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Top HIV/AIDS-Related Clinical Developments of 2010

December 8, 2010

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Attention: Quad Is in the Building

A review of:
Cohen C, Shamblaw D, Ruane P, et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, Calif. Abstract 58LB. Available at:

Just when you thought it was impossible to combine more than three HIV medications into one tablet capable of slipping past the average person's gag reflex -- at least without a major infraction of some of the most beloved laws of physics -- along comes the Quad pill. This is the nickname for a four-drug combination of tenofovir, emtricitabine, elvitegravir (formerly GS 9137, as well as JTK-303) and cobicistat (formerly GS 9350). Elvitegravir is an integrase inhibitor in development that requires pharmacological boosting with either ritonavir (Norvir) or cobicistat, an investigational booster drug.


We learned about the existence of the Quad pill in 2009, but this year the first comparative trial of the formulation was presented. The phase 2 study was double-blind, enrolling 71 treatment-naive patients who were randomized 2:1 to receive either the Quad pill or coformulated efavirenz/tenofovir/emtricitabine.

At 48 weeks, the rate of suppression of HIV RNA to less than 50 copies/mL was 90% with Quad versus 83% for the triple-drug arm (95% CI: -8.8% to 25.6%). The mean change in CD4+ cell count was greater with Quad (240 cells/mm3) than with efavirenz/tenofovir/emtricitabine (162 cells/mm3).

The Quad pill was well tolerated. As expected, CNS adverse effects were concentrated in the efavirenz arm. The change from baseline over 48 weeks for all lipid parameters that were measured (total, low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol) increased more with the efavirenz-based regimen than the Quad, except for triglycerides, which rose to a greater extent with the Quad -- likely driven by the cobicistat.

Importantly, the change in estimated glomerular filtration rate (GFR) -- the rate at which the kidney dumps what it should into the urine -- was greater with the Quad, dropping 14% compared to 4% with the efavirenz-based triple-therapy regimen. This was explained by the researchers as an artifact and not really an impact on kidney function, since cobicistat reportedly decreases creatinine secretion into the urine. (Creatinine is a marker measured in the blood to assess kidney function.)

The Bottom Line

We are entering an era in which there will be more than one single-pill, once-daily therapy for HIV infection. All of us well appreciate the psychological significance of efavirenz/tenofovir/emtricitabine, the first single-tablet daily HIV regimen for people with HIV. Having more of them will further secure the perception that HIV therapy need not mean handfuls of pills, a dedicated medicine cabinet and an alarm clock.

The development of a non-ritonavir booster, cobicistat, has also been long awaited. The problem is that cobicistat may be a bit too much like ritonavir to be truly remarkable. In this study, triglycerides (a bane of ritonavir's existence) increased with the Quad. The funky effect of the drug on GFR readings may also be an annoyance.

However, by including two new agents and in its mind-blowing medicinal chemistry, the Quad pill enforces the idea that innovation in the field of HIV therapeutics is not moribund. People are trying to make therapies that not only work, but that patients can more easily take. Additional drugs mean additional options.

As I described above, it will remain difficult to predict which of the bite-sized items on the antiretroviral menu end up being chosen by HIV care providers and their patients. Large clinical trials comparing the Quad with some first-line favorites will help determine whether four drugs beats three.

New Screening and Treatment Guidelines for Bone Disease

A review of:
McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers [abstract].
Clin Infect Dis [serial online]. October 15, 2010;51(8):937-946. Available at:

When I was a medical student doing rounds, the chief resident in orthopedics asked me what I thought was the most important organ in the body. Oblivious to the obvious, I answered, "The heart, since it pumps blood." "To the bones," he quickly replied.

While I remain skeptical of the primacy of the skeleton among all parts of our anatomy, in HIV care bones are gaining in importance. A number of studies have found the bone mineral density (BMD) of HIV-infected persons to be significantly lower than that of those without HIV, raising concerns for an increased risk of fractures.

The reasons for this relatively lower BMD among HIV-infected people remain unclear. Certainly, HIV-infected patients tend to have more risk factors for weaker bones. Call it hard living: Smoking (epidemic among people with HIV), alcohol abuse, low weight and poor nutrition can each lead to the leaching of hard minerals from bones. Many people living with HIV have also had a fair share of exposure to corticosteroids, such as prednisone (Prednisone Intensol, Sterapred), which is another risk factor. Further, low testosterone and vitamin D levels -- not uncommon in HIV-infected individuals -- can lead to osteopenia and the more severe osteoporosis.

The role of antiretrovirals in low BMD is more complex. Longitudinal studies in which patients were followed after they initiated HIV therapy have consistently found dramatic, immediate reductions in bone density. Specifically, BMD losses of 2% to 6% over the first two years of therapy have been observed -- a rate similar to the loss seen during the first couple of years after menopause. This effect does not appear to be specific to any one antiretroviral or regimen. That said, tenofovir use does lead to deeper declines in BMD compared to other drugs in its class. Fortunately, the nose dive in BMD with this and other antiretrovirals begins to level out after a time, at which point it declines at a more measured pace.

What to do about all of this bone loss has been unclear. Without a rash of broken bones among HIV-infected people to spark action, there has been little enthusiasm for screening and treatment of low BMD in this population. But now, with a new focus on aging and HIV, bone health is earning some respect. Capitalizing on this attention, a group of experts has issued a set of recommendations outlining who among those with HIV should be screened and treated for low BMD.

According to the recommendations, the following HIV-infected individuals should undergo dual-energy X-ray absorptiometry (DXA):

  1. Post-menopausal women.
  2. Men 50 years of age or older.
  3. Patients who have a history of fragility fracture (a fracture resulting from trauma that is less than or equivalent to a fall from a standing position), regardless of age or sex.

Those with a T-score that is more than one standard deviation less than normal (i.e., T-score = -1) should be evaluated for a secondary cause of low BMD. A nice list of these secondary causes is included in a table within the published recommendations.

Recommendations regarding who to treat for low BMD -- and what to treat with -- are also included.

The Bottom Line

This review and the resultant recommendations provide a strong rationale for increased screening and treatment of low BMD in HIV-infected patients and breaks through an ambivalence that has surrounded this issue. Importantly, the recommendations place an emphasis on the fracture risk caused by low BMD. As HIV-infected individuals age, their relatively lower BMD, regardless of cause, is expected to increase the rate of fractures -- which will, in turn, greatly impact their quality of life. Screening with DXA, therefore, makes sense, especially when there are effective interventions to offset bone demineralization.

Clinicians respond to recommendations and guidelines, so hopefully this paper will attract their attention. Of course, there will be some pushback and issues to be dealt with. For instance, DXA scanning may not always be covered by third-party payers. Will patients be willing (or able) to shoulder the expense of the test? Also, with low vitamin D levels being the rule rather than the exception among people with HIV, it is likely that most all patients with low BMD will require vitamin D replacement therapy before anything else is done. Those with osteoporosis may eventually receive bisphosphonates such as alendronate (Fosamax). However, the long-term safety of such treatments has been called into question, and HIV clinicians will have to be careful to learn about them and understand how to use them.

Despite the hurdles, these recommendations lay on the line what those in the know think should be done. The rest of us should listen.

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This article was provided by TheBody.
See Also
HIV/AIDS Year in Review: Looking Back on 2010 (and Ahead to 2011)
More Views on HIV Treatment Research


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