HIV disease–related drug reaction

Commonly prescribed medications for HIV, such as sulfonamides, anticonvulsants, antibacterials, antifungals, antimycobacterials, and, most notably, antiretrovirals, have an increased incidence of adverse cutaneous drug reactions in HIV-positive individuals, and even greater escalation of incidence in people with advanced disease progression in the form of AIDS.[4] The specific mechanism for how HIV infection increases risk of drug reactions in HIV-positive individuals is unclear. Many factors contribute to this increased risk of adverse drug reactions found among people with HIV. Some explanations involve poly-pharmacy, slow acetylator status, glutathione deficiency, etc.[5][6] In addition, it is also thought to be caused by immune hyperactivation, altered immunoregulatory pathways, reactivation of comorbid herpes viral infections, altered redox balance, uncontrolled immune activation, and loss of CD4+ T-helper cells. There is no single defined cause for this association.

Some prescription medications are more likely to cause these adverse drug reactions than others. Non-nucleoside reverse transcriptase inhibitors have been shown to have the highest rate of causing immune-related drug reactions in people who are HIV positive. Trimethoprim-sulfamethoxazole, also known by the brands Bactrim or Septra have caused adverse cutaneous drug reactions at an incidence of 2.6%-8% in the general population, but 43%-69% in patients with HIV infection or AIDS.[7] A retrospective study of adult patients with Pneumocystis jirovecii pneumonia and AIDS who were admitted to Veterans General Hospital in Taiwan between January 2006 to December 2011 and treated with trimethoprim-sulfamethoxazole demonstrated a high incidence of adverse drug reactions that mostly involved the skin and liver. Significant risk factors were daily dose of greater than 16 mg/kg of trimethoprim-sulfamethoxazole and an age of 34 or older. [8]

The use of antiretroviral therapies have decreased the risk of early mortality and improved the quality of life for people who are HIV-positive. A significant increase in the use of these medications have been seen over the years, from an estimated 7.7 million people receiving these antiretrovirals therapies in 2010, to approximately 24.5 million estimated people worldwide in 2018.[9] Despite the success in efforts to treat and control the disease with these medications, there are reports of people who received treatment and developed a severe adverse drug reaction such as a drug-induced liver injury (DILI). Antiretrovirals including non-nucleoside reverse transcriptase inhibitors (NNRTIs) and transcriptase inhibitors (NRTIs) have been reported to cause DILI in people with HIV. Genetic variations in drug metabolizing enzymes are associated with a higher risk of adverse drug reactions in people with HIV taking antiretrovirals, and it may become recommended under the practice of precision medicine to screen for genetic susceptibility to adverse effects based on these enzymes. The reported incidence of antiretroviral therapy induced liver injury range from 8%-23% in people with HIV. Among these people, 30% had needed to have a change in the medication plan or even discontinue their current therapy. [10]

Drug-induced liver injury is a common cause of prolonged hospital stays for people with HIV, and in more severe reactions can be life-threatening. Antiretrovirals may also cause damage to cells in a person with HIV, decreasing function of crucial cells and releasing toxins in the body. Thus, discontinuing the offending medication may cause loss of control in viral load and ultimately treatment failure. Studies have reported that efavirenz is a potential agent that caused drug induced liver injury in HIV-positive patients taking the first line antiretroviral therapy of efavirenz/tenofovir disoproxil fumarate/emtricitabine fixed‐dose combination.[11][12] Other reported risk factors for drug induced liver injury are female gender, young age, and high CD4+ count of >200 cells/mm3.[13] All classes of antiretroviral medications could cause drug induced liver injury, but some classes of medications may be more toxic than others.[14][15] Further research is needed to better understand and analyze any potential differences in risk levels between these classes of antiretrovirals.

There are multiple preventative measures that have been shown to decrease the incidences of immune medicated adverse drug reactions. Abacavir is an HIV medication that can cause adverse reactions like hives and fevers. Additionally, it is contraindicated for re-challenging, thus making it important for people seeking to start Abacavir to proceed with caution. With the advancement of precision medicine, the HLA-B57:01 genetic testing has been shown to decrease the incidence of adverse drug reactions.[22] However cost and accessibility of genetic testing are often a barrier to the populations that benefit from precision medicine the most.[23]

While some HIV medications are contraindicated for re-challenging, desensitization is a viable option when starting a new medication. Desensitization, slowly increasing the strength or dose of medication, has proven to reduce adverse drug reactions. For example, people living with HIV have a higher likelihood of developing an adverse drug reaction to cotrimoxazole. However, desensitization methods have been shown to have a lower rate of hypersensitivity when compared to trying to re-challenge cotrimoxazole.[24]

Another example of desensitization is the treatment for a 41 year-old female who had been infected with HIV for 18 years. She had gone through multiple antiretroviral therapy treatments. She had developed a cutaneous adverse reaction from other generations of nucleoside reverse transcriptase inhibitors (NRTIs). Darunavir/r was chosen for their first therapy with drug resistance and susceptibility in mind. After eight days of treatment, they were forced to halt all medication therapy as they had developed a severe pruritic cutaneous adverse reaction to darunavir/r. The thought of re-challenging was turned down due to the severity of her adverse reaction. However, with limited options, a desensitization protocol for darunavir/r was initiated. She was dosed every 30 minutes starting at 25mcg and ending at 300mcg on the first day of treatment. The treatment was completed with no problem other than generalized pruritus without rash which was contained with the use of antihistamines for a week. After the antihistamine treatment, there were no future signs of adverse reactions through continuing therapy.[25] Unlike precision medicine, there a greater number of medications that have existing desensitization protocols proven to help decrease the incidence of adverse drug reactions in people with HIV.[26]