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HIV Antiretroviral Treatment: Early Versus Later  
 
 
  ....Starting HAART when CD4s are >350 ......increases years of life by 1.21 years, increases discounted quality-adjusted life-years by 0.61...
 
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 39(5) 15 August 2005 pp 562-569
 
Mauskopf, Josephine PhD*; Kitahata, Mari MPH, MD†; Kauf, Teresa PhD‡; Richter, Anke PhD*; Tolson, Jerry PhD§
 
From *RTI Health Solutions, Research Triangle Park, NC; †Center for AIDS and STD Harborview Medical Center, University of Washington, Seattle, WA; ‡Duke Clinical Research Institute, Durham, NC; and §GlaxoSmithKline, Research Triangle Park, NC.
 
Abstract
Objectives: Cohort studies indicate that starting highly active antiretroviral therapy (HAART) when the CD4+ T-cell count is less than 200 cells/_L is associated with poor outcomes. These studies have been unable to address how early HAART should be initiated, however. This report uses a modeling approach to compare starting HAART at a mean CD4+ T-cell count greater than 350 cells/_L (early) versus less than 350 cells/_L but greater than 200 cells/_L (later).
 
Methods: A Markov model tracks people with HIV infection through 6 disease stages defined by CD4+ T-cell count ranges over a 25-year period. Transition probabilities between the disease stages for 6-month periods vary according to initial viral load. Sequences of different first-line, second-line, and salvage antiretroviral regimens are defined, and their impact on transition probabilities is estimated. HAART effectiveness is based on data from an urban hospital-based HIV clinic, supplemented by clinical trial data. The model computes the incremental cost-effectiveness of alternative treatment patterns and includes sensitivity analyses for a range of plausible alternative input values.
 
Results: Starting HAART earlier rather than later increases total lifetime costs by $19,074, increases years of life by 1.21 years, increases discounted quality-adjusted life-years by 0.61, and has an incremental cost-effectiveness ratio of $31,266 per quality-adjusted life-year. Early therapy is more cost-effective when the impact of HAART on well-being is smaller.
 
Conclusions: Initiation of HAART at a CD4+ T-cell count greater than 350 cells/_L may be cost-effective (less than $50,000 per quality-adjusted life-year) compared with initiating HAART at a CD4+ T-cell count less than 350 cells/_L but greater than 200 cells/_L and may result in longer quality-adjusted survival.
 
AUTHOR DISCUSSION
The results of the analyses using the Markov cost-effectiveness model and real-world data demonstrate that starting HAART earlier (at a CD4+ T-cell count greater than 350 cells/_L) rather than later (at a CD4+ T-cell count less than 350 cells/_L but greater than 200 cells/_L) increases total lifetime costs, increases life expectancy, and is a cost-effective strategy when this is defined as a strategy with a cost per life-year gained or cost per quality-adjusted life-year gained less than $50,000, a generally accepted benchmark in the United States. This is true under different assumptions about the treatment regimens used, duration of efficacy for first- and second-line therapy, set point viral load, and impact of HAART on disease treatment costs and individual utility. Early therapy is more cost-effective the smaller the impact of HAART on utility (or quality of life) is or the larger the negative impact on well-being is of more severe stages of HIV infection and for those with higher viral loads.
 
Our results also confirm the generally accepted view that starting HAART at a CD4+ T-cell count less than 350 cells/_L but greater than 200 cells/_L is cost-effective compared with starting at a CD4+ T-cell count less than 200 cells/_L. Our modeling exercise indicates that further life expectancy and quality-adjusted life expectancy gains can be expected when starting HAART at a CD4+ T-cell count greater than 350/_L and that this early treatment strategy is also likely to be cost-effective.
 
Unlike previous HIV Markov models,15-17 the Markov model used for this analysis allowed set point viral load to influence the rate of CD4+ T-cell count decline based on the study by Mellors et al.18 This model has several limitations, including the assumption that the relative risk of disease progression with HAART and the duration of efficacy are similar across all viral load categories and all CD4+ T-cell ranges. There is some evidence that this may not be the case, for example, that duration of effect may be longer when therapy is started earlier.31,32 Such differences would result in greater cost-effectiveness for starting HAART early (ie, lower incremental cost-effectiveness ratios than those presented in this report).
 
The model also did not compute possible reductions in life expectancy associated with long-term side effects of HAART (eg, dyslipidemia). The recent study by Schackman et al11 has shown that these effects are small and that less than 10% of the increased life expectancy attributable to HAART is likely to be lost as a result of the increased cardiovascular risk. Such a loss in life expectancy gain would not have a substantial impact on the cost-effectiveness ratios for early versus later HAART therapy.
 
Estimates of the impact of HAART on overall well-being in treated individuals are sparse,33 and the impact depends on the particular regimen being used; thus, we ran sensitivity analyses that assumed more or less loss in well-being than the 10% assumed in the base case. The results were sensitive to these changes, indicating the likely value of HAART regimens with more convenient dosing regimens and fewer side effects.
 
Finally, data on the number of different treatment regimens used and the duration of efficacy of each treatment regimen in real-world practice are limited; thus, the data used in the model are suggestive only. Our sensitivity analysis using a more effective set of regimens over a longer period indicated that the cost-effectiveness ratios are somewhat higher with the more effective and durable treatment pathways but that the ratio is still well below the $50,000 benchmark value. Total lifetime costs and life expectancy with these more effective regimens are considerably higher than with less effective and less durable pathways, as would be expected.
 
The loss of the ability to use certain drug classes because of the development of drug resistance is an important limiting factor in the duration of efficacy of HAART therapy. In this study, we chose to compare identical HAART treatment pathways started earlier or later in the disease course so as to focus on the question of when to start therapy while controlling for the different efficacies of different treatment pathways. We assumed that the person discontinues HAART after 3 different HAART regimens and experiences disease progression at the nontreated rate because of the development of drug resistance. This discontinuation occurs in our model earlier in the disease course for those starting HAART earlier than for those starting HAART later. We included a sensitivity analysis to demonstrate the impact of continuing salvage therapy and showed that although the total lifetime costs change, the cost-effectiveness of early versus later treatment changes little.
 
The results found in this study-that initiation of HAART at a CD4+ T-cell count greater than 350 cells/_L increases life expectancy and is cost-effective-are similar to those found in the modeling studies by Schackman et al10,11 but differ from those in a study presented at the 14th Annual International AIDS Conference.3 The latter study followed people who started with a CD4+ T-cell range of 350 to 499 cells/_L or 200 to 349 cells/_L for approximately 2 years. The primary end point in this study was progression to AIDS. When treating people in these CD4+ T-cell ranges with HAART, however, few people progress to AIDS within 2 years. Thus, the lack of a difference between early and later initiation of HAART in progression to AIDS may be a function of the relatively short period of observation rather than the starting points for treatment initiation. This is supported by a recent study by Palella et al7 using data from the HIV Outpatient Study (HOPS) study, with follow-up of approximately 4 years for those with a CD4+ T-cell count range between 350 cells/_L and 499 cells/_L, showing a trend toward higher mortality rates for those delaying HAART until their CD4+ T-cell count fell out of this range. Similar results have been shown by Opravil et al6 using data from the Swiss HIV Cohort Study. Thus, empiric studies with follow-up longer than 2 years are beginning to show health benefits associated with early versus later initiation of HAART. Both the Markov model used in this study and the Monte Carlo simulation model presented by Schackman et al10,11 follow each cohort for their remaining lifetime and are thus able to approximate the long-term benefits of early HAART that may not be apparent in shorter term empiric studies.
 
Our model differs from previous HIV cost-effectiveness models in using data from an urban hospital population rather than from a clinical trial population. The effectiveness of drug therapy in real-world practice is often lower than the efficacy seen in clinical trials. Our cost-effectiveness ratios are higher (less favorable) than those presented by Schackman et al,10,11 probably reflecting our use of the urban hospital population effectiveness values. Nevertheless, our study has shown that initiation of HAART at a CD4+ T-cell count greater than 350 cells/_L is likely to be cost-effective relative to later initiation, even in a real-world practice situation.
 
The results of this study indicate that physicians and patients making decisions about when to start HAART should balance the likely benefits on life expectancy with the possible negative impact on overall well-being associated with HAART. Clearly, drug regimens that have more convenient dosing regimens and fewer adverse effects can minimize the negative impact on overall well-being and thus would be likely to have greater value, assuming that their price was similar to the prices of drugs with less favorable side-effect profiles. For the time being, there seems to be little evidence to suggest that the initiation of HAART should be delayed on the basis of cost-effectiveness. This would be especially true if new drugs that have a more favorable side-effect profile become available.
 
BACKGROUND
Over the past 15 years, many drugs that inhibit the replication of HIV have been developed and approved for use in individuals who are infected with this virus. In the United States, there are currently 7 nucleoside reverse transcriptase inhibitors (NRTIs), 3 nonnucleoside reverse transcriptase inhibitors (NNRTIs), 7 protease inhibitors (PIs), and 1 fusion inhibitor approved by the Food and Drug Administration (FDA)1 used in combinations of 3 or more. Because current drug therapies are not curative, treatment of HIV infection requires a lifetime sequence of treatment regimens, with the goal of maximizing life expectancy while maintaining as high a quality of life as is possible over that remaining life expectancy.2
 
Problems with side effects related to highly active antiretroviral therapy (HAART) as well as questions as to whether the drug combinations are equally efficacious when given earlier or later in disease progression have been debated in the literature. A recent study presented at the 14th International AIDS Conference3 indicates that HAART treatment may be just as effective if started when a patient's CD4+ T-cell count is between 349 cells/_L and 200 cells/_L as compared with starting when the person has a CD4+ T-cell count of 350 cells/_L or more. This study showed that HAART treatment is less effective if the start of treatment is delayed until after the CD4+ T-cell count has fallen to less than 200 cells/_L, however. The end point for this study was progression to AIDS. Several other studies have clearly demonstrated faster disease progression when treatment is delayed until the CD4+ T-cell count is less than 200 cells/_L,4-7 but these same studies have shown mixed results for those starting treatment when their CD4+ cell count is between 499 cells/_L and 350 cells/_L compared with between 349 cells/_L and 200 cells/_L. Currently, initiation of HAART is recommended when the CD4+ T-cell count has fallen to less than 350 cells/_L or when the initial viral load is greater than 55,000 copies/mL.8,9
 
Two recent Monte Carlo simulation modeling studies comparing the cost-effectiveness of early versus later initiation of therapy10,11 estimated that early initiation of therapy (>200 cells/_L) is more cost-effective than later initiation (<200 cells/_L) because the person is held for a longer time in a disease stage that is less severe. In these reports, initiation when the CD4+ T-cell count was 500 cells/_L or 350 cells/_L, respectively, was compared with initiation when the CD4+ T-cell count was 200 cells/_L, and efficacy data from clinical trials were used in the model. These studies did not compare the cost-effectiveness of starting therapy at 500 cells/_L with starting therapy at 350 cells/_L.
 
This report uses a Markov modeling approach for tracking HIV disease progression and focuses on a comparison of starting HAART when the CD4+ T-cell count is greater than 350 cells/_L (in the range 499 cells/_L and 350 cells/_L, mean value of 425 cells/_L) and starting HAART when the CD4+ T-cell count is less than 350 cells/_L (in the range of 349 cells/_L and 200 cells/_L, mean value of 275 cells/_L). This focus is important, because although there is now general agreement that HAART should be started before the CD4+ T-cell count falls to 200 cells/_L or less, there is still some uncertainty as to the value of starting HAART for people with CD4+ T-cell counts greater than 350 cells/_L rather than less than 350 cells/_L. In addition, recommendations to start treatment at a CD4+ T-cell count above 200 cells/_L were based on empiric studies with limited follow-up times.3-7 This report estimates the cost-effectiveness of early versus later HAART start using effectiveness data from a real-world urban hospital-based HIV clinic setting. An extensive sensitivity analysis is performed to estimate the impact on the cost-effectiveness of early versus later initiation of HAART on (1) use of an alternative treatment pathway, (2) duration of effectiveness of first- and second-line treatment regimens, (3) type and duration of salvage therapy regimens that are used, (4) initial viral load of the person with HIV infection, (5) impact of HAART and its side effects on quality of life, and (6) impact of HAART monitoring and side effects on annual cost of HIV infection in each CD4 cell count range.
 
 
 
 
 
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