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Over the past several years, potent antiretroviral therapy (ART) has substantially decreased morbidity and improved survival in patients with HIV, further helping clinicians manage the infection as a chronic, manageable disease. Protease inhibitors (PIs) are a key component to ART because of their potency and high genetic barrier to antiretroviral resistance. Most guidelines recommend using ritonavir-boosted PIs, including fixed-dose lopinavir/ritonavir and atazanavir, as first-line ART in treatment-naïve patients.

When selecting ART for treatment-naïve patients, it’s important to consider dosing convenience, tolerability, and longer-term safety concerns. For PI therapy, gastrointestinal (GI) tolerability is a key consideration because of its established risk for poor adherence and treatment failure. In addition, lipid profiles should be assessed because PI-associated dyslipidemia may increase risks for cardiovascular disease.

Important New Data

In the August 23, 2008 issue of the Lancet, researchers from the CASTLE study published an investigation comparing two PI-based ART regimens in 883 HIV-infected patients who had not previously received ART. Patients received either atazanavir/ritonavir (300 mg/100 mg) once per day or lopinavir/ritonavir (400 mg/100 mg) twice per day in combination with fixed-dose tenofovir/emtricitabine (300 mg/200 mg) once a day. Using a primary endpoint of patients achieving viral loads of less than 50 copies per mL after 48 weeks of treatment, atazanavir/ritonavir once a day was as effective as lopinavir/ritonavir twice a day. The increases in CD4 cell counts from baseline observed in the atazanavir/ritonavir group were similar to that of the lopinavir/ritonavir group, and the rate of virological failure was identical in the two treatment arms.

Another key finding from the CASTLE data was that the atazanavir/ritonavir group also experienced less GI toxicity than lopinavir/ritonavir recipients. Fewer patients in the atazanavir/ritonavir group experienced treatment-related diarrhea and nausea. This is significant because these side effects can greatly affect quality of life and adherence to drug regimens. Patients receiving atazanavir/ritonavir had a slightly higher risk of developing jaundice, but this complication typically won’t cause any long-term problems. With regard to lipids, elevations in serum lipid levels were observed in both treatment arms of the CASTLE study, but there was less elevation of these levels among patients receiving atazanavir/ritonavir than in those who received lopinavir/ritonavir.

Gaining Better Clarity

Data from CASTLE and other similar analyses can be extremely helpful for clinicians as they work with patients to select treatment regimens. An important aspect of CASTLE was that it broke down the study group by gender; 31% of the study population was women, which is one of the highest percentages of women involved in an HIV clinical trial to date. The data demonstrated that there were no marked differences with regard to gender in the potency and efficacy of either of the drugs studied in CASTLE. However, it should be noted that there were subtle differences regarding tolerability. For example, women who received lopinavir/ritonavir were more likely than men receiving the same combination to experience nausea. Conversely, men receiving lopinavir/ritonavir were more likely than women receiving these drugs to experience diarrhea. This type of information can help physicians when they discuss treatment expectations with their patients. The side effects won’t happen 100% of the time, but the key is to educate patients fully so there are no surprises.

Kathleen E. Squires, MD, has indicated to Physician’s Weekly that she has received grant/research support from Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Koronis, Merck, Schering-Plough, and Tibotec. She has also been on the scientific advisory board for Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Koronis, Merck, Pfizer, Schering-Plough, Tibotec, and Tobira, and has been a consultant at Merck.