Newer nucleoside analogues show fewer adverse effects

Graeme Moyle,

New data on the adverse effects of antiretroviral therapy were fairly thin on the ground at this year’s ICAAC (September 14-17, 2003, Chicago, IL). However, there were valuable points raised, most notably with regard to the more favourable tolerability profiles of recently approved antiretrovirals and re-formulations of established agents. Notably lacking were new insights into the etiology and management of metabolic and morphological abnormalities.

Tenofovir (TDF, Viread) and the kidney: no evidence of harm from controlled data

Several clinical cohorts have reported clusters of individuals receiving tenofovir who have experienced elevations in creatinine, proteinuria or proximal renal tubular acidosis. In some of these reports, risk factors for these events appear evident, most notably prior proximal renal tubular acidosis during adefovir therapy. In some other case reports, renal toxic agents have been present, most notably fibrates, but authors of these abstracts chose to blame the renal dysfunction on tenofovir. Clearly, the best understanding of whether renal function abnormalities are more common during tenofovir use than alternative NRTIs will be derived from randomised controlled trials.

The GS 903 study is a double-blind placebo-controlled study comparing tenofovir (TDF) and d4T, each combined with 3TC and efavirenz, in treatment naïve individuals. The study has thus far completed 96 weeks of follow-up and detailed information regarding renal or possibly renal events was reported. Multiple ways of evaluating renal function during therapy were presented. In all cases no evidence of difference in events between tenofovir and d4T treated patients were observed.

The GS 903 study is a double-blind placebo-controlled study comparing tenofovir (TDF) and d4T, each combined with 3TC and efavirenz, in treatment naïve individuals. The study has thus far completed 96 weeks of follow-up and detailed information regarding renal or possibly renal events was reported. Multiple ways of evaluating renal function during therapy were presented. In all cases no evidence of difference in events between tenofovir and d4T treated patients were observed.

For no event reported were differences observed between the randomised groups, either numerically or statistically. No episodes of Fanconi’s syndrome were reported [1]. These data underline that renal events do occur during ART but ascribing these to TDF requires comparison with an appropriate control to be made. Case reports that do not investigate other possible causes of renal dysfunction, rule out concomitant agents associated with renal dysfunction and search for these events in matched subjects not receiving TDF should be treated with scepticism and caution.

Further data through 144 weeks of this study are anticipated for early 2004.

d4T extended release (Zerit XR)

The extended release formulation of stavudine (d4T XR) has been approved in a number of countries but not yet marketed due to production issues. The 100 mg once daily tablet leads to a slightly lower total exposure (with lower peak and higher trough values) of d4T relative to the standard formulation. (now called immediate release (IR)).

Equivalent efficacy has been demonstrated in two comparative studies that randomised treatment naïve individuals to either d4T XR or d4T IR in combination with 3TC and efavirenz. The 48-week results from these studies have suggested that there may be differences in the tolerability of the two d4T formulations, with fewer important adverse events in the XR arm.

Further comparative safety data from these two main studies, totaling 900 patients randomised equally to either d4T XR or d4T IR were reported. The average duration of treatment was 115 weeks.

Patients included in the studies had a median baseline CD4 cell count of 277 cells/mm3 and viral load of 4.8 log 10 cps/ml. Overall, rates of discontinuation from the studies were low with 12% of XR and 16% of IR patients discontinuing prior to week 48. Of these discontinuations 7% and 9%, respectively were related to adverse effects.

The most common treatment-related grade 2-4 adverse events were dizziness, rash, headaches, abnormal dreams, diarrhoea and nausea. Peripheral neuropathy (or ‘peripheral neurologic symptoms’ which included numbness, paresthesias, or pain in distal extremities) symptoms and physical signs were actively sought at each study visit.

Grades 2-4 neuropathy was reported in 4% of XR and 8% of IR treated patients. Only 1% of XR and 3% or IR patients discontinued d4T due to neuropathic symptoms.

Lipoatrophy has become a major obstacle to d4T use following several prospective studies that have indicated that regimens including d4T have a faster rate of fat loss over time relative to regimens based on AZT, abacavir or tenofovir.

Despite the possibility that this event is in part exposure dependent, no objective assessments of this event were included in the development programme for d4T XR. Specifically, baseline and follow up DEXA or CT scans were not performed. Lipodystrophy was not prospectively defined nor objectively confirmed. Events reported as lipodystrophy were ‘investigator defined’, similar to cases reported in the Gilead GS903 study.

Where lipodystrophy was reported, the investigator was asked to further define the event as ‘lipoatrophy’, ‘lipohypertrophy’ or mixed. ‘Lipoatrophy’ included events of facial, extremity, or subcutaneous fat loss. ‘Lipohypertrophy’ included increased abdominal girth, buffalo hump, lipomata and breast enlargement in women. Overall, lipodystrophy was reported in 11% of XR and 16% of IR patients (p=0.05), with lipoatrophy in 6% and 11%, lipohypertrophy in 3% and 2%, mixed syndrome in 2% and 3%, respectively.

Reports of ‘gynaecomastia’ (breast enlargement in males) were seen in 3% and 2% of XR and IR patients, respectively [2]. The data would indicate that whilst d4T XR may be somewhat less risky for lipoatrophy than the IR formulation, the event continues to be relatively common. Reports from the Gilead GS 903 study at 96 weeks have indicated that approximately 13% of patients in the d4T arm of that study have been diagnosed as having lipodystrophy by the investigator compared with just 1% of patients in the tenofovir arm.

Fasting grade 2 or more triglyceride elevations, an event that has been suggested to possibly relate to lipoatrophy, were reported in 5% in XR group as compared with 8% in IR group.

An event that is clearly related to mitochondrial toxicity is lactic acidosis. Several large cohort analyses have indicated that regimens containing d4T, and particularly those combining d4T and ddI, may be the greatest risk regimens for lactate elevation or lactic acidosis. This event however has been reported with all nucleoside analogue based regimens. So-called lactate events included ‘symptomatic hyperlactataemia’ (reported in two (1%) d4T XR and five (1%) IR treated individuals with one person in each group having lactic acidosis). The median time to presentation of lactate related symptoms was 44 weeks (range 34 – 57 weeks). Pancreatitis was reported in one (<1%) XR and four (<1%) IR patients [2].

In a pilot study of 22 individuals switching from AZT or d4T IR (with 3TC + Efavirenz) to a once daily regimen based on d4T XR good tolerability over 24 weeks was observed relative to 21 patients continuing their original therapy. One individual in the continuation group experienced virological rebound. One individual in the XR arm stopped d4T XR due to dizziness. No other patients in the XR arm discontinued therapy. No differences were observed between the groups with regards to other clinical adverse events. Differences in laboratory toxicity were not observed. In particular, there were no changes in lactate or fasting lipid values following the switch. DEXA scans and objective evaluations of fat mass were not performed. Adherence, as measured by MEMS caps, did not differ over the first 12 weeks of therapy [3].

Switching d4T to tenofovir

Results of the Gilead GS 903 study suggested a difference in triglycerides and cholesterol existed between d4T and tenofovir when each is combined with 3TC and efavirenz. Patients in the study randomised to the tenofovir group had smaller rises in triglycerides total and LDL cholesterol and greater rises in HDL cholesterol than individuals who received d4T.

These effects were evident at both 48 and 96 weeks and resulted in fewer patients in the tenofovir arm initiating lipid lowering therapy relative to the d4T arm. It has not yet been demonstrated if these benefits are seen when tenofovir is used as a substitution agent for d4T or other nucleoside analogues.

Evidence of the improved safety of tenofovir relative to d4T was reported in a cohort of patients from Spain. Investigators reported data on 94 individuals in whom triglycerides values were available before and after switching. The values were reported non-fasting. Triglycerides values dropped from a mean of 458.11 mg/dl (95% CI 396.73-519.58) at baseline to 278.50 mg/dl (95% CI 248.85-308.15) at 12 weeks (p<0.001). For changes in cholesterol, data were available on 70 individuals with results through week 12.

Cholesterol levels dropped from a mean of 265.73 mg/dl (95% CI 254.98 –276.48) at baseline to 230.96 mg/dl (95% CI 220.26 – 241.66) at 12 weeks (p<0.001). No virological rebound was reported after switching to tenofovir. No significant changes in CD4 were observed. The study suggests that randomised controlled investigation of the lipid benefits of tenofovir as a substitution agent for alternate nucleoside analogues is warranted.

Because some studies have suggested that triglycerides elevation in particular may be linked with the lipodystrophy syndrome, investigation of tenofovir in this setting is also warranted. This report from Spain did not provide details of any changes in patient morphology [4].

Abacavir + 3TC: a well-tolerated backbone

Several studies reported at ICAAC looked at the efficacy, tolerability and convenience of administration of abacavir plus 3TC. The pairing of these two drugs is well established from the use in their combination tablet with zidovudine, Trizivir. However, there are also plans for a combination tablet containing just abacavir and 3TC. This tablet has the potential for use as a once daily nucleoside pair.

Two studies combining abacavir and 3TC with efavirenz were reported. The first study CNA30024, compared this combination with AZT/3TC (as Combivir) plus efavirenz in treatment naïve individuals. The study included 324 individuals in the abacavir arm and 325 in the zidovudine arm with a median baseline CD4 cell count of 264/mm3 and a median viral load of 4.79 log.

Over the course of 48 weeks follow-up 13% of abacavir and 15% of zidovudine treated patients discontinued therapy due to an adverse event. The two drugs perform similarly from the efficacy standpoint although the abacavir group experienced a more substantial rise in CD4 lymphocyte count (208.5 cells/mm3) compared with the zidovudine treated patients (154.5 cells/mm3) over 48 weeks.

The most frequently reported grade 3-4 adverse events included rises in liver function tests (3% in each group), nausea (less than 1% and 2% for abacavir and zidovudine respectively), hypertriglyceridaemia (2% in each group), decreased white blood cell count (less than 1% and 2% respectively), and anaemia (0% and 2% respectively).

Events that led to discontinuation in the abacavir arm included abacavir hypersensitivity in 8%, with 2% discontinuing for nausea, 2% for rash and 1% for dizziness. Reasons for discontinuation in the zidovudine arm included anaemia in 4% with a further 3% discontinuing for each of dizziness, nausea and rash.

It is of note that this was a blinded study and initially investigators reported 10 (3%) patients in the zidovudine arm to have experienced the abacavir hypersensitivity reaction. Once the investigators were informed that these individuals were not taking abacavir these cases were adjusted [5]. Details of changes in lipids or assessments of changes in patient morphology were not reported.

The study defines the differences between abacavir and zidovudine. In general, patients initiating abacavir need only concern themselves with the adverse effect of hypersensitivity reaction. If this reaction is not experienced the drug appears to be very well tolerated. With zidovudine a wider range of problems are seen – most commonly anaemia, leukopaenia and nausea. If a simple screening test is established to rule out those individuals most likely to experience the abacavir hypersensitivity reaction one could potentially see the combination of abacavir and 3TC becoming preferred to Combivir.

A second advantage of abacavir and 3TC relative to Combivir is the potential for once daily dosing. This was explored in the ZODIAC study (CNA30021) – a randomised, placebo controlled trial, comparing abacavir administered once daily with abacavir administered twice daily in combination with 3TC and efavirenz both administered once daily. A total of 384 individuals initiated abacavir once daily and 386 individuals twice daily. Participants had a median CD4 count of 262 cells/mm3 and median viral load of 4.9 log.

No differences in the efficacy were observed between the two dosing schedules of abacavir. Similar numbers of individuals discontinued therapy in each arm and no differences in the frequency of drug-related grade 2-4 adverse events were observed. Abacavir hypersensitivity was diagnosed in 9% of individuals in the once daily and 7% of individuals in the twice-daily abacavir arms. Symptoms at presentation of hypersensitivity also did not differ between arms [6].


NRTI preference is likely to change over the next few years as we see the appearance of new combination tablets and increasing evidence that combinations based on abacavir or tenofovir had improved tolerability relative to the thymidine analogues. Data presented at this conference indicate that both tenofovir and abacavir are well tolerated and have predictable adverse event profiles. Head-to-head comparisons of regimens based on tenofovir or abacavir are now required.

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  1. Gallant J Pozniak A, Staszewski S et al for the Study 903 Team. Similar 96-week renal safety profile of tenofovir DF (TDF) versus stavudine (d4T) when used in combination with lamivudine (3TC) and efavirenz (EFV) in antiretroviral naîve patients. 43rd ICAAC, September, 2003; Abstract H-840.
  2. Brett-Smith HM , Reynolds L, Bessen L et al. Two year analysis of stavudine extended-release/prolonged release capsules (XR/PRC) as compared to stavudine immediate-release (IR): efficacy and safety. 43rd ICAAC, September, 2003; Abstract H-855b
  3. Portsmouth SD, Osorio J, et al. Once daily stavudine (d4T PRC) versus twice daily stavudine: a comparison of the efficacy, tolerability, safety and adherence. 43rd ICAAC, Abstract: H-842
  4. Moreno S , Domingo P 0et al. Dyslipidemia improvement in patients switching from  d4T to tenofovir. 43rd ICAAC, Abstract: H-843
  5. DeJesus E, Herrera G, Teofilo E, et al. Efficacy and safety of abacavir (ABC) versus zidovudine (ZDV) in antiretroviral therapy naïve adults with HIV-1 infection (Study CNA30024). 43rd ICAAC, September, 2003; Abstract H-446
  6. Gazzard BG, DeJesus E, Cahn P, et al. Abacavir (ABC) once daily (OAD) plus lamivudine (3TC) OAD in combination with efavirenz (EFV) OAD is well-tolerated and effective in the treatment of antiretroviral therapy (ART) naïve adults with HIV-1 infection (ZODIAC Study: CNA30021). 43rd ICAAC, September, 2003; Abstract: H-1722b.

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