Complications of Antiretroviral Therapy

Chinese Version

Updated August, 2009

Rosa F. Yeh, Pharm.D., BCPS, AAHIVE,  Rupali Jain, Pharm.D., BCPS, AAHIVE

First Edition (2003):  JoCarol McNabb, Pharm.D., MPA, Janell Kobayashi, Pharm.D., and

Robert W. Shafer, M.D.

Introduction

               Drug toxicity is often the most common reason for prematurely switching antiretroviral therapy (48) and is an important contributor to nonadherence and virologic failure. Antiretroviral drug toxicities can be divided into those that mandate an immediate change in therapy (e.g. lactic acidosis, pancreatitis, severe hypersensitivity), those that can be managed conservatively unless they progress (e.g. peripheral neuropathy, hepatic transaminase elevations, hyperlipidemia, renal insufficiency, some hematological abnormalities), and those that may not pose serious danger to the patient but may decrease adherence and lead to virologic failure (e.g. headache, dysphoria, gastrointestinal intolerance).

               Many of the toxicities associated with NRTIs – including lactic acidosis, peripheral neuropathy, pancreatitis, lipoatrophy, and myopathy – result from NRTI-induced mitochondrial toxicity (39, 40, 117). This toxicity appears to be caused by a combination of nucleoside analog inhibition of mitochondrial gamma polymerase and interference with exonuclease removal of each analog after incorporation (87, 98).  In vitro studies demonstrate the following hierarchy of mitochondrial DNA gamma polymerase inhibition: ddC > ddI > d4T > 3TC > tenofovir > ZDV > abacavir (87, 90, 110); however, 3TC, tenofovir, abacavir, and ZDV are efficiently removed after incorporation, reducing DNA gamma polymerase inhibition (16, 87, 98). Tissue-specific mitochondrial toxicity is a function of the cellular dependence on mitochondrial function and perhaps of the varying rates of triphosphorylation of the NRTIs in different cells (166). The molecular basis of the toxicities associated with PIs and NNRTIs is less well understood.

Guideline:  Aberg JA, et al.  Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America.  Clin Infect Dis 2009;49:651-681. 

POTENTIALLY LIFE-THREATENING TOXICITIES

Bleeding

               Intracranial hemorrhage has been reported with tipranavir/ritonavir, including some fatalities. Median onset of occurrence ranged 227 and 525 days after initiation of tipranavir/ritonavir (31, 47). The main risk factors include: central nervous system lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, alcohol abuse, and receipt of anticoagulant/anti-platelet medications, including vitamin E. Avoid use of tipranavir/ritonavir in those with risk factors, especially the oral solution of tipranavir/ritonavir which contains a vitamin E derivative (9, 31, 142).

               Increased spontaneous bleeding episodes in patients with hemophilia A and B have been observed with the use of PIs (142).  Most of the reported episodes have involved joints and soft tissues. Bleeding episodes occurred a median of 22 days after starting PI therapy and may require increased use of coagulation factors (142).

Hematological Toxicity

               Reversible anemia (uniformly associated with an MCV >100 fL) and granulocytopenia develop in about 5 to 10% of patients receiving ZDV, particularly in patients with advanced HIV infection (23). Depending on the severity of these toxicities, it is common to either reduce the dose of ZDV, substitute an alternate NRTI such as d4T or abacavir, or, in some cases, to treat the patient with erythropoietin (EPO) or granulocyte-colony stimulating factor (G-CSF). Baseline endogenous EPO levels of less than 500 IU/L are predictive of a response to EPO (36). Concomitant use of agents causing hematological toxicity such as ganciclovir, valganciclovir, trimethoprim/ sulfamethoxazole, and ribavirin should be discontinued if alternative agents exist.

Hepatitis/Hepatotoxicity

               Asymptomatic elevations of hepatic transaminases can occur in 6 to 30% of patients receiving combination antiretroviral therapy, and estimates of severe hepatotoxicity range from 2 to 18% (138). The main risk factors for hepatitis appear to be chronic infection with HCV or HBV, alcoholism, co-administration of hepatotoxic agents (especially rifampin), elevated PI concentrations, and increased baseline transaminases  (46, 71, 84, 111, 169-172, 185).  However, each of the NNRTIs, PIs, most NRTIs, and maraviroc can cause hepatitis and hepatotoxicity.

               Hepatitis, including liver failure, can occur with nevirapine and is usually seen within the first 6 to 12 weeks of administration. This occurs more frequently in patients with higher baseline CD4 counts (>250 cells/mm3 in women, > 400 cells/mm³ in men), females, and possibly those with elevated nevirapine concentrations (73, 142). The DHHS guidelines recommend close monitoring of liver-associated enzymes when starting nevirapine at baseline, 2 and 4 weeks, monthly for the first 3 months, then every 3 months thereafter (142).  Adherence to once daily administration for 2 weeks, followed by the twice daily dose escalation may also reduce the risk of hepatic events.

               Hepatitis associated with the PIs and NRTIs usually occurs with chronic administration. Of the PIs, tipranavir/ritonavir is the most frequent culprit. Grade 3 and 4 transaminase elevations were observed in 10.3% of treatment-experienced patients in two large, randomized, open-label trials and 20.3% of treatment-naïve patients through 48 weeks of treatment (9).  Increased transaminases are tipranavir dose-dependent, with a higher proportion of patients experiencing Grade 3 and 4 elevations as tipranavir concentrations increase (69). Tipranavir/ritonavir has also been associated with fulminant hepatic failure, including some fatalities (9, 31). Concomitant use in patients with HBV and/or HCV co-infection should be avoided. Liver function tests should be performed at baseline, followed by frequent monitoring during therapy.

               Patients with a history of chronic viral hepatitis or elevated transaminase levels should be counseled to avoid alcohol and hepatotoxic drugs such as acetaminophen and isoniazid. Withdrawal of antiretrovirals with HBV activity such as 3TC, FTC, or tenofovir in patients with chronic HBV can also lead to a flare in hepatitis. Thus, it is important to be aware of HBV serologies in all patients receiving HAART. Providers and patients should monitor for signs and symptoms of hepatitis, including fatigue, anorexia, nausea, jaundice, bilirubiuria, acholic stools, abdominal tenderness, and hepatosplenomegaly. Most clinicians would discontinue all drug therapy or the most likely drug causing the hepatitis when transaminase levels are ≥5 times the upper limit of normal (ULN). Re-challenge with the offending agent is not generally recommended, unless an alternative cause for the elevated transaminase levels is suspected. Transaminases should be measured monthly in patients with levels between 2-5 times ULN.

               Asymptomatic indirect (unconjugated) hyperbilirubinemia occurs frequently with atazanavir (34 to 49%) and indinavir (14%) due to inhibition of UDP-glucuronosyl transferase (UGT) 1A1, the enzyme that conjugates bilirubin (42, 146, 149, 190).  Alone this does not represent liver toxicity and does not require drug discontinuation. Hyperbilirubinemia and jaundice are concentration-related and occur more frequently with ritonavir-boosted atazanavir compared to use without ritonavir (146, 148).  Dose reduction of atazanavir is currently not recommended because the long-term efficacy of reduced doses has not been established (146).

               Maraviroc is the first FDA-approved CCR5 inhibitor indicated for combination treatment of antiretroviral-experienced adults with only CCR5-tropic HIV-1 with evidence of active infection. Clinical trials of another CCR5 inhibitor in development, aplaviroc, were halted due to increased incidence of severe hepatotoxicity (43, 187). This does not appear to be a class effect, but likely an idiosyncratic reaction due to the molecule itself (63, 77, 136).  Maraviroc does have a black box warning for concerns about hepatotoxicity but reports are limited. A single case of severe hepatotoxicity was observed in an antiretroviral-naïve study, however this was confounded by concomitant receipt of drugs associated with hepatotoxicity including isoniazid, trimethoprim-sulfamethoxazole, and high-dose acetaminophen(116, 161).

Immune Reconstitution Inflammatory Syndrome

               Immune reconstitution inflammatory syndrome (IRIS) has been reported with combination antiretroviral therapy. In the setting of an opportunistic infection (OI), initiation of ART would logically improve immune function and therefore lead to faster resolution of the OI. However, a paradoxical worsening of the OI can occur. IRIS refers to a group of clinical syndromes associated with immune reconstitution and concurrent OI, most commonly mycobacterial infections. The symptoms of IRIS are diverse and have not been precisely defined. They can be characterized by fever and worsening of clinical manifestations of the underlying OI. The clinical manifestations may be at the site of the previously known pathogen, may unmask disease at a new site, or represent an unrecognized additional pathogen. The majority of patients develop IRIS within the first 4 to 8 weeks after starting antiretroviral therapy (2).

               IRIS diagnosis is challenging and involves differentiating between progression of the initial OI, development of a new OI, unrelated organ dysfunction, or drug toxicity. Treatment for IRIS is empiric, and no well-controlled clinical trials have been performed to determine optimal treatment which can include nonsteroidal anti-inflammatory agents, corticosteroids, or cessation of ART (2).

Skin Rash/Steven’s Johnson Syndrome/Toxic Epidermal Necrosis

               Hypersensitivity reactions manifesting as rash can occur in up to 5% of patients receiving nevirapine. Higher rates of nevirapine hypersensitivity were reported before the starting dose was lowered to 200 mg per day for the first two weeks. Hypersensitivity reactions to efavirenz, delavirdine, and etravirine also occur, but at a lower rate (53, 142, 179). Hypersensitivity reactions usually occur within six weeks of starting a new drug. NNRTI hypersensitivity usually manifests as a maculopapular rash, often accompanied by fever, mucosal changes, and elevated hepatic transaminases. Female patients are at a significantly higher risk of nevirapine hypersensitivity. In one study, 15% of women compared with 3% of men had a rash after starting nevirapine (11). Some clinicians have successfully continued treatment or desensitized patients using antihistamines and low doses of corticosteroids. This practice is considered risky (118, 142, 144) and is currently not recommended by the United States treatment guidelines (142). Despite the different chemical classes of each NNRTI, some degree of cross-hypersensitivity exists. However, cross-hypersensitivity is not complete and unless a patient has had a life-threatening toxicity with one NNRTI (e.g. Steven’s Johnson syndrome (SJS) or toxic epidermal necrolysis), most physicians would be willing to re-challenge using a different NNRTI (24).  The hypersensitivity reaction can range from a maculopapular rash to life-threatening SJS. Among the NNRTI class, Steven’s Johnson syndrome occurs most frequently (although this is rare) with nevirapine (0.3% to 1%), followed by efavirenz and delavirdine (0.1%), and etravirine (less than 0.1%) (142).

               Skin rashes can also occur with PIs, including darunavir (7%), (142, 145) fosamprenavir (19%), (97, 142) and tipranavir (3%) (9).  There are case reports of these agents causing SJS, but this is a rare complication (9, 142, 145).  These agents contain a sulfonamide moiety, therefore caution is warranted when in patients with a known sulfonamide hypersensitivity.

               Maraviroc, the CCR5 chemokine receptor antagonist, is associated with rash in 11% of patients in the MOTIVATE-1 and -2 trials. The incidence of pruritis was 3.8% in clinical trials of maraviroc. Pruritic rash and other signs of a systemic allergic reaction (e.g. eosinophilia, elevated IgE) may precede the development of hepatotoxicity, and these individuals should be evaluated for hepatotoxicity (12, 142, 161).

Abacavir Hypersensitivity

               Abacavir hypersensitivity has been reported in 5 to 9% of clinical trials based on clinical symptoms and is the primary reason for drug discontinuation (80, 193). This hypersensitivity differs from many other drug-induced hypersensitivity reactions due to its presentation. Fever and rash are the most common manifestations and usually occur with other symptoms including: gastrointestinal (e.g. abdominal pain, diarrhea, nausea and vomiting), respiratory (e.g. pharyngitis, tachypnea and dyspnea), as well as systemic symptoms (e.g. chills, rigors, arthralgias, and myalgias) (82, 142, 193).  Symptoms become more severe with continued dosing. The median onset of symptoms is 9 days, with the majority occurring within the first 6 weeks of initiation. Re-challenge with abacavir following a suspected hypersensitivity reaction is absolutely contraindicated and may be fatal (142, 193).
               A highly significant association has been reported for abacavir hypersensitivity and presence of the major histocompatibility complex class I allele HLA-B*5701 (81, 103).  Two recent studies showed that HLA-B*5701 screening in a variety of populations can reduce the incidence of the hypersensitivity reaction to abacavir with high sensitivity and specificity(104, 150).  It is currently recommended to screen for HLA-B*5701 prior to abacavir initiation, and those who screen positive for the allele should not initiate abacavir. Positive status should be documented in the medical record as an abacavir allergy.  If HLA-B*5701 screening is not available or in patients who have a negative test, patient counseling, clinical judgment, and appropriate monitoring are still critically important (142).

Lactic Acidosis and Hyperlactatemia

               Hyperlactatemia is defined as a venous lactate level >18 mg/dL (2 mmol/L). Lactic acidosis is defined as an elevated venous lactate and low arterial pH (<7.30) (156).  The clinical features of lactic acidosis include weight loss, fatigue, abdominal pain, tender hepatomegaly, nausea, vomiting, and respiratory distress. Accompanying laboratory abnormalities include increased anion gap and elevated hepatic transaminases, lipase, amylase, and creatine phosphokinase. Abdominal imaging studies show diffuse fatty infiltration of the liver. Liver biopsy shows severe microvesicular and macrovesicular steatosis (120). Severe lactic acidosis accompanied by lactate levels >10 mmol/l is associated with a high mortality rate (>50%).

               NRTI-associated lactic acidosis may present with profound motor weakness resembling Guillain-Barré Syndrome(162).  Onset is usually several months after beginning antiretroviral therapy, followed by a dramatic motor weakness over several days to weeks. Symptoms include rapidly progressive ascending demyelinating polyneuropathy, respiratory paralysis requiring mechanical ventilation, even resulting in death. The most common risk factor is prolonged d4T use. Early recognition of symptoms is crucial and is managed by discontinuation of all antiretrovirals and supportive care. Recovery may take months and symptoms may be irreversible. Re-challenge with the offending agent is contraindicated (142, 162). 

               Lactic acidosis associated with hepatic steatosis has an incidence between 0.1% to 2.0% per patient per year depending on the patient population and syndrome definition (34, 101, 129).  It was first reported with ZDV monotherapy (34), but has since been reported with each of the NRTIs. It is strongly linked to NRTI-induced mitochondrial toxicity (40). Female sex, pregnancy, obesity, long-term NRTI use, d4T administration, and ddI administration are associated with an increased risk of this toxicity (40, 101, 107, 120, 129). 

               Treatment of acute lactic acidosis requires discontinuation of all antiretrovirals and supportive care. Bicarbonate infusions and hemodialysis, (35) along with vitamin coenzymes (thiamine and riboflavin), electron acceptors (vitamin C), antioxidants (co-enzyme Q), and L-carnitine have been tried without definitive benefit (17, 142).  Patients recovering from NRTI-associated lactic acidosis should either be changed to a non-NRTI containing regimen (e.g. a regimen containing an NNRTI and 1 to 2 PIs) or re-challenged cautiously after recovery with a NRTI with less mitochondrial toxicity (e.g. abacavir, tenofovir, 3TC, or FTC) (40). 

               Lactate levels about 2 to 3 times the upper limit of normal may be associated with a compensated form of hyperlactatemia (13, 85). This syndrome has been reported in 1 to 10% of patients receiving NRTIs, particularly d4T. Accurate lactate levels, especially those obtained from venous blood, are difficult to obtain. Thus, routine monitoring of lactate levels in asymptomatic patients is generally not recommended. In patients with elevated lactate levels, some physicians will replace ddI, d4T, and ZDV with less mitochondria-toxic NRTIs (40, 101, 142).

               Venous lactate levels are highly dependent on collection techniques. Proper collection procedures include: (i) having the patient avoid dehydration or exercise for 24 hours prior to venipuncture, (ii) having the patient sit relaxed for 5 minutes prior to venipuncture, (iii) avoiding fist clenching and the use of a tourniquet, (iv) collecting the sample in a chilled gray-top (sodium fluoride-potassium oxalate) tube, (v) placing the sample on ice and sending it to the laboratory for processing within 30 minutes of collection, (vi) repeating elevated levels after providing additional instructions including the avoidance of alcohol for 24 hours and food or drink for 4 hours prior to venipuncture. If proper collection procedures are not possible and hyperlactatemia or lactic acidosis are likely, arterial lactate levels should be measured.

               The ratio of mitochondrial to nuclear DNA in peripheral blood mononuclear cells is significantly reduced in patients with symptomatic hyperlactatemia (8, 40, 41, 124).  Discontinuation of NRTIs has been associated with improvement in lactic acid levels and in mitochondrial to nuclear DNA ratios. These improvements can be sustained for up to 3 months even after patients are switched to other NRTIs. Measuring the ratio of mitochondrial to nuclear DNA may serve as useful means of identifying patients at higher risk of symptomatic lactic acidosis.

Pancreatitis

               HIV-infected patients have much higher rates of pancreatitis than the general population (44, 126).  The cause of this increase is multifactorial but the NRTIs are important contributory factors. Within the NRTI class, ddI has the strongest association, particularly when administered at a high dose or with hydroxyurea (44, 89, 126). The combination of ddI and tenofovir leads to substantial increase in ddI exposure and can result in an increased risk for pancreatitis (113).  d4T also appears to increase the risk of pancreatitis, but to a lesser degree than ddI. 3TC showed a strong association with pancreatitis in a single pediatric study. High triglyceride levels observed with certain PIs, especially ritonavir, would be expected to also increase the risk of pancreatitis, but this has not yet been documented. The diagnosis of pancreatitis is based on a combination of clinical criteria and laboratory tests. Serum lipase is the most sensitive and specific blood test; abdominal CT scan, MRI, and sonogram are useful radiological tests.

               The diagnosis of pancreatitis requires the immediate discontinuation of all pancreatotoxins and in some cases all medications until the patient is once again able to take oral medications. ddI is absolutely contraindicated in patients who have had pancreatitis. The threshold for using other NRTIs in such patients depends on the circumstances. For example, patients should probably not be given the same drugs they were receiving at the time pancreatitis developed if antiretroviral therapy is the likely cause. Patients who have had lactic acidosis at the time of their presentation should not be given d4T. Some investigators believe that lipase levels should be monitored in patients at risk for pancreatitis and that persistently high levels of lipase, even in the absence of symptoms, should prompt a change to NRTIs with a lower risk of pancreatitis.

Renal Toxicity

               Indinavir is poorly water-soluble and can crystallize in the urine causing obstruction anywhere between the renal tubules and urethra (23, 42, 78).  This can lead to renal colic, painless hematuria, and, rarely, an asymptomatic rise in serum creatinine (14).  Clinically symptomatic nephrolithiasis occurs in about 10% of patients, although it may be more common in patients receiving ritonavir-boosted indinavir (165). Unless it is associated with permanent renal or urologic damage, therapy can be continued as long the patient consumes sufficient fluids (preferably ≥1.5 liters above baseline). Recurrences occur in about 50% of patients.

               Case reports of atazanavir causing nephrolithiasis have recently been published, but has yet to be well characterized(32, 33, 141). In a recent review of the U.S. Food and Drug Administration Adverse Events Reporting System, 30 cases were identified. Many patients required hospital management with ureteral stenting, lithotripsy, or endoscopic stone removal. Although this is a rare complication, healthcare providers should be aware of this potential adverse effect with atazanavir (32, 33, 141). 

               Due to the structural similarity and acknowledged nephrotoxicity of cidofovir and adefovir, tenofovir-associated renal toxicity has been evaluated with great interest. These agents are acyclic nucleotide analogues which are excreted by renal tubule cell uptake and secretion. In clinical trials, tenofovir-associated renal dysfunction was rare in antiretroviral-naïve patients(68, 184). In treatment-experienced patients, decreases in glomerular filtration rate (GFR) have been reported in the Johns Hopkins Cohort. Treatment-experienced patients may be more vulnerable to adverse effects and drug interactions, or more susceptible to kidney disease as a results of advanced HIV and its concomitant comorbidities (66, 78). Renal outcomes were compared in the HIV Outpatient Study in 593 tenofovir-treated patients and 521 HAART-treated patients not receiving tenofovir. A small but statistically significant decrease in GFR was observed, but only 1.1% of tenofovir-treated subjects discontinued the medication (189). It is hypothesized that tenofovir nephrotoxicity is associated with PI co-administration, as they compete for the same renal transporters resulting in inhibition of tubular secretion. Recent studies, however, have not supported this mechanism. Tenofovir-induced acute renal failure (known as Fanconi syndrome) is associated with proteinuria, hypophosphatemia, euglycemic glycosuria, hypouricemia, hypokalemia, and metabolic acidosis (78, 184).

TOXICITIES WITH POTENTIAL LONG-TERM COMPLICATIONS

Cardiovascular Events

               Due to successful use of combination antiretroviral therapy, HIV-infected patients are living longer. However, data suggest that long-term HAART exposure increases the risk of coronary heart disease, cardiovascular, and cerebrovascular events such as myocardial infarction and stroke (62). The D:A:D Study Group is a large prospective observational collaboration of investigators following 33,389 HIV-1-infected individuals from 212 clinics in Europe, the U.S., Argentina, and Australia. They observed a 10 to 16% increase in the rate of myocardial infarction per year of exposure to PIs, but not NNRTIs (61).  PIs are associated with more negative effects on the lipid profile such as increased total cholesterol and low-density lipoprotein cholesterol levels compared to the NNRTIs. However, the increased risk of myocardial infarction was not completely explained by these lipid changes (61).  Experimental data from animal models suggest possible direct cellular mechanisms where PIs may promote atherosclerosis (6, 191, 192). 

               Recently, the same group observed that NRTI use (ddI or abacavir) within the past 6 months was associated with an estimated 50 to 90% increased rate of myocardial infarction. This finding was not seen for the other NRTIs evaluated (ZDV, d4T, and 3TC). Although patients receiving ddI and abacavir had a higher cardiovascular risk profile compared to those receiving other NRTIs, the rate of myocardial infarction was high while patients received these drugs and decreased after they were stopped, lending more support to agent specific cardiovascular toxicity (152). Risk factors for cardiovascular events include those for cardiovascular disease such as smoking, age, hyperlipidemia, hypertension, diabetes mellitus, and family history. Patients with these risk factors should be monitored and lifestyle modifications recommended (74, 75, 151). If possible, regimens with a decreased likelihood of worsening cardiovascular risk factors should be used.

Central Nervous System (CNS) Toxicity

               Headache is a common complaint in patients initiating therapy with ZDV. ZDV-associated headache resolves in most patients. A small proportion remain intolerant and must change to another NRTI. Approximately one-third of patients receiving efavirenz have some form of dysphoric CNS side effect including poor concentration, dizziness, insomnia, nightmares, and rarely hallucinations (4). It is unusual for patients to discontinue therapy for these symptoms, because they usually subside over the first few weeks of therapy (65, 167, 173).  If they persist, however, it is common to switch to nevirapine. Patients who develop efavirenz-related CNS symptoms may have plasma drug levels several fold higher than those without symptoms (114). However, clinical monitoring of efavirenz plasma levels and dose adjustment are not routinely recommended due to lack of established guidelines. The manufacturer suggests taking efavirenz without high-fat/high caloric meals to avoid increased peak concentrations which can lead to increased CNS side effects (173).  Cytochrome P450 (CYP) isozyme 2B6 is responsible for 90% of the clearance of circulating efavirenz (183). Recently, several CYP 2B6 polymorphisms have been identified which can affect efavirenz clearance. Of these, an allelic change from G to T at codon 516 is the most significant. In patients with a homozygous genotype, CYP 2B6 activity is reduced, resulting in increased efavirenz concentrations and more frequent adverse effects (147).  Patients with a pre-existing or unstable psychiatric illness may be at a greater risk of serious psychiatric adverse events such as paranoia, aggression, and depression, although this is not an absolute contraindication (142).

Gutiérrez-Valencia A, López-Cortés LF, et al. Stepped-Dose vs. Full-Dose Efavirenz for HIV Infection and Neuropsychiatric Adverse Events: A Randomized Trial. Ann Intern Med. 2009 Jul 6. [Epub ahead of print]

Hyperlipidemia

               Untreated HIV is associated with lower cholesterol levels (including HDL) and higher triglyceride levels. Significant increases in triglyceride and LDL cholesterol levels occur during treatment with each of the available PIs (52). These increases are common and often result in cholesterol and triglyceride levels that meet the National Cholesterol Education Program (NCEP) guidelines for treatment (3, 155).  Ritonavir has been associated with the greatest increases in triglycerides and cholesterol (102, 143, 156). Nelfinavir may have effects that are less than ritonavir but more than indinavir and saquinavir. Atazanavir without ritonavir has not been associated with hyperlipidemia (142). When raltegravir was compared to efavirenz in naïve patients, serum lipids were not affected by raltegravir but lipids were significantly elevated in the efavirenz arm (108).                Anecdotal reports of premature atherosclerotic disease have been reported in patients receiving PIs. Two population-based studies assessed this risk. A retrospective study of HIV-infected male Veterans Administration patients in the U.S. did not show an association between NRTI, PI, and NNRTI use and cardiovascular or cerebrovascular disease over a median period of 17, 16, and 9 months, respectively (15). However, a large prospective European study showed a 27% increased risk of myocardial infarction per year of HAART exposure (62). Taken together these studies suggest that the benefits of HAART greatly outweighs the slight increased risk of cardiovascular morbidity and mortality that is associated with some HAART regimens; but that persons developing metabolic changes associated an increased risk of cardiovascular diseases should be managed to decrease their long-term risk of cardiovascular mortality.

               Guidelines for treating HAART-associated dyslipidemias have been published by the ACTG Cardiovascular Disease Focus Group (52) and by the IAS-USA (156). Serum lipids should be evaluated after the patient has fasted for a minimum of 8 and preferably 12 hours. The standard screening lipid profile, including measurement of total cholesterol, HDL cholesterol, and triglycerides, should be obtained before and 3-6 months after starting HAART. If the triglyceride level is less than 400 mg/dL, the LDL cholesterol level can be calculated from the measured values. If the triglyceride level is >400 mg/dL, then LDL cholesterol can be specifically measured. Patients with elevated cholesterol and triglycerides should be screened for other cardiac risk factors such as smoking, hypertension, diabetes, family history of heart disease, menopausal status, obesity, and physical inactivity and for potential exacerbating factors such as excessive alcohol use, hypothyroidism, renal disease, liver disease, hypogonadism, and the use of certain drugs (e.g. corticosteroids, beta-blockers, thiazide diuretics) (52).

               There are three complementary approaches to therapy. The first involves therapeutic life-style changes such as dietary changes, weight loss, and increased exercise (3). The second involves switching from a PI to a NNRTI or tenofovir. Switching is likely to be successful in patients with controlled viremia who have minimal previous antiretroviral exposure (24, 37, 49, 135). Switching antiretroviral agents may not be a viable option in patients receiving PIs as part of salvage therapy due to the risk of underlying drug resistance (115, 140). The third approach involves use of lipid-lowering agents, which are recommended for patients with triglyceride levels >500-1000 mg/dL or LDL cholesterol levels as specified in Table 1 (1).

               Specific medical treatment depends on whether a patient has isolated high levels of LDL cholesterol, isolated hypertriglyceridemia, or combined hyperlipidemia (Table 2). The 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors (or statins) are the drugs of choice for hypercholesterolemia. In patients receiving PIs, statin use is complicated by the fact that most are metabolized by CYP 3A4, leading to increased statin plasma concentrations and to a theoretical increased risk of skeletal muscle toxicity and rhabdomyolysis (Table 3). Lovastatin and simvastatin are the most extensively metabolized by CYP 3A4 and should be avoided. Pravastatin and atorvastatin are the preferred statins because they have the fewest interactions with most PIs, except for darunavir (60, 142, 145). Concomitant administration of daruanavir with pravastatin increases darunavir exposure by 81% (145). Therefore, it is recommended to start with the lowest dose possible and monitor closely for side effects. Fluvastatin is also an acceptable alternative agent but is the least potent of the statins. In general, patients should be started on a low initial dose of the statin (e.g. 20 mg of pravastatin or 10 mg of atorvastatin daily) and the dose should be titrated up gradually to reduce the risk of myopathy. None of the statins are known to be strong inhibitors or inducers of CYP 3A4 and are not expected to affect PI or NNRTI concentrations. The fibrates (e.g. gemfibrozil and fenofibrate) are second-line agents for treating isolated hypercholesterolemia.

               In patients with isolated hypertriglyceridemia, the fibrates are the drugs of choice, followed by statins. For patients with combined hyperlipidemia, initial treatment should begin with a statin. If ineffective after 3 months of therapy, a fibrate can be added (156). This should be done cautiously because concurrent use of statins and fibrates may also increase the risk of myopathy and rhabdomyolysis. Niacin is also effective for hypertriglyceridemia treatment, but is often not recommended because of its propensity to cause insulin resistance. An uncontrolled report, however, suggests that niacin may have the added advantage of raising HDL cholesterol levels and reducing intra-abdominal fat in HIV-infected patients with dyslipidemias (59). Omega-3 fatty acids lower plasma triglycerides in HIV patients with hyperlipidemia. In a 16-week randomized study, fish oil supplementation improved triglycerides by 20%, whereas diet and exercise only decreased triglycerides by 6%. This was accompanied by a 22% increase in plasma LDL cholesterol, however, the clinical significance of this increase is unknown (139, 186).

Review Article: Oh, J. and Hegele,R. HIV-Associated Dyslipidaemia: Pathogenesis and Treatment. The LANCET Infectious Diseases 2007; Vol.7, Issue 12, 787-796.

Stanley TL, Joy T, et al. Effects of switching from lopinavir/ritonavir to atazanavir/ritonavir on muscle glucose uptake and visceral fat in HIV-infected patients. AIDS. 2009 Jul 17;23(11):1349-57.

Insulin Resistance/Diabetes Mellitus

               Combination antiretroviral therapy has been associated with insulin resistance, hyperglycemia, and the development of diabetes mellitus. Data from large prospective cohorts have observed strong associations between NRTI exposure and an increased risk of new onset diabetes (45, 175). From the D:A:D study, d4T exposure was the most strongly associated with an increased risk of new onset diabetes (19% per year of exposure), followed by ZDV and ddI (6% per year of exposure).(45) Insulin resistance has been found in as many as 40% of patients receiving PIs (10, 50, 131, 156, 178, 182). Most of the data linking PIs with insulin resistance have been based on patients receiving older PIs, indinavir, ritonavir, and saquinavir (19, 26-28, 94, 158).  Diabetes risk may be lower with nelfinavir, amprenavir/fosamprenavir, lopinavir, and atazanavir (25, 45, 51, 91, 137, 175, 176, 181).

               Frank diabetes, clinically similar to type 2 diabetes, develops in about 1 to 6% of patients receiving PIs (50). Fasting blood glucose should be monitored 1 to 3 months after starting a new regimen, every 3 to 4 months thereafter, and more frequently in pregnant women (142). Normal fasting plasma glucose should be <100 mg/dL. Impaired fasting glucose is between 100 to 125 mg/dL. Frank diabetes is defined as a fasting plasma glucose ≥126 mg/dL or a random plasma glucose ≥200 mg/dL (7).

               Patients who are treated with PIs or who have lipodystrophy should be informed about the warning signs of hyperglycemia: polydipsia, polyphagia, and polyuria. Treatment should follow the established guidelines for treating diabetes in the general population including conservative measures such as diet modifications, weight loss, and exercise (7). If diabetes persists despite these interventions, insulin-sensitizing agents with or without discontinuation of PI therapy should be considered. Insulin, oral sulfonylureas, and metglitinides may be used in severe cases, but caution is advised to avoid hypoglycemia.

Musculoskeletal Disease

               Up to 15% of patients receiving long-term ZDV may develop myopathy resembling idiopathic polymyositis (23). Patients present with myalgias, muscle tenderness, proximal muscle weakness, and prominent muscle atrophy. Creatine phosphokinase (CPK) levels are usually elevated and a muscle biopsy demonstrates "ragged red fibers". Mitochondrial toxicity is believed to be the basis for this toxicity, which may also rarely present as a cardiomyopathy. Treatment involves substituting a different NRTI for ZDV.

               CPK elevations, myopathy, and rhabdomyolysis have been reported in patients receiving raltegravir, the first integrase inhibitor FDA-approved for combination HIV treatment in HIV-experienced individuals. In the prospective, double-blind, placebo-controlled studies conducted in antiretroviral-experienced patients, elevated CPK occurred in 3.2% in the raltegravir groups compared to 0.7% in the placebo groups, although drug-related elevations were similar between the groups (0.8% and 0.7%, respectively) (57). Significantly elevated CPK (>10 times the upper limit of normal) were also reported in phase III studies (168).

               According to the WHO diagnostic classification, osteopenia is defined as a T score that is higher than -2.5 but less than -1.0 compared to the normal mean value for young adults as measured by dual-energy X-ray absorptiometry (DEXA) scan, and osteoporosis as a T score of -2.5 or lower (134). The prevalence of osteopenia ranges 20 to 54% and for osteoporosis is 2 to 27% in HIV-infected individuals (21, 30). These rates are much higher than those seen in the general population. Women have a higher risk of osteopenia/osteoporosis, especially after menopause, and this risk can be worsened by HIV and antiretroviral therapy (20, 188).  Cortical anatomic osteoporosis is found more frequently in men, and trabecular abnormalities are typically observed in women (30).  Several studies have linked older PIs with decreases in bone mineral density (20, 123, 125).

                The NRTIs, particularly tenofovir and d4T, have also been associated with decreases in bone mineral density. In a large, international, prospective, randomized, double-blind study evaluating tenofovir and d4T for 144 weeks in combination with efavirenz and 3TC, patients receiving tenofovir had a greater average percentage decrease in bone mineral density at the lumbar spine compared to d4T (-2.2% vs -1.0%, p=0.001), although similar decreases in both groups were observed at the hip (-2.8% tenofovir vs -2.4% d4T, p=0.06). These reductions were observed after 24 to 48 weeks of treatment and were stable through 144 weeks. Bone fractures were similar between the groups (67). The pathogenesis of tenofovir-induced bone disease may be due to increased urinary loss of phosphate and chronic hypophosphatemia from drug accumulation in renal tubular epithelium and resultant renal tubular dysfunction (180). Other risk factors include: low body weight, Caucasian, southeast Asian, older age, alcohol use, smoking, caffeine, hypogonadism, hyperthyroidism, corticosteroids, vitamin D deficiency, and history of significant weight loss. HIV-associated risk factors include: low CD4 count, duration of HIV, lipoatrophy, and increased lactic acid levels (30).

               Osteonecrosis is an increasingly recognized disorder associated with long-term HIV infection and antiretroviral therapy. The areas most often affected are the femoral and humeral heads, femoral condyles, proximal tibia, and small bones in the hand and wrist (156).   A cross-sectional study using MRI detected asymptomatic avascular necrosis of the hip in 15 (4.4%) of 339 patients (122, 156). Symptomatic osteonecrosis may occur in 0.08 to 1.3% of patients (18, 159, 177). Reduced bone mineral density is usually first observed 18 months after the initiation of antiretroviral therapy, with osteonecrosis becoming clinically apparent within 3 years of drug exposure (5, 72, 159).  Symptoms are usually subtle with most patients complaining of mild to moderate periarticular pain, often in the groin region (106, 159). The role of antiretroviral therapy in osteonecrosis still remains controversial (5). Other risk factors for osteonecrosis include heavy alcohol consumption, diabetes, advanced HIV, history of steroid use, hyperlipidemia, and hypercoagulability (5, 159). HIV-infected patients with a recent history of periarticular pain and ≥1 risk factor, should undergo imaging studies to rule out osteonecrosis (106). In asymptomatic cases with less than 15% bony head involvement, MRIs should be followed every 3 to 6 months for the first year, every 6 months for the second year, and then annually thereafter (142).

               The first signs of decreased bone mineral density are likely to be fracture or new-onset skeletal pain. Avascular necrosis of the hip is the most severe manifestation of HIV-associated bone disease and often requires hip replacement. Other sites of involvement are the ankle, shoulder, clavicle, and elbow. Radiographs may show reduced bone mineral density but MRI and DEXA scans are more sensitive for this purpose (96). Treatment involves correcting possible risk factors for osteoporosis, insuring adequate intake of vitamin D and calcium, and weight-bearing exercise. Other forms of therapy traditionally used for osteoporosis (e.g. raloxifene, biphosphonates, calcitonin, and hormonal replacement) and surgical intervention may be necessary for symptomatic disease (134, 142).

TOXICITIES COMPROMISING QUALITY-OF-LIFE/ADHERENCE

Gastrointestinal Complaints

               Nearly all antiretrovirals can cause nausea, vomiting, and diarrhea. These symptoms tend to be worse at the start of therapy and improve over time. However, drug substitution becomes necessary in many patients. Persistent ZDV-induced nausea often requires a change. ddI-induced nausea has become less of a problem with the enteric-coated (EC) formulation. Nausea and diarrhea with ritonavir have become less of a problem due to lower doses of ritonavir used for pharmacokinetic benefit in combination with other PIs. Diarrhea is particularly common with nelfinavir, and is usually treated by dietary modifications, bulking agents, or loperamide.

Injection Site Reactions

               Enfuvirtide is a fusion inhibitor that is administrated via subcutaneous injection twice daily. The major side effects are injection site reactions which include erythema, induration nodules, discomfort, pruritis, and pain. In clinical trials, 98% of patients experienced injection site reactions within the first week of therapy. The reactions were described as mild to moderately painful, activities of daily living were not affected, and less than 10% of patients required analgesics. Recommendations of post-injection massage, rotating injection sites and avoiding existing injection sites have been proposed to decrease injection site reactions (12). In less than 1% of patients in the clinical trials, a hypersensitivity reaction occurred as a consequence of enfuvirtide treatment. Enfuvirtide-associated hypersensitivity typically presents with rash, fever, nausea, vomiting, chills, rigors, hypotension, and elevated liver enzymes (64).

Lipodystrophy

               Changes in body fat distribution occur in a large proportion of HIV-infected patients receiving HAART (26, 139). Data suggest that lipodystrophy consists of two different syndromes: lipoatrophy caused by NRTIs and possibly exacerbated by concurrent PIs and visceral fat accumulation caused by PIs (86, 139). Lipoatrophy appears to be associated with other NRTI-associated mitochondrial toxicities including lactic acidemia, whereas visceral fat accumulation appears to be associated with PI-induced hyperglycemia and hyperlipidemia. Patients with lipodystrophy have not been shown to have a worse prognosis than patients without this toxicity, but lipoatrophy, particularly facial lipoatrophy is often felt to be physically stigmatizing. The fat accumulation is often intraabdominal (visceral), dorso-cervical ("buffalo hump"), and in women, may manifest as breast enlargement.

               No uniform definition exists for lipodystrophy, leading to a wide range of incidence estimates. The fat loss and fat gain are continuous processes; the distinction between symptomatic vs. asymptomatic disease depends on patients' subjective complaints. Dual X-ray absorptiometry (DEXA) scans are accurate for measuring changes in total body, limb, and trunk fat mass. However, because abdominal subcutaneous and visceral fat may change in opposing directions, single-cut L4 CT scans are preferable for analyzing abdominal fat, (86, 121) although this is a primarily a research tool. Cheaper techniques such as anthropometry, bioelectric impedance testing, and ultrasonography are less accurate, but may be useful for following individual patients.

               The major risk factors for lipoatrophy include: long-term NRTI treatment (especially thymidine analogs), older age, female gender, Caucasian background, low baseline body mass index, and simultaneous use of PI therapy. Within the NRTI class, d4T has been associated with the greatest risk in multiple studies (58, 86, 88, 153-155).  ZDV, ddI, and 3TC have also been linked to lipoatrophy (86).  The median time to onset of lipodystrophy in observational studies has been about 68 weeks(26). START

               Avoidance of or switching from the thymidine analogs, d4T and ZDV, to tenofovir or abacavir may help to prevent lipoatrophy (29, 102, 105, 109, 130).  If lipoatrophy has already developed, reversal is a slow and gradual process (29,  109). Several therapeutic options which target the pathological mechanisms underlying lipoatrophy are currently being evaluated and may be promising. The thiazolidinedione pioglitazone may benefit lipoatrophy by stimulating adipogenesis as a PPARγ-agonist. In several smaller prospective, controlled studies, patients treated with pioglitazone for 6 to 12 months had increases in limb fat and no worsening in lipid profiles (22, 70, 164). Low leptin levels have been observed in HIV-infected individuals with lipoatrophy (133). Leptin is a hormone secreted by adipocytes and circulating levels are usually proportional to body fat mass and nutritional status (79, 92). Subcutaneous injection of recombinant human leptin improved insulin resistance, lipid profile, and decreased visceral fat in 2 small studies (95, 132). In vitro studies show that uridine supplementation can reverse mitochondrial toxicity, cell depletion, and lactic acidosis associated with NRTIs. In a small study of HIV-infected patients with lipoatrophy, dietary uridine supplementation was well tolerated and improved total limb, intraabdominal, and total body fat (174).  Injectable poly-L-lactic acid increases facial skin thickness for up to 2 years and is FDA-approved for this purpose (83, 119, 160). This product contains microparticles of poly-L-lactic acid which is a biocompatible, biodegradable, synthetic polymer from the alpha-hydroxy-acid family. The main adverse effects are injection procedure-related such as bruising, discomfort, and edema. The only device-related complications are small, palpable, but non-visible subcutaneous nodules (6-52%) which usually resolve either spontaneously or by subcision/massage  (83, 119, 160).

               Various strategies to improve lipohypertrophy have been evaluated in clinical studies. Physical exercise and dieting help diminish visceral fat accumulation but may be difficult to maintain. Metformin, an insulin-sensitizing agent and reducer of endogenous hepatogluconeogenesis, may also decrease visceral fat accumulation in addition to improving glucose tolerance.(33). Unfortunately reductions in limb fat have been noted in studies and may preclude routine use for lipodystrophy (93, 112) Recombinant growth hormone has been studied in small trials and may slightly improve both lipoatrophy and visceral fat accumulation (76, 99, 100, 128, 157).  Due to its potential to cause insulin resistance and glucose intolerance, it is not routinely recommended (76, 99, 100, 128, 157). Two growth hormone releasing hormone analogs are currently being evaluated to reduce visceral adiposity. Tesamorelin significantly decreased visceral adipose tissue, improved the lipid profile, and did not affect glycemic measures, although increased IgG antibodies against tesamorelin were also observed (54-56). Cosmetic surgery may also be an option for lipohypertrophy (e.g. surgical resection of dorsocervical fat). Androgen therapy cannot be recommended due to lack of safety and efficacy data (38).

Lo J, et al. Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a randomized controlled trial. JAMA. 2008;300:509-19.

Peripheral Neuropathy

               The most common neuropathy in HIV-infected patients is a distal, symmetrical, predominantly sensory axonal neuropathy. Patients complain initially of numbness and then develop burning pain in their feet, which may extend proximally and, in rare cases, involve the distal upper extremities. Neurological examination will reveal depressed or absent ankle reflexes relative to the knees, increased vibratory thresholds and reduced pain and temperature sensations. Although this syndrome was initially recognized in untreated patients with advanced HIV infection, it now occurs most commonly in association with ddC, ddI, and d4T, particularly when they are administered with hydroxyurea (127, 163). Other risk factors for neuropathy are a low CD4+ cell count (<100/mm³), heavy alcohol consumption, nutritional deficiencies (e.g. vitamin B12), use of other neurotoxic drugs (e.g. isoniazid, dapsone), and diabetes mellitus (142). Management usually requires substitution or dose reduction of one or more of the neurotoxic drugs. Symptoms may intensify in the first few weeks after drug discontinuation but will gradually improve. Treatment should begin with non-narcotic analgesics. Tricyclic antidepressants, gabapentin, lamotrigine, topiramate, tramadol, and oxcarbamazepine have also been tried with variable success. With severe neuropathy, narcotics are often necessary. Each of these measures is temporizing; discontinuing the offending drug is the only measure that reverses the underlying pathology.

TABLES

Table 1:  National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III Treatment Recommendations Based on LDL Cholesterol (Adapted from (3))

Table 2: Choice of Therapy for Hyperlipidemia (adapted from (1, 155))

Table 3: Drug Interactions of Lipid Lowering Agents with Antiretroviral (ARV) Agents

REFERENCES

1. 2001. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama 285:2486-97. [PubMed] 

2. 2008. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Recommendations of the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the HIV Medicine Association of the Infectious Diseases Society of America (HIVMA/IDSA). Available at: http://AIDSinfo.nih.gov.

3. 2002. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143-421. [PubMed]

4. Adkins JC, Noble S. Efavirenz. Drugs 1998;56:1055-64; discussion 1065-6. [PubMed]  

5. Allison GT, Bostrom MP, Glesby MJ. Osteonecrosis in HIV disease: epidemiology, etiologies, and clinical management. Aids 2003;17:1-9. [PubMed]  

6. Allred KF, Smart EJ, Wilson ME. Estrogen receptor-alpha mediates gender differences in atherosclerosis induced by HIV protease inhibitors. J Biol Chem 2006;281:1419-25.   [PubMed]  

7. American Diabetes Association. 2009. Standards of medical care in diabetes--2009. Diabetes Care 32:S13-S61.  [PubMed]

8. Ananworanich J, Nuesch R, Côté HC, Kerr SJ, Hill A, Jupimai T, Laopraynak N, Saenawat S, Ruxrungtham K, Hirschel B. Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine--a Staccato trial substudy. J Antimicrob Chemother 2008;61:1340-3. [PubMed]

9. Aptivus (tipranavir) Prescribing Information. June 2008. Boehringer Ingelheim Pharmaceuticals, Inc.  [PubMed]

10. Behrens G, Dejam A, Schmidt H, Balks HJ, Brabant G, Korner T, Stoll M, Schmidt RE. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. Aids 1999; 13:F63-70. [PubMed]

11. Bersoff-Matcha SJ, Miller WC, Aberg JA, van Der Horst C, Hamrick HJ Jr, Powderly WG, Mundy LM. Sex differences in nevirapine rash. Clin Infect Dis 2001;32:124-9.   [PubMed]   

12. Borras-Blasco J, Navarro-Ruiz A, Borras C, Castera E. Adverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infection. J Antimicrob Chemother 2008;62:879-88.  [PubMed]   

13. Boubaker K, Flepp M, Sudre P, Furrer H, Haensel A, Hirschel B, Boggian K, Chave JP,  Bernasconi E. Egger M, Opravil M, Rickenbach M, Francioli P, Telenti A.  Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis 2001;33:1931-7. [PubMed]

14. Boubaker K, Sudre P, Bally F, Vogel G, Meuwly JY, Glauser MP, Telenti AChanges in renal function associated with indinavir. Aids 1998;12:F249-54. [PubMed]

15. Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003;348:702-10. [PubMed]

16. Brinkman K, Kakuda TN. Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy? Curr Opin Infect Dis 2000;13:5-11. [PubMed]

17. Brinkman K, Vrouenraets S, Kauffmann R, Weigel H, Frissen J.Treatment of nucleoside reverse transcriptase inhibitor-induced lactic acidosis. Aids 2000;14:2801-2. [PubMed]

18. Brown P, Crane L. Avascular necrosis of bone in patients with human immunodeficiency virus infection: report of 6 cases and review of the literature. Clin Infect Dis 2001;32:1221-6. [PubMed]

19. Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, Visscher BR, Margolick JB, Dobs AS.Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 2005; 165:1179-84.

20. Brown TT, McComsey GA. Osteopenia and osteoporosis in patients with HIV: a review of current concepts. Curr Infect Dis Rep 2006;8:162-70. [PubMed]

21. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. Aids 2006;20:2165-74. [PubMed]

22. Calmy A, Hirschel B, Hans D, Karsegard VL, Meier CA. Glitazones in lipodystrophy syndrome induced by highly active antiretroviral therapy. Aids 2003;17:770-2. [PubMed]

23. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000;356:1423-30. [PubMed]

24. Carr A,Hudson J, Chuah J, Mallal S, Law M, Hoy J, Doong N, French M, Smith D, Cooper DA. HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. Aids 2001;15:1811-22. [PubMed]

25. Carr A, Ritzhaupt A, Zhang W, Zajdenverg R, Workman C, Gatell JM, Cahn P, ChavesR. Effects of boosted tipranavir and lopinavir on body composition, insulin sensitivity and adipocytokines in antiretroviral-naive adults. Aids 2008;22:2313-21. [PubMed]

26. Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. Aids 1998;12:F51-8. [PubMed]

27. Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998;351:1881-3. [PubMed]

28. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999;353:2093-9. [PubMed]

29. Carr A, Workman C, Smith DE,  Hoy J, Hudson J, Doong N, Martin A, Amin J, Freund J, Law M, Cooper DA. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 2002;288:207-15. [PubMed]

30. Cazanave C, Dupon M, Lavignolle-Aurillac V, Barthe N, Lawson-Ayayi S, Mehsen N, Mercié P, Morlat P, Thiébaut R, Dabis F; Groupe d'Epidémiologie Clinique du SIDA en Aquitaine. Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. Aids 2008;22:395-402. [PubMed]

31. Chan-Tack KM, Struble KA, Birnkrant DB.  Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: review of cases from the FDA's Adverse Event Reporting System. AIDS Patient Care STDS 2008;22:843-50. [PubMed]

32. Chan-Tack KM, Truffa MM, Struble KA, Birnkrant DB. Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration's Adverse Event Reporting System. Aids 2007;21:1215-8. [PubMed]

33. Chang H R, Pella PM. Atazanavir urolithiasis. N Engl J Med  2006;355:2158-9. [PubMed]

34. Chattha G, Arieff AI, Cummings C, Tierney LM, Jr. Lactic acidosis complicating the acquired immunodeficiency syndrome. Ann Intern Med 1993;18:37-9.[PubMed]

35. Chodock R, Mylonakis E,  Shemin D, Runarsdottir V, Yodice P, Renzi R, Tashima K, Towe C, Rich JD. Survival of a human immunodeficiency patient with nucleoside-induced lactic acidosis--role of haemodialysis treatment. Nephrol Dial Transplant 1999;14:2484-6. [PubMed]

36. Claster S.  Biology of anemia, differential diagnosis, and treatment options in human immunodeficiency virus infection. J Infect Dis 2002;185 Suppl 2:S105-9.[PubMed]

37. Clumeck N, Goebel F, RozenbaumW, Gerstoft J, Staszewski S, Montaner J, Johnson M, Gazzard B, Stone C,  Athisegaran R, Moore S. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. Aids 2001;15:1517-26. [PubMed]

38. Cofrancesco J Jr, Freedland E, McComsey G. Treatment options for HIV-associated central fat accumulation. AIDS Patient Care STDS 2009;23:5-18. [PubMed]

39. Cossarizza A, Moyle G. Antiretroviral nucleoside and nucleotide analogues and mitochondria. Aids 2004;18:137-51. [PubMed]

40. Cote HC, Brumme ZL, Craib KJ, AlexanderCS, Wynhoven B, Ting L,Wong H, Harris M, Harrigan PR, O'Shaughnessy MV, Montaner JS.  Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002;346:811-20. [PubMed]

41. Cote HC, Day AG, Heyland DK. Longitudinal increases in mitochondrial DNA levels in blood cells are associated with survival in critically ill patients. Crit Care 2007;11:R88. [PubMed]

42. Crixivan (indinavir) Prescribing Information. October 2008. Merck & Co., Inc. [PubMed]

43. Currier JA, Lazzarin, Kleim P, Steel H, Millard J, Bonny T and the ASCENT Study Team. Safety and antiviral activity of the novel CCR5 antagonist aplaviroc in combination with zidovudine/lamivudine in HIV-infected therapy naive subjects [abstract P-392]. 2006. Presented at the Eighth Int. Conf. Drug Therapy HIV Infection. [PubMed]

44. Dassopoulos T, Ehrenpreis ED. Acute pancreatitis in human immunodeficiency virus-infected patients: a review. Am J Med 1999;107:78-84. [PubMed]

45. De Wit S, Sabin CA, Weber R, Worm SW, Reiss P, Cazanave C, El-Sadr W, Monforte A, Fontas E, Law MG,  Friis-Moller N, Phillips A. Incidence and risk factors for new-onset diabetes in HIV-infected patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Diabetes Care 2008;31:1224-9. [PubMed]

46. Dear Health Care Provider letter. February 2005. Important drug interaction warning: drug-induced hepatitis with marked transaminase elevations has been observed in healthy volunteers receiving rifampin 600 mg once daily in combination iwth ritonavir 100 mg/saquinavir 1000 mg twice daily (ritonavir boosted saquinavir). Roche Laboratories Inc. [PubMed]

47. Dear Health Care Provider letter. June 30, 2006. Important safety information: intracranial hemorrhage in patients receiving Aptivus (tipranavir) capsules. Boehringer Ingelheim Pharmaceuticals, Inc. [PubMed]

48. Dieleman JP, Jambroes M, Gyssens IC, Sturkenboom MC, Stricker BH, Mulder WM, de Wolf F, Weverling GJ, Lange JM, Reiss P, Brinkman K. Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA cohort. Aids 2002;16:737-45. [PubMed]

49. Dieleman JP, Sturkenboom MC, Wit FW, Jambroes M, Mulder JW, Ten Veen JH, Juttmann J, Stricker BH, Lange JM, Van Der Ende ME.  Low risk of treatment failure after substitution of nevirapine for protease inhibitors among human immunodeficiency virus-infected patients with virus suppression. J Infect Dis 2002;185:1261-8.  [PubMed]

50. Dube MP. Disorders of glucose metabolism in patients infected with human immunodeficiency virus. Clin Infect Dis 2000;31:1467-75. [PubMed]

51. Dube MP, Shen C, Greenwald M, Mather KJ. No impairment of endothelial function or insulin sensitivity with 4 weeks of the HIV protease inhibitors atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection: a placebo-controlled trial. Clin Infect Dis 2008;47:567-74. [PubMed]

52. Dube MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT, Henry WK, Currier JS, Sprecher D, Glesby MJ. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003;37:613-27. [PubMed]

53. Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, Naldi L, Viboud C, Roujeau JC. Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. Aids 2001;15:1843-8. [PubMed]

54. Falutz J, Allas S, Blot K, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med 2007;357:2359-70. [PubMed]

55. Falutz J, Allas S, Kotler D, Thompson M, Koutkia P, Albu J, Trottier B, Routy JP, Cote P, Abribat T,  Grinspoon S. A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation. Aids 2005;19:1279-87. [PubMed]

56. Falutz J, Allas S, Mamputu JC, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S. Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation. Aids 2008;22:1719-28. [PubMed]

57. FDA Briefing Document. September 5, 2007. Isentress (raltegravir) 400 mg for treatment of HIV (NDA 22-145). Merck & Co., Inc. Available at: http://www.fda.gov/OHRMS/DOCKETS/AC/07/briefing/2007-4314b1-01-Merck.pdf.

58. Fellay J, Boubaker K, Ledergerber B, Bernasconi E, Furrer H, Battegay M, Hirschel B,  Vernazza P,Francioli P, Greub G, Flepp M, Telenti A. Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study. Lancet 2001;358:1322-7. [PubMed]

59. Fessel WJ, Follansbee SE, Rego J.  High-density lipoprotein cholesterol is low in HIV-infected patients with lipodystrophic fat expansions: implications for pathogenesis of fat redistribution. Aids 2002;16:1785-9. [PubMed]

60. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 2002;41:1195-211. [PubMed]

61. Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, Thiébaut R, De Wit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007;356:1723-35. [PubMed]

62. Friis-Møller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, Thiébaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD; Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003;349:1993-2003.  [PubMed]

63. Fry J. 2006. FDA/FCHR collaborative public meeting on long-term safety concerns associated with CCR5 antagonist development. Available at: http://www.fda.gov/ohrms/dockets/AC/07/briefing/2007-4283b1-02-03-FDA-draftreport.pdf.

64. Fuzeon (enfuvirtide) Prescribing Information. December 2008. Roche Laboratories Inc. and Trimeris, Inc.

65. Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, Lu B, McColl D, Chuck S, Enejosa J, Toole JJ, Cheng AK. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006;354:251-60. [PubMed]

66. Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40:1194-8. [PubMed]

67. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ, Cheng AK. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004;292:191-201. [PubMed]

68. Gallant JE, Winston JA, DeJesus E, Pozniak AL, Chen SS, Cheng AK, Enejosa JV. 2008. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS 2008; 22:2155-63. [PubMed]

69. Gathe JC, Jr., Pierone G, Piliero P, Arasteh K, Rubio R, Lalonde RG, Cooper D, Lazzarin A, Kohlbrenner VM,  Dohnanyi C, Sabo J, Mayers D. Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients. AIDS Res Hum Retroviruses 2007;23:216-23. [PubMed]

70. Gavrila A, Hsu W, Tsiodras S, Doweiko J, Gautam S, Martin L, Moses AC, Karchmer AW, Mantzoros CS.  Improvement in highly active antiretroviral therapy-induced metabolic syndrome by treatment with pioglitazone but not with fenofibrate: a 2 x 2 factorial, randomized, double-blinded, placebo-controlled trial. Clin Infect Dis 2005;40:745-9. [PubMed]

71. Gisolf EH, Dreezen C, Danner SA, Weel JL, Weverling GJ. Risk factors for hepatotoxicity in HIV-1-infected patients receiving ritonavir and saquinavir with or without stavudine. Prometheus Study Group. Clin Infect Dis 2000;31:1234-9. [PubMed]

72. Glesby MJ, Hoover DR, Vaamonde CM.  Osteonecrosis in patients infected with human immunodeficiency virus: a case-control study. J Infect Dis 2001;184:519-23. [PubMed]

73. Gonzalez de Requena D, Nunez M, Jimenez-Nacher I, Soriano V. Liver toxicity caused by nevirapine. AIDS 2002;16:290-1. [PubMed]

74. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005;352:48-62. [PubMed]

75. Grinspoon SK, Grunfeld C, Kotler DP, Currier JS, Lundgren JD, Dubé MP, Lipshultz SE, Hsue PY, Squires K, Schambelan M, Wilson PW, Yarasheski KE, Hadigan CM, Stein JH, Eckel RH.  State of the science conference: Initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary. Circulation 2008;118:198-210. [PubMed]

76. Grunfeld C, Thompson M, Brown SJ, Richmond  G, Lee D, Muurahainen N, Kotler DP. Recombinant human growth hormone to treat HIV-associated adipose redistribution syndrome: 12 week induction and 24-week maintenance therapy. J Acquir Immune Defic Syndr 2007;45:286-97. [PubMed]

77. Gulick RM, Su Z, Flexner C, Hughes MD, Skolnik PR, Wilkin TJ, Gross R, Krambrink A, Coakley E, Greaves WL,  Zolopa A, Reichman R, Godfrey C, Hirsch M, Kuritzkes DR. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis 2007;196:304-12. [PubMed]

78. Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA, Tashima KT, Roland M, Franceschini N, Palella FJ, Lennox JL, Klotman PE, Nachman SA, Hall SD, Szczech LA. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2005;40:1559-85. [PubMed]

79. Havel PJ. Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 2004;53 Suppl 1:S143-51. [PubMed]

80. Hernandez JE, Cutrell A, Edwards M, Fleming J, Powell W, Scott T. Clinical risk factors for hypersensitivity reactions to abacavir: retrospective analysis of over 8000 subjects receiving abacavir in 34 clinical trials [Poster H-2013]. 2003. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. [PubMed]

81. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD.  Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359:1121-2. [PubMed]

82. Hewitt RG.  Abacavir hypersensitivity reaction. Clin Infect Dis 2002;34:1137-42. [PubMed]

83. Humble G, Mest D. Soft tissue augmentation using sculptra. Facial Plast Surg 2004;20:157-63. [PubMed]

84. Invirase (saquinavir) Prescribing Information. July 2007. Roche Laboratories, Inc. [PubMed]

85. John M, Moore CB, James IR, Nolan D, Upton RP, McKinnon EJ, Mallal SA. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS 2001;15:717-23. [PubMed]

86. John M, Nolan D, Mallal S. Antiretroviral therapy and the lipodystrophy syndrome. Antivir Ther 2001;6:9-20. [PubMed]

87. Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, Anderson KS,  Johnson KA. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 2001;276:40847-57. [PubMed]

88. Joly V, Flandre P, Meiffredy V, Leturque N, Harel M, Aboulker JP, Yeni P. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS 2002;16:2447-54. [PubMed]

89. Kahn JO, Lagakos SW, Richman DD, Cross A, Pettinelli C, Liou SH, Brown M, Volberding PA, Crumpacker CS, Beall G and et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group. N Engl J Med 1992;327:581-7.  [PubMed]

90. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000;22:685-708. [PubMed]

91. Kaplan RC, Kingsley LA, Sharrett AR, Li X, Lazar J, Tien PC, Mack WJ, Cohen MH, Jacobson L, Gange SJ.  Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis 2007;45:1074-81. [PubMed]

92. Kershaw EE, Flier JS.  Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548-56. [PubMed]

93. Kohli R, Shevitz A, Gorbach S, Wanke C. A randomized placebo-controlled trial of metformin for the treatment of HIV lipodystrophy. HIV Med 2007;8:420-6. [PubMed]

94. Ledergerber B, Furrer H, Rickenbach M, Lehmann R, Elzi L, Hirschel B,  Cavassini M, Bernasconi E, Schmid P,  Egger M, Weber R.  Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study. Clin Infect Dis 2007;45:111-9. [PubMed]

95. Lee JH, Chan JL, Sourlas E, Raptopoulos V, Mantzoros CS. Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. J Clin Endocrinol Metab 2006;91:2605-11. [PubMed]

96. Lee MJ, Corrigan J, Stack JP, Ennis JT. A comparison of modern imaging modalities in osteonecrosis of the femoral head. Clin Radiol 1990;42:427-32. [PubMed]

97. Lexiva (fosamprenavir) Prescribing Information. October 2008. GlaxoSmithKline.

98. Lim SE, Copeland WC. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem 2001;276:23616-23. [PubMed]

99. Lo J, You SM, Canavan B, Liebau J, Beltrani G, Koutkia P, Hemphill L, Lee H, Grinspoon S. Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a randomized controlled trial. JAMA 2008;300:509-19. [PubMed]

100. Lo JC, Mulligan K, Noor MA, Schwarz JM, Halvorsen RA, Grunfeld C, Schambelan M. The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 2001;86:3480-7. [PubMed]

101. Lonergan JT, Behling C, Pfander H, Hassanein TI, Mathews WC.  Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin Infect Dis 2000;31:162-6. [PubMed]

102. Lundgren JD, Battegay M, Behrens G, De Wit S, Guaraldi G, Katlama C, Martinez E, Nair D, Powderly WG, Reiss P, Sutinen J, Vigano A.  European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV. HIV Med 2008;9:72-81. [PubMed]

103. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I,  Christiansen FT.  Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727-32. [PubMed]

104. Mallal S, Phillips E,  Carosi G, Molina JM, Workman C, Tomazic J, Jagel-Guedes E, Rugina S, Kozyrev O, Cid JF,  Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358:568-79. [PubMed]

105. Mallon PW, Miller J, Cooper DA, Carr A. Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS 2003;17:971-9. [PubMed]

106. Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med 1992;326:1473-9. [PubMed]

107. Marcus K, Truffa M, Boxwell D, Toerner J. Recently identified adverse events secondary to NRTI therapy in HIV-infected individuals: cases from the FDA's adverse event reporting system (AERS). 2002. Presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA. [PubMed]

108. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H; Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007;46:125-33. [PubMed]

109. Martin A,  Smith DE, Carr A, Ringland C, Amin J, Emery S, Hoy J, Workman C, Doong N, Freund J, Cooper DA. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS 2004;18:1029-36. [PubMed]

110. Martin JL, Brown CE, Matthews-Davis N, Reardon JE. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994;38:2743-9. [PubMed]

111. Martinez E, Blanco JL, Arnaiz JA, Perez-Cuevas JB, Mocroft A, Cruceta A, Marcos MA, Milinkovic A, Garcia-Viejo MA, Mallolas J, Carne X, Phillips A, Gatell JM.  Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS 2001;15:1261-8. [PubMed]

112. Martinez E, Domingo P, Ribera E, Milinkovic A, Arroyo JA, Conget I, Perez-Cuevas JB, Casamitjana R, de Lazzari E, Bianchi L, Montserrat E, Roca M, Burgos R, Arnaiz JA, Gatell JM. Effects of metformin or gemfibrozil on the lipodystrophy of HIV-infected patients receiving protease inhibitors. Antivir Ther 2003;8:403-10. [PubMed]

113. Martinez E, Milinkovic A, de Lazzari E, Ravasi G, Blanco JL, Larrousse M, Mallolas J, Garcia F, Miro JM, Gatell JM. Pancreatic toxic effects associated with co-administration of didanosine and tenofovir in HIV-infected adults. Lancet 2004;364:65-7. [PubMed]

114. Marzolini,C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001;15:71-5. [PubMed]

115. Masquelier B, Neau D, Chene G, Larbere J, Birac V, Ragnaud JM, Fleury HJ. Mechanism of virologic failure after substitution of a protease inhibitor by nevirapine in patients with suppressed plasma HIV-1 RNA. J Acquir Immune Defic Syndr 2001;28:309-12. [PubMed]

116. Mayer H. Maraviroc: a case of severe hepatotoxicity [abstract]. 2005. Presented at the First International Workshop Targeting HIV Entry. [PubMed]

117. McComsey G, Lonergan JT. Mitochondrial dysfunction: patient monitoring and toxicity management. J Acquir Immune Defic Syndr 2004;37:S30-5. [PubMed]

118. Messaad D, Reynes J, Fabre J, Bousquet J, Demoly P. Long-term safety and efficacy of nevirapine tolerance induction. Clin Exp Allergy 2002;32:733-5.  [PubMed]

119. Mest DR, Humble GM. Duration of Correction for Human Immunodeficiency Virus-Associated Lipoatrophy After Retreatment with Injectable Poly-L: -Lactic Acid. Aesthetic Plast Surg. 2008 Aug 14 [PubMed]

120. Miller KD, Cameron M, Wood LV, Dalakas MC, Kovacs JA. Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases. Ann Intern Med 2000;133:192-6. [PubMed]

121. Miller KD, Jones E, Yanovski JA, Shankar R, Feuerstein I, Falloon J. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998;351:871-5. [PubMed]

122. Miller KD, Masur H, Jones EC, Joe GO, Rick ME, Kelly GG, Mican JM, Liu S, Gerber LH, Blackwelder WC,  Falloon J, Davey RT, Polis MA, Walker RE, Lane HC, Kovacs JA. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17-25. [PubMed]

123. Mondy K, Yarasheski K, Powderly WG, Whyte M, Claxton S, DeMarco D, Hoffmann M, Tebas P. Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis 2003;36:482-90. [PubMed]

124. Montaner JS, Cote HC, Harris M, Hogg RS, Yip B, Harrigan PR, O'Shaughnessy MV.  Nucleoside-related mitochondrial toxicity among HIV-infected patients receiving antiretroviral therapy: insights from the evaluation of venous lactic acid and peripheral blood mitochondrial DNA. Clin Infect Dis 2004;38 Suppl 2:S73-9. [PubMed]

125. Moore AL, Vashisht A, Sabin CA, Mocroft A, Madge S, Phillips AN, Studd JW, Johnson MA. Reduced bone mineral density in HIV-positive individuals. AIDS 2001;15:1731-3. [PubMed]

126. Moore RD, Keruly JC, Chaisson RE. Incidence of pancreatitis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitor drugs. AIDS 2001;15:617-20. [PubMed]

127. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS 2000;14:273-8.[PubMed]

128. Moyle GJ, Daar ES, Gertner JM, Kotler DP, Melchior JC, O'Brien F, Svanberg E. Growth hormone improves lean body mass, physical performance, and quality of life in subjects with HIV-associated weight loss or wasting on highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2004;35:367-75. [PubMed]

129. Moyle GJ, Datta D, Mandalia S, Morlese J, Asboe D, Gazzard BG. Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. AIDS 2002;16:1341-9. [PubMed]

130. Moyle GJ, Sabin CA, Cartledge J, Johnson M, Wilkins E, Churchill D, Hay P, Fakoya A, Murphy M, Scullard G, Leen C, Reilly G.  A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 2006;20:2043-50. [PubMed]

131. Mulligan K, Grunfeld C, Tai VW, Algren H, Pang M, Chernoff DN, Lo JC, Schambelan M.  Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr 2000;23:35-43.[PubMed]

132. Mulligan K, Khatami H, Schwarz JM, Sakkas GK, Depaoli AM, Tai VW, Wen MJ, Lee GA, Grunfeld C, Schambelan M. The Effects of Recombinant Human Leptin on Visceral Fat, Dyslipidemia, and Insulin Resistance in Patients with HIV-Associated Lipoatrophy and Hypoleptinemia. J Clin Endocrinol Metab. 2009 Jan 27 [PubMed]

133. Nagy GS, Tsiodras S, Martin LD, Avihingsanon A, Gavrila A, Hsu WC, Karchmer AW, Mantzoros CS. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin Infect Dis 2003;36:795-802. [PubMed]

134. National Osteoporosis Foundation. 2008. Clinician's Guide to Prevention and Treatment of Osteoporosis. Available at: http://www.nof.org/professionals/Clinicians_Guide.htm.

135. Negredo E, Cruz L, Paredes R, Ruiz L, Fumaz CR, Bonjoch A, Gel S, Tuldrà A, Balagué M, Johnston S, Arnó A, Jou A, Tural C, Sirera G, Romeu J, Clotet B. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression. Clin Infect Dis 2002;34:504-10. [PubMed]

136. Nichols WG, Steel HM, Bonny T, Adkison K, Curtis L, Millard J, Kabeya K, Clumeck N.  Hepatotoxicity observed in clinical trials of aplaviroc (GW873140). Antimicrob Agents Chemother 2008;52:858-65. [PubMed]

137. Noor MA, Flint OP, Maa JF, Parker RA. Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically. AIDS 2006;20:1813-21. [PubMed]

138. Nunez M.  Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. J Hepatol 2006;44:S132-9. [PubMed]

139. Oh J, Hegele RA. HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet Infect Dis 2007;7:787-96.[PubMed]

140. Opravil M, Hirschel B, Lazzarin A, Furrer H, Chave JP, Yerly S, Bisset LR, Fischer M, Vernazza P, Bernasconi E, Battegay M, Ledergerber B, Günthard H, Howe C, Weber R, Perrin L; Swiss HIV Cohort Study. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in human immunodeficiency virus infection. J Infect Dis 2002;185:1251-60. [PubMed]

141. Pacanowski J, Poirier JM, Petit I, Meynard JL, Girard PM.  Atazanavir urinary stones in an HIV-infected patient. AIDS 2006;20:2131. [PubMed]

142. Panel on Antiretroviral Guidelines for Adults and Adolescents. November 3, 2008. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

143. Periard D, Telenti A, Sudre P, Cheseaux JJ, Halfon P, Reymond MJ, Marcovina SM, Glauser MP, Nicod P, Darioli R, Mooser V.  Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation 1999;100:700-5.[PubMed]

144. Phillips EJ, Kuriakose B, Knowles SR.  Efavirenz-induced skin eruption and successful desensitization. Ann Pharmacother 2002;36:430-2. [PubMed]

145. Prezista (darunavir) Prescribing Information. December 2008. Tibotec Pharmaceuticals, Ltd.

146. Reyataz (atazanavir) Prescribing Information. September 2008. Bristol-Myers Squibb.

147. Rodriguez-Novoa, S, Barreiro P, Rendon A, Jimenez-Nacher I, Gonzalez-Lahoz J, Soriano V.  Influence of 516G>T polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects. Clin Infect Dis 2005;40:1358-61. [PubMed]

148. Rodriguez Novoa S, Barreiro P, Rendon A, Barrios A, Corral A, Jimenez-Nacher I, Gonzalez-Lahoz J, Soriano V. Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C-->T polymorphism at the multidrug resistance gene 1. Clin Infect Dis 2006;42:291-5. [PubMed]

149. Rotger M, Taffe P, Bleiber G, Gunthard HF, Furrer H, Vernazza P, Drechsler H, Bernasconi E, Rickenbach M, Telenti A. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis 2005; 192:1381-6. [PubMed]

150. Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, Stancil B, Mosteller M, Brothers C, Wannamaker P, Hughes A, Sutherland-Phillips D, Mallal S, Shaefer M. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis 2008;46:1111-8. [PubMed]

151. Sabin CA, d'Arminio Monforte A, Friis-Moller N, Weber R, El-Sadr WM, Reiss P, Kirk O, Mercie P, Law MG, De Wit S, Pradier C, Phillips AN, Lundgren JD.  Changes over time in risk factors for cardiovascular disease and use of lipid-lowering drugs in HIV-infected individuals and impact on myocardial infarction. Clin Infect Dis 2008;46:1101-10. [PubMed]

152. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, De Wit S, Law M, D'Arminio Monforte A, Friis-Moller N, Kirk O, Pradier C, Weller I, Phillips AN, Lundgren JD. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008;371:1417-26. [PubMed]

153. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, Gastaut JA, Touraine JL.  A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999; 13:1659-67. [PubMed]

154. Saint-Marc T, Partisani M, Poizot-Martin I, Rouviere O, Bruno F, Avellaneda R, Lang JM, Gastaut JA, Touraine JL. Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS 2000;14:37-49. [PubMed]

155. Saves M, Raffi F, Capeau J, Rozenbaum W, Ragnaud JM, Perronne C, Basdevant A, Leport C, Chene G.  Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin Infect Dis 2002;34:1396-405. [PubMed]

156. Schambelan M, Benson CA, Carr A, Currier JS, Dube MP, Gerber JG, Grinspoon SK, Grunfeld C, Kotler DP,  Mulligan K, Powderly WG,  Saag MS.  Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr 2002;31:257-75. [PubMed]

157. Schambelan M, Mulligan K, Grunfeld C, Daar ES, LaMarca A, Kotler DP, Wang J, Bozzette SA, Breitmeyer JB.  Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group. Ann Intern Med 1996;125:873-82. [PubMed]

158. Schwarz JM, Lee GA, Park S, Noor MA, Lee J, Wen M, Lo JC, Mulligan K, Schambelan M, Grunfeld C. Indinavir increases glucose production in healthy HIV-negative men. AIDS 2004;18:1852-4. [PubMed]

159. Scribner AN, Troia-Cancio PV, Cox BA, Marcantonio D, Hamid F, Keiser P, Levi M,Allen B, Murphy K, Jones RE, Skiest DJ. Osteonecrosis in HIV: a case-control study. J Acquir Immune Defic Syndr 2000;25:19-25.[PubMed]

160. Sculptra (injectable poly-L-lactic acid) Product Information. June 2006. Dermik Laboratories.

161. Selzentry (maraviroc) Prescribing Information. November 2008. Pfizer Inc.

162. Simpson D, Estanislao L, Evans S, McArthur J, Marcus K, Truffa M, Lucey B, Naismith R, Tyler J, Lonergan, Clifford D, and HIV Neuromuscular Syndrome Study Group.  HIV-associated neuromuscular weakness syndrome. AIDS 2004;18:1403-1412. [PubMed]

163. Simpson DM. Selected peripheral neuropathies associated with human immunodeficiency virus infection and antiretroviral therapy. J Neurovirol 2002;8 Suppl 2:33-41. [PubMed]

164. Slama L, Lanoy E, Valantin MA, Bastard JP, Chermak A, Boutekatjirt A, William-Faltaos D, Billaud E, Molina JM,  Capeau J, Costagliola D, Rozenbaum W. Effect of pioglitazone on HIV-1-related lipodystrophy: a randomized double-blind placebo-controlled trial (ANRS 113). Antivir Ther 2008;13:67-76. [PubMed]

165. Solas C, Basso S, Poizot-Martin I, Ravaux I, Gallais H, Gastaut JA, Durand A, Lacarelle B. High indinavir Cmin is associated with higher toxicity in patients on indinavir-ritonavir 800/100 mg twice-daily regimen. J Acquir Immune Defic Syndr 2002;29:374-7. [PubMed]

166. Squires KE.  An introduction to nucleoside and nucleotide analogues. Antivir Ther 2001;6 Suppl 3:1-14. [PubMed]

167. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, Stryker R, Johnson P, Labriola DF,  Farina D, Manion DJ, Ruiz NM. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999;341:1865-73. [PubMed]

168. Steigbigel RT, Cooper DA, P. N. Kumar, J. E. Eron, M. Schechter, M. Markowitz, M. R. Loutfy, J. L. Lennox, J. M. Gatell, J. K. Rockstroh, C. Katlama, P. Yeni, A. Lazzarin, B. Clotet, J. Zhao, J. Chen, D. M. Ryan, R. R. Rhodes, J. A. Killar, L. R. Gilde, K. M. Strohmaier, A. R. Meibohm, M. D. Miller, D. J. Hazuda, M. L. Nessly, M. J. DiNubile, R. D. Isaacs, B. Y. Nguyen, and H. Teppler.  Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008;59:339-54. [PubMed]

169. Sulkowski, M. S. 2003. Hepatotoxicity associated with antiretroviral therapy containing HIV-1 protease inhibitors. Semin Liver Dis 23:183-94. [PubMed]

170. Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004;18:2277-84. [PubMed]

171. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000;283:74-80.[PubMed]

172. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD.  Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002;35:182-9. [PubMed]

173. Sustiva (efavirenz) Prescribing Information. March 2008. Bristol-Myers Squibb.

174. Sutinen J, Walker UA, Sevastianova K, Klinker H, Hakkinen AM, Ristola M, Yki-Jarvinen H.  Uridine supplementation for the treatment of antiretroviral therapy-associated lipoatrophy: a randomized, double-blind, placebo-controlled trial. Antivir Ther 2007;12:97-105. [PubMed]

175. Tien PC, Schneider MF, Cole SR, Levine AM, Cohen M, DeHovitz J, Young M, Justman JE. Antiretroviral therapy exposure and incidence of diabetes mellitus in the Women's Interagency HIV Study. AIDS 2007;21:1739-45.[PubMed]

176. Tien PC, Schneider MF, Cole SR, Levine AM, Cohen M, DeHovitz J, Young M, Justman JE. Antiretroviral therapy exposure and insulin resistance in the women's interagency HIV study. J Acquir Immune Defic Syndr 2008;49:369-76. [PubMed]

177. Timpone J, Fluhme D, Nascone J, Evans B, Kumar P. Avascular necrosis in HIV-positive patients. A potential link to protease inhibitors [abstract 680]. 1999. Presented at the Sixth Conference on Retroviral and Opportunistic Infections, Chicago, IL, February.

178. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med 2000;160:2050-6.[PubMed]

179. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, Cahn P, Lalloo UG, van der Westhuizen IP, Malan DR, Johnson MA, Santos BR, Mulcahy F, Wood R, Levi GC, Reboredo G, Squires K, Cassetti I, Petit D, Raffi F, Katlama C, Murphy RL, Horban A, Dam JP, Hassink E, van Leeuwen R, Robinson P, Wit FW, Lange JM; 2NN Study team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004;363:1253-63. [PubMed]

180. Van Rompay KK, Brignolo LL, Meyer DJ, Jerome C, Tarara R, Spinner A, Hamilton M, Hirst LL, Bennett DR, Canfield DR, Dearman TG, Von Morgenland W, Allen PC, Valverde C, Castillo AB, Martin RB, Samii VF, Bendele R, Desjardins J, Marthas ML, Pedersen NC, Bischofberger N.  Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother 2004;48:1469-87. [PubMed]

181. Vigano A,  Brambilla P, G. Pattarino, S. Stucchi, S. Fasan, C. Raimondi, C. Cerini, V. Giacomet, G. V. Zuccotti, and G. Bedogni.  Long-Term Evaluation of Glucose Homeostasis in a Cohort of HAART-Treated HIV-Infected Children : A Longitudinal, Observational Cohort Study. Clin Drug Investig 2009;29:101-9. [PubMed]

182. Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C, Bogner JR, Landgraf R, Goebel FD. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients. AIDS 1998;12:F167-73. [PubMed]

183. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 2003;306:287-300. [PubMed]

184. Winston J, Deray G, Hawkins T, Szczech L, Wyatt C, Young B. Kidney disease in patients with HIV infection and AIDS. Clin Infect Dis 2008;47:1449-57. [PubMed]

185. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM.  Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis 2002;186:23-31. [PubMed]

186. Wohl DA, Tien HC, Busby M, Cunningham C, Macintosh B, Napravnik S, Danan E, Donovan K, Hossenipour M, Simpson RJ, Jr.  Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis 2005;41:1498-504. [PubMed]

187. Yeni P, Rockstroh J, LaMarca A, Madison S, Nichols G, Millard J, McCarty D, Bonny T, and the EPIC Study Team. Safety and antiviral activity of the novel CCR5 antagonist aplaviroc in combination with LPV/r in HIV-infected therapy naive subjects [abstract P-394]. 2006. Presented at the Eighth Int. Conf. Drug Therapy HIV Infection.

188. Yin M, Dobkin J, Brudney K, Becker C, Zadel JL, Manandhar M, Addesso V, Shane E. Bone mass and mineral metabolism in HIV+ postmenopausal women. Osteoporos Int 2005;16:1345-52. [PubMed]

189. Young B, Buchacz K, Baker RK, Moorman AC, Wood KC, Chmiel J, Brooks JT, and HIV Outpatient Study.  Renal Function in Tenofovir-Exposed and Tenofovir-Unexposed Patients Receiving Highly Active Antiretroviral Therapy in the HIV Outpatient Study. J Int Assoc Physicians AIDS Care (Chic Ill) 2007;6:178-87. [PubMed]

190. Zhang D, Chando TJ, Everett DW, Patten CJ,  Dehal SS, Humphreys WG. In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 2005;33:1729-39. [PubMed]

191. Zhou H, Jarujaron S, Gurley EC, Chen L, Ding H, Studer E, PandakWM, Jr., Hu W, Zou T, Wang JY, Hylemon PB. HIV protease inhibitors increase TNF-alpha and IL-6 expression in macrophages: involvement of the RNA-binding protein HuR. Atherosclerosis 2007;195:e134-43. [PubMed]

192. Zhou H, Pandak WM, Jr., LyallV, Natarajan R, Hylemon PB.  HIV protease inhibitors activate the unfolded protein response in macrophages: implication for atherosclerosis and cardiovascular disease. Mol Pharmacol 2005;68:690-700. [PubMed]

193. Ziagen (abacavir) Prescribing Information. July 2008. GlaxoSmithKline.