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IAC/Vienna AIDS Conference: Encouraging Advances Amid Funding Worries for Global Treatment - JAMA
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Joan Stephenson, PhD
JAMA. Sept 2010;304(10):1053-1055.
AIDS 2010
18th International AIDS Conference (IAC)
July 18-23 2010
Vienna, Austria
"International AIDS Society-USA panel ....recommended initiating treatment in "highly-resourced countries" when the level of CD4 cells drops to 500/µL instead of the previous threshold for initiating therapy, 350/µL, said panel member Melanie A. Thompson, MD...... The WHO revised its HIV treatment guidelines is now recommending initiating ART for asymptomatic patients when their level of CD4 cells dwindles to 350/µL or less, rather than to 200/µL or less, the previous threshold for starting treatment. It also urges countries to progressively phase out the use of the nucleoside reverse transcriptase inhibitor stavudine.... Demonstrators protested cutbacks in funding for treatment of people living with HIV/AIDS in poorer nations.....Perhaps the most compelling news emerging from the conference was the report that for the first time, a vaginal microbicide (a gel containing the antiretroviral drug tenofovir) reduced the risk of HIV infection in women by an estimated 39% compared with a placebo gel.... discovered that the tenofovir gel has another effect that could provide further protection against HIV: it helps prevent HSV-2 infection, the most common cause of genital ulcer disease...... trial, conducted in Cambodia provides guidance to clinicians treating patients who are coinfected with both TB and advanced HIV....early vs later ART...... Participants were randomized to begin receiving ART (daily stavudine, lamivudine, and efavirenz) either 2 weeks or 8 weeks after beginning TB treatment and were followed up for 50 weeks after the enrollment of the last participant.......the earlier treatment reduced mortality by about 34% compared with the later treatment; 59 of the 332 participants who started ART 2 weeks after starting TB treatment had died (a rate of 8.28 deaths per 100 person-years) vs 90 of the 329 participants who started ART 8 weeks after TB treatment began (a rate of 13.77 per 100 person-years)..... IRIS did occur significantly more frequently in the early-treatment group (110 cases, including 5 fatal) compared with the late-treatment group (48 cases, including 1 fatal), a nearly 2.5-fold difference. "But most of the time it was quite easy to manage"
Vienna, Austria- As scientists, clinicians, policy makers, patients, and others gathered here for the XVIII International AIDS Conference (IAC), activists waving signs declaring "No Retreat, Fund AIDS" brought to mind demonstrations at IACs in past years. The message during those earlier protests was that few people living with HIV/AIDS in poor countries hardest hit by the pandemic were benefiting from the transformative power of antiretroviral drugs.
Demonstrators at the XVIII International AIDS Conference protested cutbacks by several developed countries in funding for treatment of people living with HIV/AIDS in poorer nations. (Photo credit: Steve Forrest/IAS/Workers' Photos)
In the decade or more since those days, the effort to roll out antiretroviral therapy (ART), funded by wealthier nations, has brought treatment to an estimated 5.2 million patients in low-income and middle-income nations in sub-Saharan Africa and elsewhere, according to the World Health Organization (WHO). Now, however, the recent global economic crisis and shrinking donations from donors make the already elusive goal of bringing ART to all who need treatment in these countries recede even further.
Although such concerns remained a persistent thread throughout the conference, attendees were also buoyed by encouraging new research findings, notably the first demonstration of a vaginal microbicide that appears to offer some protection against HIV infection.
NEW TREATMENT GUIDELINES
New HIV treatment guidelines announced during the conference also reflect a growing appreciation that evidence demonstrates that earlier treatment of HIV saves lives. The WHO revised its HIV treatment guidelines, greatly increasing the number of individuals in the developing world who are eligible to receive HIV treatment. The agency is now recommending initiating ART for asymptomatic patients when their level of CD4 cells dwindles to 350/µL or less, rather than to 200/µL or less, the previous threshold for starting treatment. It also urges countries to progressively phase out the use of the nucleoside reverse transcriptase inhibitor stavudine, which can have long-term and nonreversible toxicity, to less-toxic alternatives, such as zidovudine and tenofovir. The move to earlier treatment is based on evidence that earlier treatment reduces opportunistic infections and saves lives, said Gottfried Hirnschall, MD, MPH, director of the HIV department for WHO.
An International AIDS Society-USA panel also cited increasing evidence indicating that longstanding, uncontrolled HIV replication and immune activation "lead to a chronic inflammatory state, resulting in end-organ damage and comorbid conditions not previously thought to be associated with HIV infection." As a result of this new evidence, the panel revised their guidelines for ART in developed-world settings, described during a press briefing on the first day of the conference and published simultaneously in JAMA (Thompson MA et al. JAMA. 2010;304[3]:321-333). Specifically, the panel recommended initiating treatment in "highly-resourced countries" when the level of CD4 cells drops to 500/µL instead of the previous threshold for initiating therapy, 350/µL, said panel member Melanie A. Thompson, MD.
An estimated 15 million individuals with HIV living in the developing world will now qualify under the new WHO guidelines for HIV treatment, which would initially increase the overall cost of bringing ART to patients in those regions. However, said Hirnschall, it will eventually lead to cost saving because patients with HIV will require less treatment for other infections. In addition, initiating ART earlier in the course of the infection will not only save lives, it will also have prevention benefits, he said. Because treatment reduces viral load, he noted, it means that individuals with HIV infection are less likely to transmit the infection.
MICROBICIDE PROOF OF CONCEPT
Perhaps the most compelling news emerging from the conference was the report that for the first time, a vaginal microbicide (a gel containing the antiretroviral drug tenofovir) reduced the risk of HIV infection in women by an estimated 39% compared with a placebo gel. These findings were presented by researchers in South Africa and published simultaneously in the journal Science (Karim QA et al. Science. doi: 10.1126/science.1193748; published online July 19, 2010). A standing ovation by the audience that capped the presentation of results from the CAPRISA 004 trial reflected a feeling of long-awaited triumph after many years of failed attempts to develop a protective microbicide against HIV infection.
"Today, we celebrate the proof-of-concept of microbicides," said Gita Ramjee, PhD, MSc, of the HIV Prevention Research Unit of the South African Medical Research Council, who chaired the session in which the results were presented. "As someone who has been working on multiple clinical microbicide trials in South Africa for over a decade, these groundbreaking results from CAPRISA 004 mean a lot to me personally and give hope to women in South Africa and elsewhere."
Developing an effective microbicide against HIV infection has been one of the holy grails of HIV prevention research. The vast majority of all HIV infections among women worldwide are due to heterosexual intercourse. Because of biological factors, women are more likely than their male partners to acquire HIV infection during sex. And in societies in which women are economically and socially dependent on men, they are even more vulnerable because they often have limited power to refuse sex or to negotiate the use of condoms. An effective microbicide that could be used without the knowledge of a male partner could provide such women with a powerful preventive strategy.
CAPRISA 004, a phase 2b randomized, double-blinded, placebo-controlled trial, assessed the effectiveness and safety of a vaginal gel formulated with 1% tenofovir (a nucleotide reverse transcriptase inhibitor) in 889 sexually active women at risk for HIV infection at 1 urban and 1 rural site in South Africa. All participants were given a supply of single-use applicators (prefilled with tenofovir gel or placebo gel) and were instructed to apply a first dose of the product 12 hours or less before sexual intercourse and as soon as possible within 12 hours afterward (and no more than 2 doses in 24 hours). Both groups also received condoms, risk-reduction counseling, and treatment of symptomatic sexually transmitted infections, explained Quarraisha Abdool Karim, PhD, of the Centre for the AIDS Program of Research in South Africa (CAPRISA), in Durban, who presented the findings of the study with her husband and coinvestigator, Salim Abdool Karim, MBChB, PhD.
During the 30-month trial, the researchers assessed HIV serostatus, sexual behavior, and gel and condom use at monthly visits. Overall, HIV incidence was 5.6 per 100 women-years among those who received tenofovir gel vs 9.1 per 100 women-years among those who received placebo gel, which translates to an estimated 39% reduction in HIV infection in women using the tenofovir gel. Among those with high adherence (those who used the gel for more than 80% of coital acts), HIV infection was reduced by about 54%. Among women with intermediate adherence (used the gel 50%-80% of the time), the gel reduced HIV infection by about 38%; among those with low adherence (used the gel less than half the time), the infection rate was reduced by about 28%.
The gel's protective effect appeared to be independent of sexual behavior, condom use (condoms were reportedly used in about 80% of coital acts), and herpes simplex virus type 2 (HSV-2) infection. In addition, there was no statistically significant increase in the overall rate of adverse events, although the women who received the tenofovir gel had an increased incidence of mild, self-limiting diarrhea (approximately 17% vs 11%). Among those who acquired HIV infection during the trial, there was no statistically significant difference in viral load at the time HIV was detected and no tenofovir-related resistance mutations. There also was no reported increase in risky sexual behavior, an effect known as risk compensation, in which individuals who believe an intervention might provide protection will reduce their use of proven preventive measures, such as condoms.
However, the effectiveness of the tenofovir gel appeared to decline, from a 50% reduction in HIV infection at 12 months to a 39% reduction after 30 months, the researchers reported. The investigators believe this effect is linked to decreased adherence; the women who became infected with HIV during the trial were returning substantially fewer used gel applicators. In contrast, those women who maintained high levels of adherence for the entire duration of the trial maintained the 54% reduction in risk.
REDUCING HSV INFECTION
Researchers from the CAPRISA 004 trial also discovered that the tenofovir gel has another effect that could provide further protection against HIV: it helps prevent HSV-2 infection, the most common cause of genital ulcer disease.
HSV-2 infection affects about 50% to 60% of South African adults, and those with HSV-2 infection have twice the probability of acquiring HIV, noted Salim Abdool Karim. Because a precursor molecule from which tenofovir is derived is the fundamental building block of other antiviral agents, including a drug used to treat HSV-2 infection (cidofovir), the CAPRISA 004 researchers decided to see if use of the tenofovir gel could help prevent women who were not infected with HSV-2 from acquiring the infection.
The researchers collected samples at the beginning and end of the study, which were then tested for HSV-2. Of 434 women who were not infected with HSV-2 at the beginning of the study, 208 received the tenofovir gel and 226 received the placebo gel. Among these initially uninfected women, the HSV-2 incidence rate was 9.9 per 100 women in the tenofovir group vs 20.2 in the placebo group. Taking into account 4 indeterminate samples, the data indicate "an effectiveness that ranges from 47% to 51%," said Salim Abdool Karim.
Although it is reasonable to hypothesize that lowering the overall prevalence of HSV-2 would have a long-term effect on HIV, CAPRISA 004 was not designed to demonstrate that, Karim added, but it is biologically plausible. "Additional studies are urgently needed to confirm, and indeed, to extend the findings" of the tenofovir gel's effectiveness in protecting against HIV and HSV-2 infection, he said. In addition, finding ways to improve adherence levels and sustain them is also important.
"This is an extraordinarily important proof of concept," said Anthony Fauci, MD, director of the National Institute for Allergy and Infectious Diseases (NIAID), in a press briefing following the session in which the tenofovir gel findings were presented. "We still have work ahead," he added. "We can do better-we haven't hit a wall on this; there are adherence issues, there are issues of application."
Some useful information may be forthcoming from an ongoing placebo-controlled trial, the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, funded by NIAID and other agencies at the US National Institutes of Health. The trial is expected to enroll 5000 women in 4 African countries (South Africa, Uganda, Zimbabwe, and Malawi) and will test the safety and efficacy of 1% tenofovir gel used daily, regardless of when participants have sex. The study is also evaluating the use of oral antiretroviral drugs (tenofovir alone or combined with emtricitabine), a strategy known as oral preexposure prophylaxis, or PrEP, for the ability of these regimens to reduce HIV acquisition.
It remains to be seen if the level of protection from 1% tenofovir gel demonstrated in the CAPRISA 004 trial is sufficient, if adherence can be improved, and how the product would fare when used outside of a clinical trial. But if the study's findings are confirmed and tenofovir gel is made widely available to the women who need it, it "has the potential to alter the course of the HIV epidemic," said Salim Abdool Karim. "Mathematical models estimate that if we could implement tenofovir gel in a way similar to the way in which we did it in the trial, we could prevent 1.3 million new HIV infections and more than 800 000 deaths over the next 20 years in South Africa alone."
TARGETING TB
Results from another trial, conducted in Cambodia, provides guidance to clinicians treating patients who are coinfected with both TB and advanced HIV. The lung infection, the number one killer of persons with HIV, causes about 450 000 deaths each year in HIV-infected patients, according to the WHO.
The deaths of many patients who have both tuberculosis (TB) and advanced HIV disease might be prevented by starting antiretroviral therapy 2 weeks after starting TB treatment. (Photo credit: Zephyr/www.sciencesource.com)
Despite the need to get both infections under control, clinicians have delayed initiating HIV treatment for up to 8 weeks after starting TB treatment to reduce the likelihood of TB-HIV drug interactions, as well as the risk of a potentially fatal condition called immune reconstitution inflammatory syndrome (IRIS). IRIS may occur when the damaged immune system begins to recover and the patient experiences a worsening of a preexisting, sometimes unrecognized infection, frequently TB. But other data have also suggested that for HIV-TB-coinfected patients who have a severely weakened immune system, initiating ART sooner than 8 weeks after the start of TB treatment would decrease the risk of illness and death by helping the immune system fight both infections.
To help resolve the issue of whether the benefits of earlier ART treatment outweigh the risks of IRIS, researchers funded by NIAID and the French National Agency for Research on AIDS and Viral Hepatitis launched a phase 3 randomized trial called CAMELIA (Cambodian Early versus Late Introduction to Antiretroviral Drugs). They enrolled 661 HIV-TB-coinfected Cambodian men and women (median age, 35 years) at 5 sites in Cambodia, all of whom had never been treated for HIV, had received no TB treatment or had started it no more than 1 week before enrollment, and had fewer than 200 CD4 cells/µL. (The median CD4 cell count was 25/µL, indicating extremely poor immune function.) Participants were randomized to begin receiving ART (daily stavudine, lamivudine, and efavirenz) either 2 weeks or 8 weeks after beginning TB treatment and were followed up for 50 weeks after the enrollment of the last participant.
By completion of the follow-up period, the earlier treatment reduced mortality by about 34% compared with the later treatment; 59 of the 332 participants who started ART 2 weeks after starting TB treatment had died (a rate of 8.28 deaths per 100 person-years) vs 90 of the 329 participants who started ART 8 weeks after TB treatment began (a rate of 13.77 per 100 person-years), reported Francois-Xavier Blanc, MD, of Bicetre University Hospital in France.
IRIS did occur significantly more frequently in the early-treatment group (110 cases, including 5 fatal) compared with the late-treatment group (48 cases, including 1 fatal), a nearly 2.5-fold difference. "But most of the time it was quite easy to manage" and not unexpected, said Blanc.
"We can speculate that initiating [highly active antiretroviral therapy] 2 weeks after the onset of TB treatment could potentially save 150 000 of the 450 000 annual HIV/TB-related deaths," Blanc said.
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