Antiretroviral Drugs in PecFtrics Chokechai Rongkavilit and Basim I. Asmar Division of Infectious Diseases, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan, USA

Abstract. The advent of potent drugs to treat HIV and the development of increasingly effective treatment strategies have resulted in dramatic improvements in the prognosis and quality of life for HIV-infected children. The purpose of this article is to provide the primary care physicians with practical information on antiretroviral drugs that are currently used for the treatment of pediatric HIV infection.[Indlan J Pedlatr 2001; 68 (7) 9 641-647]

Key words : Antiretrovira/s; H/V; Pediatrics Management of human immunodeficiency virus (HIV) infection in infants and children is rapidly evolving and becoming progressively complex. Antiretroviral drugs, which play the major role in the treatment of HW infection, have become increasingly available for children.

Initiation of Antiretroviral Treatment Antiretroviral therapy is generally recommended in children with clinical symptoms of HIV infection. This includes those with mild symptoms such as hepatomegaly or lymphadenopathy. Some may begin treatment even when the child is asymptomatic. Others may defer treatment and periodically evaluate the child's clinical, immunologic and virologic status. Immunologic status is assessed by CD4+ T-lymphocyte measurements, while virologic status is determined by evaluating the magnitude of viral burden in plasma using quantitative HIV RNA assays. Therapy is initiated if there is an evidence of HIV-associated clinical symptoms, immune suppression, or increased viral burden. Because of the high risk for disease progression, most experts recommend treatment initiation in all children less than 1 year of age, regardless of their disease status (Table 1). A comprehensive assessment of adherence to treatment should be instituted for all children and their families before commencing antiretroviral treatment.

Monitoring Therapy The aim of therapy is long-term suppression of plasma

Reprint requests : Dr. Chokechai Rongkavilit, M.D., Division of Infectious Diseases, Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, M148201, USA, Fax : (313) 993-8846. E-mail - [email protected] Indian Journal of Pediatrics, Volume 68--July, 2001

HIV RNA below the level of detection. Assessment of initial virologic response should be performed at 4 weeks after treatment initiation; a significant reduction of plasma HIV RNA level should be expected. By 8-12 weeks of treatment, at least a 10-fold decrease from baseline level should be achieved. If this adequate initial response is witnessed, quantitative plasma HIV RNA should be monitored every 3-4 months, and it should become undetectable after 4-6 months of therapy. ~ If the response is less or if there is a virologic rebound confirmed by repeat testing, the issues of treatment compliance, drug absorption and metabolism, and drug resistance should be explored. Drug resistance warrants changing antiretroviral regimen. Genotypic a n d / o r phenotypic resistance assays may be helpful to determine which drug to use and which to avoid. CD4+ T-lymphocyte assay should also be performed every 3-4 months. However, the response may not be as swift and dramatic as the virologic response.

Antiretroviral Drugs In order to understand the pharmacology of antiretroviral drugs, it is important to recognize the biology of HIV. HIV is an enveloped single-stranded RNA virus. It contains the genes for gag, which encodes for the core nucleocapsid polypeptides, env which encodes for the surface-coated proteins, as well as pol which codes for viral reverse transcriptase, protease, and other essential enzymes. HIV enters host cells by interactive process between viral envelope glycoproteins and the host cell CD4 molecule, as well as chemokine receptors. After entry, the singlestranded viral RNA is transcribed by reverse transcriptase e n z y m e into doubled-stranded DNA. This viral DNA is inserted into the host cell's nucleus 641

Chokechai Rongkavilit and Basim I. Asmar TABLE1. Indications for Initiation of Antiretroviral Treatment in Children

9 Clinical symptoms associated with HW infection, ranging from mildly to severely symptomatic 9 Evidence of moderate to severe immune suppression, indicated by low age-adjusted CD4+ T-lymphocyte count or CD4 percentage < 25% 9 Age < 12 months-regardless of clinical, immunologic, or virologic status 9 For asymptomatic children aged > I year, two options can be considered : 1. Initiate therapy regardless of clinical status 2. Defer therapy and monitor the child's virologic, immunologic and clinical status regularly and initiate treatment if : - High HW RNA, especially > 10,000-20,000 copies/ml - Increased HW RNA > 5 folds in children < 2 years, or > 3 folds in children > 2 years - Rapid decline of CD4+ T-lymphocyte approaching moderate immune suppression - Development of clinical symptoms associated with HIV infection

Recommendedantiretroviral regimens 9 Two NRTIs (ZDV + ddI, or ZDV + 3TC, or d4T + ddI, or d4T + 3TC) plus one PI (nelfinavir, or ritonavir, or indinavir) * Efavirenz plus two NRTIs (as above) or efavirenz plus nelfinavir plus 1 NRTI Adapted from : Working Group on Antiretroviral Agents in Pediatric HIV Infection. Guidelines for the use of antiretroviral agents in pediatric HIV infection. January 7, 2000. Website : www.hivatis.org where the new HIV virions are generated. Immature virions will require protease enzyme to cleave gag-pol gene products during their maturation process. The mature viruses will subsequently infect other host cells. Currently there are 3 classes of antiretroviral drugs available for the treatment of HIV infection; nucleoside reverse transcriptase inhibitors (NRTI), non-nudeoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) (Table 2). Other groups of antiretroviral drugs, including fusion inhibitor and therapeutic HW vaccine, are currently being evaluated in clinical trials. It is recommended that the treatment regimen should be a combination of at least 3 drugs inc!uding two NRTIs plus either one PI or one NNRTI (Table 1). The combination regimen has been shown to slow disease progression, improve survival, and result in better virologic and immunologic responses in children. 27 In m a n y parts of the world, however, the cost of treatment and the access to healthcare m a y be unfortunately prohibitive. Therefore, the treatment regimens and guidelines should be realistically adapted to those circumstances. A.

Nucleoside (NRTI)

R e v e r s e Transcriptase I n h i b i t o r

The drugs in this class require intracellular phosphorylation to form active triphosphate metabolites. The active metabolite inhibits HIV replication by two known mechanisms : (1) It competes with the natural nucleosides for incorporation into HIV DNA during reverse transcription process. 642

(2)

It subsequently causes DNA chain termination because it lacks the 3'-hydroxyl group for further 5' to 3' phosphodiester linkages necessary for DNA chain elongation.

Despite their short half-lives in plasma, most NRTIs have long intracellular half-lives allowing for less frequent administration.

Zidovudine (ZD V, AZT) ZDV was the first antiretroviral drug approved for use in children and it has been a mainstay in HIV therapy and in prevention of perinatal transmission. The Pediatric AIDS Clinical Trials Group (PACTG) 076 s t u d y showed that administration of ZDV to the w o m e n during pregnancy and labour and to the infants decreased the risk of perinatal transmission by two-thirds. 8 Even the shorter course of ZDV given during late pregnancy and labour with no administration to the infants reduced the risk of transmission by half.9 In many developed countries, implementation of ZDV prophylaxis into clinical practice has contributed to a substantial decrease in reported perinatal FIW cases. ZDV is an analogue of thymidine base. It is very well tolerated in children. Its metabolism is through glucuronidation and the metabolites are excreted through the urine. Therefore, the dose should be reduced in patients with substantial hepatic or renal dysfunction. Its rare but most frequent toxicity is bone marrow suppression, which results in granulocytopenia and anemia. It generally responds to dose reduction or interruption. Other less frequent Indian Ooumal of Pediatrics, Volume 68~July, 2001

Antlretroviral Drugs in Pediatrics TABLE2. AntireUroviral Drugs and Dosages Drug

Formulation

Dose

Nucleoside reverse transcriptase inhibitor

Zidovudine

Oral solution : 10 mg/ml Capsule : 100 mg Tablet : 300 mg

Didanosine

Oral solution : 10 mg/kg Chewable tablet : 25, 50, 100, 150 mg Oral solution : 1 mg/mL Capsule : 15, 20, 30, 40 mg

Stavudine Lamivudine Abacavir

Oral solution : 10 mg/mL Tablet : 150 mg Oral solution : 20 mg/mL Tablet : 300 mg

160 mg/m 2 every 8 hours or 90-180 m g / m 2 every 6-8 hours; some use 180 mg/m 2 twice daily (not to exceed 600 mg/day) 90 mg/m 2 twice daily (1 hour before or 2 hours after meal) up to 125 mg/dose. Weight > 60 kg : 200 mg twice daily 1 mg/kg twice daily (up to 30 kg) weight 30-60 kg : 30 mg twice daily weight > 60 kg : 40 mg twice daily 4 mg/kg (max 150 mg) twice daily 8 mg/kg (max 300 mg) twice daily

Non-nucleoside reverse transcriptase inhibitor

Nevirapine Efavirenz

Oral suspension : 10 mg/ml Tablet 9200 mg Capsule : 50, 100, 200 mg

120 mg/m 2 ( max 200 mg) once a day for 14 days, then .increase to twice daily Weight 10-<15 kg : 200 mg Weight 15-<20 kg : 250 mg Weight 20-<25 kg : 300 mg Weight 25-<32.5 kg : 350 mg Weight 32.5-<40 kg 9400 mg Weight > 40 kg : 600 mg, once a day

Hard gel capsule : 200 mg Soft gel capsule : 200 mg Oral powder : 50 mg free b a s e / a scoopful Tablet 9250 mg Capsule 200, 400 mg

33 mg/kg (max 1,200 mg of soft gel) three times daily 20-30 mg/kg (max 750 mg) three times daily; some use 55 mg/kg twice daily Under study at 500 m g / m 2 (max 800 mg) every 8 hours 350-400 m g / m 2 (max 600 mg) twice daily

Protease inhibitor

Saquinavir Nelfinavir Indinavir Ritonavir Amprenavir Lopinavir/ritonavir

Oral solution : 80 mg/ml Capsule : 100 mg Oral solution : 15 mg/ml Capsule 950, 150 mg Oral solution : 400 mg lopinavir/ 100 mg ritonavir per 5 ml Capsule : 133.3 mg lopinavir/ 33.3 mg ritonavir

side effects include h e a d a c h e , liver toxicity, a n d m y o p a t h y which is possibly related to mitochondrial dysfunction. S t a v u d i n e (d4T)

d4T is a n o t h e r t h y m i d i n e analogue. Despite its c o m p a r a b l e structure with ZDV, d4T does not cause bone m a r r o w suppression to the extent that ZDV does. It is well tolerated and can be given only twice daily. Indian Journal of Pediatrics, Volume 68--July, 2001

Oral solution : 22.5 mg/kg twice daily (max 2,800 mg/day) Capsule : 20 mg/kg twice daily (max 2,400 mg/day) Weight < 15 kg : 12 mg lopinavir per kg twice daily Weight > 15 kg : 10 mg lopinavir per kg twice daily Some suggest 300 mg lopinavir per m 2 twice daily (Max dose 400 mg lopinavir/100 mg ritonavir)

d4T m a y be r a r e l y associated w i t h p e r i p h e r a l n e u r o p a t h y and pancreatitis, b o t h of w h i c h m a y require treatment interruption. Peripheral n e u r o p a t h y is clinically characterized b y n u m b n e s s , tingling, or pain at the peripheral part of extremities. In addition, there has been a possible association between the use of s t a v u d i n e , as well as o t h e r NRTIs, a n d the d e v e l o p m e n t of mitochondrial toxicity e v i d e n c e d b y lactic acidosis, severe h e p a t o m e g a l y and steatosis, x~ 643

Chokechai Rongkavilit and Basim I. Asmar

Didanosine (ddI) Didanosine is an analogue of adenosine. It is rapidly degraded in acidic environment. Therefore, the formulation contains buffering agents to increase gastric pH and, as a result, increase its oral bioavailability. The major dose-limiting toxicities of ddI are pancreatitis and peripheral neuropathy, similar to those of d4T. Due to its degradation in acid environment, ddI should be taken on an e m p t y stomach at least at 1 hour before or 2 hours after a meal. When administering chewable tablets, at least 2 tablets should be administered to ensure adequate buffering capacity. The absorption of some medications including ketoconazole, itraconazole, dapsone and fluoroquinolone may be decreased when co-administered with ddI, therefore these medications should be taken at least 2 hours before or 2 hours after ddI. Due to its relatively long-half life, ddI dosing schedule can be twice-daily and, possibly, once-daily.

Lamivudine (3TC) 3TC is cytidine analogue. It is generally well tolerated in children. The severe but uncommon side effects are pancreatitis, peripheral neuropathy, and possible mitochondrial toxicity. A combined formulation of ZDV and 3TC and a combined formulation of ZDV, 3TC and abacavir provide an added measure of convenience but the child must be able to swallow tablets for accurate dosing.

Zalcitabine (ddC) This analogue of cytidine is available only as the tablet formulation. It is used very infrequently in children.

Abacavir (ABC) ABC is the analogue of guanine. It is generally welltolerated in children. However, it carries an approximately 5% risk for a fatal hypersensitivity reaction, usually within the first 6 weeks of therapyY -12 The symptoms include fever, fatigue, malaise, nausea, vomiting, respiratory symptoms and non-specific rash. The hypersensitivity reaction can sometimes occur without rash. The condition m a y progress to anaphylaxis, hypotension, liver failure, and death. Symptoms usually worsen with continued therapy but frequently resolve u p o n withdrawal of the drug. Patients suspected of having hypersensitivity reaction should have ABC permanently stopped. Rechallenge with ABC after hypersensitivity reaction, even if unconfirmed, is not recommended as this may result in a more severe hypersensitivity reaction. The use of 644

ABC in combination with two other NRTIs is effective for treatment in adults. However, this combination may be less effective in pediatric patients, particularly in young children.

B. Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) NNRTI acts by binding directly to HIV reverse transcriptase enzyme. This results in specific, noncompetitive inhibition of the viral enzyme function. The medications in this class are nevirapine, delavirdine and efavirenz. However, only nevirapine and efavirenz are commonly used in the pediatric population. Since NNRTIs are metabolized by cytochrome P450 system, they m a y interact with numerous drugs that affect or are metabolized by cytochrome P450. Drugs having such suspected interactions are rifampin, rifabutin, oral contraceptives, cisapride, ergot, astemizole, terfenadine, triazolam, midazolam, oral anticoagulants, digoxin, phenytoin and theophylline. Particularly, NNRTIs should not be given concurrently with astemizole, terfenadine, cisapride, midazolam, triazolam or ergot derivatives as this may result in life-threatening adverse effects. While NNRTIs provide improved antiviral potency, a major disadvantage of this class of drugs is that a single codon mutation in HIV will confer crossresistance to all drugs in this class.

Nevirapine (NVP) NVP was the first NNRTI approved for children. It has been used in HIV treatment and has recently become a mainstay in the prevention of perinatal transmission particularly in the developing world. A single dose of NVP given to women during labour and a single dose to infants after birth could substantially reduce the risk of perinatal transmission. 13 Because of its gradual autoinduction, i.e., inducing its own hepatic metabolism, NVP should be started as a once-daily dose during the first 2 weeks. If there are no rash or other untoward effects, the dose can then be increased to the twice-daily dose. The major toxicity of NVP is skin rash; however this can be m a n a g e d with antihistamine. The rare but more severe cases can progress to Stevens-Johnson syndrome. In case of progressive rash, NVP should be permanently discontinued.

Efavirenz (EFV) The long half-life of EFV permits once-a-day dosing, which should improve patient's compliance. Its potency is comparable to that of protease inhibitors, Indian Journal of Pediatrics, Volume 68--July, 2001

Antiretroviral Drugs In Pediatrics making EFV one of the possible options to spare protease inhibitors for later use. In PACTG Protocol 382, 76% of NNRTI and PI-naive children receiving EFV, nelfinavir and an NRTI had plasma HIV RNA less than 400 copies/mL at 48 weeks of treatment; 63% had HIV RNA less than 50 copies/mL, s EFV is generally well tolerated in children. The most frequent side effects include skin rash, which occurs less compared with NVP, and central nervous system side effects (somnolence, abnormal dreams, confusion, hallucination, and euphoria). Pregnant women should avoid taking this drug due to its teratogenic effects seen in primates. 14 Female adolescents taking this medication should undergo pregnancy testing before initiating the drug and have adequate birth control measures while taking the drug. Additionally, its ability to induce cytochrome P450 enzymes will substantially decrease plasma concentration of most protease inhibitors when used in combination. C. Protease inhibitor (PI)

The addition of PI into the treatment regimen has significantly improved survival of pediatric patients. 3,6 During the maturation of HIV virions, HIV protease cleaves viral polypeptide products of the gag and gagpol genes to form viral structural proteins and other essential enzymes. PI therefore blocks the maturation process of HIV. All PIs are metabolized by cytochrome P450 system, therefore they possess the potential for significant interactions with other drugs. Due to lifethreatening interactions, PI should not be used concurrently with astemizole, terfenadine, cisapride, ergot derivatives, midazolam and triazolam. The side effects are generally similar among all PIs; these include gastrointestinal disturbance, liver enzyme elevation and spontaneous bleeding in hemophiliacs. Lipodystrophy as manifested by abnormal body fat distribution, hyperlipidemia and insulin resistance has been reported with PIs2 s-~7

Saquinavir (SQV) Saquinavir is available as a hard gel capsule and a soft gel capsule. The relative oral bioavailability of soft gel capsule is three times that of the drug in hard gel capsule. SQV should be taken within 2 hours of a full meal to increase absorption. Due to the lack of convenient pediatric formulations, SQV use has been limited to older children and adolescents.

Nelfinavir (NFV) Preliminary results of PACTG 377 demonstrated that half of PI-naive children receiving NFV, NRTI and Indian Journal of Pediatrics, Volume 68---July, 2001

either NVP or PI had HIV RNA < 400 copies/mL at 24 weeks. TM NFV is available in tablet formulation and powder formulation for oral solution, which can be given to younger children. ~The most common side effect is diarrhea. For oral solution, powder may be mixed with water, milk, pudding, ice cream or infant formula although the p o w d e r generally does not dissolve well.

Ritonavir (RTV) In PACTG 338 study, 42% of PI-nalve children receiving RTV, ZDV and 3TC but only 27% receiving RTV and d4T had HIV RNA < 400 copies/mL at 48 weeks7 The fact that all subjects in this study had prior antiretroviral therapy and that the adherence to the multiple-drug regimen was difficult in children may have contributed to the relatively low success rate in this study. The most c o m m o n adverse effects are nausea and vomiting, which could be due to the bitter taste of RTV oral solution. RTV is a potent inhibitor of cytochrome P450 3A, therefore it can significantly increase plasma concentrations of other PIs. As a result, the number of pills and dosing frequency of other PIs could be reduced. Studies in adults have shown the unique clinical benefit of using a small dose of RTV as a pharmacokinetic enhancer to boost the plasma levels of other PIs when given in combination. 19"2~ However, the information on RTV and PI combination in pediatric patients is relatively limited.

Indinavir (IDV) IDV is available only in capsule formulation; as a result, a large-scale pediatric trial has not been done and its use in children is limited. IDV should be taken every 8 hours on an empty stomach. Adult studies have shown that it can be given twice daily with or without meal if combined with a small dose of RTV. Nephrolithiasis (IDV crystal precipitation) occurs in 212% of patients taking IDV.2~a3 Plenty of fluid intake is required to minimize this risk. Most of nephrolithiasis from IDV can be treated medically by increasing fluid intake. Asymptomatic hyperbilirubinemia has also been reported in patients taking IDV.

Amprenavir (APV) In an open-label study, 32% of PI-naive children receiving APV and at least one new NRTI had HIV RNA < 400 copies/mL at 48 weeks. 2. APV is well tolerated by children, although a large volume/pill burden required is an impediment of its use. Due to its sulfonamide-related structure, life-threatening rash 645

Chokechai Rongkavillt and Baslm I. Asmar including Steven-Johnson s y n d r o m e m a y occur in 1% of patients. Thus, APV should be used with caution in patients with sulfonamide allergy. APV also contains vitamin E and patients should be advised not to take supplemental vitamin E while taking APV. The liquid formulation contains p r o p y l e n e glycol which m a y be excessive in y o u n g children, a n d it is not r e c o m m e n d e d for children less than 3 years of age as well as in those w i t h hepatic or renal failure. The d i f f e r e n t viral g e n o t y p i c resistance p a t t e r n of APV makes it a feasible option for PI-experienced patients with treatment failure. 2s Lopinavirlritonavir

This n e w a n t i r e t r o v i r a l f o r m u l a t i o n c o m b i n e s lopinavir, a new PI, with a small dose of ritonavir. The a d d i t i o n of r i t o n a v i r significantly increases p l a s m a l o p i n a v i r c o n c e n t r a t i o n that is in excess of the concentration needed to inhibit the replication of m a n y PI-resistant HIV variants. Therefore, it is considered as o n e of the t h e r a p e u t i c o p t i o n s for P I - e x p e r i e n c e d patients with treatment failure. 26 Because of the c o m p l e x t r e a t m e n t r e g i m e n s a n d related family issues, the compliance issues should be assessed and a d d r e s s e d for all children a n d families b e f o r e a n d d u r i n g the t r e a t m e n t course. Lack of adherence to treatment m a y lead to the d e v e l o p m e n t of drug resistance and cross-resistance, which certainly r e d u c e s s u b s e q u e n t t r e a t m e n t options. Intensive f o l l o w - u p is r e q u i r e d to assess a d h e r e n c e , d r u g tolerance and treatment response. Thus, the readiness and cooperation of the child and the family certainly plays a significant role in the success of HIV care in pediatrics. REFERENCES 1. Working Group on Antiretroviral Agents in Pediatric HIV Infection. Guidelines for the use of antiretroviral agents in pediatric HIV infection. January 7, 2000. Website: http://www.hivatis.org 2. Cohen-Stuart JW, Slieker WA, Rijkers GT et al. Early recovery of CD4+ T lymphocytes in children on highly active antiretroviral therapy. AIDS 1998; 2 : 2155-2159. 3. Watson DC, Farley JJ. Efficacy of and adherence to highly active antiretroviral therapy in children infected with human immunodeficiency virus type 1. Pediatr Infect Dis J 1999; 18 : 682-689. 4. Krogstad P, Wiznia A, Luzuriaga K at al. Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate. Clin InfeCt Dis 1999; 28 : 1109-1118. 5. Starr SE, Fletcher CV, Spector SA et al. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. N Engl J 646

Med 1999; 341 : 1874-1881. 6. de Martino M, Tovo P, Balducci M et al. Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. JAMA 2000; 284 : 190-197. 7. Nachman S, Stanley K, Yogev R et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapyexperienced HIV-infected children: a randomized controlled trial. ]'AMA 2000; 283 : 492-498. 8. Connor EM, Sperling RS, Gelber R et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331 : 1173-1180. 9. Shaffer N, Chuachoowong R, Mock PA et al. Shortcourse zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Lancet 1999; 353 : 773-780. 10. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effect of reverse transcriptase inhibitors: mitochondrial toxicity as a c o m m o n pathway. AIDS 1998; 12:1735-1744. 11. Fischl M, Greenberg S, Clumeck N e t al. Safety and activity of abacavir with 3TC/ZDV in antiretroviralna'ive subjects [abstract 127/12230]. Presented at : The 12th World AIDS Conference; June 28-July 3, 1998; Geneva, Switzerland. 12. Kline MW, Blanchard S, Fletcher CV et al. A phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with h u m a n immunodeficiency virus infection. Pediatrics 1999; 103 : e47. 13. Guay LA, Musoke P, Fleming T et al. Intrapartum and neonatal single-dose nevirapine compared with z i d o v u d i n e for p r e v e n t i o n of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999; 354 : 795-802. 14. Cadman J. Efavirenz pregnancy warning. Treatment Issues 1998; 12 : No 3. 15. Carr A, Samaras K, Burton Set al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving protease inhibitors. AIDS 1998; 12 : F51-F58. 16. Tsiodras S, Mantzoros C, H a m m e r S, Samore M. Effects of proteas e inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy : a 5-year cohort study. Arch Intern Med. 2000; 160 92050-2056. 17. Jaquet D, L(~vine M, Ortega-Rodriguez E et al. Clinical and metabolic presentation of lipodystrophic syndrome in HIV-infected children. AIDS 2000; 14 : 2123-2128. 18. Wiznia A, Stanley K, Krogstad Pet al. Combination nucleoside analogues plus nelfinavir, nevirapine or ritonavir in stable antiretroviral therapy-experienced HIV-infected children [Abstract 697]. Presented at : The 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, USA. 19. Hsu A, Granneman G, Chen S et al. Assessment of single- and multiple-dose interactions between ritonavir and saquinavir [abstract LB.B.6041].

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Presented at : XIII International AIDS Conference; July 9-14, 2000; Durban, South Africa. Van Heeswijk R, Veldkemp A, Hoetelmans R et al. The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-l-infected individuals. AIDS 1999; 13 : F95-F99. Kopp JB, Miller KD, Mican JA. Crystalluria and urinary tract abnormalities associated with indinavir. Ann Intern Med 1997; 127 : 119-125. Mueller BU, Sleasman J, Nelson RP et al. A phase I/II study of the protease inhibitor indinavir in children with HIV infection. Pediatrics 1998; 102 : 101-109. Reiter WJ, Schon-Pernerstorfer H, Dorfinger K, Hofbauer J, Marberger M. Frequency of urolithiasis in individuals seropositive for human immunodeficiency virus treated with indinavir is higher than previously

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assumed. J Urol 1999; 161 : 1082-1084. 24. Church J, Rathore M, Rubio T et al. A phase llI study of a m p r e n a v i r in protease-inhibitor-na~ve andexperienced HIV-infected children and adolescents. Presented at: The 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, USA. 25. Schmidt B, Korn K, Moschik Bet al. Low level of crossresistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors. Antimicrob Agents Chemother 2000; 44 : 3213-3216. 26. Hsu A, Isaacson J, Kempf D et al. Trough concentrationEC50 relationship as a predictor of viral response for ABT-378/ritonavir in treatment-experienced patients [abstract 171]. Presented at : The 40th Interscience Conference on Antimicrobial Agent and Chemotherapy; September 17-21~,2000; Toronto, Canada.

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