Clinical management guidelines for toxicities related to antiretrovirals

Anaemia

Background Anaemia is divided into three broad groups; anaemia caused by blood loss, anaemia caused by decreased or faulty red blood cell production and anaemia caused by destruction of red blood cells. Diminished production or increased destruction of red cells causes a hypochromic microcytic anaemia. Vitamin B12 or folate deficiency causes a macrocytic anaemia. In the setting of HIV infection in resource limited settings, common causes of anaemia are HIV itself, malaria, infection with Mycobacterium tuberculosis, mycobacterium avium complex (MAC), neoplasms and myelotoxic agents such as AZT cotrimoxazole, dapsone, amphotericin B. and pyrimethamine.(5)

Definitions Anaemia is a decrease of the haemoglobin concentration below the normal limits for CIOMS sex, age and altitude CIOMS requirements for use of Blood test findings satisfying the definition the term Anaemia is a decrease in the number of red blood cells per mm3, the amount of haemoglobin in 100 ml of blood, and/or the volume of packed red blood cells per 100 Expanded definition ml of blood (haematocrit) below the normal limits for sex, age and altitude. The lower limits are 12.0 g/dL in females and 13 g/dL in males, with local (geographic and ethnic) variations in established values.(1)

Categories and causes Major causative ARVs Zidovudine (AZT) also causes neutropenia and pancytopenia Hemoglobinopathies, thalassemias, congenital dyserythropoietic anaemia, hereditary Genetic/metabolic xerocytosis, abetalipoproteinemia, Fanconi anaemia, glucose‐6‐phosphate dehydrogenase deficiency Nutritional Iron deficiency, vitamin b‐12 deficiency, folate deficiency, malnutrition Immunological Antibody‐mediated abnormalities Physical Haemorrhage, burns, prosthetic valves and surfaces Drugs and chemicals Aplastic anaemia, megaloblastic anaemia Chronic diseases Renal disease, hepatic disease, collagen vascular diseases Malignancies Myelodysplastic neoplasims Viral HIV, hepatitis, infectious mononucleosis, cytomegalovirus Infections Protozoal malaria, leishmaniasis, toxoplasmosis Bacterial MAC, TB, clostridia, gram‐negative sepsis Other Thrombotic thrombocytopenic purpura and haemolytic uremic syndrome

Presentation and diagnosis The signs and symptoms depend on the degree of anaemia, the rapidity of its onset and the age of the patient .Pallor of skin and mucous membranes, shortness of breath, Clinical dizziness, lethargy, pulmonary oedema, heart failure and impairment of cognitive function. HB < 12.0 g/dL in females and 13 g/dL in males, with (geographic and ethnic) variations. Laboratory Macrocytosis, neutropaenia, pancytopaenia Five to ten percent of patients taking AZT develop anaemia (all grades), usually during the first 3 months of therapy, but sometimes even after years on treatment (Carr 2001, Frequency DART,) In Cambodia, 527 people in an ARV program were all switch from d4T to AZT. The incidence of any anaemia (grade 1‐4) was 21.9% with 7.1% experiencing severe anaemia (grade 3/4) Anaemia may present as early as 2 to 4 weeks but can occur after years on treatment.(Carr 2001) Neutropenia usually occurs after 6 to 8 weeks.(2) In the DART study, median haemoglobin was lowest at week 4, but then increased by a median 0.6 g/dl by 24 weeks after ART initiation, and continued rising thereafter. Timing relative to initiating ART Prevalence of grade 4 anaemia peaked at week 12 (2.0%), and declined at subsequent assessments [3]. In a meta analysis of six published studies, the mean decreases in haemoglobin in subjects receiving AZT for 24 and 48 weeks were 0.4 g/dL and 0.2 g/dL respectively [5]. Hematologic toxicities of AZT are related to pre‐treatment bone marrow reserve and to Risk Factors dose and duration of therapy. Specifically, risk factors are advanced HIV disease,

opportunistic infections associated with anaemia such as Mycobacterium Tuberculosis and Mycobacterium Avium Complex (MAC), injecting drug use, higher dose AZT (WHO recommend doses are 300mg BID or 250 mg BID), pre‐existing anaemia or neutropaenia, concomitant use of bone marrow suppressants (cotrimoxazole, ganciclovir, anti–tuberculosis therapy) or drugs that cause haemolytic anaemia (ribavirin).

Grading and clinical management Grade 1 2 3 4 Toxicity grading DAIDS (g/dL) 8.5 ‐ 10.0 7.5 ‐ 8.4 6.5 ‐ 7.4 <6.5 WHO (g/dL) 8.0 ‐ 9.4 7.0 ‐ 7.9 6.5 ‐ 6.9 <6.5 Continue AZT Substitute Substitute Substitute Grade‐driven response with monthly another NRTI if another NRTI another NRTI Hb monitoring available Transfusion Significant anaemia (haemoglobin <7.5 g/dL or reduction >25% of baseline) and/or significant neutropaenia (granulocyte count <750 cells/mm3 or reduction >50% from baseline) require a dose temporary or permanent interruption of AZT until evidence of marrow recovery is observed. Blood transfusion for grade 4 anaemia or as clinically indicated (such as if the patient is symptomatic with shortness of breath, cardiac decomposition, severe lethargy) in addition to interruption of AZT. Principles of care The choices of alternative NRTIs are d4T, ddI, abacavir and tenofovir Identify and treat other causes of anaemia Substitution of the drug causing the toxicity within first line ART regimen is recommended. It is not necessary to substitute other drugs (such as the accompanying NNRTI if is tolerated) There are insufficient data to guide dose reduction of AZT below the minimum WHO‐ recommended dose of 250 mg BID. Avoid AZT use in patients at risk Prevention Check haemoglobin prior to initiation of AZT therapy whenever possible Avoid bone marrow suppressants if possible in patients receiving AZT Monitor complete blood count (CBC) or HB or Haematocrit after the 1st few weeks, Monitoring then at least every 3 months (more frequently in patients at risk), In the absence of other causes, anaemia should resolve with cessation of AZT with or Reversibility without transfusion.

Notes on specific populations In general, the prevalence of birth defects per 100 live births among women with a first trimester exposure to any of the antiretroviral therapies included in the Antiretroviral Pregnancy Registry was 2.9 (95% confidence interval 2.4‐3.4) or 130 outcomes with defects of 4 530 live births. The prevalence of defects is not significantly different from Pregnancy and breast feeding the prevalence of defects among women with the first exposure during the second (Pregnancy Category C) and/or third trimester (2.5 per 100 live births) (prevalence ratio: 1.15, 95% CI: 0.91, 1.45).* For 3TC and AZT sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5‐fold increase in risk of overall birth defects and a 2‐ fold increase in risk of birth defects in the more common classes, cardiovascular and genitourinary systems. No such increases have been detected to date. AZT/3TC is the preferred NRTI option for pregnant women and has the most safety and efficacy data for both mother and newborn.(3) In post marketing studies of AZT for the prevention of mother to child transmission of HIV, there were no differences in pregnancy‐related adverse events among women receiving AZT and control groups.(4) AZT during pregnancy reduces the rate of mother to child transmission of HIV‐1 from 24.9% for infants born to placebo‐treated mothers to 7.8% for infants born to mothers PMCT treated with AZT. There have been no differences in pregnancy‐related adverse events between the treatment groups.(9) Toxicity of infant AZT prophylaxis consists primarily of transient hematologic toxicity, mainly anaemia, which generally resolves by age 12 weeks.(5) In two studies of AZT (plus 3TC) provided for six weeks as prophylaxis to infants, who were also exposed to ante partum AZT, anaemia was observed 15% and 69% of infants.(6‐7)

AZT–induced anaemia in the context of TB and TB therapy is uncommonly reported possibly because most physicians and ARV programs preferentially use d4T in patients Tuberculosis on TB therapy due to the overlapping haematological toxicities of AZT and TB therapy. One study from Uganda reported 2.9% anaemia (ACTG grade 4) in 34 patients receiving TB therapy and an AZT‐containing ARV regimen. (Srikantiah) In South America, treatment limiting AZT induced haematological toxicity was reported as 5% in Haiti (Severe) and 6.9% in Chile (Wolff). In Asia, one study from Thailand reported 3.6% severe anaemia (ACTG grade 4) (Nuesch) and another from India 2.9% treatment limiting anaemia. (Kumaraswamy) In Africa, treatment limiting anaemia in studies from Cote d’Ivoire was reported as 2% (Seyler) and 2.2% (Danel) 3.8% (Fassinou), 2.8% in Cameroon (Bourgeois), 3% in Kenya ((Wamalwa), 4.% in Botswana Regional or ethnic issues (Wester), 7% in the DART study in Uganda and Zimbabwe (DART virology study group), and 6.3 % (DAIDS grade3/4) in one study from Senegal, Cote d’Ivoire, Uganda and Kenya.(Sow) By the same author, any anaemia (>ACTG grade 1) occurred among 3 314 patients in a study from Uganda and Zimbabwe, with 6.6% of these being treatment limiting.(Sow) Ferradini et reported higher rates (7.8%) of treatment limiting anaemia in Malawi. *Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2009. Wilmington, NC: Registry Coordinating Center; 2008. Available from URL: www.APRegistry.com. http://www.apregistry.com/forms/interim_report.pdf (access 20/10/09)

Algorithm: Clinical management of anaemia

Acute pancreatitis

Background Pancreatitis is acute or chronic inflammation of the pancreas, which may be chemical (asymptomatic with elevation in lipase and/or amylase) or clinical (symptomatic with elevation in lipase and/or amylase), and which is due to auto‐digestion of pancreatic tissue by its own enzymes. Drug‐induced pancreatitis is usually an acute condition. Although in about 80% of cases the disease is mild, severe attacks may lead to shock with renal and pulmonary insufficiency, which may be fatal. In non‐fatal cases, clinical, morphological and functional recovery usually occurs. Chronic pancreatitis is in most cases characterized by recurrent or persisting abdominal pain. The diagnosis cannot be satisfactorily established unless there is evidence of persistent morphological change or pancreatic insufficiency, manifested by, for example, steatorrhoea or diabetes mellitus. Pancreatic enzymes in blood or urine are usually increased during attacks of acute pain, but usually to a less extent than in acute pancreatitis.

Definitions CIOMS Acute pancreatitis is an inflammatory disease of the pancreas, characterized by abdominal pain, frequently severe and of sudden onset, and almost always accompanied by increased pancreatic enzymes. CIOMS requirements for 1. Upper abdominal pain, severe and sudden, usually accompanied by vomiting, in severe use of the term cases by abdominal guarding, rigidity, rebound tenderness and diminution or loss of bowel sounds; AND 2. Increased pancreatic enzymes in the blood. Lipase is more specific than amylase, but an increase in either enzyme to at least twice the level of normal is significant. 3. Confirmatory investigations. Whenever possible, the diagnosis should be confirmed by ultrasonography or computerized tomography (CT), or other imaging techniques. Basic requirements for use of the term chronic pancreatitis The presence of two of the following three manifestations: 1. Persistent impairment of pancreatic exocrine function (clinically suspected by weight loss and signs of malabsorption) as demonstrated by appropriate tests. 2. Confirmation of morphological change in the pancreas, demonstrated by imaging. 3. Abdominal or referred pain with or without pancreatic‐enzyme changes.

Categories and causes Major causative ARVs Pancreatitis is most frequently associated with ddI and d4T.(3) Genetic/metabolic Autoimmune pancreatitis, cystic fibrosis, autoimmune disorders such as Sjögren syndrome, primary biliary cirrhosis, and renal tubular acidosis. Physical Intraductal plugging and obstruction (e.g., stones, tumours), Ischemia (from obstruction and fibrosis), abdominal trauma Drugs and chemicals • Long‐standing alcohol consumption • Medications, including azathioprine, corticosteroids, sulfonamides, thiazides, furosemides, nonsteroidal anti‐inflammatory drugs, methyldopa, and tetracyclines, • Tropical sprue Chronic diseases • Hepatitis • Biliary disease • Hypertriglyceridemia (>1000 mg/U) Malignancies Pancreatic cancer Infections • Viral infections, including HIV, mumps, coxsackievirus, cytomegalovirus (CMV), hepatitis virus, Epstein‐Barr virus (EBV), and rubella • Bacterial infections, such as mycoplasma • Intestinal parasites, such as Ascaris, which can block the pancreatic outflow Other • Idiopathic pancreatitis, lactic acidosis

Presentation and diagnosis Clinical diagnosis The main presentation of acute pancreatitis is epigastric pain or right upper quadrant pain radiating through, rather than around, to the back associated with nausea and vomiting. Other signs and symptoms include fever, tachycardia, tachypnea, hypotension, abdominal tenderness, distension, guarding, and rigidity, jaundice, diminished or absent bowel sounds. Laboratory diagnosis The principal enzyme abnormality used for making a diagnosis of pancreatitis is lipase level, as

this is the most specific.(31) Amylase levels, preferably pancreatic amylase, can be used. In patients with chronic pancreatitis, lipase levels may be elevated in the presence of a normal serum amylase level. X‐ray (patient in the upright position) may show air under the diaphragm due to viscous perforation or calcification (chronic pancreatitis). Ultrasound (or CT) may demonstrate focal or diffuse gland enlargement or the presence of pseudocysts and pancreatic abscesses. Differential diagnoses Abdominal aneurysm, hepatitis, cholangitis, cholelithiasis, cholecystitis and biliary colic, mesenteric ischemia large or small bowel obstruction, obstruction, gastroenteritis, perforated viscous, acute peritonitis, pancreatic cancer, malabsorption syndromes Frequency 1% to 7% increased risk with ddI Timing relative to Time of presentation is typically weeks to months after commencing ART. initiating ART Risk factors History of pancreatitis and/or alcoholism, severe hypertriglyceridemia, concomitant use of ddI with tenofovir without ddI dose reduction, female gender and CD4 count <50 cells/mm3 (32)

Grading and clinical management 1 2 3 4 Asymptomatic. Symptomatic plus Symptomatic plus Life threatening Enzyme elevation medical intervention medical intervention consequences (e.g., Clinical and/or radiographic required with hospitalization circulatory failure, findings consistent required haemorrhage, sepsis) with pancreatitis Elevated lipase, amylase or >1.0 – 1.5 X ULN >1.5 – 2.0 X ULN >2.0 ‐ 5.0 X ULN >5.0 X ULN pancreatic amylase Principles of care The goals of medical treatment are to modify the factors which exacerbate the natural history of the disease, to enable the pancreas to heal itself. Prevention ddI should not be used in patients with history of pancreatitis. Avoid concomitant use of ddI with d4T, tenofovir or ribavirin. Reduce ddI dose when used with TDF. Treat severe hypertriglyceridaemia.(3) Monitoring Monitoring of amylase/lipase in asymptomatic patients is not recommended

Specific populations Pregnancy Pancreatitis is a rare event in pregnancy, occurring in approximately 3 in 10 000 pregnancies. Although it is most often acute and related to gallstones, non‐biliary causes (alcohol and idiopathic) should be sought because they are associated with worse outcomes. Paediatric Pancreatitis, although uncommon during childhood, is associated with significant morbidity and mortality. The predominant causes include abdominal trauma (23%), anomalies of the pancreaticobiliary system (15%), multisystem disease (14%), drugs and toxins (12%), viral infections (10%), hereditary disorders (2%), and metabolic disorders (2%). In up to 25% of cases the etiology of childhood pancreatitis is unknown.

Lipoatrophy

Background HIV‐associated lipodystrophy is a syndrome that occurs in individuals treated with antiretroviral medications. The term lipodystrophy refers to abnormal central fat accumulation (lipohypertrophy) and localized loss of fat tissue (lipoatrophy), some patients have only lipohypertrophy, some have only lipoatrophy and many have a mixed clinical presentation. Lipoatrophy results from mitochondrial toxicity via inhibition of the human DNA polymerase gamma.(40‐41)

Definitions ACTG appendix 60 Lipoatrophy is loss of subcutaneous fat and has been described as a part of a syndrome of altered fat distribution (lipodystrophy) in HIV‐infected persons treated with combination ART. HIV‐treatment‐associated lipoatrophy involves loss of peripheral subcutaneous fat in the face, arms, legs, or buttocks and may be seen independently or in conjunction with visceral fat accumulation and other body shape changes. Lipoatrophy is generally considered to be one of the three components of the lipodystrophy syndrome, the other two being lipohypertrophy (fat accumulation) and metabolic disturbances (insulin resistance, hypercholesterolaemia and hypertriglyceridaemia).(42‐44) It can also occur in isolation.(44) Expanded definition Patient may report sunken cheeks or drawn face or indicate that family members or friends have noticed such changes. The loss of facial tissue is proximal to the nasolabial fold. Patient reports that extremities and buttocks appear thinner since the initiation or change of antiretroviral therapy and/or awareness that veins in the extremities appear more prominent. On examination, extremities appear thin and veins prominent.

Categories and causes Major causative ARVs In descending order of frequency, the NRTIs associated with lipoatrophy are d4T, ZDV, TDF, ABC, 3TC, FTC, especially when combined with EFV. Surprisingly, The ACTG 5142 study reported more lipoatrophy in patients taking efavirenz compare to those taking lopinavir/ritonavir group; when d4T or AZT were part of the regimens, but less lipoatrophy when efavirenz drug was combined with tenofovir.(45) Genetic/metabolic Cushing disease, adrenal insufficiency, hyperthyroidism, Seip‐Berardinelli syndrome, Lawrence syndrome, Dunnigan syndrome, Kobberling syndrome, Barraquer‐Simons syndrome, Launois‐ Bensaude syndrome, other hereditary syndromes causing fat loss (familial partial lipodystrophy) Nutritional Malnutrition Immunological HIV wasting syndrome Physical normal aging process Drugs and chemicals Glucocorticoid therapy Chronic diseases Scleroderma Malignancies Cancer cachexia Infections Severe chronic infection Other Eating disorders

Presentation and diagnosis Clinical diagnosis Lipoatrophy presents with loss of subcutaneous fat from the cheeks, proximal to the nasolabial fold, with prominent nasolabial creases and loss of subcutaneous fat from the arms, shoulders, thighs, and buttocks and prominence of the superficial veins in these sites. The onset is typically gradual, some months after initiation of therapy. Lipohypertrophy may be present to varying degrees, characterized by dorsocervical fat pad ("buffalo hump"), suprapubic fat pad, subcutaneous lipomata and increase fat deposition in the neck, breasts and abdomen. Laboratory diagnosis Abnormal laboratory findings associated with lipoatrophy include hyperlipidaemia, hyperglycaemia and insulin resistance. Frequency In clinical trials, the prevalence of lipoatrophy (with or without lipohypertrophy) has been reported to be between 13% and 38%. (44) Timing relative to While changes in mitochondria are detectable within weeks after initiation of antiretroviral initiating ART therapy, it may be many months or years before the fat loss is observed.(40) Risk factors(52) Therapy with thymidine analogue NRTIs (d4T, ddI, AZT) and duration of use, therapy with PIs and duration of use, lower pre‐treatment body mass index at onset of HAART, longer duration of HIV infection, white race, increased age, low CD4 cell count, Prior AIDS diagnosis.

Grading and clinical management 1 2 3 Fat loss very concerning to patient & very obvious to Patient and/or only close Physical evidence of fat others, or 25% ↓in fat friends/family notice the depletion noted by physician documented by paired changes and confirmed by patient measurement of BIA, DEXA, ultrasound (facial LA) or MRI Principles of care Currently, no pharmacological intervention has shown clinical benefit in the treatment of lipoatrophy. No specific medical treatment exists for lipoatrophy. Withdrawal of implicated ARVs has shown to be effective, at least partially, in reversing lipoatrophy. Thiazolidinediones (rosiglitazone and pioglitazone) are used to treat type‐2 diabetes. In addition to reversing hyperglycaemia they increase the number of small adipocytes and the subcutaneous adipose‐ tissue mass. (46) The best studied thiazolidinedione in patients with HIV is rosiglitazone. (47) Three out of four clinical trials reported no significant improvement in limb fat mass, although one found a benefit at 6 months in those not receiving d4T or AZT that was lost by 12 months.(47) Other drugs which have been studied and not show benefit are uridine, metformin, recombinant human growth hormone and statins. Fillers which improve the cosmetic appearance associated with lipoatrophy include autologous fat transplantation and implantation or injection of synthetic bulking agents (such as human and bovine collagen and silicone. However, the benefit is temporary requiring repeated injections over time and their use in resource constrained settings is limited by cost and availability.(48) Prevention Avoiding d4T (and to a lesser degree) and minimises lipoatrophy. In clinical trials, antiretroviral treatment initiation with regimens containing abacavir + 3TC or tenofovir + emtricitabine results in less lipoatrophy than regimens that contain d4T or AZT.(7, 8) This is not an option in many resource limited settings where d4T and AZT remain the cornerstones of first line antiretroviral therapy. Early identification of signs of fat loss and switching from d4Tor ddI to AZT, TDF or ABC if possible and as soon as possible may stabilize the fat loss. There may or may not be visual improvement following cessation of d4Tor ddI. All NRTIs including AZT, TDF, ABC 3TC and FCT may contribute to further lipoatrophy. Monitoring Clinically, the development of lipoatrophy is monitored by observation by patient and physician for early visual signs of body composition and body shape changes. Biochemical abnormalities which may accompany lipoatrophy are elevations in hepatic transaminase and serum lipids. Reversibility Switching studies have reported some improvement in lipoatrophy, but this is a limited and slow process. Peripheral fat gain to normal levels has not been achieved by switching.(44) Proactive switching (before lipoatrophy develops) may be an option in some situations. The continuation of d4Tor ddI likely will result in progressive fat loss which may be irreversible.

Specific populations Paediatric In children with HIV, both thymidine analogue NRTIs and PIs are implicated in the development of lipodystrophy.(49)