Adverse Effects with Nucleoside Analogs (‘Nukes’)

“Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among antiretroviral-treated patients with undetectable viral loads. Current use of abacavir [a nucleoside analog] was independently associated with impaired endothelial function. This finding suggests that abnormal endothelial function may underlie the clinically observed increased risk in myocardial infarction among abacavir-treated patients.”

“[Black box warning] LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS…Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of VIREAD…decreases in bone mineral density (BMD) were seen at the lumbar spine and hip…Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed…Immune reconstitution syndrome has been reported…the long term effects of TRUVADA are unknown…Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ³3% in Any Treatment Group in Study 934 (0–48 Weeks) [include] Diarrhea (7%), Nausea (8%), Fatigue (7%), Sinusitis (4%), URI (3%), Nasopharyngitis (3%), Sleepiness (3%), Headache (5%), Dizziness (8%), Depression (4%), Insomnia (4%), Abnormal dreams (4%), rash (5%)…Significant Laboratory Abnormalities Reported in ³1% of Patients in Any Treatment Group in Study 934…Any ³Grade 3 [serious] Laboratory Abnormality (25%), Fasting Cholesterol (15%), Creatine Kinase (7%), Serum Amylase (7%) [etc.]…other adverse events that occurred in at least 5% of patients receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia [joint pain], increased cough, dyspepsia [upset digestion], fever, myalgia [muscle pain], pain, abdominal pain, back pain, paresthesia [hallucination of any sense], peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis [inflamed nose] and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).”

“The most common side effects attributed to abacavir [a nucleoside analog] are gastrointestinal signs and symptoms (loss of appetite, nausea, vomiting, and diarrhoea), headache, malaise, and asthenia. These untoward events usually appear in the first few weeks of therapy, tend to resolve spontaneously, and are usually mild-to-moderate in severity [which could be because the body adapts to the drug or because patients lose patience and stop taking it]…The most serious adverse event caused by abacavir is the hypersensitivity reaction, a severe allergic reaction that has been estimated to occur in around 8% of persons who begin abacavir therapy, usually within the first 6 weeks of treatment. Its multiform clinical manifestations include fever, rash, gastrointestinal, or respiratory symptoms, and may lead to life-threatening hypotension, renal failure and death, especially in the event of rechallenge with abacavir after a prior episode of hypersensitivity…In our patient, a potentially life-threatening neutropenia occurred 4 weeks after the start of abacavir therapy and was associated with fever, skin rash, and anaemia. The neutrophil count started to increase and themajority of clinical signs and symptoms resolved within 3–4 days after stopping abacavir, whereas absolute neutrophil count and haemoglobin level became normal after 10 days. Consistent clinical manifestations, a positive HLA-B 5701 testing, and the rapid recovery of our patient suggest that these adverse events may be immune mediated, probably due to the secretion of drug-related antibodies.”

“We describe a 62-year-old male who was diagnosed with HIV-1 in 2001 and died with lactic acidosis under treatment with didanosine [ddI/Videx] and stavudine [d4T/Zerit]…Lactic acidosis is a life-threatening complication of HAART. The onset is often abrupt, with uncharacteristic muscular, cardiac or hepatic symptoms. The outcome can be fatal due to liver failure and cardiac arrhythmia. Didanosine and stavudine are strong inhibitors of polymerase-gamma, which are known to induce mtDNA [mitochondrial DNA] depletion in subcutaneous adipose tissue and in liver”

“Abacavir, an HIV nucleoside analogue reverse transcriptase inhibitor, can cause hypersensitivity reactions in 3–5% of patients started on the drug, and 90% of cases occur within the first 6 weeks after initiation (median time 11 days). The most common symptoms of abacavir hypersensitivity are fever, rash, and gastrointestinal symptoms. Respiratory symptoms such as dyspnea, cough, and pharyngitis are prominent in 30% of cases and mimic pneumonia…From our observation [on a patient], abacavir can cause acute lung injury clinically presenting as ARDS [acute respiratory distress syndrome], presumed to be a hypersensitivity reaction and pathologically showing AFOP [acute fibrinous and organizing pneumonia]. The early recognition and discontinuation of the drug is the only established treatment. None of the patients with fulminant AFOP recovered in the previous studies, but AFOP secondary to abacavir hypersensitivity was reversible in our patient. This highlights the characteristic of abacavir hypersensitivity: fulminant exacerbation with continuation of the drug and rapid recovery after discontinuation of the drug.”

“Nucleoside analogues remain an important backbone of antiretroviral therapy.”

“Adults: Selected clinical adverse events with a ³5% frequency during therapy with Epivir [lamivudine/3TC) 150 mg twice daily plus Retrovir [Zidovudine/AZT] 200 mg 3 times daily compared with zidovudine [Retrovir/AZT] are…Headache [35%], Malaise & fatigue [27%], Fever of chills [10%], Nausea [33%], Diarrhea [18%], Nausea & vomiting [13%], anorexia and/or decreased appetite [10%], abdominal pain [9%], abdominal cramps [6%], dyspepsia [5%], neuropathy [abnormal sensations such as burning or numbness in the skin – 12%], insomnia & other sleep disorders [11%], dizziness [10%], depressive disorders [9%], nasal signs & symptoms [20%], cough [18%], skin rashes [9%], musculoskeletal pain [12%], myalgia [muscle pain; 8%], arthralgia [joint pain – 5%]…”]

“WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).”

“LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS). [Atripla is a combination of two nucleoside analogs and one protease inhibitor]”

“WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).”

“In our series, almost half of the children (63 of 127) who were exposed to nucleoside analogues developed benign and self-limited hyperlactatemia. When symptomatic, nucleoside analogue–induced toxicity affected neurologic development.”

“this rare but often life-threatening syndrome, now named ‘severe nucleoside-associated lactic acidosis’ (NALA) has been reported increasingly often. Hepatic steatosis [loss of fat in liver] and lactic acidosis are thought to be caused by nucleoside reverse-transcriptase inhibitor (NRTI)-associated mitochondrial toxicity…Low levels of hyperlactatemia have been reported in 21% of NRTI-treated patients, although the majority of these patients are asymptomatic…From 1997 through 2000, we identified 12 HIV-infected patients treated with NRTIs who developed unexplained metabolic acidosis…A total of 5400 patients treated with NRTIs were observed in these [Spanish] hospitals during the study period. In all cases, known causes of lactici acidosis other than antiretroviral therapy were ruled out…Cases of NALA have been reported as soon as 1 month and as late as 20 months after the start of antiretroviral treatment…NALA can develop at any stage of HIV disease…The mortality rate among patients with lactic acidosis is very high: 33% for our series of patients and 57% for the patients described in the literature.”

“Bristol Myers Squibb (BMS) has chosen to inform doctors of rapidly ascending muscular weakness as new symptom of nucleoside-related lactic acidosis and hyperlactataemia...A review by the EMEA of nucleoside analogue-related LA [lactic acidosis] and HL [hyperlactataemia] has highlighted seven cases of rapidly ascending muscular weakness, similar to that symptoms seen with Guillain-Barré Syndrome, and a further seven cases of muscular weakness or pain which preceded the development of LA and HL...Early symptoms of LA and HL include nausea, vomiting, diarrhoea, rapid and deep breathing, stomach cramp, myalgia [muscle pain] and paresthesia [numbness]. Ascending neuromuscular weakness should now be added to this list. Severe complications which currently include pancreatitis [pancreas failure] and liver failure should now be broadened to include motor paralysis...All nucleoside analogues have been associated with symptoms of LA and HA...Severe lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, renal failure, or motor paralysis.”

“FDA and Bristol Myers Squibb are warning health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed the combination of the HIV drugs stavudine (Zerit) and didanosine (Videx or Videx EC) with other antiretroviral agents.

Lactic acidosis occurs when cells of the body are unable to convert food into usable energy. As a result, excess acid accumulates in the body and vital organs such as the liver or pancreas may be damaged. Severe lactic acidosis is an infrequent, but well-described complication of the class of HIV drugs known as nucleoside analogues. Pancreatitis is also a well-described complication of Videx and Zerit.

This new warning follows three reported cases of fatal lactic acidosis, with or without pancreatitis, that occurred in pregnant women taking Zerit and Videx in combination with other drugs used to treat HIV.”

“Fourteen HIV-infected adults treated with antiretroviral drugs were identified with symptomatic hyperlactataemia [elevated lactic acid levels that can result in fatal lactic acidosis] during a 2-year period follow-up study. The incidence of hyperlactataemia was 0.8% per year but reached 1.2% if only patients treated with a regimen including stavudine were considered. Clinical symptoms included abnormal fatigue, tachycardia [abnormally rapid heart beat], abdominal pain, weight loss, peripheral neuropathy [surface nerve damage], and more specifically exercise-induced dyspnoea [shortness of breath] occurring despite effective antiretroviral treatment [note: effectiveness is defined by elevated CD4 cell counts/reduced viral load not improved health]. FRT [functional respiratory tests] showed a metabolic deviation towards anaerobiosis with a high lactate/ pyruvate ratio. Ultrastructural mitochondrial abnormalities were seen in all four patients for whom this was examined. There was a marked decrease in complex IV activity in muscle biopsies from four of five patients, consistent with a mitochondrial dysfunction...One patient developed severe lactic acidosis...and died. Another was lost to follow-up. Among the remaining 12 patients, nucleoside analogue therapy was stopped in 10, as clinical improvement was combined with a decrease in lactate levels...The improvements observed in the next few weeks after drug withdrawal or modification suggest that antiretroviral drugs are responsible for the occurrence of symptomatic hyperlactataemia. Furthermore, symptomatic hyperlactataemia has never been diagnosed in naive untreated HIV-infected subjects followed up in our unit...Stavudine [d4T/Zerit] was strikingly involved in treating all these hyperlactataemic patients.”

“Glaxo Wellcome on Sunday played down renewed fears about its Ziagen [Abacavir, a nucleoside analog] HIV treatment and said it planned to proceed with this year's European launch of Trizivir, its new Aids drug, which contains Ziagen...Glaxo...yesterday confirmed patients had died as a result of "hypersensitive" reactions since Ziagen was launched in the US and Europe last year. There are as yet no reliable figures on the number of fatalities from the treatment but Glaxo admitted that about 4 per cent of patients had displayed symptoms such as fever and vomiting. It put the negative response to the drug at about two people in every 10,000 patients, which is 10 times higher than the figures for other drugs generally. The company said: "This is a very potent drug and clinical trials have indeed shown that it has a potential for side effects and patients have died from using it."”

“An uncommon but life-threatening syndrome of severe hepatic steatosis and lactic acidosis among patients infected with HIV-1 was first described in the early 1990s. By early 1994, at least 40 such cases had been reported to regulatory authorities, and an association with use of zidovudine and didanosine was established. An underlying mechanism involving impaired replication of mitochondrial DNA was proposed. Although stavudine (Zerit, Bristol-Myers Squibb, Princeton, New Jersey) is the second most widely prescribed antiretroviral nucleoside analogue, it has rarely been associated with the syndrome of severe hepatic steatosis and lactic acidosis. We report on four patients who developed this syndrome while receiving an antiretroviral regimen containing stavudine.”

“8 subjects (10%) discontinued the study prematurely because of adverse events, all of which were considered by the investigator to be attributable to abacavir. None of these subjects were on 300 mg twice daily. Four subjects were withdrawn because of nausea, two receiving abacavir–ZDV therapy [200 mg three times daily (cohort I) and 400 mg three times daily (cohort II)] and two receiving abacavir alone [400 mg three times daily (cohort II) and 600 mg three times daily (cohort IV)]. One subject was withdrawn due to dizziness, photophobia, and palpitations (cohort IV). Three subjects, one on abacavir–ZDV (cohort I) and two on abacavir alone (cohort IV), were withdrawn within 4 weeks of dosing because of hypersensitivity reaction (erythematous generalized rash, low-grade fever, malaise and nausea). After a temporary interruption of study drugs due to hypersensitivity, subjects were rechallenged at least once. Rechallenge with abacavir resulted in rapid onset of hypersensitivity. There were no deaths among the study subjects. Four additional subjects experienced a serious adverse event but remained in the study through week 12. Amongst abacavir–ZDV subjects, one experienced headache (cohort I) and another reported depression [300 mg twice daily (cohort III)]. Amongst abacavir monotherapy subjects, one experienced leukopenia (cohort II) and another had a syncopal episode (cohort III). Five subjects (6%) experienced grade 3 or 4 laboratory abnormalities. Three cases of hematological abnormalities were reported: amongst subjects receiving ZDV monotherapy, one had leukopenia (grade 3, but grade 4 at one evaluation) and another had decreased hemoglobin count (grade 4); one subject receiving abacavir–ZDV therapy had decreased platelet count (grade 3). Two cases of clinical chemistry abnormalities were reported: one subject receiving ZDV monotherapy had elevated alanine aminotransferase levels (grade 3), and one subject receiving abacavir–ZDV therapy had hypoglycemia (grade 3).”

“The antiretroviral drugs currently licensed in the United Kingdom [June 1996] are zidovudine (azidothymidine [AZT]), zalcitabine (ddC) and didanosine (ddI). All three are nucleoside analogues...All are very toxic. Suppression of bone marrow elements can occur with any of the three, as can peripheral neuropathy [nerve damage].”

“The median times to a first modification of the dose, including a reduction in or discontinuation of the study drug, were 33, 39 and 27 weeks for subjects assigned to receive 750 mg of didanosine [a cousin of AZT, and the second AIDS drug ever approved], 500 mg of didanosine, and zidovudine, respectively. Severe anemia was uncommon in all groups and was less common in the group receiving 750 mg of didanosine than in the zidovudine group. Recipients of the 750-mg didanosine dose had less severe leukiopenia and granulocytopenia than recipients of zidovudine. Treatment with the 500-mg dose of didanosine was associated with less severe granulocytopenia than treatment with zidovudine. The rate of pancreatitis was higher in the 750-mg didanosine group than in either the zidovudine group or the 500-mg didanosine gropu. The number of casees of pancreatitis [pancreas failure] was higher in the 500-mg didanosine group than in the zidovudine group, but the difference was not statistically significant. Fatal pancreatitis developed in two subjects receiving 750 mg of didanosine. The 750-mg and 500-mg didanosine groups both had greater increases in unfractionated serum amylase concentrations than the zidovudine recipients. The rate at which peripheral neuropathy of grade 2 or worse developed did not differ significantly between the three treatment regimens.”

“D4T [Stavudine] is a structural analogue of the naturally occurring nucleoside thymidine [one of the four building blocks of DNA]…The dose-limiting toxicity in humans is peripheral neuropathy [damage to surface nerves resulting in numbness, pain and other abnormal sensations], which was not predicted by animal toxicology”