Antiretroviral Drug Guidelines for the Treatment of HIV Infection

Antiretroviral Drug Guidelines for theTreatment of HIV InfectionShould Protease Inhibitors Always be Included in the InitialRegimen or Not?

Duncan Churchill and Jonathan Weber

Imperial College of Science Technology and Medicine, St. Mary’s Hospital, Norfolk Place, London, England

Abstract Combination antiretroviral therapy, usually consisting of 2 nucleoside analoguereverse transcriptase inhibitors and a protease inhibitor (PI), has revolutionisedthe management of patients with HIV infection. PI-containing combinations aresignificantly superior to combinations of 2 nucleoside analogues, and the lattercombination is now indicated only in very exceptional circumstances. However,long term adherence to complex regimens of antiretroviral drugs, and the emerg-ing longer term toxicity associated with PIs and to a lesser extent, problems withlong term adherence to complex regimens of antiretroviral drugs, make the useof ‘protease-sparing’ regimens attractive. Although in some cases such regimensmay be associated with a lower chance of sustained suppression of viral load,leading to the development of drug resistance and virological rebound, they allowthe preservation of a whole class of antiretrovirals for later use, avoid the risk ofPI toxicity, and their use can also help to avoid important drug interactions asso-ciated with PIs.

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The outlook for individuals with HIV infectionliving in developed countries has improved mark-edly in the past few years, with reductions in deathrates and new diagnoses of AIDS reported in manycountries, including the US,[1] Canada,[2] France,[3]

and the UK.[4] These changes have been largelyattributed to improvements in antiretroviral ther-apy, particularly the introduction of protease inhib-itors (PIs), although in some cases, initial declines indeath rates began before the introduction of this classof drugs.[2] In addition, these declines may havebeen due in part to dual nucleoside analogue drugcombination therapy. Nevertheless, PI-containingdrug combinations have had a very dramatic im-

pact, and have led to improvements in patients withpreviously-intractable complications of HIV infec-tion, including cytomegalovirus disease, crypto-sporidiosis,[5] and Kaposi’s sarcoma.[6,7]

In a number of studies, measurement of plasmaHIV viral load has been shown to correlate well withthe risk of clinical progression.[8-10] The advent ofroutine viral load testing, both to assess prognosisin untreated patients and also to assess the efficacyof treatment, has provided a powerful tool to aiddecisions about initiating and changing drug ther-apy in individual patients. Several sets of guide-lines for the use of antiretroviral drugs have beenpublished in the past 2 years, by the International

AIDS Society (IA11),[11] The Department ofHealth and Human Services (DHHS) in the USA(http://www.hivatis.org/upguidaa.html), and theBritish HIV Association (BHIVA).[12]

The IAS and DHHS guidelines strongly favourthe use of combinations which include a PI, forseveral reasons. The PIs are among the most potentavailable drugs for suppressing viral replication.Since PI-based regimens are often capable of sup-pressing viral load to unquantifiable levels, this islikely to reduce the chance of selection of resistantmutants and prolong the likely duration of viralload suppression. On the other hand, regimenswhich do not contain a PI are less likely to causesuch profound suppression of viral replication.Such regimens will often allow sufficient viral rep-lication to continue, leading to the emergence ofresistant viral mutants; in these instances, a re-bound of viral load may occur. Furthermore, theuse of non-nucleoside analogues, in regimenswhich do not suppress viral load to below the limitof quantification of sensitive assays, has been as-sociated with the development of non-nucleosideanalogue-resistant viruses and failure to sustainsuppression of viral load.[13,14]

The 1997 BHIVA guidelines suggest that re-gimens that do not include PIs may sometimes bereasonable. To some extent, the BHIVA guidelines,which were formulated in 1996 and published inApril 1997, reflect what is now outdated practice,and have now been revised.[15] Nevertheless, thereare still some scenarios in which the initial use ofcombinations of antiretrovirals without a PI maybe justifiable.

1. Two Nucleoside Analogues and a Non-Nucleoside ReverseTranscriptase Inhibitor

Several studies have addressed the efficacy ofcombinations of 2 nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor (NNRTI),including the International Conference on AIDSstudy (INCAS)[16] and trial ISS-047,[17] involvingzidovudine (AZT), didanosine (dideoxyinosine;

ddI) and nevirapine. There have also been similarstudies including delavirdine mesylate[18] andefavirenz.[19,20] In the INCAS study,[21] in drug-naive patients, the combination of zidovudine,didanosine and nevirapine lowered viral load to be-low 200 copies/ml in 51% of patients after 52weeks of treatment. A lower proportion of patientswho were evaluated at 1 year of follow-up had viralloads below this threshold, but in some patientsviral load was maintained at <20 copies/ml for over2 years.[22] Patients in the INCAS study receivingthis combination therapy had relatively low me-dian baseline viral loads (17 732 copies/ml); in theISS-047 trial, patients with higher viral loads andlower CD4+ counts were studied, and a similar pro-portion of patients had suppression of viral repli-cation to below the limit of quantification at 40weeks (although a different viral load assay with adifferent lower limit was used).[17]

In the Protocol 0021 part II study,[18] over 50%of patients treated with zidovudine, lamivudine(3TC) and delavirdine mesylate who were evalu-ated at 52 weeks (mean baseline CD4+ count of 353cells/μl, and viral load of 32 000 copies/ml) had aviral load of <40 copies/ml.[18] An on-treatmentanalysis of early results from a study of efavirenz,zidovudine and lamivudine in drug-naive pa-tients[19] with a mean baseline viral load of around50 000 copies/ml has shown that at week 24, over90% of patients had a viral load of <400 copies/ml(despite the use of low doses of efavirenz in 2 armsof the study). A similar result was seen in a recentlyreported study[20] using the same combination ofdrugs, with over 85% of patients having a viral loadof <400 copies/ml after 24 weeks treatment in anintent-to-treat analysis. This result was signifi-cantly better than that seen in patients treated withzidovudine, lamivudine and indinavir in the samestudy, with 65% of patients having a viral load of<400 copies/ml after 24 weeks.

Eradication of HIV infection with currentlyavailable drugs is unlikely to be possible unlesstreatment with complex drug combinations can besustained for many years.[23,24] As a result, the in-

148 Churchill & Weber

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creasing awareness of toxicity associated with PIs,including the development of diabetes melli-tus,[25,26] changes in body fat distribution,[27-31]

haemolytic anaemia, hyperlipidaemia,[32] bleedingin haemophiliacs,[33] abnormalities of liver func-tion, allergic reactions[34,35] and renal stones,[36-38]

means that long term suppression of viral load withPIs may be difficult to achieve in some patients.Because long term adherence to combination anti-retroviral therapy is essential to limit the chance ofdeveloping viral resistance, the tolerability of theregimen is crucial to long term success.

The objection to using regimens consisting of 2nucleoside analogues and an NNRTI in the USguidelines was largely based on the fact that a highproportion of patients on these regimens in clinicaltrials had viral loads suppressed to below the limitof quantification. While, many did not, generallybetter results have been seen with PI-based re-gimens in similar groups of patients.[39-41] In addi-tion, high-level resistance to NNRTIs can be se-lected for by incompletely suppressive regimens,limiting future options for therapy. This is impor-tant, as NNRTIs have formed an important part ofeffective drug combinations following failure ofinitial PI-based therapy;[42-45] thus, it may be betterto reserve NNRTIs for later use. Furthermore, spe-cific serious toxicities have been associated withNNRTIs, in particular rashes.[46] However, iflonger term follow-up of patients receivingefavirenz, zidovudine and lamivudine show thatthe initial high potency and good tolerability of thisregimen are sustained, it will be hard to argueagainst this regimen as a potential first-line treat-ment in drug-naive patients.

Recently, the DHHS guidelines[47] have been re-vised to include the combination of efavirenz and2 nucleoside analogues as a recommended first-line combination.

2. Three Nucleoside Analogues

A further alternative to the use of PI-based drugregimens is to use 3 nucleoside analogues. Thisapproach has an advantage in that it exposes the

patient to drugs from a single class of agent, and doesnot select for resistance to PIs or non-nucleosideanalogues. One possible combination of 3 licensednucleoside analogues which avoids the use ofdrugs with major overlapping toxicity, and drugswhich may compete for intracellular phosphoryla-tion, is stavudine (D4T), didanosine and lamivud-ine. However, there are currently few publisheddata on the efficacy of this combination.[48,49] Inone study[49] of 20 patients treated with stavudine,lamivudine and didanosine (mean baseline CD4count 151 cells/mm3, mean baseline viral load4.88 log10 copies/ml; only 9 of 20 patients weredrug-naive at entry) in a single centre in Franceshowed good early virological responses. After 24to 28 weeks of therapy there was a reduction inviral load of 2.4 log10 copies/ml, with 80% of pa-tients below the limit of detection. The combina-tion of zidovudine, didanosine and lamivudine wastaken by 133 patients in the CAESAR trial,[50] andappeared well tolerated. Available efficacy data forthese patients are as yet still limited.

A more attractive combination of 3 nucleosideanalogues would include abacavir (1592U89),which appears to be the most potent of the avail-able drugs in this class, in combination with twoother nucleoside analogues.[51,52] Clinical trials areongoing to assess the virological efficacy of thecombination of zidovudine, lamivudine and aba-cavir. If this combination is capable of producingsustained falls in viral load in the majority of pa-tients, abacavir in combination with two nucleo-side analogues might become an alternative first-line combination to a PI-based regimen.

At present, management of patients who requiretreatment for tuberculosis, and for whom there isalso an indication for antiretroviral therapy, is dif-ficult. There are major drug interactions betweenrifampicin (rifampin) and both PIs and NNRTIs,which mean that these drugs cannot generally beused together; rifampicin reduces the concentra-tions of PIs and NNRTIs. Alternative antitubercu-lous regimens, including low doses of rifabutin in-stead of rifampicin, have been proposed for

Antiretrovirals for HIV Infection 149


patients who are being treated with PIs (orNNRTIs), but there are few data on the efficacy ofthis approach. A combination of 3 nucleoside ana-logues can be used with conventional antitubercu-lous regimens, with the combination of zidovud-ine, lamivudine and abacavir having the advantageof proven efficacy in suppressing viral load.

3. Two Nucleoside Analogues andHydroxycarbamide (Hydroxyurea)

Another scenario in which regimens that do notcontain a PI may have a role in HIV infection is thecombination of two nucleoside analogues (usuallystavudine or zidovudine combined with didanos-ine) together with hydroxycarbamide (hydroxy-urea). Hydroxycarbamide acts directly as an anti-viral agent, reducing the synthesis of proviral DNAin infected cells. The drug also potentiates the ef-fect of nucleoside analogues such as didanosine, bydecreasing the concentration of intracellular deoxy-nucleotides with which phosphorylated didanosinecompetes.[53] Results from small clinical studieswith such combinations have shown significantsustained falls in viral load and modest increasesin CD4 percentage in plasma.[54-56]

The addition of hydroxycarbamide to 2 nucleosidereverse transcriptase inhibitors (NRTIs) may pro-duce an enhanced antiviral effect, but will lead to anattenuated increase in total CD4+ counts becauseof the direct cytotoxic effects of hydroxycarb-amide. This makes this regimen less appropriatefor patients with low baseline CD4+ lymphocytecounts. The advantages of hydroxycarbamide in-clude its relatively low cost, generally good toler-ability in studies to date, and the fact that its usedoes not select for viral resistance since it targets acellular enzyme. Furthermore, treatment with thisregimen does not expose the patient to NNRTIs orPIs, which may thus be preserved for future use. Atpresent, data supporting the initial use of hy-droxycarbamide and 2 nucleoside analogues arelimited, although ongoing clinical trials may helpto clarify the role of this type of regimen.

4. Two Nucleoside Analogues

The fewer drugs taken by a patient, the lowerthe chance of drug toxicity and interactions, and(probably) the greater the chance of good adher-ence to therapy. However, treatment with 2 NRTIsis unlikely to suppress viral load to unquantifiablelevels using standard assays, except in patientswith very low baseline viral loads; even in theseindividuals viral load suppression has not been sus-tained for more than a year in most patients.[57]

Moreover, when viral load has risen in patients on2 nucleoside analogues, it has often been associ-ated with the development of mutations in the viralgenome associated with resistance to at least oneof the drugs in the regimen,[58] which may compro-mise future therapeutic choices.

It is now clear that dual nucleoside analoguereverse transcriptase inhibitor combinations aresignificantly inferior, both in their effects on surro-gate markers and clinical endpoints, comparedwith PI-based triple therapy combinations.[59] Nev-ertheless, in a very few patients (particularly thosewith low viral loads), who may be unable or un-willing to adhere to a more complex regimen oftherapy, treatment with 2 NRTIs is still likely to beassociated with substantial therapeutic bene-fit,[50,60,61] even if viral load is not fully suppressed.

Many patients were started on dual nucleosidetherapy after the results of the Delta and ACTG 175study were announced,[60,61] and it may be best toleave the few such remaining individuals on theirdouble nucleoside combinations if they are not fail-ing virologically (i.e. they still have a viral loadbelow the limit of quantification). However, if viralrebound occurs, switching to an entirely new com-bination (including a PI) would then be appropri-ate. The alternative approach of simply adding a PImay allow the early selection of PI-resistance, andmay be more harmful in the longer term. One otherpossible approach is to change the entire regimendespite the fact that viral load is suppressed, in theknowledge that viral rebound is likely to occursoon if no changes are made. While this approachmay limit the development of viral resistance, it is



perhaps counter-intuitive to change what is, at thetime, a successful regimen of drugs.

5. Conclusions

Although recent dramatic improvements inantiretroviral treatment of HIV infection have beenlargely attributable to the widespread use of potentPIs, these drugs cause significant long term toxic-ity in a high proportion of patients. Drug interac-tions with PIs, and the need for frequent doses withrestrictions on timing of meals, further reduce theirappeal, particularly if they are to be taken for veryprolonged periods. Alternative strategies, usingnucleoside analogues in combination either withnon-nucleoside analogues, abacavir or hydroxy-carbamide have several advantages, and can alsoallow reservation of the class of PIs for later use.

References1. Torres RA, Barr M. Impact of combination therapy for HIV

infection on inpatient census. N Engl J Med 1997; 336:1531-2

2. Hogg RS, O’Shaughnessy MV, Gataric N, et al. Decline indeaths from AIDS due to new antiretrovirals [letter]. Lancet1997; 349: 1294

3. Mouton Y, Alfandari S, Valette M, et al. Impact of proteaseinhibitors on AIDS-defining events and hospitalizations in 10French AIDS reference centres. AIDS 1997; 11: F101-5

4. Anonymous. AIDS deaths fell by 44%, but over 2500 HIV in-fections were reported in 1997. CDR Weekly 1998; 8: 29

5. Carr A, Marriott D, Field A, et al. Treatment of HIV-1-associ-ated microsporidiosis and cryptosporidiosis with combina-tion antiretroviral therapy. Lancet 1998; 351: 256-61

6. Conant M, Opp KM, Poretz D, et al. Reduction of Kaposi’ssarcoma lesions following treatment of AIDS with ritonavir.AIDS 1997; 11: 1300-1

7. Sepkowitz K. Effect of HAART on natural history of AIDS-re-lated opportunistic disorders. Lancet 1998; 351: 228-30

8. Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load andCD4+ lymphocytes as prognostic markers of HIV-1 infection.Ann Intern Med 1997; 126: 946-54

9. Katzenstein DA, Hammer SM, Hughes MD, et al. The relationof virologic and immunologic markers to clinical outcomesafter nucleoside therapy in HIV-infected adults with 200 to500 CD4 cells per cubic millimeter. New Engl J Med 1996;335: 1091-8

10. Brun-Vezinet F, Boucher C, Loveday C, et al. HIV-1 viral load,phenotype, and resistance in a subset of drug-naive partici-pants from the Delta trial. Lancet 1997; 350: 983-90

11. Carpenter CJ, Fischl MA, Hammer SM, et al. Antiretroviraltherapy for HIV infection in 1997. Updated recommendations

of the International AIDS Society-USA panel. JAMA 1997;277: 1962-9

12. BHIVA Guidelines Co-ordinating Committee. British HIV As-sociation guidelines for antiretroviral treatment of HIV sero-positive individuals. Lancet 1997; 349: 1086-92

13. Montaner JSG, Reiss P, Cooper D, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanos-ine, and zidovudine for HIV-infected patients. The INCASTrial. JAMA 1998; 279: 930-7

14. Vella S, Floridia M, Tomino C, et al. A triple combination ofreverse transcriptase inhibitors (2 NRTI + NNRTI) inducespronounced and sustained effects on RNA and CD4 in anti-retroviral-naive patients with very advanced disease (TrialISS 047). 37th Interscience Conference on AntimicrobialAgents and Chemotherapy; 1997 Toronto: Abstract LB-7

15. Gazzard B, Moyle G, on behalf of the BHIVA Guidelines Writ-ing Committee. 1998 revision to the British HIV Associationguidelines for antiretroviral treatment of HIV seropositiveindividuals. Lancet 1998; 352: 314-6

16. Myers MW, Montaner JG. A randomized, double-blinded com-parative trial of the effects of zidovudine, didanosine, andnevirapine combinations in antiviral naive, AIDS-free, HIV-infected patients with CD4 counts 200-600 per cubicmillimetre. XI International Conference on AIDS. Vancouver,1996 Jul 7-12: Abstract Mo.B.294

17. Vella S, Floridia M, Tomino C, et al. A triple combination ofreverse transcriptase inhibitors (2 NRTI + 1 NNRTI) inducespronounced and sustained effects on RNA and CD4 in anti-retroviral-naive patients with very advanced disease (TrialISS 047). 37th Interscience Conference on AntimicrobialAgents and Chemotherapy; 1997 Sep 28-Oct 1: Toronto. Ab-stract LB-7

18. Green S, Para MF, Daly PW, et al. Interim analysis of plasmaviral burden reductions and CD4 increases in HIV-1 infectedpatients with Rescriptor (DLV) + Retrovir (ZDV) + Epivir(3TC). 12th World AIDS Conference; 1998 Jun 28-Jul 3: Ge-neva. Abstract 129/12219

19. Haas D, Hicks C, Seekins D, et al. A Phase II, double-blind,placebo-controlled, dose-ranging study to assess the anti-retroviral activity and safety of DMP 266 (efavirenz, Sustiva)in combination with open-label zidovudine (ZDV) withlamivudine (3TC) [DMP 266-005]. 5th Conference on Retro-viruses and Opportunistic Infections; 1998 Feb 1-5: Chicago(IL). Abstract 698

20. Staszewski S, Morales-Ramirez J, Tashima K, et al. A phase III,multicenter, randomized, open-label study to compare theantiretroviral activity and tolerability of efavirenz (EFV)+indinavir (IDV, versus EFV +zidovudine (ZDV) + lamivudine(3TC), versus IDV + ZDV + 3TC at 24 weeks (DMP-266-006). 12th World AIDS Conference; 1998 Jun 28-Jul 3: Ge-neva. Abstract 22336

21. Montaner JSG, Reiss P, Cooper D, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanos-ine, and zidovudine for HIV-infected patients. The INCASTrial. JAMA 1998; 279: 930-7

22. Montaner J, Reiss P, Cooper D, et al. Long-term follow-up ofpatients treated with nevirapine based combination therapy



within the INCAS trial. 5th Conference on Retroviruses andOpportunistic Infections; 1998 Feb 1-5: Chicago (IL). Ab-stract 695

23. Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replica-tion-competent HIV despite prolonged suppression of plasmaviremia. Science 1997; 278: 1291-5

24. Finzi D, Hermankova M, Pierson T, et al. Identification of areservoir for HIV-1 in patients on highly active antiretroviraltherapy. Science 1997; 278: 1295-300

25. Dever LL, Oruwari PA, O’Donovan CA, et al. Hyperglycemiaassociated with protease inhibitors in HIV-infected patients.37th Interscience Conference on Antimicrobial Agents andChemotherapy; 1997 Sep 28-Oct 1: Toronto. Abstract LB-8

26. Dube MP, Johnson DL, Currier JS. Protease inhibitor-associ-ated hyperglycaemia [letter]. Lancet 1997; 350: 713

27. Ruane PJ. Atypical accumulations of fatty tissue. 37th Intersci-ence Conference on Antimicrobial Agents and Chemother-apy; 1997 Sep28-Oct 1: Toronto. Abstract I-185

28. Hengel RL, Watts NB, Lennox JL. Benign symmetric lipomato-sis associated with protease inhibitors [letter]. Lancet 1997;350: 1596

29. Herry I, Bernard L, de Truchis P, et al. Hypertrophy of thebreasts in a patient treated with indinavir. Clin Infect Dis1997; 25: 937-8

30. Carr A, Samaras K, Burton S, et al. A syndrome of peripherallipodystrophy, hyperlipidaemia and insulin resistance inpatients receiving HIV protease inhibitors. AIDS 1998; 12:F51-8

31. Viraben R, Aquilina C. Indinavir-associated lipodystrophy.AIDS 1998; 12: F37-9

32. Sullivan AK, Nelson MR. Marked hyperlipidaemia on ritonavirtherapy. AIDS 1997; 11: 938-9

33. Ginsburg C, Salmon-Ceron D, Vassilief D, et al. Unusual occur-rence of spontaneous haematomas in three asymptomaticHIV-infected haemophilia patients a few days after the onsetof ritonavir treatment. AIDS 1997; 11: 388-9

34. Bonfanti P, Capetti A, Riva P, et al. Hypersensitivity reactionsduring antiretroviral regimens with protease inhibitors. AIDS1997; 11: 1301-2

35. Rijnders B, Kooman J. Severe allergic reaction after repeatedexposure to indinavir. Clin Infect Dis 1998; 26: 523-4

36. Daudon M, Estepa L, Viard JP, et al. Urinary stones in HIV-1-positive patients treated with indinavir. Lancet 1997; 349:1294-5

37. Tashima KT, Horowitz JD, Rosen S. Indinavir nephropathy. NEngl J Med 1997; 336: 138-40

38. Kopp JB, Miller KD, Mican AM, et al. Crystalluria and urinarytract abnormalities associated with indinavir. Ann Intern Med1997; 127: 119-25

39. Gulick RM, Mellors JW, Havlir D, et al. Simultaneous vs. se-quential initiation of therapy with indinavar, zidovudine andlamivudine for HIV-1 infection. JAMA 1998; 280: 35-41

40. Cameron DW, Japour A, Mellors J, et al. Antiretroviral safetyand durability of ritonavir (RIT)-saquinavir (SQV) in prote-ase inhibitor-naive patients in year two follow-up. 5th Con-ference on Retroviruses and Opportunistic Infections; 1998Chicago: Abstract 388

41. Reijers MHE, Weverling GJ, Jurriaans S, et al. Maintenancetherapy after quadruple induction therapy in HIV-1 infectedindividuals: the Amsterdam Duration of Antiretroviral Medi-cation (ADAM) study. Lancet 1998; 352: 195-90

42. Harris M, Durakovic C, Rae S, et al. A pilot study of nevirapine,indinavir, and lamivudine among patients with advanced hu-man immunodeficiency virus disease who have had failureof combination nucleoside therapy. J Infect Dis 1998; 177:1514-20

43. Albrecht M, Katzenstein D, Bosch RJ, et al. ACTG 364: Viro-logic efficacy of nelfinavir (NFV) and/or efavirenz (EFV) incombination with new nucleoside analogs in nucleoside ex-perienced subjects. 12th World AIDS Conference; 1998 Jun28-Jul 3: Geneva. Abstract 125/12203

44. Farthing C, Mess T, Ried C, et al. Ritonavir, saquinavir, andnevirapine as a salvage regimen for indinavir or ritonavir re-sistance. 12th World AIDS Conference; 1998 Jun 28-Jul 3:Geneva. Abstract 22356

45. Ruane PJ, Tam JT, Libraty DH, et al. Salvage therapy usingritonavir/saquinavir with a non-nucleoside reverse trans-criptase inhibitor after prolonged failure with indinavir orritonavir. 12th World AIDS Conference; 1998 Jun 28-Jul 3:Geneva. Abstract 32308

46. Warren KJ, Boxwell DE, Kim NY, et al. Nevirapine-associatedStevens-Johnson syndrome [letter]. Lancet 1998; 351: 567

47. HIV/AIDS Treatment Information Service (ATIS). Availablefrom: URL: http://www.hivatis.org/upguidaa.html [websiteupdated 1998 Dec 1]

48. Leibowitch J. The triple combination of stavudine, didanosineand lamivudine as first or second line treatment in patientswith AIDS. Stavudine in the management of HIV disease.1997 Mar 22 Cannes, France

49. Leibowitch J. The triple combination of stavudine, didanosineand lamivudine as first- or second-line treatment in patientswith AIDs. Antiviral Therapy 1997; 2 Suppl. 3: 125-8

50. CAESAR Coordinating Committee. Randomised trial of addi-tion of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: theCAESAR trial. Lancet 1997; 349: 1413-21

51. Staszewski S, Katlama C, Harrer T, et al. Preliminary long-termopen-label data from patients using abacavir (1592) contain-ing antiretroviral treatment regimens. 5th Conference onRetroviruses and Opportunistic Infections; 1998 Feb 1-5:Chicago (IL). Abstract 658

52. Fischl M, Greenberg S, Clumeck N, et al. Safety and activity ofabacavir (1592, ABC) with 3TC/ZDV in antiretroviral naivesubjects. 12th World AIDS Conference; 1998 Jun 28-Jul 3:Geneva. Abstract 127/12230

53. Lori F, Malykh A, Cara A, et al. Hydroxyurea as an inhibitor ofHuman Immunodeficiency Virus Type-1 replication. Science1994; 266: 801-5

54. Galpin J, Lori F, Globe DR, et al. Safety, sheltering and synergyof hydroxyurea with ddI or ddI plus d4Tin HIV-infected pa-tients. 5th Conference on Retroviruses and Opportunistic In-fections; 1998 Feb 1-5: Chicago (IL). Abstract 654

55. Galpin J, Lori F, Globe DR, et al. Improvement in CD4 celldiversity during 7-month trial of hydroxyurea in combination



with ddI or ddI and d4T. 5th Conference on Retroviruses andOpportunistic Infections; 1998 Feb 1-5: Chicago (IL). Ab-stract 657

56. Rossero R, McKinsey D, Green S, et al. Open label combinationtherapy with stavudine, didanosine and hydroxyurea in nucle-oside experienced HIV-1 infected patients. 5th Conference onRetroviruses and Opportunistic Infections; 1998 Feb 1-5:Chicago (IL). Abstract 653

57. O’Shaughnessy MV, Hogg RS, Rhone SA, et al. Do dual nucle-oside regimens have a role in an era of plasma viral loaddriven antiretroviral therapy? 5th Conference on Retrovirusesand Opportunistic Infections; 1998 Feb 1-5: Chicago (IL).Abstract 668

58. Brun-Vezinet F, Boucher C, Loveday C, et al. HIV-1 viral load,phenotype, and resistance in a subset of drug-naive partici-pants from the Delta trial. Lancet 1997; 350: 983-90

59. Hammer SM, Squires KM, Hughes MD, et al. A controlled trialof two nucleoside analogues plus indinavir in persons with

human immunodeficiency virus infection and CD4 cellcounts of 200 per cubic millimeter or less. N Engl J Med 1997;337: 725-33

60. Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudineplus didanosine or zalcitabine with zidovudine alone in HIVinfected individuals. Lancet 1996; 348: 283-91

61. Hammer SM, Katzenstein DA, Hughes MD, et al. A trial com-paring nucleoside monotherapy with combination therapy inHIV-infected adults with CD4 cell counts from 200 to 500 percubic millimeter. N Engl J Med 1996; 335: 1081-90

Correspondence and reprints: Dr D.R. Churchill, ClinicalTrials Centre, Winston Churchill Wing, St. Mary’s Hospital,Praed St., London W2 1NY, England.E-mail: [email protected]



Antiretroviral Drug Guidelines for the Treatment of HIV Infection

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