DOI: 10.1111/j.1610-0387.2007.06322.x Review Article 745

© The Authors • Journal compilation © Blackwell Verlag, Berlin • JDDG • 1610-0379/2007/0509-0745 JDDG | 9˙2007 (Band 5)

Keywords• antiretroviral therapy• lipodystrophy syndrome• immune reconstitution syndrome• exanthema• hypersensitivity reaction

IntroductionThe availability and use of highly activeantiretroviral therapy (ART) has drasti-cally reduced mortality and morbidity ofHIV infection. The most complete inhi-bition of viral replication by combiningat least three antiretroviral drugs if possi-ble from two different classes preventsdisease progression and the developmentof resistance, leads to involution of HIV-induced symptoms and to clinically rele-vant immune reconstruction. To date,more than 20 antiretroviral drugs fromfour different classes have been licensed.Establishing the indication, choosing theoptimal therapy for the individualpatient and monitoring of therapyrequires experience with HIV-infectedpatients. During modern ART withcompliant, initially treated patients,virologic treatment failure is rarely

observed. Therefore, in choosing indi-vidual drugs for permanent ART, sideeffects play an important role (Table 1)[1]. Side effects are frequent duringART. Over 25 % of patients discontinueART within the first year due to sideeffects [2]. All organs can be affected byART-associated side effects and interdis-ciplinary management is needed. In thisreview article aspects primarily clinicallyrelevant for dermatologists are depicted.

Side effects of ARTImmune reconstitution syndrome (IRS)Within days to up to three months afterinitiation of an efficacious ART, especial-ly in HIV-infected patients with CD4counts of less than 200 cells/ µl and highHI-viral loads, IRS occurs in up to 25 %of cases, often manifesting on skin ormucous membranes [3]. In addition to

activation of cellular immunity, changesin cytokine networking appear to beinvolved in the pathogenesis of IRS [4].Latent subclinical infections can beunmasked by immune reconstitution.On skin and mucous membranes oppor-tunistic infections such as herpes zoster,mucocutaneous herpes simplex infec-tions [5], mycobacterial diseases andleishmaniasis as well as eosinophilic fol-liculitis, foreign body granulomas, cuta-neous sarcoidosis, acute porphyrias andexacerbation of preexisting skin diseasescan occur [6]. HHV (human herpesvirus) type 8-associated Kaposi sarcomacan transiently worsen during IRS.Similarly, autoimmune diseases such aslupus erythematosus, Sweet and Reitersyndromes occurring during the courseof IRS have been reported. Atypical clinical courses complicate diagnostics in

SummaryThe use of highly active effective antiretroviral therapies (ART) has dramatical-ly decreased the morbidity and mortality of the HIV infection. Over 20 anti-retroviral substances are available in four different classes. Side effects of HIVtherapy are common and may influence the prognosis, as the medications arerequired lifelong for the still incurable infection. ART-associated allergic reac-tions, lipodystrophy syndrome and immune reconstitution syndrome are sideeffects frequently seen by dermatologists. Exanthems are challenging as drugreactions must be separated from immune reconstitution, syphilis and viralexanthems and then the causative agent must be identified from a long list ofmedications. Non-nucleoside reverse transcriptase inhibitors typically causeallergic exanthems. Mitochondrial toxicity caused by nucleoside reverse tran-scriptase inhibitors is responsible for lipoatrophy and fatty changes in the liver.Protease inhibitors cause diarrhea, abnormalities of glucose and fat metabo-lism and lipohypertrophy. Before other medications or surgical measures areundertaken to address side effects of ART, the regimen should be adjusted toinclude alternative but equally effective agents.

Side effects of HIV therapy

Stefan Esser, Doris Helbig, Uwe Hillen, Joachim Dissemond, Stephan GrabbeDepartment of Dermatology, Venereology and Allergy, University of Essen, Germany

JDDG; 2007 • 5:745–754 Submitted: 4. 10. 2006 | Accepted: 19. 1. 2007

IRIS. IRIS does not signify failure ofART and is usually accompanied by agood prognosis, which is why ARTshould be continued if possible.Intensive clinical monitoring after initia-tion of ART and prompt administrationof pathogen-specific antiinfective agentsas well as steroidal and/or non-steroidalantiinflammatory drugs, depending onseverity of IRIS, relieve symptoms andreduce the risk of permanent damage[7].

Drug class-specific side effectsLipodystrophy syndromeLipodystrophy syndrome (LDS) denotesmetabolic aberrations and abnormal fatdistribution in HIV patients duringART and can be categorized in at leasttwo pathogenetically diverse complexesof signs and symptoms (Table 2) [8]. Inlipoatrophy usually irreversible loss ofsubcutaneous fat occurs especially on thebuttocks, limbs and face [9] (Figure 1).MRT imaging also reveals loss of viscer-al fatty tissue in HIV-infected patientswith peripheral lipoatrophy. In thecourse of lipohypertrophy, fat accumu-lates potentially reversibly, especially invisceral locations, and somewhat morerarely subcutaneously in the nape of theneck (lipohypertrophy) [11] (Figures 2and 3). While simultaneous lipoatrophyand lipohypertrophy has been reported,recent studies on HIV-infected menshow no association between lipoatro-phy and increased visceral fat and viceversa [10]. Often the fat distributionabnormalities are associated with com-plex metabolic aberrations such asperipheral and hepatic insulin resistance,disturbed glucose tolerance, diabetesmellitus, hypertriglyceridemia, hyperc-holesterolemia, elevated free fatty acid,low HDL (high density lipoprotein),hyperlactatemia and in some caseslactacidemia [8, 9, 11, 12]. A prevalenceof LDS in HIV-infected individuals wasreported at 30–50 % in cross-sectionalsurveys [8, 9, 10, 11]. Due to drug inter-actions and additional side effects, treat-ment of metabolic and fat distributiondisturbances with biguanides, glitazones,insulins, nicotinic acid derivatives,omega-3 fatty acids, statins, fibrates,growth hormones, uridine or otherdrugs in combination with ART has tobe viewed critically. Substituting theantiretroviral drug probably causingLDS, while considering efficacy of ART

and possible resistances, is preferable.Occurrence of gynecomastia, asepticbone necrosis, osteopenia and osteo-porosis has been reported in associationwith LDS [8].

Fat accumulation and metabolic aberra-tions due to protease inhibitorsBesides gastrointestinal side effects, espe-cially diarrhea, protease inhibitors (PIs)cause lipohypertrophy, disturbed glucosemetabolism and hyperlipidemia [11],whose role in coronary artery disease andischemic insults in HIV patients has notyet been finally established [13]. During treatment with PIs abnormalinsulin-dependent lipid metabolismwith increased turnover of free fattyacids, increased lipolysis, reduced clear-ance of triglyceride-rich lipoproteins andchylomicrons, disturbed adipocyte dif-ferentiation and maturation as well asreduced glucose uptake of fat cells arefound. Though all PIs probably do notchange lipoprotein composition to thesame extent, systemic comparisons donot exist. Atazanavir appears to cause lessdisturbances of lipid metabolism thanother PIs [14]. There probably isdependence on the simultaneouslyadministered dose of ritonavir (rtv) toincrease plasma levels (termed boosting).Induction of insulin resistance is at leastin part due to direct effects of certain PIssuch as indinavir or boosted lopinavir(LPV/rtv) [15]. It is not an effect of theentire class, as nelfinavir and atazanavirhardly affect insulin sensitivity [8].

Management of PI therapy-associated lipo-hypertrophy and metabolic disturbancesChanging from a PI to non-nucleosidereverse transcriptase inhibitors(NNRTIs) [16] or certain nucleosidereverse transcriptase inhibitors (NRTIs)leads to improvement of disturbed lipidmetabolism as well as of insulin sensitiv-ity and to a reduction of peripheral fatloss [17]. NNRTIs show a positive effecton “protective” HDL. During treatmentwith efavirenz, hypertriglyceridemia andelevated LDL (low density lipoprotein)cholesterol can occur, but usually not asgreat as with many PIs. Regression oflipid aberrations was observed whenstavudine (d4T) was replaced by othernucleoside analogues [18].Subcutaneous fat accumulations, espe-cially at the nape of the neck, often donot regress and can partially be removed

by liposuction. Recurrence occurs inabout 50 % of patients [19]. In patientswith significant visceral lipohypertrophya marked decrease could be observed inclinical studies through administrationof recombinant human growth hor-mone; the effect was reversible on cessa-tion of treatment. Possible side effects oftreatment with growth hormone arearthralgias, edema, diabetes or a worsen-ing of simultaneous lipoatrophy [20]. Gynecomastia has been reported inwomen as well as men. HIV-infectedmales with gynecomastia often demon-strate hypogonadism with testosteronedeficiency that can be substituted aftercorrect diagnosis and exclusion of con-traindications. Gynecomastia can alsodisappear spontaneously, i.e. withoutaltering therapy [21].

Lipoatrophy and mitochondrial toxicity ofNRTIs NRTIs are often mainly blamed forlipoatrophy or LDS due to their mito-chondrial toxicity. Symptomatic hyper-lactatemia and, in rare cases, life-threat-ening lactacidemia can occur [9]. NRTIscan competitively inhibit RNA-directedDNA polymerase � in the mitochondriaand thereby their DNA replication byway of DNA depletion and prematurestop of chain lengthening. This results inimpairment of mitochondrial enzymes,uncoupling of oxidative phosphoryla-tion and induction of apoptosis.Inhibition of �-oxidation and the result-ing accumulation of free fatty acids arefurther possible consequences. Lack ofadenosine triphosphate prevents metab-olism of lactate. Hyperlactatemia andpossible lactacidemia can result. Thesemechanisms probably cause other sideeffects of NRTIs such as fatty liver(Table 3). Drug interactions betweenART and concomitant drugs, such asstatins, potentiate mitochondrial toxici-ty. Especially thymidine analogues d4Tand, to a lesser extent, zidovudine andthe so-called D-drugs [d4T, didanosine(DDI)] are held responsible for this [18,22, 23].

Management of lipoatrophy and mito-chondrial toxicity of NRTIsData from new studies appear to showthat treatment with thymidine-freeNRTIs in combination with a PI orNNRTI in treatment-naive patientsinduces lipoatrophy significantly less

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Table 1: Antiretroviral drug classes, licensed drugs and dosages (modified according to [1]).

Substance or substancegroup

Proprietaryname

Most important sideeffects

Dosage form Daily dose*

Reverse transcriptase inhibitors – Nucleosideanalogues (NRTI)

Fatty liver, rarelylactacidemia, lipodystrophysyndrome§

Abacavir (ABC) Ziagen Hypersensitivity syndrome300 mg tablets liquid

2 x 300 mg

Didanosine (DDI) VidexPancreatitis, neuropathy,lipoatrophy

400 mg capsules250 mg capsules125 mg capsulespowder

> 60 kg BW: 1 x 400 mg§§

< 60 kg BW: 1 x 250 mg or2 x 125 mgon an empty stomach

Emtricitabine (FTC) Emtriva Headache100 mg tabletsLiquid 10 mg/ml

1 x 200 mg

Lamivudine (3TC) Epivir Headache300 mg tablets150 mg tabletsliquid

1 x 300 mg or2 x 150 mg

Stavudine (d4T) ZeritNeuropathy, pancreatitis,lipoatrophy

40 mg capsules30 mg capsules

> 60 kg BW: 2 x 40 mg< 60 kg BW: 2 x 30 mg

Zidovudine (AZT) RetrovirNeutropenia, anemia, myopathy, lipoatrophy

250 mg capsulesliquid

2 x 250 mg

Combination product:lamivudine + zidovudine

CombivirHeadache, neutropenia, anemia, myopathy

150 mg/300 mg tablets 2 x (150 mg + 300 mg)

Combination product:lamivudine + zidovudine +abacavir

TrizivirHeadache, neutropenia, anemia, myopathy,hypersensitivity syndrome

150 mg/300 mg/300 mgtablets

2 x 150 mg +2 x 300 mg +2 x 300 mg

Combination product:lamivudine + abacavir

KivexaHeadache, hypersensitivitysyndrome

300 mg/600 mg tablets1 x 300 mg +1 x 600 mg

Combination product:tenofovir + emtricitabine

TruvadaHeadache, rarely disturbedrenal function,hypophosphatemia

300 mg#/200 mg tablets1 x 300 mg +1 x 200 mg

Nucleotide analogues (NtRTI)

Tenofovir (TDF) VireadRarely disturbed renal function, hypophosphatemia

300 mg tablets 1 x 300 mg#

Protease inhibitors**§§§ (PI)

Glucose intolerance, distur-bances of lipid metabolism,gastrointestinal upset,lipodystrophy syndrome§

Atazanavir (ATV) ReyatazHyperbilirubinemia,diarrhea, headaches

100, 150 or 200 mg capsules

1 x 400 mg§§§§

in combination withritonavir§§§§:atazanavir: 1 x 300 mgritonavir: 1 x 100mg

Darunavir (DRV) PrezistaDiarrhea, nausea, hyperlipidemia

tablets à 300 mgDarunavir: 2 x 600 mgRitonavir: 2 x 100 mg

Fosamprenavir (FPV)Telzir(USA: Lexiva)

Diarrhea, exanthems, hyperlipidemia

700 mg capsules

2 x 1400 mgin combination withritonavir:fosamprenavir: 1 x1400 mgritonavir: 1 x 200 mg orfosamprenavir: 2 x700 mgritonavir: 2 x 100 mg

often [18, 22, 23]. In initial treatment ofHIV infections with d4T should no longerbe administered. Generally, reversal ofalready present fat depletion, especiallyin the face, even after altering ART toinclude drugs with less mitochondrial

toxicity, is a very slow process. Even afterone year it can hardly be quantitativelymeasured.As neither modification of ART noradministration of additional drugsagainst loss of fatty tissue can significant-

ly improve lipoatrophy, which is oftenperceived as especially stigmatizing bythe patients, many of the affected turn todermatologists or plastic surgeons.Plastic surgical procedures, such as injec-tion of polylactate hydrogel or use of

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Table 1: Continued.

* Normal renal function, body weight > 60 kg.** All PIs inhibit cytochrome P450. RTV is the most potent inhibitor. Several isoenzymes are also induced by PIs. *** Use only in combination with RTV.**** Different proprietary names in Germany and Austria. ***** Use of NVP in women with a CD4 lymphocyte count > 250 cells/µl and in men with > 400 cells/µl is not recommended. § The pathogenesis of lipodystrophy syndrome is not yet fully understood. Lipoatrophy appears to result mainly from the mitochondrial toxicity

of NRTIs, while fat accumulation is probably a side effect of PIs. §§ DDI dose 1 x 250 mg daily independent of meals in simultaneous treatment with TDF. Consider additional side effects of this combination such

as pancreatitis and lymphocytopenia.§§§ In principle, due to interaction in combinations of NNRTIs and PIs, dose adjustment and possibly drug monitoring should be considered. §§§§ Not yet approved for initial therapy.# 300 mg tenofovir disoproxilfumarate is equivalent to 245 mg active substance.

Substance or substancegroup

Proprietaryname

Most important sideeffects

Dosage form Daily dose*

Indinavir (IDV) Crixivan

Nephrolithiasis, hyperbiliru-binemia, dry skin and mucous membranes,paronychia, hyperlipidemia

400 mg capsules

3 x 800 mgin combination withritonavir:indinavir: 2 x 400 mgritonavir: 2 x 100 mg

Lopinavir + ritonavir(LPV/rtv)

Kaletra tabletshyperlipidemia, nausea, diarrhea

200 mg/50 mg tablets,liquid

2 x 400 mg/100 mg

Nelfinavir (NFV) Viracept Diarrhea, nausea250 mg tabletspowder

2 x1250 mg

Ritonavir (RTV) Norvir

Diarrhea, nausea, perioraldysesthesia, hepatotoxicity,hyperlipidemia (dose-dependent)

100 mg capsulesliquid

Usually only for boostering (rtv):2 x 100 mg–2 x 200 mgliquid: 2 x 1.3 ml

Saquinavir (SQV) Invirase*** Diarrhea, nausea (usuallymild), hyperlipidemia

200 mg capsules500 mg capsules

In combination withritonavir:saquinavir: 2 x 1000 mgritonavir: 2 x 100 mg

Tipranavir (TPV) §§§§ AptivusDiarrhea, nausea, hepatictoxicity, hyperlipidemia,

250 mg capsules

In combination withritonavir:tipranavir: 2 x 500 mgritonavir: 2 x 200 mg

Reverse transcriptaseinhibitors – non-nucleoside (NNRTI) §§§

Cutaneous drug reactions

Delavirdine (DLV) Rescriptor Cutaneous drug reaction 200 mg tablets 3 x 400 mg

Efavirenz**** (EFV)Sustiva(Stocrin)

Psychotropic side effects;Cutaneous drug reaction

200 mg tablets600 mg tablets

1 x 600 mg

Nevirapine***** (NVP) ViramuneCutaneous drug reaction,hepatotoxicity

100 mg tablets2 x 200 mg14 days 1 x 200 mg,then 2 x 200 mg

Fusion inhibitors (FI) Cutaneous drug reactions

Enfuvirtide§§§§ (T-20) FuzeonLocal induration at injectionsite

100 mg ampules 2 x 100 mg s.c.

Goretex® implants, can improve appearance. The usually repetitive injec-tion of poly-L-lactic acid (New-Fill®)in the face in profound lipoatrophy hasbeen studied in clinical trials, with treat-ment results found to be subjectivelypositive by patients and objectively veri-fiable by ultrasonographic measurementof cheek thickness [21]. Usually, the vol-ume effect is partially reversible after ces-sation of treatment. Although sideeffects are rare, these treatment modali-ties belong in the hand of experienceddermatologists and surgeons in order to

minimize the risk of possible complica-tions. Implants or silicon injections arenot recommended at the present due tohigher complication rates. Systematicstudies to determine the best method donot yet exist. In any symptomatic hyperlactatemia (> 2 mmol/l) or asymptomatic high-gradehyperlactatemia (> 5 mmol/l), d4T orDDI, if being administered, should besubstituted by weaker inhibitors of �-polymerase such as tenofovir (TDF),abacavir, lamivudine (3TC) or emtric-itabine. If lactacidemia occurs, all

causative drugs such as NRTIs orantilipemic drugs should be discontin-ued immediately and the patient becared for in an intensive care setting [25].First clinical studies suggest the thera-peutic and prophylactic benefit of uri-dine substitution. Tissue probably diesdue to intracellular uridine deficiencyduring NRTI therapy. By substitutinguridine in hepatocytes and adipocytes,all metabolic defects resulting frommitochondrial DNA depletion could beprevented. Uridine administration iswell-tolerated by humans [26, 27, 28].

Drug reactionsNumerous cutaneous drug reactionsduring ART have been reported [29,30]. Severe drug reactions are over 500times more frequent in AIDS patientsthan in the general population [31].They are especially frequent with allNNRTIs, the NRTI abacavir and the PIfosamprenavir (FPV). About 3 % ofpatents treated with FPV develop a drugrash. FPV is a sulfonamide and shouldbe administered cautiously in cases ofknown sulfonamide allergy [12]. Drugsused to treat or prevent opportunisticinfections, especially cotrimoxazole, alsooften cause drug reactions. Principally,all drugs administered must be consid-ered as possible causes of drug reactions,leading to differential diagnostic prob-lems in HIV patients, who are oftentreated with multiple drugs. Infectiousdiseases, such as viral exanthems or sec-

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Table 2: Clinical and laboratory changes in HIV- associated lipodystrophysyndrome.

Fat atrophy• Face (sunken cheeks, hollow temples, sunken eyes, prominent cheek bone)• Arms and legs (prominent veins, reduced circumference)• Buttocks (loss of form, skin folds)

Fat hypertrophy• Abdomen (increased circumference of abdomen due to increased visceral

fat and, depending on degree, bloated feeling and further gastrointestinalcomplaints)

• Nape of neck (“buffalo hump”)

Associated symptoms• Breast enlargement• Hypertriglyceridemia• Hypercholesterolemia• Insulin resistance, pathologic glucose tolerance or onset of diabetes mellitus

Figure 1: Lipoatrophy of subcutaneous fat ofthe cheeks in lipodystrophy syndrome in a HIVpatient during treatment with the nucleosideanalogue stavudine.

Figure 3: Accumulation of visceral fat in lipody-strophy in an HIV patient during treatment withthe protease inhibitor indinavir (the yellow ar-rows point to visceral lipohypertrophy).

Figure 2: Buffalo hump due to hypertrophy ofsubcutaneous fat in the nape of the neck in lipody-strophy syndrome in an HIV patient during treat-ment with the boosted protease inhibitor lopinavir.

ondary syphilis and IRS must be differ-entiated from cutaneous drug reactions.

Cutaneous drug reactions due to NNRTIs NNRTIs are often employed in the ini-tial treatment of HIV infection as theyare efficacious, easy to use and morerarely cause LDS or unstable plasma lev-els as other antiretroviral agents. Sideeffects typical of the substance class ofNNRTIs are drug eruptions. In about33 % of patients on nevirapine (NVP)and in up to 50 % on delavirdine (DLV)maculopapular exanthems are observed[32]. In about 3–10 % of cases, therespective drug must be discontinued.Urticarial macular exanthems are lessfrequent (about 11 %) during treatmentwith efavirenz (EFV) and in only about2 % of patients is discontinuation neces-sary, as these reactions usually are of amilder clinical nature [12].Drug eruptions due to NNRTIs usuallymanifest within 6 weeks of initiation oftreatment as an erythematous, macu-lopapular, pruritic, confluent exanthem.Further possible symptoms are fever,myalgia, fatigue and mucous membraneulceration. Severe courses such as

Stevens-Johnson syndrome (0.5 % dur-ing NVP treatment) or acute toxic epi-dermal necrolysis (TEN) have beenreported [30]. In NVP-associated exan-thems it is important to monitor foradditional hepatotoxicity with possiblehepatic failure. Almost 1.5 % of patientstreated with NVP develop serious, life-threatening cutaneous reactions. Therisk for developing a cutaneous drugreaction towards NVP rises with increas-ing CD4 helper cell count at initiationof ART. Women react 7 times more fre-quently than men and more severely.NVP has to be discontinued 3 timesmore frequently in women than in men[33]. It is therefore not advised for use inART-naive women with a CD4 T lym-phocyte count > 250 cells/µl and inART-naive men with > 400 cells/µl [1, 34].

Management of cutaneous drug reactionsdue to NNRTIsAt present a toxicogenomic study aimsto determine if immune-mediatedmechanisms against NVP have a geneticpredisposition [HLA-DRB1 0101,HLA-Cw8, HLA-B14(65)], so that

appropriate tests before administrationof NVP can prevent hypersensitivityreactions [35, 36]. Neither prophylacticsystemic administration of glucocorti-costeroids nor antihistamines parallel toinitiation of NNRTI therapy could prevent cutaneous reactions towardsNVP in numerous clinical studies.Surprisingly, exanthems in part appearedmore frequently [37, 38]. In initiatingNVP treatment, a 14 day inductionphase with a lower daily dose of 200 mgonce daily is recommended; subsequent-ly the dose is increased to 200 mg b.i.d.[1]. The frequency of exanthems isreduced with incremental dosage sched-ules (22 %) [12]. About 50 % of cuta-neous reactions due to NNRTIs arereversible despite continuation of treat-ment, so that they can be continued incases of mild to moderate reactionsunder close physician supervision. Severe cutaneous reactions with mucousmembrane involvement, blistering, exfo-liation, conjunctivitis or clinically rele-vant signs of vasculitis, with severehepatic dysfunction, high fever orarthralgia, malaise, meningitic symp-toms and eosinophilia (DRESS

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Table 3: Side effects of individual nucleoside/-tide-like reverse transcriptase inhibitors (NRTI) associated with mitochondrial toxicity (abbreviations of drugs see Table 1). > clinically more frequent and/or more severe

Organ side effects Causative NRTIs

Neuromuscular side effects

– Peripheral polyneuropathy DDI, d4T (so-called D-drugs)

– Myopathy AZT

– Cardiomyopathy DDI, AZT

Hepatic and gastrointestinal side effects

– Steatosis All NRTIs (d4T >> other NRTIs)

– Pancreatitis DDI, d4T

Hematologic side effects

– Anemia, neutropenia AZT

Nephrologic side effects

– Proximal tubulus dysfunction, hypophosphatemia TDF

Metabolic and adipocytic side effects

– Lipoatrophy d4T >> DDI > AZT > ABC, TDF, 3TC, FTC

– Hyperlactatemia, lactacidemia d4T >> DDI > AZT > ABC, TDF, 3TC, FTC

– Hyperlipidemia d4T

syndrome = drug rash with eosinophiliaand systemic symptoms) [39] demandimmediate cessation of NNRTI. Thecausative drug should never be re-administered after a severe reaction.When discontinuing HAART, the longhalf-life of NNRTIs must be kept inmind, since a functional NNRTImonotherapy quickly leads to resistance.Therefore, in cases of NNRTI sideeffects, if possible, the entire ARTshould not be discontinued, but only thecausal NNRTI be substituted by anequipotent drug. Even though from the virologic perspec-tive, a high degree of cross-resistance ofHIV towards different NNRTIs exists,cross sensitization between EFV andNVP, despite controversial statements inthe literature, is not to be expected onthe basis of their different chemicalstructures [40]. Therefore, it is possibleto administer another NNRTI when onehad to be discontinued due to a cuta-neous reaction. While hepatotoxicityand severe cutaneous drug reactions arethe main concern with NVP, the use ofEFV is limited by psychotropic sideeffects in up to 50 % of patients withdizziness, confusion, insomnia, depres-sion up to attempted suicide as well asteratogenicity. One study describeshepatotoxicity in 15.6 % during NVPand in 8 % during EVP treatment.Several cases of fatal hepatic failure havebeen observed in patients treated withNVP [12].

Abacavir hypersensitivity (HSR)Abacavir (ABC) is a NRTI that is oftenused as a single drug or in combinationpreparations (Table 1) due to its lowmitochondrial toxicity. ABC-HSR is anidiosyncrasy observed in 5 % of patientstreated with ABC, usually within thefirst 6 weeks (median after 11 days) afterinitiation of ABC and that can take alethal course if not recognized promptly.In white Australians an associationbetween the presence of HLA-B*5701and the occurrence of ABC-HSR couldbe shown [41, 42]. If routine HLA typ-ing before initiating ABC can preventHSR in Europe is at present the subjectof a large multicenter study.Typically in ABC-HSR exanthems (70 %)are accompanied by general signs andsymptoms such as fever (80 %), fatigueand lethargy as well as gastrointestinal

symptoms such as nausea, vomiting,diarrhea and abdominal pain. Less fre-quent are respiratory symptoms such asdyspnea, cough and sore throat or fur-ther symptoms such as headache, pares-thesia, edema, renal or hepatic failure,hypotension, tachycardia and anaphylac-tic reactions. Abnormalities of the bloodcount, elevated transaminases, alkalinephosphatase, creatinine and LDH canaccompany HSR. Eosinophilia is notusually found.

Management of ABC-HSRThe diagnosis of HSR is made clinically.Continuing ABC treatment despiteHSR worsens clinical symptoms withevery further tablet dramatically and canlead to death. If ABC is discontinued intime, HSR is completely reversible in amatter of days. As supportive measures,intravenous hydration and perhaps a sys-temic glucocorticosteroid may beadministered. If ABC is not discontin-ued because HSR is not clinically clear,the patient should be closely monitored,maybe on an inpatient basis, till a cleardiagnosis is made, in order to reactimmediately to further aggravation. Re-exposition to ABC after definitive HSRcan lead to an acute, rapid and moresevere reaction than during the firstexposition, be fatal and is strictly con-traindicated. Re-exposition, when only avague suspicion of HSR exists, shouldonly be done on an inpatient basis. Forconfirming the diagnosis, pure ABC forpatch testing is now available and isbeing evaluated in the above-mentionedstudy.

Special side effects of individual drugsLocal reactions to enfuvirtide at theinjection siteFor pre-treated patients with resistances,enfuvirtide (T-20), the first representa-tive of a new class of fusion inhibitors, isavailable; it is injected subcutaneouslyb.i.d. The most frequent side effect seenin almost all patients (96 %) receiving T-20 is a local, granulomatous,eosinophilic-histiocytic hypersensitivityreaction at the injection site (injectionsite reaction = ISR) with erythema,inflammation and induration and, inpart, pruritus and pain. This developswithin 3–40 hours and usually takesdays to weeks to heal. ISRs during T-20treatment are a relevant complication

especially for patients with advancedHIV infection and little subcutaneousfat due to cachexia or lipoatrophy. Dueto this, 3–7 % of patients discontinue T-20, even though it sometimes is theonly promising antiviral treatmentoption [43]. The physician should there-fore insure that the patient is capable ofadministering the injection with theproper technique in order to minimizethe danger of local side effects [12].

Dermatologic side effects of indinavirIn addition to nephrolithiasis and renalcolics, dermatologic complications aretypical side effects of indinavir (IDV);high levels of IDV are held responsible.Therefore, measurements of IDV plasmalevels are advised in order to adjustdosage if needed. Particular frequentwhile taking this PI are retinoid-like sideeffects on skin, mucous membranes andskin appendages. Dry skin and lips arealmost obligatory. Asteatotic dermatitisis observed in 12 % of patients especial-ly in the first months of IDV treatment.Depending on IDV levels, a further 12 %develop mild, reversible, diffuse hair lossand in 1–2 % significant loss of scalpand/or body hair occurs. Paronychia andsecondary pyogenic granuloma-likelesions particularly on the great toenailsare typical (4–9 %). After substitutingIDV, there is usually a complete remis-sion of paronychia [44, 45]. Paronychiamay also be treated with topical antisep-tics or systemic antibiotics. If healingdoes not occur, surgical measures such asthe Emmert or Haneke procedures arepossible.

Hyperbilirubinemia due toatazanavir or IDVEspecially the PIs atazanavir (ATZ) andIDV inhibit the activity of uridine-5’-diphospho-glucuronosyltransferase(UGT1A1) in the liver, which leads toan elevation of indirect, unconjugatedbilirubin in the blood and rarely toicterus comparable to Gilbert disease[46, 47]. Above a bilirubin concentra-tion of 2.0 mg/dl hyperbilirubinemiacan become visible on the skin and espe-cially on the sclerae, which can be per-ceived as stigmatization by those affect-ed. In some of such cases, ATZ and IDVare substituted, even though toxicbilirubin levels (8.0 mg/dl) are notreached.

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Hyperpigmentation due to zidovudineor emtricitabineIn rare cases during administration ofthe NRTI zidovudine (AZT), even aspart of a combination drug (Table 1),Laugier-Hunziker-Baran syndrome withmelanonychia striata medicamentosa(Figure 4) and buccal mucous mem-brane lentiginosis is observed [48]. Inless than 2 % of dark-skinned HIVpatients treated with the NRTI emtric-itabine (FTC), usually in a combinationdrug (Table 1), mild palmoplantarhyperpigmentation develops which isreversible on discontinuation of FTC[49]. Case reports do exist of HIV-infected patients who develop hyperpig-mentation of nails, skin and mucousmembranes without using antiretroviraldrugs [50].

ConclusionsSide effects of HIV therapy are frequentand important for the long-term prog-nosis of the patient considering that life-long, always more effective ART isrequired as HIV is a chronic, therapeuti-cally controllable but not curable infec-tion. Before other drugs are added toART or surgical measures performed tosymptomatically treat side effects of HIVtreatment – with their own further inter-active and adverse effects – substitutingother antiretroviral drugs in a targetedfashion and taking into account efficacyand possible resistances should be con-sidered. Skin and mucous membranecomplications are numerous with andwithout ART, which is why dermatolo-gists are indispensable in the treatmentof HIV-infected patients. <<<

Conflicts of interestMember of several Advisory Boards,consultant for all firms that are involved inthe developement of antiretroviral sub-stances: Abbott, BMS, Böhringer, GSK,Gilead, MSD/Merck, Pfizer, Roche,Tibotec.

Correspondence toDr. S. EsserUniversity of EssenDepartment of Dermatology,Venereology and AllergyHufelandstraße 55D-45122 Essen, GermanyTel.: +49-20 17 23 38 78Fax: +49-20 17 23 38 45E-mail: stefan.esser@uk-essen.de

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