Primecuts – This Week in the Journals

July 12, 2010

By Dana Clutter, MD

Faculty Peer Reviewed

 As HIV/AIDS researchers around the world prepare for the upcoming 18th International AIDS Conference in Vienna from July 18-23, the HIV/AIDS epidemic has been in the spotlight. We begin with an encouraging report that the Obama administration has pledged an extra $25 million to the AIDS Drug Assistance Program (ADAP) [1]. Anxiety surrounding the placement of more and more HIV-infected Americans on record-length waitlists for ART (now totaling 2100 patients across 11 states) has been partially relieved by this measure. ADAP, which plays the vital role of providing ART to patients in the US who cannot afford it, had already been appropriated $835 million by Congress for the year. Increased numbers of uninsured and tighter state budgets have drained the program’s funds early, and patient advocates had called for an extra $126 million to eliminate the waitlists. Although this measure is sure to help, it remains uncertain whether it will be able to eliminate current waitlists as intended as the amount pledged is only a fifth of the amount many estimated would be necessary.

 Speaking of ART delivery, the WHO has recommended a public health approach for providing ART in developing countries due to the paucity of healthcare workers in such settings [2]. Central to the public health approach is training lower level healthcare workers (who are more numerous and affordable) to provide ART. As a result of this task shifting, nurses are commonly delivering ART in Africa. The Lancet features a randomized non-inferiority trial conducted at primary care clinics in South African townships aimed to compare the safety and efficacy of nurse-led ART with doctor-led ART. Patients were randomized to have ART initiated and monitored by a doctor (408 in the doctor group) or by a nurse (404 in the nurse group). The primary outcome, cumulative treatment failure, was a composite endpoint including all-cause mortality, loss to follow-up, virological failure, toxicity failure, and HIV-disease progression. Although the level of cumulative treatment failure was alarmingly high in both groups, with 44% failing in the doctor group and 48% failing in the nurse group, there was no statistical difference in the risk of treatment failure between the two groups (HR 1.09, 95% CI: 0.89-1.33). There was also no difference in immune or virological response between the two groups, suggesting that in addition to being equally safe, the programs are also equally effective. The main difference between the programs was that serious medication toxicities were reported 31% more frequently in the doctor group despite the finding that these toxicities occurred with equal frequencies between groups. This later finding may suggest that complex cases involving multiple medications may be better managed by the doctor-led ART model. The findings of this study can be generalized only to urban areas in sub-Saharan Africa with ample access to lab testing and expert medical advice, and only to nurse-led programs that require intense HIV-training, rely upon doctor initiation of ART and management protocols, and care only for patients on first line regimens. Despite this limitation, these results highlight the great potential for task-shifting ART management from doctors to nurses as ART delivery is upscaled.

 In addition to ensuring access to ART, preventative efforts, like vaccine research, remain central to the fight against HIV/AIDS. Promising progress from this field as reported in Science is the recent isolation of a human monoclonal antibody (mAb) that can neutralize a broad array of HIV-1 isolates [3]. To date, no other mAbs have been isolated that neutralize HIV-1 as “potently and broadly” as this somatic variant. The authors suspect that the ability to neutralize so many known HIV-1 isolates with a single naturally occurring antibody is likely due to the highly conserved nature of the target. Although this is a very exciting development, it remains to be seen if the production of this antibody can be elicited in vivo. [4].

 An article in this week’s JAMA, relevant to many of our patients, addresses optimal blood pressure goals for patients with CAD and diabetes [5]. The American Diabetes Association’s current target blood pressure for diabetics is below 130/80 mm Hg. This recommendation is largely guided by the finding that among a cohort of 1501 diabetics, those with a diastolic blood pressure goal of 80 had decreased cardiac risk.  Although data are limited, this guideline has been expanded to include patients with CAD. However, in patients with diabetes, hypertension, and CAD, it’s been shown that achieving a systolic blood pressure of 110 mm Hg was actually found to be associated with increased cardiac risk. This study aimed to determine the association between cardiovascular risk and blood pressure among patients with diabetes and CAD to better inform blood pressure guidelines for this group. This prospective cohort study included 6400 patients from 14 countries who were at least 50 years old, and had diabetes and CAD. During the 3-year follow up period, a goal blood pressure of less than 130/85 mm Hg was targeted with a number of antihypertensive agents. Tight blood pressure control was defined as an average systolic blood pressure under 130 mm Hg; usual control was an average systolic blood pressure between 130-140 mm Hg; and uncontrolled was an average systolic blood pressure greater than 140 mm Hg. The primary outcome, a composite endpoint including all-cause death, stroke, and MI, occurred in 12.7% of the tight control group, 12.6% of the usual control group, and 19.8% of the uncontrolled group. Although there was no increased risk of the primary outcome between the tight control and usual control groups (HR 1.11; 95% CI:0.93-1.32), there was increased risk in the uncontrolled in comparison to the usual control group (HR 1.46; 95% CI: 1.25-1.71). Although the results seem free of major confounding and the patient population is very representative of most patients with diabetes and CAD, the average follow up time of 2.6 years may not allow enough time to detect a difference in the rate of the primary outcome. Perhaps adopting a goal of “usual control” for these patients until studies with longer follow-up are completed is best.

 We finish with a quick update on screening for osteoporosis. Current guidelines regarding screening for osteoporosis, issued by the US Preventive Services Task Force (USPSTF) in 2002, are that women 60-64 years old with an increased risk of osteoporotic fracture and all women over 65 years old undergo bone density screening [6]. Notably, in 2002 the USPSTF lacked sufficient evidence to make recommendations for men or women not in the aforementioned categories. A review of studies between January, 2001, and December, 2009 related to osteoporosis screening was undertaken. The main finding was that there remains very little evidence in the form of trials related to osteoporosis screening, particularly when it comes to men. Researchers were, however, able to evaluate several risk assessment instruments in their abilities to predict low bone density and fracture. DEXA and calcaneal ultrasonography were both described as “modest” in their predictive abilities. They were also able to determine that bisphosphonates, PTH, raloxifene, and estrogen are effective in preventing primary vertebral fractures among post-menopausal women, but indicate that estrogen and raloxifene are consistently associated with adverse events. A major lesson from this update is that more trials (that include men and younger women) examining efficacy and risk of osteoporosis screening are needed. This update may also aid in selecting a medication for primary fracture prevention in post-menopausal women.

 Dr. Clutter is a first year resident at NYU Langone Medical Center

Cara Litvin, MD is the Executive Director, Clinical Correlations


1.  Pear R. U.S. to provide $25 million to help buy AIDS drugs. The New York Times (Online Ed.). 2010 Jul 8: Health (col.1).

 2.  Sanne I, Orrell C, Fox P, et al.  Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomized non-inferiority trial. Lancet. 2010 Jul; 376(9734): 33-40.

 3.  Wu X, Yahng Z, Li Y, et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. Published online ahead of print 2010 Jul 8.

 4.  Zhou T, Georgiev I, Wu X, et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. Published online ahead of print 2010 Jul 8.

5.   Cooper-DeHoff R, Yan G, Handberg E, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010 Jul; 304(1):61-68.

 6.  Nelson D, Haney E, Dana T, et al. Screening for osteoporosis: an update for the U.S.   Preventative Services Task Force. Ann Intern Med. Published online ahead of print 2010 Jul 5.

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