How does the finding of increased risk of atherosclerosis in HIV infection enter into treatment considerations? To answer this question first requires consideration of the factors contributing to dyslipidemia in HIV disease.
Initial studies showed that lipid changes in HIV-infected patients include an early decrease in high-density lipoprotein cholesterol (HDL-C) and a somewhat later decrease in low-density lipoprotein cholesterol (LDL-C), followed by increases in levels of triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) in later-stage disease (Grunfeld et al, J Clin Endocrinol Metab, 1992
). The loss of the antiatherosclerotic effect of HDL-C likely increases risk of atherosclerosis more than the reduction in LDL-C reduces the risk, and the later-stage increase in VLDL-C firmly tips the scale toward a proatherogenic effect. The effect is further amplified by the fact that HDL-C does not function optimally in the setting of infection or inflammation. Recent studies have shown statistically significant correlations between increasing plasma HIV RNA level and decreasing levels of HDL-C and LDL-C and increasing levels of TG and VLDL-C, as well as a statistically significant relationship between decreasing CD4+ cell count and decreasing levels of HDL-C (El-Sadr et al, HIV Med, 2005
The lipodystrophy associated with HIV disease is expressed as lipoatrophy that affects the lower body (especially the legs) more than the upper body (where effects are lowest in the upper trunk), rather than as a disorder of central versus peripheral fat redistribution. HIV lipoatrophy is associated with the use of stavudine. Although visceral obesity does occur in HIV disease, stavudine plays no role in it and the major predictors are age, restoration to health through antiretroviral treatment, and inactivity.
Increased visceral adipose tissue is associated with increased TG levels in HIV-infected patients and control subjects (both men and women), with TG levels higher in HIV-infected patients than in control subjects with similar amounts of visceral adipose tissue. Perhaps less well known is that increased leg subcutaneous adipose tissue is associated with reduced TG levels (Currier et al, JAIDS, 2008
; Wohl et al, JAIDS, 2008
). Hence, patients with HIV-related lipoatrophy who have strikingly lower amounts of leg adipose tissue are at particular risk of elevated TG levels.
HIV infection itself appears to be associated with elevated TG levels. An early study showed that TG levels remained stable in patients receiving placebo but decreased in patients receiving zidovudine monotherapy (in association with reduced alpha-interferon levels) (Mildvan et al, Lancet, 1992
). The addition of a protease inhibitor (PI) to nucleoside analogue reverse transcriptase inhibitor (nRTI) treatment, however, leads to a substantial increase in TG levels (Mulligan et al, JAIDS, 2000
)–a counterintuitive effect given that a reduction in HIV replication appears to lower TG levels.
Observations such as these led to a prevailing opinion that PIs were responsible for numerous metabolic abnormalities. For example, in the same study that documented a TG increase with the addition of a PI to nRTI treatment, LDL-C level was also observed to increase, appearing to pose increased CVD risk. A point that seemed to escape notice in this and other studies was that LDL-C levels in HIV-infected patients were low initially. After starting PIs, patients’ mean LDL-C levels increased to 112 mg/dL (Mulligan et al, JAIDS, 2000
), a level that would be well accepted by many physicians for their dyslipidemic patients.
It is difficult to determine whether metabolic changes observed in patients receiving PIs are the direct effect of the drugs or secondary to a reactivated immune system, restoration to health, or body composition changes. Therefore, investigators examined the effects of short-term PI administration on HIV-seronegative volunteers, studying their metabolism and body composition before and after treatment. No change was observed in body composition, indicating that fat accumulation or loss during PI treatment does not account for metabolic alterations.
In 4-week studies of HIV-seronegative subjects, ritonavir-boosted (/r) lopinavir use was associated with statistically significant increases in levels of TG, VLDL-C, and free fatty acids but not of LDL-C (Lee et al, AIDS, 2004
). Ritonavir use alone was statistically significantly associated with increased levels of TG (Purnell et al, AIDS, 2000
). In contrast, another study showed no change in TG or lipoprotein profiles associated with indinavir use (Noor et al, AIDS, 2001
) (). Studies including HIV-infected patients showed a statistically significant increase in TG levels associated with use of ritonavir but not with use of indinavir or nelfinavir (Periard et al, Circulation, 1999
). These results indicate that lipid alterations are not a class effect and that ritonavir is associated with a marked effect in raising TG levels.
Figure 1 Effects of protease inhibitors on lipid measures. A, Effects of ritonavir-boosted (/r) lopinavir and B, indinavir on levels of triglycerides (TG), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density (more ...)
These studies also showed a statistically significant or nearly significant increase in LDL-C levels associated with ritonavir, nelfinavir, or indinavir administration in HIV-infected patients but not in HIV-seronegative control subjects. These data suggest that the increase in LDL-C is not a drug effect but rather likely represents restoration to health.
Further support for the concept that LDL-C changes observed during antiretroviral treatment frequently occur as part of restoration to health–and are not associated solely with PI administration–comes from findings indicating that treatment with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is also associated with increases in LDL-C levels. A study reported in 2001 (van der Valk et al, AIDS, 2001
) showed that treatment with the NNRTI nevirapine was associated with increases in LDL-C levels of approximately 20% (similar to the increase observed with indinavir). As is well recognized, nevirapine treatment was associated with an approximately 50% increase in HDL-C levels, with smaller increases observed associated with use of the nRTI lamivudine and the PI indinavir. The NNRTI efavirenz was also associated with increased levels of HDL-C, LDL-C, and TG. The fact that increased TG levels were observed with efavirenz treatment but not nevirapine treatment indicates that increased TG level is not a class effect of NNRTIs and underscores the need to determine which drugs are associated with which lipid effects.
The situation becomes even more complicated when it is appreciated that the nRTI base in a regimen affects the lipid profile. Study 903 (Gilead Sciences, Inc, Foster City, CA) showed statistically significantly greater increases in levels of TG, total cholesterol, and LDL-C associated with the regimen that included stavudine versus the increase associated with tenofovir when each drug was administered with lamivudine and efavirenz for 48 weeks. Although these findings were widely taken as evidence of stavudine toxicity, it is important to recognize that efavirenz, which is associated with increased levels of VLDL-C and TG, was included in both regimens. The findings thus could also indicate an off-target effect of tenofovir in improving non-HDL-C level, as is indeed suggested by other, recent data. Some of the effect of stavudine on TG level is likely to be specific to the drug, however. In one study, initial increases in TG levels were greater with the nRTI combination of didanosine plus stavudine than with abacavir plus lamivudine, whereas moderate increases were observed over the long term (2 – 3 years) with both regimens (Shlay et al, JAIDS, 2005
In another long-term follow-up study, LDL-C level was initially increased in association with PI-, NNRTI-, and PI plus NNRTI-containing treatments and then drifted back toward baseline levels after 3 years to 4 years (Shlay et al, JAIDS, 2007
). Taken together, these results suggest the initial increase in LDL-C levels occurs in association with restoration to health, irrespective of the drug class used. The decline thereafter may occur as the result of a return of some of the immune responses that act to decrease LDL-C levels in HIV infection, and it is likely that ongoing infection and inflammation cause continuing dysfunction of HDL-C.
summarizes the effects on lipid levels associated with various anti-retroviral drugs. The most pronounced effect on TG level occurs with full-dose ritonavir; somewhat attenuated effects are associated with ritonavir-boosted PIs; and a neutral effect is noted with unboosted PIs. Among non-PI drugs, efavirenz and probably stavudine lead to TG elevation, whereas tenofovir may reduce the TG level. The HDL-C level is raised to the greatest extent in association with use of the NNRTIs nevirapine and efavirenz, with a smaller increase or neutral effect observed with some PI-based regimens and decreases observed in some studies of ritonavir-boosted PIs. LDL-C levels are increased in association with most PI-and NNRTI-based regimens, with the exception of atazanavir monotherapy, which appears to have a neutral effect. Tenofovir may lower LDL-C level.
Changes in Lipid Levels Associated With Antiretroviral Drugs
There are too few data on drugs in new antiretroviral classes for firm conclusions on their lipid effects. However, in one study the integrase strand transfer inhibitor (INSTI) raltegravir was associated with no increase in TG or LDL-C level and a smaller increase in HDL-C level than with efavirenz when each drug was used in combination with tenofovir and lamivudine (Markowitz et al, JAIDS, 2007
). In addition, switching from lopinavir/r to raltegravir was associated with reductions in TG and non-HDL-C levels. The investigational INSTI elvitegravir requires ritonavir boosting for once-daily dosing, and its effects on lipids are not yet known. Also unknown are the effects the investigational drug cobicistat (GS-9350) may have on lipids. The CC chemokine receptor 5 entry inhibitor maraviroc has been reported to have no effect on levels of TC, LDL-C, HDL-C, or TG (Arribas, Enferm Infecc Microbiol Clin, 2008
Considering this information, what steps should clinicians take to address the metabolic effects of antiretroviral therapy? First, it is imperative for clinicians to be thoroughly versed in drug interactions and the metabolic effects of various drugs. Reviews on the topic are useful, as is posting summary tables showing the effects of individual drugs. Some patients and their caregivers may be too quick to blame antiretroviral drugs for effects that may be more strongly associated with lifestyle factors (eg, obesity, physical inactivity, alcohol intake, and diet). Patients need to be informed that the effects of HIV disease outweigh the CVD risks associated with some antiretroviral drugs; therefore, the regimen to treat the HIV infection should be selected based on the virus, and appropriate treatment for dyslipidemia will be provided if necessary. Patient education also includes emphasis that lifestyle changes will likely be necessary as well.