Influence of alternative thresholds for initiating HIV treatment on quality-adjusted life expectancy: a decision model

Abstract

Background: The optimal threshold for initiating HIV treatment is unclear.

Objective: To compare different thresholds for initiating HIV treatment.

Design: A validated computer simulation was used to weigh important harms from earlier initiation of antiretroviral therapy (toxicity, side effects, and resistance accumulation) against important benefits (decreased HIV-related mortality).

Data sources: Veterans Aging Cohort Study (5742 HIV-infected patients and 11 484 matched uninfected controls) and published reports.

Target population: Individuals with newly diagnosed chronic HIV infection and varying viral loads (10,000, 30,000, 100,000, and 300,000 copies/mL) and ages (30, 40, and 50 years).

Time horizon: Unlimited.

Perspective: Societal.

Intervention: Alternative thresholds for initiating antiretroviral therapy (CD4 counts of 200, 350, and 500 cells/mm3).

Outcome measures: Life-years and quality-adjusted life-years (QALYs).

Results of base-case analysis: Although the simulation was biased against earlier treatment initiation because it used an upper-bound assumption for therapy-related toxicity, earlier treatment increased life expectancy and QALYs at age 30 years regardless of viral load (life expectancies with CD4 initiation thresholds of 500, 350, and 200 cells/mm3 were 18.2 years, 17.6 years, and 17.2 years, respectively, for a viral load of 10,000 copies/mL and 17.3 years, 15.9 years, and 14.5 years, respectively, for a viral load of 300,000 copies/mL), and increased life expectancies at age 40 years if viral loads were greater than 30 000 copies/mL (life expectancies were 12.5 years, 12.0 years, and 11.4 years, respectively, for a viral load of 300,000 copies/mL).

Results of sensitivity analysis: Findings favoring early treatment were generally robust.

Limitations: Results favoring later treatment may not be valid. The findings may not be generalizable to women.

Conclusion: This simulation suggests that earlier initiation of combination antiretroviral therapy is often favored compared with current recommendations.

Figure 1. Selected constructs in computer simulation

Constructs fall into 2 broad categories: genetic characteristics of the HIV strain and clinical characteristics of the patient. Genetic characteristics reflect the acquisition of mutations and affect clinical characteristics by altering the effectiveness of combination antiretroviral therapy (CART). Clinical characteristics affect the probability of dying of HIV-related or non–HIV-related causes. With the passing of time, combination antiret-roviral therapy may give rise to HIV mutations through selection pressures on viral replication. As resistance accrues, the viral replication rate increases, and this in turn increases the probability that subsequent mutations will develop. Adherence, viral resistance, and other patient characteristics together determine the level of effectiveness of combination therapies, as manifested by changes in CD4 count and viral load. The simulation does not merely extrapolate long-term mortality risks based on short-term mortality data but rather predicts long-term mortality risks based on the duration of the effectiveness of combination antiretroviral therapy and other factors, including toxicity. Although determinants of the effectiveness of combination antiretroviral therapy may be unobserved or rarely observed, they may have a profound effect on survival and quality of life.

Figure 2. Cumulative incidence of resistance mutations (A) and combination antiretroviral therapy (CART) regimens (B) after 5 years, by treatment initiation threshold and viral load

Earlier therapy leads to more resistance mutations and to more regimens being used. Resistance mutations are defined as any mutation that may give rise to antiretroviral resistance in any drug class. A change in regimen is defined as a change in 2 or more antiretroviral drugs. We show results for age 40 years; results for other age groups did not differ greatly.

Appendix Figure 1

Quantity of therapy-related toxicity required to favor earlier rather than later initiation of combination antiretroviral therapy (CART). In each bar, as the hazard ratio of therapy-related toxicities increase, the different fills indicate the preferred treatment strategy, stratified by age and viral load. Therapy-related toxicity is manifested by greater non–HIV-related mortality. The upper bound used in our base-case analyses (3.8 × non–HIV-related mortality) favors starting therapy at a CD4 count of 500 cells/mm3 at age 30 years and at age 40 years if the viral load is greater than 30 000 copies/mL. If toxicity were below 2.4 × non–HIV-related mortality, starting therapy at a CD4 count of 500 cells/mm3 would be preferred for all ages and viral loads examined.

Appendix Figure 2

Sensitivity analysis of how preferred treatment strategy varies with different parameter assumptions. The 3 separate graphs correspond to distinct assumptions about toxicity related to combination antiretroviral treatment (CART): high toxicity, as in our upper-bound base-case analysis (top); moderate toxicity (middle); and low toxicity (bottom). Within each graph, other model parameters are varied across plausible ranges. We analyzed only scenarios in which base-case results favored earlier treatment (age 30 years, all viral loads; age 40 years, viral loads of 100 000 and 300 000 copies/mL) because results favoring later treatment were unlikely to be robust. These analyses suggest that findings in favor of earlier treatment were generally stable, varying little with parameter assumptions. Values in parentheses are reference citations. *Reference refers to base-case estimate.