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About the Author

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Aaron Wong, MD, FRCPC

Dr. Aaron Wong is the residency program director in the Department of Dermatology and Skin Science at UBC where he is also a clinical assistant professor. His clinic is based at St. Paul’s Hospital and focuses on HIV Dermatology and he also has a community practice in New Westminster, B.C.

Canadian Dermatology Today, Volume 1, Issue 2, April 2020

Case for Consideration: A 30-year-old HIV-positive man with psoriasis

You are seeing a 30-year-old man with a history of established psoriasis in your outpatient dermatology clinic. The patient has well-controlled human immunodeficiency virus (HIV) and he takes a new antiretroviral (ARV) medication, Biktarvy®. The patient’s HIV in the blood is undetectable and his CD4 T-cell count is normal. His health is otherwise good.  During the clinical workup, he mentions that his partner is HIV-negative and is on pre-exposure prophylaxis (PrEP) medication and has developed brown facial spots and is wondering if the PrEP medication may have caused this and also wants to see a dermatologist.

The patient starts on combination calcipotriene / betamethasone dipropionate foam and considers phototherapy. Upon reviewing the data on Biktarvy®, you become aware that it causes “rash” and wonder about interactions with acitretin, cyclosporine, or methotrexate. Biktarvy® contains bictegravir, emtricitabine and tenofovir alenamide. It does not contain ritonavir. 

HIV and its treatment have changed significantly over the past 30 years. The virus can be fully suppressed with antiretroviral therapy (ARV), formerly known as highly active antiretroviral therapy (HAART). If ARVs are accessible and started early, collaborative cohort studies across Europe and North America demonstrate improved survival & life expectancy. There are now no threshold levels for initiation of ARVs based on CD4 T-cell count or viral load, if the ARVs are accessible to the patient. Treatment is generally recommended after diagnosis of HIV.25


Updates in HIV Acronyms

HIV-related cutaneous reactions can be due to initial infection with the virus itself, opportunistic infections (OI), or because of treatment of the virus or OIs themselves. 

Immune reconstitution inflammatory syndrome (IRIS) is a phenomenon whereby the inflammatory response is exaggerated towards an infectious organism as host immunity recovers (i.e. T helper or CD4+ cells increase) following treatment with ARVs. Those diagnosed at a later stage of HIV are more susceptible and typically this can manifest in the form of extensive infections such as herpes simplex virus infections, herpes zoster, warts, molluscum, candida, and dermatophyte infections. Non-infectious sequalae can include lupus, extensive alopecia areata, or folliculitis.1

The use of PrEP in landmark, well-conducted randomized controlled trials have demonstrated efficacy of combination tenofovir disoproxil fumarate and emtricitabine (TDF-FTC or Truvada®) in preventing HIV transmission and has been approved by Health Canada for this indication.2-4

Post-exposure prophylaxis (PEP) can be non-occupational (nPEP) or occupational. Combination tenofovir disoproxil fumarate and emtricitabine (generic or branded Truvada®) is also used for this purpose. Lifestyle and behavioral interventions still remain key to HIV prevention even with the availability of PEP and PrEP.5

Antiretrovirals – New and Old

HIV antiretroviral therapy has consisted of combinations of the following8:

Antiretroviral therapy has moved towards combining different types of ARVs into one convenient pill, taken once a day including branded medications such as:

Many of the newest QD regimens 

contain the nucleotide reverse transcriptase inhibitor (NRTI), tenofovir alafenamide (TAF), instead of tenofovir disoproxil fumarate (TDF). TAF has some advantages over TDF, including selectively activating within the cell (whereas TDF activates in the bloodstream), less nephrotoxicity & less reduction in bone mineral density. TDF, however, may lead to less elevations of cholesterol and may be beneficial in those with dyslipidemia.6,7

Generally, most ARVs are well-tolerated by patients and mucocutaneous adverse events tend to be the exception, rather than the norm. Non-nucleoside reverse transcriptase inhibitors (NNRTI) are the most common class of ARVs to cause cutaneous toxicity, particularly morbilliform eruption. The morbilliform eruption tends to resolve even when the medication is continued; thus, physicians can treat through the rash with agreeable patients. Nevirapine, in particular, has been associated with morbilliform eruption, drug hypersensitivity and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).9 In the developing world, nevirapine is a common cause of SJS / TEN in HIV / AIDS patients. The observed cluster of adverse events recorded as “rash” were used non-specifically in clinical trials that formed the basis for bringing these drugs to market, so characterization of cutaneous adverse events remains imprecise for many of these medications.

HIV & Lipodystrophy

Antiretroviral lipodystrophy manifests through a variety of changes in body and facial fat composition. Metabolic abnormalities often accompany the lipodystrophy including dyslipidemia and impaired glucose tolerance. Lipoatrophy occurs in the facial temporal and buccal fat pads, limbs and buttocks while lipohypertrophy occurs in the abdomen, dorsocervical region (“buffalo hump”), and breast tissue (gynecomastia). These findings were initially attributed to protease inhibitors (PI) but now are strongly related to NRTIs, particularly stavudine and didanosine as well as NNRTIs such as efavirenz.10,11,13

Protease Inhibitor Drug Interactions

Ritonavir is protease inhibitor that boosts the function of other PIs by inhibition of the cytochrome P450 3A4 pathway. This inhibition reduces breakdown of other PIs, thus providing the aforementioned “boosting” effect. Other drugs metabolized by this pathway, such as corticosteroids and cyclosporine, both of which are used with relative frequency in dermatology, should be approached with caution. Iatrogenic Cushing’s syndrome (ICS) has been reported with single epidural, intra-articular or intramuscular injections of 40 mg or more of triamcinolone acetonide (TAC). There are no published reports of this occurring with intralesional or topical corticosteroids. However, iatrogenic Cushing’s syndrome can occur with topical steroids in patients without HIV so the effects of ritonavir should not be disregarded.14-16 

There are currently no guidelines or data to suggest a safe dose. Consultation with the patient’s HIV provider to determine if an alternate, non-boosted regimen is advisable if intralesional therapy is being considered, particularly if the anticipated dosage is large or injections are to be given on a regular basis. If intralesional therapy is initiated, the author suggests dilution of the TAC to 2.5 mg / ml or lower, keeping the total administered dose below 15 mg and spacing out injections by 8-12 weeks. If there is a clinical suspicion of adrenal suppression or iatrogenic Cushing’s syndrome, these patients should be further investigated.

Cyclosporine is similarly affected by ritonavir-induced cytochrome P450 3A4 inhibition. Lower doses and monitoring of cyclosporine levels may be necessary to prevent toxicity if it must be used. Based on pharmacokinetic data, daily doses of cyclosporine should be reduced by 5-20%. This poses a challenge for weight-based dosing of cyclosporine which may range from 2-5 mg / kg, depending on the indication. The old adage of “start low, go slow” should be adopted, along with the monitoring of levels when ritonavir and cyclosporine are being used concomitantly.17

Stribild® contains cobicistat, elvitegravir, emtricitabine and tenofovir. Cobicistat is also a cytochrome P450 3A4 (CYP3A4) inhibitor and there have been reports of adrenal suppression with concurrent inhaled, intranasal or intra-articular corticosteroids.18,19

Other Systemic Medications and HIV

Acitretin is an established immune-modulating retinoid for treatment of psoriasis in HIV. It is not metabolized through the cytochrome P450 pathway.20 

Methotrexate (MTX) use in HIV showed poor safety outcomes or opportunistic infections in the published literature from 1987-1995.21-24 This was before advent of regular ARV therapy and thus, patients may have had poorly controlled HIV. In some cases, methotrexate doses were higher than what is normally used in dermatology. If the patient has well controlled HIV, MTX can be used provided that regular clinical and laboratory monitoring are followed. Online drug interaction checkers are helpful as well. 

Summary

HIV treatments have come a long way and there continue to be medical advances which generally herald improved outcomes for patients, but adverse cutaneous events from existing and new medications should not be overlooked.

Table 1. Mucocutaneous adverse events of anti-retroviral therapy.10,11,12

References

1. Bosamiya SS. The immune reconstitution inflammatory syndrome. Indian J Dermatol. 2011;56(5):476–479. doi:10.4103/0019-5154.87114

2. Cohen MS et al. Preexposure prophylaxis for HIV–where do we go from here? N Engl J Med. 2012 Aug 2;367(5):459-61.

3. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. Thigpen MC et al. N Engl J Med. 2012 Aug 2;367(5):423-34. 

4. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. Grant RM et al. N Engl J Med. 2010 Dec 30;363(27):2587-99.

5. Cohen, Myron S., et al. “Prevention of HIV-1 infection with early antiretroviral therapy.” New England journal of medicine 365.6 (2011): 493-505.

6. Hill, Andrew, et al. “Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety?.” Journal of virus eradication 4.2 (2018): 72.

7. Kauppinen, Kai Juhani, Pia Kivelä, and Jussi Sutinen. “Switching from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Significantly Worsens the Lipid Profile in a Real-World Setting.” AIDS patient care and STDs 33.12 (2019): 500-506.

8. http://cfenet.ubc.ca/sites/default/files/uploads/Guidelines/BCCfE_Adult_ARV_Therapeutic_Guidelines_2020-03-31.pdf

9. Hoosen K, Mosam A, Dlova NC, Grayson W. An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS. Dermatopathology (Basel). 2019;6(2):111–125.

10. Introcaso CE, et al. Cutaneous toxicities of antiretroviral therapy for HIV: part I. Lipodystrophy syndrome, nucleoside reverse transcriptase inhibitors, and protease inhibitors. J Am Acad J Am Acad Dermatol. 2010 Oct;63(4):563-9.

11. Introcaso CE, et al. Cutaneous toxicities of antiretroviral therapy for HIV: part II. Nonnucleoside reverse transcriptase inhibitors, entry and fusion inhibitors, integrase inhibitors, and immune reconstitution syndrome. J Am Acad Dermatol. 2010 Oct;63(4):563-9.

12. https://www.aids.gov.hk/ice/ice201604.pdf

13. de Waal R, Cohen K, Maartens G. Systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction. PLoS One. 2013;8(5):e63623. 

14. Yombi, J.C., Maiter, D., Belkhir, L. et al. Iatrogenic Cushing’s syndrome and secondary adrenal insufficiency after a single intra-articular administration of triamcinolone acetonide in HIV-infected patients treated with ritonavir. Clin Rheumatol 27, 79 (2008).

15. Schwarze-Zander C, et al. Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature. Infection. 2013 Dec;41(6):1183-7. doi: 10.1007/s15010-013-0506-z. Epub 2013 Jul 20.

16. Levine D, et al. Iatrogenic Cushing syndrome after a single intramuscular corticosteroid injection and concomitant protease inhibitor therapy. J Am Acad Dermatol. 2011 Oct;65(4):877-878.

17. Vogel M. et al. Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients.Liver Transpl. 2004 Jul;10(7):939-44.

18. Lewis J, et al. A case of iatrogenic adrenal suppression after co-administration of cobicistat and fluticasone nasal drops. AIDS 2014; 28: 2633–39.

19. https://www.gov.uk/drug-safety-update/cobicistat-ritonavir-and-coadminsitration-with-a-steroid-risk-of-systemic-corticosteroid-adverse-effects

20. Buccheri L, Katchen BR, Karter AJ, Cohen SR. Acitretin Therapy Is Effective for Psoriasis Associated With Human Immunodeficiency Virus Infection. Arch Dermatol. 1997;133(6):711–715. doi:10.1001/archderm.1997.03890420043005

21. Masson C, Chennebault JM, Leclech C. Is HIV infection contraindication to the use of methotrexate in psoriatic arthritis? J Rheumatol.1995;22:2191. 

22. Maurer TA, Zackheim HS, Tuffanelli L, et al. The use of methotrexatefor treatment of psoriasis in patients with HIV infection. J Am AcadDermatol. 1994;31:372-375.  

23. Duvic M, Johnson TM, Rapini RP, et al. Acquired immunodeficiencysyndrome-associated psoriasis and Reiter’s syndrome. Arch Dermatol.1987;123:1622-1632. 

24. Nakamura M, et al. Psoriasis treatment in HIV-positive patients: a systematic review of systemic immunosuppressive therapies.  Cutis. 2018 Jan;101(1):38;42;56.

25. Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV. 2017 Aug;4(8):e349-e356.