Dermatological Management of Human Immunodeficiency Virus (HIV)

B. L. Bartlett, MD¹; M. Khambaty, MD²; N. Mendoza, MSc1; A. M. Tremaine, MD¹; A. Gewirtzman, MD¹; S. K. Tyring, MD, PhD, MBA^1,3

¹Center for Clinical Studies, Houston, TX, USA
²The Institute of Human Virology, University of Maryland, Baltimore, MD, USA
³Department of Dermatology, University of Texas Health Sciences Center,
Houston, TX, USA

ABSTRACT

Atypical presentations of typical dermatological conditions are common in human immunodeficiency virus (HIV). This article will focus on three specific topics: eosinophilic folliculitis, psoriasis, and cutaneous mycoses. Their unique presentations in HIV and treatments are discussed.

Key Words:
HIV, eosinophilic folliculitis, psoriasis, cutaneous mycoses

Despite attempts at increasing awareness of HIV and its transmission, this infection continues to spread and remains a significant cause of morbidity and mortality worldwide. As of 2003, there were an estimated 1 million people living in the US with HIV infection, and nearly 40,000 cases were diagnosed in 2005.¹ HIV infection affects nearly every organ system in the body, including the skin. HIV-infected patients can pose diagnostic challenges, as their altered immune status may lead to atypical presentations of common cutaneous diseases, as well as the occurrence of uncommon or opportunistic skin disorders. Management of cutaneous disease in sero-positive patients can also be challenging, as the dermatological manifestations may be more severe, may recur with greater frequency, and may be refractory to standard treatment. The addition of highly active antiretroviral therapy (HAART) further complicates the picture as other dermatologic manifestations may arise as part of the immune reconstitution phenomenon. The scope of issues encountered in HIV positive patients is too broad to discuss in its entirety. This article will focus on three diseases and their management: eosinophilic folliculitis, psoriasis, and cutaneous mycoses.

Eosinophilic Folliculitis

Eosinophilic folliculitis (EF) is seen commonly in HIV with CD4 cell counts of <250-300/mm3.2,³ It presents as recurrent, pruritic, erythematous papules and pustules that are usually distributed on the face, shoulders, upper back, and upper extremities.³ The pruritus associated with EF can be severe and debilitating. Its etiology is not well elucidated, but some theories propose an infectious derivation. EF is an example of a dermatosis that is associated with immune-reconstitution.³ It is described as a phenomenon wherein HAART triggers a generalized immune activation as viral loads decrease and CD4 lymphocytes increase.^{4, 5} Studies have shown that EF typically flares shortly after starting antiretroviral therapy, but will resolve from 3 weeks to several months later.³ Clinicians should warn patients with EF that after starting HAART, their skin will likely worsen initially, then improve.
EF can be difficult to manage, as response to treatment is variable and it tends to recur once treatment is discontinued. Various treatments have been employed, including: isotretinoin, UVB phototherapy, itraconazole, and metronidazole, among others, with contrasting results.² The treatment of EF with potent topical corticosteroids is reportedly effective, but is accompanied by skin atrophy and hypopigmentation. This can be a problem given the distribution of EF on the face, and can be especially challenging in dark-skinned individuals.⁶ A relatively recent case study showed promising results with topical tacrolimus. Subjects who applied daily topical tacrolimus 0.1% to the face had an average lesion clearance time of 2.6 months with an absence of residual scarring. The average remission of 12.3 months was seen in subjects with well controlled viremia on HAART. The associated pruritus subsided within days.² Given these promising results and the relative safety of topical tacrolimus, clinicians may want to consider this as an alternative to corticosteroids, which can cause hypopigmentation and scarring in dark skinned patients, resulting in potential disfigurement.

Psoriasis

The prevalence of psoriasis in HIV-infected individuals is the same or slightly higher than that seen in noninfected individuals, but its clinical presentation can be more severe.^{7, 8} The severity of presentation often correlates with the degree of immunosuppression. HIV-positive patients with pre-existing psoriasis may see a flare of lesions as their CD4 count decreases and their viral load increases. A higher frequency of guttate and inverse psoriasis, as well as cases of generalized erythrodermic type psoriasis, has been reported in HIV-positive patients.⁹ Psoriasis has been the presenting manifestation of HIV in some individuals, thus HIV testing should be considered in patients that present with de novo psoriasis.⁸

Treatment of psoriasis in HIV-positive patients can be challenging, as it is often refractory to standard psoriasis treatments.⁷ When started on HAART, patients’ psoriasis tends to improve as the immune system is reconstituted.¹⁰ Case reports have shown a dramatic and rapid improvement of psoriasis in HIV-positive patients who have been either started or restarted on HAART.^{7, 10} Consequently, these reports emphasize the importance of strict adherence to antiretroviral regimens. This response is paradoxical, as drugs effective at treating psoriasis are targeted at Tlymphocytes, yet a low CD4 cell count causes worsening of the psoriasis. Although still unclear, the development of psoriasis is postulated to be an expression of the disease, which depends on the ratio of CD4 to CD8 cells. This ratio decreases in advanced HIV.11 It is also thought that TNF-á, an inflammatory cytokine associated with both psoriasis
and HIV replication, may play a role.¹⁰ Subjects on HAART should have lower viral replication and therefore, reduced levels of TNF-á. The regulatory T-cell subpopulation may also play a role, as this dedicated population is deficient in psoriasis, but expanded in the peripheral blood of HIV patients on HAART.¹⁰ Additional research will need to be conducted to further elucidate this phenomenon. Regardless, strict adherence to an antiretroviral treatment regimen is an important point to remember and to relay to patients.

Cutaneous Mycoses

Cutaneous dermatophytosis is generally more varied, extensive, and atypical in HIV than in immunocompetent hosts. As with psoriasis, the frequency of cutaneous dermatophytosis in the HIV population is not significantly greater than in noninfected individuals. Involvement of the nails is seen as proximal, subungual onychomycosis. Often the majority of the toenails are involved, which is a classic sign in HIV-infected patients.¹² Extensive lesions refractory to treatment are typical.¹³ Pruritus and pain are not always present in this population despite the potential for extensive involvement.¹²

The most common etiologic organism of cutaneous fungal infection is Trichophyton rubrum, which generally inhabits the cornified layer of the dermis. Deeper penetration into the stratum corneum occurs after the dermatophyte releases enzymes, such as keratinase.¹⁴ The skin has a number of defense mechanisms in place to prevent penetration below the epidermis, including a cell-mediated response.¹⁵ In the immunocompromised population, however, invasive fungal infections can be identified, although they are rare. It is important to recognize and treat cutaneous fungal infections early, as delay of treatment allows for the
infection to become more deeply invasive. Deep or locally invasive dermatophyte infection will typically present as nodular eruptions near the initial site of infection. Abscesses, mycetomas, and atypical lesions may also occur.¹⁴

Treatments used for various mycoses in immunocompetent individuals may not be sufficient to treat the same infections in the immunocompromised. For example, systemic therapy may be necessary even for superficial infections, whereas topicals alone would likely be adequate to treat the same infection in immunocompetent patients.¹² Resistance to oral antifungals, such as fluconazole, is a problem when it is used long-term as prophylaxis or for frequent short-term exposures. These drugs are used to treat candidal infections. In addition, immunosuppressed patients are more likely to be infected with atypical fungi.¹² Oral antifungals such as ketoconazole, fluconazole, and griseofulvin are usually effective in treating superficial and deep dermatophyte infections in this population.¹⁴ However, when systemic therapy fails to be curative, surgery may be required. Failure to eradicate the infection has led to death in patients due to septicemia and systemic dissemination.^{16, 17} In order to make a proper diagnosis and prescribe an appropriate treatment regimen, it is important that, in addition to potassium hydroxide (KOH) mounts, cultures be performed on Sabouraud’s agar to allow for specific species identification.¹⁴

In some cases, antiretroviral therapy alone is sufficient to clear dermatophyte infections in immunosuppressed patients. However, it is important to consider possible interactions between antiretrovirals and antifungals, particularly ketoconazole. Although not contraindicated, it is advisable to use the medications concomitantly with close observation, as both ketoconazole and certain antiretrovirals have an effect on cytochrome P-450, leading to increases or decreases in either ketoconazole levels and/or antiretroviral levels.¹⁸ Other antifungals such as griseofulvin and terbinafine have not been shown to interact with HIV medications, and no specific warnings exist.¹⁴ Amphotericin B, a potent broad spectrum antifungal agent is still used in certain cases. However, this drug has substantial toxicity and must be used with caution. The development of an entirely different class of antifungals, echinocandins, has had a significant impact on the therapeutic approach to fungal infections. Drugs in this class, such as caspofungin, have few side-effects and few drug interactions. However, this drug does not have an oral preparation and has a relatively narrow spectrum of activity when compared with amphotericin B.¹² The choice of an antifungal agent will depend on the patient, the organism being treated, and the severity of the infection.

Conclusion

HIV infection can lead to a myriad of dermatoses with complicated clinical presentations. The altered immune status of HIV-infected individuals leads to diagnostic and therapeutic challenges. As dermatologists, it is important to be aware of the varied dermatoses associated with HIV, as well as their management. Knowledge of HIV-associated dermatologic manifestations may be useful in helping to make the diagnosis of HIV. Additionally, recognition of the need for more intensive therapy in these patients can provide improved care, and ultimately, improved patient outcomes.

References

1. Department of Health and Human Services. Center for Disease Control Cases of HIV infection and AIDS in the United States and dependent areas, 2005.
   HIV/AIDS Surveillance Report, Volume 17, Revised Edition, June 2007.
2. Toutous-Trellu L, Abraham S, Pechere M, et al. Topical tacrolimus for effective treatment of eosinophilic folliculitis associated with human immunodeficiency virus infection. Arch Dermatol 141(10):1203-8 (2005 Oct).
3. Rajendran PM, Dolev JC, Heaphy MR, et al. Eosinophilic folliculitis: before and after the introduction of antiretroviral therapy. Arch Dermatol 141(10):1227-31 (2005 Oct).
4. Lawn SD, Wilkinson RJ. Immune reconstitution disease associated with parasitic infections following antiretroviral treatment. Parasite Immunol 28(11):625-33 (2006 Apr).
5. Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and leprosy. Arch Dermatol 140(8):997-1000(2004 Aug).
6. Grange F, Schoenlaub P, Tortel MC, et al. AIDS-related eosinophilic folliculitis: efficacy of high dose topical corticotherapy. Ann Dermatol Venereol 123(8):456-9(1996).
7. Mamkin I, Mamkin A, Ramanan SV. HIV-associated psoriasis. Lancet Infect Dis 7(7):496 (2007 Jul).
8. Rigopoulos D, Paparizos V, Katsambas A. Cutaneous markers of HIV infection. Clin Dermatol 22(6):487-98 (2004 Nov-Dec).
9. Morar N, Dlova N, Gupta AK, et al. Erythroderma: a comparison between HIV positive and negative patients. Int J Dermatol 38(12):895-900 (1999 Dec).
10. De Socio GV, Simonetti S, Stagni G. Clinical improvement of psoriasis in an AIDS patient effectively treated with combination antiretroviral therapy. Scand J Infect Dis 18(1):44-57 (2006 Jan).
11. Fife DJ, Waller JM, Jeffes EW, Koo JYM. Unraveling the paradoxes of HIV-associated psoriasis: a review of T-cell subsets and cytokine profiles. Dermatol Online J 13(2):4 (2007).
12. Venkatesan P, Perfect JR, Myers SA. Evaluation and management of fungal infections in immunocompromised patients. Dermatol Ther 18(1):44-57 (2005 Jan-Feb).
13. Trope BM, Lenzi ME. AIDS and HIV infections: uncommon presentations. Clin Dermatol 23(6):572-80 (2005 Nov-Dec).
14. Burkhart CN, Chang H, Gottwald L. Tinea corporis in human immunodeficiency virus-positive patients: case report and assessment of oral therapy. Int J Dermatol 42(10):839-43 (2003 Oct).
15. Chastain MA, Reed RJ, Pankey GA. Deep dermatophytosis: report of two cases and review of the literature. Cutis 67(6):457-62 (2001 Jun).
16. Hironaga M, Okazaki N, Saito K, et al. Trichophyton mentagrophytes granulomas: unique systemic dissemination to lymph nodes, testes, vertebrae, and bone. Arch Dermatol 119(6):482-90 (1983 Jun).
17. Rinaldi MG. Dermatophytosis: epidemiological and microbiological update. J Am Acad Dermatol 43(5 suppl1):S120-4 (2000 Nov).
18. Bartlett JG, Gallant JE. Medical Management of HIV Infection. 2007 ed. Baltimore (MD): Johns Hopkins University, Division of Infectious Diseases (2007).