The manufacturer of Coviracil (generic name emtricitabine, also known as FTC) has applied for a New Drug Application from the U.S. Food and Drug Administration (FDA). The new HIV drug is expected to be approved in early 2003. Coviracil is much like Epivir (lamivudine, 3TC), which is easy to remember when you think of the names, FTC and 3TC. They both fight hepatitis B virus and both select for the M184 resistance mutation of HIV. Therefore, Coviracil is not expected to be potent for people who've already taken Epivir -- a significant number of the people who have ever been on HIV therapy. HIV specialists say the role of Coviracil will depend on only one thing: its price.
In one large study, the two drugs were highly effective in suppressing viral load and viral rebound at 48 weeks. In another large study comparing Coviracil to Zerit (d4T, stavudine), Coviracil was more effective and less toxic (as reported in the September/October issue; see "The Buzz"). Both meds were taken with Videx (ddI) and Sustiva (efavirenz). Coviracil is an experimental once-a-day nucleoside reverse transcriptase inhibitor (NRTI), also known as nucleoside analog, or "nuke" for short. This is the same class of drugs as Retrovir, Zerit, Epivir, Combivir, etc.
Coviracil's strength and once-a-day dosing makes it an important candidate. The Coviracil/Videx-EC/Sustiva combo -- taken once a day at bedtime (seven pills) -- kept 85 percent of participants undetectable for up to two years (34/40 people). In fact, 80 percent of the 40 persons were below 50 copies. Moreover, eight of the nine who started out with more than 100,000 viral load were under 400 for the two years (but you would expect that with Sustiva). The median T-cell increase was 272 (half had more, half had less of an increase than this). Remember also that Epivir is now available as a once-daily drug as well. Reported side effects of Coviracil are central nervous system (CNS) symptoms, diarrhea and rash. In one small study, these side effects occurred in 73 percent, 37 percent and 10 percent of the participants, respectively. Elevated transaminases (an indicator of liver function) have been noted.
An expanded access program, which provides the drug free to people in great need of a new option, is now open, but only for people who are experiencing failure with Zerit or Retrovir (AZT, zidovudine), or who cannot tolerate those drugs. It is also available to people who are on Coviracil as part of a clinical trial. The program closes when the drug comes to market.
Fuzeon (generic name enfuvirtide, also known as T-20) is also expected to come to market in early 2003. Fuzeon (pronounced "fuse-ee-on") is exciting because it's in a new class of HIV drugs, so it's successful with people who've already taken many antiviral meds. As a fusion inhibitor (hence the brand name), Fuzeon blocks HIV from fusing to T-cells. However, it's taken as a self-administered twice-daily subcutaneous injection. So far, it seems that the only side effects are mild irritations at the site of injection. Moreover, T-20 was only studied with an "optimized background" of meds, and many people with advanced disease do not have another viable drug they can add on with Fuzeon. Still, it should be a boon to those with great need (low T cells or high viral load), while someone who can wait for new options -- such as a new drug to add on with Fuzeon -- may choose to do so. An expanded access program was due to open in October to offer the drug to 600 people in the U.S., out of 1,200 worldwide. Participants must have less than 100 T-cells and more than 10,000 viral load, and be unable to use an effective combination from the drugs currently on the market. Because the drug is difficult and time-consuming to make, supplies will be limited, even when it's for sale. Physicians can visit www.T20EAP.com for more information on the U.S. program and to register to participate in the program. At press time, problems with forcing prescribers to attend meetings before signing up patients were being worked out. Still, some training might be a good thing -- it takes 30 minutes to mix the solution for injection, a serious hassle for patients (although they can mix both injections at the same time). According to a press release from Fuzeon's manufacturer, "... adverse events occurring in more than 10 percent of the patients and occurring more frequently in the Fuzeon group were fatigue, insomnia, and peripheral neuropathy [but did not lead to drop outs from the study]. It was not possible to establish a causal relationship between these other adverse events and Fuzeon. In the first Phase III study, the incidence of Grade 3 and 4 laboratory abnormalities was similar between the Fuzeon and control arms. In the second, Grade 3 laboratory abnormalities were more frequent in the Fuzeon group, and Grade 4 laboratory abnormalities were more frequent in the control group." The AIDS Treatment Activists Coalition has been working on access to Fuzeon and other drugs. To sign up for the coalition's e-mail list (which has more information than is on the Web site), visit www.atac-usa.org.
A long-term study of children born to HIV-positive women found they have a heart abnormality, regardless of whether they are infected or not. According to a report by Dr. Brian Boyle for www.hivandhepatitis.com, "Study analysis showed that HIV-1 infected children had a statistically significant higher heart rate at all ages. In addition, all children born to HIV-1 infected women had a low left ventricular (LV) fractional shortening at birth, which improved in the uninfected children by age 8 months but not quite up to the normal level as seen in children in the external control group. ... Based upon the results of the current cohort study, the researchers conclude: 'Irrespective of their HIV-1 status, infants born to women infected with HIV-1 have significantly worse cardiac function than other infants, suggesting that the uterine environment has an important role in postnatal cardiovascular abnormalities.' The researchers also suggest that appropriate treatment strategies should be considered for all children born to women infected with HIV-1 as even mild LV dysfunction has shown to effect mortality over time."
The study by the National Institutes of Health (NIH) evaluated 556 children, of whom 93 were HIV-positive. For comparision, the NIH researchers also looked at 195 healthy children born to HIV-negative women. The findings were published in The Lancet medical journal last summer.
In light of controversy over HIV-positive inmates on Sustiva, written about in Positively Aware, a recent change in the drug's label now clarifies the interaction between the antiviral and marijuana tests. The label now makes it clear that other drug tests besides the ones listed may also give false positive results. At any rate, prison authorities are still required to run confirmatory tests, which they often refuse to do. See "Sustiva Seems to Cause Prisoners to Wrongly Test Positive for Marijuana Use," Nov./Dec. 2001.
The AIDS vaccine is here, but only for house cats. Fel-O-Vax prevents Feline Immunodeficiency Virus (FIV), a virus that's different from, but related to, HIV. (Note that this vaccine would have no protective effect for HIV.) Fort Dodge Animal Health, a division of Wyeth Pharmaceuticals, reported in a press release that, "According to the American Association of Feline Practitioners (AAFP), up to one in 12 cats may test positive for FIV. The virus is transmitted from one cat to another primarily through bite wounds caused by fighting. Unlike HIV, this virus is spread in high levels through saliva. But like the human form of the virus, FIV can be a deadly disease for cats as it weakens the animal's immune system." The vaccine, which has an 84 percent efficacy rate, requires three initial doses and once yearly thereafter. It is approved for cats eight weeks of age and older. It took researchers 10 years to develop an FIV vaccine which can be used around the world. Vets expressed concern that because the vaccine will cause a cat to always test positive for the virus, disease diagnosis in vaccinated felines will be complicated, as may treatment.
A report in the medical journal AIDS reminds us that the risk of rash from the non-nucleoside analogs (Rescriptor, Sustiva and Viramune) is greater for women. Rash represents an allergic reaction that in the most serious cases can lead to blindness, hospitalization and even death. The report notes that almost one in five people reported rash in studies that brought Sustiva and Viramune to market. A look at the chart records of 337 people on these two drugs found that women were five times as likely to experience rash (14.6 percent vs. 3 percent for the men). The Viramune was dose-escalated for all patients (to avoid rash).
AIDS activists in South Africa have had successes in legal battles, media campaigns and attaining access to medications. In August the South Africans joined AIDS activists from across the continent to work together to fight the epidemic there. It is estimated that 22 of the 35 million people living with HIV worldwide are from the African continent. Zackie Achmat of South Africa's Treatment Action Campaign told the Associated Press that, "All of us are trying to prevent a holocaust against poor people. HIV shows that the rich will live, but the poor will die."
Susan Scheer and colleagues remind us that many self-identified lesbians also have sex with men or engage in drug use that could lead to HIV infection. They note that, "While unknown, the biological risk of female-to-female sexually transmitted HIV is thought to be much lower than the risk of transmission between men and women. Yet studies have shown that some subgroups of women who have sex with women (WSW) exhibit high levels of sexual risk behaviors with men as well as unsafe injection drug use. Thus, if risk assumptions are based on self-reported or presumed sexual identity, possible risks for HIV infection may be underestimated in some subgroups of WSW." The study was published in the American Journal of Public Health.
reports that generic nandrolone has newly become available at some pharmacies. "The Schein brand was found in a New York pharmacy at a retail price of $13 per vial (1 ml, 200 mg/ml). This is close to the old generic price. There may be more information on the nandrolone situation at www.medibolics.com or at www.houstonbuyersclub.com," reports the newsletter. Nandrolone, used for fighting AIDS related wasting, was also sold under the brand name Deca Durabolin, which is no longer on the market.
Don't forget your flu shots. According to the Mayo Clinic, each year the flu kills as many people in the United States as does AIDS, 20,000. The U.S. Centers for Disease Control and Prevention recommends shots for infants from 6 to 23 months and their household contacts, for everyone 50 or older and for everyone older than six months with a chronic illness -- such as HIV. Still, you must talk with your doctor to see if a flu shot is recommended for you.
The experimental once-a-day protease inhibitor atazanavir (Zrivada) did well against the popular non-nucleoside Sustiva. These were preliminary results (six months) in a large clinical trial with people on HIV therapy for the first time. Atazanavir, or Taz for short, did not increase lipid levels as seen with many of the PIs on the market, or showed only slight increases. Sustiva and Taz were taken with Combivir (a combination of Retrovir and Epivir in one tablet).
Doctors couldn't believe how poorly Sustiva did in this study, especially at under 50 viral load. It has performed significantly better in every other study it's been in. All kinds of explanations were raised. The conference presenter said you can't compare across studies, to which one doctor replied, "let's say it's concerning." The researchers also tried to point the finger at different tests that were used during the study, instead of the same one for the same purpose each time. Some doctors raised the issue of reactions from different types of HIV, given that this was an international study with many participants from the developing world. All in all, as one doctor pointed out, the study was likely to be internally consistent. Therefore, if Sustiva underperformed, so did Taz.
Earlier this year there were concerns about the finding that Kaletra lowers blood levels of Agenerase. That's not good. Here, researchers looked at saving the combination by boosting levels of Agenerase with a little bit of another protease inhibitor, Norvir -- even though Kaletra already has Norvir in it. (Kaletra is a combination of the protease inhibitor lopinavir with a mini-dose of Norvir in each capsule.) The people with the additional 200 mg of Norvir had a significantly greater drop in viral load (2.5 vs. 1.4 logs) and were much more likely to be under 50 viral load. Moreover, people did well with or without extra Norvir despite having previously taken several HIV drugs and having lots of drug resistance.
Still, these are preliminary results in a small number of people (37 participants at 26 weeks). Also, the blood levels were not given. And while side effects were not detailed, adding more Norvir increases the risk of diarrhea and other gastrointestinal problems.
Sustiva (efavirenz) and Viramune (nevirapine) are both in the same class of HIV drug, the non-nucleoside analogs (or non-nukes for short). Viramune, which came to market before Sustiva, never went head-to-head with Sustiva in a large trial. As Sustiva got ready to hit the market later, its manufacturer took on the big guns, the protease inhibitors like Crixivan and Viracept -- and won every time. So the data was never clear on whether the two non-nukes are equal. Only limited data suggests that they are, and doctors have their own preferences about which drug to prescribe.
At this conference, a multi-center study from Portugal and France suggests that the two are equivalent in keeping viral loads undetectable when switching people off long term use of protease inhibitors. This was after a significant amount of time, a year and a half. Of people put on Viramune, 88.5 percent were below 400 copies viral load, vs. 94.4 percent of the people switched to Sustiva. This difference was not statistically significant. T-cells went up by 124 for the Viramune group, and down 17 for the Sustiva folks, but this was also not statistically significant (due to the small numbers of people enrolled).
However, discontinuation for any reason was relatively high for both groups: 13 of the 76 people on Viramune (17.3 percent) vs. 13 of the 54 people on Sustiva (24.5 percent), also not statistically significant.
French researchers reported that the nucleoside analogs are "increasingly recognized as a cause of mitochondrial toxicity, hyperlactatemia and hepatic steatosis [fatty liver]. In addition, cross-resistance within the [nuke] class is associated with difficulties for HAART sequencing [highly active antiretroviral therapy]." In a small study, they took 49 people who've never been on HIV therapy and five people with some treatment experience, and put them on the protease inhibitor Kaletra plus the non-nucleoside analog Sustiva, with no nucleosides.
Nearly half of the people were undetectable after a month (less than 400 viral load), but almost all were undetectable after six months. T-cells were up by 160. This was under an intent-to-treat analysis, a strict formula that takes into account all study participants, even if they drop out. (Hence, it imitates what happens in the real world.)
Serious side effects (greater than grade 2) occurred in 32 participants (59 percent). This included central nervous system (CNS) side effects (11 participants), rash (3), diarrhea (7), nausea (2) and vomiting (1). There were also high cholesterol levels in seven people, high triglicerides in four and liver problems in one. Seven participants discontinued the study: two had CNS side effects, one had rash, one had itchy skin and another stopped because of increased lipid levels. Two were non-adherent or lost to follow-up. The study will continue for a year. The researchers said that in these preliminary results, the combination of Kaletra and Sustiva is a strong one with acceptable tolerability.
A triple nuke combination with Ziagen did not hold up against a protease inhibitor or non-nuke combination.
Danish researchers noted that Ziagen (abacavir, ABC) is "usually included in triple NRTI [nuke] regimens along with zidovudine [AZT, Retrovir] and lamivudine [3TC, Epivir] despite the cross-resistance observed between ABC and the two other drugs. (In addition,) the potency of the regimen has been questioned." (Ziagen is available in combination with the two drugs in one tablet, called Trizivir, making it a convenient triple combination with only one medication.)
Here, the researchers gave Ziagen in combination with stavudine (Zerit, d4T) and ddI (Videx). The regimen was compared to the dual protease inhibitor combination of Norvir (ritonavir)/Fortovase (saquinavir), plus Retrovir and Epivir (the N/F combo). The dual PIs were given as 400 mg each twice a day. Participants in a third arm of the study used a PI/non-nuke combo consisting of Viracept (nelfinavir)/Viramune (nevirapine) plus Retrovir/Epivir (the V/V combination).
After 48 weeks, the Ziagen group had statistically significant fewer people under 20 viral load than did N/F or V/V (41 percent, 56 percent, 66 percent). Also, significantly more people discontinued any of their study drugs when compared to V/V (63 percent vs. 45 percent), but not when compared to N/F (56 percent). (Still, that's almost half of the people on the V/V arm who changed or dropped a med.) There were about 60 people in each of the three arms, all of them on HIV therapy for the first time. All in all, the researchers said that the combination of Ziagen/Zerit/Videx had more toxicity and less potency than the other two arms, and "cannot be recommended."
After four years, 72 out of 100 study participants still on Kaletra/Zerit/Epivir are doing well. Sixty-five have less than 400 viral load. Another seven are below 50 despite having gone above 400 at one point during the trial. However, 20 people left before the four years were up despite having less than 400 viral load. Average T-cells went from 281 to 721. Even people with less than 50 T-cells went from an average of 23 to 446. The most common side effects were diarrhea, nausea and abdominal pain. Participants were on HIV therapy for the first time. Results use a strict intent-to-treat analysis where missing participants or information = failure.
Preliminary results from advanced research (Phase III) were presented for the new formulation of Agenerase (amprenavir) protease inhibitor. A new formula was needed because Agenerase is taken as eight horse pills twice a day. It therefore is more popular when taken with a mini-dose of Norvir to boost its blood levels while at the same time cutting down its dosage. In this study, the pro-drug, GW433908 (908 for short), outperformed Viracept protease inhibitor at 24 weeks. That's not surprising, but the point is that 908 works well with few side effects and at a smaller dose -- two pills twice a day. That's a welcome change that's been waited for. Moreover, it's expected to do well as a once-a-day drug, boosted by Norvir or Rescriptor. Of the 908 group, 73 percent had less than 400 viral load compared to 54 percent of the Viracept group. For less than 50 viral load, the numbers were 54 percent vs. 40 percent for Viracept.
A strict intent-to-treat analysis was used. There were no changes in the median levels of triglycerides or cholesterol. Everyone was taking HIV medications for the first time, and would be expected to do well. A significant number of them, 40 percent, had more than 100,000 viral load when they entered the study. Of these, the numbers reaching less than 400 viral load were 74 percent vs. 35 percent of the Viracept group. For under 50 viral load, the figures were 42 percent vs. 11 percent. Another significant difference in this study: 31 percent of the participants enrolled were women, and 75 percent were Latinos or of African descent. Those are numbers much higher than you normally see. The most common side effects with 908 were allergy (8 percent), rash (8 percent) and nausea (5 percent). Discontinuation because of adverse events was 5 percent for 908 and 6 percent for Viracept. Discontinuation for any reason was 19 percent for 908 and 28 percent for Viracept. The drugs were taken as a triple combination with Ziagen and Epivir.