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Perspective
Initial Antiretroviral Therapy: When and With What
to Begin
At the International AIDS Society–USA course in Denver in May 2002, Donna E. Sweet, MD, discussed issues related interactions. Initiation of therapy should to the ongoing question of when to initiate antiretroviral therapy in HIV- infected individuals and factors in selecting an initial drug regimen. Current treatment guidelines offer lines (available at www.hivatis.org) state timing. Selection of the initial therapy focuses on the choice between regi- transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or pro- cons of treatment in this population. For The optimal time to initiate antiretrovi- irrespective of plasma HIV-1 RNA level.
that clinical experts differ in their recom- natal HIV transmission. The rationale for potential avoidance of drug resistanceand adverse effects and difficulty inadherence to complex drug regimens, as Table 1. Risks and Benefits of Early Versus Delayed Initiation of Antiretroviral
well as reduced cumulative cost of treat- ment. Commonly considered risks andbenefits associated with the approaches Benefits
of early versus later initiation are shown Early Therapy
• Control of viral replication may be easier • Drug-related reduction in quality of life Guidelines for Initiating
• Greater cumulative drug-related adverse • Possible delay or prevention of immune Treatment
• Earlier emergence of drug resistance if • Lower risk of resistance with optimal viral • Limitation of future antiretroviral treat- early initiation of treatment (ie, at high • Possible decreased risk of HIV transmission CD4+ cell counts and detectable viralload), largely based on recognition that Delayed Therapy
because of latent infection, viral eradica- • Avoid negative effects on quality of life • Possible risk of irreversible immune tion is not likely; that risk of near-term disease progression is low, even in rela- • Possible greater difficulty in suppressing • Preserve maximum number of future drug • Possible increased risk of HIV transmission University of Kansas School of Medicine inWichita.
Adapted from US Department of Health and Human Services, 2002. Perspective - Initial Antiretroviral Therapy Volume 10 Issue 5 November/December 2002
Project, a record review of 5110 patients less than 200/µL, odds ratios for initial tions (Schambelan et al, J Acquir Immune Defic Syndr, in press), adverse impact of antiretroviral therapy on quality of life with initial cell counts of 200 to 350/µL (Gill et al, J Acquir Immune Defic Syndr, of initiating therapy at CD4+ cell counts greater at the time of starting treatment antiretroviral therapy may safely be initi- ated with a lower probability of survival (Egger et al, 41st ICAAC, 2001). In a ret- patients at the Johns Hopkins University, load at initiation of potent antiretroviral tial response were 2.5 (95% CI, 1.59-4.04) ed with a highly significant hazard ratio initial cell count of 351 to 500/µL (refer- Is There an Advantage to
CI, 1.10-2.90) among those with levels of Starting Therapy at Higher
350/µL at initiation of therapy was asso- CD4+ Cell Counts?
ciated with a statistically nonsignificant Clinical Outcome
ease or death in 363 antiretroviral-naive 350/µL and 363 control patients not ini- counts of less than 200/µL at the start of bypass surgery for men aged 50 years.
plus a protease inhibitor (PI), or a triple- ping at least 1 drug were virologic failure ritonavir (ie, saquinavir, indinavir, lopina- ritonavir], or amprenavir) or an unboost- occurred in 1.1% versus 3.3%, respective- ly. These findings indicate that early ini- initial regimen is well-tolerated and may be particularly useful in younger patients who may be prone to suboptimal adher-ence. Prevention of Transmission
rely in part on clinical judgment regard- viral load. Other data indicate that viral initiation of treatment has the potential to reduce overall cost of treatment while ence decisions in this regard. In the trial Science, 2000). Whether antiretroviral other estimates for antiretroviral thera- need to be determined in a clinical trial.
Initial Regimens
Selection of Regimen
included in current antiretroviral thera- py guidelines may appear complicated.
In considering initial treatment options, Cost-Effectiveness
Available evidence suggests that earlierinitiation of antiretroviral therapy is Table 2. Cost-Effectiveness Ratios for Antiretroviral Therapy From Selected Studies
According to CD4+ Cell Count at Initiation with later initiation, and that antiretrovi- Intervention
ICER (US dollars/
life-year gained)
started, compares well with otheraccepted therapeutic modalities in Antiretroviral therapy initiated when CD4+ count ≥ 500 cells/µL* terms of cost per life-year gained. Usingdata from the Johns Hopkins cohort, Antiretroviral therapy initiated when CD4+ count ≥ 500 cells/µL** Kauf and colleagues (1st IAS Conf HIVPathog Treat, 2001) found that initiation Antiretroviral therapy initiated when CD4+ count >500 cells/µL† of antiretroviral therapy at CD4+ cellcounts greater than 500/µL was more Antiretroviral therapy initiated when CD4+ count <200 cells/µL‡ cost-effective than initiation at 350 to500/µL or at less than 350/µL, with a ICER indicates incremental cost-effectiveness ratio. *Freedberg et al, N Engl J Med, 2001.
**Schackman et al, Am J Pub Health, 2001. †Kauf et al, 1st IAS Conf HIV Pathog Treat, 2001. ‡Moore and Bartlett, Pharmacoeconomics, 1996.
Perspective - Initial Antiretroviral Therapy Volume 10 Issue 5 November/December 2002
60, in an intent-to-treat analysis, 63% of tance, stavudine can select for the clas- respectively. These findings suggest that inhibitor (ntRTI) recently approved by groups but occurred earlier with the nel- finavir regimen. In another study, the 4- Advantages and Disadvantages of
Initial Regimens
tages and disadvantages of initial treat- treat analysis (Parenti et al, 39th IDSA, Selection of nRTI Backbone
other drug classes for later use. Clinical endpoint data are lacking for the triple- Dual nRTI backbones (or nRTI/ntRTI antiretroviral regimens. Selection of the antiretroviral effect, tolerance, and resis- 2002), 108 patients received initial treat- (n=35), or stavudine/didanosine (n=35).
groups), and 235/µL, respectively. After Chaisson RE, Keruly JC, Moore RD. Association viral therapy for HIV disease. N Engl J Med. of initial CD4 cell count and viral load with response to highly active antiretroviral therapy.
JAMA. 2000;284:3128-3129.
Gill CJ, Griffith JL, Jacobson D, Skinner S, Gorbach SL, Wilson IB. Relationship of HIV viral Domula MR, Wasmuth JC, Jutte A, et al. A com- loads, CD4 counts, and HAART use to health- parison of AZT/3TC vs 3TC/d4T and ddI/d4T in related quality of life. J Acquir Immune Defic Syndr. combination with efavirenz as first line therapy: efficacy and safety results after 48 weeks.
[Abstract 408-W.] 9th Conference on Hogg RS, Yip B, Chan KJ, et al. Rates of disease Retroviruses and Opportunistic Infections.
progression by baseline CD4 cell count and viral Presented in May 2002. First draft prepared from tran- February 24-28, 2002; Seattle, Wash.
load after initiating triple-drug therapy. JAMA.
scripts by Matthew Stenger. Reviewed and updated by Dr Egger M. Prognosis of HIV-1 infected drug naivepatients starting potent antiretroviral therapy: Kaplan J, Hanson D, Karon J, et al. Late initia- Financial Disclosure: Dr Sweet has no affiliations with multicohort analysis of 12,040 patients.
tion of antiretroviral therapy (at CD4+ lympho- commercial organizations that may have interests related [Abstract LB-18.] 41st Interscience Conference cyte count <200 cells/µL) is associated with on Antimicrobial Agents and Chemotherapy.
increased risk of death. [Abstract 520.] 8th Conference on Retroviruses and OpportunisticInfections. February 4-8, 2001; Chicago, Ill.
Suggested Reading
Fischl M, Ribaudo H, Collier AC, et al. A ran-domized trial comparing 2 4-drug antiretroviral Kauf T, Pham S, Tolson J. Cost effectiveness of regimens in advanced HIV disease. [Abstract early versus late initiation of HAART. [Abstract Bartlett JG, Gallant JE. 2001-2002 Medical 286.] 1st International AIDS Society Conference Management of HIV Infection. 2002.
Opportunistic Infections. February 24-28, 2002; on HIV Pathogenesis and Treatment. July 7-11, Blower SM, Gershengorn HB, Grant RM. A taleof two futures: HIV and antiretroviral therapy in Freedberg KA, Losina E, Weinstein MC, et al.
Levy R, Labriola D, Ruiz N. Low two-year risk of San Francisco. Science. 2000;287:650-654.
The cost effectiveness of combination antiretro- virologic failure with first regimen HAART.
[Abstract 325.] 8th Conference on Retrovirusesand Opportunistic Infections. February 4-8, Table 3. Advantages and Disadvantages of Triple-nRTI, NNRTI-Based, and
Mannerheimer S, Friedland G, Matts J, et al.
Advantages
Disadvantages
Self-reported antiretroviral adherence corre-lates with HIV viral load and declines over time.
Triple-nRTI
Conference on AIDS. July 9-14, 2000; Durban, • Limited cross-resistance within the class Moore RD, Bartlett JG. Combination antiretrovi- ral therapy in HIV infection. An economic per- • Preserves PIs and NNRTIs for later use spective. Pharmacoeconomics. 1996;10:109-113.
NNRTI-Based
Opravil M, Ledergerber B, Furrer H, et al.
Clinical efficacy of early initiation of HAART in • Generally easier to use and adhere to • Resistance to NNRTIs requires single or patients with asymptomatic HIV infection and CD4 cell count >350 × 106/L. AIDS. 2002;16:1371- • Emergence of cross-resistance for entire Parenti DM, Ruane P, Margolis D, et al. The PI-Based
compact quad, combivir/abacavir/efavirenz(COM/ABC/EFV): preliminary 48-week results • May be difficult to use and adhere to Meeting of the Infectious Diseases Society of America. October 25-28, 2001; San Francisco, • Resistance requires multiple mutations • Targets HIV at 2 steps of viral replication • Mild to severe inhibition of cytochrome Phillips AN, Staszewski S, Weber R, et al. HIV viral load response to antiretroviral therapy • Emergence of cross-resistance with other according to the baseline CD4 cell count and viral load. JAMA. 2001;286:2560-2567.
NNRTI indicates nonnucleoside reverse transcriptase inhibitor; nRTI, nucleoside reverse tran- Richman DD, Bozzette S, Morton S, et al. The scriptase inhibitor; PI, protease inhibitor. *Some adverse effects attributed to PI-based ther- prevalence of antiretroviral drug resistance in apy, such as metabolic abnormalities, have not been proven to be strictly associated with the the US. [Abstract LB-17.] 41st Interscience use of PI-containing regimens. Metabolic abnormalities have also been described, albeit uncommonly, in patients on nRTIs alone and in patients on no antiretroviral therapy.
Chemotherapy. December 16-19, 2001; Chicago, Adapted from US Department of Health and Human Services, 2002.
Perspective - Initial Antiretroviral Therapy Volume 10 Issue 5 November/December 2002
Ross L, Liao Q, Henry K, et al. Choice of co- tion: recommendations of an International Vibhagool A, Cahn P, Schechter M, et al.
nucleoside analog in d4T-treated subjects may AIDS-USA Panel. J Acquir Immune Defic Syndr. In Abacavir/combivir (ABC/COM) is comparable to influence the pattern of thymidine analog muta- indinavir/combivir in HIV-1 infected antiretrovi- tions (TAMs) and multi-nucleoside resistance ral therapy naive adults: preliminary results of a Staszewski S, Gallant J, Pozniak A, et al. Efficacy 48-week open label study (CNA3014). [Abstract Conference on Retroviruses and Opportunistic and safety of tenofovir disoproxil fumarate 63.] 1st International AIDS Society Conference Infections. February 24-28, 2002; Seattle, Wash.
(TDF) versus stavudine (d4T) when used in com- on HIV Pathogenesis and Treatment. July 7-11, bination with lamivudine (3TC) and efavirenz (EFV) in HIV-1 infected patients naive to Ruane P, Mendonca J, Timerman A, et al. Kaletra antiretroviral therapy (ART): 48-week interim vs nelfinavir in antiretroviral-naive subjects: results. [Abstract LBOR17.] 14th International week 60 comparison in a phase III, blinded, ran- AIDS Conference. July 7-12, 2002; Barcelona, domized clinical trial. [Abstract 6.] 1st International AIDS Society Conference on HIV antiretroviral resistance: report of a World Pathogenesis and Treatment. July 8-11, 2001; Health Organization consultation organized in Sterling TR, Chaisson RE, Bartlett JG, Moore RD.
collaboration with Istituto Superiore di Sanità CD4+ lymphocyte level is better than HIV-1 and the International AIDS Society. World plasma viral load in determining when to initi- Health Organization 2001. Available at: http:// Schackman BR, Goldie SJ, Weinstein MC, Losina ate HAART. [Abstract 519.] 8th Conference on E, Zhang H, Freedberg KA. Cost-effectiveness of Retroviruses and Opportunistic Infections.
r e s i s t a n c e / w h o c d s c s r d r s 2 0 0 1 1 1 c . h t m l .
earlier initiation of antiretroviral therapy for uninsured HIV-infected adults. Am J Public Health.
2001;91:1456-1463.
US Department of Health and Human Services.
Yeni PG, Hammer SM, Carpenter CCJ, et al.
Guidelines for the use of antiretroviral agents in Antiretroviral treatment for adult HIV-1 infec- Schambelan M, Benson CA, Carr A, et al.
HIV-infected adults and adolescents. Updated tion in 2002: updated recommendations of the Management of metabolic complications asso- February 4, 2002. Available at: http://www.
International AIDS Society-USA panel. JAMA.
ciated with antiretroviral therapy for HIV-1 infec- hivatis.org. Accessed April 25, 2002.

Source: http://emilytaylorcenter.ku.edu/sites/emilytaylorcenter.ku.edu/files/sweetone.pdf