Cutaneous toxicities of antiretroviral therapy for HIV

CONTINUING MEDICAL EDUCATION

Cutaneous toxicities of antiretroviral therapy for HIV

Part I. Lipodystrophy syndrome, nucleoside reverse transcriptaseinhibitors, and protease inhibitors

Camille E. Introcaso, MD,a Janet M. Hines, MD,b and Carrie L. Kovarik, MDa,b

Philadelphia, Pennsylvania

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Antiretroviral medications for the treatment of HIV are common drugs with diverse and frequent skinmanifestations. Multiple new cutaneous effects have been recognized in the past decade. Dermatologistsplay an important role in accurately diagnosing and managing the cutaneous toxicities of thesemedications, thereby ensuring that a patient has as many therapeutic options as possible for life-longviral suppression. Part I of this two-part series on the cutaneous adverse effects of antiretroviral medicationswill discuss HIV-associated lipodystrophy syndrome, which can be seen as a result of many antiretroviralmedications for HIV, and the specific cutaneous effects of the nucleoside reverse transcriptase inhibitorsand protease inhibitors. ( J Am Acad Dermatol 2010;63:549-61.)

Learning objectives: After completing this learning activity, participants should be able to recognizecommon and dangerous cutaneous adverse effects related to nucleoside reverse transcriptase inhibitorsand protease inhibitors, including lipodystrophy syndrome, determine which of these toxicities needfurther investigation or medication cessation, and manage the treatment of these cutaneous toxicities.

Key words: antiretroviral medications; cutaneous; drug eruption; HIV; toxicities.

Over the past 2 decades, multidrug antire-troviral therapy for patients infected withHIV has become the standard of care.

Long-term viral suppression, increases in CD4 cellcounts, decreases in opportunistic infections, andimprovement in mortality have all resulted fromcombination antiretroviral therapy. Dermatologistsmust be familiar with the toxicities associated withantiretrovirals for multiple reasons. First, the epi-demic continues to be far-reaching, with 1.2 million

the Department of Dermatologya and the Division of

fectious Diseases,b Department of Internal Medicine, Univer-

ty of Pennsylvania, Philadelphia.

ing sources: None.

ines has been on the advisory board for Abbot, Boehringer

gelheim, Bristol Meyers, Gilead, and GlaxoSmithKline, and has

en a speaker for Boehringer Ingelheim, Bristol Meyer, and

laxoSmithKline. Drs Introcaso and Kovarik and the editors,

anners, and peer reviewers have no relevant financial

lationships.

int requests: Carrie L. Kovarik, MD, Departments of

ermatology and Internal Medicine, Division of Infectious

isease, University of Pennsylvania School of Medicine, 2nd fl,

aloney Bldg, 3600 Spruce St, Philadelphia, PA 19104. E-mail:

[email protected].

-9622/$36.00

10 by the American Academy of Dermatology, Inc.

0.1016/j.jaad.2010.01.061

Americans estimated to be infected in 2007 and newinfections outnumbering deaths.1 A large proportionof the affected population is taking antiretrovirals,making them commonly prescribed drugs. Second,current therapy is not curative and requires multipleagents, so most patients will need to take severaldrugs for much or all of their lives. Third, the severityof the HIV epidemic continues to pressure the USFood and Drug Administration (FDA) to approvemedications quickly, possibly without as muchinvestigation into or caution regarding adverseevents. Clinicians may encounter toxicities thatwere absent or underrepresented in preapprovalclinical trials, so that the drug prescribing informa-tion may not be the most reliable source of infor-mation about adverse effects. Fourth, there areapproximately 30 medications that fall into six clas-ses for treatment of HIV, resulting in protean com-binations of drugs, each with its own interactionsand toxicities (Table I).

Cutaneous adverse effects are one of the mostcommon toxicities of antiretroviral medications inpatients of all ages, all races, and with all of thevarious combinations of therapies available.2-9 Inaddition to the inherent risk of cutaneous side effectsfrom the medications themselves, patients with HIVare at increased risk for immune-mediated cutane-ous reactions to medications of any type, likely

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550 Introcaso, Hines, and Kovarik

because of immune dysregulation. Morbilliform ex-anthems, systemic hypersensitivity reactions, lipo-dystrophy, pigmentation changes, and injection sitereactions are examples of some of the frequentlyseen skin manifestations. These toxicities range fromthe serious and life threatening to cosmetic orannoyances; however, it has been shown that con-

CAPSULE SUMMARY

d Nuceloside reverse transcriptaseinhibitors and protease inhibitors areclasses of antiretroviral medications thatare widely used and have diverse andfrequent skin manifestations.

d Lipodystrophy syndrome is a commonadverse effect of many of the classes ofantiretrovirals and consists of metabolicand cutaneous abnormalities.

d Dermatologists play an important role inaccurately diagnosing cutaneoustoxicities of antiretroviral medications,ensuring that a patient has as manytherapeutic options as possible for life-long viral suppression.

cerns about cosmetic skin-related side effects can leadto medication noncompli-ance with devastating results:loss of virologic control, de-velopment of resistance, andloss of efficacy of multipledrugs because of cross-resis-tance.10 Dermatologists canrecognize and treat thesetoxicities, and we can workwith infectious disease spe-cialists to determine if a med-ication needs to bediscontinued. Because ofthe frequent developmentof resistance and the needto preserve as many medica-tions as possible for patients’future use, it is imperative tomake an accurate assessment
about which drug is causing a cutaneous toxicity andto withhold the drug only if necessary.
ANTIRETROVIRAL-ASSOCIATEDLIPODYSTROPHY SYNDROMEKey pointsd Antiretroviral-associated lipodystrophy syn-

drome can have a combination of lipoatro-phy, lipohypertrophy, and metabolicabnormalities

d Lipodystrophy is most strongly associatedwith certain protease inhibitors and nucleo-side reverse transcriptase inhibitors

d Poly-L-lactic acid and calcium hydroxylapa-tite are injectable fillers approved by the USFood and Drug Administration for restora-tion of facial fat loss in patients with HIV

Antiretroviral-associated lipodystrophy syndromeis one of the most common cutaneous toxicities ofantiretroviral medications. Members of the nucleo-side reverse transcriptase inhibitor (NRTI) and pro-tease inhibitor (PI) classes of medications—and, lesscommonly, nonnucleoside reverse transcriptase in-hibitors (NNRTIs)—have been implicated in causingthis syndrome. Lipodystrophy syndrome consists ofchanges in body fat composition and is often seen in

association with metabolic abnormalities.11 Thecharacteristic changes include a loss of fat in theface, limbs, and buttocks and the accumulation ofdorsocervical and abdominal visceral fat and gyne-comastia12,13 (Fig 1). Lipohypertrophy or lipoatro-phy is sometimes seen alone, but these changesoften appear together and result in patients with a

Cushingoid appearance. Themetabolic abnormalities thatmay occur include insulinresistance, hyperinsulinemiaand a resulting hyperglyce-mia, and dyslipidemia. Thesechanges can put patients atrisk for pancreatitis at anypoint during therapy and in-crease their risk of athero-sclerotic disease over yearsof treatment. In addition, therecognizable facial appear-ance of temporal and buccalfat pad wasting creates anopportunity for stigmatiza-tion of the patient by thepublic10 (Fig 2). Althoughthis constellation of signsand metabolic abnormalitieswas first associated with PI

therapy, it is now recognized as a side effect ofNRTIs, particularly stavudine and the combination ofstavudine and didanosine with or without PI therapy,and NNRTIs, specifically efavirenz.14-17 The timecourse for development of lipodystrophy rangesfrom several months to 2 years, with changes inlimb and waist circumference apparent in up to 35%of patients after 2 years of therapy.12

Management of the metabolic abnormalities ofthe lipodystrophy syndrome includes a balanceddiet, regular exercise and, when appropriate, lipid-and glucose-lowering medications. Dermatologistsshould ensure that patients who present withappearance-related effects of lipodystrophy syn-drome are adequately screened for metabolicdisease by their primary care doctors or otherappropriate specialists. It is unclear whether or notthe risks of stopping or switching antiviral therapyare balanced by the potential cardiovascular andmetabolic benefits, and such changes are not gener-ally recommended.12 Although a variety of studieshave shown fractional long-term improvements insome of the appearance-related parameters oflipodystrophy when regimens are changed, theseimprovements are modest and often not perceived assignificant by the patient.18 Dermatologists play asignificant role in the treatment of facial lipoatrophy

Fig 1. Gynecomastia in a man taking stavudine, a nucle-oside reverse transcriptase inhibitor. Courtesy of Dr PaulaDiab.

Table I. Antiretroviral therapies* for HIV as of 2010

Nucleoside reverse transcriptase inhibitorsZidovudine (Retrovir and Retrovis, GlaxoSmithKline,

Research Triangle Park, NC)Didanosine (Videx, Bristol-Myers Squibb, Princeton, NJ)Stavudine (Zerit, Bristol-Myers Squibb, Princeton, NJ)Lamivudine (Zeffix, Heptovir, and Epivir, GlaxoSmith-

Kline, Research Triangle Park, NC)Abacavir (Ziagen, GlaxoSmithKline, Research Triangle

Park, NC)Emtricitabine (Emtriva, Gilead Sciences, Foster City, CA)

Nucleotide reverse transcriptase inhibitorsTenofovir (Viread, Gilead Sciences, Foster City, CA)

Protease inhibitorsIndinavir (Crixivan, Merck & Co, West Point, PA)Ritonavir (Norvir, Abbott Laboratories, Abbott Park, IL)Saquinavir (Invirase and Fortovase, Genentech, South

San Francisco, CA)Nelfinavir (Viracept, Pfizer Inc, New York, NY)Fosamprenavir (Lexiva and Telzir, GlaxoSmithKline,

Research Triangle Park, NC)Atazanavir (Reyataz, Bristol-Myers Squibb, Princeton, NJ)Tipranavir (Aptivus, Boehringer Ingelheim Pharmaceuti-

cals Inc, Ridgefield, CT)Darunavir (Prezista, Tibotec, Yardley, PA)

Nonnucleoside reverse transcriptase inhibitorsNevirapine (Viramune, Boehringer Ingelheim Pharma-

ceuticals Inc, Ridgefield, CT)Delavirdine (Rescriptor, Pfizer Inc, New York, NY)Efavirenz (Sustiva and Stocrin, Bristol-Myers Squibb,

Princeton, NJ)Etravirine (Intelence, Tibotec, Yardley, PA)

Fusion/entry inhibitorsEnfuvirtide (Fuzeon, Roche Laboratories, Nutley, NJ)Maraviroc (Selzentry and Celsentri, Pfizer Inc,

New York, NY)Integrase inhibitors

Raltegravir (Isentress, Merck & Co, West Point, PA)Fixed-dose combination pills

Zidovudine/lamivudine (Combivir, GlaxoSmithKline,Research Triangle Park, NC)

Lamivudine/abacavir (Epzicom, GlaxoSmithKline,Research Triangle Park, NC)

Lopinavir/ritonavir (Kaletra and Aluvia, Abbott Labora-tories, Abbott Park, IL)

Emtricitabine/tenofovir (Truvada, Gilead Sciences, FosterCity, CA)

Zidovudine/lamivudine/abacavir (Trizivir, GlaxoSmith-Kline, Research Triangle Park, NC)

Emtricitabine/tenofovir/efavirenz (Atripla, Bristol-MyersSquibb Co, Princeton, NJ)

*Trade names appear in parentheses.

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by administering injectable fillers, in particular poly-L-lactic acid and calcium hydroxylapatite, which areboth approved by the FDA for the treatment of HIVlipoatrophy. The majority of studies of these treat-ments were performed in patients who continued to

use the same or similar antiretroviral regimen, show-ing that these agents can be effective even if thecausative medication is continued. Poly-L-lactic acidis an absorbable synthetic molecule that has beenshown to promote collagen production and improvefacial appearance in HIV patients with antiretroviral-associated lipodystrophy.19 In some patients, theeffects can last for up to 2 years or longer.A prospective, open-label, 18-month trial of injecta-ble calcium hydroxylapatite has also been per-formed in patients with HIV-associated faciallipoatrophy and the study revealed that this proce-dure is also safe and effective.20 The clinical effects ofinjectable calcium hydroxylapatite can last for up to1 year or longer in some patients. The expense ofthese treatments can be prohibitive; however, bothproducts offer patient assistance programs and in-formation about these programs is available on theproduct Web sites. The risks associated with each ofthese treatments are low and include bruising,bleeding, nodule formation, and misplacement ofthe product. The relative risks and benefits of thesetreatments and other fillers for antiretroviral-associated facial lipoatrophy have been recentlyand extensively reviewed by Peterson et al.18

NUCELOSIDE AND NUCLEOTIDE REVERSETRANSCRIPTASE INHIBITORSKey pointsd NRTIs and nucleotide reverse transcriptase

inhibitors (NTRTIs) cause mitochondrialtoxicity, resulting in characteristic systemicadverse reactions and likely contributing tolipodystrophy

d The cutaneous adverse effects of the NRTIsand NTRTIs are usually specific to each drug,

Fig 3. 1, Entry and fusion inhibitors prevent HIV geneticmaterial from entering the cell. 2, Nucleoside reversetranscriptase inhibitors competitively inhibit the HIV re-verse transcriptase enzyme. 3, Nonnucleoside reversetranscriptase inhibitors prevent conversion of HIV RNAto DNA. 4, Integrase inhibitors prevent the entry of theproviral DNA into the host cell’s genome. 5, Proteaseinhibitors prevent HIV proteases from cleaving viral pre-cursors within the infected CD41 cell, which is necessaryfor HIV to spread from one cell to the next.

Fig 2. Facial lipoatrophy in a patient on combinationantiretroviral medication including nucleoside reversetranscriptase inhibitors and a protease inhibitor.

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and development of skin toxicity does notnecessitate avoidance of the entire class

d Zidovudine and emtricitabine are associatedwith hyperpigmentation, particularly ofnails, palms, and soles of darkly pigmentedpatients

d Abacavir can cause a potentially fatal hyper-sensitivity reaction characterized by a mor-billiform exanthem or other skin findings

NRTIs were the first class of antiretrovirals to bedeveloped for treatment of HIV. NRTIs cause pre-mature termination of the elongating proviral DNAby competitive inhibition of the HIV reverse tran-scriptase enzyme13 (Fig 3). Some experts have sep-arated tenofovir out as a nucleotide reversetranscriptase inhibitor (NTRTI), and consider it in adistinct albeit similar class.2 There are currently sixNRTIs and one NTRTI approved by the FDA for thetreatment of HIV, with at least five new NRTIs inactive development. Zalcitabine, an NRTI that wasapproved for treatment of HIV in 1992, was taken offof the market in 2006 because of the availability ofsafer, more efficacious drugs; it caused oral andesophageal ulcers, dose-related morbilliform exan-thems, and occasional hypersensitivity syndromes.21

Many of the noncutaneous side effects of this class ofmedications occur during chronic treatment over thecourse of months to years, including peripheralneuropathy, pancreatitis, hepatic steatosis, and lacticacidemia, for which these medications carry a blackbox warning. These conditions result from mito-chondrial toxicity thought to be related to themedication’s inhibitory effect on mitochondrialDNA polymerases.2 This may also be the basis forthe lipodystrophy that is recognized as an effect ofsome of the NRTIs.12 It is also important to note thatlamivudine, emtricitabine, and tenofovir each haveactivity against hepatitis B virus, and if a patient hashepatitis B, viral activity can flare if these drugs areused and then discontinued. In general, the

cutaneous adverse effects of the NRTIs and NTRTIsare usually specific to each drug, so that if toxicityoccurs, the patient can still take other medicationswithin the class.

ZidovudineIn 1987, the NRTI zidovudine became the first

antiretroviral medication approved for treatment ofHIV. It is currently available alone or as part of twofixed-dose combination pills with other NRTIs:lamivudine or lamivudine and abacavair. It wasinitially used as monotherapy in doses three tofour times higher than what is standard now; someof the early, dose-related adverse effects are there-fore seen less frequently or are less severe thanpreviously reported. The most common adverseeffects are nausea, fatigue, anorexia, and headachein the first weeks of therapy, and anemia andneutropenia during use over months to years.2

Although lipodystrophy has been associated withzidovudine use, the association is not nearly asstrong as with stavudine, another NRTI, or some ofthe protease inhibitors.22

One of the more commonly reported cutaneousside effects with early use of zidovudine was nail andmucocutaneous hyperpigmentation. Reports in thelate 1980s and early 1990s described patients withdiscoloration of the fingernails and toenails, either in

Fig 5. Hyperpigmentation of the palms in a darklypigmented patient taking zidovudine.

Fig 4. Bands of longitudinal hyperpigmentation of thenails of a darkly pigmented patient taking zidovudine.Courtesy of Dr Eunice Tsai.

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longitudinal brown or blue bands or with diffusebrown or blue discoloration23-26 (Fig 4). Less fre-quently, these changes were seen in association withhyperpigmentation of the skin or the mucous mem-branes (Fig 5), and increasedmelanin in the epidermisand dermis of these patients was seen histologi-cally.27,28 In general, the intensity of the hyperpig-mentation seemed to correlate with the patient’sown level of pigmentation, with darker skinnedpatients having more intense hyperpigmentation.23,28

Stopping zidovudine or significantly lowering thedose led to gradual resolution of the hyperpigmenta-tion. Most of the reported patients were usingzidovudine as monotherapy in high doses, andzidovudine-associated hyperpigmentation has notbeen reported in more recent literature, perhapsbecause of a true decrease in this phenomenon atthe doses used today. When evaluating a patient withHIV and hyperpigmentation, it is important to knowthat patients with hyperpigmentation related to HIVitself have also been reported. Various clinical pre-sentations of this hyperpigmentation have been de-scribed, some of which are identical to that describedin association with zidovudine therapy.24,29,30

Zidovudine has less frequently been associatedwith other skin manifestations. One report describedeight HIV patients with reticular atrophic changes ofthe buccal mucosa with histology consistent with alichenoid reaction.31 Individual case reports andsmall series describe zidovudine being temporallyrelated to alopecia areata, intense reactions to insectbites, hypertrichosis of the eyelashes, leukocytoclas-tic vasculitis, and a variety of syndromes of feverassociated with skin findings, including lichenoiddermatitis, urticaria, morbilliform exanthems, ery-thema and edema, and toxic epidermal necrolysis(TEN).32-38 Many of these cases were supported bythe reaction occurring on rechallenge with zidovu-dine or resolving with cessation of zidovudine

therapy. No specific treatments were used in thesecases; supportive therapy through topical or sys-temic steroids, antihistamines, intravenous fluids,and pain control were used with varying degrees ofsuccess. With the variety of antiretroviral treatmentstoday, zidovudine is used less often in the developedworld and alternative therapies are often available ifpatients need to stop zidovudine.

DidanosineThe second NRTI approved for treatment of HIV,

didanosine, has relatively few cutaneous adverseeffects, and is no longer a frequently used medication.It carries a black box warning because of fatal cases ofpancreatitis and lactic acidosis associated with severesteatosis, and peripheral neuropathy is a therapy-limiting toxicity.39,40 Xerostomia has been reported inup to one-third of patients on didanosine as mono-therapy.41,42 Individual case reports have describedStevenseJohnson syndrome, cutaneous vasculitis,and papuloerythroderma of Ofuji as probable reac-tions to didanosine, and the prescribing informationnotes postmarketing reports of alopecia and anaphy-lactoid reactions.43-46 However, it is difficult to knowthe clinical relevance of these reports because theyrepresent only single cases and most are in the settingof high-dose didanosine. Lipodystrophy has beenassociated with didanosine, although not as stronglyas with stavudine and some of the PIs.14 Didanosineseems to be most strongly associated with lipodys-trophy when used in combination with stavudine orPIs.12

StavudineLike other NRTIs, stavudine is most strongly

associated with adverse effects related to mitochon-drial toxicities; specifically a symmetric peripheralneuropathy and lactic acidosis that are often causesfor cessation of therapy.15,47 The most important andcommon cutaneous side effect of stavudine is

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lipodystrophy. Recent studies have shown that com-ponents of lipodystrophy syndrome may improvewhen stavudine therapy is stopped or decreased;however, these improvements are slow and it isunclear if the syndrome is completely reversible.48-50

Stavudine was also associated with a higher inci-dence (18% vs 13%) of rash of any severity (notfurther specified) when added to lamivudine andindinavir, compared with zidovudine plus lamivu-dine and indinavir, in a trial to determine the best firstline combination of NRTIs with indinavir.51

However, the overall cutaneous effects of stavudine,other than lipodystrophy, are not significant.

LamivudineLamivudine is a well-tolerated NRTI that is ap-

proved by the FDA as part of combination therapy forHIV, and it is also used in lower doses to treat hepatitisB. It is available alone or in fixed-dose combinationwith zidovudine, abacavair, or as part of a three-drugfixed-dose combination pill with zidovudine andabacavair. Lamivudine has been associated with hairloss in rare cases, and there has been one report ofpatch testepositive allergic contact dermatitis tolamivudine.21,52 This type of testing is best performedby a clinician with expertise in the area of adminis-tering and interpreting patch tests. The prescribinginformation notes a slightly higher incidence of ‘‘rash’’of any type in patients receiving lamivudine whencompared to zidovudine alone; however, similar tostavudine, the overall cutaneous side effects oflamivudine are not significant.53 Occasional to rarenoncutaneous side effects include diarrhea, head-ache, fatigue, and sleep disturbances.54

AbacavirAbacavir is an NRTI approved by the FDA in 1998

for treatment of HIV in combination with otherantiretrovirals. It is available alone or as part of twofixed-dose combination pills with other NRTIs: eitherlamivudine or lamivudine and zidovudine.Abacavir’s most common side effects include nausea,headache, and diarrhea. Dermatologists can play akey role in the diagnosis and management of themost important adverse reaction to abacavir, a sys-temic hypersensitivity syndrome with prominentskin involvement. The case definition of abacavirhypersensitivity syndrome requires two symptomsof the following five symptom complexes: fever, rash(of any type), gastrointestinal disturbances, otherconstitutional complaints, and respiratory symp-toms. A variety of other abnormalities, includingmyalgias, arthralgias, pharyngitis, transaminitis, andhypotension have been reported, but in large trials,fever and rash occurred in more than 60% of patients

and were the most common findings.55 The rash ismost often described as ‘‘maculopapular,’’ but de-scriptions of urticaria, diffuse erythema, erythemamultiforme, or targetoid skin lesions have also beenincluded in abacavir hypersensitivity syndrome. Thissyndrome is relatively common among patientsstarting abacavir or abacavir-containing combinationpills; in nine early trials that included a total of 2670patients, abacavir hypersensitivity syndrome oc-curred in about 8% of North American patients.55

Ninety percent of these patients developed symp-toms in the first 6 weeks of treatment, and the mediantime to development of symptoms was 9 days.55

When abacavir was stopped, symptoms almost al-ways regressed completely. In addition to rapiddiscontinuation of abacavir whenever the hypersen-sitivity syndrome is suspected, supportive care withanalgesics, antihistamines, oxygen, intravenousfluids, and appropriate laboratory monitoring forliver involvement and peripheral blood count ab-normalities is indicated.54

Abacavir hypersensitivity syndrome can cause arapidly progressive, multiorgan system failure, andhas been reported to cause death related to hypoten-sion if abacavir is continued. Importantly, discontin-uation of the drug is recommended if any two of thesymptoms in the above case definition occur.Reintroduction of abacavir in patients with a historyof abacavir hypersensitivity results in an acceleratedanaphylaxis-like reaction that has resulted in rash,urticaria, respiratory compromise, circulatory col-lapse, and death, sometimes within hours of receivingone dose of abacavir.56-59 Because of this, abacavir isstrictly contraindicated in any patient in whom ahistory of hypersensitivity to the drug cannot bedefinitively ruled out. This accelerated syndrome hasalso been reported in at least two cases when abacavirwas reintroduced after treatment interruption forreasons other than the hypersensitivity syndrome,and therefore it should be considered in any patientrestarting abacavir regardless of previous history oftolerance.60,61

The emerging field of pharmacogenetics hasplayed a major role in identifying patients at riskfor abacavir hypersensitivity syndrome. The syn-drome has been linked to the human leukocyteantigen (HLA) B*5701 allele, and screening for theHLA B*5701 allele before initiating or reinitiatingtherapy—even in situations where the patient’stherapy was stopped for reasons other than hyper-sensitivity reactions—is recommended by the man-ufacturer.55,62-66 The first powered, prospective,randomized clinical trial designed to screen for anallele in order to decrease adverse pharmacologic-related events tested for the HLA B*5701 allele and

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excluded HLA B*5701epositive patients from start-ing abacavir.63,67 This study showed a statisticallysignificant difference in the development of abacavirhypersensitivity between groups prescreened forHLA B*5701 and those who were not prescreened.In the arm of the study blinded to the HLA B*5701results, 61% of patients with the HLA B*5701 alleledeveloped a hypersensitivity reaction during thecourse of abacavair treatment compared to only 4%of patients who do not carry this allele.63 Theprevalence of the HLA B*5701 allele varies by ethnicbackground; it is found in about 5% to 7% of thewhite (including Hispanic) population, in 5% to 20%of the Indian population, in less than 2% in theChinese, Korean, and Thai population, and in lessthan 1% of the overall African population.68 In astudy from Uganda published in 2008, patients werenot screened for HLA B*5701 before abacavair ther-apy, and the rate of hypersensitivity syndrome wasonly 2%.69 The SHAPE study suggests that there is analmost 100% correlation between HLA B*5701 andabacavir hypersensitivity in both white and blackNorth Americans, but further studies are necessary todetermine the role of HLA B*5701 testing in Asianand particularly in African populations.64,70-72

There is interest in developing a more specific testfor abacavir hypersensitivity in complicated patientspresenting with the very nonspecific signs of fever andrash. Patch testing has been used in several experi-mental settings to confirm abacavir hypersensitivityand appears to be an extremely sensitive and specifictest, correlating highly with results of HLA B*5701testing.73Todate, all patients reported tohaveahistoryof abacavir hypersensitivity and a positive abacavirpatch test are also HLA B*5701epositive.63,66,70

However, this is currently not recommended by themanufacturer without further studies. Patch testingwith medications usually taken orally is difficult tointerpret and is not generally used by clinicians, but itmaybeuseful in the future asmore is discovered aboutthe mechanism of drug reactions.

The US Centers for Disease Control andPrevention lists abacavir as an agent ‘‘generally notrecommended for use as postexposure prophylaxis’’in its 2005 updated guidelines for occupationalpostexposure prophylaxis of HIV.74 Abacavir hyper-sensitivity reaction does not correlate with CD4count, making it likely as common in patientsreceiving the medication for postexposure prophy-laxis as in HIV-positive populations.56 Both thepotential for a serious drug reaction and the possibleconfusion between abacavir hypersensitivity syn-drome and the symptoms of acute HIV are cited asreasons not to prescribe abacavir for postexposureprophylaxis.74

A single case report has also described a patientwith a typical clinical and histologic picture of Sweetsyndrome that resolved with cessation of abacavirtherapy.47,75

EmtricitabineIn 2003, the most recent NRTI, emtricitabine, was

approved for combination treatment in HIV patients.Emtricitabine is available alone, in combination withtenofovir, or in combination with tenofovir and theNNRTI efavirenz. Although it is not approved for thetreatment of hepatitis B virus, it has some activityagainst it, and when discontinued can cause a flare ofhepatitis B. Dry skin was seen in 5% and rashes of alltypes, including maculopapular eruptions, pruritus,pustules, urticaria, and vesicobullous disease, wereseen in 30% of patients in a phase III clinical trial;however, most were self-limited despite continua-tion of therapy.76,77 Therapy with oral antihistaminesand topical steroids may be helpful in alleviatingsymptoms of pruritus until the exanthem resolves.Across three phase III clinical trials, the incidence ofhyperpigmentation of the palms and/or soles was3.4%.78 The highest incidence was seen in darklypigmented patients, and in 17% of the cases thehyperpigmentation faded despite continued emtrici-tabine therapy.10 Other common side effects ofemtricitabine include diarrhea, dizziness, headache,and abdominal pain.79

TenofovirAlthough considered with the NRTIs, as men-

tioned above, tenofovir is technically an NTRTIbecause it uses a nucleotide analogue to block HIVreverse transcriptase. It is available alone or in fixed-dose combination with another NRTI (emtricita-bine), or with both emtricitabine and the NNRTIefavirenz. Tenofovir is approved for combinationtreatment of HIV and hepatitis B. It carries a blackbox warning for fatal lactic acidosis and, whendiscontinued, a potential for worsening of hepatitisin hepatitis B patients.80 Initial studies of tenofovir aspart of HIV therapy demonstrated a low incidence ofusually a self-limited rash (4-7%).81 A case series ofnine patients with cutaneous reactions to tenofovir,ranging from morbilliform exanthems to vesicularreactions with mucous membrane involvement andurticaria, was published in 2007. The mean time fromexposure to events was 15 days, with a range of 24hours to 6 weeks.82 Tenofovir was discontinued inthe majority of these cases and oral corticosteroidsand antihistamines were administered. In general,tenofovir is well tolerated with a low incidence ofcutaneous effects.

Fig 6. Morbilliform exanthema in a patient taking azata-navir, a protease inhibitor.

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PROTEASE INHIBITORSKey pointsd Therapy with PIs is associated with antire-

troviral lipodystrophy syndromed PIs interact with the cytochrome P-450

system and can change the metabolism ofconcomitantly administered medications,including antibacterials and antifungals

PIs were the second class of antiretrovirals devel-oped for use against HIV. HIV protease cleaves theviral precursors, allowing formation of a maturevirion in the infected CD41 cell, and is necessaryfor HIV to spread from one cell to the next (Fig 3). PIsprevent this final step in HIV replication, but whenused as monotherapy, resistance develops. There arecurrently nine PIs or PI combination pills approvedby the FDA for treatment of HIV as part of multidrugtherapy. Although PIs do not have the mitochondrialtoxicity associated with the NRTIs, they do interactwith the cytochrome P-450 system and can haveunwanted effects on levels of other medications,including antibiotics and antifungals.83 Commonside effects include nausea, diarrhea, and abdominalpain. Lipoatrophy, hypertriglyceridemia, hypergly-cemia, and dyslipidemia may be seen alone ortogether as the antiretroviral-associated lipodystro-phy syndrome.83,84 Morbilliform exanthems can beseen with PIs and may have a higher incidence inwomen; however, this is generally not a therapy-limiting side effect and is not seen as commonly aswith the NNRTIs85,86 (Fig 6).

IndinavirIndinavir revolutionized HIV therapy and made

long-term viral suppression possible. However, itsefficacy requires strict dosing every 8 hours andavoidance of certain foods. Indinavir is now aseldom-used, second-line medication because ofthe development of equally effective, longer-actingPIs with fewer interactions. Morbilliform eruptionshave been reported as a frequent effect of indinavirtreatment, and a large case series characterized thisexanthem as usually occurring in the first 2 weeks oftreatment, associated with pruritus, and usually self-limited despite continued therapy.86,87 Retinoid-likeeffects are well established in indinavir-treatedpatients, including alopecia, chelitis, xerosis, andparonychia.88-92 Garcia-Silvia et al90 estimated thatalmost one-third of patients treated with indinavirdeveloped at least two of these retinoid-like ef-fects.90 Indinavir has been shown to stimulatenaturally occurring all trans-retinoic acid, and hasbeen suggested to increase retinoid signaling path-ways by decreasing the metabolism of retinoic

acid.90,93 Aggressive moisturization and eliminationof other skin irritants can help with the chelitis andxerosis. In other cases, it may be possible to switchtherapy to a different agent, given that newer effec-tive drugs are available.

Lipodystrophy has been strongly associated withindinavir, reflected in the colloquial ‘‘Crix belly’’ thatreferred to the abdominal fat accumulation in pa-tients taking indinavir (brand name Crixivan).94

Recent large epidemiologic studies suggest thatindinavir may be more associated with lipohyper-trophy than lipoatrophy.95 A small case seriesdescribes three patients who developed multipleangiolipomas 4 to 12 months after the initiation ofindinavir therapy, further implicating indinavir inadipocyte dysfunction.96

RitonavirAlthough initially developed for its own potential

as an antiviral agent, ritonavir was found to inhibit thecytochrome P450 3A4 isoenzyme, which metabolizesother PIs and limits their bioavailability. Concomitantadministration of a low dose of ritonavir and anotherPI therefore ‘‘boosts’’ the second PI by allowing it toachieve a higher plasma concentration.97-99 Ritonaviritself is not a particularly effective antiretroviral agent,but ritonavir-boosted regimens of PIs allow for lessfrequent dosing, less stringent food requirements,and ultimately greater compliance with the secondPI.99 It is available alone or in a commonly prescribedcombination pill with lopinavir.

Circumoral paresthesias have been reported tooccur frequently, in as many at one-third of patientsin some trials, particularly at full dose, but otherwiseritonavir alone has a low incidence of cutaneous sideeffects.100 However, it is important for

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dermatologists to know if their patients are onritonavir, because its effects on the cytochromeP450 system also affect the metabolism of severalcommonly prescribed dermatology drugs.According to the ritonavir prescribing information,coadministration of ritonavir with ketoconazole,itraconazole, clarithromycin, and prednisone cancause an increase in the plasma concentrations ofthese medications.101 Coadministration of ritonavirand estrogen-containing contraception can cause adecrease in the plasma concentration of the contra-ception, making it less effective.101 Finally, the cap-sule and liquid formulations both contain smallamounts of alcohol and can induce the disulfiramreaction when given in combination with disulfiramor metronidazole.101

SaquinavirAlthough saquinavir was the first PI available, it is

now usually only prescribed as part of a ritonavir-boosted regimen because of its limited bioavailabil-ity.102 Saquinavir is generally very well tolerated andhas few cutaneous or systemic side effects. There aretwo cases of fixed drug eruptions related to saqui-navir reported; in these cases, the eruption resolveddespite continuation of saquinavir.103 In a trial of 141HIVadult patients on various doses of saquinavir andritonavir in combination, there were no moderate orsevere skin-related reactions noted.102

NelfinavirDiarrhea and nausea are the most frequent side

effects noted in patients taking nelfinavir, and cuta-neous side effects are not common.54 A low inci-dence of self-limited morbilliform rash has beennoted in both adults and children in the first fewweeks of therapy.104-106 One case report describedthree patients with generalized urticaria after startingnelfinavir and positive rechallenge tests to nelfinavir.Two of these patients were successfully desensitizedand able to continue nelfinavir therapy.105

LopinavirLopinavir is a PI that alone reaches insufficient

bioavailability to be effective, and is only available incombination pills with ritonavir. It is therefore difficultto separate its effects from those of ritonavir, but maybe important in cases where a patient may need to useritonavir in combination with other PIs after anadverse reaction to lopinavir/ritonavir. Case reportshave described systemic hypersensitivity syndromesincluding morbilliform exanthem, fever, transamini-tis, and mucocutaneous involvement in patientstreated with lopinavir/ritonavir who then went on totolerate ritonavir in combination with other PIs.107,108

Amprenavir and fosamprenavirAmprenavir was a PI that was available between

1999 and 2004. In 2004, manufacturing of amprena-vir stopped because of the wide availability of itsprodrug, fosamprenavir, which has a more favorablesafety profile and requires less frequent dosingrequirements than amprenavir. Specifically, cutane-ous side effects are less with fosamprenavir com-pared to amprenavir. Large trials estimated that 20%to 28% of patients on amprenavir developed ausually benign, self-limited rash, which was charac-terized as maculopapular, in the first few weeks oftherapy, and 1% of patients have been reported todevelop StevenseJohnson syndrome. Only 2% to 7%of those treated with various doses of fosamprenavirdeveloped a similar rash.54,109-111 Fosamprenavircarries a warning related to the presence of a sulfamoiety, and it should be used with caution inpatients with a known sulfonamide allergy.However, the actual likelihood of cross-reactivity isunknown.112 Fosamprenavir is generally adminis-tered as part of a ritonavir-boosted regimen, but cansafely be used unboosted.

AtazanavirA relatively new PI, atazanavir was approved by

the FDA in 2003 and is associated with significantlyfewer effects related to fat distribution, lipid profiles,and glucose tolerance than other PIs.113,114 It onlyrequires once daily dosing, and it can be used aloneor as part of salvage regimens with ritonavir. Themost common cutaneous effects of atazanavir areasymptomatic jaundice and scleral icterus, associ-ated with an increase in unconjugated biliru-bin.113,115 Although the jaundice and scleral icterusare not associated with significant systemic illnessand are reversible upon discontinuation of themedication, they can be particularly distressing topatients and can lead to medication noncomplianceor discontinuation of therapy.10 An incidence of 6%of mild rash that was not further characterized butdid not require treatment cessation was reported in astudy comparing atazanavir and efavirenz.113

TipranavirA novel type of PI, tipranavir was approved by the

FDA in 2006 and has activity against HIV that hasdeveloped resistance to other PIs. It is used withritonavir for salvage therapy, and has some moresevere side effects than other antiretrovirals, includ-ing a possible association with intracranial hemor-rhage and decompensated hepatitis.116 The packageinsert notes an 8% and 10% incidence in rash seen inmen and women treated with tipranavir, respec-tively. A slightly higher risk of 21% was seen in

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children. The definition of ‘‘rash’’ included urticarialrashes, morbilliform eruptions, photosensitivity, andwas sometimes associated with joint symptoms,angioedema, mucocutaneous ulceration, or pruri-tus.117 The median length of treatment before onsetof the rash was 53 days, and only 0.5% of patients inthe trial discontinued treatment because of rash.117

DarunavirDarunavir was approved by the FDA for the

combination treatment of HIV in June of 2006,making it the most recently approved PI. It has aunique sensitivity profile and has efficacy againstmultidrug resistant HIV, including cases resistant toolder PIs.118 Like lopinavir and tipranavir, darunaviris coadministered with ritonavir, although it is notavailable in a combination pill at this time. In a phaseIII clinical trial that randomized 604 patients todarunavir or lopinavir plus an optimized back-ground therapy including ritonavir, 16% of thedarunavir arm developed ‘‘rash-related events’’ com-pared to the other arm in which 7% developed rash.Two of the darunavir patients had a serious rash-related event, not otherwise specified, and requiredtreatment cessation, whereas none of the lopinavirpatients developed serious skin events.119 Anotherlarge, open label study that followed 327 HIVpatients for 24 weeks reported no serious (grade 3or 4) skin-related events, and the only minor (grade1 or 2) toxicities that occurred in 10% or more ofpatients were diarrhea, nasopharyngitis, and nau-sea.120 When pooled, 924 patients received daruna-vir and ritonavir in preapproval trials, and 7% ofthese patients reported rash of any severity, includ-ing rare cases of StevenseJohnson syndrome anderythema multiforme.121

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Answers to CME examination

Identification No. 810110

October 2010 issue of the Journal of the American Academy of Dermatology.

Questions 1-5, Introcaso CE, Hines JM, Kovarik CL. J Am Acad Dermatol 2010;63:549-61.

1. b2. d3. a

4. d5. a

Cutaneous toxicities of antiretroviral therapy for HIV

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