key: cord-0801456-ua22udlc
authors: Koch, Oliver; Sheehy, Susanne; Sargent, Catherine; Democratis, Jane; Abbas, Sarah; Schiefermueller, Jurgen; Angus, Brian J.
title: 29 Antiviral drugs
date: 2010-12-31
journal: Side Effects of Drugs Annual
DOI: 10.1016/s0378-6080(10)32029-0
sha: 13f7317a1b635f4b48d924ce11f0e4ef47bf19d6
doc_id: 801456
cord_uid: ua22udlc

Publisher Summary This chapter discusses the adverse effects of antiviral drugs used against cytomegalovirus, herpesviruses, hepatitis viruses, against HIV, and against influenza viruses. The cidofovir, drug active against cytomegalovirus, has been associated with bronchiolitis obliterans. Aciclovir and valaciclovir has been reported with renal insufficiency. Adefovir , a drug active against hepatitis viruses, is associated with the fall in creatinine clearance in patients with lamivudine-resistant HBe antigen (HBeAg)negative disease. Drugs active against HIV are comprehensively reviewed as in combination, nucleoside analogue reverse transcriptase inhibitors, nucleoside analogue reverse transcriptase inhibitors, and protease inhibitors. In a randomized controlled trial of indinavir, saquinavir and lopinavir in combination with low-dose ritonavir in 656 patients, median total cholesterol increased by 0.5 mmol/l in the patients with the highest minimum drug plasma concentrations. In patients with AIDS-associated AIDS dementia complex taking optimal stable background antiretroviral therapy including either abacavir or placebo, there was significantly more nausea in those who took abacavir.

Respiratory Cidofovir has been used to treat adenovirus pneumonia in four pediatric lung transplant recipients (1 c ). Two developed bronchiolitis obliterans, one of whom underwent retransplantation with a good outcome. The other developed tracheomalacia and required continuous low-flow oxygen and positive pressure ventilation through a tracheostomy.

Urinary tract Of six hemopoietic stem cell transplant recipients, who were given cidofovir 5 mg/kg/week for 2 weeks, then on alternate weeks for a minimum of four (range 1-7) doses, three developed adenovirus hepatitis, two had colitis and one had nephritis (2 c ). All had CD34þ selected grafts and/or graft-versus-host disease and all had a CD4 count under 100 Â 10 6 /l. The patients were pre-hydrated and Brian J. Angus Antiviral drugs and given probenecid and intravenous immunoglobulin 1-2 g/kg/week followed by 0.5 mg/kg on alternate weeks for a minimum of four doses. Two patients died of infection and four responded. None required withdrawal of treatment because of adverse effects. Baseline creatinine was slightly raised (167 µmol/l) in the patient with hepatitis and improved with cidofovir. Most of the patients had transient increases in creatinine as the number of doses increased.

Cidofovir 5 mg/kg/week or 1 mg/kg on alternate days adjusted to creatinine clear ance was used to treat 11 hemopoietic stem cell transplant recipients with invasive ade noviral infection, including three with pneu monia, one with hepatitis, four with hemorrhagic colitis and three with hemor rhagic cystitis (3 c ). All had concomitant intravenous immunoglobulin, and those with colitis had in addition one or more of oral immunoglobulin, ribavirin, or donor lymphocyte infusion. They varied in their degree of immunocompromise and the pre sence of graft-versus-host disease and some had leukocyte-depleted allografts. Six died. There was nephrotoxicity in two cases.

In a retrospective study of 19 recipients of hemopoietic stem cell transplants, mean age 42 years, who were given a mean of 4.5 (range 3-6) weekly doses of cidofovir 1 mg/ kg without probenecid for BK virus-asso ciated hemorrhagic cystitis, 84% had graft versus-host disease and were taking corti costeroids at the time of diagnosis (4 c ). There was no significant rise in creatinine in 14; 5 had renal insufficiency, but in all cases there were other potential causes. In only 3 cases could cidofovir have played a role. In those with normal renal function, 80-100% of the cidofovir was recovered from the urine, raising the possibility of therapeutic intravesicular administration. Aciclovir Psychiatric Hemodialysis has been successfully used to treat an aciclovir induced psychosis (5 A ).

• A 70-year-old man with rectal carcinoma and end-stage renal failure on hemodialysis was given intravenous aciclovir. He developed delirium, visual and auditory hallucinations, disorientation in place and time, and impaired recent memory. He recovered fully after 3 consecutive days of hemodialysis.

Urinary tract Reports of renal insuffi ciency associated with the use of intravenous aciclovir continue to appear (6 A ). In a retrospective review of 126 children there was no effect of dose per kilogram, age, or sex on nephrotoxicity (7 c ). The predictors of aciclovir nephrotoxicity were the concomitant use of nephrotoxic drugs and impaired glomerular filtration rate (GFR) at baseline.

Fetotoxicity It has been suggested that maternal use of aciclovir may be associated with necrotizing enterocolitis in the neonate (8 A ).

Immunologic An acute allergic reaction to valaciclovir has been described (9 A ).

• A 50-year-old woman developed general malaise, diffuse pruritus, angioedema of the hands and feet, and reduced consciousness and faintness within 5 minutes of taking valaciclovir 500 mg for genital herpes. Skin prick tests for aciclovir were positive.

Urinary tract As with aciclovir, renal insufficiency has been reported with valaciclovir (10 A )

• A 73-year-old Japanese man with cardio myopathy and chronic renal disease was admitted with anuria, systemic edema, and renal dysfunction after taking valaciclovir 1 g tds 5 days for Herpes zoster infection with a non-steroidal anti-inflammatory drug.

He was briefly dialysis-dependent but made a full recovery.

Adefovir (SED-15, 35; SEDA-30, 344;

Observational studies In patients with lamivudine-resistant HBe antigen (HBeAg) negative disease, adefovir 10 mg alone (n = 14) or in combination with lamivudine (n = 28) caused a fall in creatinine clearance requiring a modification in adefovir dose in two patients on combined therapy; both had underlying liver cirrhosis (11 c ). One developed reduced liver function and biopsy showed steatohepatitis. One on adefovir monotherapy developed gastric cancer. Five on combined therapy with underlying cirrhosis developed hepatocellular carcinoma, but this was not statistically significant. Adefovir 10 mg/day in combination with lamivudine 300 mg/day has been used in 11 patients with recurrent hepatitis B virus infec tion after liver transplant (12 c ). All patients with chronic hepatitis B pre-transplant underwent a period of preoperative treat ment and peri-operative prophylaxis with lamivudine and hepatitis B immunoglobulin with or without adefovir if lamivudine-resis tant. No patient had adverse effects necessi tating drug withdrawal, but one required a dosage adjustment because of a rise in creati nine from 106 to 150 µmol/l. Three had a recurrence of hepatocellular carcinoma, two of whom died 12 and 14 months after starting adefovir therapy and one of whom continued to be positive for hepatitis B virus DNA.

Drug-drug interactions Entacavir The interaction of entacavir 1 mg/day with adefovir 10 mg/day has been studied in a fixed-sequence crossover study in 26 heal thy adults (13 c ). The results suggested that combination therapy can be safely adminis tered without the need for dosage adjust ment of either drug. There was headache in nine subjects and dysmenorrhea in two when they took entecavir alone.

See 'Drugs active against influenza viruses: ion channel inhibitors', below.

Drug-drug interactions Adefovir The interaction of entacavir 1 mg/day with ade fovir 10 mg/day has been studied in a fixedsequence crossover study in 26 healthy adults (13 c ). The results suggested that com bination therapy can be safely administered without the need for dosage adjustment of either drug. There was headache in nine subjects and dysmenorrhea in two when they took entecavir alone.

Lamivudine (SED-15, 1989 , SEDA-30, 344; SEDA-31, 480)

Observational studies In 33 treatmentnaive HBeAg-positive children who took lamivudine and high-dose interferon alpha 2a combination therapy, flu-like symptoms and anorexia were the commonest adverse effects (90 and 76%); weight loss, nausea, vomiting, arthralgia, and loss of hair were also noted (14 c ) .

In an open study of the pharmacokinetics of lamivudine in 12 patients receiving peri toneal dialysis, eye redness (n = 2) and diar rhea (n = 2) were the commonest adverse events (15 c ).

Comparative studies In a double-blind, Phase III, randomized, controlled trial of lamivudine 100 mg/day (n = 687) versus tel bivudine 600 mg/day (n = 680), creatine kinase activity was raised in patients receiv ing lamivudine (3.1%) and telbivudine (7.5%) and fell spontaneously during drug treatment to grade 2 or lower in 74% of those taking lamivudine and 67% of those taking telbivudine (16 C ). Grade 3 or 4 rises in transaminases during treatment were more frequent with lamivudine than with telbivudine.

Observational studies High-dose ribavirin during an outbreak of severe acute respira tory syndrome in Toronto was associated with a high rate of adverse events: anemia (odds ratio [OR] = 3.0; 99% confidence interval [CI] = 1.5, 6.1), hypomagnesemia (OR = 21; 99% CI = 5.8, 73), and bradycar dia (OR = 2.3; 99% CI = 1.0, 5.1) (17 c ). The risks of anemia, hypomagnesemia, and bra dycardia attributable to ribavirin were 27%, 45%, and 17% respectively. The authors concluded that the use of high-dose ribavirin is appropriate only for the treatment of infectious diseases for which ribavirin has proven clinical efficacy, or in the context of a clinical trial. They further stated that ribavirin should not be used empirically for the treatment of viral syndromes of unknown origin.

Skin Occasional rashes in areas of drug contact and conjunctival irritation occurred when aerosolized ribavirin was used for 10 months in an infant with immunodeficiency (18 A ).

Musculoskeletal In a double-blind, Phase III, randomized, controlled trial of lami vudine 100 mg/day (n = 687) versus telbivu dine 600 mg/day (n = 680), raised creatine kinase activity was more common in patients who took telbivudine and it fell sponta neously during drug treatment to grade 2 or lower in 67% of those who took telbivu dine and 74% of those who took lamivu dine. Myopathy (characterized by muscle pain, weakness, and moderately raised crea tine kinase activity before and during treat ment) was reported in one patient after telbivudine therapy for 11 months. When telbivudine was withdrawn, the creatine kinase activity normalized within 1 month and the symptoms resolved over 9-12 months (16 C ).

Cardiovascular Syncope occurred in a young man after he took tenofovir, emtricitabine and nevirapine for primary human immunodeficiency virus-1 (HIV-1) infection for 6 weeks and resolved after withdrawal of the antiretroviral drugs (19 A ).

Metabolism The hemochromatosis gene polymorphism HFE 187C> G and possibly mitochondrial haplogroup J gave relative protection against lipoatrophy during antiretroviral drug therapy in a trial in which 96 patients were randomized to didanosine þ stavudine or zidovudine þ lamivudine, combined with efavirenz and/ or nelfinavir in AIDS Clinical Trials Group (ACTG) 384 sub-study A5005s (20 C ).

Stavudine had a less favorable effect on lipid profile and caused more lipoatrophy than abacavir (38% versus 4.8%) in a ran domized, open trial, stratified by viral load and CD4 cell count, in which 237 adults with HIV infection were assigned to stavudine (n = 122) or abacavir (n = 115), both com bined with lamivudine and efavirenz (21 C ).

There were dose-related increases in total cholesterol, LDL cholesterol, and triglycerides in an open study in 56 seronegative volun teers, with persistent increases 2 weeks after withdrawal (22 c ).

In a randomized controlled trial of indina vir, saquinavir and lopinavir in combination with low-dose ritonavir in 656 patients, med ian total cholesterol increased by 0.5 mmol/l in the patients with the highest minimum drug plasma concentrations (23 A ).

Gastrointestinal In a retrospective obser vational study of highly active antiretroviral therapy (HAART), 27 of 50 patients who took indinavir in combination with zidovudine and lamivudine developed nausea and were significantly more likely to stop taking the treatment than those who were taking zidovudine þ lamivudine þ tenofovir (24 c ).

In a long-term follow-up study of 200 asymptomatic HIV-positive participants for 157 weeks taking a combination of indinavir, lamivudine, and zidovudine, 40 stopped treat ment because of adverse effects, of which nausea (69%), diarrhea (37%), and abdom inal pain (28%) were the most common (25 c ).

The most common adverse events in 21 of 151 patients in a prospective study of once-daily saquinavir þ ritonavir and two nucleoside reverse transcriptase inhibitors (NRTIs) were abdominal discomfort, diar rhea, and vomiting (26 c ). Similar findings were seen by other investigators (27 A ).

Liver In 199 HIV/hepatitis C co-infected patients, failure to achieve a sustained viral response, NRTI therapy, didanosine, and stavudine were significantly associated with worsening of hepatic fibrosis in 34 (17%) (28 c ). After multivariate analysis, didanosine (OR = 3.34; 95% CI = 1.39, 7.96) and failure to have a sustained viral response (OR = 9.05; 95% CI = 2.06, 40) remained significantly associated with worsening of fibrosis.

In a retrospective study of 868 HIV-posi tive subjects (94% men), first-line therapy was efavirenz, lamivudine, and zidovudine; women of child-bearing potential were given nevirapine instead of efavirenz. An efavirenz-based regimen was used in 825 and 39 received a nevirapine-based regimen (29 C ) . During the first year 48 subjects took isoniazid prophylaxis and 214 received antituberculosis therapy (2 months of rifam picin, isoniazid, pyrazinamide, and etham butol followed by 4 months of rifampicin and isoniazid). Of a random sample of 133 tested, 17% were hepatitis B surface anti gen (HBsAg)-positive. There was grade 2 or worse hepatotoxicity in 97 subjects (11%) and 40 had a first episode of grade 3 or 4 hepatotoxicity. Antituberculosis therapy (adjusted hazard ratio [HR] = 8.5; 95% CI = 2.7, 27) and HBsAg (adjusted HR = 3.0; 95% CI = 1.3, 7.0) were strongly associated with hepatotoxicity. However, hepatotoxicity had little impact on symp toms, the need for hospitalization and the need for a change in antiretroviral drug regimen. The use of isoniazid preven tive therapy during antiretroviral drug therapy did not increase the risk of hepatotoxicity.

Three adults developed nodular regen eration of the liver while taking HAART regimens containing atazanavir, fosampre navir, and indinavir (30 A ).

Pancreas In the large EuroSIDA study there was no association between an increased incidence of pancreatitis and cumulative exposure to antiretroviral drugs generally, or to didanosine and stavudine in particular (31 C ). There were 43 (9 presumptive) pancreatic events in 9678 individuals during 33 742 person-years (1.27 per 1000 person-years). The incidences among those with no, 2 or less, and over 2 years of exposure to antiretroviral drugs, including stavudine and didanosine, were 1.24, 1.73, and 0.78 per 1000 person-years, respectively. In multivariate analysis, higher baseline CD4 cell counts were associated with a reduced risk of pancreatitis.

Urinary tract Of 445 HIV-positive patients who started to take tenofovir, 51 (11%) had reduced renal function (32 C ). Multivariate analysis showed a significant association between reduced renal function and concurrent use of amprenavir and di danosine, age over 50 years and lower baseline weight. There was an association between concomitant use of tenofovir and amprenavir and reduced kidney function in 441 patients (OR = 3.5).

Acute interstitial nephritis was seen on renal biopsy in three HIV-positive patients taking amprenavir þ tenofovir; it resolved after drug withdrawal (33 A ).

In a randomized controlled trial of in dinavir, saquinavir, and lopinavir in combi nation with low-dose ritonavir in 656 patients, there was no apparent dose-related association with renal adverse events (23 C ).

Immunologic An allergic reaction with possible cross-reactivity to didanosine and tenofovir has been reported (34 A ).

• A 25-year-old woman tested positive for HIV-1 and was given a once-a-day regimen including tenofovir plus emtricitabine and efavirenz. After 10 days she developed a diffuse rash with fever and glossitis. Efavirenz was withdrawn but her conditions worsened over the next 3 days, so both tenofovir and emtrici tabine were withdrawn, with dramatic resolu tion of symptoms within 24 hours. After 10 days she was given zidovudine plus didanosine and ritonavir-boosted fosamprenavir. After 1 week she again developed a diffuse rash and the treatment was withdrawn. She restarted zidovudine and didanosine 7 days later and within a few days the rash appeared again. Under observation she was given zidovudine and atazanavir and after 8 days lamivudine and low-dose ritonavir. She remained well, except for mild hyperbilirubinemia, during the next 5 months.

Fetotoxicity There is equivocal evidence of a relation between in utero NRTI exposure and mitochondrial dysfunction in HIVnegative children born to HIV-infected women. In 1037 HIV-negative children, possible cases with unexplained signs of mitochondrial dysfunction according to the Enquête Perinatale Française criteria were identified in a retrospective review (35 c ). Associations between possible mitochondrial dysfunction and both overall in utero NRTI exposure and the trimester of first in utero NRTI exposure were estimated by exact logistic regression. Cases (n = 20) were significantly more likely to be boys and to be born in earlier years than non-cases (n = 1017). There was no association between overall in utero NRTI exposure and mitochondrial dysfunction. In unadjusted models there were higher odds of first in utero exposure in the third trimester to lamivudine (OR = 3.76 versus unexposed; 95% CI = 1.09, 12) and to zidovudine þ lamivudine (OR = 3.29 versus unexposed; 95% CI = 0.96, 10) among cases than noncases. When adjusted for year of birth, the odds of first exposure in the third trimester to lamivudine (OR = 11; 95% CI = 1.9, 76) and zidovudine þ lamivudine (OR = 9.8; 95% CI = 1.7, 72) were significantly higher among cases than non-cases. Incomplete data precluded control of possible confounding by maternal viral load and psychoactive drug use.

Reports of renal toxicity with the combination of tenofovir and didanosine in children suggest that this combination should be avoided (36 A ). Combination of saquinavir with darunavir þ ritonavir is currently not recommended as plasma concentrations of darunavir are increased (37 c ).

Buprenorphine Atazanavir and atazanavir þ ritonavir both resulted in increased metabolite concentrations of buprenorphine, and dosage reduction of buprenorphine is recommended; there was no change in the concentrations of the protease inhibitors (38 c ).

Warfarin In two patients who were taking a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, or a protease inhibitor, nelfinavir or lopinavir þ ritonavir, and two nucleoside analogues, high doses of warfarin were required to maintain therapeutic INRs (39 A ). Warfarin has two enantiomers, R-warfarin and S-warfarin, which are substrates of CYP3A4 (R-warfarin), CYP1A2 (R-warfarin), and CYP2C9 (S-warfarin Gastrointestinal In patients with AIDSassociated dementia ADC taking optimal stable background antiretroviral therapy including either abacavir or placebo there was significantly more nausea in those who took abacavir (40 c ).

Immunologic Three patients developed painful lymphadenopathy shortly after starting to take abacavir, mimicking immune reconstitution syndrome (41 A ). They also had a fever and a rash and all were HLA-B*5701-positive. They recovered after withdrawal of abacavir. Abacavir hypersensitivity occurred in a 36-year-old man after he switched from a twice-daily to a once-daily regimen (42 A ).

In a 52-year-old woman, abacavir hyper sensitivity presented as acute fibrinous and organizing pneumonia, with dyspnea, hypoxia, and bilateral infiltrates (43 A ).

Susceptibility factors Genetic A sequence variation in the HIV reverse transcriptase codon 245 has been associated with host HLA-B*5701 in 392 HIV-infected, antiretroviral drug-naive adults, and the relation between the codon 245 variation and premature abacavir withdrawal was investigated in 982 treated individuals (44 C ). Only one of 24 subjects with B*5701 harbored virus with the clade B 'wild-type' amino acid 245V, compared with 278 of 368 who did not have B*5701. The sensitivity and specificity of codon 245 substitutions for predicting HLA-B*5701 were 96% and 75% respectively, and the positive and negative predictive values were 20% and 99.6% respectively. The authors argued that the reverse transcriptase codon 245 could be adopted as a simple, low-cost screening method to identify individuals who could be safely treated with abacavir when detection of HLA-B*5701 is not rapidly and easily available.

Drug-drug interactions Alcohol Three patients had possible reactions to alcohol while taking abacavir (45 A ). One had a disulfiram-like reaction (nausea, facial flushing, tachycardia) repeatedly on rechallenge with alcohol. Another described a feeling of being drunk after small amounts of alcohol. A third had malaise after increasing his alcohol intake. The authors suggested that abacavir might inhibit alcohol dehydrogenase. Urinary tract Fanconi syndrome and nephrogenic diabetes insipidus associated with didanosine have been reported (46 A ).

• A 40-year-old man developed polydipsia, poly uria, fatigue, and weight loss after taking dida nosine, lamivudine and boosted atazanavir for 2 years. He had hypophosphatemia, hypouricemia, hyperchloremic metabolic acidosis with a normal anion gap, normoglycemic glycosuria, and low-molecular-weight protei nuria. The plasma antidiuretic hormone (ADH) concentration was high at 4.8 pg/ml (reference range 1.4-4.4 pmol/l). The didano sine was replaced with another protease inhi bitor and the other medications remained unchanged. He improved slowly.

Drug-drug interactions Ganciclovir It has been suggested that ganciclovir and its prodrug valganciclovir inhibit purine nucleoside phosphorylase (PNP) in a similar manner to tenofovir and increase didanosine concentrations, reducing its efficacy (47 A ).

• A 68-year-old woman with HIV and cyto megalovirus enteritis was given valganciclovir, lamivudine, didanosine, and lopinavir þ ritona vir. After 3 months, her viral load fell to less than 50 copies/ml and the CD4þ cell count was 317 Â 10 6 /l. Over the next 9 months her viral load remained suppressed, but the CD4þ cell count fell to 83 Â 10 6 /l and she had symptoms of didanosine toxicity. Didanosine was replaced with abacavir, leading to complete recovery of the CD4þ cell count and resolu tion of symptoms.

Reduction of the dosage of didanosine or substitution with an alternative antiretro viral drug may be necessary when ganciclo vir is used.

Metabolism Lipodystrophy tended to occur more often in 58 HIV/hepatitis C co-infected patients who had severe weight loss than in 111 other patients (26% versus 18%), and patients who had persistent weight loss over 5% for 24 weeks after the completion of anti-hepatitis C virus (HCV) therapy were more likely to be taking a stavudine-based antiretroviral therapy (48 c ).

In another study patients with lipoatrophy had higher drug exposure to stavudine than controls (49 c ). This was reflected in the higher geometric concentration ratios (0.978 and 0.741 respectively) and a higher percentage of ratios over 1.0, representing a drug concen tration above the normal population curve (46% versus 23%). In addition, the duration of stavudine therapy was independently asso ciated with lipoatrophy. In a multivariate ana lysis, both duration of stavudine therapy and a concentration ratio over 1.0 independently correlated with lipoatrophy.

Changes in body habitus occur when sta vudine is withdrawn. In 574 HIV-positive women who stopped taking stavudine for over 2.25 years, there were significantly smaller reductions in hip and thigh circum ferences compared with the reductions that occurred at 1-2.25 years after stavudine withdrawal (50 c ).

Stavudine reduces insulin sensitivity and causes mitochondrial toxicity in healthy sub jects. In 16 participants without a personal or family history of diabetes who were randomized to stavudine 30-40 mg bd or placebo for 1 month, insulin sensitivity was significantly reduced by stavudine (51 c ). In addition, muscle biopsies in those who took stavudine showed significant reductions in mtDNA/nuclear DNA, but there were no changes in placebo-treated subjects. P mag netic resonance spectroscopy studies of mito chondrial function correlated with measures of insulin sensitivity.

In 125 patients in a retrospective study, symptomatic hyperlactatemia in 114 (91%) was associated with stavudine median dura tion 13 months (52 C ). Nine patients (7.2%) died; those who died had a higher mean lactate concentration (8.0 versus 5.1 mmol/l) and mean AlT activity (164 versus 48 U/l) at the time of diagnosis than those who sur vived. Those who died had a lower mean weight than those who survived (48 versus 59 kg). By logistic regression, mortality was associated with patients whose body weight was under 45 kg (OR = 9.1; 95% CI = 1.6, 53) and whose serum lactate was over 10 mmol/l (OR = 20; 95% CI = 2.6, 159).

Dosage regimens A meta-analysis of clinical trials conducted before and after regulatory approval of stavudine has shown that a dosage of 30 mg bd has equivalent antiviral efficacy, with some evidence of lower rates of peripheral neuropathy and lipoatrophy, to the standard dosage of 40 mg bd (53 M ). It has been suggested that this is the most appropriate dose in resourcelimited settings (54 M ). Reducing the dosage of stavudine by one-half increased fat mtDNA and bone density and decreased lactate concentrations in a study of 24 patients already taking a standard dose (55 c Hematologic Hemoglobin A2 can rise in HIV-infected patients, possibly because of therapy (56 c ). In cross-sectional and cohort studies, hemoglobin A2 was often raised in untreated patients, but a further rise during treatment was specifically attributable to zidovudine. The concentration of hemoglobin A2 may be high enough to lead to a misdiagnosis of beta-thalassemia.

Genotoxicity Micronucleated reticulocyte frequencies have been measured as a mar ker of chromosomal damage in 16 HIVinfected mother-infant pairs, of whom 13 women had taken prenatal zidovudine and 3 antiretroviral drugs without zidovudine (57 c ). All the infants received zidovudine for 6 weeks. Venous blood was obtained from women at delivery and from infants at 1-3 days, 4-6 weeks, and 4-6 months of life; cord blood was collected immediately after delivery. Ten cord blood samples (controls) were obtained from infants of HIV-negative women who did not receive antiretroviral therapy. There were 10-fold increases in micronucleated reticulocytes in women and infants who received zidovudine-containing antiretroviral therapy prenatally and no increases in the other women and infants. Micronucleated reticulocytes in the zidovudine-exposed neonates fell over the first 6 months of life to values comparable to cord blood controls. The authors concluded that transplacental zidovudine exposure is genotoxic in humans and they recommended long-term monitoring of zidovudine-exposed infants.

Teratogenicity A possible association between first trimester exposure to zidovudine and an increased risk of hypospadias based on one cohort study has been reported (58 c ). Among 2527 live births to 2353 women, defects were identified in 90 babies (3.56 defects per 100 live births). The rate of defects was 3.19 per 100 live births with first-trimester antiretroviral drug exposure, 3.54 per 100 live births with exposure later in pregnancy, and 4.05 of 100 live births with no antiretroviral drug use. Only genital abnormalities, specifically hypospadias, were significantly increased among babies born to women with firsttrimester exposure to antiretroviral drugs (7 of 382 male live births) compared with the two other groups (2 of 892 male live births). Logistic regression suggested that use of zidovudine in the first trimester was associated with hypospadias (adjusted OR = 11; 95% CI = 2.1, 54).

Pregnancy In a pharmacokinetic study of three doses of zidovudine 300 mg 3-hourly in pregnancy in six subjects, plasma zidovudine concentrations were substantially lower than previously reported during continuous intravenous therapy (59 A ). In another study in four women who took an initial 600 mg dose followed by two 400 mg doses 3-hourly, the zidovudine AUC and concentrations increased approximately in proportion to the increase in dose but varied 6-7 times (60 A ). In both cohorts, the pharmacokinetic results suggested erratic absorption.

Combined exposure to zidovudine plus co-trimoxazole caused a clinically signifi cant suppression of humoral immune responses to influenza immunization in 23 HIV-positive patients with CD4 counts above 350 Â 10 6 /l (61 c ).

Ribavirin Ribavirin did not inhibit the formation of zidovudine triphosphate in peripheral blood monocytes in 14 patients over 8 weeks (62 c Urinary tract In a pilot, open, noncomparative add-on study, in which patients who had failed treatment with at least two thymidine-associated resistance mutations were given tenofovir 600 mg/day for 4 weeks in addition to their current failing antiretroviral regimen (n = 10), one developed de Fanconi syndrome at week 2 and two developed grade one hypopho sphatemia (63 c ).

In a multicenter, observational, retro spective study of 733 HIV-positive patients taking tenofovir, 85 patients (11.6%) stopped taking tenofovir because of adverse events, including nausea, vomiting, diarrhea, and headache. There was no association between any abnormal basal analytical parameter and a greater probability of stop ping treatment (64 C ).

In a single-center, cross-sectional evalua tion of b 2 microglobinuria as a marker of proximal renal tubule damage in 92 HIVinfected children, tenofovir was significantly associated with very high abnormal values (65 C In an evaluation of the effectiveness and adverse effects of a simplification regimen with tenofovir, lamivudine, and efavirenz in 154 HAART-experienced HIV-1-infected subjects with sustained viral suppression, 9 had psychiatric adverse effects related to efavirenz, leading to drug withdrawal in most cases; the symptoms included nightmares, insomnia, nervousness, and anxiety (69 c ).

Metabolism ACTG study 5095 was a ran domized, placebo-controlled, double-blind study designed to compare three protease inhibitor-sparing antiretroviral drug regi mens (zidovudine þ lamivudine þ abacavir; zidovudine þ lamivudine þ efavirenz; zidovudine þ lamivudine þ abacavir þ efa virenz) in the initial treatment of HIV-1 infection in 1147 subjects (70 C ). There were modest rises in serum triglycerides, LDL cholesterol, and HDL cholesterol in the two efavirenz-containing arms com pared with the triple-nucleoside arm.

Urinary tract A renal calculus that occurred in a 47-year-old man taking efavirenz contained efavirenz metabolites (60%) and about 40% of unspecified proteins (71 A ). This was a between-the eyes adverse effect of type 1a, definitively implicating efavirenz (72 H ).

Breasts In cohort study from Cambodia, 2 of 343 patients developed gynecomastia while taking a regimen containing efavirenz (73 c ).

Susceptibility factors Genetic Efavirenz is metabolized by CYP2B6. The pharmacokinetics of efavirenz have been studied in 71 children with a G-to-T polymorphism at position 516 of the CYP2B6 gene, which affected its oral clearance (74 c ). Children with the T/T genotype had a slower oral clearance rate than those with the G/T genotype and the G/G genotype. The fastest clearance was found in children under 5 years of age with the G/G genotype.

The association between efavirenz-induced psychosis and a genetic polymorphism in CYP2B6 has been reported in a child (75 A ).

• A 12-year-old HIV-positive girl taking lopinavir 400 mg bd, ritonavir 100 mg bd, stavudine 30 mg bd, didanosine 250 mg/day, and efavirenz 600 mg/day developed an overt psychosis. Her serum efavirenz concentration was 7-8 times higher than expected and she had a heterozygous gene polymorphism encoding for the CYP2B6 isoenzyme, which has previously been associated with reduced clearance of efavirenz. The psychotic symptoms resolved gradually after withdrawal of efavirenz.

Antimalarial drugs Two healthy volunteers who took amodiaquine plus artesunate and efavirenz had significant asymptomatic rises in liver transaminases, which did not occur in the absence of efavirenz (76 c ).

Voriconazole In a randomized, placebocontrolled, two-period, multiple-dose within-group, fixed-dose sequence study of the interaction of voriconazole 200 mg bd with efavirenz 400 mg/day in healthy men, repeated doses of efavirenz substantially reduced the steady-state mean AUC and C max of voriconazole by 80% and 66% respectively (77 C ). Repeated therapeutic doses of voriconazole moderately increased the steady-state mean AUC and C max of efavirenz by 43% and 37% respectively. When voriconazole was co-administered with efavirenz, the incidence of adverse events was similar to that with efavirenz alone.

Liver Hepatotoxicity is a major problem with nevirapine (78 R ). The frequency of large increases in liver enzymes in patients taking efavirenz is 1-8%, whereas in patients taking nevirapine it is 4-18%.

A warning about the increased risk of hepatotoxicity in antiretroviral-naive patients who start to take nevirapine-containing combination antiretroviral therapy has been issued based on CD4 cut-off values and sex. However, it is unclear whether this higher risk also applies to stable virolo gically suppressed patients. A meta-analysis of four published randomized studies in 410 patients, including virologically suppressed patients who switched to nevirapine-con taining regimens with a follow-up of at least 3 months, has shown that the risks of hepatotoxicity within the first 3 months were 2% and 4% in those with low and high CD4 counts, respectively, with a com bined OR of 1.5 (95% CI = 0.4, 5) (79 M ). The risk of hepatotoxicity at any time dur ing the study was similar in the groups, with a combined HR of 0.8 (95% CI = 0.3, 2.5). The authors concluded that virologically suppressed patients who switch to nevira pine do not have a significantly higher risk of hepatotoxicity or rash when stratified by sex and CD4 cell count.

The aim of a retrospective study was to determine whether these recommendations are of use in preventing adverse effects (80 c ). Drug-naive patients (n = 142) who started treatment with nevirapine were divided into two groups: those with high or low CD4 counts (n = 61 and 81 respec tively). There were rashes in 4 patients in the high-CD4 group and in 12 of those in the low-CD4 group and hepatotoxicity in 3 and 5 patients respectively. The authors concluded that the advice not to use nevir apine in drug-naive patients at increased risk of toxicity on the basis of sex and CD4 cell count does not seem to be useful in preventing adverse effects.

In a retrospective study, 582 patients (72% men) received 744 nevirapine-based HAART regimens (81 c ). During 10% of treatments, there were grade 3 or greater increases in transaminase activities, an overall incidence rate of 5.3 cases per 100 person-years. This led to treatment with drawal in 3.9% of cases.

In a retrospective study of over 1000 pregnant women taking nevirapine-contain ing regimens, 93% started or continued nevirapine during the first and second trimesters (82 cA ). Concurrent chronic hepatobiliary disorders slightly increased the likelihood of hepatotoxicity. Of seven patients who had liver dysfunction, six pre viously had had hepatitis C and gall blad der disease.

Skin Widespread vitiligo after erythroderma has been attributed to nevirapine (83 A ).

• A 34-year-old man developed erythroderma, a high fever and hepatitis after taking nevirapine for 1 month. There was jaundice and a confluent macular rash on the arms, legs, trunk, and face. Histology showed a parakeratotic epidermis with focal spongiosis, necrotic keratinocytes and vacuolar degeneration of the basal layer, together with moderate edema and a perivascular mononuclear cell infiltrate, with some eosinophils in the upper dermis. The lesions faded on withdrawal of nevirapine and administration of oral glucocorticoids, but took around 6 months to finally subside.

• A 12-year-old girl took a nevirapine containing regimen for 4 months and had recurrent episodes of fever, cough, sore throat, nausea, and vomiting 2-4 weeks apart.

A chest X-ray showed mild bronchial wall thickening with left lower lobe atelectasis or a mild infiltrate. Her temperature was 40°C and she had a tachycardia of 145/minute. She had a generalized maculopapular confluent blanching rash, but no target lesions or blisters, conjunctival injection, nasal congestion, a hyperemic posterior pharynx, and several bilateral non-tender cervical lymph nodes. The liver was enlarged by 4 cm but the spleen was not palpable. The white blood cell count was 9.7 Â 10 9 /l, with a marked eosinophilia (31%). She was successfully treated with intravenous immunoglobulin and antiretroviral drug withdrawal.

Nevirapine-induced Stevens-Johnson syn drome has been reported as having been misdiagnosed as viral keratitis (85 A ).

Immunologic In a retrospective study of trough plasma concentrations of nevirapine and five oxidative metabolites in 1357 patients with rashes or liver function abnormalities during the first 6 weeks of treatment and controls matched for glucocorticoid use, CD4 cell count, sex, race, and hepatitis B/C status, 49 casecontrol pairs were studied (86 c ). Women had significantly greater exposure than men to nevirapine and four of the five metabolites at week 2, but the plasma concentrations were comparable by week 4. There were no strong relationships between plasma concentrations of nevirapine or any of its five metabolites and case-defining events. The authors commented that systemic exposure to 12-hydroxynevirapine and 4-carboxynevirapine, hypothesized to be reactive intermediates for immunemediated adverse reactions, were comparable between the cases and controls and were comparable in proportion to nevirapine exposure.

Pregnancy In a retrospective, five-center comparison in HIV-1-infected women who took nevirapine as part of combination antiretroviral therapy during pregnancy, 15 of 235 eligible women (6.4%) developed a rash and 8 (3.4%) developed hepatotoxicity, including 4 with a co-existent rash, giving a combined incidence of 19 potential cases of nevirapine toxicity during pregnancy (8.1%) (87 c ). Alternative causes of rash or hepatotoxicity were suspected in 7 cases, and only 10 mothers (5.8%) stopped taking nevirapine. Of the 170 women who started taking nevirapine during pregnancy, 13 (7.6%) developed a rash and 8 (4.7%) hepatotoxicity. Only 2 of 65 women (3.1%) with nevirapine exposure before pregnancy had had a rash.

Susceptibility factors Genetic HLA typing and demographic and immunological susceptibility factors for reactions to nevirapine and efavirenz have been studied in 21 HIV-positive patients with rashes (88 c ). Isolated rashes were significantly associated with HLA-DRB101. There were no cases of liver toxicity nor any association with the percentage of CD4 cells.

In 326 HIV-1-positive individuals, 309 of whom were Japanese, 42% of those who had hypersensitivity reactions to nevirapine had HLA-Cw8, compared with only 10% of the others and 9-14% of the general Japa nese population (89 c ). In the former group, four patients, including one who developed hepatotoxicity, had HLA-Cw*0801 and one had HLA-Cw*0803. Among the others, three patients had HLA-Cw*0801. There were no significant differences in the fre quencies of other HLA alleles between the two groups.

Drug dosage regimens Nevirapine has a long half-life and could be given once a day, but the risk of rashes and concerns over liver toxicity preclude the routine use of once-daily dosing. However, tolerance to high concentrations of nevirapine can develop when doses are increased slowly during the start of therapy. It is therefore theoretically possible that the benefits of once-daily dosing could be achieved without excess toxicity by switching to once-daily nevirapine after several months of twice-daily administration (90 R ).

However, in the DAUFIN study, a twicedaily regimen of zidovudine 300 mg þ lami vudine 150 mg þ nevirapine 200 mg was compared with a once-daily regimen of lamivudine 300 mg þ tenofovir 245 mg þ nevirapine 400 mg (91 C ). The study was stopped after early virological failure was observed in 8 of 36 once-daily patients. Resistance mutations accumulated during treatment, with high rates of K65R muta tions and severe NNRTI resistance profiles indicative of continuing viral replication caused by suboptimal nevirapine plasma trough concentrations, possibly due to non adherence. Non-B-subtype infection (sub types A and C not stated) was observed in 4 of 10 patients with virological failure. The authors suggested that once-daily dosing can be introduced after induction of viral suppression has been achieved with a twice-daily regimen.

Co-administration of nevirapine 200 mg/day with fluconazole 400 mg/day results in markedly increased trough plasma nevirapine concentrations compared with nevirapine alone (92 c ). In a retrospective study in 112 patients who were given nevirapine-based therapy with or without fluconazole 200 or 400 mg/day, mean nevirapine concentrations were 6.5 mg/l without fluconazole and 11.4 with fluconazole. One patient taking fluco nazole developed hepatitis. Six of those who did not take fluconazole developed nevira pine-related rashes. There were no differ ences in 36-week antiviral efficacy between the two groups. Liver Rises in serum unconjugated bilirubin concentrations were reported in the Pivotal Phase III Trial. The mechanism is thought to be direct inhibition of bilirubin conjugation by competitive inhibition of UDP glucuronosyltransferase. Patients with polymorphisms in the UGT 1A1 gene are more likely to develop hyperbilirubinemia (100 R ).

Urinary tract Indinavir causes nephro lithiasis and renal impairment as a result of crystallization in the urinary tract and resultant inflammation (101 A ). Continuation of the drug with some improvement in renal function is possible with drug concentration monitoring. Co-factors such as concomitant co-trimoxazole therapy and environmental temperature increase the risk (100 R ). Using indinavir þ ritonavir at the lower doses of 400 and 100 mg bd seems to reduce these adverse effects.

Hematuria and flank pain each occurred in 38 patients in a study of asymptomatic HIV-infected individuals who took indina vir in a long-term follow-up study over 157 weeks (25 c ).

Hair and nails Paronychia, alopecia, curling of straight hair, and ingrowing toenails have all been attributed to indinavir (102 R ).

Pregnancy In a study of 16 pregnant women taking indinavir, two women and eight infants developed hepatotoxicity and had increased concentrations of indinavir, suggesting increased intestinal/hepatic CYP3A activity during pregnancy (103 A ).

Metabolism Of 111 pregnant women 15 taking nelfinavir developed gestational diabetes compared with none taking zidovudine monotherapy and two of 43 taking NRTIs and NNRTIs; the risk of gestational diabetes was increased in those with hepatitis C or who had begun HAART before pregnancy (104 c ).

Nails Paronychia has been reported in a case report occurring during nelfinavir treatment (105 A ).

Drug-drug interactions Fluticasone Cush ing's syndrome and adrenal suppression can be caused if protease inhibitors increase systemic glucocorticoid concentrations. Iatrogenic Cushing's syndrome has been attributed to ritonavir by an interaction with fluticasone (106 A ).

• A 16-year-old girl who had taken various antiretroviral drugs eventually took stavudine, lamivudine, and ritonavir and then used inhaled fluticasone þ salmeterol for bronchiectasis. After 3 months she had excessive weight gain, increased appetite, fatigue, facial edema, marked acne, stretch marks on her limbs and abdomen, hypercholesterolemia, hypertriglyceridemia and amenorrhea. Cushing's syndrome was attributed to an interaction of fluticasone with ritonavir, which was changed to efavirenz. There was a gradual improvement within 30-60 days, with reduced edema and stretch marks and return of menstruation.

A similar case involved a 14-year-old girl (107 A ).

Observational studies In the ASPIRE 1 study, 7 of 17 healthy volunteers who took saquinavir þ ritonavir for 3 months developed grade 3 gastrointestinal adverse effects and seven had hyperbilirubinemia (108 c ). In the ASPIRE 2 study there was hyperbilirubinemia in 8 of 16 healthy volunteers.

Tipranavir is a non-peptide protease inhibitor approved for use in patients with resistant strains of HIV (109 R , 110 M , 111 R ). Its pharmacokinetics, efficacy, and adverse effects in children and adolescents have been reviewed (112 R ) . It can be used in combination with ritonavir.

Observational studies In a 24-week multi-center, double-blind, randomized, dose-finding trial of ritonavir-boosted tipra navir in 216 patients, the most common adverse events were diarrhea, nausea, vomiting, fatigue, and headache (113 C ).

Hematologic Tipranavir boosted with ritonavir caused an increased risk of bleed ing in 3 of 30 HIV-infected patients with hemophilia (114 c ).

Intracranial hemorrhage has been reported in a patient taking tipranavir (115 A ).

Liver Tipranavir is associated with an excess of grade 3/4 rises in liver enzyme compared with other ritonavir-boosted protease inhibitors (116 R ).

Pancreas Acute pancreatitis associated with hypertriglyceridemia has been reported in a patient taking tipranavir þ ritonavir (117 A ).

• A 42-year-old man taking tenofovir 300 mg/day, trizivir (zidovudine, lamivudine, and abacavir) one tablet bd, and tipranavir 500 mg bd þ ritonavir 200 mg bd drank six standard alcoholic drinks 2 days before admission and developed marked tenderness in the epigastric region and a raised serum lipase at 113 IU/l (reference range below 65 IU/l). An abdominal computed tomography (CT) scan showed pancreatic edema with peripancreatic fluid consistent with acute pancreatitis. Ultrasonography showed a mildly dilated common bile duct with no evidence of cholelithiasis and CT cholangiography showed no evidence of gall-stone pancreatitis. The presumed diagnosis was alcohol-induced pancreatitis. He was managed conservatively by withdrawal of medications, intravenous fluids, and slow resumption of oral intake. However, within 12 days he again developed severe epigastric pain. He denied further alcohol use. The serum concentration of triglycerides was 99 mmol/l, and retrospective testing of blood samples taken during the earlier illness also showed marked hypertriglyceridemia. Tipranavir þ ritonavir was withdrawn, efavirenz given, and tenofovir and trizivir continued. His triglyceride concentrations fell to 10.3 mmol/l 3 weeks later and 4.8 mmol/l 12 months later without specific intervention.

Skin Porphyria cutanea tarda has been reported after the introduction of tipranavir þ ritonavir to a backbone of tenofovir and lamivudine (118 A ).

• A 59-year-old heterosexual woman switched to tipranavir-containing therapy after virological failure. After 5 days she developed a rash accompanied by nausea, vomiting, malaise, and hyperamylasemia. All antiretroviral drugs were withdrawn, she improved, and treatment was restarted. Although the lesions were resolving, several blisters appeared on her hands, mainly on the fingers, along with itching and skin fragility on her arms. Aciclovir was ineffective and 1 month later the itch and blisters worsened. Urine concentrations of protoporphyrin and coproporphyrin were about 100 and 10 times higher than normal.

Drug resistance Virological response rates in tipranavir-treated individuals were reduced when isolates with substitutions at amino acid positions I13, V32, M36, I47, Q58, D60, V82, or I84 were present at baseline (119 C ). In addition, virological response rates to tipranavir were reduced when the number of baseline protease inhibitor mutations was five or more. Individuals who took tipranavir without concomitant enfuvirtide and had five or more baseline protease inhibitor mutations began to lose antiviral response at weeks 4-8. However, individuals taking enfuvirtide with tipranavir achieved more than 1.5 log 10 reductions in viral load from baseline at 24 weeks, even if they had five or more baseline protease inhibitor mutations. Virological response rates to tipranavir were reduced when the baseline phenotype for tipranavir had a greater than threefold shift in the 50% effective concentration (EC 50 ) from reference. The most common protease inhibitor mutations that were associated with virological failure were L10I/V/S, I13V, L33V/I/F, M36V/I/L V82T, V82L, and I84V.

Drug-drug interactions Interactions with tipranavir þ ritonavir have been reviewed (120 R ). Tipranavir is metabolized by CYP3A and tipranavir þ ritonavir in vitro inhibits CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A and induces glucuronidase and P glycoprotein.

inhibitors Ritonavir-boosted tipranavir, alone and in combination with comparator protease inhibitors, has been studied in 315 HIV-infected patients (121 C 

Psychiatric Oseltamivir-induced worsening of delirium has been reported in an 83-year old man, whose symptoms resolved 2 days after withdrawal (122 A ).

Japanese authorities advised against using oseltamivir in adolescents aged 10-19 years after two suicides during 2007 and more than 100 reports of neuropsychiatric events identified during post-marketing sur veillance, including delirium, convulsions, and encephalitis (123 r ). However, it is not clear whether these events were due to the influenza or the drug; in Phase III trials, there were similar incidences of neurologi cal and psychiatric events in both treated and untreated patients (124 R ). Of 1113 patients enrolled in a Japanese neuramini dase inhibitor treatment study, 11 had neuropsychiatric symptoms, in 4 cases before the start of treatment (125 C ). The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have advised doctors to monitor patients for abnormal behavior throughout treat ment (123 r ).

Gastrointestinal Acute hemorrhagic colitis has been associated with oral oseltamivir in a 61-year-old man, who developed abdominal pain, diarrhea and hematochezia after taking two doses of oseltamivir (126 A ).

In a systematic review of three trials of neuraminidase inhibitors for preventing and treating influenza in 1500 children, 977 of whom had laboratory-confirmed influenza, those who took oseltamivir had vomiting more often than untreated children but withdrawal was rarely required (127 M ).

Drug resistance Resistance occurs in under 1% of healthy adults but occurs more often in children, from 5.5% up to 18% in one study, although a lower dosage regimen was used in that study. Resistance is often seen among immunocompromised patients. It was reported in two of eight patients infected with H5N1 and was associated with a fatal outcome. Resistance is associated with loss of fitness (128 R ). In 2008 widespread resistance emerged in H1N1 influenza, but it remains to be seen whether its circulation is sustained after the emergence of oseltamivir-sensitive swine vH1N1.

Susceptibility factors Genetic There was no evidence of a difference in AUC 1!20 of oseltamivir or its active metabolite oseltamivir carboxylate between 14 Japanese subjects and 14 Caucasian subjects, or between children aged 1-2 years old and adults (129 c ).

Systematic reviews A meta-analysis of the adverse effects of zanamivir in children showed that it was no worse than placebo (127 M Comparative studies In a randomized controlled trial in patients with chronic hepatitis C treated with interferon-alfa 2a alone (n = 53), with amantadine 100 mg bd (n = 111), with ribavirin (n = 106) or with amantadine þ ribavirin (n = 108), there was a sustained virological response in 13%, 6%, 18%, and 22% respectively (130 C ). This was statistically different between interferon þ amantadine and triple therapy but not between interferon þ ribavirin and triple therapy. The spectra and frequencies of adverse effects were similar in all four treatment arms. However, six patients withdrew because of adverse effects, three of them in an arm containing amantadine.

In two groups of non-responders with HCV genotype 1 chronic infection taking interferon and ribavirin, with or without amantadine 200 mg/day, viral load fell more markedly in the group taking triple therapy including amantadine, but the response rates at the end of treatment were not signifi cantly different (131 c ). Although analysis of the viral ion channel p7 showed selective pressure during therapy, no specific resi dues appeared to be linked to the effect of amantadine on the virus. The authors sug gested that this implied that the antiviral effect of amantadine is non-specific and related to reduced endosomal acidification and therefore reduced transport of hepatitis C by a pH-dependent pathway.

In a multicenter study of 75 non-respon ders with chronic hepatitis C randomized to interferon monotherapy (n = 26), dual ther apy with ribavirin (n = 24) and triple therapy with additional amantadine 200 mg/day (n = 25), amantadine did not increase the frequency or severity of adverse effects (132 C ).

In 22 patients with chronic hepatitis C genotype 1b, with high viral loads treated with interferon-beta for 4 weeks followed by interferon-alfa 2b, ribavirin, and amantadine 150 mg/day for 22 weeks, there was a sustained virological response in 7. Only one patient had to stop taking amantadine, because of the adverse effect of light-headedness (133 c ).

In 15 renal transplant recipients with chronic hepatitis C, doses of ribavirin monotherapy (n = 7) or ribavirin þ amantadine (n = 8) were adjusted according to creatinine clearance (134 c ). There was no difference between treatment groups with respect to liver enzymes, hepatitis C viremia, liver his tology, or renal function. Anemia, the main adverse effect, was most notable in those with a creatinine clearance below 50 ml/ minute. Other adverse effects included leukopenia, mood disorders and profuse sweating. Only one of those who received combination therapy were still taking aman tadine after 12 months; two completed treatment but with ribavirin alone. Four of those taking monotherapy completed treat ment. Neither regimen was clearly superior to no treatment, but the study was small and probably underpowered.

Sensory systems In a post-marketing surveillance study of patients with a new diagnosis of corneal disease and new prescriptions for amantadine over 2 years, 36 (0.27%) of 13 137 patients developed Fuchs dystrophy (corneal edema) (135 C ). The relative risk of corneal edema was 1.7 (95% CI = 1.1, 2.8); in 12 patients (0.09%) the diagnosis was made in the first month.

Drug resistance Amantadine is unreliable in the management of influenza because of the emergence of widespread resistance. This is notable in the H3N2 subtype and most H5N1 subtypes, but some seasonal H1N1 remains sensitive to amantadine (128 R 

Treatment of adenovirus pneumonia with cidofovir in pediatric lung transplant recipients

infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir

Low-dose cidofo vir treatment of BK virus-associated hemor rhagic cystitis in recipients of hematopoietic stem cell transplant

Acyclovir-induced neuropsychosis success fully recovered after immediate hemodialy sis in an end-stage renal disease patient

Acute renal failure caused by intravenous acyclovir for disseminated var icella zoster virus infection

Determi nants of aciclovir-induced nephrotoxicity in children

Entérocolite ulcéronécrosante chez un nouveau-né à terme. Rôle de l'acy clovir? [Necrotizing enterocolitis in a full term infant. Is acyclovir involved?

Immediate allergy from valacyclovir

Oliguric acute renal failure following oral valacyclovir therapy

Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg negative chronic hepatitis B

Adefovir dipivoxil therapy in liver transplant recipients for recurrence of hepatitis B virus infection despite lamivudine plus hepatitis B immu noglobulin prophylaxis

Absence of a pharmacokinetic interaction between entecavir and adefovir

Lamivudine and high-dose interferon alpha 2a combination treatment in naive HBeAg-positive immunoactive chronic hepatitis B in children: an East Mediterra nean center's experience

Pharmacokinetics of lamivu dine in subjects receiving peritoneal dialysis in end-stage renal failure

Telbivu dine versus lamivudine in patients with chronic hepatitis B

Adverse events associated with high-dose ribavirin: evidence from the Toronto out break of severe acute respiratory syndrome

Long-term therapy with aerosolized riba virin for parainfluenza 3 virus respiratory tract infection in an infant with severe com bined immunodeficiency

Syncope as a prob able side effect to combination antiretro viral therapy initiated during primary HIV 1 infection

Kallianpur ARAIDS Clinical Trials Group 384 and A5005s Study Teams. Hemochromatosis gene poly morphisms, mitochondrial haplogroups, and peripheral lipoatrophy during anti retroviral therapy

Del Río LABCDE (Aba cavir vs. d4T (stavudine) plus efavirenz) Study Team. Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study

Antiretroviral drug levels and interactions affect lipid, lipoprotein, and glucose metabolism in HIV-1 seronegative subjects: a pharmacoki netic-pharmacodynamic analysis

MaxCmin1 and 2 trial groups. Phar macokinetics of two randomized trials evaluating the safety and efficacy of indina vir, saquinavir and lopinavir in combination with low-dose ritonavir: the MaxCmin1 and 2 trials

Assess ment of adverse events associated with anti retroviral regimens for postexposure prophylaxis for occupational and nonoccu pational exposures to prevent transmission of human immunodeficiency virus

for the Protocol 060 Study GroupEfficacy, safety, and tolerability of long-term combination antiretroviral therapy in asymptomatic treatment-naive adults with early HIV infection

Clinical and pharmacokinetic data support once-daily low-dose boosted saquinavir (1,200 milli grams saquinavir with 100 milligrams ritonavir) in treatment-naive or limited protease inhibitor-experienced human immunodeficiency virus-infected patients

Dose reduction effective in alleviating symptoms of saquinavir toxicity

French National Agency for Research on AIDS; Viral Hepa titis-HC02-Ribavic Study Team. Progres sion of fibrosis in HIV and hepatitis C virus-coinfected patients treated with inter feron plus ribavirin-based therapy: analysis of risk factors

Hepato toxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepa titis B

Nodular regenerative hyperplasia of liver as a consequence of ART

The role of antire troviral therapy in the incidence of pancrea titis in HIV-positive individuals in the EuroSIDA study

Amprenavir and di danosine are associated with declining kid ney function among patients receiving tenofovir

Acute interstitial nephritis of HIV-positive patients under atazanavir and tenofovir therapy in a retrospective analysis of kidney biopsies

Possible allergic cross-reaction to didanosine and tenofovir in an HIV-1-infected woman

Seage 3rd GR. In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunc tion in HIV-uninfected children

Adverse events experi enced by three children taking tenofovir and didanosine in combination

Phar macokinetic interaction between darunavir and saquinavir in HIV-negative volunteers

Interaction between buprenor phine and atazanavir or atazanavir/ritona vir

Pos sible antiretroviral therapy-warfarin drug interaction

Factors in AIDS dementia com plex trial design: results and lessons from the abacavir trial

B*5701-associated abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase

Are disulfiram-like reactions associated with abacavir-containing antiretroviral regi mens in clinical practice?

Fanconi syndrome and nephrogenic diabetes insipidus associated with didanosine ther apy in HIV infection: a case report and literature review

CD4þ cell count decline despite HIV suppression: a prob able didanosine-valganciclovir interaction

Severe weight loss in HIV/HCV-coinfected patients trea ted with interferon plus ribavirin: incidence and risk factors

Stavudine plasma concentrations and lipoatrophy

Hernández-Mora dine discontinuation to anthropometric MG, Novoa SR, Quintana FB, Lahoz JG, changes among HIV-infected women

complicating the abacavir hypersensitivity reaction

Abacavir hypersensitiv ity reaction after switching from the twicedaily to the once-daily formulation

Acute fibrinous and organizing pneumonia as a rare presen tation of abacavir hypersensitivity reaction

A simple screening approach to reduce

Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial func tion in muscle of healthy adults

Risk factors for mortality in symptomatic hyperlactatemia among HIV-infected patients receiving antiretroviral therapy in a resource-limited setting

Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treat ment

Safety of stavudine in the treatment of HIV infection with a special focus on resource-limited settings

Blunted humoral response to influenza vaccination in patients exposed to zidovu dine plus trimethoprim-sulfamethoxazole

AIDS Clinical Trials Group 5092s Study Team. Pharmacokinetic evaluation of the effects of ribavirin on zidovudine triphosphate formation: ACTG 5092s Study Team

Efficacy and safety of tenofovir double-dose in treatment-experi enced HIV-infected patients: the TENO PLUS study

Castillo Muñoz A, toxicity in HIV-infected subjects: a rando-Baños Roldán U, Artacho Criado S. Analisis mized, controlled study

Increased haemoglobin A2 percentage in HIV infection: disease or treatment?

Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to pre vent mother-to-child transmission of HIV

Assessment of birth defects according to maternal therapy among infants in the Women and Infants de las causas y factores predictivos de discon tinuacion del tratamiento con tenofovir en pacientes VIH pretratados

Increased beta-2 microglobulinuria in human immunodeficiency virus-1-infected children and adolescents treated with tenofovir

Neuropsychiatric side effects of efavirenz therapy

Pharmacokinetics of oral zidovudine administered during labour: a preliminary study

Teratogenicity risk of antiretro viral therapy in pregnancy

Efficacy and safety of a once daily regimen with efavirenz, lami vudine, and didanosine, with and without food, as initial therapy for HIV Infection: the ELADI study

Effectiveness and safety of simplification therapy with once-daily tenofovir, lamivu dine, and efavirenz in HIV-1-infected patients with undetectable plasma viral load on HAART

Metabolic effects of protease inhibitor-spar ing antiretroviral regimens given as initial treatment of HIV-1 Infection (AIDS Clin ical Trials Group Study A5095)

Efavir enz urolithiasis

Anecdotes that provide definitive evidence

Positive outcomes of HAART at 24 months in HIV-infected patients in Cambodia

Efavirenz pharmacokinetics in HIV-1-infected chil dren are associated with CYP2B6-G516T polymorphism

Psychosis in a 12-year-old HIV-positive girl with an increased serum concentration of efavirenz

Hepatotoxicity due to a drug interaction between amodia quine plus artesunate and efavirenz

Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy male subjects

Liver toxicity induced by non-nucleoside reverse tran scrptase inhibitors

Hepatotoxicity of nevirapine in virologically suppressed patients according to gender and CD4 cell counts

Risk of side effects associated with the use of nevirapine in treatment-naive patients, with respect to gender and CD4 cell count

Reasons for disconti nuation of nevirapine-containing HAART: results from an unselected population of a large clinical cohort

Safety issues about nevirapine administration in HIV-infected pregnant women

Widespread viti ligo after erythroderma caused by nevira pine in a patient with AIDS

Nevira pine-associated rash with eosinophilia and systemic symptoms in a child with human immunodeficiency virus infection

Nevirapine induced Stevens-Johnson syndrome in an HIV patient

Case-control exploration of relationships between early rash or liver toxicity and plasma concentra tions of nevirapine and primary metabo lites

Safety of nevirapine in pregnancy

HLA-DRB1*01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz

HLA-Cw8 primarily associated with hypersensitivity to nevirapine

Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety review

Once-daily dosing of nevirapine in HAART

Plasma nevirapine levels, adverse events and efficacy of antiretroviral therapy among HIV-infected patients concurrently receiving nevirapine-based antiretroviral therapy and fluconazole

Phar macokinetics of darunavir (TMC114) and atazanavir during coadministration in HIVnegative, healthy volunteers

Alo pecia associated with ritonavir-boosted ata zanavir therapy

Pharmacokinetic interaction between rifampicin and ritonavir-boosted atazanavir in HIV-infected patients

Increased incidence of cutaneous mycoses after HAART initiation: a benign form of immune reconstitution disease?

Fosamprenavir calcium plus ritonavir for HIV infection

Experience of indinavir/ritonavir 400/ 100 mg twice-daily highly active antiretro viral therapy-containing regimen in HIV-1 infected patients in Bamako, Mali: the NOGOMA study

Lack of indinavir-associated nephrological complications in HIVinfected adults (predominantly women) with high indinavir plasma concentration in Abidjan

Indinavir: the forgotten HIVprotease inhibitor. Does it still have a role?

Néphropathie tubulo-interstitielle associée a l'indinavir

Dermatologic adverse effects of antiretroviral therapy: recognition and management

Pharmacokinetics and safety of indinavir in human immunodefi ciency virus-infected pregnant women

Obste tric and perinatal complications in HIVinfected women. Analysis of a cohort of 167 pregnancies between

Paronychia in an HIV-infected patient under nelfinavir ther apy

Iatrogenic Cushing's syndrome in a adolescent with AIDSs on ritonavir and inhaled fluticasone. Case report and literature review

Cushing syndrome and severe adrenal suppression caused by fluti casone and protease inhibitor combination in an HIV-infected adolescent

Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers

Tipranavir: a new option for the treatment of drug-resistant HIV infection

Tipranavir: the first nonpeptidic protease inhibitor for the treatment of protease resistance

Tipranavir: a review of its use in the management of HIV infec tion

Tipra navir: a new protease inhibitor for the pediatric population

Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients

Increased risk of bleeding with the use of tipranavir boosted with ritonavir in haemophilic patients

Intracranial haemorrhage possibly related to tipranavir in an HIV-1 patient with cryptococcal meningitis

Tipranavir: a new protease inhibitor for the treatment of antiretroviral-experienced HIV-infected patients

Acute pancreatitis caused by tipranavir/ritonavir-induced hypertriglycer idaemia

Porphyria cutanea tarda in an HIV-1-infected patient after the initiation of tipranavir/ritonavir: case report

Food and Drug Administration analysis of tipranavir clini cal resistance in HIV-1-infected treatmentexperienced patients

Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir enhanced tipranavir

Pharmacokinetics, safety, and efficacy of tipranavir boosted with ritonavir alone or in combination with other boosted protease inhibitors as part of optimized combination antiretroviral therapy in highly treatmentexperienced patients

Oseltamivir-induced delirium in a geriatric patient

Tamiflu and neuropsychiatric disturbance in adolescents

The role of oseltamivir in the treatment and prevention of influenza in children

A comparison of the effectiveness of zanamivir and oseltami vir for the treatment of influenza A and B

Acute hemorrhagic colitis associated with oral administration of osel tamivir for the treatment of influenza A

Symmonds-Abrahams M. Neur aminidase inhibitors for preventing and treating influenza in children

Antivirals for influenza

Similarity in pharmacokinetics of oseltami vir and oseltamivir carboxylate in Japanese and Caucasian subjects

Induction doses of interferon alpha-2a in combination with ribavirin and/ or amantadine for the treatment of chronic hepatitis C in non-responders to interferon monotherapy: a randomized trial

Hepatitis C virus p7 membrane protein 553 quasispecies variability in chronically infected patients treated with interferon and ribavirin, with or without amantadine

A randomized trial of induction doses of interferon alone or in combination with ribavirin or ribavirin plus amantadine for treatment of nonresponder patients with chronic hepatitis C

Triple therapy of initial high-dose interferon with ribavirin and amantadine for patients with chronic hepatitis C

Combination therapy with ribavirin and amantadine in renal trans plant patients with chronic hepatitis C virus infection is not superior to ribavirin alone

Postmarketing sur veillance of corneal edema, Fuchs dystrophy, and amantadine use in the Veterans Health Administration