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The Ideal Nucleoside/Nucleotide Backbone
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Part 8 of 8
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 37 Supplement 1 1 September 2004
Gallant, Joel E MD
From the Johns Hopkins University School of Medicine, Division of Infectious Diseases, Baltimore, MD.
Summary
The selection of the nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI) backbone is an important step in constructing a regimen for the treatment of HIV infection. No single NRTI/NtRTI backbone has attributes that make it ideal for every patient, but each has its advantages. Data from clinical trials provide needed guidance on backbone selection and the choice of a 3rd agent to complete a highly active antiretroviral therapy (HAART) regimen. This article reviews available data published since 2000 that address NRTI/NtRTI backbone performance and safety when included in HAART regimens. Based on these trials, the characteristics of different options are compared with an ideal backbone and put into context with other considerations for successful regimen selection and improved outcomes in treatment-naive patients. Practical strategies are offered for implementing contemporary regimens in settings outside clinical trials.
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The goal of highly active antiretroviral therapy (HAART) is to suppress HIV replication and prevent progression to AIDS and death by combining >=3 agents from the available classes of antiretrovirals. The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) form the backbone of most of today's antiretroviral regimens. The ideal backbone should be convenient, safe, tolerable, accessible, and durable and should preserve future options. In this article, current backbone options will be analyzed with regard to how they compare with the ideal. There are now nucleoside/nucleotide analogues approved by the US Food and Drug Administration (FDA). All drugs in the NRTI/NtRTI class are taken once or twice daily, with the exception of zalcitabine, which is rarely used.
Backbone selection is driven by a number of patient-, virus-, and medication-related factors. Ideally, these considerations should lead to the use of a potent regimen to which the patient is adherent because of its simplicity, convenience, and low side-effect profile. Considerations for successful regimen selection are shown in Table 2. The list is by no means exhaustive, but it points out the multiple, overlapping issues to consider when developing treatment plans in settings outside of clinical trials.
Table 2. Factors Influencing Backbone Selection and Success
Viral Factors
--ART resistance
--Cross-resistance with other agents in the class
Drug Factors
--Activity against the patient's virus
--Potency
--Pharmacokinetics
--Safety & tolerability
--Drug-drug interactions
--Access
--Convenience: pill burden, dosing frequency, food restrictions
Patient Factors
--Treatment readiness/adherence
--Baseline viral load & CD4 count
Provider Factors
--Practice patterns
--Provider experience
DUAL-NRTI BACKBONES
ZDV/3TC
The combination of zidovudine (ZDV) plus lamivudine (3TC) is the most extensively studied of the dual-NRTI backbones and has been a gold standard backbone for many years. The 2 drugs are available separately or as a fixed-dose coformulation (Combivir). AIDS Clinical Trials group 384 (ACTG 384) was designed partly to compare 2 NRTI backbones, stavudine (d4T) plus didanosine (ddI) vs. ZDV/3TC, each combined with efavirenz (EFV), nelfinavir (NFV), or both, in treatment-naive patients.
In the first part of the study, Robbins et al compared the effectiveness of 4 distinct 3-drug sequencing strategies over a median follow-up of 2.3 years in 620 HIV-infected, treatment-naive patients. The primary measure of a sequence's success was the amount of time before the second regimen failed: the longer the delay, the more successful the sequence. Secondary measures included the amount of time before the first regimen failed, ability to suppress viral replication, development of antiretroviral resistance, and drug toxicity. In this study ZDV/3TC + EFV retained effectiveness for a longer period than ZDV/3TC + NFV or d4T + ddI + either EFV or NFV. In part 2 of ACTG 384, a series of 4-drug treatments were no more potent than sequential 3-drug regimens in part 1. In several secondary measures, such as time to first regimen failure and development of drug resistance, the 4-drug regimens outperformed all 3-drug regimens except ZDV/3TC + EFV, supporting the efficacy of this first-line backbone.
Limitations of the ZDV/3TC combination include twice-daily dosing and ZDV-associated side effects, such as nausea, fatigue, and anemia. Although there are no food restrictions, ZDV is often better tolerated when taken with food. Cardiomyopathy and skeletal muscle myopathy are less frequently seen with the lower doses of ZDV used today. ZDV also causes mitochondrial toxicity, including lipoatrophy and hyperlactatemia/lactic acidosis, though not as frequently as d4T. Current US Department of Health and Human Services (DHHS) guidelines categorize ZDV/3TC as a preferred dual-NRTI combination.
d4T + 3TC
d4T + 3TC should prove to be another convenient once-daily option when d4T extended-release formulation (Zerit XR, Bristol-Myers Squibb) becomes available. However, d4T is associated with more mitochondrial toxicity than other NRTIs, resulting in an increased risk of peripheral neuropathy, lipoatrophy, and lactic acidosis. Lipid profiles were also shown to be less favorable with d4T than with tenofovir disoproxil fumarate (TDF) in the GS 903 study. Nevertheless, current DHHS guidelines categorize standard (immediate-release) d4T + 3TC as a preferred dual-NRTI combination based on extensive experience and efficacy data.
TDF + Either 3TC or FTC
Gilead Sciences Study 903 (GS 903), a 3-year study of 600 treatment-naive patients, was designed to compare d4T + 3TC vs. TDF + 3TC as backbone options in combination with EFV. After 144 weeks of follow-up, comparable rates of viral load suppression were seen in each arm (73 vs. 69% <50 copies/mL in the TDF and d4T arms, respectively, by intent-to-treat [ITT], missing = failure analysis). Compared with those taking TDF, d4T recipients had significantly higher fasting total cholesterol and triglyceride levels. Whereas TDF recipients had an average weight gain of 2.9 kg at week 144, d4T recipients gained only 0.6 kg (P = 0.001), and dual-energy x-ray absorptiometry scans showed significantly more limb fat in the TDF group at weeks 96 and 144 (P < 0.001). Among patients experiencing virologic failure, none had thymidine analogue mutations (TAMs), although nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance and M184V were common in both arms among those who experienced virologic failure. In addition, in the TDF arm, K65R was observed in 17% of virologic failures, representing 2.7% of the TDF-treated patients. Overall, these data support the use of TDF + 3TC as a first-line backbone. Its once-daily dosing makes it a convenient, safe, and durable backbone choice, especially for patients in whom dyslipidemia and lipoatrophy may be a concern.
The combination of TDF and 3TC is well tolerated and is not known to be associated with mitochondrial toxicity. TDF-induced nephrotoxicity has been reported, especially in patients with other medical problems or preexisting renal dysfunction. Current DHHS guidelines categorize TDF + 3TC as a preferred dual-NRTI combination when given with EFV.
There is less clinical experience with the combination of TDF + FTC. However, this combination has been combined with lopinavir/ritonavir (LPV/r) in a study comparing once-daily vs. twice-daily LPV/r, with good results. Moreover, given the comparability of 3TC and FTC, extrapolating the GS 903 data to the TDF + FTC combination is justifiable. A fixed-dose single-pill coformulation of these two agents is being considered for approval by the FDA (it was approved recently).
ABC + 3TC
Several comparative studies have examined the use of the combination of abacavir (ABC) and 3TC, prompting its recent addition as an alternative backbone in the most recent DHHS guidelines. ABC/3TC is currently under consideration by the FDA for approval as a once-daily fixed-dose combination (it was approved also recently).
In the ZODIAC study (CNA30021; Ziagen Once Daily in Antiretroviral Combination Therapy), 770 treatment-naive patients received EFV and were randomly allocated to receive once- or twice-daily ABC as part of an ABC/3TC backbone. The virologic response to the once-daily regimen was found to be noninferior to the twice-daily regimen, with 66 and 68% of patients achieving viral loads <50 c/mL, respectively. 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. Eleven of 16 genotyped patients (69%) in the once-daily ABC arm had the M184V mutation, compared with 5 of 15 (33%) in the twice-daily arm. Nine patients in each arm had EFV-associated mutations.
CNA30024 was a randomized, double-blind study that compared ABC/3TC with 3TC/ZDV in 649 patients receiving EFV. 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 ZDV/3TC (ITT = exposed). Virologic response among patients with baseline HIV RNA levels >100,000 c/mL was also comparable between the 2 study arms. There was a significantly greater CD4 count increase in patients randomly assigned to the ABC-containing backbone, which could not be explained by ZDV-associated hematologic toxicity, as there was a similar difference in CD4% increase between the 2 arms. The frequencies of the most common adverse events, including rash, were similar in the 2 groups. (Other comparative studies of the combination of ABC + 3TC with EFV, a PI, or a 3rd NRTI/NtRTI are reviewed below or elsewhere in this issue [see articles by Ruane and DeJesus, Young, and Wainberg and Turner].
ddI + 3TC
The introduction of once-daily enteric-coated (EC) ddI (Videx EC, Bristol-Myers Squibb) makes ddI + 3TC a convenient option for most patients, although ddI EC must be taken on an empty stomach, which may complicate dosing when ddI EC is combined with a drug that must be taken with food. Other drawbacks to the use of ddI include ddI-associated peripheral neuropathy, pancreatitis, and potential for lipoatrophy. Although ddI + 3TC has been well tolerated and effective in noncomparative trials, data from controlled trials are lacking. As a result, this combination is categorized as an alternative initial regimen in the DHHS guidelines.
d4T + ddI
In ACTG 384, the combination of either NFV or EFV with the NRTI backbone of ddI + d4T was less effective than the combination of 3TC/ZDV + EFV. In addition, adverse events, notably peripheral neuropathy and pancreatitis, occurred more frequently in patients who began treatment with ddI + d4T than in those who began treatment with ZDV/3TC. Lipoatrophy was observed in both NRTI arms, though it occurred more rapidly in those randomly assigned to receive to ddI + d4T. This NRTI backbone was also found to be less effective and more toxic than ddI + emtricitabine (FTC) in the FTC 301 trial. As a result of these findings as well as those from other studies, the DHHS guidelines no longer recommend the combination of ddI + d4T either as a preferred or an alternative dual-NRTI backbone (Panel on Clinical Practices 2004).
ZDV + ddI
Since ZDV and ddI were the first antiretrovirals available, there is long experience with this older combination, though mostly in the setting of dual-NRTI therapy prior to the use of triple-drug HAART. There are no available data on the use of ZDV with the newer EC formulation of ddI EC. ZDV is dosed twice daily, usually with food, whereas ddI is given once daily on an empty stomach, making this combination somewhat inconvenient. This combination is not recommended as either a preferred or an alternative NRTI backbone in the current DHHS guidelines.
TDF + ddI
The combination of TDF +ddI is attractive in that both drugs can be administered once daily. However, clinical data on this backbone are lacking, and a small pilot study of a once-daily combination of TDF + ddI + 3TC in treatment-naive patients demonstrated unacceptably high rates of virologic failure and drug resistance, raising concerns about the fact that both drugs select for the K65R mutation. There is also an unexpected drug interaction between TDF and ddI, with increased blood levels of ddI and the potential for increased ddI toxicity. When TDF and ddI are used in combination, the ddI dose should be reduced to 250 mg using ddI EC.14 There are no dosing recommendations for individuals weighing <60 kg. The interaction between TDF and ddI allows both drugs to be taken with food and achieves ddI levels similar to those seen with the standard 400-mg ddI dose taken on an empty stomach. Given the lack of clinical data and the concerns about selection for K65R, this regimen is not recommended as a first-line NRTI option for treatment-naive individuals. However, it may sometimes be useful in treatment-experienced patients, since both drugs are active in the presence of 3TC resistance and are less compromised by the presence of ZDV- and d4T-associated mutations than other NRTIs. (See article by Wainberg in this issue.)
TDF + ABC
TDF + ABC is another attractive combination because of the potency and tolerability of both drugs, as well as the potential for once-daily administration. However, data from 3 clinical trials involving the combination of TDF + ABC + 3TC demonstrated high rates of virologic failure and drug resistance, possibly because both drugs select for the K65R mutation (see Triple-NRTI Regimens). In light of these concerns and the lack of clinical data, this NRTI backbone should not be used in treatment-naive patients.
ABC + ddI
The backbone of ABC + ddI has not been studied in treatment-naive patients. Since both drugs can select for K65R or L74V, the resistance concerns discussed above (ABC + TDF, TDF + ddI) apply to this regimen, which should not be used in treatment-naive patients.
FTC + ddI
FTC was approved by the FDA in 2003. A fluorinated cytidine analogue, FTC is given once daily, has longer intracellular and plasma half-lives than 3TC, and appears to be well tolerated.
FTC 301 was a randomized, double-blind, comparative trial of FTC once daily vs. d4T twice daily combined with once-daily ddI and EFV in 571 treatment-naive individuals. The proportion of patients experiencing virologic failure through week 48 was 5.3% in the FTC arm and 12.7% in the d4T arm (P < 0.05). Genotypic analysis was performed on 46 of the 49 patients with confirmed virologic failure. Of the 33 genotypically evaluable patients in the d4T arm for whom therapy failed, 32 (97%) had reverse transcriptase mutations compared with 69% (9/13) in the FTC arm (P < 0.05). Not surprisingly, the M184V mutation was observed only in the FTC arm (46%; 6/13), while TAMs were observed in 8% (1/13) of the FTC arm and 21% (7/33) of the d4T arm.
The most common adverse events in patients receiving FTC were mild-to-moderate headache, diarrhea, nausea, and rash; approximately 1% of patients discontinued participation because of these events. With the exception of skin discoloration, which was reported with higher frequency in the FTC subgroup, adverse events were reported with similar frequency in the FTC arm and the d4T arm. Skin discoloration, manifested by hyperpigmentation on the palms or soles, was observed predominantly in nonwhite patients. These results demonstrate that the NRTI backbone of once-daily FTC + ddI was statistically superior to the combination of ddI + twice-daily d4T, with a significantly lower rate of virologic failure and emergence of fewer resistance mutations.
TRIPLE-NRTI REGIMENS
Triple NRTIs as the Sole Regimen
The use of triple nucleoside combinations as a sole regimen has been studied in a number of trials. The most extensively studied and widely used triple-NRTI combination has been ABC/3TC/ZDV, coformulated as Trizivir (GlaxoSmithKline). This regimen has been quite popular, in part because of its convenience, low pill burden, and reduced cost to patients compared with the cost of the individual components purchased separately. However, this regimen has been shown to be less effective than some preferred HAART regimens. According to current DHHS guidelines, ABC/3TC/ZDV or d4T + 3TC + ABC are acceptable as alternative initial treatment regimens if protease inhibitor (PI)- or NNRTI-based regimens cannot be used. The high rates of virologic failure and drug resistance seen with the triple-NRTI combinations TDF + 3TC + ddI and TDF + ABC + 3TC led to the recommendation that these combinations be avoided as sole therapy. The results of some of these trials are discussed briefly in this section.
In the CNAB 3005 trial, ABC + coformulated ZDV/3TC and indinavir (IDV) + ZDV/3TC had comparable suppression of viral load to <400 copies/mL at 48 weeks. In the more rigorous ITT analysis, 50% of patients in both groups had undetectable viral loads. However, in patients with baseline viral loads >100,000 copies/mL, the proportion of patients achieving viral loads <50 copies/mL was greater in the IDV arm (45 vs. 31%, respectively).
ACTG A5095 compared ABC/3TC/ZDV with ZDV/3TC + EFV and ABC/3TC/ZDV + EFV as initial therapy. Virologic failure was significantly more common in the ABC/3TC/ZDV than in the pooled EFV arms: 82 (21%) vs. 85 (10%). Time to virologic failure was shorter in those receiving ABC/3TC/ZDV than in those in the pooled EFV arms, which was true for the overall comparison as well as for those with baseline viral loads above and below 100,000 copies/mL (P < 0.001).
The CLASS study (Clinically Significant Long-Term Antiretroviral Sequential Sequencing) compared d4T, EFV, and ritonavir-boosted amprenavir (APV/RTV), each combined with the dual-NRTI backbone of ABC + 3TC. At 48 weeks ABC + 3TC + d4T was equivalent to ABC + 3TC + APV/RTV. Both combinations, however, were less effective than ABC + 3TC + EFV in achieving viral suppression to <50 copies/mL in all patients and to <400 copies/mL in those with baseline viral loads >100,000 copies/mL. In patients with viral loads <100,000 copies/mL at entry, 91% achieved viral loads <50 copies/mL with ABC + 3TC + d4T.
Similarly, in the Atlantic Trial, the triple combination of d4T + ddI + 3TC did not perform as well as PI- or NNRTI-containing regimens.19 A post hoc analysis found that the triple-NRTI regimen was inferior with respect to virologic suppression regardless of whether the baseline viral load was above or below 100,000 copies/mL.
Several trials have evaluated combinations of TDF and 3TC plus either ddI or ABC, and all have demonstrated poor results with high rates of NRTI resistance. In ESS30009, 345 treatment-naive patients were randomly assigned to receive TDF or EFV plus a fixed-dose combination of ABC/3TC, all given once daily. An unplanned interim analysis involving 192 patients with at least 8 weeks of virologic data found that 50 (49%) of 102 patients in the TDF arm exhibited virologic nonresponse, which was defined as one of the following: a <2.0 log10 decline in viral load by week 8; a >1.0 log10 rebound from viral load nadir at any subsequent visit; or confirmed viral load >400 copies/mL after 2 consecutive measurements <50 copies/mL. In comparison, virologic nonresponse was observed in only 5 (5.4%) of 92 patients in the EFV arm. Preliminary genotypic analysis of virologic nonresponders in the TDF group at week 12 revealed the presence of the K65R and M184V mutations in 64%, with M184V alone in the remaining 36%.
In the Tonus study, 38 HIV-infected patients received ABC + 3TC + TDF once daily for 12 months. Virologic failure was defined as never achieving a viral load <400 copies/mL or a rebound >0.7 log10 copies/mL after a viral load decrease. The trial was also prematurely interrupted after an unplanned interim analysis revealed that 12 of 36 patients were experiencing virologic failure at 24 weeks. In specimens available from 12 patients with virologic failure between month 3 and month 6, 11/12 had both K65R and M184V mutations and 1 had the M184V mutation alone. At month 1, 32/37 patients had plasma trough concentrations (Cmin) considered adequate for all 3 drugs. Results from an earlier pilot trial involving this regimen were similar to those from Tonus and ESS30009.
An uncontrolled pilot study of a once-daily regimen of ddI + 3TC + TDF demonstrated even higher rates of virologic failure, as well as the frequent emergence of the M184V and K65R mutations. Taken together, these data point to the low genetic barrier to resistance as the most likely cause of failure: ABC, TDF, and ddI all select for the K65R mutation, which reduces susceptibility to all 3 drugs as well as to 3TC. These triple-NRTI regimens should not be used alone, and it remains unclear whether they may be acceptable when combined with a 4th agent.
In summary, there are 2 broad categories of triple-NRTI regimens. Those containing a thymidine analogue (eg, ABC/3TC/ZDV and d4T + 3TC + ABC) appear to have acceptable efficacy, especially in patients with low baseline viral loads, but are considered to be alternatives to preferred PI- and NNRTI-based regimens based on lower potency. In contrast, the nonthymidine analogue-containing regimens (ABC + 3TC + TDF, ddI + 3TC + TDF, and presumably ABC + 3TC + ddI) should not be used at all because of unacceptably high rates of virologic failure. Triple-NRTI regimens containing both ddI and d4T should be avoided because of high rates of toxicity associated with that combination.
Triple-NRTI Combinations as Backbones in 4-Drug Regimens
In a recent pilot study, COL40263, 88 treatment-naive patients were treated with coformulated ABC/3TC/ZDV + TDF once daily. After 6 months of treatment, 78 and 67% of patients achieved viral loads <400 copies/mL and 50 copies/mL, respectively. Ten patients (11%) had early virologic nonresponse, defined as failure to achieve at least a 2 log10 copies/mL drop in viral load by week 8 of treatment. Of these patients, 6 had baseline viral loads >100,000 copies/mL. Resistance data were available for 8/10 patients with early virologic nonresponse. At baseline, 6/8 (75%) had wild-type virus and 2/8 (25%) had mutant virus (K103N and Y215T/A reversion mutation). At withdrawal or at the last post-week 24 visit, 1/8 (13%) had K65R, 2/8 (25%) had wild-type virus, 2/8 (25%) had >1 TAM without M184V, and 3/8 (37%) had >1 TAM with M184V.
Thus, it is clear that this 4-drug regimen is more effective than the 3-drug combination of ABC + 3TC + TDF, possibly because the addition of ZDV modifies resistance pathways, decreasing the likelihood of emergence of K65R and increasing the overall barrier to resistance. However, it cannot be determined from this uncontrolled trial whether this regimen is more or less effective than ABC/3TC/ZDV alone. In addition, the resistance mutations seen in patients for whom therapy with this regimen failed are of some concern in that 1 patient had K65R, which is normally prevented by ZDV, and 5/8 had TAMs, which are uncommon with early failure of ABC/3TC/ZDV alone. It is possible that once-daily dosing of ZDV did not provide the same resistance-modifying effects seen with ZDV dosed twice daily.
An important but unanswered question is whether the efficacy of HAART can be increased when NNRTIs or PIs are combined with a backbone of 3 NRTIs instead of 2. This is especially important in patients who initiate therapy with very high baseline viral loads or low baseline CD4 cell counts, in which case the efficacy of many standard HAART regimens may be reduced. The ongoing ACTG 5095 trial, which is now comparing ABC/3TC/ZDV vs. 3TC/ZDV, both in combination with EFV, should help answer this question.
PRIMARY RESISTANCE
Primary resistance (resistance transmitted at the time of infection) has become an increasingly important consideration in the choice of initial therapy. Data from specific population studies and clinical trials suggest that primary resistance is increasing during the HAART era. These rates are highly population dependent and do not necessarily represent overall rates of resistance.
The frequency of antiretroviral resistance in newly infected patients in North America has been estimated to be as high as 11%. Little et al determined the prevalence of such resistance in a retrospective analysis of pretreatment phenotypic and genotypic testing in 337 treatment-naive patients with primary HIV infection between May 1995 and June 2000 in 10 North American cities. Responses to treatment were evaluated in a subgroup of 202 patients. (See article by Wainberg in this issue.)
The frequency of high-level phenotypic resistance to >=1 drug increased from 3.4% during 1995-1998 to 12.4% during 1999-2000, and the frequency of multidrug resistance increased from 1.1 to 6.2%, respectively. Among patients with multidrug resistance, none identified before 1999 had high-level resistance by phenotype for >=1 drug in all 3 antiretroviral classes. In contrast, 75% of patients with multidrug resistance identified in 1999 or 2000 had high-level phenotypic resistance to all 3 classes of antiretrovirals.
The frequency of genotypic resistance mutations increased from 8.0% during 1995-1998 to 22.7% during 1999-2000, and the frequency of multidrug resistance detected by genotypic testing increased from 3.8% during 1995-1998 to 10.2% during 1999-2000. Among patients infected with drug-resistant virus, the time to viral suppression after initiating antiretroviral therapy was longer and the time to virologic failure was shorter. Little et al concluded that the proportion of new HIV infections that involve drug-resistant virus is increasing in North America, that initial antiretroviral therapy is more likely to fail in patients who are infected with drug-resistant virus, and that resistance testing is now indicated for recently infected patients before starting therapy.
In another report, Little et al assessed the persistence of detectable resistance mutations in the absence of antiretroviral treatment among subjects infected with drug-resistant virus. All 11 patients had at least 1 major drug resistance mutation identified by genotyping at presentation with corresponding phenotypic resistance. Longitudinal samples were collected for a median of 225 days (range 82-1346 days) after infection and analyzed for persistence of transmitted drug-resistant variants. Among the 11 patients with transmitted NNRTI resistance, the average time to reversion of K103N variants to a mixed K103N/K population was 375 days following the estimated date of infection (range 158-592 days). Only 1 of the 11 patients had complete reversion to wild-type virus, which occurred after >1000 days. In the 4 patients with protease resistance mutations, no reversion was detected at 64, 191, 327, and 342 days after infection. Average time to reversion of NRTI resistance among the 3 patients infected with NRTI-resistant virus was 362 days.
Reversion of transmitted resistance is gradual and usually incomplete, resulting in the persistence of mixtures of wild-type and resistant variants. These data have made a compelling case for resistance testing at the time of diagnosis, even in chronically infected, treatment-naive individuals. Genotyping is the preferred way to assess transmitted resistance, since it is more sensitive to resistance mutations present at low levels (mixtures). When resistance testing is performed in treatment-naive patients, it should be conducted as soon as possible, regardless of whether the patient is in need of immediate therapy. Delaying resistance testing may lower the yield due to eventual reversion of resistant mutants to wild-type virus.
CONCLUSIONS
The challenge for providers is to make use of up-to-date clinical trial data to select treatment regimens in clinical practice. The growing number of viable NRTI backbone options improves our ability to individualize therapy for our patients. While DHHS guidelines provide a framework for regimen selection, many other considerations must be weighed in choosing a regimen for an individual patient (table 2).
Either 3TC or FTC is likely to remain the cornerstone of most NRTI backbones because of the efficacy, convenience, tolerability, and resistance advantage of these agents. FTC is currently categorized as an alternative to 3TC, which is preferred in the DHHS guidelines, as long-term experience with FTC is more limited. However, FTC does have some hypothetical advantages, such as its long intracellular half-life and its anticipated coformulation with TDF. Either 3TC or FTC can be combined with ZDV, d4T, TDF, ABC, or ddI. The last 2 drugs are currently listed as alternatives in the DHHS guidelines, though data supporting the use of ABC + 3TC as a dual-NRTI backbone are accumulating, and a once-daily single-pill coformulation is now being considered by the FDA (both ABC/3TC & TDF/FTC approved as only daily fixed dose combinations).
It is expected that there will soon be 3 coformulated NRTI backbones: ZDV/3TC, ABC/3TC, and TDF/FTC. Availability of these new products should have a significant impact on choice of therapy by clinicians, who are likely to choose 1 of these 3 backbones in most patients. Since all 3 will probably be highly potent when combined with a 3rd potent agent, the choice of NRTI backbone will be based on considerations such as tolerability, long-term toxicity, convenience, baseline resistance, and expected resistance profile with virologic failure.
Combinations that do not include either 3TC or FTC are unlikely to be widely used in treatment-naive patients, given the lack of data. In addition, there are concerns about increased selection of K65R or L74V with combinations such as ABC + TDF, ddI + TDF, and ABC + ddI. The question of whether a triple-NRTI backbone may be more effective than a dual-NRTI backbone, especially in patients who start therapy with advanced disease, is still unanswered. The NRTI/NtRTI combination of ABC/3TC/ZDV + TDF has shown promise in that it is a simple, potential once-daily regimen that spares NNRTIs and PIs. However, the limited data available on this regimen suggest that it is less effective in patients with high baseline viral loads, which is generally an indication of lower overall potency.
Of course, the success or failure of antiretroviral therapy is not determined by choice of regimen alone. Other key elements of the treatment plan include resistance testing as soon as possible after diagnosis of HIV infection, a discussion of potential side effects and plan for their management, and a schedule for monitoring viral load, CD4 cell count, and toxicity. Most important is adherence counseling, since suboptimal adherence is a major cause of both treatment failure and drug resistance. Fortunately, the growing number of potent, convenient, and well-tolerated treatment regimens, including the expanded number of NRTI backbones, should make adherence to antiretroviral therapy easier for HIV-infected patients.
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