Top HIV/AIDS-Related Clinical Developments of 2010
December 8, 2010
A review of:
HIV-related body shape issues have not gone away. A significant proportion of my patients complain about an accumulation of belly fat that is disproportionate to fat gain elsewhere on their bodies. Some are just plain fat, but a number of them do have a strange distribution of adipose tissue concentrated in the deep abdomen. Other than the easier-to-say-than-to-do admonishments to exercise and cut down on the Doritos, there has not been much to offer such patients. Sure, there is recombinant growth hormone, but it carries a host of side effects (arthralgias, myalgias, pedal edema), is not indicated for fat accumulation and costs a king's ransom.
Along comes tesamorelin (Egrifta), which triggers the release of growth hormone from the pituitary, thus producing a smoother and more physiologic increase in growth hormone levels than direct hormone injections can. The drug was approved in late 2010 by the FDA to reduce excess abdominal fat in HIV-infected patients with abdominal lipohypertrophy.
In two large, placebo-controlled clinical trials that enrolled HIV-infected patients with excess abdominal fat (with "excess" defined in men as having a waist circumference of 95 cm or greater and waist-to-hip ratio of 0.94 or greater, and in women as having a waist circumference of 94 cm or greater and a waist-to-hip ratio of 0.88 or greater), tesamorelin was found to significantly reduce visceral adipose tissue (VAT). In fact, those who used it experienced a 2-cm decrease in waist size (on average) over approximately six months.
Importantly, the drug was fairly well tolerated, with the main issues being injection site reactions, itching and myalgias. Unlike recombinant growth hormone, tesamorelin use did not result in wasting of subcutaneous adipose tissue (SAT). It did, however, increase glucose levels and levels of insulin-like growth factor 1 (IGF-1) in some people, the significance of which remains unclear. Whether the drug also will help reduce fat accumulation in other locations, such as the neck, has not been studied.
The Bottom Line
Body fat still matters, and many HIV-infected patients have had no choice but to live with their disproportionately big bellies as a sad price to pay for long-term survival. While tesamorelin will not be able to turn flab into Jersey Shore-worthy abs, for some, a reduction of a few centimeters of fat off the waist would be worth its weight in gold.
Speaking of which: At press time, it remains unclear how much tesamorelin will cost or what patient support will be made available. One hopes that those marketing tesamorelin will wisely and generously choose to extend availability of the drug to patients just like those they enrolled in their studies.
A review of:
There are dozens of clinical trials involving HIV medications, but precious few that look at when to start these drugs. Landmark studies for those with CD4+ cell counts below 200 cells/mm3 firmly established combination antiretroviral therapies for those with AIDS. For those with higher CD4+ cell counts, HIV treatment has been justified largely by observational cohort data rather than randomized clinical trials. In fact, there had not been a randomized trial comparing the timing of the initiation of HIV therapy for those with CD4+ cell counts above 200 cells/mm3. Until now.
The GHESKIO (Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes) research group in Haiti enrolled 816 HIV-infected, antiretroviral-naive patients with CD4+ cell counts between 200 cells/mm3 and 350 cells/mm3. The volunteers either immediately initiated HIV therapy with zidovudine, lamivudine (3TC, Epivir) and efavirenz or deferred treatment until 1) their CD4+ cell counts fell below 200 cells/mm3, 2) they developed clinical AIDS or 3) another indication for treatment arose.
More than half (58%) of the cohort was comprised of women. The mean CD4+ cell count at baseline was 281 cells/mm3 and was well balanced between the arms. Almost all participants received trimethoprim-sulfamethoxazole (Bactrim, Septra) for opportunistic infection prophylaxis and were screened for latent tuberculosis; those with a positive PPD (purified protein derivative) skin test (about a quarter of the cohort) received isoniazid (Tubizid).
During the course of the trial there were 29 deaths: 23 in the defer-treatment arm and 6 in the early-treatment arm (P = .001). In the Kaplan-Meier analysis, 93% in the defer-treatment group versus 98% of those in the early-treatment group were alive at 36 months. The unadjusted hazard ratio for the risk of death with deferral compared with early treatment was 4.0 (95% CI, 1.6 to 9.8). This means that the risk of death was four times greater among those assigned to delay HIV therapy. The causes of death in both arms were varied and included a host of infectious and non-infectious etiologies (including homicide, trauma and suicide). There were 17 infectious disease-related deaths in the deferral arm, but only one in the early-treatment group. There were also 36 cases of incident tuberculosis in the defer-treatment group and 18 in the early-treatment group (P = .01 by the log-rank test).
In the deferral arm, 160 volunteers (39%) eventually started antiretroviral therapy; of these, 147 had a CD4+ cell count that fell below 200 cells/mm3.
For those in the early-treatment group, 8% had a severe adverse reaction to the antiretrovirals, most commonly anemia.
The Bottom Line
Within the raging debate regarding the optimal time to start HIV therapy, the results of this trial provide the strongest data to date on the benefits of HIV therapy in the 200 cells/mm3 to 350 cells/mm3 range. While we in the medical community have been treating patients with such counts, we have done so without the benefit of a randomized trial.
Certainly, there are limitations to extrapolating these results. The study was done in Haiti and the findings have the greatest significance for the treatment of HIV in resource-limited areas. Further, many of those in the deferral arm had counts that dropped well below the 200 cells/mm3 CD4+ cell count threshold, when the risk of badness is highest.
However, the benefits of HIV therapy seen in the study jive with the findings of the large cohort studies done in North America and Europe, and endorse an earlier rather than delayed approach to the treatment of HIV. That said, as we increase the CD4+ cell count starting line beyond 200 and 350, we again find ourselves in a gap between observational studies and randomized trials. The recently launched START trial, which compares HIV therapy initiation at CD4+ cell counts above 500 cells/mm3 versus waiting until counts fall below 350 cells/mm3, will pick off where the GHESKIO study ended.
This article was provided by TheBody.
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