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Friday, 5 July 2013

Low-Dose Drug Combo Safe in Kids with HIV (CME/CE)

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Published: Jul 5, 2013

By Ed Susman, Contributing Writer, MedPage TodayReviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San FranciscoThis study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.A low-dose treatment regimen with lopinavir/ritonavir antiretroviral therapy appears to have similar efficacy with fewer adverse events than standard dosing in HIV-infected children.Note that children treated with the lower dose of the protease inhibitor had significantly lower cholesterol and triglyceride levels.

KUALA LUMPUR -- A low-dose treatment regimen with lopinavir/ritonavir antiretroviral therapy appears to have similar efficacy with fewer adverse events than standard dosing in HIV-infected children, researchers said here.

In the intention-to-treat analysis, 89 of 101 children (88.1%) on the low-dose regimen achieved undetectable viral loads using the 50 copies/ml assay (P=0.38) compared with 90 of 98 children treated with the standard dose of lopinavir/ritonavir (Kaletra), said Thanyawee Puthanakit, MD, from Chulalongkorn University in Bangkok, and colleagues.

"This study demonstrated non-inferiority in virologic efficacy of low dose compared to standard dose lopinavir/ritonavir tablets as maintenance therapy," she reported at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention.

In terms of adverse effects, the study showed that children treated with the lower dose of the protease inhibitor had significantly lower cholesterol levels. She said that 34.4% of children on the standard dose had cholesterol levels greater than 200 mg/dl at the end of the 48 week trial compared with 20.6% of children treated with the low-dose regimen (P=0.03).

In addition, triglyceride levels greater than 150 mg/dl were observed among 60.4% of the children on the standard dosing regimen and in 44.3% of those on the low dose of lopinavir/ritonavir (P=0.03), Puthanakit reported.

"This dosing regimen conferred adequate lopinavir blood level with reduced drug cost, and reduced potential long-term complications such as dyslipidemia," she said.

"Lopinavir/ritonavir is the most commonly used HIV regimen used in children," Puthanakit pointed out.

In the trial, which was conducted from December to June 2011, the children assigned to the standard, weight-based dose received an average of 284 mg/m2 twice daily. The children in the low-dose group received an average of 210 mg/m2. The lower dose represents about 70% of the recommended treatment dose in the U.S., Puthanakit said.

Of the 199 patients in the study, seven children in both arms were lost to follow-up.

The average age of the children was 13.2 years and their CD4-positive cell counts was 786 cells/mm3. All were on protease inhibitor regimens. The background nucleoside reverse transcriptase inhibitors included zidovudine and lamivudine; zidovudine and didanosine; lamivudine and tenofovir; lamivudine alone; and lamivudine and didanosine.

The study was devised as a way to deliver maintenance therapy for children whose HIV was well controlled, with all of the children at baseline having undetectable HIV plasma viral loads using the 50 copies/mm3.

Puthanakit noted that the study results could only be generalized to children with controlled, undetectable viral loads and should not, at this time, be expanded to include children with high viral loads who may just be beginning antiretroviral therapy.

Diana Gibb, MD, from the Medical Research Council Clinical Trials Unit in London also cautioned that the results "would not apply to the use of liquid lopinavir/ritonavir therapy since this study was done with tablets that have a higher bioavailability."

Puthanakit concurred, noting that her study did not include infants and young children who are treated with liquid formulations of the antiretroviral regimen.

The study was part of the long-standing HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT).

The study was funded by Thai governmental agencies.

Puthanakit and Gibb reported no conflicts of interest.

Primary source: International AIDS Society
Source reference:
Puthanakit T, et al "A randomized study comparing low dose versus standard dose lopinavir/ritonavir among HIV-infected children with virological suppression" IAS 2013; Abstract MOAB0101.

BMD Correlates with Number of HIV Regimens (CME/CE)

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Published: Jul 3, 2013 | Updated: Jul 3, 2013

By Ed Susman, Contributing Writer, MedPage TodayReviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.The number of HIV treatment regimens a patient undergoes appears to correlate with loss of bone mineral density.Note that the study did not find that current use of or cumulative exposure to antiretrovirals, antiretroviral class, or specific antiretroviral agents independently predicted lower bone mineral density.

KUALA LUMPUR -- The number of HIV treatment regimens a patient undergoes appears to correlate with loss of bone mineral density (BMD), researchers reported here at the International Aids Society Conference on HIV Pathogenesis, Treatment, and Prevention.

In the multivariate analysis involving 210 patients with HIV infection, the parameter estimate for BMD loss at the femoral neck was -0.011 g/cm2 for each regimen a patient had taken (95% CI minus 0.022-minus 0.0003, P=0.05), reported Aoife Cotter, MD, a fellow in infectious diseases at University College Dublin.

"Unexpectedly, we did not find that current use of or cumulative exposure to antiretrovirals, antiretroviral class, or specific antiretroviral agents independently predicted lower bone mineral density," Cotter told MedPage Today at her poster presentation.

In addition to the multivariate analysis finding of lower BMD at the femoral neck, Cotter and colleagues also noted that the lumbar spine BMD loss was also associated with the number of HIV regimens. At the lumbar spine there was a loss of 0.015 g/cm2 (P=0.03), she reported.

Cotter reviewed data in the prospective HIV UPBEAT (Understanding the Pathology of Bone Disease in HIV-infected Subjects) which enrolled HIV-positive and HIV-negative participants from similar demographic backgrounds. The median age of the HIV-infected patients was 39, mean BMI was 26 kg/m2, 58.6% were men, 60.5% were Caucasians, 39.5% were of African ethnicity, 34.8% were current smokers.

Cotter said the researchers considered that the number of HIV regimens might be a surrogate measure for time with HIV infection, but in performing the multivariate analysis they did not find a correlation that was statistically significant.

"We suggest that these findings are consistent with data demonstrating greater reductions in bone mineral density associated with antiretroviral-induced HIV suppression occurring with multiple antiretroviral regimens," she said.

In the multivariate analysis, the researchers did not see a significant difference in bone mineral density loss when comparing injecting drug users with non-injecting drug users with HIV infection (P=0.54); with baseline CD4-positive T-cell counts- (P=0.21); with nadir CD4 cell counts (P=0.09); duration since HIV diagnosis (P=0.86); cumulative antiretroviral exposure (P=0.40); cumulative nucleoside reverse transcriptase inhibitor exposure (P=0.41); cumulative tenofovir exposure (P=0.34); cumulative non-nucleoside reverse transcriptase inhibitor exposure (P=0.63), or cumulative protease inhibitor exposure (P=0.11).

In commenting on the study, Ian Woolley, MBBS, professor of medicine at Monash University in Melbourne, Australia, told MedPage Today, "The number of HIV regimens may be a surrogate for lack of adherence by these patients."

He added, "There are usually two reasons why patients change regimens. It is because of resistance or because of toxicity. It is also possible there is a phenotype that is more likely to develop toxicity."

He noted that resistance often arises when patients are not adherent in taking their antiretroviral medications.

Cotter and Woolley had no disclosures.

Primary source: International AIDS Society
Source reference:
Cotter A, et al "Number of different antiretroviral regimens rather than cumulative exposure to antiretrovirals associated with lower bone mineral density in HIV-positive subjects" IAS 2013; Abstract MOPE078.

Investigational HIV Treatment Promising (CME/CE)

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Published: Jul 3, 2013 | Updated: Jul 3, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.In this double-blind, phase III study in HIV-1 infected, treatment-experienced but integrase-naive adults, dolutegravir, an investigational integrase inhibitor given once daily, was superior to twice-daily raltegravir.

KUALA LUMPUR -- The investigational anti-HIV drug dolutegravir outperformed raltegravir (Isentress) in a randomized trial among patients needing salvage therapy, a researcher said here.

After 48 weeks of therapy, HIV patients who had failed earlier regimens were significantly more likely to control their virus if they were taking dolutegravir, according to Pedro Cahn, MD, of Fundación Huesped in Buenos Aires.

At the same time, there were no major differences in the rate of adverse events in the so-called SAILING trial, Cahn reported at the 7th International Aids Society Conference on HIV Pathogenesis, Treatment, and Prevention.

Both drugs are members of a relatively new class of anti-HIV drugs, the integrase inhibitors. Raltegravir was the first approved integrase inhibitor, and a second drug in the class, elvitegravir, is so far only approved as part of a fixed-dose combination.

Dolutegravir is regarded as an attractive alternative because it is given once daily, at 50 milligrams, compared with 400 milligrams twice a day for raltegravir.

To test the comparative efficacy of the two drugs, Cahn and colleagues enrolled 715 treatment-experienced patients who had not yet been given an integrase inhibitor for a randomized, double-blinded, double-dummy trial.

The primary endpoint was the proportion of patients who reached an undetectable level of plasma RNA, defined as fewer than 50 copies per milliliter.

Along with the integrase inhibitor, patients were given an optimized two-drug background in which at least one drug had to be fully active, Cahn told reporters.

After 48 weeks of treatment, he said, 64% of patients taking raltegravir had reached the primary endpoint, compared with 71% of those taking dolutegravir (P=0.03).

The treatment difference was significant, Cahn said, allowing the investigators to conclude that "superiority can be claimed for dolutegravir on a statistical basis."

Interestingly, among patients whose background regimen included the protease inhibitor darunavir (Prezista) -- and who had no resistance to the drug -- there was no difference in efficacy between raltegravir and dolutegravir, Cahn told MedPage Today.

That's probably because darunavir itself is very potent in salvage therapy, Cahn said, so that its benefit swamps any difference between the integrase inhibitors.

Both integrase inhibitors are "extremely safe," he said, with very few patients stopping therapy because of adverse events -- 3% in the dolutegravir arm and 4% in the raltegravir arm.

The most commonly reported adverse events were diarrhea and upper respiratory tract infection, which occurred at similar rates in the two treatment arms, Cahn reported.

The study adds to the "very promising data" on dolutegravir, commented Jintanat Ananworanich, MD, PhD, of the Thai Red Cross AIDS Research Center in Bangkok, who was not part of the study but who moderated a press conference at which some details were presented.

The drug has shown very rapid reductions in viral load at low doses, Ananworanich told MedPage Today, which might allow it to be used at lower cost than other members of the class.

As a pediatrician, she added, she's following it closely because it also appears to very effective in children.

The study was supported by GlaxoSmithKline. Cahn has previously disclosed financial relationships with Abbott, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Pfizer, Pharmasset, Schering-Plough, and Tibotec.

Ananworanich made no disclosures.

Primary source: International AIDS Society
Source reference:
Cahn P, et al "Dolutegravir (DTG) is superior to raltegravir (RAL) in ART-experienced, integrase naive subjects: week 48 results from SAILING" IAS 2013; Abstract WELBB03.

North American Correspondent for MedPage Today, is a three-time winner of the Science and Society Journalism Award of the Canadian Science Writers' Association. After working for newspapers in several parts of Canada, he was the science writer for the Toronto Star before becoming a freelancer in 1994. His byline has appeared in New Scientist, Science, the Globe and Mail, United Press International, Toronto Life, Canadian Business, the Toronto Star, Marketing Computers, and many others. He is based in Toronto, and when not transforming dense science into compelling prose he can usually be found sailing.

HIV Drugs Getting Better (CME/CE)

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Published: Jul 5, 2013

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Note that this large meta-analysis demonstrated that preferred HIV regimens are indeed superior to alternative regimens in terms of suppressing viral replication.There is a suggestion that the newer integrase inhibitors are more efficacious than other classes when added to the standard backbone of HIV therapy.

KUALA LUMPUR -- The efficacy of HIV drugs in clinical trials has increased markedly over time, according to a meta-analysis of 144 studies with more than 40,000 participants.

Efficacy -- defined as the proportion of patients able to suppress HIV to undetectable levels -- was about 47% in trials conducted before 2000, according to Frederick Lee, MD, of the St. Vincent's Centre for Applied Medical Research, Sydney, in Australia.

In studies after 2008, efficacy was about 82%, Lee reported at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention.

Interestingly, the so-called "preferred" regimens of the U.S. Department of Health and Human Services (DHHS) guidelines panel outperformed the "alternative" regimens, which in turn did better than other combinations, Lee reported.

Lee noted that guidelines are based on serial assessments of individual trials, so a meta-analysis of all available trials should increase the ability to evaluate outcomes in subpopulations of patients and identify predictors of treatment success.

He and colleagues looked at all reported prospective drug trials in treatment-naive HIV patients with at least 48 weeks of follow-up and an intent-to-treat efficacy analysis.

All told, they found 144 phase II, III, and IV studies with 216 treatment groups, starting with 10 trials from the pre-1996 era through to 17 in 2009 and 2010.

On average, follow-up was 82 weeks and efficacy on treatment was 60%, Lee reported. About 25% of participants stopped treatment during their trial, usually because of adverse events and less commonly because the drugs weren't working to suppress the virus.

The nucleoside reverse transcriptase inhibitor backbone of tenofovir and emtricitabine was significantly more efficacious than most other backbones, with the exception of emtricitabine and didanosine, which was equally good, Lee and colleagues found.

The third drug in triple-drug therapy until recently has usually been either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor, and analysis suggested they were equally efficacious at 61% and 67%, respectively.

Considered as a group the new integrase inhibitors yield efficacy of about 81%, Lee and colleagues found, which was significantly better (at P=0.002) than either of the other two classes.

Finally, an analysis of preferred DHHS regimens over time showed efficacy of 75%, compared with 65% for alternative regimens, and 55% for other treatment options.

The difference between the preferred and alternative regimens was significant (P<0.001), Lee reported.

The study finding delivers good news in one sense, commented Dan Kuritzkes, MD, of Brigham and Women's Hospital in Boston -- it shows that guidelines committees are doing a good job.

As a member of the DHHS guidelines panel, Kuritzkes said he was gratified to find that "it turns out that a bunch of experts sitting around and looking at data actually get it right."

The study "is confirmatory that we are having better drugs, more friendly drugs, and easier (drugs) to use," commented Pedro Cahn, MD, of Fundación Huesped in Buenos Aires and a former president of the IAS.

Those improvements are "the reason we are seeing increasing efficacy over time," he told MedPage Today.

The study was supported by the National Health and Medical Reserach Council of Australia. Lee made no disclosures.

Cahn has reported financial links with Abbott, Pfizer, GlaxoSmithKline, Pharmacia, and Roche.

Primary source: International AIDS Society
Source reference:
Lee FJ, et al "Efficacy of initial antiretroviral therapy: a meta-analysis of 40,124 adults with up to 144 weeks' follow-up" IAS 2013; Abstract WEAB0104.

Low-Dose Drug Combo Safe in Kids with HIV (CME/CE)

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Published: Jul 5, 2013

"This dosing regimen conferred adequate lopinavir blood level with reduced drug cost, and reduced potential long-term complications such as dyslipidemia," she said.

"Lopinavir/ritonavir is the most commonly used HIV regimen used in children," Puthanakit pointed out.

Of the 199 patients in the study, seven children in both arms were lost to follow-up.

Puthanakit concurred, noting that her study did not include infants and young children who are treated with liquid formulations of the antiretroviral regimen.

The study was part of the long-standing HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT).

The study was funded by Thai governmental agencies.

Puthanakit and Gibb reported no conflicts of interest.

Single HIV Pill Not Always Best (CME/CE)

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Published: Jul 5, 2013

This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.This retrospective study demonstrated similar rates of medication discontinuation whether HIV-positive patients were taking a single-pill or multipill regimen.Note that all patients in the single-pill regimen group were taking Atripla, limiting the ability to determine whether the discontinuation rate was due to side-effects unique to this drug.

KUALA LUMPUR -- HIV patients taking single pills containing three drugs are thought to be less likely to stop taking their medications than those on more complicated regimens, but that may not be completely accurate, researchers said here.

In a retrospective, observational study, people taking the most widely used single pill were just as likely to switch therapies as were those on multipill regimens, according to Benoit Trottier, MD, of Clinique Medicale L'Actuel in Montreal, and colleagues at the AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention.

On the other hand, it was true that taking the single pill containing efavirenz, tenofovir, and emtricitabine (Atripla) was more likely to result in sustained control of HIV than multipill regimens, he reported.

But even there, one multipill regimen did just as well, Trottier reported.

There are currently three such single-pill regimens on the market: Atripla (Complera): A combination of efavirenz, tenofovir, and emtricitabineStribild: A combination of elvitegravir, cobicistat, tenofovir, and emtricitabine

Trottier and colleagues used their clinic records to see what happened to new HIV patients who started on Atripla, or one of three other recommended first-line regimens that have a higher number of pills.

The primary endpoint of the study was the time to stopping the first regimen, while a secondary endpoint was the loss of virological control.

Of the 575 patients who started therapy at the clinic from 2007 through March 2012, 32% stopped their initial regimen -- 35% of the 187 who started on Atripla and 31% of the 388 who started on another regimen.

That difference wasn't significant, but when the researchers compared Atripla with individual multipill regimens, they found that one -- based on the integrase inhibitor raltegravir (Isentress) -- was actually significantly less likely to lead to switching treatment.

The main reasons for switching treatment were side effects and toxicities, Trottier noted.

The single-pill regimen was significantly better in maintaining viral control as patients on multipill regimens were overall 85% more likely to have a virological failure.

But again, the raltegravir-based regimen did as well as Atripla, he reported, while the other multipill regimens were significantly worse.

The main problem with the study is that it doesn't distinguish between the effects of a single tablet regimen as such and the effects of the component drugs, commented Joel Gallant, MD, of Johns Hopkins University School of Medicine, who was not part of the study but who moderated the session at which it was presented.

"You couldn't necessarily extrapolate these findings to other (single tablet regimens)," he told MedPage Today, noting that efavirenz is known to have distressing central nervous system adverse effects not shared by most other HIV drugs.

But he added that the analyses that have suggested such regimens have more durable and effective results may suffer themselves from selection biases -- physicians tend to put highly motivated patients on Atripla knowing they are unlikely to miss doses.

If adherence is likely to be an issue, he added, doctors might choose regimens that are more forgiving.

Trottier agreed that the lack of data on other single-pill combinations is "a limit of our study."

But, he told MedPage Today, that's because other single tablet regimens have only recently reached the market so he and colleagues have limited numbers of patients on which to base an analysis.

Trottier said the study and the researchers had no external support from industry.

Gallant has disclosed commercial relationships with Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck, RAPID Pharmaceuticals, and Sangamo Biosciences.

Primary source: International AIDS Society
Source reference:
Trottier B, et al "Single tablet regimens do not necessarily translate into more durable HIV treatments" IAS 2013; Abstract TUPDB0106.

Early HIV Treatment Restores Immune System (CME/CE)

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Published: Jul 5, 2013

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.Note that this prospective cohort study demonstrated superior HIV control and CD4 counts among patient initiated on HIV therapy prior to achieving CD4 counts <500/mm3 -- adding to the potential value of earlier initiation of therapy.Be aware that the study findings may reflect inherent differences between those with higher baseline CD4 counts and those with lower baseline CD4 counts as it lacked an adequate control group.

KUALA LUMPUR -- Antiretroviral therapy can restore aspects of a normal immune system in some patients with chronic HIV, as well as reduce the size of the viral reservoir, a researcher said here.

The catch is they have to start with a relatively intact immune system, with at least 500 CD4-positive T cells per microliter of blood, according to Laurent Hocqueloux, MD, of the Centre Hospitalier Régional in Orleans, France.

But the finding, from a prospective observational cohort study, suggests such patients might be most likely to benefit from future interventional trials aimed at eradicating the virus, Hocqueloux argued at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention.

Hocqueloux and colleagues have previously shown that treatment early in HIV infection leads to a weak viral reservoir and a good restoration of the immune system.

In some patients treated very early, that has led to what the researchers are calling "post-treatment control" -- the ability to go off HIV therapy without having the virus resume growing in the body.

But, Hocqueloux said, they wondered if some patients who had reached what is considered chronic infection might also see immune restoration and a weak viral reservoir.

To find out, they studied 309 patients treated with antiretroviral drugs from 2005 through 2012 and asked what proportion would regain a normal CD4 count of at least 900 cells, a normal ratio of CD4 to CD8 cells of more than 1.0, and fewer than 2.3 log10 copies of HIV DNA per million peripheral blood mononuclear cells (PBMCs).

Patients were stratified by their lowest CD4 count before starting therapy -- fewer than 200, 200 to 499, and 500 or more.

At study entry, Hocqueloux reported none of the patients met the primary endpoint.

But after 4 years of treatment, 30% of those who started with more than 500 cells did so, compared with 7% of those in the middle category, and 2% of those in the lowest group. The trend was significant at P=0.0001.

Patients who started with 500 of more CD4 cells wound up with a median count of 1,100 cells, a CD4/CD8 ratio of 1.25, and an HIV DNA load of 2.51 log10 copies per million PBMCs.

Those who started with fewer than 500 cells were significantly worse on all three benchmarks, Hocqueloux said.

He cautioned that the study had a cohort design, had short follow-up, and still needs to be confirmed in other cohorts.

But at a minimum, the study confirms the value of early treatment, before the immune system is too badly degraded, he said. And the findings may point toward good candidates for trials of therapeutic vaccines or strategies aimed at "emptying" the viral reservoir and leading to remission.

Indeed, the study found a "very dramatic difference" between those with high and low initial CD4 counts in terms of the outcome of therapy, commented Robert Murphy, MD, of Northwestern University Feinberg School of Medicine in Chicago.

But patients who met the study's endpoint are unlikely to be able to control the virus on their own, without the aid of HIV therapy, because they are already chronically infected, Murphy told MedPage Today.

Still, he agreed with Hocqueloux that they might be the best choices for proof-of-concept studies aimed eradicating the viral reservoir, he said. "To prove the concept," he said, "you have to pick the patients most likely to succeed and these are those patients."

For that reason, he added, "this is a really, really important study."

The study was supported by the French national AIDS research agency. Hocqueloux did not make any financial disclosures.

Murphy reported financial links with Gilead.

Primary source: International AIDS Society
Source reference:
Hocqueloux L, et al "In chronically HIV-1-infected patients long-term antiretroviral therapy initiated above 500 CD4/mm3 achieves better HIV-1 reservoirs' depletion and T cell count restoration" IAS 2013; Abstract WEAB0102.