This is the year of two new classes of HIV drugs coming to market. Not just two new drugs, but drugs from two entirely new categories of medications not currently available in the pharmacy.
That’s especially good news for the people who’ve been on many different HIV meds and are running out of older drugs or are recycling them. Because of this, in addition to their potency and tolerability, the two drugs have caused tremendous excitement among medical providers and treatment advocates. If fully FDA approved, we might see a new era in HIV therapy, with the promise of restoring health to people who have run out of options, or are starting to do so. In addition, new drugs in older drug classes are expected in the next year or so.
As usual, not everyone will benefit from both new drugs. And, it can be tricky to take any of the new options. If you can, you should try to wait for at least two drugs you’ve never taken before, or to which your virus is not resistant.
Maraviroc up to bat
The first medication lined up for the pharmacy is maraviroc, which in April was recommended for accelerated approval by an advisory panel of the U.S. Food and Drug Administration (FDA). The FDA has always gone on to approve an HIV drug recommended for accelerated approval—especially when the recommendation to approve the drug was unanimous.
Maraviroc is expected to be approved by the end of June. It was already available through an expanded access program (www.maraviroceap.com). The other new drug expected to be approved this year is Merck’s integrase inhibitor raltegravir, or MK-0518. Maraviroc, from Pfizer Inc., is expected to have a limited market, at least initially, more so than raltegravir.
Maraviroc is a receptor blocker, or CCR5 inhibitor. It blocks (inhibits) HIV from latching on to one of the receptors found on the outside of T-cells. Remember, HIV has to attach to the T-cells before it can enter them.
HIV uses receptors on the outside of the cell to attach itself. If HIV cannot attach, then it cannot enter the cell and make more copies of itself. Think of it like a boat dragging an anchor just above the bottom. As long as there is nothing but sand, the anchor just dangles and the boat keeps drifting along. If the anchor snags a rock, them bam—the boat stops.
HIV just cruises along in the blood until it encounters the right kind of receptor. When it does, it can latch on and enter the cell. It latches on to the CD4+ receptor on T-cells. Then it needs to latch on to one of two known co-receptors, CCR5 or CXCR4.
All the other drugs work either after the virus has attached to the cell (Fuzeon) or is already inside the cell (including raltegravir).
“Hey, baby—what’s your tropism?”
For some people’s virus, the co-receptor the virus is looking for is called CCR5 (pretty boring name, right?). For other people’s virus, the co-receptor the virus is looking for is instead a close cousin called CXCR4. This is called viral tropism. (“Tropic” is pronounced with a long “o” sound, as in “Ohio”.) And still for others, their virus may be able to use either or both types of receptors.
Maraviroc only blocks one of these—the CCR5 receptor. If your virus uses only CCR5, then maraviroc may be a drug that can work for you. If your virus uses the other receptor (CXCR4) or both, then maraviroc is less likely to work. How do you find out “what’s your tropism?” Your doctor will have to run a special blood test. That’s one of the drawbacks of the drug. People must first be tested to see whether or not they have CCR5-tropic HIV. The test is new, expected to be expensive and in the studies took a couple of weeks to get done. Also, in Pfizer’s research, about half of the people trying to be in the studies were turned down because their virus did not exclusively use the CCR5 receptor. At press time, the test was still experimental.
Resistance
What effect the blocking of CCR5 has in the long run is still unknown. The search for the inhibitor began when it was found that people who were born with alterations in their CCR5 receptors were much less likely to become infected with HIV or to progress to AIDS if infected. During Pfizer’s studies testing maraviroc in CCR5-tropic patients, the virus changed in a few patients. The virus began using both CCR5 and CXCR4 or just CXCR4. This is called a change in tropism. Exactly what this means is unclear. Virus that uses the CXCR4 receptor may be more aggressive and cause faster worsening of HIV. Some of the patients on the Pfizer studies whose virus did change are still doing well, but stay tuned as they continue to be followed for long-term effect.
Data
Pfizer presented early (24 week) data for maraviroc to the FDA panel and the 14th Annual Retrovirus Conference (CROI) in February.
The CROI report showed that people who took maraviroc nearly doubled, or more than doubled, their chances of achieving undetectable viral load compared to those on optimized therapy only (the placebo group). These were advanced, highly treatment-experienced patients.
The MOTIVATE 1 study took place in the U.S. and Canada, while MOTIVATE 2 took place in Europe, the U.S., and Australia. “MOTIVATE” stands for “Maraviroc plus Optimized Therapy in Viremic Antiretroviral Treatment Experienced Patients.”
There were three groups in each study, all of whom had an optimized background therapy. That is, everyone’s treatment changed for the better as much as possible, whether or not they were given maraviroc. The first group was the placebo group (optimized therapy alone), the second was the maraviroc once a day group (QD), and the third was maraviroc twice a day (BID). People in MOTIVATE 1 and 2 started out with an average of roughly 63,000 viral load.
MOTIVATE 1
The number of people going to less than 400 viral load (undetectable) in MOTIVATE 1 was 31% for placebo, 55% for maraviroc QD, and 60% for maraviroc BID.
The percentage of those going under 50 (undetectable in the more sensitive viral load test) was 25% for placebo, 42% for QD, and 49% for BID.
Overall, they had almost a one log drop (a significant decrease) in viral load in the placebo group, but almost two log drop on maraviroc (highly significant). A one log drop from 63,000 equals roughly 6,300 viral load, and a two log drop, roughly 631.
These are still small numbers: a total of 118 persons in the placebo group, 232 in the QD group, and 235 in the BID group. Those numbers include the large amount of drop-outs, about 40% overall (approximately 60% of the placebo group and 35%—or a third—of the maraviroc groups). Drop-outs due to adverse events did not exceed 5% in any of the treatment groups in either study.
MOTIVATE 2
The number of people going to less than 400 viral load in MOTIVATE 2 was 23% for placebo, 56% for maraviroc QD, and 62% for maraviroc BID.
The percents going under 50 viral load was 21% for placebo, 46% for QD, and 41% for BID.
Overall, they had almost a one log drop (a significant decrease) in viral load in the placebo group, but almost two log drop on maraviroc (highly significant).
There were 91 persons in the placebo group, 182 in the QD group, and 191 in the BID group. These include the people who discontinued the study (65% of the placebo group, and almost a third of the maraviroc groups).
Changing therapy
As expected, the more drugs that people could add which were effective in fighting their virus, the better they did in the study. When someone’s virus develops drug resistance to some of the HIV medications, that person’s options, obviously, become more limited.
It’s long been known to try to include at least two active drugs (lacking resistance) when changing therapy. Maraviroc’s being in a new drug class, however, changes the situation. U.S. HIV treatment guidelines suggest that in people with advanced HIV disease (less than 100 T-cells) and higher risk of clinical progression (disease), “Adding a drug with activity against drug-resistant virus (e.g., a potent ritonavir-boosted PI) and a drug with a new mechanism of action (e.g., HIV entry inhibitor) to an optimized background antiretroviral regimen can provide significant antiretroviral activity [emphasis ours].” (Visit www.nih.gov.)
As reported earlier from CROI by Positively Aware, Pfizer found that, “In a combined analysis of the two studies, the most pronounced differences in viral load reduction between those on drug and those on placebo were seen in those with one to two active drugs in their OBT: for those with one active drug in their OBT, 43% reached a viral load less than 50 copies/mL in both the once-daily and twice-daily groups vs. 9% in the placebo group; for those with two active drugs in their OBT, 52% of those on maraviroc once-daily and 53% of the twice-daily group achieved a viral load less than 50 copies/mL vs. 19% for the placebo group.”
Also, “fewer patients receiving maraviroc experienced treatment failure compared to those receiving placebo; however, more patients on maraviroc had a change in tropism result to D/M [dual/mixed-tropic virus] or X-4 [CXCR4-tropic virus] at time of failure.”
In the MOTIVATE studies, adding Fuzeon—an injectable HIV drug that’s generally saved for more advanced patients—did not make much of a difference, as it has with other new drugs. Nor did a person’s viral load level at the start of the study, whether above or below 100,000 (a high number).
Is it a placebo? Or is it maraviroc?
One study site principal investigator, pharmacist Patrick Clay of Kansas City University of Medicine and Biosciences (Missouri), said the three patients in the study at his site thought they were on placebo, until he showed them their viral load results. Their viral load dropped drastically, even though they had not changed their background therapy. Although still blinded (neither the staff nor the study participants know whether they’re receiving placebo or maraviroc), the patients have maintained or increased their T-cell count, with no changes in tolerability or lab tests. These participants are now out to 52 weeks of study participation, and “still doing well,” said Clay.
Side effects
People taking maraviroc experienced headache, dizziness, nausea, fatigue, and weakness, but generally at the same rates as those on placebo did.
Unfortunately, however, the CCR5 drug class was tainted by serious side effects seen with two other CCR5 inhibitors that were also being studied. These consisted of cardiac problems and liver toxicity, as well as simply lacking the desired level of potency.
Some potential study participants, however, shied away from maraviroc because of the toxicities in the other compounds, Clay said, but he pointed out that drugs in the same class can have very different side effect profiles. Maraviroc has not shown the toxicities of the other CCR5 inhibitors.
Further reading
For more information, see the Positively Aware 2007 Annual HIV Drug Guide, or request one by mail. |
