Abstract
HIV Treatment Response Similar in Men and Women
A new study, which demonstrated it is possible to recruit large numbers of women into a clinical trial evaluating treatments for HIV infection, found no significant gender-based differences in response to darunavir and ritonavir—at least among those who remained in the trial to the end. Nearly one third of women dropped out, compared with less than one fourth of the men enrolled. However, women dropped out of the GRACE (Gender, Race and Clinical Experience) study at higher rates than men for reasons other than drug failure, indicating that more must be done to retain women in clinical trials that shed important light on the effectiveness of drugs in development or those on the market.
Conducted between October 6, 2006, and December 19, 2008, at 65 sites in the United States, Puerto Rico and Canada, the study examined the drugs' effectiveness, their adverse effects, and tolerability in both men and women. The researchers recruited 429 HIV-positive subjects who had previously taken HIV therapy. Of the subjects, 287 (66.9%) were women and 142 (33.1%) were men. Overall, 84% were black or Hispanic. In most studies of HIV medications, women account for less than 25%. Study participants received 600 mg of darunavir and 100 mg of ritonavir twice daily. In addition, etravirine, tenofovir, and emtricitabine were available for use as needed.
The percentages of women and men who were able to suppress the HIV virus during the study were generally similar. However, a significantly higher proportion of women than men discontinued the study (32.8% versus 23.2%). When the researchers examined the treatment response of all the participants who entered the trial—including those who eventually dropped out—they found that response rates in women appeared lower than response rates in men (50.9% versus 58.5%). But this difference appeared to be due to the higher dropout rate among women. When they excluded participants who discontinued the study for reasons other than virologic failure, the response rates were similar in women and men (73.0% versus 73.5%). Adverse side effects were also comparable between the genders.
The study was published in the September 21 issue of Annals of Internal Medicine 2010;153:349–357.
Nevirapine Benefits Some HIV-Infected Children Who have Achieved Viral Suppression
HIV-infected children in South Africa who were exposed to the drug nevirapine at birth and then received a protease inhibitor (PI) for viral suppression achieved lower rates of viremia if they were switched to nevirapine, compared to children who continued on the PI-based regimen. Since PI-based therapies are more expensive, switching to nevirapine may lead to cost savings and more children treated.
Current guidelines for nevirapine-exposed (at birth) infants advise that treatment be initiated with regimens based on ritonavir-boosted lopinavir. There are many limitations of continuing to use PI-based regimens indefinitely in young children, including unpleasant taste, concerns about metabolic toxicities with long-term use during critical periods of child development, and high cost. The latter is a major disadvantage to implementing optimal primary therapy recommendations in several sub-Saharan African countries.
Researchers from the University of the Witwatersrand, Johannesburg, South Africa conducted a clinical trial to examine whether nevirapine-based therapy would be as effective as ritonavir-boosted lopinavir in maintaining viral suppression among nevirapine-exposed children if only initiated once viral suppression had been achieved with the initial PI-based regimen. The trial was conducted between April 2005 and May 2009 at a hospital in Johannesburg among 195 children who achieved viral suppression of less than 400 copies per milliliter for 3 or more months from a group of 323 nevirapine-exposed children who initiated PI-based therapy before 24 months of age. Control group children continued to receive ritonavir-boosted lopinavir, stavudine, and lamivudine (n = 99). Among the children that switched therapies, nevirapine was substituted for ritonavir-boosted lopinavir (n = 96). Children were followed up for 52 weeks after randomization.
There was better virologic suppression in the switch group than the control group, based on a primary end point of plasma viremia of greater than 50 copies per milliliter. Confirmed viremia of more than 1000 copies per milliliter was more common among children in the switch group than the control group. According to the findings, the switch group had a better CD4 cell response. Viremia greater than 50 copies per milliliter in the control group was associated with older age. Factors associated with confirmed viremia of greater than 1000 copies per milliliter in the switch group were inadequate adherence and drug resistance before treatment.
The study was published in JAMA 2010;304:1082–1090.
WHO Revises HIV Treatment Guidelines
Prompted by clinical research into the early initiation of antiretroviral therapies performed at the GHESKIO clinic in Port-au-Prince, Haiti, the World Health Organization (WHO) has revised its treatment protocols for HIV patients. The changes are based on final results from the 4-year study led by researchers at Weill Cornell Medical College in New York City.
Rather than waiting until a patient's CD4+ T cells fall below the 200 cells/mm3 threshold (as the previous WHO guidelines suggest), immediately initiating antiretroviral therapy greatly improves the efficacy of these medications. In addition, the study also linked early intervention with a decreased rate of TB.
Between 2005 and 2008, researchers recruited 816 HIV-1–infected patients at the GHESKIO clinic. All had CD4 counts between 200 and 350, had no history of AIDS illness, and were antiretroviral naïve. Study participants were randomly divided into two groups; those in the first group began treatment immediately with zidovudine, lamivudine, and efavirenz. Those in the second (control) group received treatment only when their CD4 counts measured 200 or lower. Of the 408 subjects in the control group, 160 reached that point and received therapy during the study.
In December 2009, 7 months after the researchers concluded their data gathering, WHO and the U.S. Department of Health and Human Services (DHHS) both updated their HIV treatment recommendations to reflect the GHESKIO conclusions. Specifically, for HIV-1–infected patients, antiretroviral therapy is best initiated at a CD4 count of 350 or lower.
The study was published in the New England Journal of Medicine 2010;363:257–265.
Revaccination Could Benefit HIV-Infected Children
HIV-infected children receiving highly active antiretroviral therapy (HAART) may require revaccination to maintain immunity against preventable diseases. There remains no standard or official recommendation on revaccination of children receiving HAART. Researchers at the Johns Hopkins Bloomberg School of Public Health reviewed published data to assess these children's immune responses to vaccines and found that most children treated with HAART remained susceptible to vaccine-preventable diseases but responded well to revaccination.
Researchers reviewed 38 published studies to establish whether children infected with HIV on HAART have protective immunity to vaccine-preventable diseases and to assess short-term and long-term immune responses to vaccination of children given HAART. Short-term was defined as less than or equal to 3 months and long-term was defined as greater than 3 months. They found that starting HAART in infancy, before receipt of routine childhood vaccines, might preserve immunity to vaccine-preventable diseases. Currently, WHO recommends giving most routine childhood vaccines to children infected with HIV, but does not make recommendations on revaccination.
The study was published in Lancet Infectious Diseases 2010;10:630–642.
Compound May be Suitable for Vaginal Microbicide
A promising anti-HIV compound, called a PIE 12-trimer, may eventually be effective as part of vaginal microbicide gel. The compound is being developed by researchers at the University of Utah. Animal safety studies are being planned to be followed by human clinical trials in 2 to 3 years. According to the Utah team, PIE12-trimer is ideally suited for use as a vaginal microbicide to prevent HIV infection. The group is particularly focused on preventing the spread of HIV in Africa.
The compound blocks HIV from infecting new cells. Researchers incorporated into it a “resistance capacitor” that promotes efficacy even in the presence of drug-resistant virus.
Peptide drugs have great therapeutic potential, but are often hampered by their rapid degradation in the body. D-peptides are mirror-image versions of natural peptides that cannot be broken down, potentially leading to higher potency and longevity in the body. Despite these potential advantages, no D-peptides have yet been developed. PIE12-trimer consists of three D-peptides (PIE12) linked together that block a “pocket” on the surface of HIV critical for HIV's gaining entry into the cell. Due to the high conservation of the pocket region across strains, PIE12-trimer worked against all major HIV strains worldwide, from Southeast Asia and South America to the United States and Africa.
The research was published in the August 18 ahead of print edition of the Journal of Virology.
Recent FDA Approvals and Changes
The FDA granted tentative approval for a fixed dose combination formulation of lamivudine, nevirapine, and stavudine tablets (150 mg/200 mg/30 mg) indicated for use alone as a complete regimen or in combination with other antiretrovirals for the treatment of HIV-1 infection. Two companies were approved to manufacture the generic: Hetero Drugs Limited of Hyberdad, India and Macleods Pharmaceuticals Limited of Daman, India. Both formulations qualify for consideration for purchase under the President's Emergency Plan for AIDS Relief, or PEPFAR program.
Generic atazanavir sulfate capsules (300 mg) were also approved in August. This formulation is manufactured by Emcure Pharmaceuticals Ltd. of Pune, India.
The Isentress (raltegravir potassium) tablet label has been updated with the week 96 safety and efficacy results in treatment-na=ve and treatment-experienced patients. In the treatment-na=ve trial 021, the proportion of subjects with HIV RNA less than 50 copies per milliliter was 82% for the Isentress 400 mg twice daily regimen compared to 78% for the efavirenz arm. The treatment difference and 95% confidence interval was 3.8% (−2.8%, 10.4%).
In the treatment-experienced pooled analysis of trials 018 and 019, the proportion of subjects with HIV RNA less than 50 copies per milliliter was 55% for the Isentress 400 mg twice daily + optimized background regimen compared to 27% for the optimized background regimen arm. Section 6 of the label was updated to include the Week 96 safety results.