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New Nucleoside/Nucleotide Backbone Options: A Review of Recent Studies
  Part IV
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 37 Supplement 1 1 September 2004
Ruane, Peter J MB, MRCPI*; DeJesus, Edwin MD, FACP†
*Private practice, West Hollywood, CA, and †Infectious Disease Consultants Research Initiative, Altamonte Springs, FL.
The nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI) class continues to serve as an important component of the standard of care for HIV infection. Combinations of dual NRTIs/NtRTIs with protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most commonly used regimens in clinical practice. In recent years, clinical outcomes data on previously novel NRTI/NtRTI backbone combinations have provided clinicians with new options to address potency, tolerability, and convenience of antiretroviral therapy. However, the tolerability, drug-drug interactions, and resistance profiles of specific regimens using new NRTI/NtRTI combinations must be weighed against the needs and preferences of individual patients. This review summarizes recent efficacy and safety data on emerging NRTI/NtRTI combination backbones, including tenofovir DF (TDF) with lamivudine (3TC), abacavir with 3TC, didanosine (ddI) with 3TC, ddI with emtricitabine (FTC), and TDF with FTC.
The nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI) class has always been the cornerstone of anti-HIV therapy. NRTI monotherapy and dual therapy provided the standard of care for HIV infection until the mid-1990s. Today, NRTIs/NtRTIs serve as the backbone of combination antiretroviral therapy (ART) regimens, which usually consist of 2 NRTIs/NtRTIs with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI), or in some circumstances a triple-nucleoside combination. Currently 7 NRTIs, 1 NtRTI, and 2 NRTI coformulations are licensed in the United States (Table 1). In patients with no previous HIV therapy experience, the Department of Health and Human Services (DHHS) treatment guidelines recommend as preferred regimens lamivudine (3TC) + either zidovudine (ZDV), stavudine (d4T), or tenofovir DF (TDF) + efavirenz (EFV), or 3TC in combination with ZDV or d4T + lopinavir/ritonavir (LPV/r). Other dual-NRTI options, including abacavir (ABC) + 3TC, didanosine (ddI) + 3TC, and combinations that include emtricitabine (FTC) instead of 3TC, are classified as alternative NRTI backbones.
With the exception of ZDV and zalcitabine (ddC),all Food and Drug Administration (FDA)-approved NRTIs/NtRTIs have formulations that allow them to be administered once daily, creating the opportunity for less complex NRTI backbones. Once-daily coformulations of ABC/3TC and TDF/FTC are in advanced stages of development.
Although treatment guidelines for NRTIs/NtRTIs are based on the overall record of clinical safety and efficacy, in clinical practice each regimen should be tailored to the individual patient's requirements. Selection of the best available NRTI/NtRTI backbone for a particular patient requires consideration of potency, toxicity, pill burden, dosing frequency, resistance profiles, pregnancy, drug use, concomitant illnesses and medications, individual patient preferences, and any other patient-specific concerns. The characteristics of newer NRTI/NtRTI agents and combinations should be considered in weighing the relative strengths and weaknesses of these backbone combinations. This review summarizes recent studies of new NRTI/NtRTI backbone options and provides information as to their potential role in initial HIV therapy or after first-regimen failure.
The combination of TDF and 3TC allows convenient, once-daily dosing. A double-blind, randomized, active-controlled clinical trial compared the efficacy and safety of TDF + 3TC with d4T + 3TC, each in combination with EFV. Study 903 included 600 treatment-naive patients with a mean CD4 count of approximately 280 cells/mm3 and mean HIV plasma RNA levels of 81,300 copies/mL (c/mL). Approximately 6% of the patients were unable to tolerate EFV and switched to nevirapine (NVP) during the study. In the first 16-32 weeks, virologic suppression rates remained similar and stable in both arms, measured by 50- and 400-c/mL HIV RNA assays.3 In an intent-to-treat (ITT) analysis at week 144, the proportion of patients with HIV-RNA <400 c/mL and <50 c/mL, respectively, were 76 and 73% for the TDF + 3TC group and 72 and 69% for the d4T + 3TC group. These results may be explained by the simplicity, tolerability, and potency of the regimens. At week 144, 18 and 21% in the TDF + 3TC and d4T + 3TC arms, respectively, had discontinued for any reason. Investigator-defined lipodystrophy developed in 3% of those on TDF vs. 19% of those on d4T. A significantly greater percentage of patients receiving d4T experienced high triglyceride levels than those receiving TDF.3 The mean increase in triglycerides was 134 mg/dL in the d4T + 3TC arm and 1 mg/dL in the TDF + 3TC arm (P < 0.001). Bone mineral density decreased in both arms, but the decrease was <3% in both arms and nonprogressive. The K65R mutation appeared in 8 patients (2.7% of those treated with TDF) in the TDF + 3TC arm by week 96, and no additional cases of this mutation were observed through week 144. All patients with K65R also had NNRTI resistance mutations, with or without M184V.
A small, prospective, open-label study of TDF + 3TC + ddI in 24 antiretroviral-naive patients was terminated early because of high rates of virologic failure (91% of patients at 12 weeks); resistance testing of 21 patients demonstrated M184V/I in 20, 10 of whom also had K65R.5 These results provide further evidence that nonthymidine analogue-containing triple-NRTI regimens should not be used alone, presumably because of their low genetic barrier to resistance.
The combination of ABC and 3TC has been shown to be a potent NRTI backbone in studies with a PI, an NNRTI, or another NRTI (ZDV or d4T). There are no food requirements for ABC or 3TC. Once-daily administration of 3TC is approved, and although once-daily dosing of ABC awaits FDA approval, pharmacokinetic data support once- and twice-daily dosing of ABC, which were equally effective in one study.
Two randomized open-label clinical trials in treatment-naive patients demonstrated the efficacy and safety of twice-daily ABC + twice-daily 3TC as a backbone in combination with fosamprenavir (FPV). In the NEAT (APV 30001) study, 249 antiretroviral-naive patients were randomly assigned to receive FPV or nelfinavir (NFV). A total of 46% had baseline viral loads >100,000 c/mL. In the ITT analysis (rebound or discontinuation = failure [RD = F]) at week 48, 66% of those randomly assigned to FPV and 51% of patients in the NFV group achieved viral suppression to an HIV plasma level of <400 c/mL. A total of 14 and 28% of patients experienced virologic failure in the FPV and NFV groups, respectively. Using the same analysis, the proportion of patients with HIV RNA <50 c/mL was 55% for FPV and 41% for NFV. The occurrence of drug-related adverse events of at least moderate severity was similar in both arms, with the exception of diarrhea, which occurred in 18% of patients in the NFV arm vs. 5% of those in the FPV arm (P = 0.002). Hypersensitivity to ABC was reported in 9 and 5% of patients on FPV and NFV, respectively. This difference was not statistically significant. The higher percentage of rash in the FPV arm (7 vs. 2%) may indicate that some of the hypersensitivity reactions in the FPV arm were misdiagnosed.
n the SOLO (APV 3002) study, once-daily ritonavir (RTV)-boosted FPV (FPV/r) was compared with twice-daily NFV in a similar cohort of 660 patients.9 As in the NEAT study, >40% of those in the SOLO study had baseline viral loads >100,000 c/mL. At 48 weeks, 69% of patients receiving FPV/r and 68% of those receiving NFV had plasma HIV levels <400 c/mL (ITT, RD = F). Fifty-eight percent of patients receiving FPV/r and 55% of patients receiving NFV had viral suppression to <50 c/mL (ITT, RD = F). Reports of drug-related adverse events of at least moderate severity in the FPV/r and NFV arms, respectively, included diarrhea in 9 and 16% (P = 0.008), hypersensitivity to ABC in 7 and 6%, and rash in 2% of patients in each arm.
The ABC + 3TC twice-daily backbone regimen in SOLO and NEAT was well tolerated. Within the combined patient populations of NEAT and SOLO taking ABC (n = 898), ABC-specific reverse transcriptase (RT) mutations were rare, with 5/898 (<1%) exhibiting K65R or L74V. The selection of M184 I/V was significantly less frequent in the group receiving FPV/r compared with the group receiving NFV in SOLO (13 vs. 56%, P < 0.001).
The CLASS trial (ESS40001) was a 96-week randomized, open-label study in which 291 treatment-naive patients were randomly assigned to receive ABC/3TC in combination with EFV, boosted amprenavir (APV/r), or d4T. In the 48-week analysis (ITT, missing = failure [M = F]), treatment with the EFV combination resulted in suppression of HIV RNA to <50 c/mL in 78% of patients compared with 62 and 61% for the PI and NRTI arms, respectively (overall P = 0.047). The overall frequency of adverse events was comparable among the 3 study groups, and ABC-related hypersensitivity was reported in 6-8% of patients. Genotypes of isolates from 33/47 patients with virologic failure revealed the following ABC/3TC-related mutations: 1 patient with K65R, 1 patient with L74V, 2 patients with Y115F, and 11 patients with M184V.
CNA30024 was designed as a randomized, double-blind study to determine noninferiority of ABC + 3TC + EFV compared with ZDV + 3TC + EFV in 649 patients.13 At 48 weeks, 70% of patients receiving the ABC/3TC backbone achieved plasma viral levels <50 c/mL, compared with 69% of those randomly allocated to 3TC/ZDV (ITT = exposed). The proportion of patients with virologic response was also comparable between the 2 study arms in patients with baseline HIV RNA levels >100,000 c/mL. Notably, there was a significantly greater CD4 count gain in patients randomly assigned to the ABC-containing backbone. This difference could not be explained by ZDV-associated hematologic toxicity, as there was a similar percentage difference in CD4 increase between the 2 arms. The frequency of the most common adverse events, including rash, was similar in the 2 groups.
Once-daily ABC and 3TC
Two studies have shown once-daily ABC combined with once- or twice-daily 3TC to be virologically potent and well tolerated in combination with EFV. In an open-label trial (ESS30009), 95% of treatment-naive patients randomly assigned to receive the once-daily fixed-dose coformulation of ABC/3TC in combination with EFV achieved viral suppression to <50 c/mL at 16 weeks. In contrast, only 29% of patients randomly assigned to receive ABC/3TC with TDF reached <50 c/mL at week 16. The reason for the poor response to the triple-NRTI regimen is unclear, although the most likely explanation appears to be the low genetic barrier to resistance. All 3 studies that have included this regimen have shown a high rate of selection of M184V and K65R. Available data, though incomplete, show no evidence of plasma or intracellular interactions between these drugs. TDF should not be used in a triple regimen with ABC/3TC, but the potency of TDF + ABC + 3TC in regimens containing a PI, an NNRTI, or a 4th NRTI is not yet established. An interim safety analysis from one small study (COL40263) provides initial support for the concept that ZDV in combination with TDF, 3TC, and ABC may improve virologic outcomes and provide protection against the emergence of the K65R mutation in treatment failure. In this single-arm study, a once-daily quadruple-NRTI regimen of ABC/3TC/ZDV + TDF was given to a population of 88 patients with advanced HIV infection, 59% of whom had baseline viral loads >100,000 c/mL and 37% of whom had baseline CD4 counts <200 cell/uL. At week 24, viral loads were <400 c/mL in 74% of patients and <50 c/mL in 60%. Genotypic data from 8 patients revealed that 1 patient had the K65R mutation, 2 had wild-type virus, and 5 had at least 1 TAM. However, it cannot be determined from this uncontrolled trial whether these results are better or worse than what would have been seen with ABC/3TC/ZDV alone.
In the Ziagen Once Daily in Antiretroviral Combination Therapy (ZODIAC) study (CNA30021), 770 treatment-naive patients received EFV and were randomly assigned to once- or twice-daily ABC as part of an ABC/3TC backbone. The virologic response of a once-daily ABC-containing regimen was found to be noninferior to the twice-daily regimen, with 66 and 68% of patients achieving viral loads <50 c/mL, respectively (Fig. 4). Virologic failure occurred in 10% of those on once-daily ABC and 8% of those on twice-daily ABC. Low viral loads in patients with virologic failure prevented genotypic or phenotypic analysis of most on-therapy samples. Genotypes were obtained for 16 patients on once-daily ABC and 15 on twice-daily ABC. There were no significant differences between the study arms in number of patients with treatment-emergent resistance to any drug; the most common NRTI resistance mutations seen were M184V (48.4%) and L74V (25.8%). Other mutations were rare: K65R was seen in 1 patient, and Y115F and TAMs were each seen in 1 patient in each study arm. Treatment-emergent mutations were similar in the once- and twice-daily ABC groups. Eleven of 16 genotyped patients (69%) in the once-daily ABC arm and 5/15 (33%) in the twice-daily arm had the M184V mutation. Nine patients in each arm had EFV-associated mutations.
ddI and 3TC
The combination of ddI and 3TC has been studied as a possible backbone option. A randomized, open-label, single-center trial conducted in 102 antiretroviral-naive patients with advanced HIV infection compared 3 ART regimens: once-daily ddI + 3TC + EFV, twice-daily 3TC/ZDV + once-daily EFV, or twice-daily 3TC/ZDV + NFV. The EFV-containing regimens resulted in better virologic outcomes than the NFV-based therapy, regardless of whether the backbone was administered once daily or twice daily. At 52 weeks, the proportions of patients achieving virologic suppression to <50 c/mL were 74% for ddI + 3TC + EFV and 3TC/ZDV + EFV, and 50% for 3TC/ZDV + NFV (ITT, M = F; P = 0.02).
Three studies demonstrated the efficacy of a once-daily ddI + 3TC NRTI backbone in combination with EFV. One study was an 18-month trial of 40 treatment-naive patients with advanced HIV infection in Senegal. At month 15, 69% of patients had plasma HIV RNA <50 c/mL and a mean increase in CD4 count of 199 cells/mm3. The second study was a 48-week pilot study of 75 treatment-naive patients with advanced HIV infection. In these patients, treatment with ddI + 3TC + EFV resulted in a substantial immunologic improvement. An HIV RNA of <50 c/mL was achieved in 77% of patients at week 48 (ITT analysis). Another open-label phase 4 study examined once-daily ddI + 3TC + EFV in 52 treatment-naive patients. At 24 weeks, 81% of patients had viral loads <50 c/mL by ITT (noncompleter = failure [NC = F]) analysis. The mean viral load decreased from 4.8 log10 c/mL at baseline to 1.7 log10 c/mL at 24 weeks, accompanied by a rise in CD4 count from 308 cells/mm3 to 498 cells/mm3.
ddI + FTC
When given in combination with EFV, a once-daily backbone regimen of ddI + FTC compared favorably with ddI + d4T in 571 treatment-naive patients. The trial was prematurely unblinded owing to greater virologic response in the FTC arm. Seventy-six percent of patients randomly assigned to ddI + FTC + EFV achieved HIV RNA levels <50 c/mL, compared with 54% of those receiving ddI + d4T + EFV. A greater proportion of patients receiving ddI + d4T + EFV discontinued owing to adverse events (17 vs. 7%). A once-daily regimen of ddI + d4T + EFV is attractive for its simplicity, but this combination is limited by treatment-emergent toxicity, including peripheral neuropathy. Although d4T has been approved in a once-daily formulation, it is not currently commercially available. The combination of ddI and d4T is not as well tolerated as other NRTI/NtRTI combinations. DHHS guidelines classify this NRTI combination as one that should be avoided because of the higher risk of peripheral neuropathy, pancreatitis, and hyperlactatemia.
A once-daily coformulation of TDF and FTC is being investigated in clinical trials. Currently, there are limited clinical data on this combination. In a pilot study of a once-daily PI-based regimen, 190 ART-naive patients receiving a backbone of TDF and FTC were randomly assigned to receive LPV/r once or twice daily. At week 48, 70% of patients in the once-daily PI group achieved viral loads <50 c/mL, compared with 64% of patients in the twice-daily PI group (ITT, NC = F). The most frequent adverse event was diarrhea, which occurred significantly more often in patients in the once-daily PI group compared with the twice-daily PI group (16 vs. 5%, P = 0.04). Although significant increases in total cholesterol and triglycerides were seen in all treatment groups, the increases were less than those seen in a separate study in which a similar cohort of patients received LPV/r with a backbone of d4T + 3TC.26 LPV/r increases the area under the curve (AUC) of TDF by 34%. In this study, acute renal failure was observed in 1 patient from each treatment arm and resolved upon drug discontinuation. One of these patients had a baseline creatinine clearance of 40 mL/min, but the TDF dose was not adjusted, as is now recommended.
ABC/3TC/ZDV-Based Quadruple Therapy TOP
Studies are ongoing to determine whether initial ART with a quadruple-drug regimen provides additional benefit for certain patient types. There is particular interest in the potential benefit of this strategy in patients with high baseline viral loads or low CD4 cell counts, advanced disease or AIDS-defining illness, and those who may have been infected with drug-resistant strains of HIV. ACTG 5095, an ongoing, randomized, placebo-controlled, double-blind trial, is comparing ABC/3TC/ZDV + EFV with 3TC/ZDV + EFV in treatment-naive patients. A third arm, ABC/3TC/ZDV, was discontinued due to an inferior response vs. each of the EFV-containing arms, although only pooled data have been reported on the EFV-containing arms. At baseline, 1148 patients were stratified into groups with viral loads above or below 100,000 c/mL. Forty-three percent of patients had baseline viral loads >100,000 c/mL. Virologic failure was defined as a confirmed viral load >200 c/mL at >=16 weeks on therapy. After a median follow-up of 32 weeks, 10% of patients experienced virologic failure in the pooled EFV arms. The EFV-containing arms were reported to be superior to the triple-nucleoside arm in both baseline viral load strata.
Three open-label, single-arm, 48-week studies have examined the combination of ABC, 3TC, ZDV, and EFV in initial therapy. In the first study, which included 31 patients, the median baseline viral load was 4.69 log10 c/mL, and the median baseline CD4 count was 322 cells/mm3. An ITT (switch = failure) analysis indicated that 77% had viral loads <50 c/mL on EFV, ABC, and 3TC/ZDV at week 48.28 The second study, which assessed the same quadruple regimen using coformulated 3TC/ZDV for 24 weeks, followed by a switch to coformulated ABC/3TC/ZDV for 24 weeks, included 38 patients with a median baseline HIV RNA of 5.1 log10 c/mL and a median CD4 count of 285 cells/mm3. After 48 weeks, the proportion of patients with viral loads <50 c/mL was 63% (ITT, M = F). The 3rd study, using ABC/3TC/ZDV + EFV, was the 48-week induction phase of an ongoing induction/maintenance study and included 447 patients.30 The median baseline CD4 count was 210 cells/mm3 and the median baseline HIV RNA was 5.08 log10 c/mL. By ITT (M = F) analysis, 61% of patients reached <50 c/mL at week 48. There was a 37% discontinuation rate in this study population.
Backbones Containing a Thymidine Analogue

Safety and tolerability are key considerations when choosing an NRTI/NtRTI backbone. Patient concerns about toxicity and morphologic changes can lead to suboptimal adherence, which is a predictor of virologic failure and treatment-emergent resistance. The safety profiles of individual NRTIs have been established through their early use in monotherapy and dual therapy and their current use in ART backbones. In general, the long-term experience with and safety profile of 3TC suggest that it has the fewest side effects of the NRTIs and does not cause clinically relevant mitochondrial toxicity. The combination of 3TC with ZDV has been the cornerstone of ART for many years and has a well-characterized safety profile based on outcomes of large randomized trials. Some safety concerns with NRTI/NtRTI backbones reflect class effects of these agents, such as toxic effects on mitochondria (see article by McComsey and Lonergan in this issue). Individual nucleoside and nucleotide analogues vary in their short- and long-term side effects. ZDV is associated with anemia and neutropenia. It can also cause lipoatrophy and lactic acidosis, though with less frequency than d4T. ABC is associated with a hypersensitivity reaction in 3-5% of patients. Pancreatitis is significantly associated with ddI, and lipoatrophy, hyperlipidemia, and mitochondrial toxicities are more common with d4T than with other NRTIs.1 The risks of peripheral neuropathy, pancreatitis, and lactic acidosis are greatly increased when ddI is combined with d4T. The etiologic role of NRTI/NtRTI therapy in body fat changes seen in HIV-infected patients remains actively debated. Although comparisons across studies are only suggestive, lipoatrophy has been consistently more strongly associated with d4T than with 3TC, ZDV, or TDF, and prospective studies have shown that dual therapy with ddI + d4T led to greater limb fat loss than 3TC/ZDV and that investigator-defined lipodystrophy was more common with d4T + 3TC than with TDF + 3TC.
Backbones Containing TDF
In pooled results from clinical trials of TDF (studies 902 and 907), adverse events were predominantly gastrointestinal (nausea, diarrhea, and vomiting) and were not a significant cause of discontinuation; the incidence of these events was similar to that in the placebo arm. In these studies, 7% of patients had grade 1 creatinine elevations, but no patient developed grades 2-4 serum creatinine levels. In addition, grade 3/4 hypophosphatemia occurred in <1% of patients receiving TDF, no grade 4 glycosuria was observed, and 7% of patients had grade 3 glycosuria. One percent of patients discontinued because of renal events, and Fanconi syndrome occurred in 1 patient. Creatinine clearance was not measured in this study. An open-label study suggested that TDF tolerability is similar in patients with advanced HIV disease, most of whom were receiving a PI.
A prospective observational study of 476 HIV-infected patients receiving TDF or another unspecified NRTI demonstrated a modest decline in creatinine clearance in both groups, but there was no significant difference between the 2 treatment groups. Another study found that a glomerular filtration rate of <80 mL/min was an independent predictor of TDF-related nephrotoxicity among men with serum creatinine in the normal range.
Backbones Containing FTC
The recently approved agent FTC is similar to 3TC and has been shown to be safe and well tolerated. Hyperpigmentation of the palms and soles has been observed in about 3% of patients. Other safety data on this agent are accumulating. To date, few drug-drug interactions have been identified with FTC. FTC and 3TC should not be used in the same backbone, as the mutational profiles of these 2 agents are nearly identical.
Backbones Containing ABC
Approximately 3-5% of patients taking ABC develop a hypersensitivity reaction, usually in the first 6 weeks of ABC therapy. The most frequent major symptoms of hypersensitivity are fever, rash, gastrointestinal symptoms, malaise, fatigue, and headache. Hypersensitivity reactions to other drugs, specifically NNRTIs, may sometimes be confused with ABC hypersensitivity. However, it should be noted that patients with NNRTI hypersensitivity typically present with rash without other systemic symptoms, while ABC hypersensitivity is a systemic illness. In a retrospective study of ABC discontinuations, causality was unclear and hypersensitivity doubtful in approximately one-third of patients. A retrospective study of 34 clinical trials with >=24 weeks of ABC exposure examined data on > 8000 patients. Five percent of patients experienced a clinical syndrome compatible with hypersensitivity, and reduced risk was associated with African ethnicity, male gender, and advanced HIV disease at baseline.47 The observations that only a subset of individuals taking ABC develop hypersensitivity and that those who are initially intolerant remain at low risk in ongoing therapy led to suspicion of a genetic predisposition. Two independent studies have shown that HLA-B*5701 strongly predicts susceptibility to hypersensitivity in patients receiving ABC.
A 48-week randomized trial (the ABCDE Study) compared toxicity of ABC and d4T when either was combined with 3TC + EFV in 237 patients. Patients treated with ABC had significantly less lipoatrophy and blood lactate elevation than those receiving d4T. These results were similar to those found in CT or dual-energy x-ray absorptiometry studies demonstrating improvement in lipoatrophy when d4T or a PI was replaced by ABC.
Options for NRTI/NtRTI backbones have been expanded by the indications for once-daily ddI, 3TC, and TDF, the recently approved (but not commercially available) extended-release formulation of d4T (d4T XR), and FTC, and the data supporting once-daily use of ABC. The use of once-daily NRTIs/NtRTIs can greatly simplify ART regimens, but also raises concerns about how to optimize their pharmacokinetic benefits and avoid potential drug-drug interactions. For example, once-daily TDF and ddI can be included in an NRTI/NtRTI backbone, but based only on pharmacokinetic data available on this combination. In addition, it is not currently recommended as a dual-NRTI/NtRTI backbone in treatment-naive patients and a small study found a virologic failure rate of 43% (6/14) in patients on a regimen of TDF, ddI, and EFV. It is recommended that the dose of ddI be reduced to 250 mg when these agents are combined. In healthy individuals who took both enteric-coated (EC) ddI 250 mg and TDF 300 mg without food or with a light meal, ddI AUC increased 14% and decreased 11%, respectively, relative to ddI EC 400 mg alone given without food. Administration of a 250-mg dose of ddI EC with TDF (staggered or simultaneously, with or without a meal) results in drug exposure similar to that of ddI EC 400 mg. Coadministration of TDF with 3TC, FTC, or d4T exerts no clinically relevant effects on the pharmacokinetics of these drugs. Coadministration of TDF with LPV/r resulted in elevated exposure to TDF (32% increase in AUC). Coadministration of atazanavir (ATV) with TDF can lower the AUC and Cmin of ATV by 25%. If TDF and ATV are to be used concomitantly, ATV should be boosted with RTV. The combination of ATV/r plus TDF was not associated with increased TDF-related toxicity among treatment-experienced patients in a large comparative trial.
The studies reviewed here provide important insights into the safety and tolerability of newer NRTI/NtRTI combinations, but future use of NRTI/NtRTI backbones will depend on additional long-term trial results. With additional data supporting the tolerability, potency, and favorable resistance profiles of these novel combinations, they will likely occupy an important place in creation of safe and convenient ART regimens.
Data supporting the backbone of 3TC + TDF presently include its use in combination with EFV. Both TDF and 3TC are administered once a day, increasing the appeal of this combination. Although study 903 examined the twice-daily formulation of 3TC in combination with TDF, there is no reason to believe that efficacy would differ with once-daily 3TC in a comparable patient setting.
New formulations are in development, such as once-daily coformulations of ABC/3TC and TDF/FTC, and preliminary studies are encouraging. Presently, data on TDF + FTC are limited to use with LPV/r, but this NRTI backbone appears to be effective and well tolerated. Phase 3 clinical trials are under way to evaluate TDF/FTC in combination with EFV. Once-daily ABC/3TC has demonstrated efficacy and safety with EFV. When dosed once or twice daily, ABC/3TC has been shown to be potent in combination with other NRTIs (ZDV, d4T), PIs (APV/r, NFV, and FPV), and with EFV.
An unacceptably high rate of virologic failure has been observed in trials using the triple-nucleoside combinations of TDF, ABC, and 3TC as well as ddI, 3TC, and TDF in treatment-naive patients. Although the reason for the high rate of virologic failure with these triple-NRTI regimens is unclear, it is commonly believed that the low genetic barrier against the K65R and M184V mutations was responsible for the poor results. The use of any 2- or 3-drug combination of ABC, TDF, and ddI either as part of a triple-NRTI regimen or in combination with a PI or an NNRTI requires further investigation.
The growing menu of NRTI combinations offers opportunities for improving the potency, durability, and convenience of ART but also complicates considerations of tolerability, drug-drug interactions, and implications for sequencing and resistance. An increase in the number of viable treatment options brings higher expectations for patients and providers. Regimens will be expected to be safe and tolerable, have a low pill burden and simple dosing schedule, be salvageable with other drugs, and have few side effects. Recent encouraging data have suggested that newer NRTI/NtRTI backbone combinations will provide additional options for patients so that therapy can continue to be individualized to meet specific treatment needs.
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