Changing from protease inhibitor treatment

Longer term follow-up of patients with body fat changes who have switched from a protease inhibitor (PI) to a PI-sparing combination shows that body fat maldistribution does not improve after six to twelve months in the vast majority of cases.

Comparisons between these studies are difficult to make because studies used different methods to assess body fat changes, some studies lacked control groups and many studies were observational rather than randomised. Only one randomised study using the most reliable method for assessment of visceral and subcutaneous fat (MRI) has been conducted, and this study found no reduction in visceral fat (Carr 2001). Studies of nucleoside analogue switching are discussed below.

Switch studies have shown variable trends in cholesterol and triglyceride levels. Randomised studies of abacavir substitution have shown significant reductions in total cholesterol, and two of three studies showed a reduction in triglyceride levels too (Lafeuillade 2001; Opravil 2002; Clumeck 2001; Pulvirenti 2001). This has been confirmed in a substudy of a large Spanish trial, in which levels of non-HDL cholesterol were reduced two years after replacing PIs with abacavir (Fisac 2005). The same study showed favourable increases in HDL cholesterol and in total to HDL cholesterol ratios after switching to efavirenz or nevirapine.

Reductions in cholesterol and triglyceride levels have been less consistent in studies of efavirenz or nevirapine substitution. Two randomised studies of nevirapine substitution have shown improvements in cholesterol and triglycerides (Barreiro 2000), but only one of these studies included a comparison arm in which people remained on PI treatment (Negredo 2002). No randomised studies have cholesterol or triglyceride reductions after a switch to efavirenz. However, the majority of studies that have measured HDL cholesterol show a distinct class effect of NNRTIs: sustained increases in HDL cholesterol despite little reduction in total cholesterol (Fisac 2005).

Insulin resistance does not necessarily improve after switching therapy. The only randomised study to report on insulin sensitivity found that it had improved 12 months after a switch to abacavir, efavirenz or nevirapine, but this study did not have a control group that remained on PI treatment (Martinez 2002). A cohort study in which all patients switched to efavirenz showed no improvement in insulin sensitivity after 12 months (Estrada 2002). In contrast, other uncontrolled cohort studies have reported improvements after switches to nevirapine or efavirenz.

In the majority of individuals who switch, viral load remains undetectable; one study found that individuals randomised to switch to efavirenz were significantly less likely to experience viral rebound within 48 weeks of switching when compared to those who remained on PI treatment (Becker 2000), and a similar trend was seen in two other randomised studies, one of efavirenz and one of nevirapine substitution (Katlama 2000; Barreiro 2000). Two randomised studies of abacavir substitution have also reported superior viral load responses in the switch group (Pulvirent 2001; Clumeck 2001). However one study of abacavir substitution showed that individuals with prior nucleoside analogue experience had a higher risk of viral rebound (Opravil 2002).

Quite a few of the switch studies asked patients if they found it easier to adhere, or if the drugs were difficult to take, or if quality of life had improved. In each case they reported improved satisfaction with the new therapy, because it was easier to take.

Despite these advantages, however, a recent Italian study has suggested that switching from PI- to NNRTI-based therapy may be less effective than use of lipid-lowering drugs in managing lipid elevations. The study, which randomised 132 patients with high triglyceride and cholesterol levels to switch from their PI to nevirapine or efavirenz, or to add pravastatin (Lipostat) or bezafibrate (Bezalip) to their PI-based HAART regimen, showed greater decreases in triglycerides and LDL cholesterol in the NNRTI group (Calza 2005).

There was little evidence to support a switch from one protease inhibitor to another until the arrival of atazanavir, a new protease inhibitor developed by Bristol-Myers Squibb. Individuals who switched from nelfinavir to atazanavir experienced significant lipid reductions within 12 weeks, and average levels returned to pre-treatment baseline levels (Wood 2004). See Atazanavir - overview in Drugs used by people with HIV: Protease inhibitors for further details.

Why switching protease inhibitors may not restore body fat

In an attempt to explain poor results after stopping or switching PI therapy, Carr and colleagues have suggested that fat loss is either irreversible, or may take more than six months to reverse. Another possibility is that some aspects of these fat and metabolic disorders may not be associated with protease inhibitor treatment nor with elevated lipids. Instead, nucleoside analogues or other factors may be causing these disorders.

Switching nucleoside reverse transcriptase inhibitors?

Evidence from several small studies has suggested some benefit from switching away from d4T treatment, but the numbers treated in these studies were small, with no matched control groups or randomisation.

Well-controlled studies looking at the strategy of changing nucleosides are very thin on the ground. Although the data is preliminary and in some cases inconsistent and conflicting, current evidence suggests that switching away from d4T to another NRTI seems to produce modest benefits in fat wasting.

In the MITOX study, 111 patients were randomised to switch from d4T or AZT to abacavir or stay on these drugs, and no one changed any of their other drugs. After 24 weeks, people who switched had 390 grams of limb fat more than the d4T/AZT group, and significant increases in subcutaneous leg, arm and abdominal fat as measured by CT scan, but patients did not report noticeable improvements (Carr 2002).

Individuals who had switched to abacavir had a mean increase in limb fat at week 104 of 1.26kg (+/- 2.02kg) compared to 0.46kg (+/-1.38kg) for the patients who remained on a thymidine analogue. This difference was statistically significant (p = 0.008). However, individuals self-assessment of lipodystrophy at week 104 not did differ significantly between the abacavir and thymidine analogue arms, and self-assessed changes in lipodystrophy correlated poorly with changes in limb fat observed using the DEXA scans (Martin 2004).

There was a 10% rate of hypersensitivity in this study this may vary across populations - and a 20% rate of adverse events among people who switched, versus 6% in those who stayed with their existing therapy.

In a second Australian study, 37 patients taking d4T/3TC plus nelfinavir or indinavir or AZT/3TC/indinavir were randomised to switch d4T and their protease inhibitor for AZT and abacavir, or to stay on existing therapy, so that everyone who switched ended up taking AZT/3TC/abacavir. After 48 weeks on the new regimen, intent-to-treat analysis showed that leg fat in the control group had continued to decline by an average of 10g a month, whereas it increased by an average of 7g a month in the switch group (p = 0.05). The change in leg fat percentage was not statistically significant. Arm fat increased in the switch group (+12g/per month), but did not change substantially in the control group (John 2003). The extreme modesty of the fat gains recorded in this study were underlined by the on-treatment analysis of percentage fat changes. Patients who switched to abacavir gained just 95g (0.23%) in fat mass per leg after 48 weeks. Abdominal fat did not change significantly over the 48 week period.

The authors point out that two processes appeared to be at work after the switch, depending on the baseline regimen. In those whose baseline regimen did not include d4T, the effect of a switch to abacavir appeared to be the sparing of further fat loss. However, in individuals receiving d4T and a protease inhibitor at baseline, fat restoration was the predominant effect of a switch, perhaps due to more substantial fat loss prior to the switch.

A second observation in this study concerned the timing of fat restoration: the larger fat gain occurred after week 24, leading the authors to suggest that the rate of fat restoration may pick up speed as time goes on. Fat restoration occurs more quickly in the arms, they say, than in the legs.

In an American study with no control group, 118 people replaced d4T with either abacavir or AZT. After 48 weeks, those who switched showed much greater improvements than those seen in the two studies described previously. Fat levels in the arms had increased by 35.3% from baseline, whilst trunk fat and leg fat had increased by 16.4% and 12% respectively. CT scans indicated that the total increase in subcutaneous fat was 4%, whilst visceral fat declined by 2%. Seventy nine per cent of participants experienced an increase in subcutaneous fat, and 54% experienced a decrease in visceral fat (McComsey 2002b). Five out of 86 patients experienced abacavir hypersensitivity reactions.

A British study conducted by Graeme Moyle randomised 30 people with high cholesterol and lipoatrophy to switch from d4T to abacavir. Body fat changes were monitored by DEXA scan at baseline and weeks 12, 24, 36 and 48. Leg fat increased significantly in patients who switched from d4T to abacavir (+1.08kg, or +52%) after 48 weeks, but declined slightly in those who continued d4T treatment or switched to AZT and abacavir. These moderate changes were not noticed by patients, who reported no significant changes in several measures of body fat including leg fat (Moyle 2003).

Should you stop your drugs?

As discussed above, it is currently unclear whether stopping or switching particular drugs resolves metabolic irregularities or fat redistribution. Consequently, stopping anti-HIV therapy completely is not generally advised by medical experts. The decision to stop treatment should only be made in close consultation with an HIV specialist doctor.

There are few data on the effects of treatment interruptions on lipodystrophy.

A study of 26 people who interrupted PI therapy for a median of seven weeks found that although cholesterol and triglyceride levels improved significantly in the short period off treatment, body fat distribution and glucose metabolism did not improve (Hatano 2000).

Ten men with NRTI-associated wasting lost an average of 6kg. Three months after ceasing treatment, average weight gain was 2.5kg (Carr 2000).

NRTI-sparing regimens

There has been recent interest in testing whether dropping NRTIs altogether can deliver improvements in body fat distribution and halt lipoatrophy.

ACTG 5125s was a metabolic substudy of ACTG 5116, which randomised individuals with advanced HIV disease to switch from their existing stable therapy to either ritonavir-boosted lopinavir (Kaletra) with efavirenz (Sustiva) or efavirenz plus two NRTIs. The study recruited 62 participants.

At baseline the median total limb fat was 6kg, measured by dual energy X-ray absorpiometry (DEXA) scans. This increased by a median of 562g in those who switched to Kaletra / efavirenz, compared with a median loss of 246g in those who continued to receive NRTIs in their regimen (p = 0.097).

Among 46 patients who had been followed for a median of 104 weeks, those in the non-NRTI arm gained a median of 782g of limb fat, whilst those in the NRTI arm had lost a median of 900g of limb fat compared to baseline (p = 0.002) (Tebas 2005).

Another study, AACTG 5110, randomised 77 patients with viral loads below 500 copies/ml on d4T or AZT-containing regimens to switch this NRTI to abacavir (Ziagen), or to discontinue their current drug regimen and begin the NRTI-sparing combination of Kaletra and nevirapine (Viramune).

After 24 weeks, computed tomography (CT) scans showed that the 37 patients receiving the NRTI-sparing regimen had experienced a median increase of 8% in subcutaneous thigh fat (p = 0.06). This was compared to no change in the abacavir group.

Subcutaneous abdominal fat tissue increased in both groups (p < 0.05), but the effect was greater in the NRTI-sparing group (17 vs. 9%, p = 0.008). Similarly, the ratio of visceral to total fat improved in both groups (p < 0.01), but the decrease was greater in the abacavir group (-9 vs. 12%, p < 0.001).

The switch to the NRTI-sparing regimen was found to be immunologically safe, leading to a significant increase in CD4 cell count (8 cells/mm3, p = 0.03) after 24 weeks. Similar proportions of both groups also maintained undetectable viral loads (93 vs. 92%).

AACTG 5110 is the first study to detect an improvement in lipoatrophy after only 24 weeks. However, the researchers warn that an 8% increase in limb fat from a very low baseline is modest, and unlikely to be detected by the patient (Murphy 2005).

Research on switching NRTIs

Carr (2002) conducted a randomised, open-label study of 111 HIV-infected adults with moderate or severe fat wasting (lipoatrophy) who were taking d4T or AZT. Participants were randomised to switch d4T or AZT for abacavir (300mg twice daily) while continuing their other drugs or to continue with their existing therapy. At week 24, DXA scan showed that the people who switched to abacavir had a significant increase in limb fat relative to those who continued d4T or AZT (+0.39kg vs +0.08kg), as well as increases in subcutaneous arm, leg and abdominal fat. The authors concluded that lipoatrophy would take years to resolve at this rate of improvement.

McComsey (2002c) reported improvement in lipoatrophy among 118 people who switched from d4T to abacavir (n=86) or AZT (n=32). DXA at week 48 showed a + 35.3% increase in arm fat from baseline, whilst trunk fat and leg fat had increased by 16.4% and 12% respectively. CT scans indicated that the total increase in subcutaneous fat was 4%, whilst visceral fat declined by 2%. Seventy nine per cent of participants experienced an increase in subcutaneous fat, and 54% experienced a decrease in visceral fat. 95% of participants maintained viral load below 400 copies at week 48.

John (2003) studied 37 people who had been taking d4T/3TC/indinavir, or d4T/3TC/nelfinavir or AZT/3TC/indinavir and were randomised to replace d4T with AZT and their protease inhibitor (PI) with abacavir or continue therapy. After 48 weeks on the new regimen, intent to treat analysis showed that leg fat in the control group had continued to decline by an average of 10g a month, whereas it increased by an average of 7g a month in the switch group (p=0.05). The change in leg fat percentage was not statistically significant. Arm fat increased in the switch group (+12g/per month), but did not change substantially in the control group. On-treatment analysis results were substantially similar. The extreme modesty of the fat gains recorded in this study were underlined by the on-treatment analysis of percentage fat changes. Patients who switched to abacavir gained just 95g (0.23%) in fat mass per leg after 48 weeks.

Moyle (2003) randomised 30 patients with viral load below 50 copies/ml either to switch from d4T to abacavir (group 1), to switch from a PI or NNRTI to abacavir (group 2), or to switch from d4T and a PI to AZT and abacavir (group 3). The study recruited participants with cholesterol levels above 5.2mmol/l and/or lipoatrophy who were receiving a d4T-containing regimen. At baseline 20 patients were receiving protease inhibitors (11 nelfinavir, six indinavir and three ritonavir/saqinavir) and ten were receiving NNRTIs (seven efavirenz and three nevirapine). Participants had received a PI or NNRTI-containing regimen for a mean of 29.7 months, and had a mean cholesterol level of 6.39 mmol/l (LDL cholesterol 4.2, HDL cholesterol 0.88, triglycerides 3.6mmol/l). Body fat changes were monitored by DEXA scan at baseline and weeks 12, 24, 36 and 48. Leg fat increased significantly in patients who switched from d4T to abacavir (+1.08kg, or +52%) after 48 weeks, but declined slightly in those who continued d4T treatment (group 2) or switched to AZT and abacavir (group 3). Central fat, measured by CT scan, did not change significantly in any group. Patients reported no significant change in fat levels in the face, buttocks, arms or legs over 48 weeks of follow-up. In patients who stopped taking a PI or NNRTI, LDL cholesterol levels fell substantially (-1.6, -1.1 mmol/L), as did total cholesterol (-1.7, -1.6 mmol/L), but in patients who changed from d4T to abacavir (group 1), LDL cholesterol did not fall, and total cholesterol showed a trend towards increase (+0.74mmol/l). Although measures of statistical significance are reported only for the pooled values, the authors state that the reductions in total and LDL cholesterol were significant. Triglyceride reductions in patients who continued d4T but switched from PI or NNRTI to abacavir were statistically significant. Insulin levels fell substantially in patients who replaced a protease inhibitor or NNRTI with efavirenz. All other metabolic parameters remained substantially unchanged.

Saint-Marc (1999) discontinued d4T in 36 people on with lipoatrophy with a median follow-up of 11 months. Triglycerides fell by 29%, lactates by 37%, while cholesterol, glucose and insulin levels were unchanged. Subcutaneous fat increased by about one-third, and fat mass also increased by over one-third. Eleven individuals reported major body fat improvement and 21 reported partial improvement.

Polo (1999b) reported on 10 HIV-infected people on HAART including ddI/d4T who developed body fat changes and metabolic abnormalities. The nucleosides were switched to AZT/3TC while the protease inhibitor was not changed. After six months, increases in total body fat, decreases in waist size, increases in limb size and decreases in triglycerides occurred.

Research on switching PI to NRTI or NNRTI

Fisac (2002) reported interim results from an ongoing randomised study in which participants switched from a PI-based to a PI-sparing regimen including abacavir (n=29), efavirenz (n=32) or nevirapine (n=32). 12 people discontinued their PI-sparing regimen during follow-up. At 6 months, insulin sensitivity, HDL cholesterol, LDL cholesterol and total cholesterol:HDL cholesterol had improved significantly. Insulin improved in all three groups. HDL cholesterol increased in the two NNRTI groups but decreased in the abacavir group. Triglycerides fell only in the nevirapine group.

Negredo (2002b) randomised 77 individuals with 12 months of viral load continuously suppressed below 50 copies to continue PI therapy or switch to nevirapine or efavirenz, and conducted DEXA scans at baseline to assess fat distribution. There was no significant difference in the rate of viral rebound between the three arms after 9 months. Total cholesterol and LDL cholesterol levels fell significantly in the nevirapine arm, but not in the other arms. In a sub-study of 56 patients diagnosed with body fat changes at baseline (as defined by an objective scale developed from a cohort of Spanish patients with severe lipodystrophy), there was no significant improvement in body fat redistribution after 9 months when assessed by DEXA scan and anthropometric measures.

Martinez (2002b) reported a prospective, randomised study of 460 HIV-infected people with CD4 counts below 200 who replace a protease inhibitor (PI) with either nevirapine, efavirenz or abacavir. Twelve months after the switch, intent-to-treat analysis showed that approximately three-quarters of each group had maintained viral suppression, although the on-treatment analysis showed a trend to greater suppression among those on nevirapine or efavirenz. The rate of discontinuations due to side-effects were 16% nevirapine, 17% efavirenz and 6% abacavir (p=0.009). The proportion of patients with cholesterol above 240mg/dL also favoured abacavir: 24% nevirapine, 22% efavirenz and 9% abacavir (p=0.01).

Raffi (2000) reported on the Maintavir study, an open label study which has now followed 73 patients for approximately 18 months after a switch from PI to an NNRTI-based regimen. All switchers had a history of viral load suppressed below 400 copies for at least one year prior to switching (69 of 73 were below 50 copies), and had been on PI treatment for an average of 22 months. Sixty-three switched to nevirapine and 10 to efavirenz, and in most cases did not make any changes to the NRTI backbone. Ten out of 73 switchers experienced viral load rebound, which was significantly more likely in patients who had some experience of antiretroviral therapy. Seven of the 18 cases of lipodystrophy diagnosed at baseline were said to have improved during the study, but no baseline DEXA measurements were conducted that would allow an objective assessment. All the improvements were seen in the patients with fat accumulation. Three cases of lipoatrophy appeared after the switch, but no cases of fat accumulation developed. There was no significant change in cholesterol levels in this study (although they were in the normal range at baseline), but triglyceride levels did fall significantly by month 6 and returned to the normal range.

Greiger-Zanlungo (2002) switched 29 people who had been taking PI-containing combinations for a year to PI-sparing regimens with nevirapine (n=14), efavirenz (n=6) or abacavir (n=8). 86% maintained viral suppression at 37 months follow-up. Elevated cholesterol and triglycerides initially improved after the switch but returned to baseline by month 12. There was no difference in metabolic parametres between the 3 groups.

Bickel (2000) switched 26 people on a PI-based regimen with viral load below 50 to abacavir plus efavirenz. All maintained undetectable viral load at week 24 except for 2 people who ceased therapy due to abacavir hypersensitivity and one who had viral rebound due to non-adherence. Diabetes resolved in 2 of 4 diabetic patients and preliminary analysis indicated lipids were declining. Five of 8 patients with body fat changes reported improvements and 2 reported stabilisation.

Mahajan (2001) reported on an observational study of 14 women on protease inhibitor (PI)-containing regimens with body habitus changes and 13 women on treatment without body fat changes. During 3.5 years follow-up, two previously unaffected women developed symptoms at about 2 years. 8 of 14 women changed their PI for an NNRTI but only 2 had improvements in lipodystrophy. Lipid levels remained abnormal 13 months after the switch. The control group without lipodystrophy showed similar lipid abnormalities to the affected women.

Tashima (2002) found that 5 of 14 women with lipodystrophy who switched from a PI-based regimen to an NNRTI-based regimen had complete resolution of lipodystrophy after an average of 22 months on the PI-sparing regimen. 3 of the women were taking d4T/3TC and 2 were taking AZT/3TC.

Carr (2001) enrolled 81 highly treatment experienced people with PI-associated lipoatrophy and/or fat accumulation into a switching study. 40% were randomised to continue PI/NRTI treatment and 60% switched to abacavir/adefovir/nevirapine/hydroxyurea. After 6 months, the switch group had a greater decline in fat and lean mass compared with the control group, possibly due to nausea and vomiting associated with the new combination. The switch group also had a CD4 decline of 70 cells, possibly due to HU. Central fat adiposity declined in the switch group, as did visceral fat, cholesterol and glucose intolerance. Triglycerides and total cholesterol levels declined more in the switch group, while HDL cholesterol increased in both groups. Interestingly, patients believed that their fat maldistribution had improved, even though DEXA measurements showed no significant change.

Also see Moyle (2002b) and John (2002) above, in which people switched d4T and/or a PI for abacavir.

Research on switching PI to abacavir

Walli (2001) conducted a pilot study of 31 HIV-infected people taking PI-based therapy, 16 of whom replaced their PI with abacavir. Median insulin sensitivity had increased in the abacavir group at 6 months, while fasting total cholesterol and triglycerides had fallen significantly at 3 months. In the PI group, no significant changes occurred.

Clumeck (2001) reported 48 week data from the CNA30017 study in which 211 patients were randomised to switch to abacavir or stick to existing PI-based HAART. Treatment failure was more likely in the PI arm (23% vs 12%, p=0.03) and time to treatment failure was longer in the abacavir group. There was a significantly greater improvement in cholesterol and non-fasting triglycerides in the abacavir group, although both groups had triglyceride levels within the normal range at baseline. Drug-related side-effects led to discontinuation of treatment in 8 of the abacavir recipients and 14 of the PI recipients. 60% of the abacavir group experienced significant improvement in central obesity, and all cases of lipoatrophy resolved at week 24, although one new case of facial lipoatrophy appeared in the abacavir group. 5/13 cases of lipoatrophy improved in the PI group over 48 weeks.

Opravil (2000) randomised 163 individuals with a history of more than 6 months of continuous viral load suppression below 50 copies on PI-based HAART to switch to abacavir-based HAART, (and were able to take Trizivir when it became available), or to stay on PI-based HAART. After 68 weeks there was no difference in the rate of viral load rebound between the two groups (29% PI vs 25% ABC), but cholesterol levels were significantly more likely to have fallen within four weeks of randomisation in the abacavir group ( to the mid-average level), although HDL cholesterol levels did not fall. There was a greater risk of viral load rebound in abacavir recipients who had taken antiretroviral drugs prior to commencing PI-based HAART. In such cases AZT resistance mutations coupled with the M184V mutation appear combined to undermine the effectiveness of abacavir.

Also see Moyle (2002b) and John (2002) above, in which people replaced d4T and/or a PI with abacavir.

Research on switching PI to nevirapine

Negredo (2002) studied 34 people with lipodystrophy who were randomised to replace a PI with nevirapine or continue current treatment. At week 24, the switch group experienced significant reductions in total cholesterol, LDL cholesterol, the number of circulating LDL cholesterol particles and VLDL-1 triglycerides. HLD cholesterol and the size of HDL particles increased significantly.

Cotton (2000) conducted a meta-analysis of trials switching individuals from a PI to nevirapine. Of 446 people, data was available on 364 at week 12. Of the 364, 94.5% had undetectable viral loads at week 12. Mean cholesterol and triglycerides levels fell slightly (20 mg/dl and 60 mg/dl). Body shape changes were inconsistent; one study showed improvement by DEXA, one showed improvement in waist-hip ratio and observed improvement was reported in 2 studies.

Ladisa (2000) reported on 24 individuals who switched to nevirapine and 4 who switched to efavirenz after experiencing metabolic side effects related to PI therapy and a matched control group who continued PI therapy. Lipid and glucose levels had returned to normal within 9 months. Approximately a quarter of both groups had viral load rebound above 80 after 24-36 weeks.

Tebas (2000) switched 39 people with viral suppression and body fat/metabolic disorders from PI- to nevirapine-containing regimens. After a median follow-up time of 30 weeks, 1 person stopped due to hepatitis, 1 due to viral rebound and six switched to efavirenz due to rash. Triglycerides fell by 44%, glucagon levels by 23%, and HDL cholesterol increased by 26%. LDL cholesterol, insulin, proinsulin and abdominal fat did not change. Original reports indicated that fat maldistribution actually worsened, but the most recent report was that body fat did not change after the switch in therapy. Researchers speculated that the body fat changes may be irreversible.

Ruiz (2001) enrolled 106 in a randomised study to determine the effect on body fat and lipids of switching from d4T/3TC/PI to d4T/ddI/nevirapine. All participants had viral load below 500 for at least 6 months at baseline. 48-week data did not show significant improvements in body fat distribution in the switch group. Cholesterol and triglycerides fell in the group randomised to switch to nevirapine (p<0.05) although there was no significant difference between the lipid values of the two groups at the end of the study. Switchers reported improved quality of life attributed to their simplified drug regimen.

Gatell (1999) presented 21 month data on 23 people with lipodystrophy (15 with fat wasting and abdominal fat accumulation, 2 with abdominal fat accumulation and 6 with peripheral fat wasting). Prior to switching from a PI to nevirapine, all had viral load below 200 and high triglycerides, 78% had high cholesterol, 30% had impaired fasting glucose. A year after switching, those percentages were 17%, 22% and 0%. Cholesterol had fallen by 30%, triglycerides by 62%, fasting insulin resistance by 57%. The 13 people on d4T had significantly smaller decreases in lipids a year after switching.

Barreiro (2000) randomised 138 people on PI therapy with viral loads below 50 to switch their PI for nevirapine, or to remain on their PI. Viral rebound was 8% in the nevirapine group and 12% in the PI group 3 months after switching, and 11% and 29% 6 months after switching. Poor adherence was the most common cause of viral rebound. Moderate lipid falls occurred in both groups and half the nevirapine group and none of the PI group reported body shape improvement, although the measures by which body fat changes were judged are not reported.

Research on switching PI to efavirenz

Rachlis (2000) reported 24 week data from DMP266-049 (3), in which 207 individuals with a history of more than 6 months viral load below 50 copies were randomised to switch to efavirenz or remain on a PI. By a non-completer equals failure analysis, the efavirenz group had a significantly better viral load response (89% vs 81%). However, using an As Observed analysis, there was no difference in response. The data on lipid changes reported non-fasting measurements. Average baseline cholesterol measurements were within the normal range, and did not change significantly during the follow-up period. HDL cholesterol levels increased significantly however.

Hirschel (2002) compared 184 people who switched their PI for efavirenz and 368 people who continued on PI therapy. Those continuing on PI treatment were more likely to experience virological failure while injecting drug users were more likely to stop efavirenz, often due to side-effects.

Estrada (2002) conducted an observational study of 41 people with severe lipoatrophy, high lipids and insulin resistance. All had been taking a protease inhibitor (PI)-based anti-HIV regimen. The PI was replaced by efavirenz for one year. Lipid profile and insulin resistance had not changed at one year, while subcutaneous fat loss had worsened.

Katlama (2000) randomised 134 NNRTI-naive people to switch to efavirenz or continue PI therapy. After 6 months, 97% of the efavirenz group and 83% of the PI group had sustained viral loads below 50. CD4 count rose in the PI by about 50 but remained stable in the efavirenz group. HDL cholesterol rose in the efavirenz group mean cholesterol levels rose slightly (10mg/dL) in both groups.

Knetchen (2000) switched 42 people from PI to efavirenz, 39 remaining below 50 after 24 weeks. Non-fasting triglycerides fell from 322 to 252 mg/dL and HDL cholesterol rose from 37 to 43 mg/dL.

Maggiolo (2000) studied 31 patients treated with PIs. At baseline, mean triglycerides levels were 219 mg/dL. At switch from PI to efavirenz that had risen to 718 and 12 people had lipodystrophy. A month after switching, triglycerides levels fell to 362 and remained steady out to 8 months. Total cholesterol levels did not change.

Gharakhanian (2000) presented 24-week data on 33 patients who switched from a PI to efavirenz. At 10 months, there was no significant changes in weight, fat distribution, nor lipid and insulin abnormalities.

Martinez (2000) reported significant improvement in central fat accumulation in 11/20 (55%) patients who switched from a PI-containing regimen to efavirenz, but no improvement in peripheral fat wasting after 24 weeks. Approximately 30% had decreased triglycerides and improved insulin resistance, but cholesterol and glucose didn't change.

Bonnet (2000) conducted a prospective switching study of 43 people with lipodystrophy and elevated triglycerides. Six months after switching from a PI to efavirenz, there was no improvement in either lipid levels or lipodystrophy by physical examination or DEXA scan.

Moyle (2001) a group of 20 patients treated at the lipodystrophy clinic at the Chelsea and Westminster Hospital, London, found that a switch from a protease inhibitor to efavirenz produced some improvements in lipodystrophy. Viral suppression was maintained in all 19 patients who reached 24 weeks (one person died). Improvements in waist measurement and total body weight were noted after 12 weeks. Cholesterol increased by 0.6mmol/L and triglycerides by 1.55mmol/L. Wide inter-patient variability in visceral fat was reported. 6/7 with glucose intolerance achieved normal glucose tolerance by week 24. However there was no significant change in lipid abnormalities after switching to an NNRTI-based regimen.

Harris (1999) studied 18 people with PI toxicity (most commonly lipodystrophy) who switched to efavirenz. One person ceased efavirenz due to CNS side-effects. After a median of 5.5 months follow-up, all had maintained viral load below 500 and 13/17 had partial of complete resolution of PI-related side-effects.

Rey (2001) switched 55 people from a protease inhibitor to efavirenz. Average baseline triglycerides were 2.53mmol/L and cholesterol was 5.81mmol/L. Six months after switching, triglycerides fell to 2.12 and cholesterol to 5.40. However, incomplete results at 6 months makes these figures unreliable.

Research on switching between PIs

Murphy reported on AI424-044, a phase II study designed to assess safety and efficacy of atazanavir in patients treated for more than 72 weeks and in those who switched from nelfinavir to atazanavir. 63 individuals switched from nelfinavir to atazanavir. Total cholesterol declined by 16%, LDL cholesterol by 21% and triglycerides by 28%, whilst HDL cholesterol increased by 5% in this group of patients.

Adda (2000) reviewed changes in 31 patients in the Rothschild Lipodystrophy cohort (n=650) who replaced another PI with amprenavir. Seven of 31 experienced regression of body fat changes after sis months as measured by skin fold tests and waist hip ratio, 19 remained stable and 1 worsened. NRTIs were also changed. No significant improvements in cholesterol or triglycerides compared to baseline were reported at month 6.

Duncombe (2000) studied 21 people who switched from dual protease combinations to nelfinavir-containing combinations. One-third reported a slight improvement in appearance, and although triglyceride levels fell, cholesterol did not change.

Bloch (1999) also reported lower triglycerides and stabilised lipodystrophy among 13 men who switched from their current PI to nelfinavir. Cholesterol and glucose levels did not alter significantly.

References

See References - body fat and metabolic changes.