R e view K E Y WORDS HIV infection, Antiretrovira/ drugs and therapy oj the skin Antiretroviral drugs and tliera-py oftlieskin MA Gonzalez Intxaurraga, L Olmos Acebes, R. Luzzati and G. Trevisan SUMMARY The highly active antiviral therapy (HAART) has dramatically improved the prognosis of Human immuno- deficiency virus infections. This therapy includes representatives of all the three main groups of antiviral drugs: Nucleoside Reverse Transcriptase lnhibitors (NRTls), Non-Nucleoside Reverse Transcriptase ln- hibitors (NNRTls) and Protease lnhibitors (Pls). These drugs may cause serious side effects, especially in patients with impaired laboratory tests. lnter- actions with other drugs and various disturbances of metabolism are not rare. Clinicians should be familiar with the possible complications and use such drugs carefully. nucleoside Introduction reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, protease inhibitors, side effects, drug reactions Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of HUMAN IM- MUNODEFICIENCY VIRUS (HIV) disease, therefore AIDS case reports and AIDS deaths have been reduced in industrialized countries w ith the introduction of multidrug combination regimens (1) . These drugs may cause some serious side effects and may interact w ith an important number of mecli- cines. To minimize potential problems, the clinician shoulcl consider clinical issues such as drug toxicity, laborato1y abnormalities and drug interactions between antiretroviral regimens and o ther agents that often re- quire close moclification or substitution ofvarious clrugs (2) . Dermatologists play a critical role in the physical examination of HIV-positive inclividuals because mani- festations on the skin ancl mucous membranes occur in up to 90% of patients infected w ith the HIV. Skin dis- eases in the HIV-infected pacient are important even though some disorclers have decreased in incidence or have experienced complete remission following initia- tion of HAART. Mucocutaneous disorders can create both physical and psychological morbidity and mortal- ity, for this reason they require aclequate treatment (3). Dermatologists should be familiar w ith the current knowledge of antiretroviral drugs and their interactions with different medicines used frequently in manage- ment of mucocutaneous disorclers. Acta Dermatoven APA Vol 11, 2002, No 2 - - - -------- --- ---- 35 Antiretroviral drug s and therapy oj the skin Antiretroviral drug therapy The three main groups of antiretroviral drugs are Nucleoside Reverse Transcriptase Inhibitors (NRTis), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTls) and Protease Inhibitors (Pls) (Table 1). The main mechanism of action of NRTIS is the inhi- bition of replication of retroviruses, including HIV, by interfering whit vira! RNA-directed DNA polymerase (re- verse transcriptase), NNRTIS also inhibit replication of HIV-1 by acting as a specific, non-competitive, reverse transcriptase inhibitor, by disrupting the catalytic site of the enzyme. Pis are selective and competitive inhibi- tors of HIV protease. This enzyme plays an essential role to prevent cleavage of protein precursors essential for HIV maturation, infection of new cells and replica- tion. The recommended antiretroviral drug regimens for initial treatment of established HIV infection including a PI with two NRTis, an NNRTis with two NRTis, or a three NRTis regimen (4). Drug interactions may occur when antiretrovirals are co administered with a wide variety of other drugs, in- cluding classical dermatological therapies. Dermatological drugs in HIV-injected patients Mucocutaneous diseases in the HIV-infected patient using combination drug regimens (HAARD often, have to be treated with systemic agents. Sometimes the treat- ment of dermatological manifestations in these patients becomes problematic due to pharmacological interac- tions. The main groups of drugs used for the most com- mon skin conditions that develop in HIV-infected indi- viduals are antibiotics, oral antifungal agents, antihista- mines , immunosuppressive drugs, thalidomide, retinoids and systemic glucocorticoids (S). Antibiotics Staphylococcus aureus is the most common micro- organism causing cutaneous and systemic infections in HN-infected patients. This bacterial pathogen can cause infections just below the stratum corneum, like impe- tigo, or in hair follicles, like folliculitis, furuncles or car- buncles that generally respond to treatment with dicloxacillin, amoxicillin plus clavulanic acid, cephal- exin, erythromycin, clarithromycin, ciprofloxacin or clindamycin. Some experts recommend trimethoprim- sulfamethoxazole to treat skin infections caused by methicillin-resistant Staphylococcus aureus. Erythromycin and doxycycline are appropriate Antiretroviral drugs Group Drugs Trade name ·-·-··Zidovudine . __ , __ ··- ··-·· Retrovir .. .. Didanosine Videx M-----•--••••••---••----••• -----••--•- •--• •--••---•~ N-• --••-•• N --<••-••-•- NRTis Zak i tabine - . Hi VI Stavudine Zerit •- · - ··-- " ' ----•-•--- - ·----- - ·~ •· c - - --• ·• ··•-------·•-•- ·• -•·•·- Lamivudine RniVJr ·----·--·-·1-·- ...... _ . ...:cc.e.o..:.::, ........ .... ·-1 Abacabir Ziagen ,- .... Ii~_virapine _,_ .. _ Viramun~ __ _ NNRTis __ D_e~l~a~v_ir~d __ in_e~--1 _, __ RescripJ:or .... Efavirenz Sustiva Indinavir Crixi van --==.c=-=-- .. . ......... . Ritonavir Norvir .--•-~·• ·-•--•-•--· ·• v - Pls ••••--- Nel fi navir __ ..,_ Virac~P! ...... Sa uinavir Invirase., Fortovase _Am_J)Jenavir ·-··. Agenerase_ Looinavir + Ritonavir Kaletra Table 1. Major groups of antiretroviral drugs. agents to treat Bacillary angiomatosis. It is a bacterial infection caused by organisms of the genus Bartonella that occur more frequently in immunocompromized patients. The penicillin continues to be the treatment of choice for all forms of infection with Treponema pallidum (6). Oral antifungal agents Oropha1yngeal candidiasis is the most common in- fection in HIV-infected individuals. Oral imidazoles such as ketoconazole, fluconazole or it:raconazole are effec- tive for treatment of infections caused by yeast of the genus Candida (7). In the cases of resistance to imida- zoles, amphotericin B is given. After candidiasis c1y ptococcosis is the second most common fungal opportunistic infection and responds well to systemic treatmentwith intravenous amphoteri- cin, oral fluconazole or itraconazole. Terbinafine is an excellent antimycotic agent against dermatophytes. Antihistamines Antihistamines have been used in HIV-seropositive patients for the relief of pruritus caused by different conditions that include xerosis, eosinophilic folliculi- tis, atopic dermatitis, prurigo nodularis, scabies, and insect bites. Immunosuppressive drugs Cyclosporine is an effective immunosuppressive agent commonly used to treat refractory cases of pso- riasis. The use for psoriasis developed in HIV infected Review 36 ----- ------------------------------Acta Dermatoven APA Vol 11, 2002, No 2 R eview Antiretroviral drugs and therapy oj the skin Recommended regimens are comprised of one choice e ach from columns A and B Recommended Column A Column B Efavirenz Stavudine + Didanosine -·· --~··-·--·· ··- - .... -- - Indinavir Sta vudine + Lamivudine - ··----· - -- --- Strongly recommended N elfinavir Zidovudine + Didanosine ·- --------- - -- - - Ritona vir + Indina vir Zidovudine + Lamivudine - ---·- - - - -- Ritonavir + Saquinavir Abacavir D idanosine + Lamivudine - -- -- -- -- A_~_pre E_a_ vir Zidovudine + Zalcitabine -- .. Delavirdine ----·----·•--- ·~-- ... - ------·-·-- ·~--·- . Recommended as alternatives N elfina vir + Saquinavir - -- ·~~.~~••.~---·-~ -- -- __ N evir3 pine __ --- ·-·-••·-~•-·· Ritonavir - - ---- -· - - -·- Saquinavir Hydroxyurea + othe_!:" antiretroviral drugs N on recommended: insufficient data Ritona vir + Indina vir - --· - -- - Rito11a vir + N elfina vir Sa uinavir Sta vudine + Zidovudine -• ··--·- ·- - --·-·- -· Zalzita bine + Lamivudine N 011 recommended: should 11011 be offered - ··-,-~·••<'•·-·•~··~ •.-·--~·- ----·-·-•··~-•·-·- - Zalzitabine + Stavudine -·•-•·•·••· . -•··• •·-·-·•·••·•· '•"'-·•••-··-·· ··-· ·--·--•··•-•~·-••~-··-•··• _,. -- Zalzitabine + Dida11osine Table 1. Recommended regimens for treatment of HIV infections. patients is limited to selected cases, due the risk of caus- ing increased immunosuppression and because el- evated cyclosporine levels have been linked to neph- rotoxicity and neurotoxicity. Cyclosporine can be used also in cases of severe and refractory atopic dermatitis (8). Thalidomide Prurigo nodularis is a pruritic dermatosis in w hich treatment is problematic. The HIV-associated prurigo nodularis responds well to treatment with thalidomide. Systemic therapy with thalidomide has been found to be an effective treatment in cases of aphthous ulcers of the mouth and oropharynx in AIDS and in some cases of Kaposi's sarcoma. This drug has a potent anti-inflammatory activity, it also has antiangiogenic properties and at the same time thalidomide may inhibit HIV replication. The use in HIV- infected individuals is limited because it can increase the neuropathic effects of zalcitabine, stavudine and didanosine (9). Retinoids The oral retinoids can be safe and effective in cases of psoriasis that do not respond to topical treatment and in cases of eosinophilic folliculitis that have not re- sponded to other therapies. Retinoids produce hyperlipidemia and !iver toxicity that may limit their use in patients receiving HAART particularly with protease inhibitors and NNRTis whose metabolism involves the hepatic cytochrome p450 en- zymatic pathway (10). Systemic glucocorticoids Skin manifestations in HIV-infected patients com- monly treated w ith oral glucocorticoids include cuta- neous drug-induced eruptions and urticaria/ angio- edema. The most common implicated agents are trimethoprim-sulfamethoxazole and amoxicillin-clavu- lanate. The use of glucocorticoids is limited because they can cause hyperglycemia. Hyperglycemia, new onset diabetes mellitus, diabetic ketoacidosis, and exacerba- tion of pre-existing diabetes mellitus are strongly asso- ciated with the use of protease inhibitors (11). lnteractions Caution should be exercised when using of the fre- quent dermatological therapies in patients receiving Acta Dermatoven A PA Vo l 11, 2002, No 2 ---------------- --- ------ --- - ----- 3 7 Antiretroviral drug s and therapy oj the skin HAART. The risk of applying dermatological therapies must be weighed against the potentially favorable effects. Knowledge of the pharmacokinetics of the antiret:ro- virals is an absolute necessity to understand how specific HIV-related medications interact with other drugs (12). Nucleoside Reverse Transcriptase Inhibitors NRTis do not seem to be inducers or inhibitors of the cytochrome P450 system. Ali NRTis, with the excep- tion of zidovudine, are mostly eliminated through the urine. Zidovudine is conjugated by glucuronidation, and the conjugate is eliminated by renal excretion (10). Amino glycosides, amphotericin B and cotrimo- xazole are nephrotoxic, therefore these drugs should be used with caution during NRTis therapy and the patients must be monitored accordingly. Non-Nucleoside Reverse Transcriptase Inhibitors NNRTis are extensively biotransformed by the !iver via cytochrome P450 metabolism. Nevirapine and efavirenz are inducers ofhepatic cytochrome P450 3A4, and efavirenz inhibits also the CYP isoenzymes 2C9, 2C19, and 3A4. Delavirdine is an inhibitor of cytochrome P450 isoenzymes from the CYP 3A family. - Ketoconazole inhibits some cytochrome P450 iso- zymes and subsequently increases p lasma levels of nevirapine in 15-30 percent. Nevirapine decreases the concentration of ketoconazole in 63 percent because this NNRTI induces hepatic cytochrome P450 3A4. This association is contraindicated. - Itraconazole has small affinity for the cytochrome P450 system, there fore simultaneous administra tion with NNRTis is not contraindicated but may require !iver enzymes monitoring. - Clarithromycin is an inhibitor of cytochrome P450 isozymes from the CYP3A family, and in association with nevirapine elevates the plasma concentration in 26 per- cent. Instead clarithromycin plasma concentration is reduced in 30 percent. Therefore careful monitoring is recommended. Clarithromycin in association w ith efavirenz reduce clarithromycin plasma concentration in 39 percent. Therefore it w ill be better to choose other antibiotics in association with efavirenz. - Astemizole and terfenadine are contraindicated because given concurrently with NNRTis may result in higher plasma concentrations of those antihistamines promot- ing adverse effects like ventricular tachycardia (13, 14) . Protease Inhibitors Pis are metabolized by the cytochrome P450 enzyme system. Ali are inhibitors of CYP3A4 and can impede the biotransformation of other drugs that undergo this isoenzyme metabolism. Ritonavir is the most potent 3A4 inhibitor and saquinavir is the weaker. Ritonavir and nelfinavir are also inducers of CYP3A4. Ritonavir inhib- its also slightly 2D6, 2C9/ 10 and 2C19 isoenzymes and may induce CYP1A2. Nelfinavir is partially metabolized by the CYP2C19 isoenzyme (15). - Astemizole and terfenadine are contraindicated be- cause Pis are potent 3A4 inhibitors and given concur- rently may promote adverse effects of this antihistamines like ventricular tachycardia. - Loratadine is metabolized through the !iver cytochrome P450 enzyme system in small quantity. The simultaneous administration with ritonavir, the most potent 3A4 inhi- bitor is not contraindicated but require close monitoring. - The concentration of ketoconazole is increased three times if administrated w ith ritonavir. Ketoconazole should be used with caution and the limit-dose will be 200 mg daily. Ketoconazole increases three times the concentration of saquinavir, although no dose adjust- ment is required . Ketoconazole increases serum concen- tration of amprenavir in 31 percent and amprenavir in- creases the levels of ketoconazole in 44 percent. The significance of these findings is under investigation. - Itraconazole and miconazole have a small affinity for the cytochrome P450 enzyme system. The concentra- tion of these antifungal agents may be slightly increased by Pis simultaneous administration , therefore close monitoring is required. - Clarithromycin levels are increased in 77 percent with ritonavir. A dose adjustment and close monitoring of the !iver tests are required. Etythromycin and azithro- mycin levels are also increased. Concomitant adminis- tration of others Pls w ith clarithromycin does not re- quire close acljustment. - Clindamycin is metabolized in the !iver by the P450 isoenzyme CYP3A4 ancl co aclministration with Pis im- plicates a slight increase of serum concentration with elevated risk of cliarrhoea . - Cyclosporine is primarily metabolizecl by hepatic P450 3A4 isoenzyme. Pls are mainly inhibitors of this enzyme, therefore they will increase cyclosporine levels. Cyclo- sporine shoulcl be used in patients receiving Pis only if strictly necessa1y ancl with close monitoring (16, 17). Conclusions Little specific etata are available on the drug interac- tions between antiretroviral drugs and dermatological therapies. Significant clrugs interactions occur cluring metabo- lism because many clrugs are metabolized by CYP3A4, one of the major isoenzymes of the CYP 450 group, there- fore some of these interactions coulcl easily be preclicted basecl on the knowledge of this isoenzyme (18). The most important problem is the association with some Hl-type antihistamines (terfenadine ancl aste- mizole) but currently their clermatological use is restric- R eview 38 --------- ----------- - ----------- ---Acta Dermatoven APA Vol 11, 2002, No 2 R evie w ted because in recent years others antihistamines with less side effects have been developed. Associations with others drngs are , normally, non con- traindicated but most of them require close monitoring. Dermatologists frequently are faced with the need for management of cutaneous and mucous lesions in REFERENCES Antiretroviral drug s and therapy of the skin HIV infected patients . At the same time HAART therapy induces an arrest of progression of immunodeficiency and significant restoration of immune function. There- fore, antiretroviral therapy has the priority and the choice of others meclicines will be done regarding the com- patibility with those drugs (19). l. Holtzer CD, Roland M. 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A U T H O R S ' Maria Angeles Gonzalez lntxaurraga, MD, ClinicaDermatologica, Ospedale A D D R E S S E S di Cattinara, Trieste JtaZ:y Luis Olmos Acebes, MD, Projessor and Head oj STD service, Dermatologia University Hospital San Carlos, Madrid, Spain R. Luzzati, A1alattie lnfettive, Ospedale Maggiore, Trieste, Italy Giusto Trevisan, MD, Professor and Chainnan, Glinica Dermatologica, Ospedale di Cattinara, T'rieste Jtaly Acta Dermatoven APA Vol 11, 2002, No 2 ---- ------------------------ ------ 39