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Virus Hides in Infant Blood, HIV-Blocking Protein, ART Class and Risk of MI

The AIDS ReaderThe AIDS Reader Vol 17 No 6
Volume 17
Issue 6

Drug-resistant HIV strains that pass from mother to infant can go undetected in the baby’s immune system cells and remain there for years, according to a study by Deborah Persaud, MD, of Johns Hopkins University School of Medicine and colleagues (Reuters. April 30, 2007).

AIDS Virus Hides Quickly Inside Babies’ Blood
Drug-resistant HIV strains that pass from mother to infant can go undetected in the baby’s immune system cells and remain there for years, according to a study by Deborah Persaud, MD, of Johns Hopkins University School of Medicine and colleagues (Reuters. April 30, 2007).

The practice of treating both mother and baby at delivery has slowed mother-to-child HIV transmission (MTCT) in the United States, although MTCT remains a major cause of infection in the developing world. Without treatment, about 25% of newborns become infected, either during birth or through breast-feeding.

In addition, drug-resistant HIV is on the rise globally. Resistant strains can develop in patients with HIV and then pass from person to person. Persaud and colleagues studied 21 HIV-infected infants in 10 US states. Five of the infants had been infected with drug-resistant HIV through their mothers. The researchers found that the infants’ virus moved quickly to inactive or resting CD4 T cells. While the virus was resistant to NNRTIs, protease inhibitors were effective.

“The initial transmitted drug-resistant virus will likely never be cleared from that infant with currently available treatments,” said Persaud (Persaud D, Palumbo P, Ziemniak C, et al; Pediatric AIDS Clinical Trials Group P1030 Team. J Infect Dis. 2007;195:1402-1410). [CDC HIV/Hepatitis/STD/TB Prevention News Update, Wednesday, May 9, 2007]

Researchers Find Protein That Blocks HIV
German researchers recently discovered a chain of 20 amino acids circulating in human blood that, in a test tube, inhibited HIV surface features that the virus needs to infect human cells (Russell S. San Francisco Chronicle. April 20, 2007:A-7). The peptide, which was discovered among filtrates processed during kidney dialysis, showed antiviral activity against various HIV strains, including drug-resistant HIV.

University of Ulm researcher Frank Kirchhoff and colleagues call the peptide VIRIP. In test tube analyses, the peptide inhibited 60 strains of HIV. By changing just 2 amino acids, investigators were able to increase its anti­viral potency 100-fold, said Kirchhoff (Munch J, Standker L, Adermann K, et al. Cell. 2007;129:263-275).

VIRIP, which can be manufactured in a laboratory, has been licensed to VIRO Pharmaceuticals GmbH and Co. The firm is studying the peptide in animals to determine whether it is safe enough for a preliminary human safety trial. While the results are promising so far, a market-ready drug would require 5 years or more in successful animal testing and human clinical trials, Kirchhoff said.

Like the drug Fuzeon, VIRIP inhibits the HIV surface protein gp41, which HIV uses to infect human cells. VIRIP could be used to inhibit HIV cell entry earlier than Fuzeon, which inhibits gp41 at a later stage, said Warner Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology in San Francisco. As a peptide, though, VIRIP would likely be costlier to produce than most AIDS drugs and would probably be sold as an injectable medication. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Tuesday, April 24, 2007]

Antiretroviral Drugs and Risk of Myocardial Infarction
“We have previously demonstrated an association between combination antiretroviral therapy and the risk of myocardial infarction,” researchers said, although “it is not clear whether this association differs according to the class of antiretroviral drugs.” The investigators thus sought to study the association of cumulative exposure to protease inhibitors (PIs) and NNRTIs with the risk of myocardial infarction (MI) (DAD Study Group; Fris-Moller N, Reiss P, Sabin CA, et al. N Engl J Med. 2007;356:1723-1735).

Data through February 2005 were collected from prospective observation of 23,437 HIV-positive patients. The researchers calculated incidence rates of MI during the follow-up period, as well as the associations between MI and exposure to PIs or NNRTIs.

During 94,469 person-years of observation, 345 patients had MIs. The incidence of MI increased from 1.53 per 1000 person-years for patients not exposed to PIs to 6.01 per 1000 person-years for those exposed to PIs for more than 6 years.

After adjusting for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of MI per year of PI exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23). The relative rate per year of NNRTI exposure was 1.05 (95% CI, 0.98 to 1.13). The effect of exposure to each drug class was further reduced by adjusting for serum lipid levels: for PIs, the rate was 1.10 (95% CI, 1.04 to 1.18) and for NNRTIs, 1.00 (95% CI, 0.93 to 1.09).

“Increased exposure to protease inhibitors is associated with an increased risk of myocardial infarction, which is partly explained by dyslipidemia,” the researchers concluded. “We found no evidence of such an association for nonnucleoside reverse-transcriptase inhibitors; however, the number of person-years of observation for exposure to this class of drug was less than that for exposure to protease inhibitors.” [CDC HIV/Hepatitis/STD/TB Prevention News Update, Friday, April 27, 2007]

FDA Panel Backs HIV Drug
An independent 12-member panel of medical experts assembled by the FDA recommended approval of Pfizer Inc’s HIV drug maraviroc (Dooren JC. Wall Street Journal. April 25, 2007:A4). The candidate is the first of a new class of drugs that interfere with HIV when it enters human im­mune cells through the CCR5 receptor. Some HIV strains use the CXCR4 receptor, which maraviroc does not block.

The FDA granted maraviroc priority review status, shortening the time it takes to consider a drug application. The priority designation is applied to drugs that are seen as an advance over existing therapies. The FDA has reviewed maraviroc for 4 months, said Katie Laessig, a team leader in the agency’s antiviral products division. The FDA could process maraviroc’s application by late June.

The FDA is not required to follow the drug panel’s advice, but it often does so. Pfizer, which would market maraviroc as Celsentri, proposed the drug be used in patients with advanced HIV infection or in those whose treatment regimens have failed. An estimated 40,000 US patients meet that description.

If the FDA approves maraviroc, HIV-positive patients would need to be screened to determine whether their strain uses the CCR5 pathway.

The agency said it remains concerned about possible side effects from the CCR5 inhibitor, including potential liver damage, heart problems, and infection, that undercut GlaxoSmithKline PLC’s earlier CCR5 candidate.

Clinical studies of maraviroc showed a possible “modest increase in liver-related side effects,” said the agency. In addition, the FDA said there is the “potential” that maraviroc could disturb the heart’s rhythm, which could lead to heart problems. Because CCR5 inhibitors interact directly with the human immune system, the FDA cautioned that such drugs could raise the risk of infection, lymphoma, and other blood cancers. Those complications have not been found with maraviroc.

If maraviroc is approved, Pfizer proposes examining patients for 5 years for potential side effects. [CDC HIV/ Hepatitis/STD/TB Prevention News Update, Wednesday, April 25, 2007]

New HIV Drug Shows “Unprecedented” Results
Raltegravir, the first in a new class of HIV drugs, “achieved virological suppression even in patients with limited options,” according to a commentary accompanying a new study of the drug (Agence France Presse. April 13, 2007). The commentary’s authors predicted ralteg­ravir could “have a major role in salvage therapy” (Cahn P, Sued O. Lancet. 2007;369:1235-1236).

Previously, no drug has successfully inhibited integrase, 1 of the 3 types of enzymes-along with reverse transcriptase and protease-that HIV needs for replication.

Participants in the study-178 patients with advanced HIV infection that was resistant to standard treatment-were divided into 4 groups (Grinsztejn B, Nguyen BY, Katlama C, et al; Protocol 005 Team. Lancet. 2007;369:1261-1269). All patients received a basic “background treatment”; 3 groups received doses of ralteg­ravir ranging from 200 mg to 600 mg, and 1 group received a placebo.

At 24 weeks, 65% of the patients who received ralteg­ravir had achieved HIV RNA levels below the measur­able threshold (50 copies/mL) as well as dramatically improved immune system responses. This was almost 5 times as many as among those who received the placebo.

“Clearly, we are in a new era of antiretroviral therapy,” wrote Cahn and Sued, who predicted that barring unexpected side effects or resistance issues, “raltegravir will have a major role in salvage therapy, particularly in combination with another new drug.” [CDC HIV/Hepatitis/ STD/TB Prevention News Update, Thursday, April 19, 2007]

Study Casts Doubt on Abstinence-Only Programs
A national study that observed 2000 students from elementary or middle school to high school found that abstinence-only sex education does not prevent teens from having sex, nor does it increase or decrease the odds of condom use if teenagers do have sex (Stepp LS. WashingtonPost. April 14, 2007:A02).

The much-anticipated study was authorized by Congress in 1997. Its release comes as questions are being raised about the effectiveness of the programs. Currently, the federal government spends $176 million annually on abstinence education, while millions more are spent each year through matching state and local grants.

Eight states that used to receive federal abstinence money now decline to accept the funds. A bill introduced in Congress with bipartisan support seeks to allocate money for sex education that teaches abstinence as well as contraception. In addition, federal abstinence funds are up for congressional renewal under the Title V grant.

The study, conducted by Mathematica Policy Research Inc., surveyed children in 4 communities-2 urban, 2 rural. All participants received the family life ser­vices available in their community, and slightly more than half also received abstinence-only education. At the end of the study, when the average participant was almost 17 years old, half of the participants in each group had remained abstinent. The study’s results are available online at: http://www.mathematica-mpr.com/publications/PDFs/impactabstinence.pdf.

The average age of sexual debut for teens in both groups was 15. Of those who were sexually active, almost half said they used condoms only “sometimes” or “never.” Less than a quarter of teens in both groups reported using a condom every time they had sex. Students in both groups were knowledgeable about the risks of having sex without using a condom or other means of protection. More than a third of the sexually active teens reported having had 2 or more partners.

The adolescents who participated in abstinence programs did not use condoms less frequently than did other kids, the study found. They did, however, show slightly higher knowledge about sexually transmitted disease prevention. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Monday, April 16, 2007]

Government Unworried by Abstinence Report
A Health and Human Services Department (HHSD) official, responding to a report that found some abstinence-only programs do little to discourage teenage sex, said that the 4 programs studied were among the first of their kind and are not representative of all such efforts (Fox M. Reuters. April 16, 2007).

Newer sex education programs are often more comprehensive, said Harry Wilson, associate commissioner at the Administration on Children, Youth and Family at HHSD. The department monitors all programs to ensure they are working, he said. “We are trying to collect as much data as we can. We have got a study of 400 curricula going on.”

The report was issued recently by Mathematica Policy Research Inc, which interviewed 1200 teens in 2 rural and 2 urban communities in the United States who had taken part in abstinence-only sex education 4 to 6 years earlier. When they compared the teens’ behaviors to those of 800 similar students who had not received abstinence education, the researchers found few differences: About 25% in both groups had already had sex with 3 or more partners; just 23% of those who were sexually active reported always using a condom; and average age of sexual debut for both groups was just under 15.

Advocates of more comprehensive sex education said the report shows that abstinence-only programs do not work and are a waste of money.

Wilson noted that the 4 programs studied did not extend beyond middle school-before most adolescents were likely to become sexually active. Any form of sex education will likely need to continue through high school to be effective, he said. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Tuesday, April 17, 2007]

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