNRTIs are characterized by similar pharmacokineticparameters, including excellent oral absorption, a long half-life,and metabolism by the cytochrome P-450 enzyme system.NNRTIs have the potential for serious drug interactions due tocytochrome P-450 enzyme induction (nevirapine), inhibition (de-lavirdine), or both (efavirenz). NNRTIs are also associated withthe rapid development of viral resistance, especially if they arenot part of a maximally suppressive regimen; resistance requiresonly a single amino-acid codon substitution. For example, theK103N mutation is associated with resistance to nevirapine, de-lavirdine, and efavirenz. Because of the high degree of cross-resistance between the currently available NNRTIs, it is doubtfulthat a second NNRTI will provide any virological benefit afterresistance has developed. However, HIV-1 strains resistant toNRTIs often remain susceptible to NNRTIs. The NNRTIs arealso characterized by their adverse effect profiles; all 3 can causerash and can increase transaminase levels. The adverse effects ofNNRTIs are noted in table 4.

Nevirapine. Nevirapine has an advantageous pharmaco-logical profile that includes convenient administration (1 tablettwice daily), excellent bioavailability, good CNS penetration,and a prolonged half-life (2530 h), which makes once-dailydosing possible [85, 86]. Nevirapine also induces its own me-tabolism; maximal induction occurs within 24 weeks after in-itiation of treatment, which is why the recommendation is to



ownloaded from



give 50% of the dose for the first 2 weeks of therapy [87]. Thismethod of dose escalation has improved tolerability of nevi-rapine by decreasing the incidence of rash. As with other an-tiretrovirals, nevirapine is associated with a number of druginteractions. Nevirapine is considered a moderate inducer ofthe cytochrome P-450 3A4 isoenzyme; however, few drug in-teraction studies have been conducted. Nevirapine has beenfound to decrease indinavir AUC; however, there was largebetween-patient variability. Because of this finding, it is rec-ommended to increase indinavir to 1000 mg q8h if it is givenconcomitantly with nevirapine [3]. Nevirapine has also beenshown to induce symptoms of opiate withdrawal in patientsreceiving methadone treatment [88]. Careful consideration ofdrug interactions is needed, particularly for those drugs thatare metabolized by the cytochrome P-450 3A4 isoenzyme.

Nevirapine is well tolerated; rash is the most common adverseeffect that requires discontinuation of treatment. Other com-mon adverse effects include increased transaminase levels, head-ache, diarrhea, and nausea [87, 89, 90]. These effects usuallydiminish in a few weeks and are more prevalent at initiationof treatment. Nevirapine can be taken with food, which mayalleviate nausea. Mild adverse effects can be treated sympto-matically; however, if adverse effects persist, particularly rash,it may be necessary to change to another NNRTI or anotherantiretroviral regimen. Data is lacking regarding cross-sensitiv-ity between NNRTIs. One report had 9 of 19 patients whodiscontinued nevirapine due to rash and switched to efavirenzalso developed a mild-moderate rash, however, only two pa-tients discontinued therapy because of rash [98].

The rash associated with nevirapine occurred in up to 32%of patients in 1 clinical study [89]; however, the overall incidenceof rash is 17% [91]. The rash tends to occur early, usually inthe first 6 weeks of therapy. Patients should be instructed thatif any rash develops during the 2-week induction period, thedose should not be escalated until the rash resolves. There areno known risk factors for the development of the nevirapine-associated rash. In general, most nevirapine-associated rashesare mild to moderate in severity; they are maculopapular,erythematous cutaneous eruptions, with or without pruritus[87]. The rash typically appears on the trunk, face, and ex-tremities. Severe rashes have occurred that require discontin-uation of treatment (overall incidence, 7%) [87]. Life-threat-ening and rare fatal skin reactions, such as Stevens-Johnsonsyndrome and toxic epidermal necrolysis, have occurred in pa-tients treated with nevirapine [92]. The incidence of Stevens-Johnson syndrome across all trials was 0.5% [91].

Elevation of transaminase levels has been observed, but in-creases occurred at rates similar to those observed in non-nevirapine-containing treatment arms [91]. However, cases ofsevere acute hepatitis associated with nevirapine have been re-ported in the literature [93]. For patients with pre-existing liverdisease, close monitoring for the first 6 months is recommended.

Management of the nevirapine-associated rash should be

based on the type and severity of symptoms. Grades 12 (mildto moderate) rashes are usually self-limited, and the rash usuallyresolves without discontinuing nevirapine treatment. Symptomsmay be relieved with oral antihistamines or topical steroidcream. Some investigators have postulated that prophylaxiswith antihistamines or corticosteroids during the inductionphase may reduce the incidence of rash, but this hypothesis hasnot been formally evaluated.

Rash accompanied with fever, severe pruritus, vomiting, se-vere gastrointestinal manifestations, oral lesions and/or ulcer-ation, blistering, or muscle or joint pain requires discontinua-tion of nevirapine therapy. Rechallenge with nevirapine in thesecases should not be performed. It is important for the clinicianto instruct patients to call immediately if rash or other consti-tutional symptoms occur so that they can be properly evaluatedand treatment can be discontinued, if necessary, to prevent pos-sible escalation to Stevens-Johnson syndrome.

Delavirdine. Delavirdine, like nevirapine, has excellent bio-availability and can be taken with or without food. However,delavirdine is different from nevirapine because it has poorpenetration into the CSF, inhibits the cytochrome P-450 3A4isoenzyme, approved for 3-times-a-day dosing, and has a largepill burden (12 tablets per day) [94]. The bioavailability of de-lavirdine increases by 20% when a slurry is prepared, whichis accomplished by allowing delavirdine to disintegrate in water[94].

The most common reported adverse effects of delavirdine arerash (18% of cases), nausea (7%), diarrhea (4%), headache (6%),fatigue (4%), and increases in transaminase levels (5%) [94, 95].Delavirdine is considered to be well tolerated. The rash, whichhas an incidence that has been observed to be as high as 44%,is described as erythematous, maculopapular, mildly pruritic,and mild to moderate in intensity [96]. It typically develops715 days after the onset of drug therapy and, like the nevi-rapine-associated rash, often resolves without discontinuingtherapy. The rash has occurred in all dosing groups and isneither dose-dependent nor dose-limiting (only 4.3% of patientsdiscontinued treatment because of rash) [94]. In contrast totherapy with nevirapine, dose titration is not necessary, nordoes it significantly reduce the incidence of rash. It has beenobserved that continuing delavirdine treatment without inter-ruption does not lead to a higher incidence of complicationsor delay resolution, as compared with an alternative approachof discontinuing delavirdine treatment until the rash has re-solved, followed by reintroducing delavirdine [96].

Delavirdine is also different from nevirapine because it in-hibits the cytochrome P-450 3A4 isoenzyme [97]. Increasedplasma concentrations, which are potentially harmful, are ex-pected for a number of drugs that are metabolized by the cy-tochrome P-450 3A4 isoenzyme (e.g., astemizole, midazolam,triazolam, alprazolam, cisapride, and dihydropyridine calciumchannel blockers) [94]. The inhibitory effects of delavirdine onenzymes can also be advantageous when it is used in combi-



ownloaded from



nation therapy with PIs. Other significant drug interactionsinclude antacids, which decrease delavirdine absorption. There-fore, if delavirdine and didanosine are given concomitantly,administration should be separated by at least 1 h. In addition,both rifabutin and rifampin are not recommended to be givenconcomitantly with delavirdine because they substantially de-crease delavirdine plasma concentrations (by 80% and 96%,respectively) [94].

The management of the delavirdine-associated rash is thesame as described for the nevirapine-associated rash. Althoughthe incidence of severe rash is lower than that associated withnevirapine, any patient who develops severe rash with fever,blisters, or other constitutional symptoms should discontinuedelavirdine treatment and see their medical provider.

Efavirenz. Efavirenz received FDA approval in September1998. Forty-eight week data from on-treatment and intent-to-treat analyses were similar for efavirenz in combination withzidovudine and lamivudine and superior compared with indi-navir, zidovudine, and lamivudine [83]. Efavirenz is recom-mended as a preferred agent for the initial treatment of HIVinfection [3]. Efavirenz also has a favorable pharmacokineticprofile that includes excellent absorption, no food restrictions,and a long half-life that allows for once-daily dosing [98]. How-ever, efavirenz is metabolized by the cytochrome P-450 3A4isoenzyme and is a mixed inhibitor and inducer, which makespotential drug interactions difficult to predict. Because mal-formations were observed in fetuses from efavirenz-treated pri-mates, efavirenz is contraindicated in pregnancy, and womenof child-bearing age should use adequate contraception whilereceiving efavirenz treatment [98]. The adverse effects of efa-virenz are similar to those of other NNRTIs, but it also com-monly causes unusual CNS side effects.

CNS adverse effects occurred in 52% of patients receivingefavirenz treatment in clinical trials [98]. Symptoms includeddizziness, confusion, abnormal thinking, impaired concentra-tion, agitation, hallucinations, nightmares, vivid dreams, andeuphoria. Of patients in clinical trials, 2.6% had to discontinueefavirenz treatment because of CNS adverse effects.

Skin rash occurred in 10% of patients in controlled clinicaltrials [98]. Severe rash that included symptoms of blistering orulcerations occurred in 1% of patients. The rash is most likelyto occur in the first 2 weeks of therapy. Efavirenz also canincrease transaminase levels, which require monitoring partic-ularly in patients coinfected with hepatitis B or C virus.

Data supported by pharmacokinetic studies will be impor-tant to determine significant drug interactions with efavirenz.Fiske et al [99] have shown that efavirenz decreases the indi-navir AUC by 31%; when coadministered, the dosage of in-dinavir should be increased to 1000 mg q8h. Efavirenz alsosignificantly decreases saquinavir AUC by 62% and thereforeshould not be coadministered with this agent [99] and am-prenavir AUC 36%, requiring dose modification [3]. Efavirenzdecreases rifabutin AUC by 38% when coadministered; it is

recommended that the dosage of rifabutin be increased to 450mg once a day. Recent data have also shown that efavirenzdecreases methadone plasma levels, which has resulted in symp-toms of opiate withdrawal [100].

CNS adverse effects usually appear within the first few daysof therapy and generally resolve after 24 weeks. The admin-istration of efavirenz is recommended once daily at bedtime tominimize the CNS side effects. Administering efavirenz as adivided dose or initiating a lower lead-in dose followed by doseescalation has not been shown to decrease the incidence orseverity of symptoms. It is important for clinicians to educatetheir patients about the adverse effects of efavirenz and thatthey are likely to decrease with continued therapy. Low dosesof haloperidol, benzodiazepines, tricyclic antidepressants, andantihistamines have all been used anecdotally to ameliorateCNS adverse effects with some benefit.

Protease Inhibitors (PIs)

Inhibitors of HIV aspartyl protease are the most potent in-hibitors of HIV replication and have been the subject of recentreviews [101106]. Like all antiretrovirals, PIs require appro-priate dosing to prevent the development of resistance muta-tions. Because of the highly error-prone action of reverse tran-scriptase and the high replication rate (1010 virions daily), HIVis said to be unforgiving [101]. Wild-type HIV in treatment-naive patients contains polymorphisms at all amino-acid basepairs, and typically >4 mutations are required for resistanceto PIs [107]. As a consequence, patients and physicians musttake every possible step to ensure full adherence to PI treatmentby using appropriate doses from the outset of therapy. The riskof producing resistant HIV overshadows the potential dangerof adverse events or other reasons for incomplete patient ad-herence. Therefore, the first principle of the management ofadverse effects of PIs is clear: do not decrease the dose in aneffort to reduce adverse effects. In all cases, there are only 2options: (1) continue to administer full doses as determined byappropriate pharmacological study, or (2) switch to therapywith an alternative agent or agents. Increasing the dose of ri-tonavir to mitigate the adverse effects is an obvious exceptionto these rules.

Adverse effects of all PIs are common (table 5). In addition,numerous reports have identified a syndrome of metabolic dis-orders in patients receiving PI treatment, which appears to oc-cur in association with all PIs and has also uncommonly beendescribed in drug-naive patients and in patients receiving treat-ment with PI-sparing regimens [108] (see below).

Other infrequent adverse events associated with PIs are note-worthy. A syndrome of increased and uncontrollable bleedinghas been described in hemophiliacs receiving HAART [109].The mechanism is unclear; patients generally have advancedHIV infection, are receiving multiple therapies, and are oftenaffected by frequent bleeding episodes before HAART. Severe



ownloaded from



Table 5. Common adverse effects of protease inhibitors (PIs).

PI, adverse effect % of patients affected

SaquinavirDiarrhea 20Nausea 11Abdominal pain 9Dyspepsia 8Flatulence 8Headache 5Fatigue 5Elevated AST and ALT levels 26

IndinavirNephrolithiasis 35Diarrhea 5Vomiting 4Hyperbilirubinemia 10Abdominal pain 9Nausea 12Headache 6

RitonavirNausea 2326Diarrhea 1321Taste perversion 515Elevated AST and ALT levels 56Asthenia 914Headache 56Vomiting 1315Anorexia 68Perioral dysesthesia 36Hypertriglyceridemia 28Hypercholesterolemia 2

NelfinavirDiarrhea 1432Nausea 37

AmprenavirRash, total 18Nausea 1033Headache 744Rash, severe 6Vomiting 15


hemarthrosis and intracranial hemorrhage have been reported[109]. Case-by-case analysis of a hemophiliacs response toHAART and frequent consultation with the primary hematol-ogist are clearly required.

At recommended doses, PI serum levels may vary 3-fold to10-fold. Recent data that show an association between antiviraleffect and therapeutic drug level have raised interest in moni-toring of drug levels for antiviral effect and have renewed in-terest in investigating possible associations between drug levelsand adverse effects (see below) [110112]. Drug interactions arecommon with all PIs, although ritonavir has the greatest po-tential for interactions with the largest number of drugs. Unlikethe NRTIs, PIs are not excreted by the kidney; therefore nodose alterations are required in patients with renal insufficiency.

As noted above, the occurrence of moderate-to-severe sideeffects of PIs may best be managed in this era of multipletreatment options by switching therapy. On the other hand,because adverse effects occur in association with all agents andtend to decrease during the first 46 weeks of therapy, the cli-nician is justified in treating mild to moderate adverse effects

symptomatically when possible and preserving future treatmentoptions.

Saquinavir. Saquinavir was the first PI to be approved bythe FDA in November 1995. The original formulation of sa-quinavir has been replaced in favor of the soft-gel formulation(Fortovase; Roche Laboratories, Nutley, NJ). Although thebioavailability is substantially improved with the soft-gel for-mulation, the rate of bioavailability remains low (8%12%), theside effect profile is similar, and the dosing requirements arestill difficult, requiring 6 tablets 3 times daily with a large high-fat meal [113, 114]. These difficulties have limited the use ofsoft-gel formulation of saquinavir as a single PI, although itsuse in combination therapy remains common (see dual PI sec-tion). The most common adverse effects are gastrointestinal:20%25% of patients experience nausea, vomiting, abdominalbloating and pain, dyspepsia, and diarrhea. The gastrointestinaleffects of the soft-gel formulation are moderate to severe in10%20% of patients. Other adverse effects include headache(12% of patients) and elevated transaminase levels (2%6%).In addition, both forms of saquinavir have been associated witha moderately high incidence of metabolic abnormalities in com-parison with other PIs (see below). Whether the high-fat dietrequired for the soft-gel formulation plays a role is yet to bedetermined.

Mitigation of gastrointestinal adverse effects is difficult.Some success is reported anecdotally with antidiarrheals, suchas loperamide, but there is no clear benefit from histaminereceptor blockade or antacids. Headache is usually mild andresponds to acetaminophen or nonsteroidal anti-inflammatorydrugs. Hepatic enzyme levels should be monitored in all patientsreceiving treatment and more closely followed in patients withpre-existing liver disease. Management of the metabolic ab-normalities is discussed below.

Saquinavir is a weak inhibitor of the cytochrome P-450 sys-tem and is associated with relatively mild drug interactions [3].

Indinavir. Indinavir is one of the better tolerated PIs. Theadverse effects of indinavir include headache, nausea and gas-trointestinal distress, elevations in hepatic transaminase levels,nephrolithiasis, asymptomatic hyperbilirubinemia, dry skin,and taste perversion [115]. Nephrolithiasis, which occurs in10%15% of all patients and in 5% when high-risk patientsare excluded, is the most serious adverse effect. However, in a3-year follow-up study of 33 patients receiving treatment withindinavir, zidovudine, and lamivudine, the incidence of ne-phrolithiasis was 39% [116]. Indinavir can crystallize in theurine and form stones or sludge, which is caused by precip-itation due to the increased concentrations of drug in the renaltubules. Indinavir absorption is impaired when it is taken withfood; in particular, foods with a high-fat content. Therefore,indinavir should be taken on an empty stomach or with a fat-free snack.

Indinavir-related nephrolithiasis can be minimized or pre-vented by instructing patients to drink 40 oz (1.5 L) of fluids



ownloaded from



daily. Avoidance may be prudent in patients with underlyingrenal disease or a structural genitourinary deficiency, in whomadditional renal impairment may be serious and irreversible.Other adverse effects of indinavir are generally mild and in-frequently require intervention. Headache is usually self-limitedand responds to analgesics, and taste perversion rarely leadsto discontinuation of therapy. Hyperbilirubinemia is generallyof no clinical consequence; monitoring of liver function duringinitiation of treatment is indicated for patients with underlyingliver disease. Indinavir has also been associated with the met-abolic disorders of HAART (see below).

Indinavir is also a weak inhibitor of the cytochrome P-4503A4 isoenzyme. Caution is therefore needed when indinavir isadministered with other medications that are metabolized bythese enzymes. Medications not recommended for concomitantuse include rifampin, phenytoin, carbamazepine, midazolam,triazolam, terfenadine, and ergot alkaloids [3].

There is much interest in using indinavir for dual PI com-binations, for example indinavir and ritonavir. Among otherpotential benefits, ritonavir (400 mg twice daily) with indinavir(400 mg twice daily) blunts both the peak and trough concen-trations of indinavir, which may allow for twice-daily dosingand may reduce or eliminate the strict food and fluid dosingrequirements (see dual PI section); other doses of this combi-nation, such as indinavir 800 mg with ritonavir 200 mg twicedaily, are under study [117].

Ritonavir. Numerous adverse effects have limited the use-fulness of ritonavir as a single agent at the recommended dosage(i.e., 600 mg b.i.d.). These side effects include asthenia, nausea,vomiting, diarrhea, perioral dysesthesia, headache, dizziness,and taste perversion [118]. Occasionally, patients tolerate full-dose ritonavir quite well, but there is no way to predict reliablyat present who will have significant adverse effects, which oc-casionally are severe and poorly tolerated. Other adverse effectsinclude abnormal liver enzyme levels and metabolic disorders(see below). Most comparisons of the prevalence of the met-abolic disorders have found that the frequency of these dis-orders in association with ritonavir is higher than that in as-sociation with other PIs [119]. Many of the adverse effectsassociated with ritonavir, much like those associated with zi-dovudine, decrease during the first weeks of administration.

Perhaps the most important initial action to reduce ritonavir-associated side effects is a gradual dose escalation. Cliniciansshould initiate ritonavir at a dosage of 300 mg twice daily for4 days, then 400 mg for 4 days, and 500 mg for 5 days followedby 600 mg twice daily thereafter. The most significant side ef-fects occur with doses 1400 mg. Again, for this reason, thedosage of ritonavir of 400 mg twice daily is preferred in com-bination with saquinavir (or possibly other agents) because itsadverse effects are relatively well tolerated. Anecdotally, choc-olate milk and Nutella are reported to improve the palatabilityof ritonavir. Ritonavir capsules require refrigeration but maybe kept at room temperature for 24 h.

In August 1998, manufacturing problems caused cessationof the production of ritonavir capsules, and ritonavir liquid(400 mg/5 mL), which has an unpleasant aftertaste but requiresno refrigeration, was available for substitution. Strategies tominimize the aftertaste of ritonavir liquid are diverse and pa-tient-specific; these strategies may include having the patienteat hard candy, chocolate, or peanut butter candy or drinkchocolate milk, or instilling the liquid with a syringe or dropperin the posterior oral cavity behind the taste buds. In June 1999,a revised formulation of the ritonavir capsule received approvalfor use from the FDA. The pills are formulated as 100 mg andrequire refrigeration; the adverse effects are comparable withthose of the previous capsule formulation. Thus, one of theserious limitations to ritonavir use (i.e., the foul taste of theliquid formulation) has been overcome. Some patients preferthe oral liquid form, and its use in those patients and in childrenwill continue.

Mitigation of the adverse effects of ritonavir with other med-ications has proven to be difficult. Analgesics will help relieveheadache and abdominal pain, and antiemetics and antispas-modics may decrease the gastrointestinal side effects. At pre-sent, no treatment has been shown to reduce perioral dyses-thesia or taste perversion.

Ritonavir is a potent inhibitor of the several cytochromeP-450 isoenzymes and therefore is associated with numerousdrug interactions. The list of contraindicated medications isvery long and includes rifampin, triazolam, terfenadine, andergot alkaloids. Clinicians must tell patients to consult withthem before taking any prescription or over-the-counter med-ications [3].

Nelfinavir. Nelfinavir is a generally well-tolerated PI, withmild diarrhea occurring in 14%32% of patients [120]. The di-arrhea is characterized by loose stools 34 times daily. In thepivotal nelfinavir studies, 11% of patients discontinued therapybecause of adverse reactions, of which 2% were diarrhea [121].Other adverse effects of nelfinavir are infrequent, occurring in!3% of patients and with no greater incidence than with trialcontrols (such as zidovudine and lamivudine).

Nelfinavir-associated diarrhea can be readily controlled withantidiarrheal agents, such as diphenoxylate atropine or loper-amide. Patients starting treatment with nelfinavir should beinformed of the possibility of diarrhea and be given prescrip-tions for these agents with the first prescription of nelfinavir.Nelfinavir-associated diarrhea is nonetheless an important con-sideration in the initiation of HAART, particularly for patientswith pre-existing gastrointestinal illness and wasting (in whoma mild to moderate increase in diarrhea can have an adverseimpact on the quality of life and on nutritional recovery). Forsuch patients, aggressive antidiarrheal therapy should be un-dertaken from the start of nelfinavir treatment, and some con-sideration to alternative agents should be given.

Nelfinavir is also a weak inhibitor of the cytochrome P-450system and therefore is associated with numerous drug inter-



ownloaded from



actions. Contraindicated medications include rifampin, tria-zolam, terfenadine, and ergot alkaloids [3].

Amprenavir. Amprenavir was approved for use by theFDA in February 1999. Amprenavir in combination with dualNRTI therapy was associated with sustained viral load sup-pression similar to that associated with the other approved PIs.The usual dose is 1200 mg (8 150-mg tablets twice daily) [122].Side effects include rash, gastrointestinal problems, fatigue,headache, paresthesias, and mood disorders. In general, theseside effects are more pronounced during the first 2 weeks oftreatment and decrease somewhat thereafter.

The rash occurs in 28% of patients, of whom 4% have grade3 or 4 rashes. To date, 3% of patients have discontinued treat-ment because of rash. Stevens-Johnson syndrome occurs in 1%of patients receiving amprenavir treatment and 4% of patientswith an amprenavir-related rash. The rash is usually maculo-papular and mild to moderate in severity. The incidence of rashassociated with amprenavir is higher than that associated withother PIs because of a sulfa moiety in amprenavir; however,patients with known allergy to sulfa drugs may take ampren-avir. Gastrointestinal side effects include nausea (38%73% ofpatients), vomiting (20%29%), and diarrhea (33%56%). Gas-trointestinal symptoms led to discontinuation of treatment in11% of patients in 2 pivotal trials (PRO3001 and PRO3006)[122]. Headache occurred in 7%44% of patients and was mildto moderate in severity. Perioral dysesthesias were observed in26%30% of patients and rarely led to discontinuation of treat-ment. Psychiatric side effects, including depression and moodalteration, occurred in 4%15% of patients and were infre-quently associated with discontinuation of treatment.

Amprenavir therapy may safely be continued for patientswith mild rash without pruritus or systemic symptoms, such asfever or vomiting. If treatment is interrupted because of mildamprenavir-associated rash, the drug can be readministeredwithout an increased risk of severe rash. Antihistamines mayameliorate the mild discomfort of pruritus. On the other hand,if there is moderate-to-severe rash that involves mucous mem-branes or is accompanied by fever, chills, vomiting, or intensepruritus, treatment should be discontinued, and rechallengeshould be avoided. Stevens-Johnson syndrome should be man-aged with conventional use of antihistamines and systemiccorticosteroids.

The mild gastrointestinal side effects of amprenavir may re-spond to antiemetics and antidiarrheal therapies. Nausea isdifficult to control and may be decreased by dosing immediatelyafter meals. Moderate to severe nausea, vomiting, and diarrheamay require discontinuation of treatment. Headache is usuallyself-limited and responds to analgesics, such as acetaminophenor nonsteroidal anti-inflammatory drugs. There is too little datato date on the appropriate management of amprenavir-relatedmood disorders and dysesthesias.

New protease dosing strategies and dual PI combinations.The growing recognition of the importance of adherence to

HAART has generated intense interest in simplifying dosingintervals and reducing pill burdens. Peterson et al. [123] recentlyreported results of long-term follow-up study of twice-dailyversus 3-times-daily therapy with nelfinavir in combination withstavudine and lamivudine for 286 patients. Perhaps most im-portantly, the side effects of both doses were equivalent, withany diarrhea occurring in 45% of patients and serious diarrheaoccurring in 11%12% of patients in both groups. After 48weeks, there were no significant differences in the percentageof patients with viral loads below the level of detection. Theaccompanying data on plasma pharmacokinetics were com-parable for both regimens. On the basis of these and othersupporting data, many clinicians have begun to use nelfinavirat the 1250-mg twice-daily dosage, and twice-daily dosing re-cently received FDA approval.

Clinicians are well advised to view new dosing strategies withskepticism and follow the original dosing recommendations un-til alternative strategies have been subjected to thorough study.Twice-daily indinavir dosing appeared promising in preliminaryuncontrolled trials of 1000 or 1200 mg twice daily, but asso-ciated pharmacological data suggested that the drug levels oftenfell below the IC90 for indinavir [123]. A controlled clinical trialshowed that twice-daily indinavir dosing was significantly in-ferior to indinavir every 8 h; this trial has been halted, andtwice-daily indinavir dosing is not recommended [124].

Some dual PI combinations offer the potential advantagesof decreasing dose frequency, reduced adverse effects, and com-parable potency. Among dual PI combinations, the most ex-tensive experience is with 400 mg of ritonavir and 400 mg ofsaquinavir given twice daily. Mellors et al. [125] recently re-ported 72-week follow-up data for 100 patients receiving treat-ment with ritonavir and saquinavir, which showed that 90% ofpatients had viral loads !200 copies/mL at 72 weeks. The meanincrease in CD41 cell count was 185 cells/mL, and adverseevents were infrequent; 10%12% of patients had gastrointes-tinal events. Nineteen percent of patients had a minor increasein viral load within 72 weeks, after which intensification oftreatment was instituted with stavudine and lamivudine; ofthese patients, 78% had reductions in viral loads below the levelof detection.

The combination of ritonavir and saquinavir is also beingstudied in a first-line capacity. Kirk et al. [126] reported resultsof a comparison of the combination of ritonavir and saquinavirwith ritonavir or indinavir alone with 2 NRTIs; at 24 weeks,ritonavir and saquinavir with 2 NRTIs had reduced viral loads82% below the level of detection; saquinavir with 2 NRTIs hadreduced viral loads 71%; ritonavir with 2 NRTIs, 67%. Therewere also fewer serious adverse events: ritonavir and saquinavirwith 2 NRTIs, 12.9%; saquinavir with 2 NRTIs, 16%; ritonavirwith 2 NRTIs, 25%. Twenty-one PI-naive patients treated withritonavir (400 mg b.i.d.) and saquinavir (400 mg b.i.d.) with 2nucleoside inhibitors were followed up for 2 years at CookCounty Hospital (Chicago); the rate of adverse events was 12%,



ownloaded from



and 76% of patients had viral loads below the level of detection(500 copies/mL) [127].

Numerous other studies of dual PI combinations are underway. The combination of nelfinavir and saquinavir (soft-gelformulation) appears to be efficacious in clinical studies [128].Because there is only a modest pharmacological interaction,these combinations are associated with only a modest reductionin pill burden or a change in dietary requirements. Similarly,these preliminary data suggest changes in the adverse effectprofiles, with 35%45% of patients having diarrhea and dis-continuation of treatment by 15%18% of patients (which maybe a disincentive for these combinations). Further study is none-theless warranted.

Another combination under study is ritonavir and indinavirwith which peak and trough levels of indinavir that are up to10 times greater than the indinavir IC90 are achieved with dos-ages of 400 mg of both drugs b.i.d. [117]. This combinationhas potent antiviral efficacy. In 1 uncontrolled study, 57 patientswere treated for a mean of 42 weeks without the usual foodand fluid requirements, and nephrolithiasis did not occur [129,130]; data on clinical outcomes are pending, and further studyis warranted. More recently, alternate dosing strategies for ri-tonavir and indinavir are under study, including 1200 mg ofritonavir and 800 mg of indinavir b.i.d. [131].

Finally, not all PI combinations are promising; indinavir andsaquinavir are antagonistic in vitro, and this combinationshould be avoided [3]. Similarly, indinavir and nelfinavir havebeen studied in a twice-daily combination with promising pre-liminary pharmacological data [132]; however, the failure oftreatment with indinavir twice daily led this combination to beabandoned, since it did not confer other desired benefits: re-duction of pill burden, decreased dose frequency, no food re-quirements, comparable potency, and reduced adverse effects.

New Adverse Events (as of 1999)

New reports of unexpected adverse effects have emerged asHAART has become more widespread. Recently, a number ofmetabolic abnormalities (i.e., fat maldistribution, hyperlipide-mia, and glucose intolerance) have been described in patientsreceiving PI-containing HAART. These abnormalities have 3common elements: (1) glucose intolerance and rare diabetes ordiabetic ketoacidosis, (2) hyperlipidemia with hypertriglyceri-demia and hypercholesterolemia, and (3) fat redistribution withaccumulation of abdominal fat and buffalo humps, loss ofperipheral fat in the face, arms, legs, and buttocks, as well asectodermal dysplasia characterized by ingrown toenails [119,133139]. Breast enlargement has been described in women andrarely in men [140]. Note that each manifestation can occur inthe absence of the other 2 and that it remains uncertain whetherthe syndrome should be so defined.

Carr et al. [133, 141] recently reported that 68% of patientstreated with PIs for an average of 11 months had fat redistri-

bution when they were assessed by sensitive dual energy ra-diographic absorptiometry, and a large cohort study in Franceshowed a similar prevalence (58%) [119]. However, other in-vestigators have reported substantially lower prevalences ofthese changes (i.e., 17%32%) [137, 138, 140]. This constellationof symptoms has been primarily described in patients receivingPI treatment (including all known members of the class), al-though there are case reports of the syndrome in patients re-ceiving PI-sparing regimens (including 16% of patients receivingdual NRTIs in an Australian cohort [142]). In a well-controlledWomens Interagency HIV study, in which extensive pretreat-ment metabolic data were available, 16% of women reportedan abnormal habitus, including breast enlargement of 2 sizesin 71% of those reporting changes [140]; 41% had elevatedcholesterol levels, and 38% had triglyceride levels greater thanbaseline values.

Whether these findings are linked to so-called metabolic dis-orders, as has been proposed [133], or are disparate manifes-tations of PI therapy or viral load reduction is as yet unknownand unproven. Nonetheless, they are worthy of close attentionby clinicians, particularly because of the real possibility of sig-nificant short- and long-term clinical consequences. For ex-ample, anecdotal reports of premature cardiovascular diseasein patients receiving PI treatment have emerged [143]. Henry[144] described 4 patients with hypertriglyceridemia-associatedpancreatitis. Some of these abnormalities in lipid concentrationwould place patients into distinctly higher risk classificationsfor cardiovascular disease. When the observed increases in lipidlevels were analyzed in a model of cardiovascular disease fromthe Framingham study [145], the estimated increase due to in-creased lipid levels alone was only 1.4 cases per 100,000 pop-ulation every 10 years. To date, diet and exercise alone havenot been associated with reversals of hyperlipidemia, althoughmodest reductions in lipid levels of 10%20% have been ob-served with atorvastatin, gemfibrozil, and other agents thatlower lipid levels [146]. Importantly, one-half of the 14 casesof diabetic ketoacidosis that were reported to the FDA in 1997occurred in patients with no known risk or predisposition todiabetes.

Management of Metabolic Disorders

Given the current uncertainty regarding the prevalence, in-cidence, and clinical significance of these events, the followingrecommendations can be made. First, baseline lipid levels andrandom glucose levels should be determined before patientsstart PI treatment, and these patients should be monitored forchanges in fat distribution and abnormalities in carbohydrateor lipid levels. Medical management should include examina-tion of the patients diet and recommendations for a low-fatdiet and regular exercise; oral hypoglycemic agents or agentsthat lower lipid levels may be necessary and should be usedaccording to current medical standards, such as those of the



ownloaded from



Table 6. Common adverse effects of hydroxyurea and adefovirdipivoxil.

Agent, adverse effect % of patients affected

HydroxyureaAnemia 1015Thrombocytopenia 1015Stomatitis 8Rash 6Granulocytopenia 1015Headache 5Nausea 12Elevated ALT and AST levels 2

Adefovir dipivoxilProximal tubular dysfunction 1838Diarrhea 5Elevated ALT and AST levels 4Nausea 58Elevated CK level 2

NOTE. ALT, alanine aminotransferase; AST, aspartate aminotransferase;CK, creatine kinase.

National Cholesterol Education Program [146]. Data do notexist at present to evaluate the relative contribution of each ofthese interventions. Nonetheless, in view of the potential forsimple management measures of some of the observed changes,treatment for patients who are presently virologically and clin-ically stable should not be changed unless there is a compellingrationale for doing so (e.g., severe hypertriglyceridemia withpancreatitis, recurrent diabetic ketoacidosis or refractory dia-betes mellitus, or accelerated ischemic heart or vasculardisease).

Currently, it is not known whether discontinuation of PItreatment will reverse the metabolic adverse events. Preliminarydata from studies of switches from PIs to NNRTIs or abacavirsuggest that virologic control is maintained in 190% of patients,triglyceride and cholesterol decline modestly (1020 mg/dl), butno clear change in fat maldistribution has been observed [147,148]. In addition, there are anecdotal reports of improvementwith discontinuation of treatment and/or administration ofagents that lower lipid levels [149]. For patients at high riskfor cardiovascular disease, extra vigilance may be necessary. Aswith all patients, general measures to reduce the risk of car-diovascular disease should be pursued aggressively, such asstopping smoking and treating hypertension.

Two other antiretroviral agents were available for cliniciansin 1999, either by nonapproved use of an existing drug or byrelease according to compassionate protocol. These agents arehydroxyurea and adefovir dipivoxil (table 6).

Hydroxyurea. Hydroxyurea (Hydrea; Bristol-MyersSquibb, Princeton, NJ) is an antimetabolite used in the treat-ment of hematoproliferative disorders, such as polycythemiavera and sickle-cell disease. Its use in the treatment of HIVinfection has evolved with the recognition of its inhibition ofribonucleotide reductase, the cellular enzyme in the productionof nucleotides that also mediates the metabolism of didanosineand other antiviral agents. By inhibiting ribonucleotide reduc-tase, the intracellular pool of nucleic acids (particularly aden-osine) decreases. This decrease increases the likelihood that di-danosine, an adenosine analogue, will be incorporated into theviral RNA, thus halting viral replication [150]. Recent clinicaldata have shown that hydroxyurea enhances the antiviral effectof didanosine by increasing suppression of the viral load by0.5 log, even in patients with prolonged past treatment withdidanosine [151]. Importantly, hydroxyurea reduces the overalllymphocyte count; therefore, it is not associated with increasesin absolute CD41 cell counts, as are other antiviral therapies.However, CD41 cell percentages do increase significantly inpatients who are treated with didanosine and hydroxyurea.

Hydroxyurea has a well-known adverse effect profile for pa-tients with myeloproliferative disorders [152], but a completedescription of adverse effects in people with HIV disease is stilllacking. The most important adverse event is myelosuppressionof all lineages, which occurs in 10%15% of patients and isreversible with discontinuation of treatment. Other reported

adverse effects that occur at moderate frequency include di-arrhea, stomatitis, and maculopapular pruritic rash. In addi-tion, hydroxyurea is associated with complications of therapyarising from its antimetabolic effect on rapidly reproducing celllines, such as hyperuricemia, aggravation of gout, and urate-induced renal disease. To date, these complications have notbeen described in patients with HIV disease.

The absence of several key pieces of data has limited the useof hydroxyurea. The optimal dose has yet to be established,although dosages of 11200 mg/d are associated with more fre-quent adverse events. The most commonly used dosage at pre-sent is 500 mg b.i.d.; dose-ranging studies are under way. Sim-ilarly, the full extent of the side effect profile in HIV diseasehas not been characterized. These data should be availablewithin 1 year.

Hydroxyurea-associated cytopenias have been reported torespond to erythropoietin and granulocyte colony-stimulatingfactor, although the long-term use of these agents is discour-aged. In general, hydroxyurea should be used with caution astreatment for patients with pre-existing cytopenias, whetherfrom infection due to HIV, parvovirus, or other causes; patientswith these conditions should be monitored closely for cyto-penia, particularly within the first 2 months of hydroxyureause. Hydroxyurea-associated diarrhea is generally mild and isreadily controlled with antidiarrheal agents. Although the rashassociated with hydroxyurea is generally well tolerated and re-sponsive to antihistamines and topical steroids, discontinuationof treatment is necessary in severe cases with systemic mani-festations or mucosal involvement.

Adefovir dipivoxil. Adefovir dipivoxil is a novel nucleotidereverse transcriptase inhibitor that has modest activity againstHIV (viral load reduction, 0.5 log) and also has activityagainst cytomegalovirus and hepatitis B virus [153155]. Nu-cleotide analogues differ from the NRTI class, because nucle-otides require only 2 phosphorylation steps via ubiquitous cel-lular enzymes and therefore may have greater activity in a



ownloaded from



broader range of cell types. Adefovir dipivoxil is a pro-drugthat has 2 pivalic acid moieties attached to improve bioavail-ability. Pivalic acid derivatives have been associated with re-duced serum carnitine concentrations; therefore, L-carnitine(500 mg) daily is given concomitantly with adefovir dipivoxil[156]. A novel resistance profile makes it potentially attractivefor combination regimens, as does its once-daily dosing profile.

Renal toxicity is the most important adverse effect of adefovirdipivoxil; it has been described in 38% of patients treated for 16months. It presents as interstitial nephritis that causes a dose-and duration-dependent disorder similar to Fanconis syndrome(i.e., elevation of creatinine concentration with or without renaltubular dysfunction, proteinuria, glycosuria, and/or wasting ofelectrolytes, particularly phosphate, bicarbonate, or potassium).Of 83 events in a phase III trial of 120 mg of adefovir dipivoxil,21 took 12 months to resolve, and some proximal tubular damagemay be irreversible [157, 158]. The symptoms were more prev-alent after patients had been receiving therapy for 124 weeks.The original dose under study was 120 mg, but for one-half ofthe patients the original doses had to be reduced to 60 mg. Fur-ther studies are required to evaluate the overall antiviral efficacyof adefovir dipivoxil at this dose level.

Other adverse effects of adefovir dipivoxil include gastro-intestinal symptoms, such as nausea and diarrhea, headache,abdominal pain, and elevations of creatine kinase and hepaticenzyme levels. The gastrointestinal symptoms occur in 5%8%of patients and are mild in severity; in the expanded accessprogram, !1% of 2000 patients receiving adefovir dipivoxiltreatment had grade 3 or 4 gastrointestinal side effects [156].Elevations in creatine kinase levels occur in 2% of patients andare transient and asymptomatic. Elevations in liver enzyme lev-els occur in 4% of treated patients and are mild and welltolerated.

An unexpected interaction between adefovir dipivoxil anddelavirdine was observed recently in the AIDS Clinical TrialsGroup 359 Study that resulted in a 42% lower level of dela-virdine than expected [159].

The management of adefovir dipivoxilrelated nephrotox-icity is discontinuation of treatment. As noted above, most ofthe proximal tubular disorder appears to be reversible withdiscontinuation of treatment. Generally, metabolic acidosis andhypophosphatemia are mild and tolerated; in severe cases, re-placement of phosphate and treatment of acidosis acutely areneeded. Proximal tubular function returns to normal in 40%and 90% of patients by 4 weeks and 14 weeks after cessationof therapy, respectively. Elevations of creatine kinase levels aregenerally mild and asymptomatic. Elevations of hepatic enzymelevels require monitoring during the initiation of therapy, andmore careful monitoring is needed for patients with pre-existingliver disease.

Therapeutic Drug Monitoring

Several recent studies have renewed interest in the potentialfor clinical use of therapeutic drug monitoring of antiretroviral

therapies. Early studies of PIs demonstrated striking variabilityin drug plasma levels, from 3-fold to >10-fold. Because theaction of these drugs depends on intracellular concentrations,the clinical importance of this variability is unclear, althoughtheir role in adverse effects was more clearly associated with adose response. More recently, 3 studies found an associationbetween PI levels and changes in viral load [110112], althoughother investigators have found no such association. In 2 studies,higher nelfinavir levels correlated with greater declines in viralload [110, 112]. In another study [111], inadequate viral loadresponses to saquinavir were associated with trough levels be-low the known IC50 of saquinavir. Both of these latter studieswere uncontrolled and retrospective, but they raise the possi-bility that inadequate drug levels may lead to inadequate treat-ment responses and that clinical monitoring at certain periodsmay be of value in clinical management, both for the inter-pretation of treatment failures and for mitigation of adverseeffects.

There are several potential limitations to therapeutic drugmonitoring for the class of PIs, including the above-noted var-iability, potential costs, logistical difficulties of linking druglevels to meaningful trough and peak concentrations, and un-certain correlation between serum levels and intracellular ac-tivity. Nonetheless, further study of the association betweendrug levels and virological and clinical outcomes is needed inthe future. In particular, the possibility should be explored thatexcessive adverse effects or suboptimal virological responsescould be evaluated by determination of serum levels and com-pensated by dose increases.

Summary and Implications for Treatment

We have outlined several strategies to reduce or prevent ad-verse effects of HAART and to improve adherence to HAART.In each case, before adding medications to therapy or pre-maturely discontinuing treatment, the clinician shouldre-examine the dose (relative to the patients weight and renalfunction, when appropriate), the recommendations for foodadministration, and the relevant details of the patients life,such as his or her values and priorities, daily milestones orhabits that may be used for pill-taking strategies, past behaviorswith medication adherence, and other pertinent personalinformation.

Although the occurrence of new adverse effects, such as met-abolic disorders, is of concern, an overreaction by physiciansor patients might make matters worse. At present, careful studyof the extent and clinical impact of the problem is needed,whereas the remarkable successes of the last 2 years are rec-ognized and further extended. Patients whose conditions areclinically and virologically stable should continue with theircurrent treatment regimens unless the metabolic disorders aresevere or unacceptable to the patients

Documents

11 Management of the Adverse Effects of Antiretroviral Therapy and Medication