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Clinical Science

Clinical Impact and Cost-Effectiveness of Making Third-Line Antiretroviral Therapy Available in Sub-Saharan Africa

A Model-Based Analysis in Côte d'Ivoire

Ouattara, Eric N. MD, PhD*,†,‡; Ross, Eric L. BA§; Yazdanpanah, Yazdan MD, PhD‖,¶; Wong, Angela Y. BS§; Robine, Marion BS§; Losina, Elena PhD§,#,**,††,‡‡; Moh, Raoul MD, PhD‡,§§; Walensky, Rochelle P. MD, MPH§,**,††,‖‖,¶¶; Danel, Christine MD, PhD*,†,‡; Paltiel, A. David PhD##; Eholié, Serge P. MD, MSc‡,§§; Freedberg, Kenneth A. MD, MSc§,**,††,‖‖,***,†††; Anglaret, Xavier MD, PhD*,†,‡

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1, 2014 - Volume 66 - Issue 3 - p 294-302
doi: 10.1097/QAI.0000000000000166

Abstract

INTRODUCTION

In sub-Saharan Africa, issues of laboratory monitoring for patients on antiretroviral therapy (ART), adherence reinforcement and access to second-line and third-line ART are closely related. Three factors complicate the decision to switch from 1 line of ART to another in patients who have failed therapy. First, the limited availability of viral load tests for routine monitoring makes it difficult to document true virologic failure, as immunologic criteria have poor sensitivity and specificity for the diagnosis of virologic failure.1 Second, even when virologic failure is documented, the lack of access to resistance tests makes it difficult to distinguish between patients with poor adherence and no resistance and patients with treatment-compromising resistance. This unknown factor complicates the question of when and how to switch to subsequent lines of drugs.2,3 Third, the prices of second- and of third-line regimens are 3× and 10× higher, respectively, than that of first-line. Therefore, programs and health authorities prioritize access to first-line ART, which in turn may discourage physicians from documenting failure appropriately in the absence of further lines of drugs.4–6

As a result, most virologic failures of ART are diagnosed late.6 A delayed regimen switch or continuing the same regimen with no virologic efficacy in patients with virologic failure leads to accrued resistance.7–10 This in turn leads to increased mortality in HIV-infected patients and to the spread of resistant viruses in the population.11 There is an urgent need to evaluate the effectiveness and cost-effectiveness of different treatment strategies after ART failure in settings with no resistance tests to help countries appropriately use second- and third-line regimens.12–14

In this study, we used a validated model of HIV disease and treatment to examine the clinical impact and cost-effectiveness of making third-line ART available to HIV-infected adults who have documented second-line failure in Côte d'Ivoire, West Africa.

METHODS

Analytic Overview

We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International model15,16 to answer the following questions:

  • What are the likely long-term, patient- and population-level benefits associated with reinforcing second-line adherence and/or making third-line ART available in HIV-infected patients with observed second-line failure in Côte d'Ivoire?
  • Under what conditions would it be cost-effective, according to international standards, to provide these patients with third-line ART?

To address the first question, we simulated a cohort of HIV-infected adults failing second-line ART in Côte d'Ivoire. ART failure was diagnosed immunologically (CD4 counts) and then confirmed virologically. We compared projected outcomes under alternative assumptions regarding both the availability of third-line drugs and the implementation of a systematic “adherence intervention” phase before switching to third-line ART. Outcomes were 10-year cumulative survival, life expectancy (LE), costs, and incremental cost-effectiveness ratios (ICERs) measured in US dollars per years of life saved ($/YLS).

To address the second question, we conducted extensive sensitivity analyses, varying model input parameters widely and noting their effect on the resultant ICER estimates. We applied international standards to denote a strategy as “cost-effective” if its ICER was less than 3 times the 2011 annual per capita gross domestic product (GDP) of Côte d'Ivoire ($3585/YLS) and “very cost-effective” if its ICER was less than the annual per capita GDP ($1195/YLS).17,18

Model Description

The CEPAC-International Model is a microsimulation model of HIV infection incorporating natural history and treatment.15,16 Simulated patients are randomly generated from an initial distribution of age, sex, CD4 count, and plasma HIV RNA level (viral load), and are followed on a monthly basis from the time of entry into the model until death. In the absence of successful ART, patients' CD4 counts decline at a rate determined by their viral load level.19 Current CD4 count determines the risk of developing an HIV-related disease or dying from HIV infection.20 ART decreases morbidity and mortality indirectly by means of viral load suppression and CD4 count increase, and directly by reducing the incidence of HIV-related morbidity.21,22 The clinical decision to switch from 1 line to further lines of ART can only be made if there is evidence of failure. That is, the model tracks the “true” updated CD4 count and viral load for each patient, but clinical decisions are based on CD4 and viral load values observed through periodic laboratory testing.23 Patients in the model may be lost to follow-up at any time and return to care on the occurrence of a severe HIV-related opportunistic disease. Additional details of model structure have been previously published and are available online (http://web2.research.partners.org/cepac).15,16

Strategies

In patients diagnosed as failing second-line ART (ie, WHO criteria for clinical and/or immunological failure, and then confirmation of a viral load ≥1000 copies/mL), we compared 4 strategies (Fig. 1): (1) continue second-line ART (C-ART2), (2) continue second-line ART with a 6-month adherence reinforcement phase (AR-ART2), (3) immediate switch to third-line ART (IS-ART3), and (4) continue second-line ART with a 6-month adherence reinforcement phase, and then continue second-line ART in patients successfully resuppressed, or switch to third-line ART in patients with persistent failure (AR-ART3). The adherence reinforcement phase was modeled as a 6-month period during which patients were seen every month for counseling and educational training on adherence and had weekly phone and/or SMS contacts with social workers for the entire 6-month duration. At the end of the 6-month period, a repeat viral load test was performed. In the AR-ART3 strategy, patients with a >2 log10 copies per milliliter decrease in plasma viral load and/or an observed viral load <1000 copies per milliliter at the end of the adherence test phase were maintained on second-line, whereas the others were switched to third-line ART.

F1-8
FIGURE 1:
Simulation profile C-ART2: continue second-line ART. AR-ART2: adherence reinforcement and continue second-line ART. IS-ART3: immediate switch to third-line ART. AR-ART3: adherence reinforcement, third-line ART if failure persists.

Input Parameters

Age and gender were from the VOLTART cohort, a large HIV cohort that includes all adults who started ART at the CePReF clinic in Abidjan.2 Input parameters on natural history of HIV disease were derived from published Côte d'Ivoire studies (Table 1; see Table A1-1, Appendix, Supplemental Digital Content,https://links.lww.com/QAI/A518).2,20,24–26 Drug costs were derived from the Médecins Sans Frontières and the Clinton Health Access Initiative databases.4,5 Inputs on second-line and third-line ART efficacy were derived from the literature (Table 1; see Table A1-1, Appendix, Supplemental Digital Content,https://links.lww.com/QAI/A518).4,5,7,27–30 Direct nonmedical costs and indirect costs were not included. All costs were expressed in 2011 US dollars. Additional details are available in previous publications.15,16

T1-8
TABLE 1:
Main Model Input Parameters

In the base case analysis, we considered ART regimens that conform with current national guidelines in Côte d'Ivoire: 2 nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine or tenofovir + lamivudine or emtricitabine) + efavirenz for first line, 2NRTIs + lopinavir/ritonavir for second line, and a combination of 2 recycled NRTIs + raltegravir + darunavir/ritonavir for third line.23,30 Patients on ART were routinely monitored with biannual CD4 counts. Viral load testing was available but was only used to confirm virologic failure (viral load ≥1000 copies/mL) in patients with immunologic failure (a 50% decrease from peak CD4 count, a return to CD4 count nadir, a CD4 count ≤100/μL)23 or clinical failure (the occurrence of a WHO stage III or IV disease after at least 12 months on ART).23

In addition, we assumed that 60% of patients with viral load ≥1000 copies per milliliter on second-line ART had no resistance to lopinavir/ritonavir, and that 50% of these patients would reach a viral load <1000 copies per milliliter at the end of the adherence reinforcement procedures (6 months).8 Therefore, the efficacy of the 6-month “adherence reinforcement” phase was estimated as 60% × 50% = 30%.8

Main Outcomes

The simulation began at the time of the first observed failure of second-line ART. There were 2 types of main outcomes: clinical and economic. Clinical outcomes included LE and 10-year cumulative survival; both outcomes were assessed starting at the time of second-line ART failure. Economic outcomes were total costs and ICER. The ICER was computed by ordering the strategies by increasing cost and comparing each strategy to the next, less costly, nondominated strategy.31 Dominated strategies were those that were less effective and more costly than another strategy or less costly but incrementally less cost-effective than a more effective strategy.32 All measures of resource use and outcomes used to compute ICERs were discounted at an annual rate of 3%.31

Secondary Outcome

As a secondary analysis, we assessed the impact that third-line strategies would have on secondary HIV transmission. We projected 2-year and 10-year cumulative HIV transmissions under each strategy and report the relative reduction in new transmissions for each strategy relative to C-ART2. This cumulative number of secondary HIV cases was calculated based on a direct model output (updated level of plasma viral load) and from the literature (viral load strata-specific risk of HIV transmission) (see Appendix A2, Supplemental Digital Content,https://links.lww.com/QAI/A518).33 Secondary HIV cases were not included in the cost-effectiveness analysis.

Analytic Steps

The analysis consisted of 4 stages:

  1. Initialization phase: in this stage, we used inputs and the assumptions defined above to simulate a cohort of 1,000,000 adults who started first-line ART and were monitored with biannual CD4 counts and targeted viral load for failure. Using these inputs, we determined the characteristics of patients who accessed second-line ART and then failed, at the time when second-line ART virological failure was actually diagnosed (observed second-line failure).
  2. Base case analysis: in this stage, we simulated 4 cohorts of 1,000,000 patients with observed second-line failure. For this analysis, the “baseline” was the time at which second-line ART virologic failure was diagnosed. Patients' baseline characteristics were obtained at the end of the initialization phase and were the same for all 4 cohorts. Using these characteristics and inputs regarding the efficacy, toxicity, and cost of second-line and third-line ART, we assessed model outputs for each of the 4 strategies.
  3. Scenario analysis: in this stage, we examined whether the results of the base case analysis were robust to 2 different alternative monitoring contexts: (1) settings where viral load testing was not available, but in which CD4 count could be routinely measured and (2) settings in which viral load testing was routinely measured biannually. For these analyses, initialization runs were done to determine the characteristics of patients with observed second-line ART failure in different monitoring contexts.
  4. Sensitivity analyses: in 1-way sensitivity analyses, we varied all major parameters in the model to examine at which point the strategy considered the most cost-effective in the base case analysis would become cost-effective or very cost-effective, according to international standards. These parameters included patient and drug regimen characteristics, as well as program characteristics. The ranges examined in 1-way sensitivity analyses were either based on the 95% confidence intervals around a reported parameter or were examined at the extreme values found in the literature. Finally, we included all highly sensitive variables identified in 1-way analyses in multiway sensitivity analyses.

RESULTS

Initialization Phase: Pre-ART Characteristics and Characteristics at Observed Second-Line Failure

We simulated a cohort of HIV-infected adults, 75% women, who started ART with a mean CD4 count of 154 per microliter (SD, 102), and who were monitored with CD4 counts every 6 months and with viral load tests for confirmation of failure. For this cohort, the mean time from ART initiation to observed second-line failure was 10.6 years (SD, 6.3), and the mean CD4 count at observed second-line failure was 240/μL (SD, 195/μL). Because viral load testing was used for failure confirmation, all patients diagnosed as failing second-line had a viral load of more than 1000 copies per milliliter (true virologic failure) (Table 1).

Base Case Analysis: Outcomes After Observed Second-Line Failure

Compared with C-ART2, AR-ART2 increased 10-year survival from 6.0% to 17.0%, increased discounted LE from 49.6 to 64.2 months, and had an ICER of $1100/YLS (Table 2). Compared with AR-ART2, AR-ART3 further increased 10-year survival to 37.2%, increased discounted LE from 64.2 to 90.4 months, and had an ICER of $3600/YLS. Compared with AR-ART3, IS-ART3 increased lifetime costs and decreased both 10-year survival and LE, and was thus considered a “dominated” strategy. Initially, survival for the IS-ART3 exceeded that of AR-ART3, but by 7 years, the survival of AR-ART3 exceeded that of IS-ART3 (see Figure A5, Appendix, Supplemental Digital Content,https://links.lww.com/QAI/A518). Undiscounted results can be found in Table A3 (see Appendix, Supplemental Digital Content,https://links.lww.com/QAI/A518). With C-ART2, the estimated number of secondary HIV cases 10 years after observed second-line failure was 347/1000 persons. Compared with C-ART2, the percentage of secondary HIV cases averted at 10 years with AR-ART2, AR-ART3, and IS-ART3 was 5.8%, 16.8%, and 15.1% (Table 2).

T2-8
TABLE 2:
Outcomes of Different Treatment Strategies in Patients With Observed Second-Line ART Failure: Base Case Analysis and Analyses in Different Contexts of Monitoring (Discounted Life Expectancy and Lifetime Cost)

Scenario Analysis: Outcomes in Settings With Different Contexts of Monitoring

In settings where viral load monitoring was completely unavailable and patients were monitored only with biannual CD4 counts, mean time from ART initiation to observed second-line failure was 10.5 years (SD, 6.1), and mean CD4 count at observed second-line failure was 240/mm3 (SD, 210). Because viral load was not available for failure confirmation, 6.2% of patients diagnosed as failing second-line ART had a viral load <1000 copies per milliliter (ie, they did not have “true virologic failure”) although they met criteria for immunological failure (see Table A1-2, Appendix, Supplemental Digital Content,https://links.lww.com/QAI/A518).

In a context where viral load was used for routine monitoring, mean time from ART initiation to observed second-line failure was 7.7 years (SD, 5.3), and mean CD4 count at observed second-line failure was 495/μl (SD, 255). Because viral load was available for failure confirmation, all patients diagnosed as failing second-line had true virologic failure (see Table A1-2, Appendix, Supplemental Digital Content,https://links.lww.com/QAI/A518).

In both contexts, IS-ART3 was dominated by AR-ART3, and AR-ART2 was cost-effective. When viral load testing was not available, AR-ART3 had approximately the same ICER ($3700/YLS) as in the base case analysis (with targeted viral load available). When viral load was routinely available, the ICER of AR-ART3 ($4800/YLS) was above the 3× GDP per capita cost-effectiveness threshold (Table 2).

Sensitivity Analyses

Figure 2 shows the effects of 1-way sensitivity analyses on the cost-effectiveness of AR-ART3, in a context of CD4 count monitoring every 6 months with viral load confirmation of failure. Compared with AR-ART2, the ICER of AR-ART3 was most sensitive to the cost of third-line ART drugs. AR-ART3 became cost-effective (ICER <3× the Côte d'Ivoire GDP) if the monthly cost of third-line ART drugs decreased by <1%, to $163. The ICER of AR-ART3 was also sensitive to the efficacy of third-line ART and to second-line ART cost. Additional results from 1-way sensitivity analyses can be found in Table A4 (see Appendix, Supplemental Digital Content,https://links.lww.com/QAI/A518).

F2-8
FIGURE 2:
One-way sensitivity analyses of cost-effectiveness in the strategy consisting of adherence reinforcement and switch to third-line ART in patients in whom failure persists (AR-ART3). Variation of the incremental cost-effectiveness ratio of the AR-ART3 strategy compared with AR-ART2, when varying the input parameters, is shown. In this figure, we included the input variation that led to a variation in the ICER higher than $100/YLS. AR-ART3: adherence reinforcement, third-line ART if failure persists; PY, person-years.

Figure 3 shows multiway sensitivity analyses simultaneously varying third-line ART cost and third-line ART efficacy, second-line ART cost, or adherence reinforcement efficacy. Here, we define the “recommended strategy” as the strategy that conferred the greatest survival benefit, while maintaining an ICER below the cost-effectiveness threshold (ICER <3× GDP).

F3-8
FIGURE 3:
Multiway sensitivity analysis: variation of third-line ART cost with third-line ART efficacy, second-line ART cost, or adherence reinforcement phase efficacy. The recommended ART strategy as a function of third-line cost and either third-line ART efficacy, second-line ART cost, or the adherence reinforcement phase efficacy is displayed. Values on the x axis and y axis are multipliers with reference to the base case value (eg, 1.0 corresponds to the value used in the base case analysis). The colored areas denote the strategy that confers the greatest benefit, among those whose ICER is below the cost-effectiveness threshold ($3585/YLS). AR-ART3: adherence reinforcement, third-line ART if failure persists.

A modest decrease in the price of third-line ART consistently led AR-ART3 to become the recommended strategy, even with wide variation in third-line ART efficacy and second-line regimen cost. With decreases in the cost of third-line, while keeping the adherence reinforcement efficacy constant, AR-ART3 became the recommended strategy. If the efficacy of the adherence intervention were to increase, then the cost of third-line would have to decrease for AR-ART3 to remain cost-effective. Otherwise, AR-ART2 became the best strategy.

DISCUSSION

We examined alternative approaches to the care of patients with observed second-line ART failure in settings with limited access to ART and laboratory monitoring tests. In particular, we considered combining access to third-line ART with an adherence reinforcement, which could help distinguish between patients who could still benefit from their current second-line regimen and those who truly need to switch to third-line ART.

We found that combining access to third-line ART with an intense adherence reinforcement phase would provide the greatest long-term survival benefits to patients with observed second-line ART failure. This phased intervention reached the cost-effectiveness threshold with a minimal decrease in the price of the third-line drugs. If third-line drugs were not available in the country, reinforcing adherence to second-line ART in patients with observed second-line failure would be a cost-effective intervention. In addition, our study also suggests that reinforcing adherence in patients with observed second-line failure and making third-line ART available to patients who need it could substantially decrease the number of secondary HIV cases and therefore provide population-level benefits.34

Our results suggest that an adherence reinforcement program could be an important tool to decide whether to switch regimens in case of second-line failure. Adherence interventions can improve long-term survival by delaying the switch to third-line ART in patients without resistance to second-line and who therefore do not yet need it. However, unlike genotype testing, an adherence intervention cannot be used to adapt ART regimens according to resistance profiles and therefore cannot spare specific drugs for further lines of treatment.35

Because this analysis started at the time of second-line failure documentation, patients with observed second-line failure had different baseline characteristics depending on the context of monitoring. Thus, our sensitivity analysis simulating different cohorts in different monitoring contexts did not aim to compare the efficacy of different types of monitoring, but rather to examine the robustness of our findings in different contexts of monitoring. We found that our conclusions would likely be the same if viral load testing was either completely unavailable or routinely available. We also found that our main results were robust to wide variations in third-line ART efficacy, adherence reinforcement efficacy, and second-line drugs costs.

Our study has several limitations. First, the efficacy of the adherence intervention phase was difficult to estimate for 2 reasons. (1) Previous studies reported wide variation in the resistance rate to protease inhibitors in patients failing second-line ART.8,11,36 Estimating the proportion of patients failing second-line ART with no resistance to protease inhibitors who could respond to an adherence reinforcement intervention was equally challenging.37,38 (2) The large scale applicability of such interventions still remains to be documented. Therefore, we adopted a conservative approach, assuming a low efficacy for the intervention, and conducted a wide range of sensitivity analyses on this parameter. Second, we did not consider all possible combinations of parameter variation in multiway sensitivity analyses. Instead, we focused our 2-way sensitivity analyses on the treatment parameters that we found to be most critical to driving the variation in main outcomes. However, parameters that did not have an impact in 1-way sensitivity analyses are unlikely to have much influence on the results in multiway analyses. Third, the CEPAC-International Model does not explicitly control for important socioeconomic parameters such as level of education and access to care for individuals, although it implicitly accounts for access through clinical factors such as CD4 count at presentation to care. This may limit how representative our simulated cohort is of the general population in Côte d'Ivoire. Interested readers may also wish to refer to several publicly available sources for additional detail on the CEPAC-International Model, its assumptions, and their limitations.15,16,22,39

In conclusion, combining access to third-line ART with a strategy including an intense adherence reinforcement phase would provide substantial long-term survival benefits. Minimal reductions in the cost of third-line ART agents would render such an approach cost-effective in Côte d'Ivoire. In resource-limited settings with poor access to resistance tests, additional research to evaluate the cost-effectiveness of alternative treatment strategies after ART failure could inform more appropriate use of second- and third-line regimens.

ACKNOWLEDGMENTS

The authors are grateful to the entire Thilao ANRS 12269 study group, including Xavier Anglaret, Avelin Aghokeng Amani Anzian, Lambert Assoumou, Guillaume Bado, Aliou Balde, Brigitte Bazin, Aïda Benalycherif, Emmanuel Bissagnene, Marie-Laure Chaix, Mamadou Cissé, Géraldine Colin Dominique Costagliola, Seydou Coulibaly, Christine Danel, Jean-François Delfraissy, Fodié Diallo, Mouhamadou B. Diallo, Zelica Diallo, Oumar Dogoni, Serge P. Eholié, Frederic Ello, Arlette Emième, Claudine Essomba, Mame Basty Koita Fall, Mohamadou Fomba, Eric Delaporte, Delphine Gabillard, Nogaye Gaye, Pierre-Marie Girard, Ndèye Fatou Ngom Guèye, Sophie Karcher, Christine Katlama, Romuald Konan, Tiefing Konate, Charles Kouanfack, Sinata Koulla-Shiro, Roland Landman, Jérôme Le Carrou, Almoustapha Issiaka Maiga, Anne-Geneviève Marcelin, Maryvonne Maynart, Eugène Messou, Daouda K. Minta, Raoul Moh, Bara Ndiaye, Larissa N'guessan-Koffi, Gilles Peytavin, Mohamadou Fomba, Maguy Ngolle, Eric Ouattara, Claire Rekacewicz, Moussa Seydi, Thomas d'Aquin Toni, Coumba Toure-Kane, Roland Tubiana, Abdoulaye M. Traoré, Jean-Richard Traoré, Adrien B. Sawadogo, Laurence Slama, Yazdan Yazdanpanah, and Jacques Zoungrana. The authors extend our gratitude to the entire CEPAC-International Team and investigators, including Jason Andrews, Ingrid Bassett, Linda-Gail Bekker, Andrea Ciaranello, Timothy Flanigan, Emily Hyle, Nagalingeswaran Kumarasamy, Marc Lipsitch, Neil A. Martinson, Kenneth Mayer, Eugène Messou, Stephen Resch, George R. Seage III, Soumya Swaminathan, Milton C. Weinstein, and Robin Wood.

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    Keywords:

    antiretroviral therapy; second-line ART failure; third-line ART; adherence reinforcement; HIV in sub-Saharan Africa

    © 2014 by Lippincott Williams & Wilkins