HIV disease–related drug reaction: Difference between revisions

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HIV disease–related drug reaction is an adverse drug reaction caused by drugs used for the treatment of HIV/AIDS.

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 immune-mediated adverse drug reactions than the general public.^[2]^[3]

Types of Reaction and offending medication

Immune-mediated drug hypersensitivity

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]

Drug-induced liver injury

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.

Table of antiretroviral medications with a known adverse drug reaction in HIV-positive people.^[16]
Drug	Type of Reaction
Nevirapine	Drug induced liver injury, Hypersensitivity
Efavirenz	Drug induced liver injury, Hypersensitivity
Zidovudine	Drug induced liver injury
Stavudine	Drug induced liver injury
Didanosine	Drug induced liver injury
Abacavir	Hypersensitivity
Indinavir	Drug induced liver injury
Tipranivir	Drug induced liver injury
Aplaviran	Drug induced liver injury

Diagnosis

Diagnosis of HIV drug caused drug induced liver injury (DILI):

The most important way to figure out whether the ART drug causes the drug DILI is to do the blood test to see the AST and ALT level. If the AST and ALT level increase, the HIV drugs are causing the hepatotoxicity.^[17] In addition to the high level of AST and ALT level, the bilirubin and gamma-glutamiltranspeptidase (GGT) may also increase when doing the ART HIV treatment. Normally, the hepatic toxicity may be suspected if the bilirubin and GGT levels are higher than the normal level. However, some studies has shown that the ART drug may inhibit the UDP-glucuronosyltransferase, which causes the indirect and total bilirubin to increase.^[18] Moreover, the increase of GGT may be the indication of cholelithiasis and the cholelithiasis could be further worse to damage the hepatocyte. However, increasing the GGT may have variable reasons and the mechanism of how ART causes high GGT is still unknown, but the gold standard to determine if the cholelithiasis occurs is the alkaline phosphatase.^[17]

Diagnosis of zidovudine related anemia:^[19] zidovudine counters HIV in two ways. It can directly inhibit reverse transcriptase from converting viral RNA to DNA so that HIV cannot integrate into human DNA. In addition, zidovudine works as a DNA replication chain terminator. Because of its DNA chain terminator feature, the bone marrow may be suppressed so that its production of red blood cells is decreased. Moreover, zidovudine may also increase the destruction of red blood cells,^[20] which may continue to decrease the red blood cell count.

Complete blood count (CBC)
Blood smear

Blood smears in cases zidovudine-related anemia usually show a megaloblastic macrocytic anemia associated with the vitamin B12 and folic acid deficiency and the mechanism of how these occur is still unknown.

Diagnosis of nucleoside reverse transcriptase inhibitor (NRTI) related lactic acidosis:^[21] The NRTI can increase lactate production by disrupting the normal mitochondrial metabolic pathway and the NAD+/NADH cycle. These impair the lipid beta-oxidation and oxidative phosphorylation, and long chain fatty acids are unable to be broken down so that the preferred metabolic pathway for oxidation is changed to glycolysis. Glycolysis produces excessive lactic acid, leading to the lactic acidosis.

Test results that indicate lactic acidosis, are:

Blood pH < 7.35
lactate level > 45–54mg/dL
Increased anion gap

There are two types of lactic acidosis most commonly seen are termed 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 tissues and that the biochemical metabolic pathway is shifted to glycolysis to generate ATP. Therefore, this shifting increases the lactic acid level and leads to lactic acidosis. Type B lactic acidosis is most likely caused by the exogenous toxins, such as the NRTI itself. 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. Since the type A lactic acidosis is most likely caused by the ischemia, we can use the additional imaging and blood test to screen the ischemia condition. If no ischemia is found out, the type A lactic acidosis can be eliminated.

Prevention

Precision medicine

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]

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 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]

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.^[27] Introducing new medications 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. However, monitoring is still required to prevent complications that may arise from the worsening of adverse drug reactions.^[2]

Vulnerable populations

Aging leads to changes in the body's physiologic functions. Elderly people (over 65 years of age) have decreased liver function and decreased renal clearance of drugs compared to their younger counterparts.^[28] 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.^[28] 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. Older age, smoking, and longer duration of HIV infection are associated with increased risk of developing multiple conditions in addition to HIV, such as hypertension, dyslipidemia, diabetes mellitus, kidney disease, cardiovascular disease, respiratory disorders, bone disorders or cancer. ^[28]

References

^ "Antiretroviral Drugs to Treat HIV Infection", National Institute of Allergy and Infectious Diseases (NIAID), U.S. Department of Health and Human Services, 2016-10-25, retrieved 2023-07-31
^ ^a ^b Peter J, Choshi P, Lehloenya RJ (August 2019). "Drug hypersensitivity in HIV infection". Current Opinion in Allergy and Clinical Immunology. 19 (4): 272–282. doi:10.1097/ACI.0000000000000545. PMC 7236403. PMID 31145192.
^ Hoosen K, Mosam A, Dlova NC, Grayson W (2019). "An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS". Dermatopathology. 6 (2): 111–125. doi:10.1159/000496389. PMC 6827458. PMID 31700852.
^ Hoosen, Koraisha; Mosam, Anisa; Dlova, Ncoza Cordelia; Grayson, Wayne (2019-06-26). "An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS". Dermatopathology. 6 (2): 111–125. doi:10.1159/000496389. ISSN 2296-3529. PMC 6827458. PMID 31700852.
^ Hoosen, Koraisha; Mosam, Anisa; Dlova, Ncoza Cordelia; Grayson, Wayne (2019-06-26). "An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS". Dermatopathology. 6 (2): 111–125. doi:10.1159/000496389. ISSN 2296-3529. PMC 6827458. PMID 31700852.
^ van der Ven, A.J.Am.; Koopmans, P.P.; van der Meer, J.W.M.; Vree, T.B. (August 1991). "Adverse reactions to co-trimoxazole in HIV infection". The Lancet. 338 (8764): 431–433. doi:10.1016/0140-6736(91)91046-W. hdl:2066/14860. PMID 1678095. S2CID 205037568.
^ Hoosen, Koraisha; Mosam, Anisa; Dlova, Ncoza Cordelia; Grayson, Wayne (2019-06-26). "An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS". Dermatopathology. 6 (2): 111–125. doi:10.1159/000496389. ISSN 2296-3529. PMC 6827458. PMID 31700852.
^ Chang, Hui-Min; Tsai, Hung-Chin; Lee, Susan Shin-Jung; Kunin, Calvin; Lin, Pei-Chin; Wann, Shue-Ren; Chen, Yao-Shen (June 2016). "High daily doses of trimethoprim/sulfamethoxazole are an independent risk factor for adverse reactions in patients with pneumocystis pneumonia and AIDS". Journal of the Chinese Medical Association. 79 (6): 314–319. doi:10.1016/j.jcma.2016.01.007. ISSN 1726-4901. PMID 27025225.
^ Pillaye, Jamie N.; Marakalala, Mohlopheni J.; Khumalo, Nonhlanhla; Spearman, Wendy; Ndlovu, Hlumani (August 2020). "Mechanistic insights into antiretroviral drug‐induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. ISSN 2052-1707. PMC 7344109. PMID 32643320.
^ Pillaye, Jamie N.; Marakalala, Mohlopheni J.; Khumalo, Nonhlanhla; Spearman, Wendy; Ndlovu, Hlumani (August 2020). "Mechanistic insights into antiretroviral drug‐induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. ISSN 2052-1707. PMC 7344109. PMID 32643320.
^ Pillaye, Jamie N.; Marakalala, Mohlopheni J.; Khumalo, Nonhlanhla; Spearman, Wendy; Ndlovu, Hlumani (August 2020). "Mechanistic insights into antiretroviral drug‐induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. ISSN 2052-1707. PMC 7344109. PMID 32643320.
^ Sonderup, Mark W.; Wainwright, Helen; Hall, Pauline; Hairwadzi, Henry; Spearman, C. Wendy N. (May 2015). "A clinicopathological cohort study of liver pathology in 301 patients with human immunodeficiency virus/acquired immune deficiency syndrome". Hepatology. 61 (5): 1721–1729. doi:10.1002/hep.27710. ISSN 0270-9139. PMID 25644940. S2CID 5062159.
^ Sonderup, Mark W.; Wainwright, Helen; Hall, Pauline; Hairwadzi, Henry; Spearman, C. Wendy N. (May 2015). "A clinicopathological cohort study of liver pathology in 301 patients with human immunodeficiency virus/acquired immune deficiency syndrome". Hepatology. 61 (5): 1721–1729. doi:10.1002/hep.27710. ISSN 0270-9139. PMID 25644940. S2CID 5062159.
^ Pillaye, Jamie N.; Marakalala, Mohlopheni J.; Khumalo, Nonhlanhla; Spearman, Wendy; Ndlovu, Hlumani (August 2020). "Mechanistic insights into antiretroviral drug‐induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. ISSN 2052-1707. PMC 7344109. PMID 32643320.
^ Yimer, Getnet; Gry, Marcus; Amogne, Wondwossen; Makonnen, Eyasu; Habtewold, Abiy; Petros, Zelalem; Aderaye, Getachew; Schuppe-Koistinen, Ina; Lindquist, Lars; Aklillu, Eleni (2014-04-08). Vermund, Sten H. (ed.). "Evaluation of Patterns of Liver Toxicity in Patients on Antiretroviral and Anti-Tuberculosis Drugs: A Prospective Four Arm Observational Study in Ethiopian Patients". PLOS ONE. 9 (4): e94271. Bibcode:2014PLoSO...994271Y. doi:10.1371/journal.pone.0094271. ISSN 1932-6203. PMC 3979833. PMID 24714066.
^ Pillaye JN, Marakalala MJ, Khumalo N, Spearman W, Ndlovu H (August 2020). "Mechanistic insights into antiretroviral drug-induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. PMC 7344109. PMID 32643320.
^ ^a ^b Núñez M (January 2006). "Hepatotoxicity of antiretrovirals: incidence, mechanisms and management". Journal of Hepatology. 44 (1 Suppl): S132–S139. doi:10.1016/j.jhep.2005.11.027. PMID 16364487.
^ Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, et al. (October 2001). "Mechanism of indinavir-induced hyperbilirubinemia". Proceedings of the National Academy of Sciences of the United States of America. 98 (22): 12671–12676. Bibcode:2001PNAS...9812671Z. doi:10.1073/pnas.231140698. PMC 60112. PMID 11606755.
^ Tamir Z, Alemu J, Tsegaye A (January 2018). "Anemia among HIV Infected Individuals Taking ART with and without Zidovudine at Addis Ababa, Ethiopia". Ethiopian Journal of Health Sciences. 28 (1): 73–82. doi:10.4314/ejhs.v28i1.9. PMC 5866291. PMID 29622909.
^ Ghodke Y, Anderson PL, Sangkuhl K, Lamba J, Altman RB, Klein TE (December 2012). "PharmGKB summary: zidovudine pathway". Pharmacogenetics and Genomics. 22 (12): 891–894. doi:10.1097/FPC.0b013e32835879a8. PMC 3696524. PMID 22960662.
^ Claessens YE, Chiche JD, Mira JP, Cariou A (June 2003). "Bench-to-bedside review: severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors". Critical Care. 7 (3): 226–232. doi:10.1186/cc2162. PMC 270672. PMID 12793872.
^ Stainsby CM, Perger TM, Vannappagari V, Mounzer KC, Hsu RK, Henegar CE, et al. (January 2019). "Abacavir Hypersensitivity Reaction Reporting Rates During a Decade of HLA-B*5701 Screening as a Risk-Mitigation Measure". Pharmacotherapy. 39 (1): 40–54. doi:10.1002/phar.2196. PMC 6590466. PMID 30414209.
^ Bain LE, Nkoke C, Noubiap JJ (March 2017). "UNAIDS 90-90-90 targets to end the AIDS epidemic by 2020 are not realistic: comment on "Can the UNAIDS 90-90-90 target be achieved? A systematic analysis of national HIV treatment cascades"". BMJ Global Health. 2 (2): e000227. doi:10.1136/bmjgh-2016-000227. PMC 5435269. PMID 28589026.
^ Lin D, Li WK, Rieder MJ, et al. (Cochrane HIV/AIDS Group) (April 2007). "Cotrimoxazole for prophylaxis or treatment of opportunistic infections of HIV/AIDS in patients with previous history of hypersensitivity to cotrimoxazole". The Cochrane Database of Systematic Reviews (2): CD005646. doi:10.1002/14651858.CD005646.pub2. PMID 17443608.
^ Lorber M, Haddad S (January 2013). "Hypersensitivity and desensitization to darunavir in a case of HIV infection with triple-class drug resistance: case description and review of the literature". Journal of the International Association of Providers of AIDS Care. 12 (6): 378–379. doi:10.1177/2325957413488189. PMID 23778241. S2CID 44812281.
^ Yunihastuti E, Widhani A, Karjadi TH (January 2014). "Drug hypersensitivity in human immunodeficiency virus-infected patient: challenging diagnosis and management". Asia Pacific Allergy. 4 (1): 54–67. doi:10.5415/apallergy.2014.4.1.54. PMC 3921866. PMID 24527412.
^ Coughlan R, Cameron S (January 2016). "Key data from the 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV". Antiviral Therapy. 21 (1): 75–89. doi:10.3851/IMP3031. PMID 26857256. S2CID 32178281.
^ ^a ^b ^c Back D, Marzolini C (February 2020). "The challenge of HIV treatment in an era of polypharmacy". Journal of the International AIDS Society. 23 (2): e25449. doi:10.1002/jia2.25449. PMC 6996317. PMID 32011104.

[1] "Antiretroviral Drugs to Treat HIV Infection", National Institute of Allergy and Infectious Diseases (NIAID), U.S. Department of Health and Human Services, 2016-10-25, retrieved 2023-07-31

[Peter_2019-2] Peter J, Choshi P, Lehloenya RJ (August 2019). "Drug hypersensitivity in HIV infection". Current Opinion in Allergy and Clinical Immunology. 19 (4): 272–282. doi:10.1097/ACI.0000000000000545. PMC 7236403. PMID 31145192.

[Hoosen_2019-3] Hoosen K, Mosam A, Dlova NC, Grayson W (2019). "An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS". Dermatopathology. 6 (2): 111–125. doi:10.1159/000496389. PMC 6827458. PMID 31700852.

[4] Hoosen, Koraisha; Mosam, Anisa; Dlova, Ncoza Cordelia; Grayson, Wayne (2019-06-26). "An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS". Dermatopathology. 6 (2): 111–125. doi:10.1159/000496389. ISSN 2296-3529. PMC 6827458. PMID 31700852.

[5] Hoosen, Koraisha; Mosam, Anisa; Dlova, Ncoza Cordelia; Grayson, Wayne (2019-06-26). "An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS". Dermatopathology. 6 (2): 111–125. doi:10.1159/000496389. ISSN 2296-3529. PMC 6827458. PMID 31700852.

[6] van der Ven, A.J.Am.; Koopmans, P.P.; van der Meer, J.W.M.; Vree, T.B. (August 1991). "Adverse reactions to co-trimoxazole in HIV infection". The Lancet. 338 (8764): 431–433. doi:10.1016/0140-6736(91)91046-W. hdl:2066/14860. PMID 1678095. S2CID 205037568.

[7] Hoosen, Koraisha; Mosam, Anisa; Dlova, Ncoza Cordelia; Grayson, Wayne (2019-06-26). "An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS". Dermatopathology. 6 (2): 111–125. doi:10.1159/000496389. ISSN 2296-3529. PMC 6827458. PMID 31700852.

[8] Chang, Hui-Min; Tsai, Hung-Chin; Lee, Susan Shin-Jung; Kunin, Calvin; Lin, Pei-Chin; Wann, Shue-Ren; Chen, Yao-Shen (June 2016). "High daily doses of trimethoprim/sulfamethoxazole are an independent risk factor for adverse reactions in patients with pneumocystis pneumonia and AIDS". Journal of the Chinese Medical Association. 79 (6): 314–319. doi:10.1016/j.jcma.2016.01.007. ISSN 1726-4901. PMID 27025225.

[9] Pillaye, Jamie N.; Marakalala, Mohlopheni J.; Khumalo, Nonhlanhla; Spearman, Wendy; Ndlovu, Hlumani (August 2020). "Mechanistic insights into antiretroviral drug‐induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. ISSN 2052-1707. PMC 7344109. PMID 32643320.

[10] Pillaye, Jamie N.; Marakalala, Mohlopheni J.; Khumalo, Nonhlanhla; Spearman, Wendy; Ndlovu, Hlumani (August 2020). "Mechanistic insights into antiretroviral drug‐induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. ISSN 2052-1707. PMC 7344109. PMID 32643320.

[11] Pillaye, Jamie N.; Marakalala, Mohlopheni J.; Khumalo, Nonhlanhla; Spearman, Wendy; Ndlovu, Hlumani (August 2020). "Mechanistic insights into antiretroviral drug‐induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. ISSN 2052-1707. PMC 7344109. PMID 32643320.

[12] Sonderup, Mark W.; Wainwright, Helen; Hall, Pauline; Hairwadzi, Henry; Spearman, C. Wendy N. (May 2015). "A clinicopathological cohort study of liver pathology in 301 patients with human immunodeficiency virus/acquired immune deficiency syndrome". Hepatology. 61 (5): 1721–1729. doi:10.1002/hep.27710. ISSN 0270-9139. PMID 25644940. S2CID 5062159.

[13] Sonderup, Mark W.; Wainwright, Helen; Hall, Pauline; Hairwadzi, Henry; Spearman, C. Wendy N. (May 2015). "A clinicopathological cohort study of liver pathology in 301 patients with human immunodeficiency virus/acquired immune deficiency syndrome". Hepatology. 61 (5): 1721–1729. doi:10.1002/hep.27710. ISSN 0270-9139. PMID 25644940. S2CID 5062159.

[14] Pillaye, Jamie N.; Marakalala, Mohlopheni J.; Khumalo, Nonhlanhla; Spearman, Wendy; Ndlovu, Hlumani (August 2020). "Mechanistic insights into antiretroviral drug‐induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. ISSN 2052-1707. PMC 7344109. PMID 32643320.

[15] Yimer, Getnet; Gry, Marcus; Amogne, Wondwossen; Makonnen, Eyasu; Habtewold, Abiy; Petros, Zelalem; Aderaye, Getachew; Schuppe-Koistinen, Ina; Lindquist, Lars; Aklillu, Eleni (2014-04-08). Vermund, Sten H. (ed.). "Evaluation of Patterns of Liver Toxicity in Patients on Antiretroviral and Anti-Tuberculosis Drugs: A Prospective Four Arm Observational Study in Ethiopian Patients". PLOS ONE. 9 (4): e94271. Bibcode:2014PLoSO...994271Y. doi:10.1371/journal.pone.0094271. ISSN 1932-6203. PMC 3979833. PMID 24714066.

[Pillaye_2020-16] Pillaye JN, Marakalala MJ, Khumalo N, Spearman W, Ndlovu H (August 2020). "Mechanistic insights into antiretroviral drug-induced liver injury". Pharmacology Research & Perspectives. 8 (4): e00598. doi:10.1002/prp2.598. PMC 7344109. PMID 32643320.

[Núñez_2006-17] Núñez M (January 2006). "Hepatotoxicity of antiretrovirals: incidence, mechanisms and management". Journal of Hepatology. 44 (1 Suppl): S132–S139. doi:10.1016/j.jhep.2005.11.027. PMID 16364487.

[18] Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, et al. (October 2001). "Mechanism of indinavir-induced hyperbilirubinemia". Proceedings of the National Academy of Sciences of the United States of America. 98 (22): 12671–12676. Bibcode:2001PNAS...9812671Z. doi:10.1073/pnas.231140698. PMC 60112. PMID 11606755.

[19] Tamir Z, Alemu J, Tsegaye A (January 2018). "Anemia among HIV Infected Individuals Taking ART with and without Zidovudine at Addis Ababa, Ethiopia". Ethiopian Journal of Health Sciences. 28 (1): 73–82. doi:10.4314/ejhs.v28i1.9. PMC 5866291. PMID 29622909.

[20] Ghodke Y, Anderson PL, Sangkuhl K, Lamba J, Altman RB, Klein TE (December 2012). "PharmGKB summary: zidovudine pathway". Pharmacogenetics and Genomics. 22 (12): 891–894. doi:10.1097/FPC.0b013e32835879a8. PMC 3696524. PMID 22960662.

[21] Claessens YE, Chiche JD, Mira JP, Cariou A (June 2003). "Bench-to-bedside review: severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors". Critical Care. 7 (3): 226–232. doi:10.1186/cc2162. PMC 270672. PMID 12793872.

[22] Stainsby CM, Perger TM, Vannappagari V, Mounzer KC, Hsu RK, Henegar CE, et al. (January 2019). "Abacavir Hypersensitivity Reaction Reporting Rates During a Decade of HLA-B*5701 Screening as a Risk-Mitigation Measure". Pharmacotherapy. 39 (1): 40–54. doi:10.1002/phar.2196. PMC 6590466. PMID 30414209.

[23] Bain LE, Nkoke C, Noubiap JJ (March 2017). "UNAIDS 90-90-90 targets to end the AIDS epidemic by 2020 are not realistic: comment on "Can the UNAIDS 90-90-90 target be achieved? A systematic analysis of national HIV treatment cascades"". BMJ Global Health. 2 (2): e000227. doi:10.1136/bmjgh-2016-000227. PMC 5435269. PMID 28589026.

[24] Lin D, Li WK, Rieder MJ, et al. (Cochrane HIV/AIDS Group) (April 2007). "Cotrimoxazole for prophylaxis or treatment of opportunistic infections of HIV/AIDS in patients with previous history of hypersensitivity to cotrimoxazole". The Cochrane Database of Systematic Reviews (2): CD005646. doi:10.1002/14651858.CD005646.pub2. PMID 17443608.

[25] Lorber M, Haddad S (January 2013). "Hypersensitivity and desensitization to darunavir in a case of HIV infection with triple-class drug resistance: case description and review of the literature". Journal of the International Association of Providers of AIDS Care. 12 (6): 378–379. doi:10.1177/2325957413488189. PMID 23778241. S2CID 44812281.

[26] Yunihastuti E, Widhani A, Karjadi TH (January 2014). "Drug hypersensitivity in human immunodeficiency virus-infected patient: challenging diagnosis and management". Asia Pacific Allergy. 4 (1): 54–67. doi:10.5415/apallergy.2014.4.1.54. PMC 3921866. PMID 24527412.

[27] Coughlan R, Cameron S (January 2016). "Key data from the 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV". Antiviral Therapy. 21 (1): 75–89. doi:10.3851/IMP3031. PMID 26857256. S2CID 32178281.

[Back_2020-28] Back D, Marzolini C (February 2020). "The challenge of HIV treatment in an era of polypharmacy". Journal of the International AIDS Society. 23 (2): e25449. doi:10.1002/jia2.25449. PMC 6996317. PMID 32011104.

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 === Immune-mediated drug hypersensitivity ===
-Commonly prescribed medications for HIV, such as sulfonamides, anticonvulsants, antibacterials, antifungals, antimycobacterials, and, most notably, antiretrovirals, have an increased incidence of adverse [[Skin|cutaneous]] drug reactions in HIV-positive individuals, and even greater escalation of incidence in people with advanced disease progression in the form of [[HIV/AIDS|AIDS]].<ref>{{Cite journal |last=Hoosen |first=Koraisha |last2=Mosam |first2=Anisa |last3=Dlova |first3=Ncoza Cordelia |last4=Grayson |first4=Wayne |date=2019-06-26 |title=An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS |url=https://www.karger.com/Article/FullText/496389 |journal=Dermatopathology |language=en |volume=6 |issue=2 |pages=111–125 |doi=10.1159/000496389 |issn=2296-3529|pmc=6827458 }}</ref> 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 [[Polypharmacy|poly-pharmacy]], slow acetylator status, glutathione deficiency, etc.<ref>{{Cite journal |last=Hoosen |first=Koraisha |last2=Mosam |first2=Anisa |last3=Dlova |first3=Ncoza Cordelia |last4=Grayson |first4=Wayne |date=2019-06-26 |title=An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS |url=https://www.karger.com/Article/FullText/496389 |journal=Dermatopathology |language=en |volume=6 |issue=2 |pages=111–125 |doi=10.1159/000496389 |issn=2296-3529|pmc=6827458 }}</ref><ref>{{Cite journal |last=van der Ven |first=A.J.Am. |last2=Koopmans |first2=P.P. |last3=van der Meer |first3=J.W.M. |last4=Vree |first4=T.B. |date=August 1991 |title=Adverse reactions to co-trimoxazole in HIV infection |url=https://linkinghub.elsevier.com/retrieve/pii/014067369191046W |journal=The Lancet |language=en |volume=338 |issue=8764 |pages=431–433 |doi=10.1016/0140-6736(91)91046-W|hdl=2066/14860 |hdl-access=free }}</ref> 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 cell|T-helper cells]]. There is no single defined cause for this association.
+Commonly prescribed medications for HIV, such as sulfonamides, anticonvulsants, antibacterials, antifungals, antimycobacterials, and, most notably, antiretrovirals, have an increased incidence of adverse [[Skin|cutaneous]] drug reactions in HIV-positive individuals, and even greater escalation of incidence in people with advanced disease progression in the form of [[HIV/AIDS|AIDS]].<ref>{{Cite journal |last1=Hoosen |first1=Koraisha |last2=Mosam |first2=Anisa |last3=Dlova |first3=Ncoza Cordelia |last4=Grayson |first4=Wayne |date=2019-06-26 |title=An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS |url=https://www.karger.com/Article/FullText/496389 |journal=Dermatopathology |language=en |volume=6 |issue=2 |pages=111–125 |doi=10.1159/000496389 |pmid=31700852 |issn=2296-3529|pmc=6827458 }}</ref> 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 [[Polypharmacy|poly-pharmacy]], slow acetylator status, glutathione deficiency, etc.<ref>{{Cite journal |last1=Hoosen |first1=Koraisha |last2=Mosam |first2=Anisa |last3=Dlova |first3=Ncoza Cordelia |last4=Grayson |first4=Wayne |date=2019-06-26 |title=An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS |url=https://www.karger.com/Article/FullText/496389 |journal=Dermatopathology |language=en |volume=6 |issue=2 |pages=111–125 |doi=10.1159/000496389 |pmid=31700852 |issn=2296-3529|pmc=6827458 }}</ref><ref>{{Cite journal |last1=van der Ven |first1=A.J.Am. |last2=Koopmans |first2=P.P. |last3=van der Meer |first3=J.W.M. |last4=Vree |first4=T.B. |date=August 1991 |title=Adverse reactions to co-trimoxazole in HIV infection |url=https://linkinghub.elsevier.com/retrieve/pii/014067369191046W |journal=The Lancet |language=en |volume=338 |issue=8764 |pages=431–433 |doi=10.1016/0140-6736(91)91046-W|pmid=1678095 |hdl=2066/14860 |s2cid=205037568 |hdl-access=free }}</ref> 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 cell|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.<ref>{{Cite journal |last=Hoosen |first=Koraisha |last2=Mosam |first2=Anisa |last3=Dlova |first3=Ncoza Cordelia |last4=Grayson |first4=Wayne |date=2019-06-26 |title=An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS |url=https://www.karger.com/Article/FullText/496389 |journal=Dermatopathology |language=en |volume=6 |issue=2 |pages=111–125 |doi=10.1159/000496389 |issn=2296-3529 |pmc=6827458 |pmid=31700852}}</ref> A [[Retrospective cohort study|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. <ref>{{Cite journal |last=Chang |first=Hui-Min |last2=Tsai |first2=Hung-Chin |last3=Lee |first3=Susan Shin-Jung |last4=Kunin |first4=Calvin |last5=Lin |first5=Pei-Chin |last6=Wann |first6=Shue-Ren |last7=Chen |first7=Yao-Shen |date=June 2016 |title=High daily doses of trimethoprim/sulfamethoxazole are an independent risk factor for adverse reactions in patients with pneumocystis pneumonia and AIDS |url=https://journals.lww.com/02118582-201606000-00005 |journal=Journal of the Chinese Medical Association |language=en |volume=79 |issue=6 |pages=314–319 |doi=10.1016/j.jcma.2016.01.007 |issn=1726-4901|doi-access=free }}</ref>
+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.<ref>{{Cite journal |last1=Hoosen |first1=Koraisha |last2=Mosam |first2=Anisa |last3=Dlova |first3=Ncoza Cordelia |last4=Grayson |first4=Wayne |date=2019-06-26 |title=An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS |url=https://www.karger.com/Article/FullText/496389 |journal=Dermatopathology |language=en |volume=6 |issue=2 |pages=111–125 |doi=10.1159/000496389 |issn=2296-3529 |pmc=6827458 |pmid=31700852}}</ref> A [[Retrospective cohort study|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. <ref>{{Cite journal |last1=Chang |first1=Hui-Min |last2=Tsai |first2=Hung-Chin |last3=Lee |first3=Susan Shin-Jung |last4=Kunin |first4=Calvin |last5=Lin |first5=Pei-Chin |last6=Wann |first6=Shue-Ren |last7=Chen |first7=Yao-Shen |date=June 2016 |title=High daily doses of trimethoprim/sulfamethoxazole are an independent risk factor for adverse reactions in patients with pneumocystis pneumonia and AIDS |url=https://journals.lww.com/02118582-201606000-00005 |journal=Journal of the Chinese Medical Association |language=en |volume=79 |issue=6 |pages=314–319 |doi=10.1016/j.jcma.2016.01.007 |pmid=27025225 |issn=1726-4901|doi-access=free }}</ref>
 === Drug-induced liver injury ===
-The use of [[Antiretroviral|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.<ref>{{Cite journal |last=Pillaye |first=Jamie N. |last2=Marakalala |first2=Mohlopheni J. |last3=Khumalo |first3=Nonhlanhla |last4=Spearman |first4=Wendy |last5=Ndlovu |first5=Hlumani |date=August 2020 |title=Mechanistic insights into antiretroviral drug‐induced liver injury |url=https://onlinelibrary.wiley.com/doi/10.1002/prp2.598 |journal=Pharmacology Research & Perspectives |language=en |volume=8 |issue=4 |doi=10.1002/prp2.598 |issn=2052-1707 |pmc=7344109 |pmid=32643320}}</ref> 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 [[Hepatotoxicity|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. <ref>{{Cite journal |last=Pillaye |first=Jamie N. |last2=Marakalala |first2=Mohlopheni J. |last3=Khumalo |first3=Nonhlanhla |last4=Spearman |first4=Wendy |last5=Ndlovu |first5=Hlumani |date=August 2020 |title=Mechanistic insights into antiretroviral drug‐induced liver injury |url=https://onlinelibrary.wiley.com/doi/10.1002/prp2.598 |journal=Pharmacology Research & Perspectives |language=en |volume=8 |issue=4 |doi=10.1002/prp2.598 |issn=2052-1707 |pmc=7344109 |pmid=32643320}}</ref>
+The use of [[Antiretroviral|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.<ref>{{Cite journal |last1=Pillaye |first1=Jamie N. |last2=Marakalala |first2=Mohlopheni J. |last3=Khumalo |first3=Nonhlanhla |last4=Spearman |first4=Wendy |last5=Ndlovu |first5=Hlumani |date=August 2020 |title=Mechanistic insights into antiretroviral drug‐induced liver injury |journal=Pharmacology Research & Perspectives |language=en |volume=8 |issue=4 |pages=e00598 |doi=10.1002/prp2.598 |issn=2052-1707 |pmc=7344109 |pmid=32643320}}</ref> 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 [[Hepatotoxicity|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. <ref>{{Cite journal |last1=Pillaye |first1=Jamie N. |last2=Marakalala |first2=Mohlopheni J. |last3=Khumalo |first3=Nonhlanhla |last4=Spearman |first4=Wendy |last5=Ndlovu |first5=Hlumani |date=August 2020 |title=Mechanistic insights into antiretroviral drug‐induced liver injury |journal=Pharmacology Research & Perspectives |language=en |volume=8 |issue=4 |pages=e00598 |doi=10.1002/prp2.598 |issn=2052-1707 |pmc=7344109 |pmid=32643320}}</ref>
-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/emtricitabine/tenofovir|efavirenz/tenofovir disoproxil fumarate/emtricitabine]] fixed‐dose combination.<ref>{{Cite journal |last=Pillaye |first=Jamie N. |last2=Marakalala |first2=Mohlopheni J. |last3=Khumalo |first3=Nonhlanhla |last4=Spearman |first4=Wendy |last5=Ndlovu |first5=Hlumani |date=August 2020 |title=Mechanistic insights into antiretroviral drug‐induced liver injury |url=https://onlinelibrary.wiley.com/doi/10.1002/prp2.598 |journal=Pharmacology Research & Perspectives |language=en |volume=8 |issue=4 |doi=10.1002/prp2.598 |issn=2052-1707 |pmc=7344109 |pmid=32643320}}</ref><ref>{{Cite journal |last=Sonderup |first=Mark W. |last2=Wainwright |first2=Helen |last3=Hall |first3=Pauline |last4=Hairwadzi |first4=Henry |last5=Spearman |first5=C. Wendy N. |date=May 2015 |title=A clinicopathological cohort study of liver pathology in 301 patients with human immunodeficiency virus/acquired immune deficiency syndrome |url=https://journals.lww.com/01515467-201505000-00031 |journal=Hepatology |language=en |volume=61 |issue=5 |pages=1721–1729 |doi=10.1002/hep.27710 |issn=0270-9139}}</ref> Other reported risk factors for drug induced liver injury are female gender, young age, and high CD4+ count of >200 cells/mm3.<ref>{{Cite journal |last=Sonderup |first=Mark W. |last2=Wainwright |first2=Helen |last3=Hall |first3=Pauline |last4=Hairwadzi |first4=Henry |last5=Spearman |first5=C. Wendy N. |date=May 2015 |title=A clinicopathological cohort study of liver pathology in 301 patients with human immunodeficiency virus/acquired immune deficiency syndrome |url=https://journals.lww.com/01515467-201505000-00031 |journal=Hepatology |language=en |volume=61 |issue=5 |pages=1721–1729 |doi=10.1002/hep.27710 |issn=0270-9139}}</ref> All classes of antiretroviral medications could cause drug induced liver injury, but some classes of medications may be more toxic than others.<ref>{{Cite journal |last=Pillaye |first=Jamie N. |last2=Marakalala |first2=Mohlopheni J. |last3=Khumalo |first3=Nonhlanhla |last4=Spearman |first4=Wendy |last5=Ndlovu |first5=Hlumani |date=August 2020 |title=Mechanistic insights into antiretroviral drug‐induced liver injury |url=https://onlinelibrary.wiley.com/doi/10.1002/prp2.598 |journal=Pharmacology Research & Perspectives |language=en |volume=8 |issue=4 |doi=10.1002/prp2.598 |issn=2052-1707 |pmc=7344109 |pmid=32643320}}</ref><ref>{{Cite journal |last=Yimer |first=Getnet |last2=Gry |first2=Marcus |last3=Amogne |first3=Wondwossen |last4=Makonnen |first4=Eyasu |last5=Habtewold |first5=Abiy |last6=Petros |first6=Zelalem |last7=Aderaye |first7=Getachew |last8=Schuppe-Koistinen |first8=Ina |last9=Lindquist |first9=Lars |last10=Aklillu |first10=Eleni |date=2014-04-08 |editor-last=Vermund |editor-first=Sten H. |title=Evaluation of Patterns of Liver Toxicity in Patients on Antiretroviral and Anti-Tuberculosis Drugs: A Prospective Four Arm Observational Study in Ethiopian Patients |url=https://dx.plos.org/10.1371/journal.pone.0094271 |journal=PLoS ONE |language=en |volume=9 |issue=4 |pages=e94271 |doi=10.1371/journal.pone.0094271 |issn=1932-6203 |pmc=3979833 |pmid=24714066}}</ref> Further research is needed to better understand and analyze any potential differences in risk levels between these classes of antiretrovirals.
+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/emtricitabine/tenofovir|efavirenz/tenofovir disoproxil fumarate/emtricitabine]] fixed‐dose combination.<ref>{{Cite journal |last1=Pillaye |first1=Jamie N. |last2=Marakalala |first2=Mohlopheni J. |last3=Khumalo |first3=Nonhlanhla |last4=Spearman |first4=Wendy |last5=Ndlovu |first5=Hlumani |date=August 2020 |title=Mechanistic insights into antiretroviral drug‐induced liver injury |journal=Pharmacology Research & Perspectives |language=en |volume=8 |issue=4 |pages=e00598 |doi=10.1002/prp2.598 |issn=2052-1707 |pmc=7344109 |pmid=32643320}}</ref><ref>{{Cite journal |last1=Sonderup |first1=Mark W. |last2=Wainwright |first2=Helen |last3=Hall |first3=Pauline |last4=Hairwadzi |first4=Henry |last5=Spearman |first5=C. Wendy N. |date=May 2015 |title=A clinicopathological cohort study of liver pathology in 301 patients with human immunodeficiency virus/acquired immune deficiency syndrome |url=https://journals.lww.com/01515467-201505000-00031 |journal=Hepatology |language=en |volume=61 |issue=5 |pages=1721–1729 |doi=10.1002/hep.27710 |pmid=25644940 |s2cid=5062159 |issn=0270-9139}}</ref> Other reported risk factors for drug induced liver injury are female gender, young age, and high CD4+ count of >200 cells/mm3.<ref>{{Cite journal |last1=Sonderup |first1=Mark W. |last2=Wainwright |first2=Helen |last3=Hall |first3=Pauline |last4=Hairwadzi |first4=Henry |last5=Spearman |first5=C. Wendy N. |date=May 2015 |title=A clinicopathological cohort study of liver pathology in 301 patients with human immunodeficiency virus/acquired immune deficiency syndrome |url=https://journals.lww.com/01515467-201505000-00031 |journal=Hepatology |language=en |volume=61 |issue=5 |pages=1721–1729 |doi=10.1002/hep.27710 |pmid=25644940 |s2cid=5062159 |issn=0270-9139}}</ref> All classes of antiretroviral medications could cause drug induced liver injury, but some classes of medications may be more toxic than others.<ref>{{Cite journal |last1=Pillaye |first1=Jamie N. |last2=Marakalala |first2=Mohlopheni J. |last3=Khumalo |first3=Nonhlanhla |last4=Spearman |first4=Wendy |last5=Ndlovu |first5=Hlumani |date=August 2020 |title=Mechanistic insights into antiretroviral drug‐induced liver injury |journal=Pharmacology Research & Perspectives |language=en |volume=8 |issue=4 |pages=e00598 |doi=10.1002/prp2.598 |issn=2052-1707 |pmc=7344109 |pmid=32643320}}</ref><ref>{{Cite journal |last1=Yimer |first1=Getnet |last2=Gry |first2=Marcus |last3=Amogne |first3=Wondwossen |last4=Makonnen |first4=Eyasu |last5=Habtewold |first5=Abiy |last6=Petros |first6=Zelalem |last7=Aderaye |first7=Getachew |last8=Schuppe-Koistinen |first8=Ina |last9=Lindquist |first9=Lars |last10=Aklillu |first10=Eleni |date=2014-04-08 |editor-last=Vermund |editor-first=Sten H. |title=Evaluation of Patterns of Liver Toxicity in Patients on Antiretroviral and Anti-Tuberculosis Drugs: A Prospective Four Arm Observational Study in Ethiopian Patients |journal=PLOS ONE |language=en |volume=9 |issue=4 |pages=e94271 |doi=10.1371/journal.pone.0094271 |issn=1932-6203 |pmc=3979833 |pmid=24714066 |bibcode=2014PLoSO...994271Y |doi-access=free }}</ref> Further research is needed to better understand and analyze any potential differences in risk levels between these classes of antiretrovirals.
 {| class="wikitable sortable"
 |+Table of antiretroviral medications with a known adverse drug reaction in HIV-positive people.<ref name="Pillaye_2020">{{cite journal |vauthors=Pillaye JN, Marakalala MJ, Khumalo N, Spearman W, Ndlovu H |date=August 2020 |title=Mechanistic insights into antiretroviral drug-induced liver injury |journal=Pharmacology Research & Perspectives |volume=8 |issue=4 |pages=e00598 |doi=10.1002/prp2.598 |pmc=7344109 |pmid=32643320}}</ref>
@@ Line 59: / Line 59: @@
 Blood smears in cases zidovudine-related anemia usually show a megaloblastic macrocytic anemia associated with the vitamin B12 and folic acid deficiency and the mechanism of how these occur is still unknown.
-Diagnosis of nucleoside reverse transcriptase inhibitor (NRTI) related lactic acidosis:<ref>{{cite journal | vauthors = Claessens YE, Chiche JD, Mira JP, Cariou A | title = Bench-to-bedside review: severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors | journal = Critical Care | volume = 7 | issue = 3 | pages = 226–232 | date = June 2003 | pmid = 12793872 | pmc = 270672 | doi = 10.1186/cc2162 }}</ref> The NRTI can increase lactate production by disrupting the normal mitochondrial metabolic pathway and the NAD+/NADH cycle. These impair the lipid beta-oxidation and oxidative phosphorylation, and long chain fatty acids are unable to be broken down so that the preferred metabolic pathway for oxidation is changed to glycolysis. Glycolysis produces excessive lactic acid, leading to the lactic acidosis.
+Diagnosis of nucleoside reverse transcriptase inhibitor (NRTI) related lactic acidosis:<ref>{{cite journal | vauthors = Claessens YE, Chiche JD, Mira JP, Cariou A | title = Bench-to-bedside review: severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors | journal = Critical Care | volume = 7 | issue = 3 | pages = 226–232 | date = June 2003 | pmid = 12793872 | pmc = 270672 | doi = 10.1186/cc2162 | doi-access = free }}</ref> The NRTI can increase lactate production by disrupting the normal mitochondrial metabolic pathway and the NAD+/NADH cycle. These impair the lipid beta-oxidation and oxidative phosphorylation, and long chain fatty acids are unable to be broken down so that the preferred metabolic pathway for oxidation is changed to glycolysis. Glycolysis produces excessive lactic acid, leading to the lactic acidosis.
 Test results that indicate lactic acidosis, are: