Part II: Case Studies
Case 1. Switching From Lopinavir/Ritonavir to Atazanavir + Ritonavir to Manage Increased Lipids
JW arrives for a routine clinic evaluation. He is a 52-year-old high school teacher who was diagnosed with HIV infection in 2002 after it was noted during a routine dental visit that he had oral candidiasis.
When JW was first diagnosed, his initial CD4+ cell count was 110 cells/µL and his plasma HIV RNA was 197,000 copies/mL. After a discussion with his physician regarding the benefits and risks of various HIV treatment strategies, it was jointly decided that he would embark on an aggressive antiretroviral regimen because of his low CD4+ cell count and high viral load. He was prescribed the fixed-dose combinations of zidovudine/lamivudine (AZT/3TC, Combivir) + lopinavir/ritonavir (LPV/r, Kaletra).
Within 6 months of commencing antiretroviral therapy, his CD4+ cell count had risen to above 500 cells/µL, his HIV viral load became undetectable by ultrasensitive assays and these parameters remained stable during clinical follow-up.
JW has a history of hypertension that has been controlled with a beta-blocker. He has no history of either diabetes or tobacco abuse, nor does he have a family history of early cardiovascular disease. However, he is about 15 pounds over his ideal body weight and generally sedentary.
In December 2004, JW experienced the acute onset of angina while at rest. He was evaluated emergently but a myocardial infarction was ruled out. In follow-up, a coronary angiography demonstrated single vessel disease that was treated with angioplasty. He is now on full-dose aspirin daily.
His lipid panel at the time of the angina incident, as well as prior to his initiation of HIV therapy, is listed below.
| ||TC (mg/dL)||LDL-C (mg/dL)||HDL-C (mg/dL)||TG (mg/dL)|
|6 months prior to ART||233||124||38||288|
|Dec. 2004 (2 years after ART initiated)||362||195||39||437|
|TC = total cholesterol; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; TG = triglycerides; ART = antiretroviral therapy|
Not long after his cardiac catheterization, he returns to the clinic and would like to discuss the relationship between his HIV, HIV therapy, lipid parameters and cardiovascular disease. His cardiologist wants him to reduce his low-density lipoprotein cholesterol (LDL-C) and triglyceride levels with diet and lipid-lowering medication. However, the patient wants to know if his antiretroviral therapy regimen can be modified instead, since he is aware that his lipids have increased since he started HIV therapy.
Currently, there are 2 major approaches to the management of dyslipidemia in a patient like JW. In one approach, he could continue on his successful antiretroviral regimen, embark on a low-fat diet and a daily exercise program, and initiate lipid-lowering therapy with a statin such as atorvastatin (Caduet, Lipitor) or pravastatin (Pravachol). (Both lovastatin [Altocor, Mevacor] and simvastatin [Vytorin, Zocor] are contraindicated due to drug-drug interactions with protease inhibitors [PIs].)
Alternatively, his treatment could be altered, with the aim of substituting the lopinavir/ritonavir -- the biggest culprit in the rise of the atherogenic lipids in this case.
There were 2 studies presented at CROI that added to previously reported data regarding the lipid benefits of a switch from either PIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs) to atazanavir (ATV, Reyataz).
In one presentation, Senison et al discussed the results of a study of patients with elevated LDL-C and suppressed HIV viremia, who had been on a single PI or a ritonavir (RTV, Norvir)-boosted PI plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). These patients were randomized to switch their PI to unboosted atazanavir 400 mg daily immediately at study entry or after 24 weeks.1
In the deferred switch arm, patients' LDL-C levels remained essentially unchanged compared to the about 15% decline in patients who were switched to atazanavir. Similarly, triglyceride levels dropped by about 35% in the switch arm compared to no change in the continued PI arm.
In the other CROI study, this one by Martinez et al, a switch to ritonavir-boosted atazanavir from PI, NNRTI and all NRTI-based regimens among patients with dyslipidemia and suppressed HIV-RNA levels produced somewhat less dramatic reductions in lipid parameters at 12 weeks (20% reduction in triglycerides and 11% drop in LDL-C) although deeper declines were seen at 12 months.2 In both studies, there was no increased risk of virologic failure or drug resistance observed.
In JW's case, reductions in LDL-C and triglycerides of the magnitude demonstrated in these 2 studies would help, although these strategies alone would probably not get him to target levels.
However, the increased cardiovascular risk associated with elevated lipids is a continuum. Significant reductions in lipids, even when they are shy of stated goals, are clearly beneficial. In addition, any improvements in lipids following antiretroviral therapy modification will compliment lifestyle changes and may reduce the dose of any required lipid-lowering medications.
JW's lopinavir/ritonavir is discontinued and he is prescribed atazanavir 300 mg + ritonavir 100 mg once daily. He is kept on the zidovudine/lamivudine. He is also scheduled for a consultation with a nutritionist and urged to join a gym.
Boosted atazanavir was preferred in this case because of JW's high baseline HIV-RNA level. The plan is to reassess his viral load 2, 4 and 8 weeks after the switch and look at his fasting lipids in 6 weeks. If the repeat lipid levels do not improve substantially with the antiretroviral therapy modification and aggressive lifestyle modification, switching to 400 mg of atazanavir daily without ritonavir may be attempted, in addition to initiation of lipid-lowering therapy.
Case 2. Switching From Stavudine + Lamivudine + Nevirapine to Tenofovir + Lamivudine + Nevirapine to Manage Lipoatrophy
At the time of his HIV diagnosis 6 years ago, GW began a combination of zidovudine (AZT, Retrovir) + lamivudine (3TC, Epivir) + nevirapine (NVP, Viramune). He liked the simplicity of this regimen and was adherent to the regimen. Soon after starting the regimen, however, he developed severe anemia. This was resolved with the substitution of zidovudine with stavudine (d4T, Zerit). Currently, his CD4+ cell count is 422 cells/µL and his viral load is below 50 copies/mL.
Over the past 12 to 18 months, GW has been complaining that his face is looking thinner. Friends, family and co-workers have been asking if he is loosing weight, even though his weight is stable. The frequent questions regarding his health disturb him as he has revealed his HIV status to only a small circle of friends.
A comparison of his driver's license photograph taken 2 years ago and his current appearance demonstrates hollowing of both his cheeks and temples. On examination, he also has thin arms and legs, with prominent veins as well as a slightly protruding abdomen without evident organomegaly or acsities.
He has read that stavudine is a major cause of fat wasting of the face and extremities. Members of his HIV support group have urged him to ask that this drug be stopped.
The only intervention to consistently demonstrate somewhat of a reversal in HIV therapy-related lipoatrophy or peripheral fat wasting has been the switch from stavudine to abacavir (ABC, Ziagen).3,4
Data from several studies presented at CROI add additional substitution strategies for patients who are experiencing lipoatrophy. Two studies looked to see if there were any benefits of switching from stavudine to tenofovir (TDF, Viread).
In the RAVE Study, patients with a viral load below 50 copies/mL who had moderate to severe peripheral fat wasting and were on a thymidine analog plus PI or NNRTI-containing antiretroviral therapy regimen were randomized to swap their thymidine analog for either abacavir or tenofovir while continuing their other antiretroviral therapy.5 Both switch strategies were found to lead to improvements in limb fat, although tenofovir led to greater improvements in lipid parameters. However, when comparing the study arms, it should be noted that randomization was not stratified by stavudine use and that more of the tenofovir-assigned patients switched from stavudine. This imbalance in baseline stavudine exposure likely gives the tenofovir arm an advantage over the abacavir arm when considering the reversal of lipoatrophy. That said, it still remains clear that switching from nucleoside analogs, and stavudine in particular, to tenofovir can lead to peripheral fat gains.
The second study also substituted stavudine for tenofovir. The researchers then compared the changes in body shape of patients who switched to tenofovir to the body shape changes of patients who remained on stavudine, either at the standard dose of 40 mg twice a day, or to a third study arm in which stavudine was dose reduced to 30 mg twice a day.6 Again, tenofovir led to significant improvements in peripheral fat, as assessed by dual energy X-ray absorptiometry (DEXA) scanning, as did the lower-dose stavudine. The improvements from tenofovir and those from the lower-dose of stavudine seemed equivalent.
Other, more radical antiretroviral therapy switch strategies for lipoatrophy were also reported, including an AIDS Clinical Trials Group (ACTG) in which the switch from stavudine or zidovudine to abacavir versus a nucleoside-free regimen of lopinavir/ritonavir + nevirapine was studied.7 Subcutaneous limb fat increased in the PI + NNRTI arm, but for reasons that are still unclear, there was no increase in subcutaneous limb fat in the abacavir arm. Lipid elevations may complicate therapy with lopinavir/ritonavir + nevirapine and may reduce enthusiasm for this particular switch.
Another ACTG switch study enrolled patients who had been receiving the following aggressive antiretroviral therapy regimens -- 2 NRTIs + indinavir (IDV, Crixivan); 2 NRTIs + indinavir + nelfinavir (NFV, Viracept); or indinavir + efavirenz (EFV, Sustiva, Stocrin). The researchers either switched participants to lopinavir/ritonavir + efavirenz or had them continue with their NRTIs + efavirenz.8 Limb fat was again seen to increase in the PI + NNRTI group, but in the NRTI + efavirenz group continued appendicular fat wasting was observed. Again, the PI + NNRTI regimen was associated with an increase in atherogenic lipids. As in most every switch study, viral rebound was not a problem.
The choice was made to switch the stavudine to either abacavir or tenofovir, since evidence supports either modification. Both of these agents are available in a once-daily fixed-dose combination with lamivudine: abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa) and tenofovir/lamivudine (TDF/3TC, Truvada). Nevirapine twice a day was continued.
David A. Wohl, M.D., is an assistant professor of medicine at the University of North Carolina at Chapel Hill, and co-directs HIV services for the North Carolina Department of Corrections.
Please read both the Research Update and the Case Studies sections of this article.
Sension M, Grinsztejn B, Molina J, et al. AI424067: improvement in lipid profiles after 12 weeks of switching to atazanavir from boosted or unboosted protease inhibitors in patients with no previous PI virologic failure and hyperlipidemia at baseline. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 858.
Martinez E, Azuaje C, Antela A, et al. Effects of switching to ritonavir-boosted atazanavir on HIV-infected patients receiving antiretroviral therapy with hyperlipidemia. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 850.
Carr A, Workman C, Smith DE, et al, for the Mitochondrial Toxicity (MITOX) Study Group. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy. JAMA. July 10, 2002;288(2):207-215.
McComsey GA, Ward DJ, Hessenthaler SM, et al, for the TARHEEL (ESS40010) Study Team. Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL Study. Clin Infect Dis. January 15, 2004;38(2):263-270.
Moyle G, Sabin C, Cartledge J, et al, and the Rave Study Group. A 48-week, randomized, open-label comparative study of tenofovir DF vs abacavir as substitutes for a thymidine analog in persons with lipoatrophy and sustained virological suppression on HAART. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 44LB.
Milinkovic A, Lopez S, Vidal S, et al. A randomized open study comparing the effect of reducing stavudine dose vs switching to tenofovir on mitochondrial function, metabolic parameters, and subcutaneous fat in HIV-infected patients receiving antiretroviral therapy containing stavudine. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 857.
Murphy R, Zhang J, Hafner R, et al, and the AACTG 5110 Study Team. Switching to a thymidine analog-sparing or a nucleoside-sparing regimen improves lipoatrophy: 24-week results of a prospective randomized clinical trial, AACTG 5110. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 45LB.
Tebas P, Zhang J, Yarasheski K, et al, and the Adult AIDS Clinical Trials Group. Switch to a protease inhibitor-containing/nucleoside reverse transcriptase inhibitor-sparing regimen increases appendicular fat and serum lipid levels without affecting glucose metabolism or bone mineral density. The results of a prospective randomized trial, ACTG 5125s. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 40.