News from the 13th International AIDS Conference, July 9-14, Durban, South Africa
The National Cancer Institute reported a very high rate of cancer in children with HIV -- 2.5% (124 out of 4,954 children whose records were reviewed). But a doctor in the audience noted that the figure was much higher -- four times more -- than was seen in any other published report, and noted that when he and other researchers looked at cases of cancer in HIV positive children, the majority of the cancer diagnoses could not be confirmed.
Other U.S. researchers noted that with improved HIV therapies, there will be greater concern over the potential for pain and other quality of life problems in people living with the virus, but that no one has looked at pain in children. PACTG 219 (Pediatric AIDS Clinical Trials Group) found in a survey that children with a CD4 percentage of less than 15% (severely immune suppressed) were almost three times more likely to report pain. (In children, CD4 percentage is more important than T-cell counts.) Overall, 20% (one in five) of the children experienced pain. The research is important because adults are frequently unable to notice pain in children.
A big question: do children born to mothers on HIV drugs get hurt by the medications? Most research shows that they don't. But researchers from the Netherlands reported immune system damage and blood cell malfunctions (such as much less CD4 T-cells) in negative children of positive moms. The report started a storm of controversy in the audience. Among the issues raised was the fact that this was a one-time look at the umbilical cord blood at birth; the researchers are still looking at how fast the children's immune system recovers; and that these may be transient problems (the presenter said they will look at that).
Brazilian researchers found a high level of blood lipid changes (51%) in children and adolescents on anti-HIV drugs (as is found in adults). Those with a longer history of symptomatic disease had a greater risk of lipid problems (more cholesterol or triglycerides, a type of fat). Actual changes in physical appearance was greater in the kids taking a protease inhibitor (five out of 29, compared to one out of 37 using only two nucleoside analogues -- such as Zerit and Epivir). "Protease inhibitors seem to play a significant role in the development of abnormal body fat distribution," the presenter said.
Researchers reported good preliminary results in children, even those who previously took medications (a group that tends to show less benefit), with the newest protease inhibitor, lopinavir (formerly known as ABT-378/r), expected to be approved by the FDA (Food and Drug Administration) soon. After four months, undetectable viral load (less than 400) was seen in 57% of kids who had previously taken a protease inhibitor, 77% of kids who had taken a nucleoside analog, and 79% of kids who had never taken anti-HIV therapy before. The children's starting viral load was not given. The PI-experienced children received Viramune in addition to lopinavir and two nucleoside analogs. A doctor in the audience said that much higher doses of the manufacturer's current protease inhibitor, Norvir, had to be used in infants because the company didn't have enough research to provide adequate pharmacokinetics (how the drug works in the blood) in that population. He cautioned that since very few children here were less than two years old, and only one was less than six months old, the pharmacokinetic data may again end up being different once the drug is on the market. In response to a question, the presenter said the drug is not very palatable (tasty), but can be easily masked and that children, who are now a year into the study, no longer complain about taste.
Mexican researchers found good results with the use of the cancer drug hydroxyurea (Hydrea) in 24 children. They had greater weight gain, growth, increases in T-cells and CD4 percentages, less viral load and less disease after nine months on hydroxyurea (30 mg/kg a day) with Videx and Zerit. The researchers reported good tolerance (plus, no cases of pancreatitis) and noted the lower cost of using hydroxyurea than using one of the potent HIV drugs, an issue raised by other doctors at the conference in terms of adult therapy.
The most exciting news for preventing transmission from mother to child came from a study finding that three doses of Viramune (nevirapine) was similar to a more expensive and inconvenient combination of AZT with Epivir. (In the U.S., AZT monotherapy is minimum standard of care for preventing transmission, but at least a triple drug combination is preferred, both because it's a higher standard of care for the mother and because it reduces transmission more effectively than just using AZT.) In the SAINT Study (South African Intrapartum Nevirapine Trial), more than 1,000 pregnant women were given therapy while in labor. They received either one tablet of Viramune during labor and one tablet within 24-48 hours of giving birth (with the babies receiving a single 6 mg dose of Viramune within 24-48 hours of birth), or the women were given a 600 mg dose of AZT upon entering labor, with 300 mg every three hours thereafter, plus Epivir twice a day during labor, and then both drugs twice a day for seven days after birth (with the babies getting 12 mg AZT and 6 mg Epivir twice a day, also for seven days). There were no serious drug-related side effects. There was a 7% transmission at birth, which increased 42 weeks after birth to 13.3% for Viramune and 10.2% for AZT/Epivir (no statistical difference). Forty percent of the mothers breastfed, although they were offered infant formula at cost. The findings caused a stir of excitement among delegates, especially those from developing countries -- including the doctors, because of the ease and inexpensiveness of the highly effective Viramune regimen (a total of less than $10 for the three doses).
Also comparing well with AZT in short-course therapy was Zerit, Videx and a combination of Zerit/Videx. (Short-courses are studied in an attempt to decrease the cost of the original, longer U.S. trial with AZT that set the standard for preventing transmission.) In this study (also in South Africa), the drugs were given from the 34-36th week of pregnancy, but not during labor. The drugs were also given to the infants for the first six weeks of life. Baby formula was provided. Overall, there was a 3.6% transmission in more than 200 babies. Researchers said all drugs were safe and well-tolerated, and the "d" drugs (Zerit is d4T and Videx is ddI) had as much anti-HIV activity and decreases in transmission as did AZT. There were almost no drug related side effects.
In another study, breastfeeding was found to negate the benefits of AZT. In an analysis of two clinical trials that used short-course AZT in the sub-Saharan countries of Cote d'Ivoire and Burkina-Faso, there was no statistical difference in transmission at 24 months after birth between the women who used AZT (9.4%) and those who were given placebo (fake drug, 8.6%). Researchers noted that women with greater HIV viral load (the amount of virus in their blood) had a greater risk of transmission. It is preferable for HIV positive mothers to breastfeed in developing countries if the families have no access to infant formula or clean water.
German researchers took a small group of people off their meds for four to six weeks, then back on for six months. In the group with less than 50 viral load (HIV in the blood, considered undetectable here), only 58% were again undetectable after six months. Overall, they had a median rise of 0.4 log in viral load, which is statistically significant (not good). During the interruption itself, the increase was a scary 2.4 logs. They also lost an average of 11 T-cells at the end of six months. However, their lipid profile improved. They had lowered their triglyceride and cholesterol levels.
In the U.S., four people were put through three cycles of interruption, with four weeks on therapy followed by four weeks off. All started out with undetectable viral loads (considered under 400, in this case) and more than 400 T-cells. After 20 weeks, two of them did not show an increase to above undetectable (called "rebound") after one interruption, but did after the second and third (for a maximum of 14,000 and 25,000 viral load). The other two had a rebound during all three interruptions, with a maximum of 86,000 and 135,000. Viral load came back down with therapy for all four people, but not always to undetectable.
The following News Briefs are not from the International AIDS Conference.
It's pretty well known that an allergic reaction to Ziagen (abacavir) can be fatal if people stop taking the drug and then go back on it. Recently the manufacturer had to add previously unrecognized symptoms of hypersensitivity (respiratory problems) to the drug's warning label. But now the warning has been strengthened. Allergic reactions either were not being recognized or mistaken for other conditions, and people have died as a result when they started taking Ziagen again after an interruption. Sometimes the interruption had nothing to do with a reaction to the drug, as when someone stops taking anti-viral medications while another condition is brought under control. And if that person or the doctor didn't recognize a hypersensitivity reaction before, or took it for something else, like bronchitis or pneumonia -- well, you see the problem. The person goes back on the drug and, usually within hours, suffers a severe or even fatal reaction. Once again, respiratory warning signs include cough, difficulty breathing and sore throat. Other warning signs are fever, fatigue or malaise (overall ill feeling, as with a flu), and gastrointestinal symptoms (nausea, vomiting, diarrhea or stomach pain). Rash is sometimes, but not always, a symptom. For more information, call the Glaxo Wellcome Customer Response Center toll-free at (1-888) TALK2GW (825-5249).
New changes for people who work begin in September. The following is from a press release issued by the Social Security Administration (visit www.ssa.gov/pressoffice/ADA.htm). The "substantial gainful activity" (SGA) level will be raised for the first time ever, based on any annual increases in the national average wage index. (Blindness is excluded.) Currently, the SGA is monthly earnings of $700 or more, at which point people are ineligible to continue receiving benefits. Minimum monthly earnings for a Trial Work Period (TWP) go up from $200 to $530, and maybe more later on (also based on the wage index). The maximum monthly earned income exclusion for students receiving Supplemental Security Income (SSI) will increase from $400 to $1,290, and the yearly exclusion increases from $1,620 to $5,200.
The newest protease inhibitor may be in pharmacies soon. Lopinavir (formerly known as ABT-378/r) was recently submitted for FDA approval. Each capsule includes a small amount of the manufacturer's current protease inhibitor, Norvir (ritonavir). The brand name is Kaletra. A previously reported brand name was rejected because it was too close to that of an existing drug. The FDA doesn't like this because people have died after getting the wrong drug when the correct name was misread on a prescription.