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Nucleoside analogues in 2008.

INTRODUCTION

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have been the backbone of antiretroviral therapy since the advent of HIV treatment (Table 1). The evolution of HIV therapy has seen the use of this class of drugs as monotherapy [1], dual therapy [2,3] and triple therapy, in combination with non-nucleoside reverse transcriptase inhibitors (NNRTI) [4-6] and with protease inhibitors (PI) [7,8]. The last decade has witnessed the rise and fall of individual drugs as we have learnt more about both their efficacy against HIV and their individual toxic effects. Nucleoside-sparing regimens have been studied for over a decade [5,9-14], and have several potential advantages, as they avoid nucleoside analogue toxicity, and preserve this class of drug for later lines of therapy. However, this is at the cost of reduced potency in most studies compared to more conventional comparator regimens, and increased toxicity, principally hyperlipidaemia. In contrast, nucleoside-only regimens have also been studied over a similar period [15-17]. The ACTG 5095 trial showed that Trizivir (TZV; ZDV/3TC/ABC) was significantly less likely to suppress viral load to <50 copies/ml than either TZV/EFV or Combivir/EFV at both high and low viral loads. Non-thymidine triple NRTI combinations (for example ABC/3TC/TDF or ddI/3TC/TDF) have also been shown to have high virological failure rates [18,19]. For these reasons, there are now few indications for triple NRTI regimens. One advantage of triple nucleoside analogue regimens is that drug-drug interactions are relatively limited in comparison to NNRTI- or PI-based regimens, and they may thus have a limited role in patients who need to take interacting drugs (e.g. rifampicin for the treatment of tuberculosis). In these circumstances, Trizivir/TDF may be a preferable option, as it has been shown to be a more potent regimen than Trizivir alone [20,21].

Currently the first-line combinations recommended by widely used guidelines [22,23] include a backbone of two NRTIs combined with either EFV or a ritonavir-boosted PI. The recommended dual NRTI backbones specify ABC or TDF with either 3TC or FTC.

WHY ABC OR TDF?

Despite the fact that many years' experience of using ZDV and d4T in various combinations have been accumulated, these drugs have been superseded by ABC and TDF in the light of data proving equivalent or greater potency, reduced risk of long-term toxicity and better early tolerability. For example, d4T/3TC is a well-studied nucleoside combination with equal antiviral effectiveness to TDF/3TC and ABC/3TC when combined with EFV, but with significantly greater toxicity, including peripheral neuropathy and lipoatrophy [24,25].

TDF/ddI is a convenient once-daily two-tablet combination. However, several studies where this two-NRTI backbone has been used with an NNRTI as the third agent have demonstrated an unacceptably high failure rate, with the development of early resistance that was more marked in patients with more advanced disease [26]. There is also potential for TDF to potentiate ddI-related toxicity, notably pancreatitis, although the risk of ddI toxicity is increased if its dose is not reduced to account for the enhanced absorption of ddI when taken with TDF [27].

Both ddI/3TC and ddI/FTC are well tolerated and have very high efficacy [28,29] but have significant disadvantages also. The licence for ddI states that it should be taken on an empty stomach, and the drug has significant potential for long-term mitochondrial and liver toxicity [30]. There are currently no data to support the use of ABC/ddI in naive patients.

TDF with EFV and either 3TC or FTC have been shown to have high and durable virological activity with good tolerability and minimal long-term toxicity with up to 3 years of follow-up [25,31]. A total of 602 HIV-positive individuals with a viral load above 5000 copies/ml were randomly allocated to receive TDF/3TC/EFV or d4T/3TC/EFV. Patients with abnormal liver or kidney function were excluded. At week 48, the proportion of patients with a viral load below 50 copies/ml was 76.3% and 79.7% for the TDF and d4T arms, respectively. Similar results were seen at weeks 96 and 144. Approximately one quarter of patients in both arms experienced an adverse event. The TDF-treated patients had a much more favourable lipid profile, with significantly lower increases from baseline in mean triglycerides, mean total cholesterol, mean LDL cholesterol and a higher mean increase in HDL cholesterol, than was seen in the d4T-treated patients. Side-effects associated with mitochondrial toxicities (peripheral neuropathy, lipodystrophy and lactic acidosis) occurred much more frequently in the d4T arm (28%) than the TDF arm (6%, P<0.001). In total, 19% of d4T-treated patients developed lipodystrophy compared to 3% of the patients taking TDF (P<0.001). Using a whole-body DEXA scan, significantly more fat loss was seen in the d4T arm than the TDF arm at week 96 (P<0.001) and week 144 (P<0.001). The renal safety of both of the study drugs was comparable at week 144.

ABC/3TC has also been shown to give effective lasting virological control. In studies where the third drug was either EFV or a boosted PI, the proportion of patients who failed virologically was 4-10% at 48 weeks, with 68-70% having viral loads <50 copies/ml [32-34].

Both TDF and ABC have been shown to partially reverse thymidine-induced lipoatrophy in switch studies [35-37]. In the Australian MITOX study, 111 HIV-positive patients with evidence of fat-wasting from the limbs and who were taking a HAART regimen including AZT or d4T, were randomly allocated to either switch the thymidine analogue for ABC or remain on AZT or d4T. Individuals who had switched to ABC had a significant increase in limb fat at week 104 compared to the patients who remained on a thymidine analogue (P=0.008). No differences in CD4 cell count, viral load or blood lipids were observed between the two arms at week 104.

TDF/FTC OR ABC/3TC?

For both Truvada (TDF/FTC) and Kivexa (ABC/3TC), the individual components have been shown to be bioequivalent with the fixed-dose combinations [38]. The HEAT study [39] showed equal potency of Truvada and Kivexa over 48 weeks when combined with Kaletra (LPV/r). This study also looked at the virological efficacy of the two combinations in patients with viral loads above 100,000 copies/ml and showed them to be comparable. Similar proportions of patients taking each product (Kivexa, 12%; Truvada, 11%) experienced virological failure. Treatment was stopped before 48 weeks by 4%of patients taking Kivexa and 6%of those taking Truvada due to side-effects. Patients were not screened for HLA-B*5701 and 4% of patients taking Kivexa were diagnosed with a suspected ABC hypersensitivity reaction, as were 1% of patients taking Truvada. Cholesterol and triglyceride levels increased in both groups of patients, but were marginally higher in patients taking Kivexa. Recently however, an interim analysis of the ACTG A5202 trial reported that those patients on ABC/3TC with a viral load >100,000 copies/ml were significantly less likely than those on TDF/FTC to achieve a viral load below 1000 copies/ml after 16 weeks of treatment, and a viral load below 200 copies/ml after 24 weeks of treatment.

Although TDF/3TC or FTC regimens have excellent efficacy when combined with EFV, this does not seem to be the case with TDF/3TC/NVP. The DAUFIN study was a small French prospective, randomised, open-label clinical trial comparing Combivir/NVP with TDF/3TC/NVP [41]. The study of treatment-naive patients was prematurely terminated when the once-daily TDF/3TC/NVP regimen resulted in an unexpectedly high rate of early non-response with a high incidence of K65R and M184V mutations. A total of 9/36 failures (25%) was seen in the TDF arm. The reason for the high failure rate remains unclear, and was not explained by nevirapine trough concentrations. Those with virological failure had lower baseline CD4 cell counts (110 vs. 223 cells/mm3) and higher baseline viral loads (262,747 vs. 51,189 copies/ml) than those with virological success (P=0.004 and 0.002, respectively).

These results were similar to those presented from a previous study [42].

TDF AND RENAL TOXICITY

Registrational studies of TDF suggested that the drug had a very low propensity to cause significant renal toxicity. However, after licensing, numerous case reports of renal failure and Fanconi syndrome in patients on the drug were published. Cohort studies have subsequently suggested that serious toxicity occurs in 0.5% of patients, which is similar to other NRTIs [43-45], while other studies have found a small but significant reduction in renal function over time in comparison with other NRTIs [46,47].

The Johns Hopkins HIV Clinical Cohort reported data on patients with an estimated glomerular filtration rate (GFR) greater than 50ml/minute/1.73 [m.sup.2] (calculated by the modification of diet in renal disease [MDRD] equation), who had started NRTI-containing combination therapy. Of this group, 627 (565 treatment-experienced, 62 treatment-naive) were taking TDF and 311 (211 experienced, 100 naive) were taking alternative NRTIs. There was no difference in baseline GFR (115 vs. 114 ml/minute/1.73 [m.sup.2], P=0.27) or how long they had been on therapy (median 506 days TDF vs. 519 days NRTI, P=0.25) [48]. There were greater GFR declines in treatment-experienced patients on TDF than in those on other NRTIs (15 vs. 11 ml/min/1.73 [m.sup.2], P<0.01; 14% vs. 9% decline, P<0.001), with the greatest decline occurring at around 20 weeks. No significant differences were seen in treatment-naive patients (15 vs. 14 ml/minute/1.73 m2, P<0.10). Other risk factors for GFR decline were CD4 cell counts <50 cells/mm3, diabetes, and age greater than 45 years. TDF was still associated with greater GFR declines (in treatment-experienced people only) after adjusting for these and other variables. Although statistically significant, this GFR decline may not be of clinical significance. The decline was small, most commonly occurred within the first 6months of treatment and was not progressive. A second study looking at the decline in GFR (using the Cockcroft-Gault [CG] equation and MDRD) with antiretroviral therapy found the time to sustained reductions of GFR was significantly shorter for patients taking TDF than for those who were not (10ml/min decrease in 52% vs. 21% over 2 years; P<0.001). Boosted-PI use was identified as a risk factor (hazard ratio=1.63 by CG calculation; P=0.01, HR=2.21 by MDRD; P<0.0001) [49]. This decline in GFR associated with TDF and boosted PI use was also confirmed when the estimated GFR declined more quickly in patients taking this combination compared with individuals taking TDF and NNRTI (by CG: 13.9 vs. 6.2 ml/minute/year, P=0.033; by MDRD: 15 vs. 4 ml/minute/1.73 [m.sup.2]/year, P=0.018) [50]. Treatment history (naive vs. experienced), baseline CD4 counts and viral load were not risk factors associated with renal impairment in this study; although older age was (GFR decline of 1 ml/minute/year of age, P=0.001).

A retrospective cohort study from San Diego also found low-dose ritonavir to be a risk factor for kidney toxicity with TDF-containing regimens in patients without pre-existing renal disease, while TDF alone posed no additional risk [51].

TDF should, therefore, be used cautiously (if at all) in patients who have, or are at risk of developing, renal disease, including those co-prescribed potentially nephrotoxic agents. Estimation of GFR and monitoring of proteinuria should be performed prior to initiating TDF, with regular monitoring throughout treatment [52].

ABC HYPERSENSITIVITY

A hypersensitivity reaction (HSR) may occur in the first 6 weeks of treatment with ABC (median 11 days from drug commencement) and all patients need counselling about this possibility. It is independent of dosing frequency and the summary of product characteristics states an HSR rate of 5.4%. Pharmacogenetic analysis has identified a close association between HSR and carriage of the Class 1 HLA-B*5701 allele, which, to a large extent, explains the racially-defined differences in susceptibility [53]. In a randomised prospective trial, HLA-B*5701 screening excluded skin-test positive HSR patients (negative predictive value 100%) as well as significantly reducing the rate of clinically suspected hypersensitivity reactions (from 7.8% to 3.4%) [54]. Although data in racially diverse populations are limited, a retrospective study in Black patients with documented clinical hypersensitivity using skin-patch testing validated the use and negative predictive value of HLA-B*5701 screening in this group as well [55,56]. It is now considered standard of care to perform HLA-B*5701 testing on all individuals prior to commencing ABC and, if positive, ABC should be avoided.

METABOLIC COMPLICATIONS

Switching from nucleoside analogues to either ABC or TDF has been shown to reverse lipodystrophy, but are there differences in switch responses?

In the RAVE study [37], patients who had been taking ZDV showed better recovery of limb fat when they switched to ABC. In contrast, those who had been taking d4T showed better recovery of limb fat when they switched to TDF.

Also, improved lipid profiles were seen in individuals switching to TDF.

After 48 weeks, total cholesterol levels had fallen by a mean of 0.5mmol/l in the patients allocated to switch to TDF. In contrast, those switching to ABC showed a mean rise of 0.2mmol/l (P=0.003). Levels of low-density lipoprotein cholesterol also fell by a mean of 0.3mmol/l in the TDF arm, compared to a mean rise of 0.1mmol/l in the ABC arm (P=0.04). Similar patterns were seen for high-density lipoprotein cholesterol and triglyceride levels, but these were not statistically significant. Of the 52 patients switching to TDF, 2% started taking lipid-lowering therapy after 273 days; in contrast 15% of the 53 patients switching to ABC started lipid-lowering therapy after a median of 92 days.

The DAD study (Data Collection on Adverse Events of Anti-HIV Drugs) is a collaboration of 11 prospective cohorts from across Europe, Australia and the USA, totalling over 30,000 participants. It reported that ABC and ddI appear to increase the absolute risk of myocardial infarction by 90% and 49%, respectively [57]. No such increase was seen with ZDV or d4T, and the additional risk due to ABC and ddI largely disappeared after the drugs were discontinued. The analysis did not look at TDF. The risks of myocardial infarction associated with recent ABC and ddI use remained after adjustment for HIV viral load, CD4 cell count, dyslipidaemia and other metabolic factors. The excess risk attributable to these two drugs was, however, most pronounced in patients with high underlying cardiovascular risk. Although all cohort studies may be subject to hidden bias, it is unlikely that the results might be due to the fact that patients at higher cardiovascular risk might be more likely to be placed on ABC for reason of its perceived safer cardiovascular profile, as adjusting for known cardiovascular risk factors had little effect on the outcomes. Also, myocardial infarction risk was seen to decrease after ABC cessation. Pooled data from studies of ABC did not suggest any increase in rates of myocardial infarction, but these studies were relatively short-term, did not set out to examine the risk of myocardial infarction and had significantly less power to show an effect than the DAD study [58]. Taken together, the data from DAD, ACTG 5202 and the switch studies suggest that individuals with a high risk of myocardial infarction should avoid ABC where other options exist that, on balance, pose less risk (e.g. TDF/FTC, although TDF was not studied in DAD); in contrast, this issue is far less important in those whose conventional risk factors suggest a low risk of myocardial infarction.

Co-morbidity other than cardiovascular disease may lead one to avoid the use of ABC or actively choose TDF. Treatment success using ribavirin in hepatitis C is lower in individuals on ABC, due to intracellular competition between the two drugs [59]. Patients who are co-infected with hepatitis B and HIV should normally be treated with TDF and 3TC or FTC, even if there is evidence of mutation in the HIV genome associated with resistance to these agents [60].

The relative cost of different NRTIs is also becoming an increasingly important factor in defining treatment pathways in naive patients [22].

TREATMENT-EXPERIENCED PATIENTS

The choice of antiretroviral drugs used in the compilation of a second or subsequent regimen will take into account several factors including the reason behind the failure of the first-line regimen. Tolerability and previous side-effects encountered by the individual, adherence issues, comorbidities, drug interactions and future treatment options will all play a part in the decision. A detailed antiretroviral treatment history as well as information from resistance tests is needed to determine which available therapies are likely to be potent, as routine resistance assays do not detect resistant viruses present at low levels (<20-30% of the total virus population), even if these resistant viruses were previously dominant. Limited data indicate that minority resistant quasispecies including NNRTI resistance mutations and M184V may affect virological responses [61].

The principles of antiretroviral therapy prescribing dictate that if a new regimen is required due to tolerability issues, then the offending drug can be exchanged for another, whilst the remainder of the regimen remains unchanged. If the reason for therapy change is virological failure, the regimen should be constructed using at least two (or preferably three) active agents guided by HIV resistance testing and by the patient's previous treatment history. The use of an agent from a new drug class is likely to be more effective [62-64].

When considering the NRTI class, two or three drugs from this class are likely to be used in second- or third-line regimens and are often a part of subsequent therapy combinations.

Cohorts with detectable viral load while on HAART show a high prevalence of drug resistance [65]. A trend towards declining rate of resistance has been observed in drug-experienced patients in the UK, as a result of improved management of antiretroviral therapy and treatment failure [66].

There are data on the development of NRTI mutations following the use of a TDF- or ABC-containing regimen. In the Gilead 903 study, there was an overall virological failure rate in those using a TDF first-line therapy of 9.7% at 48 weeks. In those failing EFV/TDF/3TC, the K65R mutation occurred in 2.4%. This was mainly observed in those with CD4 cell counts of <50 cells/[mm.sup.3] and viral loads >100,000 copies/ml [67]. K65R has not been observed in patients with pre-treatment wild-type virus when receiving TDF/FTC with either a boosted PI or EFV in GS-934. Similar proportions of patients taking Kivexa and Truvada (12% vs. 11%) experienced virological failure, but those failing on Truvada were more likely to have developed an M184V mutation [31].

The L74V mutation is seen in <1% at 48 weeks in patients on EFV/ABC/3TC or a boosted PI (overall virological failure rate 4.0-9.9%) [32,33]. Both K65R and L74V mutations lead in reducing susceptibility to multiple NRTIs, making later treatment choices complex.

In subsequent regimens, new drug classes are more and more likely to be used with or without an NRTI. With the development of these new drug classes has come the realistic aim of viral undetectability for all patients. NRTIs are likely to be combined in these regimens because of what we know about the effect on viral replicative capacity and their activity against resistant viral variants [68]. It has been shown that removal of 3TC from a failing antiviral regimen leads to an average increase of 0.5 log10 in viral load [69] suggesting that 3TC could be used in fragile or salvage regimens even in the presence of high-level genotypic resistance. There are also data to support the use of TDF in this way as it may produce a viral load drop of 0.7 [log.sub.10] even in the presence of TAMs (with the exception of M41L and L210W) [70].

Tolerability and long-term toxicity also need to be considered when choosing second-line and subsequent regimens. Given our current understanding of the toxicity issues of ZDV, d4T and ddI, the construction of regimens without the use of these drugs is preferable, if not always possible.

Conventional thinking has suggested that two nucleoside analogues should make up the backbone of all initial and most subsequent treatment regimens, and this is reflected in current treatment guidelines [22,23]. This view has been challenged by studies of monotherapy with boosted PIs [71], which have been demonstrated to have potency that is only slightly inferior to conventional regimens with two NRTIs. It may be that a single nucleoside analogue and a boosted PI will be sufficient to maintain virological suppression. This would save costs and reduce the potential for drug toxicity; however, it is an approach that remains to be explored widely in clinical studies.

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Correspondence to: Dr Zoe Warwick, Lawson Unit, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, UK.

Email: zoe.warwick@bsuh.nhs.uk
Table 1: Current licensed NRTIs available in the UK.

Drug Abbreviation Trade name

Zidovudine ZDV Retrovir
Stavudine d4T Zerit
Lamivudine 3TC Epivir
Emtricitabine FTC Emtriva
Didanosine ddI Videx/Videx EC
Abacavir ABC Ziagen
Tenofovir TDF Viread
ZDV/3TC Combivir
ABC/3TC Kivexa
TDF/FTC Truvada
ZDV/3TC/ABC TZV Trizivir
FTC/TDF/efavirenz Atripla
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Title Annotation:LEADING ARTICLE
Author:Warwick, Zoe; Churchill, Duncan
Publication:Journal of HIV Therapy
Geographic Code:4EUUK
Date:Mar 1, 2008
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