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ICAAC 2008: Continuous HAART Associated with Elevated Risk of Bone Loss in SMART Treatment Interruption Trial

Evidence has accumulated over the past several years showing that antiretroviral treatment interruption guided by CD4 cell count is a risky strategy that can lead to a higher risk of both AIDS-defining opportunistic illnesses and serious conditions such as cardiovascular disease that are not traditionally considered HIV-related, but may be due to inflammation and other abnormalities associated with ongoing viral replication.

Researchers initially explored structured treatment interruption in an effort to spare patients some of the side effects, inconvenience, and costs of life-long therapy. But most studies to date have demonstrated few such benefits, especially given the development of more tolerable and easier to use drugs.

The latest analysis from the large SMART trial, however, indicates that continuous HAART may increase the risk of bone loss (osteopenia, or the more serious osteoporosis). Data were presented this week in a late-breaking poster at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in Washington, DC.

Research looking at bone mineral density (BMD) in people with HIV has produced conflicting results. Several studies have shown that HIV positive people have lower BMD compared with the general population, but it is not clear whether this is related to HIV infection itself, antiretroviral therapy, an accelerated aging process, or other unknown factors.

Briefly, the SMART study included 5472 HIV positive participants with a CD4 cell count above 350 cells/mm3 at baseline who were randomly assigned to either stay on continuous antiretroviral therapy (the "viral suppression" arm), or to interrupt treatment when their CD4 count was above 350 cells/mm3, resuming when it fell below 250 cells/mm3 (the "drug conservation" arm). The study was halted prematurely in January 2006 after interim results showed that people who periodically stopped therapy had both a higher rate of AIDS-related opportunistic infections or death and serious heart, liver, and kidney disease.

The substudy presented at ICAAC included 275 SMART participants, of whom 214 had sufficient available bone data (98 in the continuous therapy arm, 116 in the treatment interruption arm). Most (81%) were men, the median age was 44 years, and about 45% smoked (a known risk factor for bone loss).

Hip and spine BMD were measured annually using dual-energy x-ray absorptiometry (DEXA), and trabecular BMD of the spine was assessed using quantitative computed tomography (CT). The investigators used longitudinal models to compare BMD changes in the 2 arms, and assessed the incidence of reported fractures in the study as a whole. Further, they evaluated associations between BMD decline and cumulative antiretroviral drug use in the continuous therapy arm.

At baseline, 12% of the patients had osteoporosis, median t-scores (a standard measure of bone density) were -0.5 for the femur, -0.9 for the spine by CT, and -0.7 for the spine by DEXA. Participants were followed for a mean of 2.4 years.


• In the continuous therapy group, patients received ART for 93% of total follow-up time, compared with 37% in the treatment interruption group.

• In the continuous therapy group, femur BMD declined by 0.9% per year, spine BMD by CT declined by 2.9% per year, and spine BMD by DEXA decreased by 0.4% annually.

• BMD decreases were significantly smaller in the treatment interruption group, especially during the first year when most were not yet on therapy.

• Over the entire follow-up period, the estimated differences in BMD changes in the treatment interruption group compared with the continuous therapy group were:

• Femur: 1.4% (P = 0.002);

• Spine by CT: 2.9% (P = 0.01);

• Spine by DEXA: 1.2% (P = 0.05).

• No consistent significant associations were observed between BMD decline and use of specific antiretroviral drugs.

• In the study as a whole, during a mean 2.8 years of follow-up, 10 of 2753 patients in the continuous therapy arm and 2 of 2720 in the treatment interruption group reported fractures as grade 4 adverse events.

• The rate of fractures was nearly 5 times higher in the continuous therapy arm compared with the treatment interruption arm (0.13 vs 0.03 per 100 person-years; hazard ratio 4.9; P = 0.04).

Based on the results of this analysis, the researchers concluded that, "Continuous antiretroviral therapy is associated with decline in BMD and possibly more fractures relative to intermittent, CD4-guided antiretroviral therapy."

Given the now-obvious detrimental effects of treatment interruption, however, they emphasized that "Intermittent antiretroviral therapy is not recommended due to increased risk of AIDS and death observed in the SMART study."

Univ. of Minnesota, Minneapolis, MN; St. Vincent's Hosp. and Univ. of NSW, Sydney, Australia.



B Grund and A Carr (for INSIGHT/SMART Study Group). Continuous Antiretroviral Therapy (ART) Decreases Bone Mineral Density: Results from the SMART Study. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-2312a.

ICAAC 2008: Long-term Safety of Investigational CCR5 Antagonist Vicriviroc in Treatment-experienced Patients

Schering-Plough's investigational CCR5 antagonist vicriviroc has demonstrated potent activity against HIV in laboratory studies and clinical trials of treatment-experienced patients. More than 200 patients received vicriviroc in Phase II trials. In a poster presented at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008), taking place this week in Washington, DC, researchers described long-term safety data from this population.

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PrEP using Tenofovir plus Emtricitabine May Offer Benefits even if HIV Infection Occurs

Animal studies of pre-exposure prophylaxis (PrEP) using tenofovir (Viread), with or without emtricitabine (Emtriva), have produced promising results, and large clinical trials in humans are currently underway. Prevention strategies using antiretroviral drugs are unlikely to be 100% effective, due to variations in efficacy, adherence, and other factors. But there is growing evidence that PrEP may have benefits even for individuals who become infected.

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ICAAC 2008: Efficacy and Safety of Boosted Darunavir (Prezista) Are Comparable to Lopinavir/ritonavir (Kaletra) at 96 Weeks: ARTEMIS Trial

Tibotec's second-generation protease inhibitor darunavir (Prezista) was approved in June 2006 for treatment-experienced HIV patients, to be administered at 600 mg boosted with 100 mg ritonavir twice-daily. As previously reported, in the Phase III ARTEMIS trial darunavir/ritonavir demonstrated safety and efficacy comparable to that of lopinavir/ritonavir (Kaletra) at 48 weeks. In a late-breaker session at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008), taking place this week in Washington, DC, researchers presented longer-term 96-week data from the study. Follow-up is scheduled to continue through 192 weeks.Boosted darunavir has also been studied in treatment-naive individuals, and earlier this month received approval for use in this patient population.

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How Safe is HIV Serosorting for Men who have Sex with Men?

HIV “serosorting” -- in which HIV positive people have unprotected sex only with other positive people, and negative people only with other negatives -- has been proposed as a strategy for reducing the risk of HIV transmission. The method is far from foolproof, however, requiring that individuals accurately know and honestly convey their current status.

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October 15 is National Latino AIDS Awareness Day -- CDC Study Looks at HIV/AIDS in U.S. Hispanic/Latino Population

Wednesday, October 15, is National Latino AIDS Awareness Day. This observance presents an opportunity to increase awareness of the disproportionate burden of HIV/AIDS within the Hispanic/Latino community.

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Antiretroviral Therapy during Pregnancy Significantly Reduces Mother-to-child HIV Transmission, but is Linked to Low Birth Weight

Since the mid-1990s, it has been known that prophylactic use of certain antiretroviral drugs during pregnancy -- namely zidovudine (AZT; Retrovir) and nevirapine (Viramune) -- dramatically reduces the risk of mother-to-child HIV transmission. However, outcomes in women who use triple combination antiretroviral therapy during pregnancy are less well characterized.

In a report published in the September 12, 2008 issue of AIDS, researchers with the French/African Ditrame Plus and MTCT-Plus Projects studied pregnancy outcomes in 326 HIV-1-infected pregnant women receiving antiretroviral therapy in Abidjan, Cote d'Ivoire.

Between March 2001 and July 2003, HAART was not yet available, and women who would have been eligible for combination therapy based on their own disease status instead received a short-course of zidovudine (with or without lamivudine) plus a single dose of nevirapine during labor to prevent mother-to-child transmission (PMTCT group; n = 175). Between August 2003 and August 2007, women eligible for HAART received combination therapy (HAART group; n = 151). All infants received zidovudine and nevirapine after birth, and women were advised to either feed formula or exclusively breast-feed (shown to be safer than mixed feeding of breast milk plus other foods). Median CD4 cell counts were similar in the 2 groups (177 vs 182 cells/mm3, respectively).

The researchers recorded the frequencies of low birth weight (<2500 g), very low birth weight (below 2000 g), stillbirth, and infant mortality within the first year. Risk factors associated with low birth weight were investigated using a logistic regression model.


• At 12 months, 3 infants (2.3%) became infected with HIV in the HAART group compared with 25 infants (16.1%) in the PMTCT group (P < 0.001).

• The rate of very low birth weight was similar in the 2 groups.

• The rate of low birth weight was nearly twice as high in HAART group compared with the PMTCT group (22.3% vs 12.4%; P = 0.02).

• In a multivariable analysis, after adjusting for maternal CD4 count, WHO disease stage, age, and body mass index (BMI), the following factors were significantly associated with low birth weight:

• HAART initiated before pregnancy (adjusted odds ratio [AOR] 2.88);

• HAART started during pregnancy (AOR 2.12);

• Low maternal BMI at the time of delivery (AOR 2.43).

• The rate of stillbirth was similar in both groups, at about 3%.

• The overall infant mortality rate during the first year was about 7%.

• Low birth weight and HAART use were not associated with a greater risk of infant death, though being HIV infected led to greater mortality.

Based on these findings, the study authors concluded that "HAART in pregnant African women with advanced HIV disease substantially reduced mother-to-child transmission, but was associated with low birth weight."

HIV transmission is less likely to occur when viral load is fully suppressed, and mothers are more likely to achieve undetectable viral load with combination HAART than with only zidovudine/nevirapine.

Given the highly significant reduction in the rate of HIV infection in babies born to women on HAART, and given that low birth weight infants were not more likely to die, this study indicates that the benefits of HAART for pregnant women outweigh the risks.



DK Ekouevi, PA Coffie, R Becquet, and others. Antiretroviral therapy in pregnant women with advanced HIV disease and pregnancy outcomes in Abidjan, Côte d'Ivoire. AIDS 22(14): 1815-1820. September 12, 2008 (Abstract).

Routine Opt-out Screening in Emergency Rooms Identifies Few Additional People with HIV

Routine opt-out HIV screening in an urban emergency department -- testing not targeted specifically to people thought to be at risk -- identified only a "modest" number of additional cases compared with standard diagnostic testing, according to a U.S. study reported in the July 21, 2010 Journal of the American Medical Association (JAMA) HIV/AIDS theme issue, released to coincide with the XVIII International AIDS Conference (AIDS 2010) last month in Vienna. Most of the additional people found to be infected had late-stage disease, suggesting that a better method is needed to identify HIV positive individuals sooner so they can benefit from timely care.

AIDS 2008: Didanosine (Videx EC) + Emtricitabine (Emtriva) + Atazanavir (Reyataz) Inferior for Initial HIV Treatment: PEARLS Trial

For a variety of reasons, physicians may recommend an alternative initial antiretroviral regimen rather than one of the first-line regimens recommended by current treatment guidelines. A once-daily regimen of didanosine (ddI; Videx-EC), emtricitabine (Emtriva), and unboosted atazanavir (Reyataz) has potential advantages over other alternative regimens, but the efficacy of this combination is unknown.

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