User:Gcwu/HIV disease-related drug reaction

Definition
Drug reactions are a major cause of mortality and morbidity around the world. Special populations of people, such as those who are HIV-positive can be up to a hundred times more susceptible to HIV disease-related adverse drug reactions than the general public.

Immune-mediated Drug Hypersensitivity Reactions
The use of highly active antiretroviral therapies have seen an increased incidence of adverse cutaneous drug reactions (ACDR) in HIV-positive individuals, and even greater escalation of incidence in people with advanced disease progression in the form of AIDS.

Some prescription medications are more susceptible to causing these adverse drug reactions than others. Trimethoprim-sulfamethoxazole, also known by the brands Bactrim or Septra have shown to have an ACDR incidence of 2.6%-8% in the general population, to which incidence increased to 43%-69% in patients with HIV/AIDS. A retrospective study with conducted in Taiwan that looked at adult patients with Pneumocystis jirovecii pneumonia (PJP) and AIDS that were admitted to Veterans General Hospital in Taiwan between January 2006 to December 2011. The study discovered that a high incidence of adverse drug reactions occurred in patients with PJP and AIDS that were treated with trimethoprim-sulfamethoxazole, to which most reactions involved the skin and liver. Significant risk factors that were concluded were daily dose of greater than 16 mg/kg of trimethoprim-sulfamethoxazole and an age of 34 years or older. === Drug-Induced Liver Injury === The use of anti-retroviral 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 anti-retrovirals therapies in 2010, to approximately 24.5 million estimated people worldwide in 2018. Despite the success in efforts to treat and control the disease with these medications, there are reports of people who received treatment who developed a severe adverse drug reaction such as a drug-induced liver injury. The reported incidence of anti-retroviral 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.

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. 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. Other reported risk factors for drug induced liver injury are female gender, young age, and high CD4+ count of >200 cells/mm3.

=== Anemia === The use of zidovudine (ZDV) has been shown to increase the chance of having anemia. The study has demonstrated that compared to the HIV patient receiving non-ZDV treatment, HIV patients who receive ZDV are more likely to have severe anemia.

=== Lactic acidosis === The use of nucleoside reverse transcriptase inhibitor (NRTI) can potentially increase the lactate production because NRT is able to disrupt the normal mitochondrial breathing pathway based on the bench study. Moreover, the bedside clinical study further indicates the cause and effect association between the NRT and the lactic acidosis.

Causes
Drugs commonly used in HIV treatment that cause HIV disease-related drug reactions are sulfonamides, anticonvulsants, antiretrovirals, antibacterials, antifungals, and antimycobacterials.

Mechanism
Lactic acidosis: Since the NRTIs can impair the normal mitochondrial pathway and disrupt the NAD+/NADH cycle, these can further impair the lipid beta-oxidation and oxidative phosphorylation. Thus, the long chain fatty acid is unable to be broken down so that the pathway needs to be changed to glycolysis. The excess glycolysis can produce the excessive lactic acid, leading to the lactic acidosis eventually.

Diagnosis
Diagnosis of NRTI related lactic acidosis:

There are a couple of standard to do the diagnosis of lactic acidosis, which will be listed in the following.


 * 1) Blood pH < 7.35
 * 2) lactate level > 45-54mg/dL
 * 3) Increased Anion gap

There are two types of lactic acidosis that are most commonly seen in the real clinical setting and they are type A and type B lactic acidosis. Type A lactic acidosis is mainly caused by the systemic ischemia since the oxygen has trouble being delivered to the tissue so that most of the biochemistry pathway will be shifted to the glycolysis pathway to generate ATP. Therefore, this shifting can increase the lactic acid level and lead to the lactic acidosis. However, the type B lactic acidosis is most likely caused by the exogenous toxins, such as the NRTI. Since the treatment of the lactic acidosis is to mainly treat the underlying causes, it is important to differentiate the type A and type B lactic acidosis carefully when diagnosing the lactic acidosis so that the best treatment plan can be made for the patient. Moreover, we can differentiate the type A and type B lactic acidosis through some imaging and blood test to find out any ischemia condition in the patient. If not, it is very likely that the patient is experiencing the type B lactic acidosis.

Precision Medicine
There are multiple preventative measures that have been shown to decrease in incidences of immune-mediated 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. However cost and accessibility of genetic testing are often a barrier in the populations that benefit from precision medicine.

Desensitization
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 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. Unlike precision medicine, there is a greater number of medications that can use the method of desensitization to reduce adverse drug reactions.

An 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 therapy with drug resistance and susceptibility in mind. After eight days of treatment, they were forced to halt all medication therapy as had developed a severe pruritic cutaneous adverse reaction to darunavir/r. The thought of rechallenging 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 treated with antihistamine for a week. After the antihistamine treatment, there were no future adverse reactions through continuing their therapy.

Treatment
When considering the treatment of an adverse drug reaction, there needs to be an analysis of weighing the risks versus benefits. Many people living with HIV have co-morbid conditions that may lead to increasing the need for therapy. Introducing new medication to people living with HIV may increase the burden of poly-pharmacy. The majority of cutaneous adverse reactions are benign, thus treatment is often not required for. However, monitoring is still required to prevent complications that may arise from worsening of the adverse drug reaction.

Special Populations
Aging leads to changes in the body's physiologic function. Elderly people (over 65 years of age) have decreased liver function and decreased renal clearance of drugs compared to their younger counterpart. Due to these physiologic changes, pharmacokinetics and pharmacodynamics can be impacted, leading to and increased or decreased drug effect and an increased risk of experiencing adverse drug reactions. It is important to consider these physiologic changes when prescribing or administering medications to treat HIV in HIV-positive individuals above 65 years of age.