News Briefs

Conference Coverage on the Web

Three major HIV/AIDS conferences have taken place since the last issue of BETA: the 16th International AIDS Conference, held August 13-18 in Toronto; the annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 27-30 in San Francisco; and the 8th Congress on Drug Therapy in HIV Infection (HIV8), held November 1-16 in Glasgow.

The International AIDS Conference -- the largest ever, with more than 24,000 participants -- emphasized global access to treatment and HIV prevention (see "New Approaches to HIV Prevention"), but also included numerous presentations on the latest antiretroviral treatment strategies and investigational agents. ICAAC and HIV8 are more specialized meetings devoted to medical management of HIV disease, including HIV/hepatitis coinfection. Due to the large amount of information presented at these meetings, BETA's news summary is necessarily incomplete; for more, see the Web sites listed below.

16th International AIDS Conference: www.aids2006.org
HIV8: www.abstracts2view.com/hiv
ICAAC: www.icaac.org

Ryan White funding reauthorized

After more than a year of delay and debate, on December 9, the 109th Congress reauthorized the Ryan White CARE Act for an additional three years. The compromise bill resolves an ongoing dispute between states (such as California and New York) that encompass the urban centers that bore the brunt of the early HIV/AIDS epidemic, and Southern and rural states that have been more heavily impacted in recent years. Cities such as San Francisco and New York feared the loss of established programs without continued funding, while rural areas claimed they received less money per HIV/AIDS case than the original epicenters.

The final legislation shifts some money to smaller states, while strengthening a "hold harmless" provision that allows better-funded states to receive at least 95% of their 2006 funding levels. All people diagnosed with HIV will be counted when determining funding allocations, regardless of how data are reported, and a four year transition period will permit states with code-based reporting systems to switch to names-based reporting without penalty. The compromise measure will provide funding for three years, rather than the usual five-year authorization period, to force legislators to restructure the program sooner.

CDC issues new HIV testing recommendations

In late September, the U.S. Centers for Disease Control and Prevention (CDC) published new recommendations urging health-care providers to make HIV antibody testing a routine part of medical care for all individuals aged 13 to 64, with an opt-out provision. Under previous guidelines, testing was only recommended for individuals with specific risk factors. The CDC also loosened requirements for pre-test counseling and written consent for HIV testing, bringing it more in line with procedures for other infectious diseases (see "In Their Own Words").

"These new recommendations will make routine HIV screening feasible in busy medical settings where it previously was impractical," said the CDC's Kevin Fenton, MD. "Making the HIV test a normal part of care for all Americans is also an important step toward removing the stigma still associated with testing."

The CDC estimates that some 250,000 HIV positive people in the U.S. do not know they are infected, and therefore do not take advantage of early treatment or take precautions to prevent transmission of the virus. Studies have shown that nearly 40% of people test positive for HIV within a year of progressing to AIDS, and people who are unaware of their serostatus may account for as many as 70% of new sexually transmitted HIV infections.

The "Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings" were published in the September 22, 2006, issue of the CDC's Morbidity and Mortality Weekly Report.

New policy for HIV-positive visitors to U.S.

To mark World AIDS Day on December 1, the White House announced that President George W. Bush would issue an executive order lifting the requirement that HIV positive foreign visitors must obtain a special waiver to enter the U.S. For 20 years, HIV has been included in a list of "dangerous contagious diseases" used to prohibit people from obtaining visas, permanent residency, or U.S. citizenship. HIV positive visitors could apply for a waiver, but this entailed a cumbersome application process, an often lengthy waiting period, and a permanent passport stamp revealing one's HIV status.

Under the new policy, HIV positive visitors will be able to obtain a "categorical waiver" for business or tourist visas for up to 60 days; it is not yet clear whether such individuals will still be required to declare their HIV status. "We applaud President Bush for his order rescinding this outright ban on HIV positive foreigners entering the United States," said AIDS Healthcare Foundation president Michael Weinstein. "Although we would like to see an even more enlightened approach on this issue, this executive order is a vast improvement over current law."

Updated HIV treatment guidelines

On October 10, the U.S. Department of Health and Human Services (DHHS) issued an updated version of its "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents."

Among the major changes are the addition of boosted atazanavir (Reyataz) and fosamprenavir (Lexiva) to the list of preferred components of first-line regimens, along with lopinavir/ritonavir (Kaletra) and efavirenz (Sustiva). Tenofovir DF (Viread) plus emtricitabine (Emtriva) and AZT (Retrovir) plus 3TC (Epivir) remain the preferred first-line nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbones. Nelfinavir (Viracept), boosted saquinavir (Invirase), and the triple- NRTI combination AZT/3TC/abacavir (Trizivir) were removed from the list of alternative first-line components, although they may still be appropriate for selected patients.

In addition, the panel added new data about the recently approved protease inhibitor (PI) darunavir (Prezista) and the fixed-dose tenofovir/3TC/efavirenz combination pill (Atripla), as well as new safety information regarding intracranial hemorrhage in patients taking tipranavir (Aptivus).

The same month, the National Institutes of Health issued updated "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection." Changes include revised recommendations on when to initiate therapy in treatment-naive children, treatment of HIV positive adolescents, and the addition of information about newly approved drugs.

Finally, the Public Health Service Task Force updated its "Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States ." This revision includes new pharmacokinetic and toxicity data for various antiretroviral agents.

For the latest guidelines for HIV treatment in adults, adolescents, children, and pregnant women; postexposure prophylaxis (PEP) for occupational and non-occupational exposure; and opportunistic illness prevention, see www.aidsinfo.nih.gov.

Three new expanded access programs available

Three new expanded access programs (EAPs) are or soon will be available to provide experimental antiretroviral agents to treatment-experienced individuals who lack viable treatment options.

In August, Merck opened an EAP for its experimental HIV integrase inhibitor, MK-0518 (see news item below). Participants will receive 400 mg twice-daily MK-0518 plus optimized background therapy (OBT). To qualify for the program, known as EARMRK, individuals must have documented resistance or intolerance to at least one drug in each of the three major antiretroviral classes, and must be on a failing regimen and at risk for clinical or immunological disease progression. OBT regimens should include two new drugs to which a patient's virus remains susceptible, and participants may combine MK-0518 with investigational antiretroviral agents available through other companies' EAPs. For further information and exclusion criteria, see www.earmrk.com or call 1-877-EARMRK1.

In September, Tibotec initiated an EAP for its investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125. Participants will receive 200 mg twicedaily TMC125 in combination with an investigator-selected OBT regimen. Eligible individuals may be either on a failing regimen or undergoing a treatment interruption, and must have prior experience with at least two PI-containing regimens, exposure to at least three classes of antiretroviral drugs, or past experience with PIs and NRTIs plus inability to use approved NNRTIs due to resistance or intolerance. This EAP will serve as an open-label Phase III clinical trial (TMC125-C214). For further information, exclusion criteria, and enrollment sites, see www.clinicaltrials.gov/ct/show/NCT00354627.

Finally, Pfizer announced in late November that it would open an international EAP for its investigational CCR5 antagonist, maraviroc, which is currently undergoing Phase III trials. Pending regulatory approval of the EAP protocol, the company expects to begin enrollment within the first quarter of 2007. Study patients will receive open label maraviroc twice daily in addition to OBT. Eligible participants must have CCR5-tropic HIV and have limited or no treatment options due to drug resistance or intolerance. Check www.pfizer.com for updates.

FDA approves Atazanavir 300-mg single-capsule formulation

The U.S. Food and Drug Administration (FDA) in October approved a new 300-mg single-capsule formulation of atazanavir (Reyataz) for use in combination antiretroviral therapy. The new formulation is the first one-pill, once-daily PI dosing option, and is intended for use with a boosting dose of ritonavir (Norvir). The new 300-mg capsule can be used in place of two 150-mg capsules in treatment- experienced individuals and patients whose regimens also include tenofovir.

GSK discontinues development of Brecanavir

On December 18, GlaxoSmithKline (GSK) announced that it would discontinue its work on brecanavir (GSK 640385), an investigational PI the company was developing in collaboration with Vertex Pharmaceuticals. Although the drug had reached Phase II trials, GSK cited "insurmountable issues regarding formulation," saying it was unable to develop an oral formulation capable of delivering desired drug levels in patients with multidrug-resistant HIV. "We conducted extensive studies in an effort to identify a formulation that would maximize therapeutic benefit for people living with HIV, especially those who are heavily treatment experienced," GSK said in a statement to HIV patient advocates. "Ultimately, our formulation work could not overcome the limitations of the brecanavir molecule which make consistent delivery of target drug levels unachievable."The company said it would work with investigators to identify and implement alternative treatment arrangements for current clinical trial participants.

More promising data on MK-0518

At the 2006 Conference on Retroviruses and Opportunistic Infections, researchers presented data showing that the integrase inhibitor MK-0518 was effective in treatment experienced patients with drug-resistant virus (see "MK-0518 and GS-9137: Two Promising Integrase Inhibitors in the Pipeline," BETA, Summer 2006). At the International AIDS Conference, Martin Markowitz, MD, presented latebreaking results showing that the drug also suppresses HIV in individuals receiving treatment for the first time (abstract THLB0214).

In a double-blind Phase II trial, 198 treatment-naïve participants with HIV viral loads of at least 5000 copies/mL and CD4 cell counts of at least 100 cells/mm³ were randomly assigned to receive one of four doses of MK-0518 (100, 200, 400, or 600 mg twice daily) or else efavirenz; all participants also took tenofovir and 3TC. HIV RNA levels fell rapidly, with viral load decreasing by more than 2 logs in all MK-0518 dose arms. A similar proportion of patients achieved HIV suppression below 50 copies/mL in the MK-0158 arms (85%-95%) and the efavirenz arm (92%) by week 16, and the reduction was maintained at week 24. CD4 cell increases were similar across all arms, ranging from 75-135 cells/mm³. The study drug was generally well tolerated, with similar rates of severe adverse events in the MK-0518 and efavirenz arms (4% vs 3%). The study will continue through 96 weeks.

Several studies presented at ICAAC provided further information on this new agent. One analysis (abstract A-372) showed that MK-0518 does not inhibit or induce cytochrome P450 enzyme activity, suggesting that it will have limited interactions with other antiretroviral agents. Three small studies (abstracts A-373, A-374, A-375) demonstrated that MK-0518 was well tolerated and did not produce significant interactions when administered with ritonavir, efavirenz, ritonavir-boosted tipranavir, or tenofovir. Finally, researchers showed that MK-0518 at doses of 100 mg-600 mg twice-daily plus tenofovir did not increase serum total cholesterol or triglyceride levels, unlike efavirenz (abstract H-256a).

Merck expects to file for approval of MK-0518 later this year.

SMART data confirm risk of treatment interruption

Treatment interruption is a risky strategy, according to data from the large international SMART study. Results from SMART were first reported at the 2006 Retrovirus conference (see "Structured Treatment Interruptions: After SMART," BETA, Summer 2006). Further data were presented at the International AIDS Conference (abstracts WEAB0203, WEAB0204, THPE0047, THPE0145), and complete findings were published in the November 30, 2006, issue of the New England Journal of Medicine.

The international trial included 5472 HIV positive adults with initial CD4 cell counts above 350 cells/mm³. One group was randomly assigned to defer antiretroviral therapy as long as CD4 cell counts remained above this level, and to start treatment when counts fell below 250 cells/mm³ (drug conservation arm). The rest received continuous therapy (viral suppression arm). The drug conservation arm was prematurely discontinued in January 2006 after it became apparent that these participants had more than twice the risk of opportunistic illnesses (OIs) and death.

Within two months of interrupting therapy, the percentage of participants with viral loads below 400 copies/mL decreased from 71.8% to 6.0% in the drug conservation arm. On average, the CD4 count was 206 cells/mm³ lower in this group. OIs or death due to any cause occurred in 120 participants (4.4%) in the drug conservation arm, compared with 47 (1.7%) in the continuous therapy group (3.3 vs 1.3 per 100 person-years, respectively). While the increased OI rate was not surprising, participants in the drug conservation arm also had an unexpectedly higher rate of cardiovascular, kidney, and liver problems, which are often assumed to be associated with antiretroviral therapy. The elevated risk of disease and death in the treatment interruption arm was particularly pronounced among individuals with higher CD4 cell counts and lower viral loads before study entry. These findings "provide clear and compelling evidence" that CD4-guided treatment interruption is deleterious, concluded authors Waafa El-Sadr, MD, and colleagues.

Much -- but not all -- of the difference in the rate of OIs and death in this study could be explained by differences in CD4 counts and viral loads during follow-up. At the Toronto conference, coauthor Jens Lundgren, MD, said there must be a "missing link" to explain the higher risk of adverse outcomes among individuals undergoing treatment interruption. Some experts have speculated that chronic inflammation associated with HIV infection, or perhaps some type of immune impairment not reflected in the CD4 count, may play a role.

At the same meeting, another research team presented data from the DART study (abstract THLB0207), which was also prematurely discontinued in 2006. In this trial, conducted in Uganda and Zimbabwe , 813 treatment-naive participants who reached CD4 counts above 300 cells/mm³ after 48 or 72 weeks of antiretroviral therapy were randomly assigned to continue treatment or to interrupt and re-initiate therapy in 12-week cycles. Twelve patients in the continuous therapy arm developed new or recurrent AIDS defining illnesses or died, compared with 31 in the treatment interruption arm (3.2 vs 8.2 per 100 person-years, respectively). Although most participants were able to take intermittent antiretroviral therapy without developing AIDS-defining events, treatment interruption was associated with a 2.6-fold increased risk of disease progression, leading the researchers to conclude that this strategy "cannot be recommended."

Two other recent studies also cast a dim light on a different treatment interruption strategy, in which individuals on failing therapy with highly drug-resistant HIV take a treatment break in the hope that their virus will revert to a drug-susceptible "wild-type" strain before resuming therapy. In the October 2006 Journal of Acquired Immune Deficiency Syndromes (JAIDS), investigators with the CPCRA 064 study reported that for patients with multi-drug resistant HIV, treatment interruption before changing regimens "does not confer any apparent benefits with regard to virological response or delayed disease progression" and "has a prolonged negative impact on CD4 cell count recovery." Likewise, in the November 1, 2006, Journal of Infectious Diseases, Constance Benson, MD, and colleagues reported that in the ACTG A5086 study, a 16-week interruption of failing therapy before starting an optimized regimen did not improve virological response, and that multi-drug resistant HIV re-emerged soon after resuming treatment.

However, as reported in the August 5, 2006, issue of The Lancet, data from the Staccato trial showed that individuals who underwent treatment interruption using a higher CD4 cell threshold did not experience more AIDS-defining events. This study, conducted by the HIV Netherlands Australia Thailand Research Collaboration, included 430 participants with initial viral loads below 50 copies/mL and CD4 cell counts greater than 350 cells/mm³. Participants were randomly assigned to either receive continuous therapy or stop treatment until their CD4 counts fell below this level. More than 90% of participants in both arms maintained undetectable viral loads after a median 22 months of follow-up. No AIDS defining events or HIV-related deaths occurred in either arm, and emergence of drug resistance was similar between arms. But treatment-related adverse events occurred more frequently in the continuous therapy arm, while the treatment interruption group had lower CD4 cell counts and more minor manifestations of HIV infection, such as candidiasis. Based on these findings, the researchers suggested that treatment interruption with careful CD4 count monitoring may be a viable strategy for selected patients.

Protease inhibitor monotherapy

In an effort to simplify antiretroviral therapy and avoid long-term toxicities, researchers have explored less-complex regimens, including monotherapy using a single boosted PI. This strategy was discussed in "Revisiting Monotherapy: Heresy or Revised Orthodoxy?" in the Winter 2006 issue of BETA.

At the HIV8 meeting in Glasgow, two research teams presented further data on lopinavir/ritonavir monotherapy. Joseph Gathe, MD -- one of the first to explore the PI monotherapy strategy -- presented long-term follow-up data from the IMANI I trial (abstract P62), which included 30 antiretroviral-naive participants who started single-agent therapy with lopinavir/ritonavir. By week 48, 10 patients had discontinued therapy. The remaining 20 patients (18 of whom stayed on monotherapy and two of whom added tenofovir) all had HIV viral loads below 400 copies/mL by week 48, and 90% had viral loads below 50 copies/mL. At the time of the report, 15 of the 18 monotherapy patients had remained under observation for 152-216 weeks; 14 had HIV RNA levels below 50 copies/mL at the last measurement (though seven experienced transient viral load "blips"). The one individual with detectable HIV RNA was described as "0% adherent" due to lack of access to the drug. All patients experienced continued CD4 cell recovery, and no significant toxicity or drug resistance was observed.

Researchers also presented data from the MONARK trial, an ongoing 96-week open-label study in Europe (abstract PL13.3). In this trial, 83 treatment-naive participants were randomly assigned to receive lopinavir/ritonavir monotherapy, while 53 took standard triple-combination therapy using lopinavir/ritonavir plus ATZ/3TC. After 48 weeks, virological suppression was similar in both arms, though those receiving monotherapy had more episodes of low-level viremia. At week 48, participants in the monotherapy arm reported fewer symptoms and improved overall health. The investigators concluded that "patients' quality of life, estimated by the number of self-reported side effects and perception of global health, was better with lopinavir/ritonavir monotherapy when compared with a triple regimen of lopinavir/ritonavir plus AZT/3TC."

In related news, ACTG 5201 investigators reported results from a study of atazanavir monotherapy in the August 16, 2006, Journal of the American Medical Association. In this open-label, multicenter trial, 34 patients on HAART who had maintained virological suppression for at least 48 weeks on their first PI-based regimen switched to once-daily ritonavir-boosted atazanavir at study entry, then discontinued their NRTI backbone drugs after six weeks; all but one completed 24 weeks of therapy. At week 24, 31 participants (91%) had continued HIV suppression, while three (9%) experienced virological rebound. CD4 cell counts remained stable. Plasma atazanavir concentrations at the time of treatment failure were low or undetectable in two of these patients, but resistance testing did not identify PI-resistance mutations. No participants discontinued monotherapy due to adverse events, and there were no significant changes in blood lipid levels. "These preliminary data suggest that simplified maintenance therapy with atazanavir/ritonavir alone may be efficacious for maintaining virologic suppression in carefully selected patients with HIV infection," the authors wrote.

Best outcomes with NNRTIs or boosted PIs

A decade after the advent of HAART, there remains some uncertainty about which are the optimal combination antiretroviral regimens for individuals starting treatment for the first time. To explore this issue, John Bartlett, MD, and colleagues have conducted periodic meta-analyses of data from studies of various regimens, culled from medical journals and conference abstracts. The latest update, published in the October 24, 2006 issue of AIDS, included 53 trials -- with a total of 14,264 treatment-naive participants -- comparing triple-combination regimens comprised of a dual-NRTI backbone plus either a third NRTI, an NNRTI, or a boosted or unboosted PI.

Overall, more than half the subjects (55%) achieved HIV RNA levels below 50 copies/mL after 48 weeks of therapy; this percentage increased in studies with later publication dates, indicating that treatment has improved over time. Significantly more patients receiving NNRTIbased or boosted PI-based regimens achieved undetectable viral loads (64% for each), compared with those receiving triple-NRTI regimens (54%) or unboosted PIs (43%). In addition, CD4 cell count increases were significantly greater among patients receiving boosted PIs (200 cells/mm³), compared with unboosted PIs (179 cells/mm³), NNRTIs (173 cells/mm³), or triple-NRTI regimens (161 cells/mm³). While good adherence is known to promote better outcomes, a regimen's convenience -- a