Clinical and virologic outcomes after changing first antiretroviral regimen at 7 sites in the Caribbean, Central, and South America Network (CCASAnet)

1 1 Clinical and virologic outcomes after changes in first antiretroviral regimen at 7 2 sites in the Caribbean, Central and South America Network (CCASAnet) 3 4 Marcelo Wolff, M.D., Bryan E. Shepherd, Ph.D., Claudia Cortés, M.D., Peter Rebeiro, 5 M.H.S., Ph.D., Carina Cesar, M.D., Sandra Wagner Cardoso, M.D., Ph.D., Jean W. 6 Pape, M.D., Denis Padgett, M.D., Juan Sierra-Madero, M.D., Juan Echevarria, M.D., 7 Catherine C. McGowan, M.D., for The Caribbean, Central and South America Network 8 for HIV Epidemiology (CCASAnet) 9 10 Fundación Arriarán/Facultad de Medicina, Universidad de Chile, Santiago, Chile; 11 Vanderbilt University, Nashville, TN, U.S.A.; Fundación Huésped, Buenos Aires, 12 Argentina; Instituto de Pesquisa Clinica Evandro Chagas-Fundação Oswaldo Cruz, Rio 13 de Janeiro, Brazil; Le Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections 14 Opportunistes, Port-au-Prince, Haiti; Instituto Hondureño de Seguridad Social and 15 Hospital Escuela, Tegucigalpa, Honduras; Instituto Nacional de Ciencias Médicas y 16 Nutrición, Mexico City, México; Instituto de Medicina Tropical Alexander von Humboldt, 17 Lima, Peru. 18 19 20 Corresponding author: 21 22 Catherine C. McGowan, M.D. 23 A2200 Medical Center North 24 Division of Infectious Diseases 25 Vanderbilt University Medical Center 26 Nashville, TN 37232 27 Tel: (615) 322-2035 28 Fax: (615) 343-6160 29 Email: c.mcgowan@vanderbilt.edu 30 31 32 Some of the data herein were presented as an oral abstract at the HIV Drug Therapy in 33 the Americas conference, held June 13-15, 2013 in Sao Paulo, Brazil. 34 35 36 This work was supported by the National Institute of Allergy and Infectious Diseases 37 (NIAID) as part of the International Epidemiologic Databases to Evaluate AIDS (IeDEA): 38 U01 AI069923. 39 40 The authors report no conflicts of interest related to this work. 41 42 Running head: Outcomes after changes in first antiretroviral regimen in Latin America 43 AC CE PT ED


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Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and 3 mortality in persons living with HIV worldwide (1-5), and become more widely available 4 in resource-limited settings. An estimated 12.9 million people globally, and 11.7 million 5 from low-and middle-income countries, were receiving HAART by 2014 (6).

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The HIV epidemic in Latin America and the Caribbean accounts for approximately 6% of 8 HIV-infected persons worldwide, an estimated 70% of whom are aware of diagnosis and 9 44% of whom are receiving HAART in the region (6-8). Expanded access programs to 10 HAART have been in place in Latin America for over a decade, leading to a regional 11 coverage of 56% of those eligible by the end of 2013 (8,9).

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Despite the successes of HAART, high incidence of early mortality (10-13) and frequent 14 change of initial therapy (14,15) have been consistently observed in many regions,

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including Latin America and the Caribbean. HAART initiation at more advanced disease 16 stages may lead to poorer tolerability, slower and blunted treatment response, and 17 higher risk of disease progression and mortality (11,16). HAART-related toxicities and 18 intolerance may lead to poor adherence, viral resistance, virologic failure, and 19 diminished likelihood of future treatment success. Many studies have shown the frequent 20 need for partial or total change of initial regimens, with toxicity, more frequently than 21 failure, being the main reason (8,14,(17)(18)(19). However, clinical and virologic outcomes 22 while on those modified regimens, except when changed due to failure, are not well-23 characterized in "real world" settings. Most current understanding comes from studies of 24 specific drug combinations or controlled scenarios, usually after failure of initial therapy 25 (20)(21)(22)(23)(24)(25)(26)(27). Few studies, though, have investigated outcomes after initial regimen 26 modification due to toxicity or other non-failure reasons, the largest being from cohorts in 27 high-income countries (28). Evaluation of outcomes after changes in first HAART in 28 routine clinical practice is urgently needed and was the main objective of this study. We  39 www.iedea.org) (29). CCASAnet sites contributing data to this study were Hospital 40 Fernandez and Centro Médico Huésped, Buenos Aires, Argentina (HF/CMH-Argentina);

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Instituto de Pesquisa Clinica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, 4 performed by VDCC to ensure data accuracy. Institutional review board approval was 1 obtained from each site and from Vanderbilt University.

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Antiretroviral-naïve adults (≥18 years) initiating their first HAART regimen  4 between 1996 and 2014 at participating sites and subsequently modifying at least one 5 drug, thereby starting a second regimen (ART-2), were eligible for inclusion. Patients 6 participating in any clinical intervention protocol were excluded from analyses. All 7 patients from IMTAvH-Peru were included in analyses though clinical trial participation 8 was not documented, but estimated as less than 5%.

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Clinical AIDS at initiation of ART-1 was defined as CDC stage C, WHO stage IV, or a 11 specification of AIDS. HAART was defined as protease inhibitor (PI)-based (one 12 ritonavir-boosted or unboosted PI plus two nucleoside reverse transcriptase inhibitors

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[NRTI]), non-nucleoside reverse transcriptase inhibitor (NNRTI)-based (one NNRTI plus 14 two NRTIs), or other combinations (including triple NRTI regimens and all other 15 regimens containing at least three drugs), in accordance with national or international 16 guidelines over the study period.

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Nadir pre-HAART CD4 + lymphocyte count (CD4) was the lowest measurement prior to, 19 or no more than seven days after, initiating ART-1. CD4 at start of ART-2 was the 20 measurement closest to, but no more than 180 days before, or seven days after. Pre-

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HAART HIV-1 RNA viral load (VL) was defined as the measurement closest to ART-1 22 initiation, but no more than 180 days before; VL measurements after ART-1 initiation 23 were not included. VL at start of ART-2 was defined using the same time intervals.

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Study outcomes included all-cause mortality, modification of ART-2 regimen, and 26 virologic failure. Virologic failure was defined as one of: 1) VL was never <400 copies/mL 27 after six months of therapy; 2) VL was once <400 copies/mL, but two consecutive 28 measurements subsequently were >400 copies/mL; 3) VL was once <400 copies/mL, 29 but a single measurement subsequently was >1000 copies/mL. The cutoff of 400 30 copies/mL was the lower limit of quantitation for assays in use at many of the sites 31 during the study period. Patients modifying ART-2 before virologic failure were censored 32 at the time of regimen modification for virologic failure analyses. Loss to follow-up 33 (LTFU) was defined as no record of visit (clinic, laboratory, or pharmacy) within the year 34 prior to the site-specific database closing date; patients who were lost to follow-up were 35 censored at last visit.

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The probability of death after starting ART-2 was estimated using Kaplan-Meier 38 methods, with time 0 defined as the start of ART-2. When estimating the cumulative 39 incidences of LTFU, regimen change, and virologic failure as events of interest, death 40 was treated as a competing event (30,31). Risk factors for death, virologic failure, and 41 change of ART-2 were assessed using Cox proportional hazards models. All models 42 were stratified by CCASAnet site. Primary adjusted models included sex, age at start of 43 ART-2, CD4 at start of ART-2, change in CD4 from ART-1 to ART-2, year of ART-2 start, 44 months between start of ART-1 and start of ART-2, clinical AIDS at start of ART-1, and 45 primary reason for changing regimens (classified as toxicity, failure, other, or unknown).

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These covariates were chosen for inclusion a priori based on perceived clinical 47 relevance and availability. Adjusted analyses used multiple imputation to account for 48 missing CD4 and clinical AIDS values (32); 10 imputation replications were used. Age 49 and CD4 were included in the models using restricted cubic splines with 4 knots to relax 50 linearity assumptions (33); CD4 was also square root-transformed. The time between 51 A C C E P T E D 5 the start of ART-1 and ART-2 was log-transformed and included using splines with 3 1 knots. Associations between continuous variables and outcomes were assessed using 2 p-values from likelihood ratio tests; hazard ratio estimates and 95% confidence intervals 3 (95% CI) are given in the text and tables for selected covariate levels. Proportional 4 hazards were assessed using Schoenfeld residuals and a correlation-with-time test (34).

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There was some evidence that hazards between reasons for changing to ART-2 were 6 not proportional in the mortality analysis; results were similar when separate baseline 7 hazards were assumed for reasons for changing to ART-2. GHESKIO-Haiti did not 8 routinely measure VL and was excluded from analyses of virologic failure. All analyses 9 were performed using R Statistical Software; analysis scripts are available at 10 http://biostat.mc.vanderbilt.edu/ArchivedAnalyses.

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Fifty-eight percent of patients were male and median age at start of ART-2 was 38 years 17 (interquartile range [IQR] 32-46). CD4 at start of ART-2 was low (median 196 cells/µL;

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Thirty-nine percent of patients started ART-2 due to toxicity of previous regimen; 24 hematologic toxicities were most common, comprising 32% of toxicity-motivated 25 switches. Eleven percent started ART-2 due to failure of ART-1: 4.5% due to virologic 26 failure and 6.7% due to clinical/immunologic failure. Forty-four percent started ART-2 for 27 other reasons (availability of preferred agent/regimen, 20%; drug interactions/co-28 morbidities, 5%; unavailability of drugs, 3%; pregnancy-related, 3%; abandonment/non-29 adherence, 1%). Reason for changing to ART-2 was unknown for 6% of patients. More 30 details on reasons for changing from ART-1 to ART-2 are provided in the Supplemental

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A total of 494 (8.9%) patients died after starting ART-2. Estimated probabilities of 11 mortality one, three, and five years after starting ART-2 were 0.051, 0.084, and 0.105, 12 respectively. Figure 1 shows estimated probabilities of mortality, by study site and 13 reason for starting ART-2. Among those with a known reason, those who changed due 14 to toxicity had the highest risk of mortality during the first several years of ART-2, though 15 mortality risk was similar between those switching due to toxicity and failure by 5 years 16 (0.117 and 0.116, respectively). Mortality was consistently lower for those changing due 17 to "other" reasons.

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AIDS prior to ART-1 and older age were also associated with mortality.

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Cumulative incidences of virologic failure while on ART-2, by study site and by reason 34 for starting ART-2, are shown in Figure 2. Cumulative incidences of virologic failure one, 35 three, and five years after starting ART-2 were 9.1%, 18.9%, and 24.8%, respectively, 36 although risks were variable by site, ranging at 5 years from a low of 19% in IHSS/HE-

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In analyses controlling for patient characteristics (Table 3), reason for starting ART-2 44 was strongly associated with virologic failure while on ART-2 (p<0.001). The hazard of 45 virologic failure on ART-2 for a patient starting ART-2 due to failure of ART-1 was 2.06 46 times that of a patient starting ART-2 due to toxicity (95% CI 1.52-2.79). Younger age, earlier calendar year, lower CD4 at ART-2 initiation, and smaller change in CD4 from 48 ART-1 to ART-2 were also independently associated with an increased hazard of 49 virologic failure.

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This study evaluated multiple outcomes after modifying at least one drug in an initial

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ART regimen for any reason in patients from a large Latin American and Caribbean 22 cohort, and compared outcomes according to the reason for change from ART-1 to ART-23 2. Significant risk of second regimen change, virologic failure, and mortality were 24 observed after modifications of initial ART regimen. Reasons for changing the second 25 regimen were often similar to those for changing the first; changing to a second regimen 26 due to failure was a strong predictor of subsequent virologic failure. Persons changing 27 due to toxicity had a higher risk of death than persons changing due to failure.

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However, there are few studies of outcomes following first HAART change of any drug in 32 the initial regimen due to non-failure reasons (28).

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Nearly 40% of patients in our study changed their initial regimen due to 35 toxicity/intolerance. Toxicity has been consistently reported as the main reason for 36 change of first HAART globally (14,17,19,38,39), although many of these earlier studies 37 involved treatment with older, more toxic antiretroviral agents such as didanosine,    Organization (41 , the execution and logistics involved are not trivial in resource-limited 6 settings (42). Further, despite the implication of these findings that prescription of an 7 initial regimen with maximal antiviral activity and a low side-effect/toxicity profile would 8 be the surest bulwark against accelerated disease progression, again, the plausibility of 9 implementing this practice is greatly dependent on the most readily available 10 antiretroviral agents (43,44). In some of the countries with contributing cohorts for this 11 study, the ability to initiate ART-1 using second-generation NNRTIs, integrase inhibitors,

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Mortality in the first year after starting ART-2 was 5.1%, less than that observed in the 18 first year after starting ART-1, estimated as 8% in an earlier CCASAnet study (11), but 19 still fairly high. Early mortality after starting ART-2 and throughout follow-up was quite 20 variable across sites, illustrating the remarkable heterogeneity across the region. Loss to 21 follow-up of patients on ART-2 was high (15% overall), and our results suggest that 22 better approaches for patient retention and linkage are needed.

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Not surprisingly, known predictors of mortality at HAART initiation (including lower CD4, 25 older age, and AIDS) remained predictors of mortality among patients starting a second 26 regimen. Patients with an unknown reason for starting ART-2 were observed to have the 27 highest risk of mortality, possibly reflecting data collection issues or less engagement in 28 care. Patients who modified their regimens for a known reason other than failure or 29 toxicity had the lowest risk of mortality, which is not to be unexpected given that nearly 30 half of these other changes were due to the availability of a preferred regimen.

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Virologic failure was common after ART-2 initiation, reaching a cumulative incidence of 33 25% at 5 years. Failure on ART-1 was a strong predictor of failure on ART-2: cumulative 34 incidence of virologic failure 3 years after changing from ART-1 to ART-2 due to failure 35 was nearly 45%, and the hazard of virologic failure for these patients was twice that of 36 those who changed to ART-2 due to toxicity. These results may in part reflect non-

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This study provides policy makers and funders with additional evidence that patients 43 should be started on regimens with the greatest likelihood of enhancing CD4 recovery, 44 maintaining viral suppression, and minimizing side-effects, thereby promoting efficient 45 resource usage in resource-limited settings. This evidence is compelling because it 46 includes data on reasons for regimen switches and granular details of the regimen 47 constituents/classes associated with clinical outcomes among more than 5,500 patients 48 in seven countries spanning more than 15 years. While addressing questions 49 encountered by clinical care providers, this cohort study also contributes valuable 50 information on the nature of HAART response among a particularly vulnerable 51 A C C E P T E D 9 population (those who require HAART regimen changes) in a less-studied region that is 1 still of major importance in the HIV/AIDS epidemic (46).

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Our study has several weaknesses inherent to retrospective observational studies.

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Decisions to change ART were not controlled by investigators, classification of reasons 5 for changing regimens were not uniform across sites, some data were missing and had 6 to be imputed using multiple imputation techniques, many patients were lost to follow-up 7 (rates of failure and death typically differ in those lost than those remaining in care [47-8 48]), and data on adherence or resistance genotyping were not collected. Differences in 9 frequency of viral load monitoring across sites could lead to variability in identification of 10 virologic failure. Our cohort includes urban sites and may not be representative of the 11 respective countries or the region as a whole. Finally, the observation of higher risks of 12 virologic failure after switching to regimens containing more potent drugs may be a 13 symptom of confounding by indication, wherein patients doing poorly are those more 14 likely to be placed on highly potent therapies (49). We attempted to reduce this 15 confounding by adjusting all models using CD4 prior to ART-2 and CD4 change between 16 ART-1 and ART-2.

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In conclusion, in this large study of patients modifying their first antiretroviral regimen in