Trends in First-Line Antiretroviral Therapy in Asia: Results from the TREAT Asia HIV Observational Database

<div><p>Background</p><p>Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes.</p><p>Methods</p><p>Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥6 months were included. Predictors of treatment failure and treatment modification were assessed.</p><p>Results</p><p>Data from 4662 eligible patients was analysed. Patients started ART in 2003–2006 (n = 1419), 2007–2010 (n = 2690) and 2011–2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7–23.5] events per 100 patient/years in 2003–2006, 15.8 [14.9–16.8] in 2007–2010, and 11.6 [9.4–14.2] in 2011–2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33–0.81], p = 0.004 for 2011–2013 versus 2003–2006), older age (1.56 [1.19–2.04], p = 0.001 for ≥50 years versus <30years), female sex (1.29 [1.11–1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06–1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28–20.54], p<0.001 for stavudine-based regimens versus tenofovir-based).</p><p>Conclusions</p><p>The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of treatment modification due to adverse event, but not to reductions in treatment failure.</p></div

First-line ART use by year of initiation (n = 4662).

<p>a) Drug classes. NRTIs not represented as there was a single patient that initiated a regimen without an NRTI; b) NRTI. Not represented are didanosine (2.9% of patients overall) and zalcitabine (0.02%); c) NNRTI. Not represented is rilpivirine (0.13%); d) PI. Not represented are indinavir (0.66%), nelfinavir (0.39%), tipranavir (0.39%), saquinavir (0.17%), fosamprenavir (0.17%) and full-dose ritonavir (0.11%). ART = antiretroviral therapy; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-NRTI; PI = protease inhibitor; 3TC/FTC = lamivudine/emtricitabine; d4T = stavudine; AZT = zidovudine; TDF = tenofovir; ABC = abacavir; EFV = efavirenz; NVP = nevirapine; LPV = lopinavir; ATV = atazanavir; DRV = darunavir.</p

First-line regimen by period of initiation (n = 4662).

<p>A <i>(d4T/AZT/TDF)/NNRTI</i> regimen comprises d4T/AZT/TDF + another NRTI + NNRTI. A <i>PI-based</i> regimen comprises dual NRTI + PI. <i>Other</i> regimen refers to all other ART. d4T = stavudine; AZT = zidovudine; TDF = tenofovir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor.</p

Competing risk models of treatment failure and treatment modification due to adverse event (n = 4662).

<p>All models were adjusted for study site. Baseline CD4 cell count and adherence were not significant in univariate analysis for either outcome but are presented out of interest, as is the missing adherence category. Exposure category <i>Other</i> includes those exposed to blood products and unknown exposures. A <i>(d4T/AZT/TDF)/NNRTI</i> regimen comprises d4T/AZT/TDF + another NRTI + NNRTI. A <i>PI-based</i> regimen comprises dual NRTI + PI. <i>Other</i> regimen refers to all other ART. ^¤Included in final treatment failure model; ^◊Included in final modification due to adverse event model; ^¥Adjusted for co-variables included in the final model; *Time updated; †p overall for linear trend; ‡p overall for heterogeneity; HR = hazard ratio; ART = antiretroviral therapy; IDU = intravenous drug use; HCV = hepatitis C virus; PI = protease inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; d4T = stavudine; AZT = zidovudine; TDF = tenofovir.</p><p>Competing risk models of treatment failure and treatment modification due to adverse event (n = 4662).</p

Baseline data (n = 4662).

<p>Exposure category <i>Other</i> includes those exposed to blood products and unknown exposures. A <i>(d4T/AZT/TDF)/NNRTI</i> regimen is d4T/AZT/TDF + another NRTI + NNRTI. A <i>PI-based</i> regimen is a dual NRTI + PI regimen. <i>Other</i> regimen refers to all other ART regimens. IQR = interquartile range; IDU = intravenous drug use; HBV = hepatitis B; HCV = hepatitis C; ART = antiretroviral therapy; PI = protease inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; d4T = stavudine; AZT = zidovudine; TDF = tenofovir.</p><p>Baseline data (n = 4662).</p

Comparison by geographic region of characteristics at first visit, ART start, age 10 years, and last visit of adolescents living with perinatally acquired HIV.

<p>ART, antiretroviral therapy; IQR, interquartile range; S&SE Asia, South and Southeast Asia; WHO, World Health Organization.</p

Profile of geographic regions included in the CIPHER global cohort adolescent analysis (<i>N</i> = 38,187 adolescents).

<p>Profile of geographic regions included in the CIPHER global cohort adolescent analysis (<i>N</i> = 38,187 adolescents).</p

Flow diagram of inclusion of adolescents living with perinatally acquired HIV (<i>N</i> = 38,187).

<p>CIPHER, Collaborative Initiative for Paediatric HIV Education and Research.</p

Adolescent characteristics at first visit, ART start, age 10 years, and last visit and cumulative incidence of outcomes (mortality, transferred out, LTFU), compared by CIG.

<p>Adolescent characteristics at first visit, ART start, age 10 years, and last visit and cumulative incidence of outcomes (mortality, transferred out, LTFU), compared by CIG.</p

Comparison by CIG of characteristics at first visit, ART start, age 10 years, and last visit of adolescents living with perinatally acquired HIV.

<p>ART, antiretroviral therapy; CIG, country income group; IQR, interquartile range; WHO, World Health Organization.</p