For the past decade, substantial effort has been devoted to the rapid scale-up of antiretroviral therapy (ART) access in areas where it is most needed. The UNAIDS report for 20131 states that 4.9 million people were living with HIV in the Asia Pacific region in 2012. Of these, 1.25 million where receiving ART. Roughly 4% of patients on ART are on second-line therapy.2
The 2013 World Health Organization (WHO) guidelines recommend that initial ART consist of a nonnucleoside reverse transcriptase inhibitor (NNRTI) and 2 nucleoside reverse transcriptase inhibitors (NRTIs).3 The rate of virological suppression on first-line ART commonly exceeds 80% at 1 year on treatment among patients retained in care.4 After failure on an NNRTI-containing regimen, the WHO advises that second-line ART consist of a boosted protease inhibitor (PI) in combination with 2 NRTIs, at least 1 of which is new to the patient.3 In wealthier areas, it is recommended that second-line ART consist of the most active drugs available based on genotypic analysis, treatment and adverse event history, and availability of additional classes of drugs.5
PIs, including the current WHO preferred PIs—ritonavir-boosted lopinavir (LPV/r) and ritonavir-boosted atazanavir (ATV/r), have been available to varying degrees across Asia for over a decade. In a study of second-line regimens containing LPV/r at a center in Cambodia, 85.7% of the 70 HIV-infected study participants had an undetectable viral load at 24 weeks.6 However, significant challenges remain. A 2010 Cochrane review concluded that although outcomes of second-line regimens with boosted PIs are generally favorable, there is limited evidence to evaluate second-line ART in patients who fail first-line WHO-recommended treatment.7 Further, very little of the currently available literature describes second-line ART outcomes in HIV-infected patients in Asia.6,8–10
Identification of treatment failure in Asia is frequently determined by clinical and immune changes, which may occur long before or long after the loss of virological suppression.11–15 A delay in recognizing treatment failure can result in the accumulation of resistance mutations that jeopardize next-line options and efficacy,11,16–19 a greater risk of mortality,20 and may increase the transmission of (resistant) HIV. A 2012 study out of India found 24 (53%) of 45 viremic second-line patients genotyped had triple-class resistance to NRTIs, NNRTIs, and PIs.10 In contrast, switching to second-line ART before it is indicated unnecessarily increases the use of expensive and less tolerated second-line agents and may result in a quicker progression to treatment exhaustion.
The number of patients requiring second-line ART in Asia will increase as the number of patients accessing ART grows. To maximize patient benefit and the use of regional resources, it is important to optimize the timing of second-line ART initiation and use the most effective compounds available. The aims of this analysis are to describe the second-line ART regimens used in a regional cohort in Asia and evaluate rates and predictors of treatment failure.
The study population consisted of patients on second-line ART who were enrolled in the TREAT Asia HIV Observational Database (TAHOD) and/or the TREAT Asia Studies to Evaluate Resistance-Monitoring (TASER-M). These cohorts have been described previously.21,22 Briefly, TAHOD is an observational study of patients with HIV involving 21 adult treatment centers in 12 countries and territories in Asia, which aims to assess the natural history of HIV disease in treated and untreated patients in the region. Retrospective and prospective data are collected at each site. Recruitment started in September 2003. TASER-M was a multicenter, cohort study monitoring the development of HIV drug resistance in patients taking ART. Patients eligible for first- or second-line ART initiation were enrolled sequentially. Data on any previous antiretroviral use were collected retrospectively. Patient recruitment commenced in March 2007 and ceased in 2011. Follow-up data continue to be collected as TASER-M was merged with TAHOD in 2012. Currently, each TAHOD site has contributed data from 100 to 450 patients. Data are transferred to the data management center at the Kirby Institute, Sydney, Australia, twice annually in March and September.
TAHOD (and former TASER-M) patients from the March 2013 data transfer were included in this analysis if they experienced treatment failure while on first-line ART and subsequently used a regimen for ≥6 months that contained ≥3 antiretroviral drugs and at least 1 drug class that was new to them. Day 1 of first-line ART was when the first regimen containing ≥3 antiretrovirals used for >14 days was initiated. Patients that underwent a drug class change on first-line ART without documentation of treatment failure were excluded. Treatment breaks and regimen modifications that did not involve a drug class change were ignored for first- and second-line ART. Because treatment-monitoring protocols between TAHOD sites differ substantially and have changed over time, we applied a strict, multifaceted definition of treatment failure based on the current WHO guidelines.3 The first occurrence of virological, immunological, or clinical failure while on first- or second-line ART was considered the date of failure. Where multiple failure types were documented on the same day, priority was given to virological, immunological, and then clinical failure. Virological failure was considered a viral load >1000 copies per milliliter after 6 months of ART, confirmed within 6 months; immunological failure was defined as CD4 cell count <100 cells per cubic millimeter or less than baseline CD4 cell count after 6 months of ART, confirmed within 6 months, and clinical failure comprised a new or recurrent WHO stage 3 or 4 illness or death after 6 months of ART. Baseline was considered the first day of second-line ART.
The window period for baseline CD4 cell count and viral load was between 3 months before, and 2 weeks after, second-line ART initiation. The measurement taken closest to second-line ART initiation was used. Patients were considered hepatitis B coinfected if they had any record of a positive hepatitis B surface antigen test in the database and hepatitis C coinfected if they had any record of a positive hepatitis C antibody test.
Cumulative incidence functions were used to evaluate rates of failure. Other types of failure were considered competing events when individually assessing virological, immunological, clinical, and immunovirological failure. Cox regression stratified by study site was used to evaluate predictors of second-line ART failure. Patients with missing data were included, but hazard ratios (HRs) for missing categories are not reported. Follow-up time was measured from second-line ART start or enrollment date (if already on second-line ART at enrollment) until treatment failure or censoring. Censoring occurred at the last recorded clinic visit while still on second-line ART or at the time of a drug class change without failure.
Predictors to be used in the multivariate model were selected based on a significance level of ≤0.15 in the univariate analysis. Predictors were retained in the multivariate model if ≥1 categories exhibited a P value ≤0.05. Multivariate HRs were used to estimate the absolute risk of failure based on the survival probabilities at 12, 24, and 36 months of second-line ART in the reference group.
Stata software version 12.1 (StataCorp, College Station, TX) was used for all statistical analysis.
Of 7320 patients that had a history of ≥6 months of first-line ART use, 302 (4.1%) had documented evidence of treatment failure with subsequent use of a second-line regimen for ≥6 months and at least 1 day of prospective follow-up. Baseline data are presented in Table 1. The majority of eligible patients were male (76.5%) and exposed to HIV via heterosexual contact (71.5%). Median age at second-line ART initiation was 39.2 [interquartile range (IQR): 34.1–44.5] years, median CD4 cell count was 146 (IQR: 58–268) cells per cubic millimeter, and median HIV viral load was 16,224 (IQR: 2060–84,656) copies per milliliter. Hepatitis B and C status was positive in 22 (9.3%) of 237 patients tested and in 25 (11.4%) of 220 patients tested, respectively. Most patients (n = 228, 75.5%) initiated ART with an NNRTI-based regimen, and median time on first-line ART was 3.5 (IQR: 2.2–5.4) years. Median time from confirmation of first-line failure to second-line initiation was 9.9 (IQR: 2.0–29.4) months. A total of 221 (73.2%) patients were switched to a dual NRTI plus PI regimen, 58 (19.2%) a dual NRTI plus NNRTI regimen, and 23 (7.6%) to an alternative second-line regimen. Alternative regimens included single NRTI plus NNRTI and/or PI (14; 60.9%), triple NRTI (4; 17.4%) and dual NRTI plus raltegravir (5; 21.7%).
Figure 1 shows the initial second-line ART regimens used by year of start. Before 2007 (n = 105), dual NRTI plus PI (51.4%) was the most commonly used second-line combination. LPV/r (9.5%) and ATV/r (7.6%) use was outweighed by that of other PIs (34.3%). The other PIs used mostly comprised indinavir (80.6%). In the same period, dual NRTI plus NNRTI was used by 36.2% of patients; efavirenz was used by 23.8% of patients and nevirapine by 12.4%. Alternate second-line regimens were used by 12.4% of the patients. Between 2007 and 2010 (n = 147), dual NRTI plus PI (83.7%) remained the most commonly used second-line regimen though LPV/r (51.7%) and ATV/r (21.1%) use dominated over other PI (10.9%) use. Indinavir (31.3%) and darunavir (31.3%) made up the majority of the other PIs used. Dual NRTI plus NNRTI was used by 11.6% of the patients, and this mostly comprised efavirenz-based therapy (10.9%). Other second-line regimens were used by 4.8% of the patients. After 2010 (n = 50), dual NRTI plus PI (88.0%) regimens comprised LPV/r (50.0%), ATV/r (26.0%), and unboosted ATV or LPV (12.0%). Dual NRTI plus efavirenz was used by 4.0% of the patients and dual NRTI plus nevirapine by 2.0%. Other second-line ART was used by 6.0% of the patients. Overall, the most commonly used NRTIs for second-line ART were lamivudine/emtricitabine (76.5% of all the patients), tenofovir (44.4%), zidovudine (32.1%), stavudine (12.9%), and abacavir (12.3%).
The median viral load monitoring frequency was 1.5 (IQR: 0.3–2.3) tests/patient/year. Among those with any viral load result during follow-up (n = 233, 77.2%), the median viral load monitoring frequency was 1.9 (IQR: 1.1–2.6) tests/patient/year. One hundred ten (36.4%) patients had <2 viral loads documented while on second-line ART. Two hundred eighty-nine (95.7%) patients had a follow-up CD4 cell count, and the median CD4 monitoring frequency was 2.0 (IQR: 1.4–2.9) tests/patient/year. During second-line ART, 53 (17.5%) patients had <2 CD4 cell counts documented.
The cumulative incidence of treatment failure and subincidences of virological failure, immunological failure, and clinical failure are shown in Figure 2. Over a total follow-up time of 924.2 years, 81 patients experienced second-line treatment failure, including 12 deaths. The rate of treatment failure was 8.8 [95% confidence interval (CI) 7.1 to 10.9] per 100 patient/years, and the rate of mortality alone was 1.1 (95% CI: 0.6 to 1.9) per 100 patient/years. Median follow-up time on second-line was 2.3 (IQR: 1.1–4.4) years. Median time on second-line regimen without any drug substitutions or treatment breaks was 1.8 (IQR: 0.8–3.2) years. The rates of virological, immunological, and clinical failure per 100 patient/years were 2.1 (95% CI: 1.3 to 3.2), 3.3 (95% CI: 2.3 to 4.6), and 3.5 (95% CI: 2.5 to 4.9), respectively. Immunovirological failure occurred at a rate of 5.3 (95% CI: 4.0 to 7.0) per 100 patient/years.
Predictors of second-line treatment failure are outlined in Table 2. In the final multivariate model, age 41–50 years (HR: 5.50 vs. age <30 years, 95% CI: 1.51 to 20.07, P = 0.010), age >50 years (HR: 7.50 vs. age <30 years, 95% CI: 1.93 to 29.19, P = 0.004), baseline viral load >10,000 copies per milliliter (HR: 2.90 vs. <1000 copies per milliliter, 95% CI: 1.17 to 7.18, P = 0.021), and an initial dual NRTI plus non-LPV/r, non-ATV/r PI second-line regimen (HR: 3.17 vs. LPV/r or ATV/r plus dual NRTI, 95% CI: 1.65 to 6.06, P = 0.001) were associated with a significantly greater risk of failure. In a sensitivity analysis using only data from patients with baseline viral load available, similar results were observed (data not shown). Patients with <95% adherence during second-line were at a greater risk of failure compared with those with ≥95% adherence, but this association was not significant (univariate HR: 1.61, 95% CI: 0.34 to 7.65, P = 0.551). Similarly, longer time from first-line failure to second-line ART initiation (univariate HR: 0.96, 95% CI: 0.56 to 1.67, P = 0.896 for >18 months vs. <6 months) and baseline CD4 cell count ≤200 cells per cubic millimeter (univariate HR: 1.33 vs. >200 cells/mm3, 95% CI: 0.78 to 2.29, P = 0.296) were not significant predictors of second-line ART failure. Baseline CD4 cell count remained nonsignificant as a replacement for baseline viral load in the final multivariate model (HR: 1.13 vs. >200 cells/mm3, 95% CI: 0.64 to 1.99, P = 0.669).
Both linear trends of increasing failure risk with older age and increasing failure risk with rising baseline viral load were significant (P < 0.001 and P = 0.031, respectively). The absolute risks of failure for patients with baseline viral load <1000 copies per milliliter after 12, 24, and 36 months of second-line ART were 6.3%, 17.1%, and 21.3%, respectively (Fig. 3). For the same time points, Cox model estimates for absolute risk of failure were 13.4%, 34.1%, and 41.2% for those with baseline viral load 1000–10,000 copies per milliliter, and 17.1%, 42.0%, and 50.0% for those with a baseline viral load >10,000 copies per milliliter.
Over 70% of eligible second-line patients used a dual NRTI plus PI regimen. The use of LPV/r or ATV/r was particularly dominant beyond 2006. The rate of mortality was 1.1 deaths per 100 patient/years. The overall rate of second-line treatment failure was 8.8 failures per 100 patient/years; however, the risk of failure was significantly elevated in older patients, those with a viral load >10,000 copies per milliliter at second-line initiation, and those using a PI other than LPV/r or ATV/r.
Compared with other PIs, LPV/r and ATV/r exhibit an equivalent or superior efficacy, better safety, a more convenient dosing schedule, and a higher genetic barrier to resistance.23–26 The current WHO guidelines indicate that LPV/r or ATV/r is the preferred PI to be used in combination with 2 NRTIs after failure on a first-line NNRTI-based regimen.3 The high proportion of first-line NNRTI use and second-line LPV/r and ATV/r use reported in this study indicates good compliance with these guidelines. A reasonable extension of the WHO advice is that second-line ART should comprise 2 NRTIs and an NNRTI where a PI-based regimen was used as first-line therapy. A previous analysis of TAHOD found the common use of PI-based first-line ART in the 90 seconds, and early 2000s has been almost entirely displaced by the regional scale-up of first-line NNRTI-based therapy.27 Therefore, it is not surprising that we found a much higher proportion of patients initiated dual NRTI plus NNRTI as second-line before 2007 (36.2%) compared with those in later time periods (11.6% in 2007–2010, 6.0% after 2010).
Approximately 50,000 of the 1.25 million patients currently on ART in Asia are using a second-line regimen.1,2 Applying the rate of second-line treatment failure and mortality reported here, and assuming 53% of failing patients exhibit triple-class drug resistance,10 an estimated 2040 patients per year will require third-line ART in the region. Our results differ, however, from those of earlier work in resource-limited settings. Pujades-Rodriguez et al9 analyzed data from 632 second-line patients enrolled in Médecins sans Frontiéres cohorts in East Africa, Southern Africa, West/Central Africa, and Asia (Cambodia, Myanmar, Laos). Treatment failure occurred at a rate of 16.1 per 100 patient/years; almost double of what we report here. Thirty-month mortality occurred at a rate of 4.4 deaths per 100 patient/years, 4 times the rate that we report for overall mortality. Importantly, work out of South Africa and Zambia indicates that mortality rates on second-line ART may differ substantially between clinical sites (from 0.65 to 4.52 deaths per 100 patient/years in Wandeler et al28). Rates of immunovirological failure between our cohort and the Médecins sans Frontiéres cohort were the same (5.3 per 100 patient/years). This suggests that the difference in treatment failure rates is entirely due to different rates of clinical failure. Unlike us, Pujades-Rodriguez et al9 did not include death in their definition of clinical failure; thus, the rate of WHO stage 3 and 4 events was much higher in their cohort. Because their data were mostly from resource-limited African countries, this may be representative of regional differences in the occurrence of late stage WHO events and our inclusion of data from several high-income Asian countries.
Pujades-Rodriguez et al9 reported that the most important predictors of treatment failure were a nelfinavir-based second-line regimen, low CD4 cell count at second-line initiation, and poor adherence. Concurrently, we found that an initial second-line regimen based on a PI other than LPV/r or ATV/r was strongly predictive of treatment failure. Ferradini et al6 found that 85.7% of 70 HIV-infected study participants at a center in Phnom Penh had an undetectable viral load after 24 weeks of second-line ART containing LPV/r. Recent evidence from southern Africa also suggests that regimens without tenofovir may impair the durability of second-line ART.28 Baseline CD4 cell count was not associated with failure in our final model; however, another important measure of HIV disease status, baseline viral load, was associated. Despite the widely acknowledged importance of good adherence in maintaining ART efficacy, <95% adherence during second-line ART was not significantly associated with treatment failure in our analysis. This was due to the large number of patients with missing adherence data and the very low rate of poor adherence among those that had data available.
Madec et al29 recently published a systematic review that estimated the incidence of switching to second-line ART in sub-Saharan Africa was 2.65 per 100 patient/years. Comparing this against the regional estimates of 12-month virological failure rate, which range from 5.0% to 24.5%,30–33 it seems that the number of patients who switched to second-line is only a fraction of those in need, even taking into account that a portion of patients may achieve virological suppression with improved adherence to a failing regimen.34 Similarly, in Asia, treatment modification after confirmed failure is frequently subject to delay.35 In a study of 16,591 patients starting ART in sub-Saharan Africa, cumulative mortality at 1 year was 2.2% in patients on a nonfailing first-line regimen, 4.2% in patients who switched from a failing first-line regimen to a second-line regimen, and 11.7% in those who remained on a failing first-line regimen (P < 0.0001).20 Although patients that experienced a delay in second-line initiation in our analysis did not fare worse than those switched within 6 months of first-line failure, we did observe a significant association between high viral load at switch and treatment failure. An explanation for this is that, because HIV rapidly acquires resistance mutations when able to replicate in the presence of ART,11,16–19 a higher viral load at second-line initiation is indicative of added drug resistance. Unfortunately, we did not have sufficient sequencing data to evaluate this further. It is also possible that high viral load at switch was a marker for patients that adhere poorly to ART. Although adherence was not associated with treatment failure in our model, self-report (as is used in TAHOD) is known to overstate adherence36 and >40% of patients did not have any adherence data available.
Our results indicate that it may be important to switch over to second-line ART while the virus remains partially suppressed. A 2009 study by the International Epidemiologic Databases to Evaluate AIDS study group found that switching over to second-line regimens occurred earlier and at higher CD4 cell counts in ART programs with viral load monitoring compared with that in programs without it.37 However, early switching may also lead to quicker exhaustion of treatment options. The WHO recommends appropriate adherence counseling before confirmation of virological failure.3 Supporting this notion, Gupta et al34 recently reported that 27% of Ugandan patients with virological failure (viral load >1000 copies/mL) at week 48 of a trial comparing first-line nevirapine or abacavir with zidovudine and lamivudine achieved resuppression by week 96 without switching. Although suitable for a minority, adherent patients experiencing first-line treatment failure require treatment modification. Simplification of the second-line regimen could help ease the cost of treatment, improve adherence, prevent unnecessary adverse effects, reduce the potential for drug interaction, and preserve future treatment options. In 2012, Bartlett et al8 reported that LPV/r monotherapy achieved virological suppression in 107 of 123 (87%) patients from Asia and Africa who had started the regimen after virological failure on NNRTI-based first-line. Further work comparing the efficacy of LPV/r monotherapy, and other treatment simplification measures, to currently recommended second-line ART, is in progress.38–42
Interpretation of the above results and discussion should take into account several limitations. Many patients lacked data on laboratory testing, adherence, and drug resistance, and median follow-up time was only 2.3 years. Also, definitions of ART failure and second-line ART are inconsistent in practice and in the literature. This limits the comparability of failure and switch rates between different clinical sites and studies. Indeed, TAHOD and TASER-M are multicenter, observational cohorts, and therefore, patient characteristics and patient care were heterogeneous even in our study population. Nevertheless, given the large number of sites involved, and because we have used documented evidence of failure, applied tight criteria to define second-line treatment, and stratified our risk factor analyses by study site, we believe our results are a reasonable reflection of ART use and failure rates in Asia.
Most patients failing first-line ART in Asia are started on a PI-based second-line regimen, consistent with the current WHO guidelines. Increased access to viral load monitoring across the region to facilitate early detection of first-line ART failure and subsequent treatment switch would lead to earlier switches and maximize the durability of second-line therapy. Although second-line ART is highly effective in Asia, the current rate of failure emphasizes the need for third-line ART in a small portion of patients and the likelihood of increasing numbers of such patients in the future.
TAHOD/TASER study members:
A. Kamarulzaman, S.F.S. Omar, S. Vanar, I. Azwa, and L.Y. Ong, University Malaya Medical Center, Kuala Lumpur, Malaysia; B.L.H. Sim and R. David, Hospital Sungai Buloh, Sungai Buloh, Malaysia; C.V. Mean, V. Saphonn, and K. Vohith, National Center for HIV/AIDS, Dermatology and STDs, Phnom Penh, Cambodia; E. Yunihastuti‡, D. Imran, and A. Widhani, Working Group on AIDS Faculty of Medicine, University of Indonesia/Cipto Mangunkusumo Hospital, Jakarta, Indonesia; F.J. Zhang, H.X. Zhao, and N. Han, Beijing Ditan Hospital, Capital Medical University, Beijing, China; J.Y. Choi, S. Na, and J.M. Kim, Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea; M. Mustafa and N. Nordin, Hospital Raja Perempuan Zainab II, Kota Bharu, Malaysia; N. Kumarasamy, S. Saghayam, and C. Ezhilarasi, YRG Centre for AIDS Research and Education, Chennai, India; O.T. Ng, P.L. Lim, L.S. Lee, and M.T. Tan, Tan Tock Seng Hospital, Singapore; P.C.K. Li and M.P. Lee, Queen Elizabeth Hospital and K.H. Wong, Integrated Treatment Centre, Hong Kong, China; P. Kantipong and P. Kambua, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; P. Phanuphak, K. Ruxrungtham, A. Avihingsanon, P. Chusut, and S. Sirivichayakul, HIV-NAT/Thai Red Cross AIDS Research Centre, Bangkok, Thailand; R. Ditangco‡, E. Uy and R. Bantique, Research Institute for Tropical Medicine, Manila, Philippines; R. Kantor, Brown University, Rhode Island, USA; S. Oka, J. Tanuma, and T. Nishijima, National Center for Global Health and Medicine, Tokyo, Japan; S. Pujari, K. Joshi, and A. Makane, Institute of Infectious Diseases, Pune, India; S. Kiertiburanakul†, S. Sungkanuparph, L. Chumla, and N. Sanmeema, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; T.P. Merati†, D.N. Wirawan, and F. Yuliana, Faculty of Medicine, Udayana University and Sanglah Hospital, Bali, Indonesia; R. Chaiwarith, T. Sirisanthana, W. Kotarathititum, and J. Praparattanapan, Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; T.T. Pham, D.D. Cuong, and H.L. Ha, Bach Mai Hospital, Hanoi, Vietnam; V.K. Nguyen, V.H. Bui, and T.T. Cao, National Hospital for Tropical Diseases, Hanoi, Vietnam; W. Ratanasuwan and R. Sriondee, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; W.W. Wong, W.W. Ku, and P.C. Wu, Taipei Veterans General Hospital, Taipei, Taiwan; Y.M.A. Chen and Y.T. Lin, Kaohsiung Medical University, Kaohsiung City, Taiwan; A.H. Sohn, N. Durier, B. Petersen, and T. Singtoroj, TREAT Asia, amfAR—The Foundation for AIDS Research, Bangkok, Thailand; D.A. Cooper, M.G. Law, A. Jiamsakul, and D.C. Boettiger, The Kirby Institute, UNSW Australia, Sydney, Australia. † Current Steering Committee Chairs; ‡ CoChairs.
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