A Guide To Lower Extremity Cutaneous Manifestations In Patients With HIV Infections

Reportedly 20 percent of people with HIV are unaware of the infection. Podiatrists may play a key role in recognizing the cutaneous manifestations of HIV and AIDS in the lower extremity and facilitating appropriate referrals. Accordingly, this author reviews various dermatological side effects and presents salient treatment options.

   Acquired Immune Deficiency Syndrome (AIDS) is the loss of the body’s ability to fight infections due to the infection caused by the Human Immunodeficiency Virus (HIV). AIDS is a major health problem worldwide and was first identified in the United States in 1981. Of all the industrialized countries in the world, the U.S. is home to the largest number of people living with HIV. It is estimated that every 9.5 minutes, someone in the U.S. is infected with HIV.

   More than 1 million people in the U.S. are living with HIV. Out of these people living with HIV, one out of five are unaware they are infected.

   At the end of June 2008, the Centers for Disease Control and Prevention (CDC) estimated that 549,196 people are living with AIDS in America.1

   The management of HIV/AIDS involves the complex coordination of many healthcare professionals.2,3 The podiatric physician can provide education to the public and medical colleagues regarding lower extremity manifestations of AIDS. Moreover, podiatric physicians can play an important role by identifying patients who are infected with HIV by being alert to the specific lower extremity signs and symptoms that may signal the presence of the disease.

   Unfortunately, accurate diagnosis and proper treatment of skin diseases in both HIV and AIDS can be especially challenging and often frustrating because the presentation of common dermatoses is often exaggerated into florid cutaneous eruptions. The recognition of HIV-related skin changes may empower the podiatric physician to refer a patient to an infectious disease specialist. This could lead to the diagnosis of HIV infection in the early stages, thus allowing for initiation of appropriate antiretroviral therapy.

   In addition to having a strong grasp of the pathogenesis of cutaneous skin changes in the patient with HIV, physicians must be familiar with the clinical presentations and symptoms of specific lower extremity cutaneous manifestations. Finally, one also needs to be aware of cutaneous manifestations caused by available antiretroviral agents that patients may be taking to treat HIV.

A Pertinent Overview Of Cutaneous Manifestations With HIV

   Researchers have reported that HIV infection is associated with a number of common dermatological disorders.4,5 Cutaneous manifestations are common in patients with HIV infection and tend to be more frequent as immunodeficiency progresses.6 The spectrum of skin changes in HIV infection is quite wide. Some of these conditions (Kaposi’s sarcoma in particular) are unique and are considered pathognomonic for HIV disease.

   On the other hand, many common skin conditions that occur in healthy individuals also occur in people infected with HIV. However, these skin conditions are frequently more severe and may be more difficult to treat. Patients with HIV disease often have several simultaneous or sequential cutaneous conditions with a progressively more intransigent clinical course.

   Researchers have also postulated that skin diseases can warn of the progression of HIV disease. Also bear in mind that many skin diseases are more likely to occur as the white blood cells or CD4 count decreases. These two observations were validated clinically in a cross-sectional descriptive study by Rad and colleagues.7 The results of this investigation demonstrated that 66 (94.3 percent) patients had at least one skin problem. The study authors noted that fungal infections were the most common cause of skin manifestations. The eight most common types of muco-cutaneous problems were gingivitis, pallor, itching, photosensitivity, seborrheic dermatitis, candidiasis, folliculitis and tinea versicolor.7 Finally, the mean CD4 cell count (expressed with a P <0.05) was lower in individuals with viral and bacterial skin diseases.7

   During the course of the lower extremity examination of patients with HIV infection, podiatrists may notice the increased prevalence of dry skin as a chief complaint. Using the Fat Redistribution and Metabolic Change in HIV infection (FRAM) cohort, Lee and co-workers assessed the prevalence of dry skin in 1,172 patients with HIV infection and 297 control patients between 2000 and 2002.8 Researchers employed self-reporting questionnaires to assess for changes in skin over the past five years with bidirectional scales including the terms: dry, no change and moist. The clinicians performing an overall assessment of skin used a similar scale.8 The study authors determined that self-reported dry skin was more prevalent in HIV-infected patients than control patients. A multivariable analysis revealed that HIV infection was associated with self-reported dry skin.8

   Typically, xerosis is most prominent on the anterior lower legs but it may be quite widespread. The xerosis is more severe and may be associated with dermatitis in the winter months. Excessive frequent bathing with deodorant or antibacterial soaps is a frequent precipitating factor and patients should discontinue this practice.

   Simple measures can be very helpful when advising the HIV-infected patient with dry itchy skin. These patients should wash quickly with warm water and avoid long, hot showers or baths. Recommend the use of a soap substitute, which preserves the skin’s natural moisturizing factors. One can combine soap substitutes with an emulsifiable bath oil and regular use of a moisturizer.

   Patients should apply mild topical steroid ointments (1 to 2.5% hydrocortisone or 0.025% triamcinolone) to areas of dermatitis three times a day and should cover all dry areas of the body with a moisturizing lotion or cream after bathing and at bedtime. Patients in the advanced stage of HIV disease may present with dry and thickened skin of the palms and soles as one would see with acquired ichthyosis. Physicians can recommend or use the same treatment modalities to help achieve symptomatic relief for these patients.

   When it comes to resource poor settings, Nnoruka and colleagues suggest that physicians should consider mucocutaneous disorders of HIV among the key clinical indicators for the prediction of underlying immune status and disease progression.9 The objective of their investigation was to identify and correlate mucocutaneous disorders to CD4-positive cell count and total lymphocyte count in HIV/AIDS patients in southwest Nigeria. They found that papulopruritic itch accounted for 32.2 percent (73/227) among patients with CD4+ cell counts of 51-200 cells/mm3 while seborrheic dermatitis occurred most significantly with CD4 cell counts of 201-500 cells/mm3 (43.1% vs. 12%) relative to those with lower CD4+ counts (51-200 cells/mm3). The study authors readily observed mucocutaneous lesion counts of >100 cells/mm3 in the advanced stage of HIV.

   A final population specific study conducted in Cameroon concluded that skin problems are common in individuals with HIV infection and that patients with advanced stages of skin problems had relatively low mean CD4 cell counts.10 A second finding with this Cameroon population was that mucocutaneous disorders like vaginal candidiasis and herpes zoster occurred early in HIV infection while Kaposi’s sarcoma is common in patients with advanced HIV infection.10

   While non-infectious cutaneous abnormalities are not prognostic of the rapid progression of immunosuppression, they may be specific markers of the stage of HIV disease. Cutaneous abnormalities like seborrheic dermatitis or xerosis may worsen as HIV infection progresses or they may present suddenly, intensely and severely to a point of lethality.

   It must be noted that with improvements in antiretroviral treatment of HIV, as demonstrated with good viral control and preservation of the immune system, skin problems associated with opportunistic infections and many other skin problems associated with HIV have become far less common, less severe and are easier to treat.

   Podiatric physicians must also remember that cutaneous manifestation of HIV disease may be less responsive to the usual treatment modalities.

What The Literature Reveals About Tinea, Onychomycosis And HIV

   Lower extremity cutaneous manifestations of HIV disease include tinea, warts, scabies, Reiter’s syndrome, Kaposi’s sarcoma and allergic contact dermatitis.

   Tinea infection of the feet and toenails is common in people with HIV infection. However, it is not a specific marker of HIV infection because it is also common among people without HIV infection. Researchers have reported that the prevalence of onychomycosis in patients with HIV infection ranges between 15-40 percent.11,12

   Tinea of the nail primarily involves the nail plate. Nails become opaque and thickened, and may split or crumble. Proximal subungual onychomycosis is usually a sign of HIV disease.13 Common with tinea involvement of the toenails is an associated tinea infection of the soles or toe webs manifested by chronic maceration, scaling, blistering, and or thickening of the skin. The use of topical imidazole cream twice a day can facilitate improvement of tinea infection of the soles of the feet.

   Tinea unguium associated with AIDS is clinically more aggressive and therapeutically more difficult to treat than in the general population.14 Tinea unguium in patients with HIV is common, chronic and usually does not require therapy unless the infection causes discomfort.

   If the podiatric physician elects to employ oral therapy to treat the toenail infestation/infection, it may be prudent to investigate all the possible theoretical and probable drug-drug interactions that may result from combining antifungal agents and antiretroviral agents. Barber and colleagues present a discussion of onychomycosis treatment in special populations including those infected with HIV.15 Despite a lack of abundant data, these authors state the literature that does exist demonstrates that one can use oral terbinafine, oral itraconazole and ciclopirox 8% nail lacquer safely and effectively in special populations. They do caution clinicians to assess each presentation on a case-by-case basis.

   Researchers investigated the use of terbinafine in a series of 21 HIV-positive patients who were diagnosed with tinea unguium for one year in Madrid.14 All patients underwent a subsequent clinical follow-up for six months. The results showed a high percentage of clinical and mycological cures, as well as maintenance of the response after follow-up. The study authors noted no drug interactions or significant adverse effects related to the drug.

Warts And HIV: What You Should Know

   Verrucae vulgaris are common, benign, painless growths that are caused by the papillomavirus. When warts occur in individuals with HIV infection, they tend to be bigger, more numerous and widespread. These warts may be resistant to standard treatments and recurrence after treatment is common. De Socio and colleagues describe a 42-year-old man with AIDS and Hodgkin's lymphoma who presented with severe, recalcitrant cutaneous warts, which resolved following treatment with local 1% cidofovir.16

When Scabies Occurs In People With HIV

   If scabies occurs in people with HIV infection, it will usually present with the typical pattern of pruritic papules with accentuation in the intertriginous areas, genitalia and finger webs. The infestation may exaggerate and become more widespread and refactory to treatment with advance immunosuppression.

   Applying Lindane® (gamma benzene hexachloride) from the neck down for eight to 24 hours is therapeutic. For those patients who do not respond to Lindane therapy, they may benefit from topical application of permethrin 5% cream (Elimite®) from the neck down for eight to 24 hours. Elimite is safe for patients over two months of age as well as pediatric patients with HIV infection.

   True crusted atypical or Norwegian scabies, which appear as widespread hyperkeratotic, scaly maculopapular eruptions or crushed plaques, can occur in patients with advanced HIV infection. These crusts teem with mites and are highly contagious. Therefore, patients with Norwegian scabies should be isolated until therapy is complete. Despite the treatment being difficult, it is recommended to apply permethrin 5% cream weekly until cutaneous manifestations clear.

   Marchell and co-workers describe the atypical presentation and difficulty in treating painful plaques on soles of the feet of a patient who was HIV-positive and had scabies infestation.17

A Closer Look At Reiter’s Syndrome In Patients With HIV

   Reiter’s syndrome consists of the triad of arthritis, conjunctivitis, and urethritis. It occurs predominantly in genetically predisposed “HLA-B27 positive” men although researchers have reported cases in children and women occurring commonly after genitourinary or gastrointestinal infections. Dermatologic manifestations are common. They include keratoderma blennorrhagicum, circinate balanitis, ulcerative vulvitis, nail changes and oral lesions.18 Treatment is difficult, especially in HIV-positive patients. The prognosis varies. Fifteen to 20 percent of patients may develop severe chronic sequelae.18

   Typically, the palms and soles of the feet develop superficial pustules that are dry and form keratotic papules. Over time, these papules coalesce until the soles are diffusely thickened and scaled, evolving into the condition known as keratoderma blennorrhagicum. The nails are commonly affected. Extensive subungual debris may be present along with horizontally ridged nail plates.

   Florell and colleagues present an interesting case report of a 34 year-old man who presented with keratoderma blennorrhagicum.19 Success and resolution of the skin lesions occurred when the authors treated the patient with the combination of clobetasol propionate ointment (applied to the skin lesions twice a day) with 25 mg of oral acitretin daily, and the initiation of antiretroviral therapy.19

Pertinent Insights On Kaposi’s Sarcoma And HAART

   Kaposi’s sarcoma is a neoplasm of endothelial cells involving any portion of the cutaneous surface and some times other internal organs. This tumor varies in color from pink to dark red to purple to brown. They may be flat macules, raised papules or nodules, and vary greatly in size. Lesions may tend to arise along the lines of cleavage and form oval papules. The lesions of Kaposi’s sarcoma do not hurt or itch unless they become large.

   The development of HIV-related disease has changed dramatically since the introduction of highly active antiretroviral therapy (HAART) into clinical practice. Since the use of protease inhibitors became widespread, physicians have seen a 30 to 50 percent reduction in Kaposi's sarcoma. The results of recent studies indicate that HAART may be a useful alternative both to immune response modifiers during less aggressive stages of Kaposi’s sarcoma and to systemic cytotoxic drugs in the long-term maintenance therapy of advanced Kaposi’s sarcoma.

   Bower and colleagues recently published a prospective cohort study that evaluated the clinical outcomes of patients with histologically confirmed AIDS-related Kaposi’s sarcoma who have been diagnosed since the introduction of HARRT.20 With this prospective investigation, researchers found a high success rate of HAART in a large cohort of AIDS-related Kaposi’s sarcoma patients over a prolonged period of follow-up.

   The use of HARRT therapy for Kaposi’s sarcoma is geared to help control symptoms, reduce edema, eliminate pain and clear lesions. However, the prevailing sentiment is these therapies are not curative. If treatment is necessary, treating physicians commonly use radiation and systemic alpha-interferon or chemotherapy.

When Allergic Contact Dermatitis Occurs

   Contact dermatitis is exceedingly common in the U.S. It is one of the top ten causes for patient visits to their primary care physicians.21 Shoe dermatitis is a common type of contact dermatitis. Shoe dermatitis is caused by contact of the foot with shoes or the chemicals used during the manufacturing and finishing of shoes. Rubber remains a common cause of shoe dermatitis, especially with such preservative antioxidants as monobenzyl-hydroquinone.

   Once you have confirmed the diagnosis of shoe dermatitis, treatment management goals include alleviation of pruritus and resolving inflammation.

   Curr and Nixon describe a 41-year-old HIV-positive man, who presented with a two-month history of a generalized pruritic rash, which had started on his feet.22 Using patch testing, the authors diagnosed allergic contact dermatitis to the textile dye basic red 46, which was likely present in the patient’s dark-blue-colored socks. They achieved complete resolution of his symptoms with avoidance of these socks, a topical steroid ointment and emollient cream.

What About Cutaneous Manifestations Caused By Medications For HIV?

   Luther and Glesby published a summary that looked at a significant number of patients with skin pathology, some of which can be attributed directly or indirectly to antiretroviral therapy.23 This published report recounts that non-nucleoside reverse transcriptase inhibitors exhibit a class effect with regard to skin adverse manifestation and the spectrum of disease can vary from mild morbilliform rash to Stevens-Johnson Syndrome.2,3,23 Also bear in mind that some protease inhibitors have been implicated in causing rash while indinavir causes retinoid-like manifestations such as paronychia, ingrown toenails, alopecia and curling of straight hair.3,23

   Zidouvudine has become one of the standard medications used in HARRT therapy for patients with AIDS and for those with asymptomatic HIV infection. One of the interesting side effects of using zidovudine is alterations in nail pigmentation, which occur primarily in African-American patients. Rahav and Maayan describe a case report of progressive pigmentation of both fingernails and toenails in a Caucasian patient.24

   The degree of hyperpigmentation of the nails and skin is related to the dosage of azidothymidine (AZT). Patients note a decrease in hyperpigmentation when the dose is decreased and the pigmentation clears if the drug is discontinued. This hyperpigmentation appears to be related to increased melanogenesis in the areas of hyperpigmentation and not drug deposition.

Paronychia: Is It A Common Side Effect Of HIV Medications?

   A review of the literature reveals case reports and retrospective cohort accounts of patients receiving antiretroviral therapy for HIV infection and the subsequent development of paronychias.25-34

   Zerboni and colleagues reported the onset of paronychia in 12 HIV-positive patients who were receiving lamivudine during a three-month period.25 The clinical presentation of paronychia involved one great toe in five patients, both great toes in five patients, and fingernails as well as toenails in two patients.25,29,33 Further, these patients did not have any risk factors for paronychia development.

   Bouscarat and co-workers described 42 HIV-positive individuals who presented with great toe paronychia secondary to ingrown nails and they had received the HIV treatment indinavir.26,29,33 These patients had no prior episodes of paronychia, psoriasis or local trauma.26 The medium time of onset for drug-induced ingrown toenails was 120 days.26 These authors suggest that inhibition of endogenous proteases may be the explanation for initial hypertrophy of the nail fold and the subsequent development of similar lesions of pyogenic granuloma.26,29

   Bouscarat and co-workers also suggest that disturbances of retinoic acid metabolism may be the underlying mechanism for the nail changes one sees with patients receiving indinavir.26,33 Sass and colleagues say paronychia with pyogenic granuloma in the presence of indinavir therapy may be induced by impairment of the oxidative metabolism of retinoic acid through the inhibition of cytochrome p450 3A as opposed to impaired formation of 9-cis-retinoic acid.30

   In a study of 50 HIV-infected men who were referred for the treatment of paronychia between the years 1995 to 1999, Sibel and colleagues noted that these patients’ drug regimens included combinations of the following medications: indinavir, stavudine, didanosine, lamivudine, zidovudine, nevirapine, delavirdine, nelfinavir and ritonavir.29

   Colson and co-workers assessed a retrospective cohort of managed care patients who received protease inhibitors from 1996 through 1998.33 They identified 288 adults during this timeframe and that indinavir appeared to be part of their drug regimen 63 percent of the time. A total of 30 patients in this population had at least one documented paronychia of the great toe during this timeframe.33 These authors concluded that indinavir (and not lamivudine) was strongly associated with great toe paronychia. James and colleagues reported five cases of ingrown toenails associated with indinavir-ritonavir combination therapy.

   Garcia-Silva and co-workers report that paronychias occur in 4 to 9 percent of the patients who receive indinavir.34 They suggest this adverse effect is not related to other epidemiological variables such as the patient’s sex, age, immune status or other risk factors. Even through the exact mechanism of indinavir induced retinoid-like effects is unclear, the following hypotheses for paronychia pathogenesis include: interference with the retinoid metabolism by enhancing retinoic acid signaling pathway; increasing retinoic acid synthesis; or reducing cytochrome p450 mediated retinoic acid oxidative metabolism.34

Key Insights On Cutaneous Immune Reconstitution Inflammatory Syndrome

   Various researchers have described cutaneous immune reconstitution inflammatory syndrome in association with a range of infectious, inflammatory, neoplastic and autoimmune disorders. Podiatric physicians have come to realize that the introduction of HAART has altered the pattern of dermatologic disease among patients with HIV-infection.

   Huiras and colleagues have noted that while the majority of patients with HIV infection benefit substantially from highly active antiretroviral therapy-induced immune recovery, a subset of patients experience unmasking of new skin disease or paradoxical worsening of existing dermatologic conditions, attributable to immune reconstitution inflammatory syndrome.35 In a review of the current literature regarding the dermatologic manifestations of immune reconstitution inflammatory syndrome, these authors concluded that dermatologic immune reconstitution inflammatory syndrome continues to evolve as the diversity of reported cutaneous immune reconstitution inflammatory syndrome associated disorders expands.

In Conclusion

   The recognition of HIV-related skin changes empowers the podiatric physician to refer a patient to an infectious disease specialist and possibly facilitate diagnosis of HIV infection in the early stages. It is this empowerment of the podiatric physician by sharing current information on the management of cutaneous skin changes of the lower extremity that was the main impetus for the preparation of this review. Thus, an overview pathogenesis of cutaneous skin changes in the HIV patient has been discussed with emphasis on specific lower extremity cutaneous manifestations along with iatrogenic medication induce cutaneous manifestations caused by available antiretroviral agents.

Dr. Smith is in private practice in Ormond Beach, Fla.

References:

1. CDC. HIV/AIDS Surveillance Report, 2005. Vol. 19 Atlanta: US Department of Health Services, CDC: 2009; 1-66. Available at https://www.cdc.gov/hiv/topics/surveillance/resourcess/reports/. Accessed July 13, 2009. 2. Smith RG. The Podiatrist and the HIV/AIDS Patient. Podiatry Management 2003; 22 (2): 137-150. 3. Smith RG. Recognizing lower extremity effects of antiretroviral drugs. Podiatry Today 2008; 21: (1) 62-77. 4. Spira R, Mignard M, Doutre MS, et al. Prevalence of cutaneous disorders in apopulation of HIV-infected patients. Southwestern France, 1996. Groupe d’Epidemiologie Clinique du SIDA en Aquitaine. Arch Dermatol 1998; 134 (10): 1208-1212. 5. Costner M, Cockerell CJ. The changing spectrum of the cutaneous manifestation of HIV disease. Arch Dermatol 1998; 134 (10): 1290-1292. 6. Pallangyo KJ. Cutaneous findings associated with HIV disease including AIDS: experience from Sub Saharan Africa. Trop Doct. 1992; 22 (Suppl 1): 35-41;60. 7. Rad F, Ghader E, Moradi, G et al. The relationship between skin manifestations and CD4 counts among hiv positive patients. Pak J Med Sci 2008; 24 (1): 114-117. 8. Lee D, Benson CA, Lewis CE, et al. Prevalence and factors associated with dry skin in HIV infection: the FRAM study. AIDS 2007; 21 (15): 2051-2057. 9. Nnoruka EN, Chukwuka JC, Anisuiba B. Correlation of mucocutaneous manifestation of HIV/AIDS infection with CD4 and disease progression. Int J Dermatol. 2007; 46 (Suppl 2): 14-18. 10. Josephine M, Issac E, George A, et al. Patterns of skin manifestations and their relationships with CD4 counts among HIV/AIDS patients in Cammeroon. Int J Dermatol 2006: 45 (3): 280-284. 11. Kaplan MH, Sadick N, McNutt NS et al. Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS). J Am Acad Dermatol 1987; 16 (3 Pt 1): 485-506. 12. Prose NS, Abson KG, Scher RK. Disorders of the nails and associated with human immunodeficiency virus infection. J Dermatol 1992; 31 (7): 453-457. 13. Scher RK, Coppa LM. Advances in the diagnosis and treatment of onychomycosis. Hosp Med 1998; 34(4):11-20. 14. Herranz P, Garcia J, De Lucas R, et al. Toenail onycomycosis in patients with acquired immune deficiency syndrome: treatment with terbinafine. Br J Dermatol. 1997; 137(4):577-580. 15. Barber K, Claveau J, Thomas R. review of treatment for onychomycosis: consideration for special populations. J Cutan Med Surg 2006; 10 (Suppl 2): S48-S53 16. De Socio GV, Simonetti S, Rosignoli D et al. Topical cidofovir for severe warts in a patient affected by AIDS and Hodgkin’s Lymphoma. Int J STD AIDS. 2008: 19 (10): 715-716. 17. Marchell NL, Lupon J, Elgart ML. Painful plaques on the soles of an HIV-positive man. Arch Dermatol. 2002; 138 (7): 973-978. 18. Wu IB, Schwartz RA. Reiter’s syndrome: the classic triad and more. J Am Acad Dermatol. 2008; 59 (1): 113-121. 19. Florrell SR. Krueger GG, Egan CA. Keratoderma Blennorrhagicum. N Engl J Med 2003; 349 (24): 2367-2368. 20. Bower M, Weir J, Francis N et al. The effect of HAART in 254 consecutive patients with AIDS-related Kaposi’s sarcoma. AIDS 2009 June 20. 21. Smith RG. Shoe dermatitis: A review of current concepts. The Foot 2008; 18 (1): 40-47. 22. Curr N, Nixon R Allergic contact dermatitis to basic red 46 occurring in an HIV-positive patient. Australas J Dermatol. 2006; 47(3):195-7. 23. Luther J, Glesby MJ. Dermatologic adverse effects of antiretroviral therapy: recognition and management. Am J Clin Dermatol 2007; 8 (4): 221-233. 24. Rahav G, Maayan S. Nail pigmentation associated with zidovudine: a review and report of a case. Scand J Infect Dis 1992; 24 (5): 557-561. 25. Zerboni R, Angius A, Cusini M et al. Lamivudine-induced paronychia. Lancet 1998; 351(9111):1256. 26. Bouscarat F, Bouchard C, Bouhour D. Paronychia and pyogenic granuloma of the great toes in patients treated with indinavir. N Engl J Med 1998; 338(24):1776-1777. 27. Tosti A, Piraccini B, D’Antuono A, et al. Paronychia associated with antiretroviral therapy. Br J Dermatol 1999: 40(24):1165-1168 . 28. Alam M, Scher RK. Indinavir-related recurrent paronychia and ingrown toenails. Cutis 1999; 64(4):277-278. 29. Sibel S, Macher A, Goosby E. Paronychia in patients receiving antiretroviral therapy for human immunodeficiency virus infection. JAPMA 2000; 90(2):98-99. 30. Sass JO, Jakob-Solder B, Heitger A, et al. Paronychia with pyogenic granuloma in a child treated with indinavir: retinoid-mediated side effect theory revisited. Dermatology 2000: 200(1):40-42. 31. Dauden E, Pascual-Lopez M, Martinez-Garcia C, et al. Paronychia and excess granulation tissue of the toes and fingers in patient with indinavir. Br J Dermatol 2000; 142(5):1063-1064. 32. James CW, McNelis KC, Cohen DM et al. Recurrent ingrown toenails secondary to indinavir/ritonavir combination therapy. Ann Pharmacotherapy 2001; 35(7-8):881-884. 33. Colson AE, Sax PE, Keller MJ, et al. Paronychia in association with indinavir treatment. Clin Infect Dis 2001; 32(1):140-143. 34. Garcia-Silva J, Almagro M, Pena-Penabad C et al. Indinavir-induced retinoid-like effects: incidence, clinical features and management. Dru Saf 2002; 25(14):993-1003. 35. Huiras E, Preda V, Maurer T, et al. Cutaneous manifestations of immune reconstitution inflammatory syndrome. Curr Opin HIV AIDS 2008 3 (4): 453-460.