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Should We Mess with Success?

Experts grapple with whether to change the regimens for three patients who had undetectable viral loads and normal or near-normal CD4-cell counts and were tolerating their treatments well.

Three patients present for regular outpatient care. As described below, all have stable HIV disease, with undetectable viral loads and normal or near-normal CD4-cell counts. None has experienced virologic failure on any treatment or has a known history of drug resistance. All are without side effects on their current regimens.

For each patient, would you switch or alter the current regimen? If yes, to what? Please comment briefly on the reason or reasons behind your decision.

We have asked three experts — Drs. Joel E. Gallant, F. Lisa Sterman, and Benjamin Young — what they would do.

PATIENT 1

Patient 1 is a 50-year-old man who has been taking abacavir, 3TC, and efavirenz since 2001. He has no renal disease but does have hyperlipidemia (well controlled with atorvastatin). His father died of a myocardial infarction (MI) at age 48.

Dr. Gallant: I would switch this patient to coformulated tenofovir/FTC/efavirenz (Atripla). He has several risk factors for MI, including hyperlipidemia and family history, not to mention age, sex, and the HIV infection itself. We now have several large studies that, although not definitive, suggest an increased risk for MI with abacavir use, especially in patients who are already at increased risk. For example, the initial analysis from the DAD study showed a continuous risk with ongoing abacavir use, and the more recent analysis showed a cumulative risk — meaning that the risk increases with continued therapy. The fact that the patient has done well since 2001 is not reassuring; his underlying risk will only increase as he gets older. Because this patient has no apparent contraindications to tenofovir use, I would view a switch from abacavir to tenofovir as a correction of a modifiable cardiac risk factor.

Dr. Sterman: I would change the regimen to coformulated tenofovir/FTC/efavirenz. Factoring in comorbidities that threaten a patient’s overall health is a common dilemma for today’s HIV practitioners. This 50-year-old gentleman has a very strong family history of coronary artery disease (CAD); he himself has hyperlipidemia, which is treated with a statin. His lifestyle, BMI, and other risk factors for CAD are not mentioned. A growing number of large cohort studies are showing potentially increased risk for MI during the first 6 months after initiation of abacavir; these and other data also suggest the possibility of a cumulative risk for CAD among patients with ongoing abacavir exposure. No studies have shown a strong association between tenofovir/FTC/efavirenz and CAD. In addition, coformulation of medications decreases pill burden, increases adherence to the entire regimen, and lowers patient co-pay amounts.

Dr. Young: I would not change this patient’s medications. He has done very well on his current antiretroviral regimen; his undetectable viral load 8 years into treatment is general proof of tolerability, effectiveness, and adherence. This patient is noted to have some significant cardiovascular risks, but the absence of smoking, hypertension, and diabetes is noteworthy. Hence, although some observational studies have suggested that recent abacavir use is associated with increased cardiovascular disease risk in persons with five or more risk factors, I don’t believe that this case necessarily warrants a proactive change in treatment. I would certainly discuss recent data about abacavir and heart disease risk with the patient, because patients need to be informed about the risks and benefits of therapy and should have other modifiable risk factors optimized. Nevertheless, this case highlights the shifting emphasis on long-term survival and non–HIV-related health risks. At age 50, this patient should have a comprehensive health work-up, including — but not limited to — cardiovascular, bone, mental health, and cancer screenings.

PATIENT 2

Patient 2 is a 63-year-old man who has been taking efavirenz and lopinavir/ritonavir since 2002. While on an earlier regimen — d4T, 3TC, and indinavir — he developed a severe neuropathy, which left him with residual numbness and tingling in his feet. He now needs to go on an inhaled corticosteroid to treat increasingly refractory asthma.

Dr. Gallant: I would switch this patient to tenofovir/FTC/efavirenz, if I was confident that he had no drug resistance. He is apparently on the somewhat awkward and antiquated combination of efavirenz and lopinavir/r — not because of resistance but because of adverse effects from previous d4T use. Assuming that he has no drug resistance (I would review his treatment history carefully before making a decision), he could switch from a boosted PI to NRTIs to avoid the drug interaction between inhaled steroids and ritonavir. This interaction leads to greater systemic absorption of steroids, potentially causing Cushing syndrome or adrenal insufficiency. However, if review of his treatment history reveals the possibility of NRTI resistance (i.e., if he shows incomplete suppression on his initial regimen), then I would be uncomfortable using tenofovir/FTC/efavirenz alone and would consider combining it with a fourth agent, possibly raltegravir.

If a ritonavir-boosted PI were necessary, I would minimize the dose of ritonavir by using a once-daily boosted PI, such as darunavir or atazanavir (with dose adjustment for the atazanavir–efavirenz interaction). I would avoid fluticasone, instead using an inhaled steroid less likely to interact with ritonavir, such as beclomethasone.

Dr. Sterman: Assuming no baseline genetic resistance, I would change this patient’s regimen to tenofovir/FTC/efavirenz. Such a switch would offer greater convenience, a much lower pill count, and once-daily dosing. More important, the patient will now be starting inhaled corticosteroids for worsening asthma. Without a regimen change, a drug interaction with ritonavir would be likely, potentially leading to increased systemic steroid exposure and complications from corticosteroid excess. The neuropathy that developed while the patient was taking 3TC, d4T, and indinavir can probably be attributed to the d4T.

Dr. Young: I would change the regimen to tenofovir/FTC/efavirenz. Several factors lead me to this decision. I’ll assume that alternative strategies for treating asthma have been explored. The need to initiate inhaled corticosteroid treatment raises the possibility of very significant adverse drug–drug interactions with lopinavir/r, particularly if fluticasone is used. Additionally, by today’s standards, the patient’s current antiretroviral regimen carries a heavy pill burden and is associated with extra risk for adverse effects. Neither tenofovir nor FTC is associated with significant risk for peripheral neuropathy. In the absence of compelling evidence of NRTI resistance or renal insufficiency, a switch from the boosted PI to either of these fixed-dose combinations should retain virologic potency and tolerability while decreasing pill burden.

PATIENT 3

Patient 3 is a 35-year-old woman who has been taking abacavir, 3TC, and twice-daily ritonavir-boosted fosamprenavir since starting this regimen in a clinical trial 5 years ago. Each week, she misses about two afternoon doses of the boosted fosamprenavir.

Dr. Gallant: I would switch this patient to abacavir, 3TC, and once-daily boosted darunavir or atazanavir. Another option would be to work with her on her adherence to the current regimen. For example, I would be curious as to why she’s taking a dose in the afternoon, which for many people is an awkward time to take medications. However, this patient’s pattern of nonadherence suggests that she would do better on a once-daily regimen, and several alternatives are available that shouldn’t compromise her virologic suppression. I would avoid efavirenz — it’s taken in the evening, and she seems to do better with morning doses. Because she presumably has no PI resistance, I would prefer to give her a once-daily boosted PI containing only 100 mg of ritonavir. With use of fosamprenavir/ritonavir 1400/100 mg once daily, no change in PI would be necessary. Although that option is reasonable, it hasn’t been studied as extensively as either darunavir/ritonavir 800/100 mg daily or atazanavir/ritonavir 300/100 mg daily, both of which compared favorably with lopinavir/r in large, head-to-head trials (ARTEMIS and CASTLE). However, before switching regimens, I would talk with the patient about how she takes her medications. Both darunavir and atazanavir must be taken with food. If that is a problem for her, I would use once-daily boosted fosamprenavir, which can be taken without regard to meals.

Dr. Sterman: I would switch this patient to a once-daily regimen of fosamprenavir 1400 mg (two 700-mg tablets), ritonavir 100 mg, and abacavir/3TC (1 tablet). A change is very important for this woman, who has been missing two doses of fosamprenavir each week. Adherence studies show that although resistance to the boosted PI portion of this type of regimen occurs infrequently, resistance to 3TC and eventually to abacavir can develop if patients miss as few as one or two doses weekly. This patient was antiretroviral naive when she began the fosamprenavir trial 5 years ago. Because she has tolerated a twice-daily regimen well, a logical move would be to change her to once-daily dosing with the same combination of drugs. Such a switch would be the easiest way to promote long-term success and minimize new drug exposures. Finally, the 3TC and abacavir in the patient’s regimen can be changed to the coformulated Epzicom.

Dr. Young: I would change the regimen to once-daily, morning-dosed abacavir, 3TC, and fosamprenavir/ritonavir 1400/100 mg. Although this patient has done very well on her treatment regimen, she is missing about 2 of 14 — nearly 15% — of her weekly doses of fosamprenavir. This degree of nonadherence likely places her at risk for treatment failure and the emergence of drug resistance. I would invest the time to explore the reasons for nonadherence, reinforce the need for adherence, and address any underlying issues that might be playing a role. The use of once-daily fosamprenavir (dosed with 100 mg of ritonavir) is approved by the FDA and supported by evidence from clinical trials; additional evidence shows that patients can switch from other boosted-PI regimens to this one without incurring significant risk for treatment failure. Because this patient seems not to be missing her other daily (morning) dose, consolidating her medications to once-daily dosing and reducing ritonavir from 200 mg to 100 mg daily should improve her adherence without departing from a regimen that has otherwise been virologically successful for 5 years.

TELL US WHAT YOU WOULD DO

How would you manage these patients? Submit your comments below.

Joel E. Gallant, MD, MPH, is Professor of Medicine and Epidemiology, Division of Infectious Diseases, Johns Hopkins University School of Medicine in Baltimore. He serves as a consultant, is on the data safety and monitoring board or the advisory board, or receives research funding or honoraria from several companies that manufacture or market several antiretroviral drugs, including abacavir, atazanavir, darunavir, fosamprenavir, lopinavir/r, tenofovir/FTC/efavirenz, and 3TC.

F. Lisa Sterman, MD, MPH, has been in private practice and has conducted HIV clinical research in San Francisco since 1997. She is affiliated with California Pacific Medical Center and UCSF. She reports no potential conflicts of interest.

Benjamin Young, MD, PhD, is an Assistant Clinical Professor of Medicine at the University of Colorado and cares for patients at Denver Infectious Disease Consultants. He is also Head of Medical Affairs for Health Connections International, a Dutch nongovernmental organization dedicated to strengthening healthcare systems and improving responses to the HIV, tuberculosis, and drug-use epidemics in the developing countries of Central Asia. He serves as a consultant, is on the speakers’ bureau, or receives grant or research funding from several companies that manufacture or market antiretroviral drugs, including abacavir, fosamprenavir, lopinavir/r, tenofovir/FTC/efavirenz, and 3TC.

Published in AIDS Clinical Care July 6, 2009

Reader Remarks:

Read all Reader Remarks on this article

• choice of treatment
  FJ frippiat, MD ID specialist University hospital Liège Belgium, 8 Jul 2009 12:39 PM EST
  I've some concern about the use of EFZ or fAPV/r since these drugs induce dyslipidemia at the same level than... [more]
• patients,1,2,3
  Alvin M., practitioner, 9 Jul 2009 6:25 PM EST
  patient (1) good therapy leave alone. patient (2) start with lyrica 75mg b.i.d.< to 500 to 600 mg as tolerated.start... [more]
• Should We Mess with Success?
  Helen C. Azzam, 9 Jul 2009 6:25 PM EST
  Patient 1: Given the risk of MI with abacavir and this patient's risk factors (lipids, famHx), I would change the... [more]
• Don"t fix what isn't broken.
  William J. DeMedio, private practice, 9 Jul 2009 6:25 PM EST
  The current goal in HIV therapy is to eliminate viral load, minimize disease progression, prevent opportunistic infections, and minimize antiretroviral... [more]
• Changing treatments
  Antoine. M Donot, Belgian prison, 9 Jul 2009 6:25 PM EST
  Pt 1: CV risk, so I would recommend switching ABC to TDF. PT 2 : no change. PT 3: Because... [more]
• Changing treatment
  Alastair Miller, Royal Liverpool University Hospital, Liverpool L22 8QP, 9 Jul 2009 6:25 PM EST
  Case 1 - need to know more about him to make a good CV risk assessment but at 50 it... [more]
• Three patients stable on ARV
  Dr. J.J. Ongole, Specialist; Head, HIV and TB Programs, Piet Retief, South Africa, 9 Jul 2009 6:25 PM EST
  The three patients are clinically stable on treatment with full viral load suppression and good immune response measured by CD4... [more]