HIV Articles  
PrEP, Microbicides and IL-2
  HIV Prevention at CROI 2009 - written by Jared Baeten, MD PhD Connie Celum, MD MPH University of Washington (02/20/09)
Current PrEP trials are using oral tenofovir (Viread), oral co-formulated emtricitabine-tenofovir (Truvada), or intravaginal tenofovir gel, the last an indication of the direction that the topical microbicide field has taken into incorporating antiretroviral agents into its products. The scale of the current trials is large, with >20,000 participants anticipated to enroll across the eight trials; however, each trial is distinct in its study population and route of HIV exposure, including men who have sex with men, injection drug users, high- and low-risk women, and HIV serodiscordant couples
Complete Protection against Repeated Vaginal Simian HIV Exposures in Macaques by a Topical Gel Containing Tenofovir Alone or with Emtricitabine - (02/11/09)
Single Dose Tenofovir Disoproxil Fumarate (TDF) with and without Emtricitabine (FTC) in HIV-1 Infected Pregnant Women and Their Infants: Pharmacokinetics (PK) and Safety - (02/24/09)
Microbicide PRO 2000/0.5% Gel Shows Promise - (03/02/09)
Extra CD4s With IL-2 Confer No Clinical Benefit in Two Randomized Trials - written by Mark Mascolini - (02/12/09)
HIV Studies: Progress in Microbicides, Dead End for an Immune-Boosting Strategy
Joan Stephenson, PhD
JAMA. April 8 2009;301(14):1421-1422.
Montreal, CanadaŃAfter years of disappointing attempts to develop a vaginal microbicide that helps protect women from HIV infection, researchers announced preliminary findings from the first trial to show promising results.
In addition to these findings, presented at the 16th Conference on Retroviruses and Opportunistic Infections, other encouraging news on the prevention front came from studies in macaque monkeys that found that antiretroviral drugs, given by mouth or in a vaginal gel, offered some protection to the animals from infection with SHIV, a virus containing components of HIV and a related monkey virus that mimics HIV infection and causes serious illness in macaques.
With no effective HIV vaccine on the horizon, an effective microbicide would be a major component in prevention efforts. Because microbicides can be applied without the knowledge of a sexual partner, they could be particularly useful for those women who cannot refuse sex or negotiate condom use with their male partners.
Encouraging findings from a study of an anti-HIV microbicide are particularly welcome in a field in which all products tested to date offered no protection against HIV infection.
In the new study, a phase 2/2b trial known as HPTN 035, funded by the US National Institutes of Health and conducted between February 2005 and September 2008, researchers enrolled 3099 HIV-negative women at 7 sites in Africa and the United States. Women were randomly assigned to 1 of 4 groups: 2 groups received either an experimental microbicide gel called BufferGel or an experimental microbicide gel called PRO 2000, a third group received a placebo gel, and the fourth group received no gel.
The 2 gels have different modes of action: BufferGel increases the natural acidity of the vaginal tract in the presence of seminal fluid, which can help inactivate HIV; PRO 2000 is a negatively charged polyanionic polymer designed to bind to positive charges on the surface of HIV particles to prevent their entry into host cells. All participants were given condoms, counseled on safer sex practices, and tested and treated for sexually transmitted infections throughout the study.
The women were followed up for an average of 20.4 months. A total of 194 infections occurred during the study: 36 per women-years of follow-up in the PRO 2000 group, 54 per women-years in the BufferGel group, 51 per women-years in the placebo gel, and 53 per women-years among no-gel group. Compared with the placebo gel or no gel at all, BufferGel had no detectable effect in preventing HIV, but PRO 2000 reduced the occurrence of HIV infection by about 30%, said Salim Abdool Karim, MBCHB, PhD, of the University of KwaZulu-Natal in South Africa.
The 30% reduction in risk of HIV infection in women using PRO 2000 did not quite reach statistical significance because the trial's relatively small size was not powered to detect such a difference, Karim explained. PRO 2000 "is a promising candidate," he said, "but additional evidence is needed to conclusively determine whether it is an effective microbicide."
However, a subgroup analysis supports PRO 2000's potential as an anti-HIV microbicide, Karim noted. Adherence to gel use (measured by self-report of use during the last coital act and during the 7 days preceding a quarterly visit) was 81% across the groups. Women who used the PRO 2000 gel less often had a 9% reduction in HIV infection compared with those who used a placebo gel; women who used the PRO 2000 gel more often had a 44% reduction in HIV infection compared with those who used placebo gel. Among women who often did not use condoms, those who had a high use of the PRO 2000 gel had a 78% reduction in HIV infection compared with those using the placebo gel.
Results from an ongoing phase 3 trial of PRO 2000 of 9395 women in South Africa, Tanzania, Uganda, and Zambia, sponsored by the UK Microbicides Development Programme, are expected to be available later this year. If its effectiveness is confirmed, the gel might be a "niche product" for some women who are unable to abstain from intercourse or use condoms, Karim said.
Other microbicide researchers are studying whether gels that contain antiretroviral drugs might provide protection against HIV infection. Findings from a study in macaque monkeys presented here showed that a vaginal gel containing 1% tenofovir-alone or in combination with 5% emtricitabine (FTC) was highly effective in preventing infection with SHIV, reported Charles Dobard, PhD, of the Centers for Disease Control and Prevention (CDC) in Atlanta.
In the study, led by Dobard and Walid Heneine, PhD, also of the CDC, 6 macaques received the tenofovir-only gel and 6 received the tenofovir/FTC gel; 11 animals (9 receiving a placebo gel and 2 receiving no gel) served as controls. Gel was applied 30 minutes before vaginal exposure to SHIV, which occurred twice weekly for 10 weeks. After a median of 4 exposures, 10 of the 11 untreated animals became infected. None of the 12 animals receiving the antiretroviral-containing gels were infected, even after 20 exposures.
Monitoring of blood levels of the antiretrovirals indicated that most of the drugs remained in the vaginal tissue and very little (<0.03%) entered the bloodstream, thus reducing the likelihood that exposure to the drugs in the microbicide would lead to drug resistance, said Dobard.
In other studies in macaques, Gerardo Garcia-Lerma and colleagues at the CDC examined the effectiveness of oral preexposure prophylaxis (PrEP) regimens of human dosing levels of a drug formulation of tenofovir plus FTC (Truvada) in preventing rectal SHIV infection. Five groups of 6 monkeys received 1 of 5 regimens (treatment 2 hours before and 22 hours after exposure; treatment 22 hours before and 2 hours after exposure; treatment 72 hours before and 2 hours after exposure; treatment 2 hours before and 22 hours later; or postexposure treatment only, 2 hours and 26 hours after exposure).
Of the 32 monkeys in the control group (9 real-time and 23 historical), 31 become infected. In contrast, those given PrEP 72 hours or 22 hours before exposure were about 15 to 16 times less likely to become infected than controls. Those receiving treatment 2 hours before and 22 hours after exposure and those treated only after SHIV exposure were only about 4 times less likely than controls to become infected.
"We showed, using an animal model, that intermittent PrEP with oral Truvada is a promising chemoprevention strategy," said Garcia-Lerma. The study also showed a wide window of protection of at least 3 days, which reflects the long intracellular half-life of the drug, but giving the drug before exposure was important for maximum protection.
Several human trials of PrEP are currently under way in different risk groups and settings, including heterosexuals in Botswana, injection drug users in Thailand, serodiscordant couples in Kenya and Uganda, and men who have sex with men in the United States.
Disappointing findings from 2 large phase 3 clinical trials revealed that interleukin 2 (IL-2) immunotherapy provides no additional benefit to HIV-infected persons who are already taking antiretroviral drugs.
Scientists had hoped that giving IL-2 to patients with HIV who were receiving combination antiretroviral treatment might reduce the rate of AIDS-related opportunistic infections and death because higher CD4 T-cell counts have been associated with better clinical outcomes in HIV infection, and because IL-2 is known to boost the number of a patient's CD4 T cells.
The 2 studies, called ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) and SILCAAT (Subcutaneous, Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts Under Active Antiretroviral Therapy) collectively enrolled more than 5800 HIV-infected participants at sites in 25 countries. Participants were randomly assigned to receive highly active antiretroviral therapy alone or in combination with a synthetic form of IL-2.
At enrollment, ESPRIT participants had early-stage infection (CD4 T-cell counts of at least 300/µL). CD4 cell counts increased in both groups of patients (those who received IL-2 and those who did not), but the CD4 T-cell counts of those who received the cytokine were substantially greater, with an average difference in T-cell count of 160/µL, reported Marcelo Losso, MD, of Hospital JosŽ Maria Ramos Mej’a, in Buenos Aires. Despite having consistently higher CD4 T-cell counts, there was no significant difference between the 2 groups in the clinical end points of incidence of HIV-associated opportunistic infections and death.
SILCAAT participants had later-stage HIV infection (CD4 T-cell counts between 50/µL and 299/µL) at enrollment, and the CD4 T-cell counts of those who received IL-2 increased an average of 59/µL higher than those in the control group, reported Yves Levy, MD, of H™pital Henri Mondor, CrŽteil, France. However, as in ESPRIT participants, that difference did not translate to lower rates of HIV-associated opportunistic infections and death.
"This suggests that IL-2Đexpanded CD4+ cells are qualitatively different than those generated by antiretroviral therapy," said Levy.
Based on these findings, the National Institute for Allergy and Infectious Diseases has discontinued a third clinical trial of IL-2 in patients with HIV infection.
  iconpaperstack view older Articles   Back to Top