Abstract
Some HIV‐Exposed Infants in Africa Are Not Getting Nevirapine
Researchers at the University of Alabama at Birmingham have discovered that only about half of HIV‐exposed infants in some African countries received a minimal dose of the prevention drug nevirapine. Only 51% of HIV‐exposed infants received the minimal regimen of nevirapine to protect them. As for women who had been prescribed nevirapine before birth, the study found that many had no sign of nevirapine in their umbilical cord samples.
The study is based on 27,893 cord samples from mother–infant pairs treated at clinics in the African countries of Cameroon, Cote d'Ivoire, South Africa, and Zambia. The samples are from 43 randomly selected clinics where single‐dose nevirapine is used to prevent mother‐to‐child transmission, along with additional prophylaxis drugs. These were collected between June 2007 and October 2008. Complete data for cord‐blood results included 3,196 HIV‐seropositive mother–infant pairs.
Significant factors associated with failed nevirapine coverage included a maternal age younger than 20 years and maternal age between 20 and 25 years, fewer than six antenatal care visits, vaginal delivery, and an infant birth weight of less than 2,500 g.
More details on the study can be found in the July 21, 2010, issue of the Journal of the American Medical Association 2010;304(3):293–302.
HIV‐Neutralizing Antibodies Discovered
Scientists from the National Institute of Allergy and Infectious Diseases (NIAID) have discovered three previously unknown human antibodies that neutralize HIV. Two of the antibodies have been found to target a broad range of HIV strains, making them valuable as possible vaccine compounds. The newly identified antibodies are unique in their breadth of neutralizing activity. One of the antibodies, called VRC01, displays potency and broad coverage across HIV strains.
The NIH Vaccine Research Center tested blood samples from HIV‐infected people around the globe for antibodies against nearly 200 strains of HIV to determine how many strains each patient could neutralize. The blood from donor 45 was found to have a broadly neutralizing antibody. This donor's blood was then used to prepare monoclonal antibodies. These were identified by screening 25 million of the antibody‐producing cells of donor 45 for production of broadly neutralizing antibodies specific for HIV envelope proteins. The screen identified three antibody‐producing cells with the desired activity. VRC01 and VRC02 neutralized 91% of HIV strains, whereas VRC03 neutralized 57%. These findings, and those of another group, previously published over the past year, establish a proof of the principle that it is possible for the human body to generate broadly neutralizing antibodies. However, the researchers note that the design of a vaccine that can induce antibodies with similar specificity will require significantly more effort.
According to the researchers, VRC01 partially mimics the CD4 interaction with gp120. After a change occurs in CD4‐defined orientation, VRC01 focuses on the vulnerable site of initial attachment. This allows the antibody to overcome the glycan and conformational masking that usually diminishes the ability of most CD4–binding‐site antibodies to neutralize viral strains. The contact between VRC01 and gp120 is mainly through V‐gene–derived regions that are substantially altered from their genomic precursors. Broad neutralization of HIV‐1 can be achieved when individual antibodies are targeted to the functionally conserved CD4 binding site of gp120.
The findings were published in two articles appearing online ahead of publication on July 8 in Science.
NAT Testing Increases HIV Detection Yield
Community‐based HIV‐testing programs generally use only HIV antibody testing. However, nucleic acid testing (NAT) can detect the presence of HIV earlier. Researchers at the University of California San Diego School of Medicine have studied 3,151 patients who sought HIV testing in community‐based clinics in or near San Diego to examine the yield of testing with a rapid test plus NAT and to see whether patients would be willing to access their results by phone or computer. NAT testing increased the HIV‐detection yield by 23%. In addition, a large majority of study participants received their negative test results by automated phone or Internet systems.
The patients were first tested for HIV with a rapid saliva test. If the result was positive, a counselor informed the patient, and blood was obtained for a standard HIV test. If the result was negative, blood was obtained for an NAT.
Of the 3,151 participants that were tested, 79 had newly diagnosed cases of HIV. Of these, 64 had positive results from a rapid HIV test, whereas 15 had positive results only by NAT. Persons with positive results from NAT were notified within 1 week. Nearly one fourth of persons with identified cases of HIV had positive results only by NAT testing. More than two thirds of patients with negative NAT results (60%) retrieved them via computer or voice mail. Among the individuals with HIV infection, 35 (44%) persons were in the acute and early stages.
Most participants in the San Diego study (56%) and those with HIV (91%) were men having sex with men. According to the UCSD researchers, those with higher incomes, younger ages, no testing at substance‐abuse rehabilitation centers, no recent syphilis, and no methamphetamine use were more likely to access negative NAT results by either Internet or voice‐mail systems.
The study was published in the June 14 issue of the Annals of Internal Medicine 2010;152:778–785.
48‐Week Data Released on PROGRESS Study of Kaletra and Isentress
Researchers have released 48‐week findings comparing an HIV regimen of Kaletra (lopinavir/ritonavir), and Isentress (raltegravir) with a traditional HIV regimen of Kaletra and the nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) in Truvada (tenofovir and emtricitabine) in antiretroviral‐naïve adult patients.
Efficacy data were collected over the first 48 weeks of the 96‐week PROGRESS (
PROGRESS is a global, multicenter, 96‐week open‐label study of approximately 200 HIV‐infected patients. Among the findings was that a similar proportion of patients had HIV‐1 RNA levels of less than 40 copies/ml when treated with Kaletra and Isentress, compared with Kaletra and Truvada. Both groups, on average, had a similar positive immune response, as measured by their increase in CD4+ T‐cell counts. The safety and tolerability, including incidences of treatment‐emergent moderate‐to‐severe medication‐related adverse events, were generally similar between regimens. Lipid (cholesterol and triglyceride) elevations were observed more frequently in the Kaletra and Isentress group.
The results were presented at the 18th International AIDS Conference in Vienna, Austria, July 18–23.
Verxve Study Shows Efficacy and Safety of Extended‐Release Nevirapine
Results from the VERxVE study show that once‐daily nevirapine extended‐release formulation (Viramune XR, 400 mg QD) is not inferior to the currently used twice‐daily immediate‐release (IR, 200 mg BID) nevirapine through 48 weeks.
The study enrolled 1,068 participants from the United States, Europe, Africa, and Australia, all of whom were antiretroviral‐naïve HIV‐1–infected adults (older than 18 years). Entry criteria included baseline viral load of more than 1,000 copies/ml and CD4 count less than 400 cells/mm3 for male subjects and less than 250 cells/mm3 for female subjects. All participants received a 14‐day lead‐in dose of 200 mg Viramune once daily, and 1,011 were randomized to receive either 400 mg QD (extended release) or 200 mg BID (immediate release). Both nevirapine formulations were used in combination with Truvada. Median baseline viral load was 4.7 log10 copies/ml for both arms (XR and IR). Demographics, other disease characteristics, and length of exposure to study drug were also similar between arms.
At week 48, virologic response was 81% (409 of 505) for the nevirapine extended‐release formulation compared with 75.9% (384 of 506) for the immediate‐release preparation. An adjusted difference of 4.9% was in favor of the nevirapine extended‐release formulation (95% CI, −0.1% to 10.0%). The 400‐mg QD nevirapine extended‐release formulation demonstrated adequate trough drug exposure through 48 weeks. Efficacy was consistent across gender, baseline viral load, and country of origin. Both formulations demonstrated a similar adverse‐event profile. No new side effects were identified.
An increased mean absolute HDL‐c from baseline of 13.4 mg/dl was found for the immediate‐release nevirapine, and 11 mg/dl, for the nevirapine extended‐release formulation. Mean increases in LDL cholesterol were 10 mg/dl in each of the treatment groups. The total mean cholesterol over HDL‐c ratio decreased in both treatment groups by 14% in the IR group and 12% in the XR group.
The adverse event (AE) profiles of both formulations were similar. Investigator‐defined, drug‐related AEs were observed in 19.8% with the nevirapine extended‐release formulation versus 24.3% for the immediate‐release nevirapine. The overall rate of symptomatic hepatic events was 1.6% for the nevirapine extended‐release formulation versus 2.8% for the immediate‐release nevirapine. The rate of rash was 8.3% versus 8.8%, respectively.
The findings were presented at the recent 18th International AIDS Society (IAS) conference in Vienna, Austria, July 18–23.
Recent FDA Approvals and Changes
On July 8, the Food and Drug Administration (FDA) granted tentative approval for a fixed‐dose combination product of lamivudine, nevirapine, and zidovudine tablets for oral solution (30 mg/50 mg/60 mg) in pediatric patients. The generic tablet is manufactured by Matrix Laboratories Limited of Hyderabad, India. This is the first tentative approval of this fixed‐dose combination product for pediatric use. Although not allowed to be marketed in the United States, the tentative approval does qualify the product for consideration for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR).
The FDA approved a new, “fourth generation” HIV diagnostic assay on June 18. The ARCHITECT HIV Ag/Ab Combo Assay is the first HIV diagnostic assay that simultaneously detects both antigen and antibodies for HIV. The new test is also the first diagnostic test approved by the FDA for use in children as young as 2 years and in pregnant women.
This single, automated test is a highly sensitive, chemiluminescent microparticle immunoassay intended to be used as an aid in the diagnosis of HIV‐1/HIV‐2 infection, including acute or primary HIV‐1 infection. It is specific for the detection of the HIV‐1 p24 antigen as well as antibodies to HIV‐1 groups M and O, and as antibodies to HIV‐2. Levels of p24 antigen increase early after initial infection, before HIV antibody is produced. Because it detects HIV‐1 p24 antigen, in addition to antibodies, the ARCHITECT HIV Ag/Ab Combo Assay can be useful in extending diagnosis to earlier, acute‐phase infection with HIV before antibodies produced by the infected patient emerge. This reduces the window period after initial infection and before the detection of infection based on formation of detectable antibodies. The median detection time was demonstrated to be 7 days earlier (range, 0 to 20 days) compared with the third‐generation enzyme immunoassay antibody tests with which they were compared.
Although the assay is not intended to be used for routine screening of blood donors, it is approved as a donor‐screening assay for HIV‐1/HIV‐2 infection in urgent situations in which licensed blood‐donor screening tests are unavailable or their use is impractical. The ARCHITECT HIV Ag/Ab Combo Assay is manufactured by Abbott Laboratories.