Round-up
HIV drugs battle it out, breastfeeding, and more
by Enid Vázquez
Isentress vs. Sustiva
Sustiva is the drug to beat in the world of HIV. How did the newer and mighty Isentress do?
After almost three years (144 weeks), Isentress was found to be non-inferior to Sustiva. “Non-inferior” is a study standard of the U.S. Food and Drug Administration (FDA). The small study (198 participants, three-quarters of them put on Isentress) is still in Phase 2. (Studies are completed after Phase 3 or 4.) At 144 weeks, 78% of the Isentress group vs. 76% of the Sustiva group had a viral load of less than 50. The participants were treatment-naïve, meaning that they were taking HIV therapy for the first time. The medications were taken with a background of Viread and Epivir.
Once-daily Kaletra for treatment-experienced people
The dose of many HIV medications can be taken either once or twice a day, depending on drug interactions or whether a person has previously been on antiviral therapy. Doctor and patient preference has been for once-a-day dosing. So it’s good news that Kaletra once a day was found to be non-inferior to Kaletra twice a day in treatment-experienced people. Results came from 600 participants, a large number in a clinical trial. At 48 weeks, 55% of the once-daily group and 52% of the twice-daily group had a viral load of less than 50.
Boosted Prezista monotherapy vs. standard HAART
Every once in a while, a big HIV no-no—using one drug by itself—is tried and actually found to be effective. Nothing’s been proven so far that can be taken to the bank, or the FDA, let’s say. Still, medical providers and patients continue to look for ways to make treatment as simple as possible.
In the MONET study, European researchers took 256 individuals with undetectable viral load (less than 50) for at least 24 weeks and switched them to either boosted Prezista by itself or with two nucleoside HIV drugs as background medication. Turns out that Prezista monotherapy worked as well as the triple drug combination. Good news, but more research needs to be done before anyone can try this at home.
At 48 weeks, 86% of the monotherapy group and 88% of the HAART (highly active antiretroviral therapy) group had an undetectable viral load. Eleven of the monotherapy patients and seven of the HAART patients had two viral loads above 50, but only two individuals in each group had sustained elevations over 400.
French researchers also looked at boosted Prezista monotherapy, with similar results.
In the MONOI-ANRS 136 study, 225 participants were put on either boosted Prezista by itself or with a background of two other HIV medications. At 48 weeks, boosted Prezista monotherapy was non-inferior to triple-drug therapy.
These results, however, were for the 204 participants who remained on therapy. When looking at the intent-to-treat group—the entire 225 participants—the results were not as good. This included the participants who withdrew from the study for a variety of reasons, with or without viral load failure or adverse events. Intent-to-treat is a higher statistical standard.
In the three monotherapy patients with virological failure (2.7%), all reached undetectable viral loads (less than 50 copies) after adding two other drugs. None of the triple-drug patients had virological failure, which was defined as more than one viral load result above 400 copies, a change of therapy, or discontinuation.
Kaletra vs. Reyataz
The popular HIV drugs out there continue to be tested against one another. Bristol-Myers Squibb pits its Reyataz against Kaletra in the CASTLE study. At 96 weeks, Reyataz was found to be non-inferior to the older Kaletra in treatment-naĂŻve people. 74% of the Reyataz group vs. 67% of the Kaletra group reached a a viral load of less than 50.
For those who began the study with less than 50 CD4+ T-cells, however, Reyataz did better at lowering viral load: 78% (45 individuals) vs. 58% (23) of the Kaletra group had an undetectable viral load. Other differences for this group were the drop-out rate (16% vs. 33%) and the Grade 2-4 adverse event rate (25% vs. 43%). There was no difference in results for the rest of the study participants.
When looking at the people who actually stayed on medication (instead of dropping out or moving, etc.), the percentage of undetectable viral loads ranged from 82% to 94%. Although study participants were treatment-naĂŻve, and therefore expected to do very well in treatment, they had advanced HIV disease. In CASTLE, Reyataz was given with a small booster dose of Norvir. Kaletra already has a Norvir booster in it. Truvada was provided as the background medication.
Reyataz vs. Viramune
Speaking of head-to-head studies, Viramune has been behind the eight ball for a long time. At IAS, 48-week results with 569 participants were presented for ARTEN, a study comparing Viramune to Reyataz. Viramune was found to be non-inferior to Reyataz, although the number of discontinuations was greater for the Viramune group. However, more people were taken out of the study early because of Viramune’s lack of efficacy. At 48 weeks, 67% of the Viramune group and 65% of the Reyataz group had a viral load of less than 50. The participants who began the study with more than 100,000 viral load also did well: 60% of the 230 in the Viramune group vs. 52% of the 115 in the Reyataz group. Reyataz was given with a Norvir booster dose. In ARTEN, Viramune was given once or twice a day, with similar results in the two groups, although it does not have a once-daily dose approved by the FDA. Truvada was the background medication provided.
Reyataz works after dumping the Norvir
In another effort to simplify treatment, researchers found that Reyataz worked just as well after dropping its Norvir booster dose. The 419 participants in the ARIES study had undetectable viral load (less than 50) at 36 weeks of taking boosted Reyataz with Epzicom. At that time, half of them dropped the booster dose. At 84 weeks, results were similar between the two groups: 86% of the unboosted Reyataz group vs. 81% of the boosted group had less than 50 viral load. Participants were treatment-naĂŻve.
Five days a week
More simplification at work: skipping two days of medications was not a problem. Don’t get too excited, though, as community advocates are divided on the strategy. Some worry about the effect of weekends off medication—will people go overboard?
The FOTO study (Five days On, Two days Off) enrolled 60 individuals with less than 50 viral load for at least three months, all of them on Atripla (a combination of Sustiva and Truvada in one pill). They were divided into two groups, one continuing therapy as usual and the other taking their meds for five days and then skipping them for two.
According to the report, “The availability of antiretrovirals with prolonged half-lives [length of time in the body] allows testing less than daily dosing… . The FOTO strategy maintains virologic suppression through 48 weeks. There was a strong preference to take 2 days off treatment per week even when on a simple one-pill once-daily regimen. The 28% cost savings for this strategy has broad potential implications for the developed and developing world.”
Intelence, Isentress, and boosted Prezista
In the small ANRS 139 TRIO study, French researchers put 100 individuals on a regimen of boosted Prezista and Isentress with Intelence. These were treatment-experienced individuals with many drug-resistant mutations in their virus. The background regimen varied. At 48 weeks, 86% had a viral load of less than 50. The researchers wrote, “The [Isentress], [Intelence], and [Prezista/Norvir] combination was well tolerated and provided potent and durable virological [viral load] suppression in patients with resistant viruses and limited treatment options.”
Intelence
Intelence, from the same class of HIV medication as Sustiva and Viramune, is newer. It’s also effective against virus that’s resistant to those two meds. Combined 96-week results from two advanced (Phase 3) studies with Intelence showed better results for treatment-experienced people adding it to their regimen, compared to placebo. For the Intelence group, 57% achieved undetectable (less than 50) viral load, compared to 36% adding a placebo to their treatment.
Good news on Ziagen/Epzicom and the heart
An encouraging word was heard on Ziagen (abacavir or ABC), which is part of Epzicom and Trizivir.
Last year, a huge international database reported that people taking Ziagen had an increased risk of a heart attack. This D:A:D Cohort finding (International Data Collection on Adverse Events of Anti-HIV Drugs) was presented in February 2008. The medical community was startled, since there was no known mechanism by which Ziagen may contribute to heart disease. The report also noted that people on Ziagen had higher rates of cardiovascular risks, such as smoking, diabetes, and high blood pressure.
Several presentations at this IAS conference brought forth new information on the matter.
A study conducted by the Veterans Administration (VA) led to a “duh” moment. Follow the bouncing ball, if you will:
- Chronic kidney disease (CKD) increases the risk of a heart attack.
- Ziagen’s primary competitor, Viread (part of Truvada and Atripla), has a potential for kidney toxicity (although that hasn’t been seen in any significant numbers).
- Therefore, people who are at increased risk of a heart attack in the first place, because of pre-existing kidney problems, are more likely to be put on Ziagen. (In fact, the analysis found a statistically significant greater percentage of people with CKD being put on Ziagen vs. Viread.)
The researchers found no statistically significant increase in the risk of a heart attack with Ziagen. As one doctor noted about the findings, providers should not forget about renal disease as a potential co-factor to heart disease. The VA cohort had 19,424 patients; results are based on findings between 1996-2004.
What about the risk factors for a heart attack? Ziagen does not affect several risk factors examined by Spanish researchers. They looked at several markers of cardiovascular disease and concluded that, “These results do not support a role of recent ABC/3TC [Epzicom] use in promoting inflammation, endothelial dysfunction, hypercoagulability, or insulin resistance in virologically suppressed HIV-infected patients.” The 48-week results came from the BICOMBO study, in which people with undetectable viral load were randomly given either Epzicom or Truvada.
Oh, Canada! Canadian researchers looked at the drug class that Ziagen comes from, the nucleosides (short for nucleoside reverse transcriptase inhibitors, or NRTIs). They found a greater risk of heart attack with any exposure to Ziagen, Viread, and Zerit. However, when looking at current use of medication, only Videx was associated with increased risk of a heart attack. The findings came from the Quebec Public Insurance Database (QPHID). There were 142 heart attacks in the 6,168 persons with HIV in the database. The average age was 10 years older for those having a heart attack (52 years old vs. 42 for the control group).
Viva la France for their work. The French Hospital Database on HIV had earlier this year found no association with heart attacks with cumulative exposure to seven NRTIs: Ziagen, Viread, Videx, Epivir, Zerit, zalcitabine (no longer on the market), or Retrovir (zidovudine or AZT). Nor was there an effect with medications from other HIV drug classes: Sustiva (also in Atripla), Viramune, Crixivan, Viracept, and Invirase. There was a higher risk with Agenerase (57% increased risk) and Kaletra (37% higher risk). The researchers adjusted for several factors, including high blood pressure, smoking, and use of cocaine or IV drugs.
Breastfeeding
Various studies continued to show a reduction in HIV transmission during breastfeeding when antivirals were given to the mother or the infant. Breastfeeding by HIV-positive women is not recommended, but in many poor countries is not seen as a choice.
Also, in regard to mother-to-infant transmission, Kenyan researchers, in conjunction with the U.S. Centers for Disease Control and Prevention (CDC), reported on traditional practices that may transmit the virus to the child. These practices include pre-chewing food, sometimes by an HIV-positive individual with bleeding present in the mouth (earlier found to have caused infant infection here in the U.S.) and a variety of surgical procedures without sterile equipment by traditional healers. The procedures were skin scarification and the oral operations of uvula removal and “false” (natal or neonatal) teeth extraction, which can increase the infant’s risk of infection. The uvula is an extension of the soft palate that hangs over the root of the tongue.
TB and HIV
More good news for the Southern Hemisphere: HIV therapy has been associated with a decline in tuberculosis (TB). U.S. and South African researchers reported that, “The HIV epidemic is driving tuberculosis epidemics to alarming incidence and prevalence rates in sub-Saharan Africa. …Wide-scale availability of ART [antiviral therapy] appears to be associated with a decrease in prevalence of microbiologically confirmed TB in this community, predominantly in the HIV-infected population.” 
