A new study looking at sex differences when using the newest HIV drug on the market, Prezista (darunavir), began enrolling in late September. GRACE (Gender, Race, and Clinical Experience) will look at Prezista/ritonavir (600/100 mg twice-daily) plus an Optimized Background Regimen (OBR) for 48 weeks. It is an open-label Phase IIIB trial to evaluate sex differences in efficacy, safety, and tolerability of Prezista/r by sex and/or race over a 48 week period, with its primary endpoint defined as viral load less than 50 copies at week 48.

There are a number of secondary immunologic and virologic endpoints, but one of the really interesting things about GRACE is its unique design. GRACE will enroll 420 individuals from approximately 50 sites in the U.S, Puerto Rico, Mexico, and Canada, with 70% of them women, so each site will need to enroll three women for every man in the study.
Many are watching to see how this Tibotec study plays out, as it could help serve as a model for other companies when designing future trials. Historically studies for HIV drugs have been woefully lacking when it comes to women and people of color, for various reasons ranging from trial design, to recruitment and retention of study participants. Both the CORE Center and Rush University Medical Center will be sites for GRACE in Chicago.

Men and women 18 years or older with a viral load above 1,000 can participate in the study. You cannot be using another protease inhibitor, or have used or currently use Fuzeon (T-20). Prior use of Prezista, TMC125, or Aptivus (tipranavir) is also not allowed. Women who are pregnant or breast-feeding are also excluded.

Two new drugs are currently recruiting for their Expanded Access Programs (EAP), and a third is expected to begin enrolling early next year. Early access to drugs in development has traditionally been made available to those who have limited options available to them with current drugs on the market.

The TMC125-C214 study looks at Tibotec’s TMC125 (etravirine), an NNRTI (non-nucleoside reverse transcriptase inhibitor) currently in Phase III. TMC125 has been shown to be effective in those with NNRTI resistant virus. Individuals must be 3-class experienced (PI, NRTI and NNRTI); or two-class experienced with primary NNRTI resistance who meet all other inclusion criteria. For a full list of inclusion/exclusion criteria as well as study sites visit www.clinicaltrials.gov and search for NCT00354627.

The U.S. Centers for Disease Control and Prevention (CDC) in September issued recommendations for routine HIV testing in health care settings. CDC expects routine testing to help identify the one in four people with HIV in this country whom it estimates do not know they are infected (about a quarter-million individuals) and to diagnose infections earlier. Testing is recommended for people ages 13 to 64, regardless of risk, to help normalize HIV screening. CDC also recommends dropping pre-test counseling and written consent, which it called “significant obstacles” to testing. There are also recommendations to increase diagnosis in pregnant women and to further reduce mother-to-infant transmission in pregnancy.
The CDC reported that, “Increasing the proportion of people who know their HIV status is an essential component of comprehensive HIV treatment and prevention efforts in the United States. … However, today, nearly 40% of individuals diagnosed with HIV are diagnosed within one year of infection progressing to AIDS, when it may be too late for them to fully benefit from treatment. Additionally, studies show that most people who learn they are infected take steps to protect their partners, while people who are unaware of their infection are estimated to account for between 50 percent and 70 percent of new sexually transmitted HIV infections.”
The American Academy of HIV Medicine issued a statement in support of the new recommendations, but noted that AAHIVM “remains concerned about successful linkages to medical care and prevention services for new positives, as well as around patient privacy, informed consent, and funding to support care for the newly diagnosed. …Despite these concerns, the Academy recognizes the overwhelming necessity of identifying unrecognized HIV infections as a benefit to the public’s health and its access to life-saving therapies.”

In one of a continuing number of small studies looking at the use of Kaletra by itself, researchers cautiously reported that, “[Kaletra] monotherapy may be effective in selected patients.” Monotherapy under current guidelines in the U.S. and abroad is a no-no, but has been tried with Kaletra because of properties associated with the drug and because of an often-desperate need to find a less complicated and less expensive alternative to combination treatment.

The protease inhibitor drug did not do as well as a triple combination with the non-nucleoside medication Sustiva, but nevertheless did well. “With robust pharmacokinetics, high potency and high genetic barrier to resistance, [Kaletra] is a good candidate for evaluation as monotherapy for HIV infection,” states the research abstract for the study.

After two years, 50% of the people on Kaletra monotherapy had less than 50 viral load. For the participants on the Sustiva combination, 61% had less than 50.

All participants were taking HIV medication for the first time, the kind of patients who should do best with treatment. The individuals put on Kaletra took it along with two other HIV drugs (AZT and Epivir) for at least 24 weeks before going on monotherapy. (The strategy of starting out with more drugs and whittling them down to fewer meds is called “induction/maintenance.”) They needed to achieve at least three monthly viral loads under 50 before moving on to monotherapy.

Of 92 persons given Kaletra, 79 remained on therapy for 96 weeks. The number of Sustiva patients remaining in the study for 96 weeks was 32 (the starting number was not given, but participants were randomized so that there was one Sustiva patient for every two Kaletra patients, with a total of 155 persons enrolled in the study). The percent of drug-related discontinuation was 3% for Kaletra vs. 2% for Sustiva.

For people with “breakthrough” viral load above 50 but below 500, 11/12 went back under 50 with continuing monotherapy while two out of four were resuppressed with Kaletra combination treatment. There were more breakthroughs with monotherapy than with the Sustiva regimen.

William Cameron presented the study in a Late Breaker session. (In terms of simplicity and powerfulness, it’s ironic that Sustiva is now available with two other drugs as one pill, once a day, called Atripla. Sustiva cannot, however, be taken by pregnant women or those wanting to become pregnant, and one of the other drugs in Atripla, Viread, may possibly be problematic for people with kidney malfunction or those who are prone to it.

In another Late Breaker report on Kaletra monotherapy, a Kaletra combination was found to be more effective. At 48 weeks, 71% of the people on monotherapy had less than 50 viral load, compared to 75% of those on the triple combination of Kaletra with AZT and Epivir.

In looking only at those who remained on their therapy for the entire 48 weeks, however, the numbers were 84% for monotherapy and 98% for combination. This study, MONARK, reported a high discontinuation rate—19% for Kaletra alone and 30% for Kaletra combination therapy. (Discontinuations are not necessarily due to toxicity or adverse events, but this was not reported.) These participants were also on therapy for the first time. J.F. Delfraissy reported on the study, and said more research needs to be done to determine the best use of Kaletra monotherapy for treatment-naïve people (on meds for the first time—those with drug experience are in a different boat).

The Only Kaletra (OK04) study looked at people on Kaletra and two nucleoside HIV drugs (such as AZT) with suppressed virus (below 50 viral load) for more than six months. Of 198 persons enrolled in the study, half continued triple therapy while the other half were put on Kaletra alone. At 48 weeks, 85% of the Kaletra only group was below 50 viral load compared to 90% of those on triple therapy. Four patients on monotherapy with confirmed rebound virus (considered above 500 in this study) were put back on combination treatment and returned to less than 50 viral load.

Kaletra’s the protease inhibitor drug to beat, since it’s the first choice for a PI (for people on HIV medication for the first time) in the HIV treatment guidelines of the U.S. Department of Health and Human Services (DHHS).

Now GlaxoSmithKline (GSK) released head-to-head results of its PI, Lexiva, against Kaletra (the KLEAN study). In this large study (roughly 440 persons on each drug), Lexiva was found to be non-inferior to Kaletra. (The concept of “non-inferiority” is a requirement of the U.S. Food and Drug Administration, or FDA.) Both PIs were taken with one tablet daily of Epzicom, which contains two nucleoside analogs (Epivir and Ziagen), which are also—surprise—made by GSK.

At one year (48 weeks), 66% of all participants had less than 50 viral load. Both study groups had similar T-cell increases (ranging from 106 to 287). Joseph Eron presented the Phase III study results as a Late Breaker report. The KLEAN study was also published in The Lancet medical journal. People of color made up 42% of study participants.

Grade 2–4 adverse events were rather high: 13% for the Lexiva group and 10% for the Kaletra group, but a smaller number, 5% of each group, discontinued due to AEs. Rash is common with Lexiva, a sulfa drug, while diarrhea and vomiting is common with Kaletra, and all PIs except Reyataz are associated with increased lipid levels (cholesterol and triglyceride). There was a 6% hypersensitivity reaction (HSR) to the Ziagen in Epzicom, which can be serious (see the annual drug guide at www.tpan.com). People needing to switch drugs because of HSR can probably switch to a near-equal medication, Truvada, which is made by a different drug company.

Sustiva and Kaletra are both recommended as the first drug to take for people on HIV therapy for the first time, per DHHS guidelines. So which is better?

In a head-to-head study, researchers from the Adult AIDS Clinical Trials Group (AACTG) reported that combination therapy with either medication had similar effectiveness and safety, but that a Kaletra regimen tended to have a shorter time to virologic failure (viral load rebound), as well as completion (time on the drug). These results were reported as a “trend towards;” they were not statistically significant.

At 96 weeks, 89% of the people on Sustiva had less than 50 viral load, compared to 77% of individuals on Kaletra—a statistically significant difference. Kaletra had a statistically significant greater increase in T-cells, however, 285 vs. 239 for Sustiva. The median follow-up in the study was 112 weeks. Nearly 800 individuals participated in the trial. The time to treatment-limiting toxicity was similar for all groups in the study (Kaletra plus Sustiva was also studied).

Sharon Riddler reported the results during a Late Breaker session.