Ungsedhapand, Chaiwat MD*; Srasuebkul, Preeyaporn MSc*; Cardiello, Peter MD, MPH*†; Ruxrungtham, Kiat MD*‡; Ratanasuwan, Winai MD, MPH§; Kroon, Eugene D. M. B. MD*†; Tongtalung, Metta MSc*; Juengprasert, Nittaya MS§; Ubolyam, Sasiwimol MSc*; Siangphoe, Umaporn MSc*; Emery, Sean PhD‖; Lange, Joep M. A. MD, PhD†; Cooper, David A. MD, DSc‖; Phanuphak, Praphan MD, PhD*‡; Behalf of the HIV-NAT 002 and HIV-NAT 003 Study Team
Treatment of HIV infection consisting of at least 3 antiretrovirals, known as highly active antiretroviral therapy (HAART), has dramatically reduced HIV-related morbidity and mortality in developed countries. 1,2 Before HAART became more available in many low- and middle-income countries, including Thailand, the HIV Netherlands Australia Thai-land Research Collaboration (HIV-NAT) was formed to design and conduct clinical trials of HIV treatments in Thailand according to internationally accepted good clinical practice (GCP) standards. 3 HIV-infected patients have been enrolled in a number of randomized clinical trials to determine the efficacy and safety of a variety of regimens and strategies that include antiretroviral and immunotherapeutic treatments.
The current study evaluated the long-term efficacy and safety of dual–versus triple–nucleoside reverse transcriptase inhibitor (NRTI) combinations in antiretroviral treatment–naive HIV-infected patients. It also set out to examine predictive factors of treatment success using the available treatment regimens. Long-term data were available from 2 randomized clinical trials conducted through the HIV-NAT collaboration.
MATERIALS AND METHODS
Patients and Methods
We conducted a retrospective analysis of the original individual patient data from 2 randomized open-label clinical trials of dual- or triple-NRTI combinations in 184 antiretroviral-naive HIV-infected patients with 144 weeks of follow-up.
The HIV-NAT 002 trial began in September 1996. Seventy-eight patients with CD4 counts between 150 and 350 cells/μL were allocated randomly to 1 of the 5 treatment arms of high and low doses of didanosine (ddI) and stavudine (d4T) or ddI alone. The HIV-NAT 003 trial began in July 1997. One hundred six HIV-infected patients with CD4 cell counts between 100 and 500 cells/μL were randomized to receive open-label zidovudine (ZDV), lamivudine (3TC), and ddI or ZDV and 3TC for 48 weeks. Specific details of these studies have been described elsewhere. 4,5
After 48 weeks of study, patients were randomized to either immediate or deferred switching of their antiretroviral regimen. HIV-NAT 002 patients switched from ddI and d4T to ZDV and 3TC. In HIV-NAT 003, patients switched from ZDV and 3TC to ddI and d4T or from ZDV, 3TC, and ddI to d4T, 3TC, and abacavir (ABC), 300 mg, administered twice daily.
Patients considered to represent protocol treatment failures at week 48, defined by a rise of ≥1 log10 HIV-1 RNA above the lowest level achieved on study, were excluded from randomization but switched to new regimens similar to immediate switching.
Patients in the deferred switching group continued their original dual or triple NRTIs and switched to new treatment when their HIV-1 RNA level rose ≥1 log10 above nadir achieved on study or ≥10,000 copies/mL when nadir was <500 copies/mL. Patients in the immediate switch group were able to return to their original dual- or triple-NRTI regimen after 96 weeks of study. In patients failing either dual-NRTI regimen, hydroxyurea (HU), 500 mg, administered twice daily was added to the last failing regimen. As a salvage regimen, d4T, 3TC, ddI, and HU were provided to those patients failing either triple-NRTI regimen.
Plasma HIV-1 RNA Measurement
Plasma HIV-1 RNA was measured using the Quantiplex HIV-1 RNA 2.0 (branched DNA [bDNA]) assay (Chiron Diagnostics Corporation, Emeryville, CA; lower limit of quantification 500 copies/mL) throughout the first 96 weeks of the HIV-NAT 002 cohort and the first 48 weeks of the HIV-NAT 003 cohort. Thereafter, assessment of plasma HIV-1 RNA was made using the Quantiplex HIV-1 RNA 3.0 (bDNA) assay, with a lower limit of quantification of 50 copies/mL.
The absolute number and percentage of peripheral blood CD4+ and CD8+ lymphocytes were enumerated using flow cytometry (FACSort and FACScan; BD Immunocytometry Systems, San Jose, CA).
For the purposes of this combined analysis, plasma HIV-1 RNA results were transformed to log10 copies/mL. Baseline was defined as the time of beginning the treatment. This was week 0 for both the HIV-NAT 002 and 003 cohorts. Analyses compared all patients receiving dual-NRTI combinations with those receiving triple-NRTI combinations and were based on an intention-to-treat (ITT) analysis, in which the plasma HIV-1 RNA of patients who dropped out was assumed to be more than the limit of quantification and the other last laboratory values were carried forward after the date of dropout. Responders were defined as patients who achieved <50 copies/mL of HIV-1 RNA at 144 weeks of study.
All analyses were performed using Statistical Product and Service Solutions (SPSS) for Windows software, version 9.0 (SPSS Inc., Chicago, IL). Comparisons between treatment groups for the percentage of patients with HIV-1 RNA <50 copies/mL at week 144, adverse events, and HIV-related events were tested by χ2 analysis. Differences between treatment groups in change from baseline CD4 cell count were adjusted and tested by the Mann-Whitney U test.
Univariate analyses and multivariate logistic regression were used to identify predictors of treatment success, defined as a plasma HIV-1 RNA value <50 copies/mL at week 144. The variables included HIV-1 RNA <50 copies/mL at week 144 as the dependent variable and HIV-1 RNA at baseline (≤10,000 copies/mL, >10,000 copies/mL; ≤20,000 copies/mL, >20,000 copies/mL; ≤30,000 copies/mL, >30,000 copies/mL; and ≤50,000 copies/mL, >50,000 copies/mL), CD4 cell count at baseline (≤350 cells/μL, >350 cells/μL), study protocol (HIV-NAT 002, HIV-NAT 003), therapy (dual NRTIs, triple NRTIs), Centers for Disease Control and Prevention (CDC) clinical category (category A, category B/C), switch strategy (immediate switching, deferred switching), and viral load responses (≤500 copies/mL, >500 copies/mL) at weeks 4 and 12 as independent variables. In the multivariate logistic regression model, study protocols were entered in the model to correct for baseline differences, and other variables with a P value <0.05 in the univariate analysis were entered in the model by using a stepwise selection procedure. The best cutoff point of HIV-1 RNA at baseline as a predictor in the multivariate logistic model was considered from the fit between the outcomes predicted by that model and that observed in the dataset. The goodness-of-fit of all logistic regression models was assessed by the Hosmer-Lemershow test, where P > 0.1 indicates an agreeable model fit.
Time to viral load suppression (TTS) was defined as the time from onset of treatment until the first of 2 consecutive HIV viral loads suppressed to <500 copies/mL. If the final measurement for a patient was >500 copies/mL and the patient had not previously demonstrated a response, TTS was defined as 144 weeks. Time to treatment failure (TTF) was defined as the time from treatment initiation to the time of loss of virologic response (2 consecutive HIV-1 RNA measurements >500 copies/mL preceded by any measurement <500 copies/mL and never followed by 2 consecutive visits showing suppressible viremia to below 500 copies/mL; the date of the first measurement was taken as the date of failure) or discontinuation from the study for any reason. Patients who never achieved a TTS were considered to have had a TTF at day 0. If a patient achieved a TTS and did not subsequently fail, TTF was defined as the time at that patient's last viral load date. Duration of response (DUR) was defined as the time from onset of viral load suppression (<500 copies/mL) to the time of TTF. TTS, TTF, and DUR were analyzed by the log-rank test. Observations were censored at the last follow-up visit (week 144).
In total, 131 patients received dual-NRTI therapy (78 from the HIV-NAT 002 cohort and 53 from the HIV-NAT 003 cohort) and 53 patients (from the HIV-NAT 003 cohort) received triple-NRTI therapy (Fig. 1). Baseline clinical and demographic characteristics are summarized in Table 1. Patients in the dual-NRTI group had lower CD4 cell counts than patients in the triple-NRTI group (P = 0.014). Both treatment groups had similar distributions with respect to gender, age, HIV risk factors, plasma HIV-1 RNA, and CDC clinical category.
Reported adverse events were in keeping with published data for the drugs used in this study. A total of 18 laboratory events classified as grade 3 or 4 occurred during the study, mostly in the first year of treatment. Most of these grade 3 or 4 laboratory events were raised liver enzymes (5 of 53 triple-NRTI patients and 2 of 131 dual-NRTIs patients; P = 0.022). More diarrhea was reported in the triple-NRTI group (5 of 53 triple-NRTI patients and 3 of 131 dual-NRTI patients; P = 0.045). Clinical lipodystrophy was detected in 9 patients (4.9% of patients; 6 of 53 triple-NRTI patients and 3 of 131 dual-NRTI patients; P = 0.018). Other adverse events in both groups were comparable. Headache was the only adverse event judged by the investigators to have a possible, probable, or definite relation to the study drugs as observed in more than 10% of patients (11.41%; 5 of 53 triple-NRTI patients and 16 of 131 dual-NRTI patients; P = 0.625). Three patients (1 of 53 triple-NRTI patients and 2 of 131 dual-NRTI patients) developed clinical hepatitis possibly related to the antiretroviral treatment. One patient in the dual-NRTI group was hospitalized for acute pancreatitis. An ABC hypersensitivity reaction was reported in only 1 of 28 patients who received ABC.
HIV Disease Progression and Death
Nine (4.9%) patients developed a CDC clinical category C (AIDS-defining) event over 144 weeks. The distribution of these events between the triple-NRTI (1 case of tuberculosis and 1 case of esophageal candidiasis) and dual-NRTI (5 cases of tuberculosis and 2 cases of HIV wasting syndrome) groups was not statistically significant (P = 0.732).
A death from respiratory failure after an uncharacterized lung infection occurred in another hospital in a patient from the triple-NRTI group. In the dual-NRTI group, 1 patient died of complications (acute renal failure with acute respiratory distress syndrome) of malaria infection and 1 from possible Pneumocystis carinii pneumonia in another hospital.
CD4 Cell Count
The CD4 cell count increased over time, with a median gain of 96, 126, and 83 cells/μL in the triple-NRTI group and a median gain of 85, 85, and 57 cells/μL in the dual-NRTI group at 48, 96, and 144 weeks of follow-up, respectively (Fig. 2B). Analysis of median absolute CD4 count at 144 weeks of treatment showed a superior response in the triple-NRTI group, with 388 (interquartile range [IQR]: 325–502) and 346 (IQR: 245–448) CD4 cells/μL in the triple- and dual-NRTI groups, respectively (P = 0.018; see Fig. 2A).
The proportions of patients with poor CD4 responses at 144 weeks (CD4 cell count increased <50 cells/μL from baseline) 6 were 41.5% versus 48.1% in the triple- and dual-NRTI groups, respectively (P = 0.517).
Plasma HIV-1 RNA
The proportions of patients with a plasma HIV-1 RNA level <500 copies/mL at weeks 0 through 96 and <50 copies/mL at weeks 108 through 144 are shown in Figure 2C. At 144 weeks of treatment, 32 of 53 patients (60.4%) in the triple-NRTI group versus 24 of 131 patients (18.3%) in the dual-NRTI group reached an HIV-1 RNA level <50 copies/mL (odds ratio [OR] = 6.79; 95% confidence interval [CI]: 3.35–13.77; P < 0.01). Log10 HIV-1 RNA copies/mL at week 144 were 1.70 (IQR: 1.70–2.55) and 2.79 (IQR: 1.87–3.50) in the triple- and dual-NRTI groups, respectively (P < 0.01).
Duration of Virologic Suppression
Figure 3A shows Kaplan-Meier product-limit estimates of the time from the onset of treatment to reach 2 consecutive HIV-1 RNA levels <500 copies/mL (TTS). Median time was 4 weeks (IQR: 4–12 weeks) and 4 weeks (IQR: 4–16 weeks) in the triple- and dual-NRTI groups, respectively (P = 0.6705). The TTF shown in Figure 3B for the triple-NRTI group (median = 144 weeks, IQR: 144–144 weeks) was significantly longer than that for the dual-NRTI group (median = 108 weeks, IQR: 36–144 weeks; P = 0.0001). The DUR in the triple-NRTI group (median = 144 weeks, IQR: 128–144 weeks) was also significantly longer than that in the dual-NRTI group (median = 104 weeks, IQR: 28–144 weeks; P = 0.0002; see Fig. 3C).
Predictors of Treatment Success
Table 2 shows the result of univariate logistic regression predictors of plasma HIV-1 RNA <50 copies/mL at 144 weeks of treatment. In multivariate analyses, all 4 cutoff points of baseline HIV-1 RNA of ≤50,000, ≤30,000, ≤20,000, and ≤10,000 copies/mL are significantly associated with treatment success at week 144. The model that best fits the data in the multivariate logistic regression predictors of an HIV-1 RNA level <50 copies/mL at week 144 includes an HIV-1 RNA level ≤30,000 copies/mL at baseline (OR = 2.9, 95% CI: 1.2–7.4; P = 0.0214), triple-NRTI therapy (OR = 14.5, 95% CI: 5.0–41.8; P < 0.001), CDC clinical category A (OR = 3.0, 95% CI: 1.2–7.5; P = 0.0160), and attainment of an HIV-1 RNA level <500 copies/mL in plasma at week 12 (OR = 3.9, 95% CI: 1.2–12.8; P = 0.0228). The Hosmer-Lemeshow goodness-of-fit statistic for this model was 1.97 (df = 8; P = 0.9818), whereas the Hosmer-Lemeshow χ2 results of the other 3 models that include baseline HIV-1 RNA levels ≤50,000, ≤20,000, and ≤10,000 copies/mL were 5.17 (df = 8; P = 0.7391), 3.90 (df = 8; P = 0.8663), and 5.13 (df = 7; P = 0.6443), respectively.
Developing countries have numerous competing priorities for managing their HIV epidemic and inadequate resources to treat all HIV-infected patients. The main priority is to treat symptomatic AIDS patients and maximize the use of accessible and affordable treatment regimens. More research is needed to answer strategic questions of when to start HIV treatment and with what treatment regimen in developing countries.
The use of 2 NRTI combinations alone is not recommended in current guidelines. 7 To spare protease inhibitor (PI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) drugs, maximize adherence, and reduce toxicities associated with PI therapy, an ABC-containing triple-NRTI combination is recommended as an alternative initial regimen. 7 High rates of early virologic failure have recently been observed in clinical studies of the once-daily triple-nucleoside/nucleotide regimen containing ABC, 3TC, and tenofovir disoproxil fumarate (TDF) in antiretroviral-naive patients, however. 8,9
This study demonstrated that among antiretroviral-naive patients with HIV infection, treatment with triple-NRTI combinations was superior to treatment with dual-NRTI combinations in reducing HIV-1 RNA load. The proportions of triple-and dual-NRTI therapy patients who reached <50 copies/mL at 144 weeks were 60% and 18%, respectively. The observed virologic success of triple-NRTI therapy compares favorably with other HAART in treatment-naive patients studied in several long-term 3-year follow-ups of clinical trial and observational cohorts. 10–12
Several studies have evaluated antiretroviral treatment on the basis of the duration of viral suppression. 13–16 Despite no difference in the median time to viral suppression <500 copies/mL (TTS) in either group, triple-NRTI therapy had a significantly longer TTF and more durable virologic response (DUR) compared with dual-NRTI therapy. The TTF and DUR in our study do not solely reflect the effect of initial treatment regimens but are influenced by the switching of treatment and the statistical method to censor data at 144 weeks.
The dual- and triple-NRTI regimens used in this study were generally well tolerated with few severe treatment-limiting clinical or laboratory adverse events. The addition of HU to the failing dual-NRTI (n = 10) and triple-NRTI (n = 3) regimens seemed safe but did not improve the durability of HIV-1 RNA and CD4 count responses (data not shown). Consequently, HU was withdrawn from the protocol after week 144.
In the pre-HAART era, plasma viral load and CD4 count before therapy predicted the likelihood of developing AIDS-related illnesses and death in patients who received no treatment or NRTI therapy. 17 In our study of NRTI-only regimens in patients with relatively low baseline plasma HIV-1 RNA levels (median = 4.1 log10 copies/mL) and moderate immunodeficiency (lower quartile, CD4 count >200 cells/μL), few clinical HIV disease progression and death outcomes were observed.
Several factors are known to contribute to successful virologic treatment outcomes. 18 In patients receiving NRTI-only regimens, the likelihood of achieving an undetectable viral load is associated with low baseline viral load, high baseline CD4 count, and being naive to NRTIs. 19–22 Results of the present study suggest that the likelihood of 3-year viral load suppression to undetectable levels was greater in those who were asymptomatic, in those receiving triple NRTI therapy, in those with a baseline viral load ≤30,000 copies/mL, and in those who attained a viral load of <500 copies/mL at week 12 of treatment. Contrasting with previous observations in the Delta Trial 23 and a meta-analysis study of HAART, 24 the relation between virologic outcome and baseline CD4 count in our study is less apparent. A high baseline CD4 count >350 cells/μL is not independently predictive of virologic success.
A limitation of the analysis presented here is the pooling of data from 2 separate clinical trials. The conduct of these 2 studies was largely identical, except for the 2 different versions of a bDNA HIV-1 RNA assay (with lower limits of detection of <500 copies/mL and <50 copies/mL) used to monitor virologic responses. Another limitation of the study is that during the first year of treatment, standard d4T and ddI doses were not used in recipients in the dual-NRTI group. A further limitation to the findings of this study may be that triple-NRTI therapy recipients were able to access ABC therapy on failure, whereas this was not available to patients failing any of the dual-NRTI regimens in this study. This study was essentially an assessment of treatment strategy (2 NRTIs vs. 3 NRTIs), and the provision of an ABC regimen to failing triple-NRTI therapy recipients is consistent with that strategic approach.
The success of a “rescue” ABC-containing regimen after virologic failure was demonstrated in 3 of 9 patients who received d4T, 3TC, and ABC and achieved a viral load <50 copies/mL at week 144 (2 of 7 patients who changed regimens at week 48 for virologic failure before week 48 and 1 of 2 deferred switchers who changed regimens at week 72 for virologic failure).
The long-term efficacy results of triple-NRTI therapy in this study extend those of the earlier 48-week study 5 and may be partly influenced by the switching strategy. At 48 weeks, the proportion of patients treated with ZDV, 3TC, and ddI who attained a plasma HIV-1 RNA level <50 copies/mL was 54.7% (29 of 53 patients, ITT population). At 144 weeks, continued viral suppression was maintained in 60.4% (32 of 53 patients, ITT population). This degree of HIV-1 suppression was similar in the group of patients who continued ZDV, 3TC, and DDI (continued treatment group, 13 of 20 [65%] patients) and those who changed to d4T, 3TC, and ABC (changing treatment group, 19 of 27 [70.4%] patients) after week 48 (P = 0.7583, on-treatment population [excluding 1 patient who was lost to follow-up in the continued treatment group, 1 patient who died in the changing treatment group, and 4 patients who discontinued before week 48]). The changing treatment group had more statistically significant changes in viral load from baseline (week 48, when switching randomization occurred) than the continued treatment group (median = 0, IQR: −1.44 to 0 vs. median = 0, IQR: 0–0.89 log10 HIV-1 RNA copies/mL in the changing treatment group and continued treatment group, respectively; P = 0.0008, on-treatment population).
Our data suggest that triple- and dual-NRTI therapy may benefit some patients. We observed a stable disease course characterized by absence of HIV disease progression, low viremia, and a maintained CD4 count similar to those of previous reports. 25,26 Many of these patients may continue their NRTI alone–based therapy, maintaining durable viral suppression to <50 copies/mL with stable CD4 responses as demonstrated in dual- or triple-NRTI–experienced patients in the ACTG 364 study. 27
Nevertheless, we do not ascribe this beneficial outcome to superior HAART regimens. Rather, we believe that this outcome supports a policy for the use of antiretroviral therapy based on HAART regimens. Much of the virologic failure observed in this study can be attributed to the suboptimal use of antiretroviral agents. The tendency of HIV to generate drug-resistant mutations may remain the major factor limiting the response to antiretroviral therapy. Suboptimal antiretroviral therapy with incomplete suppression of viral replication leads to the accumulation of resistant and cross-resistant mutations, which, in turn, decreases the genetic barrier for the subsequent drug regimens. 28 In resource-limited settings, the use of suboptimal antiretroviral therapy on a population basis in Thailand has shown a substantial survival benefit 29 in the cost of increased prevalence of NRTI mutations 30 and may result in the transmission of drug-resistant virus. In the absence of drug resistance screening, this may damage the effectiveness of antiretroviral drug provision programs.
In conclusion, triple-NRTI therapy with ZDV, 3TC, and ddI or d4T, 3TC, and ABC in antiretroviral-naive HIV-infected patients is more effective in inducing a sustained virologic response to at least 144 weeks than the dual-NRTI combinations of ZDV, 3TC or ddI, and d4T.
The authors thank Apicha Mahanontharit, Areerat Sonjai, Chayanout Thitivorn, Chokechai Rongkavilit, Chris Duncombe, Jettanong Klaewsongkram, Jintanat Ananworanich, Mark Boyd, Mark Newell, Nongluk Yimsuan, Pannipa Chulasugandha, Somsong Teeratakulpisarn, Suchada Manothaya, Sunee Sirivichayakul, Supranee Buranapraditkun, Surapee Tiengrim, Tanaporn Yangyuantaworn, Tarika Samor, Theeradej Boonmangum, Theshinee Chuenyam, Titipak Sae Pae, Wandee Yiemwanichnan, Wassana Worarien, and Wichai Thechasathit, who assisted in the clinical study; Anja Schreijer, David Young, Jacqueline Tromp, Johan Schuijtemaker, Karlijn van der Vliet, Maarten Scholing, Oddeke van Ruler, Philip Law, Radjin Steingrover, Sanne van der Zwan, Xander Eyssen, and Yiyi Chen, who monitored the database; Gerrit-Jan Weverling, who wrote the randomization program and, with Elly Hassink, Gerben-Rienk Visser, Mana Khongphattanayothin, Matthew Law, Nadine Pakker, and Remko van Leeuwen, advised on statistical design, analysis, and interpretation of data; Piyalamporn Havanond, Scott Hammer, and Surapol Suwanagool, who were members of the HIV-NAT 002 week 24 interim analysis Data and Safety Monitoring Board; Chris Duncombe, who reviewed the manuscript; and Chaiyos Kunanusont, Dorothy Bray, Jean-Marc Steens, Martin Gartland, Niwat Montreewasuwat, Praradchaya Pasook, Sunettra Chinnapha, Suthichai Chokekijchai, Wipaporn Rungsiyapornrat, Urampa Kattinanond, and Wiput Phoolcharoen, who facilitated the study.
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