Nucleoside reverse transcriptase inhibitors

Protease inhibitor therapy is not the sole factor associated with body fat changes. The Sixth Conference on Retroviruses and Opportunistic Infections in 1999 heard of over 60 cases of lipodystrophy in people taking antiretroviral therapy that did not include protease inhibitors. Subsequent data confirmed earlier reports linking nucleoside analogues to lipodystrophy, lipoatrophy and metabolic irregularities.

Several studies have demonstrated body fat changes in people who have never taken protease inhibitors:

• A Spanish prospective study of 295 patients who started triple regimens that did not contain PIs found that 15% had developed lipodystrophy after an average follow-up of 19 months with d4T treatment, and greater than twelve months antiretroviral treatment associated with an increased risk of lipodystrophy. ¹
• A Spanish study reported alterations in fat tissue in 14% of 335 people who had been on long-term NRTI therapy. Nine people developed fat accumulation, 12 fat loss, and 25 combined fat loss and accumulation with fat loss taking longer to develop. Women were more likely to experience body fat changes. ²

One study, which looked at people who switched from an NRTI-only regimen to an NRTI-sparing regimen, provided an opportunity to observe the NRTI contribution to lipodystrophy. People who failed on a two- or three-NRTI regimen switched to a combination of ritonavir-boosted indinavir and efavirenz. Small increases in leg fat and visceral fat were seen, but were offset by increases in LDL and total cholesterol, triglyceride and glucose levels. ³

In general, the thymidine analogues (AZT and d4T) have been more implicated than other NRTIs in lipoatrophy and blood fat alterations. ^4 5 6 In particular, d4T is most strongly associated.A substudy of the large ACTG 5202 trial found no significant differences between tenofovir/FTC (Truvada) and abacavir/3TC (Kivexa) in terms of their effect on limb fat.⁷

The precise mechanism by which nucleoside analogues might cause fat loss is unclear. One suggestion is that nucleoside analogues may damage the DNA of mitochondria in fat cells (adipocytes) that store fat in the limbs. NRTI-related fat loss has been linked to alterations in mitochondrial DNA, high levels of lactate in the blood and liver dysfunction.^8 9 3

At least two major studies - ACTG384 and Gilead 903 - have indicated that d4T (stavudine, Zerit) is more strongly associated with body fat changes, specifically fat loss (lipoatrophy), than other NRTIs.

In a sub-study of the large ACTG384 clinical trial, 156 patients were randomised to one of two nucleoside analogue backbones, AZT/3TC or d4T/ddI. They were then randomised again to add either nelfinavir, efavirenz or both to that backbone (a total of six treatment arms). Limb fat levels (measured by DEXA scan) initially increased after starting treatment. But by 64 weeks, limb fat levels in people taking ddI/d4T had fallen to 13% below baseline, while the AZT/3TC group had limb fat levels 2% above baseline.¹⁰

The Gilead 903 trial compared tenofovir to d4T in people also taking efavirenz and 3TC. At week 96, 12% of patients in the d4T arm had developed investigator-defined lipodystrophy, compared to 1% of patients in the tenofovir arm. Also at week 96, tenofovir-treated patients had gained more weight (6lbs versus 1lb) and had an average of 6lbs greater limb fat as shown by DEXA scan.¹¹

These two studies convinced many clinicians that d4T does have a causative role in fat wasting, and that the drug should not be used where other treatment options exist, especially for first-line treatment. Treatment guidelines have subsequently recommended that the use of d4T in first-line therapy should be avoided wherever possible.

Several other prospective studies have also linked d4T and fat wasting. CPCRA 058 reported that d4T/ddI-treated patients lost significantly more subcutaneous fat compared to abacavir/3TC treated patients, after a median of 33 months. Ninety-six patients were studied in more detail in a metabolic sub-study. By every measure (skin fold thickness, waist and hip measurements, and total body fat using bioimpedance assay [BIA]), the d4T/ddI treated patients had lost fat after 33 months, whilst the abacavir/3TC group had gained fat.

A prospective non-randomised study conducted in Western Australia tracked 53 male treatment-naive patients who initiated treatment with regimens that contained AZT or d4T. The vast majority of patients also received 3TC. Patients were followed for at least 24 months, and the study only analysed patients who took the drug throughout the 24 months follow-up (an on-treatment analysis). Limb fat was reported by DEXA scan. At baseline, participants had approximately 22% fat content in their legs. During the first year of treatment, individuals tended to gain weight. As time went on, leg fat declined in both treatment groups, falling to 13% in the d4T group and 19% in the AZT group after 24 months. No difference could be detected when fat loss was analysed according to concomitant use of protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Although individuals with AIDS, and older individuals, had lower leg fat levels at baseline, these individuals did not lose fat faster or more profoundly, suggesting that these host factors do not dictate fat loss.

The researchers also analysed fat loss in 59 patients who had received prior treatment with AZT before commencing a triple HAART regimen. Those who switched to d4T after prior AZT treatment had greater fat loss and a greater decline in leg fat as a proportion of total fat than patients who continued on AZT for 30 months. It has been argued that fat loss associated with d4T in large cohort studies is actually attributable to the duration of prior AZT treatment; this finding goes some way to refuting that view.¹²

A number of other observational studies have also found a link between fat wasting and treatment with d4T, yet not all studies find this link.^{13 14 15 16}  The French NOVAVIR study found little difference in amount of fat loss experienced on d4T or AZT.¹⁷ This randomised study compared people switching to d4T/3TC or AZT/3TC after approximately two years of exposure to AZT, ddI or ddC. After 30 months follow-up, the only body fat measurement that differed between the two groups was the thigh skinfold fat measurement: d4T recipients had less thigh fat. There was a significant difference in body fat by clinician assessment; 70% of d4T recipients had fat loss compared with 44% of the AZT recipients. It should be noted that this was not a blinded study.

More recently, a case-controlled study of cervical lipomatosis (‘buffalo hump’) identified lipoatrophy and duration of d4T use as the only predictive factors for this condition.¹⁸