News Briefs
For the latest updated guidelines for HIV treatment in adults, adolescents, children, and pregnant women; postexposure prophylaxis (PEP) for occupational and nonoccupational exposure; and opportunistic illness (OI) prevention, visit www.aidsinfo.nih.gov.
Conference Coverage
Several conferences addressing HIV/AIDS and viral hepatitis have taken place since the previous issue of BETA. The 2nd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment was held July 13-16 in Paris, preceded by the 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. The 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held September 14-17 in Chicago. Others included the 41st Infectious Diseases Society of America (IDSA) annual meeting in San Diego, the 54th American Association for the Study of Liver Disease (AASLD) conference in Boston, and the 9th European AIDS Conference sponsored by the European AIDS Clinical Society (EACS) in Warsaw, all in October 2003. Due to the large volume of information presented at these meetings, BETA will cover only selected highlights. See the Web sites below for more complete conference coverage.
IAS:
www.ias2003.org
www.hivandhepatitis.com/2003icr/2ndias/main.html
www.thebody.com/confs/ias2003/ias2003.html
Lipodystrophy Workshop:
www.hivandhepatitis.com/2003icr/5thadverse/main.html
www.natap.org/2003/lipo/ndxlipo.htm
ICAAC:
www.icaac.org/ICAAC.asp
www.hivandhepatitis.com/2003icr/43_ICAAC/main.html
www.thebody.com/confs/icaac2003/icaac2003.html
IDSA:
www.idsociety.org/me/am2003/toc.htm
www.hivandhepatitis.com/2003icr/41_IDSA/main.html
AASLD:
www.aasld.org/meetings/annualmeeting/livermeetingbody.htm
www.hivandhepatitis.com/2003icr/03_assld/main.html
www.natap.org/2003/AASLD/ndxAASLD.htm
EACS:
www.eacs.ws
www.hivandhepatitis.com/2003icr/EACS_9/main.html
www.natap.org/2003/EACS/ndxEACS.htm
Best First-Line Regimens
Azra Ghani, Ph.D., from Imperial College in London (abstract H-849) reported at ICAAC that for people newly starting antiretroviral therapy, regimens containing nevirapine (Viramune), efavirenz (Sustiva), or lopinavir (Kaletra) appear to be the most effective first-line choices. In a retrospective study of 1,119 subjects in the U.S. and the Netherlands between 1999 and 2002, Ghani and colleagues found that those taking nevirapine, efavirenz, or lopinavir were more likely to achieve viral loads under 500 copies/mL than those taking nelfinavir (Viracept) or indinavir (Crixivan) boosted with low-dose ritonavir (Norvir). Those taking efavirenz and nevirapine, both non-nucleoside reverse transcriptase inhibitors (NNRTIs), were also significantly less likely to experience viral rebound than those taking nelfinavir or boosted indinavir. In this study, no significant differences were seen between lopinavir and the two NNRTI regimens in terms of time to virological failure. [Ed. Note: a report in the December 11, 2003 edition of the New England Journal of Medicine suggested that AZT (zidovudine, Retrovir)/3TC (lamivudine, Epivir)/efavirenz is the best first-line regimen.]
Protease Inhibitors
At the IAS conference, Bonaventura Clotet, M.D., Ph.D., of Hospital Universitari Germans Trias i Pujol in Badalona (abstract 118) reported that a regimen containing atazanavir (Reyataz) boosted with low-dose ritonavir compares favorably to lopinavir (the Kaletra pill is formulated with a small dose of ritonavir). Dr. Clotet and colleagues found that among 358 treatment-experienced subjects without high-level protease inhibitor (PI) resistance, a 24-week interim analysis revealed that viral suppression and CD4 cell increases were similar in the atazanavir and lopinavir arms (viral load less than 400 copies/mL in 64% and 62%, and less than 50 copies/mL in 39% and 42%, respectively); less antiviral activity was seen in those taking atazanavir plus saquinavir (Fortovase or Invirase). Subjects taking atazanavir had lower total cholesterol, LDL ("bad") cholesterol, and triglyceride levels, but higher HDL ("good") cholesterol compared with those taking lopinavir. Atazanavir is advantageous because it can be taken once daily (although this may also prove possible with lopinavir, as noted below).
In a late-breaker presentation at the same meeting, Mike Youle, M.D., of the Royal Free Hospital in London (abstract LB23) reported final results from the MaxCMin2 study comparing different PI regimens. Dr. Youle and colleagues found that among more than 300 subjects (27% treatment-naive, 73% treatment-experienced, 32% with prior PI failure), those taking lopinavir achieved greater viral suppression than those taking saquinavir/ritonavir after 48 weeks (60% vs. 53%, respectively, with viral loads below 50 copies/mL). In addition, nearly twice as many in the saquinavir/ritonavir arm discontinued due to adverse side effects. Also at the IAS conference, Charles Flexner, M.D., of Johns Hopkins University in Baltimore (abstract 843) reported that higher doses of lopinavir may be able to overcome PI resistance. His results suggest that taking more Kaletra combination pills may work better than adding more ritonavir to boost lopinavir levels.
Challenging the standard rule that antiretroviral therapy should always include more than one drug, Joseph Gathe, M.D., from Therapeutic Concepts in Houston (abstract H-845) presented controversial data at ICAAC from a study of lopinavir "monotherapy" (although, as noted above, the Kaletra pill contains a low dose of ritonavir). Dr. Gathe and colleagues found that among 22 treatment-naive subjects with a wide range of viral load levels and CD4 cell counts who completed 24 weeks of therapy with lopinavir alone, only one did not achieve a viral load under 400 copies/mL; about half had viral loads below 50 copies/mL. The one subject who did not achieve an undetectable viral load started with a high HIV RNA level (500,000 copies/mL) and dropped to about 1,500 copies/mL. It is hypothesized that because lopinavir reaches high concentrations in the blood, it is less likely to promote the development of resistance. In this study, only one genotypic resistance mutation and no evidence of phenotypic resistance was seen. Solo lopinavir "exhibited virological efficacy comparable to triple therapy," Dr. Gathe concluded.
In other lopinavir news, at the October EACS meeting Daniel Podzamczer, M.D., from Hospital Universitario de Bellvitge in Barcelona (abstract F1/3) reported data suggesting that it may be possible to use the drug just once daily. In a pilot study of 190 subjects randomized to receive 800/200 mg lopinavir/ritonavir once daily or 400/100 mg lopinavir/ritonavir twice daily, the two dosing schedules appeared comparably effective at 24 weeks. Using an intent-to-treat analysis, 57% in both arms achieved viral loads below 50 copies/mL; in an as-treated analysis, the rates were 68% and 70% for the once-daily and twice-daily arms, respectively. Among the smaller number of subjects followed for 32 weeks, the corresponding as-treated rates were 82% and 81%. However, 11% discontinued due to adverse events in the once-daily arm, compared with only 3% in the twice-daily arm.
Finally, at ICAAC, Joseph Eron, M.D., from the University of North Carolina at Chapel Hill (abstract H-844) presented data from a study of 100 subjects who had taken lopinavir for more than five years. About two-thirds maintained undetectable viral loads after 252 weeks (67% under 400 copies/mL, 64% under 50 copies/mL) and none of these developed resistance.
Other Antiretrovirals
Researchers at IAS presented results from Gilead Science's Phase III study 903 showing that tenofovir DF (Viread) is as effective as d4T (stavudine, Zerit), but is associated with fewer adverse side effects. Anton Pozniak, M.D., from Chelsea and Westminster Hospital in London and colleagues (abstract 559) randomized study subjects to receive tenofovir or d4T (both with 3TC and efavirenz). After 96 weeks, an intent-to-treat analysis including 600 subjects found that the two regimens had similar efficacy: 82% in the tenofovir arm and 78% in the d4T arm achieved viral loads below 400 copies/mL.
However, according to an analysis by Schlomo Staszewski, M.D., from Goethe-Universität in Frankfurt and colleagues (abstract 562), participants receiving tenofovir had less elevated triglyceride, total cholesterol, and LDL cholesterol levels, and also experienced less wasting of fat in the limbs (lipoatrophy). In addition, Joel Gallant, M.D., from Johns Hopkins presented data at ICAAC from the same study (abstract H-840) showing that tenofovir does not appear to cause more kidney toxicity than d4T -- a potential concern since there have been several reported cases of kidney damage in people taking tenofovir. In this study, subjects in the tenofovir and d4T arms had similar rates of biochemical abnormalities associated with kidney toxicity. Nevertheless, tenofovir should be used with caution and doses should be adjusted in people with pre-existing kidney dysfunction (see item on tenofovir label changes, below).
At the Paris lipodystrophy workshop, Andrew Carr, M.D., from St. Vincent's Hospital in Sydney (abstract 16) presented data from another study that cast a shadow over d4T. Dr. Carr and colleagues found that after two years, individuals who switched from d4T to abacavir (Ziagen) regained about one-third of lost limb fat, while visceral abdominal fat did not change.
Therapy for heavily treatment-experienced individuals remains a major challenge in HIV medicine. At ICAAC, Jean-Michel Molina, M.D., Ph.D., from Hôpital Saint-Louis in Paris (abstract H-447) reported that adding ddI (didanosine, Videx) to a failing regimen could produce significant reductions in viral load. In the Jaguar study, Dr. Molina and colleagues found that about one-third (33 out of 111) of treatment-experienced subjects with viral loads between 1,000 and 100,000 copies/mL despite therapy achieved undetectable viral loads (below 400 copies/mL) four weeks after adding ddI to their regimens, compared with about 5% (3 out of 58) who added a placebo. This benefit was seen despite the fact that a majority of the subjects had previously used ddI. (Research from IAS and ICAAC on the unexpectedly poor showing of triple-NRTI regimens is covered in a news item below.)
Finally, looking at the newest class of antiretroviral drugs, Benoit Trottier, M.D., from Clinique l'Actuel in Montreal (H-835) presented data from the TORO 1 and TORO 2 studies at ICAAC showing that treatment-experienced individuals can continue to benefit from T-20 (enfuvirtide, Fuzeon). At 48 weeks, about one-third (201 out of 661) of subjects receiving T-20 plus an optimized background regimen maintained or achieved viral loads below 400 copies/mL. Eighty percent of those who had achieved viral suppression at 24 weeks continued to benefit, along with five new responders. However, it is known that HIV can develop resistance to T-20. At the same conference, Jay Lalezari, M.D., of Quest Clinical Research in San Francisco (H-444) reported data on T-1249, a second-generation entry inhibitor that binds to a different section of HIV's gp41 envelope protein and works against T-20-resistant virus. Dr. Lalezari and colleagues found that among 53 subjects with viral loads between 5,000 and 500,000 copies/mL while taking T-20, about three-quarters experienced at least a 1 log (90%) decrease in HIV RNA (mean 1.26 logs) ten days after switching to T-1249. No serious adverse side effects were reported, although injection site reactions were common. [Ed. Note: in early January 2004, trials of T-1249 were stopped due to problems with the drug's formulation.]
Once-Daily Regimens
Study results continue to confirm that once-daily regimens are the cutting edge of HIV treatment. In a late-breaker presentation at ICAAC, Brian Gazzard, M.D., from Chelsea and Westminster Hospital (abstract H-1722b) reported results from the ZODIAC study showing that once-daily abacavir appears safe and effective. The current recommended abacavir dosing schedule is one 300 mg tablet twice daily; Dr. Gazzard and colleagues tested a once-daily 600 mg dose. Among the 770 participants in this study, 66% of those who received once-daily abacavir achieved viral loads below 50 copies/mL at 48 weeks, compared with 68% of those taking abacavir twice daily. In both arms, about 10% experienced viral rebound. Subjects in the once-daily arm gained 188 CD4 cells/mm3, compared with 200 cells/mm3 in the twice-daily arm. The percentages experiencing an abacavir hypersensitivity reaction were similar in both arms. The researchers concluded that once-daily abacavir offers "an important new treatment simplification option." GlaxoSmithKline is currently working on a once-daily combination pill containing abacavir plus 3TC.
As Edwin DeJesus, M.D., from IDC Research in Altamonte Springs reported at the same conference (abstract H-446), in a large, multicenter Phase III study (CNA30024) abacavir/3TC/efavirenz suppressed HIV replication as well as AZT/3TC/efavirenz (viral loads below 50 copies/mL in 70% and 69%, respectively), but those in the abacavir arm experienced greater CD4 cell increases (209 vs. 155 cells/mm3 ). Dr. Gazzard's and Dr. DeJesus' data together suggest that abacavir/3TC/efavirenz may be an effective, completely once-daily regimen.
Treatment Interruption
Treatment interruption remains controversial, although a consensus is emerging that treatment breaks seem to provide little or no benefit and may, in fact, be harmful. For example, at the IAS meeting Bernard Hirschel, M.D., of Geneva University Hospital in Switzerland (abstract LB04) reported data from the Staccato study showing that subjects who received treatment in one-week-on, one-week-off cycles were more likely to experience virological failure. More than half the cycling subjects (19 out of 36) had two successive viral load measurements over 500 copies/mL after the completion of an off-treatment week. The one-week-on, one-week-off schedule "showed an unacceptably high failure rate," according to the researchers, and was therefore halted.
In the August 28, 2003 issue of the New England Journal of Medicine, Jody Lawrence, M.D., of the University of California at San Francisco (UCSF) and colleagues also reported that treatment interruptions may be harmful. In CPCRA study 064, participants with multidrug-resistant HIV and viral loads above 5,000 copies/mL were randomly assigned to interrupt treatment for four months before starting a new regimen or to start a new regimen immediately. Disease progression or death occurred in about 16% of subjects (22 out of 138) in the delayed change arm compared with about 9% (12 out of 132) in the immediate change arm. Those in the treatment interruption arm also had lower CD4 cell counts. "In patients infected with multidrug-resistant HIV, structured interruption of treatment was associated with greater progression of disease and did not confer immunologic or virologic benefits or improve the overall quality of life," the authors concluded. Said Anthony Fauci, M.D., of the National Institute of Allergy and Infectious Diseases, "The general message from this study is if you have drug-resistant virus, stopping therapy does not help, period, because the virus rebounds and the infection progresses."
Yet treatment discontinuation may be appropriate under certain circumstances, particularly if therapy was started with a high CD4 cell count, when it may not have been needed in the first place. Franco Maggiolo, M.D., from Ospedali Riuniti in Bergamo (H-448) reported data from the BASTA study at ICAAC. In this trial, 114 subjects with CD4 cell counts above 800 cells/mm3 and undetectable viral loads while on highly active antiretroviral therapy (HAART) were randomized to stop (76 participants) or continue therapy (38 participants). Treatment was restarted when an individual's CD4 cell count fell below 400 cells/mm3. Overall, 21% resumed therapy during the 18-month follow-up period. Dr. Maggiolo and colleagues found that the nadir (lowest ever) CD4 cell count predicted how much time elapsed before treatment was restarted. Those with CD4 nadirs below 200 cells/mm3 restarted in about seven months, compared with about 14 months for those with nadirs of 200-350 cells/mm3 and about 18 months for those with nadirs of 350-500 cells/mm3. No one with a CD4 nadir above 500 cells/mm3 had to resume therapy.
In another interesting treatment strategy study, Javier Martínez-Picado, Ph.D., from Hospital Universitari Germans Trias i Pujol reported at the IAS meeting (abstract LB05) and in the July 15, 2003 issue of the Annals of Internal Medicine that individuals who alternated between two different HAART regimens maintained virological suppression longer than those who took either regimen continuously. In the SWATCH study, 161 participants from Spain and Argentina were randomized to receive 3TC/ddI/efavirenz or 3TC/AZT/nelfinavir continuously, or to alternate between the two regimens every three months. Subjects receiving the two continuous regimens had similar rates of virological suppression, but virological failure was delayed in those who alternated regimens. Participants in all three arms had similar CD4 cell counts and rates of adverse side effects.
Resistance and Superinfection
At the IAS meeting, David van de Vijver, M.D., from the University Medical Center in Utrecht (abstract LB01) reported that nearly 10% of 1,633 newly diagnosed HIV-positive subjects in the CATCH cohort (from 16 European countries and Israel) were resistant to at least one antiretroviral drug, even though they had never been treated for HIV. Infection with resistant virus was higher among those most recently infected; those who seroconverted (became HIV positive) within the previous year had a resistance rate of nearly 11%, compared with a 7.5% resistance rate among those infected for more than a year. By drug class, 6.9% were resistant to nucleoside reverse transcriptase inhibitors (NRTIs), 2.6% were resistant to NNRTIs, 2.2% showed PI resistance, and 1.7% were resistant to two or more classes. Resistance rates were highest among those with subtype B HIV, the most prevalent type in Europe and the U.S.
There were also several presentations at IAS concerning HIV superinfection, in which a person infected with one strain of the virus subsequently contracts another strain (it may also refer to simultaneous infection with more than one strain, also known as coinfection). Luc Perrin, M.D., from University Hospital in Geneva (abstract 73) reported on five injection drug users (out of a cohort of 136) who experienced sudden increases in viral load. Two of these had previously controlled their infections without therapy, maintaining viral loads below 50 copies/mL and CD4 cell counts above 500 cells/mm3, but experienced sudden viral load escalations and rapid CD4 cell declines -- common manifestations of initial HIV infection -- upon infection with a second strain of HIV. According to reports from other researchers, coexisting strains of HIV can recombine to form hybrid strains. Harold Burger, M.D., from Albany Medical College (abstract 71), for example, reported on a hybrid subtype A/subtype C strain detected in a female sex worker from Kenya.
Experimental Drugs
Progress on several experimental drug candidates was reported at the IAS and ICAAC meetings, with attention focusing on new entry inhibitors. Dr. Pozniak (abstract H-443) presented results at ICAAC from a short-term study of Pfizer's CCR5 chemokine blocker, UK-427,857. Antiviral activity was seen in 24 asymptomatic HIV-positive subjects treated for ten days, with a mean viral load decrease of 1.42 logs in the arm receiving 100 mg and 0.42 logs in the 25 mg arm. Higher drug levels where achieved when the drug was taken without food. As expected, UK-427,857 was active only against HIV that uses the CCR5 -- not the CXCR4 -- coreceptor to enter cells. In a study of UK-427,857 safety in HIV-negative volunteers, D. Russell from Pfizer and colleagues (abstract H-874) found that the agent (at doses of 100 mg or 300 mg twice daily) was well tolerated and produced no serious adverse effects after 28 days. In particular, no heart rhythm abnormalities were seen -- as they were in studies of a previous CCR5 blocker candidate -- and there were no significant changes in blood lipids (fats).
Finally, R.J. Hazen from GlaxoSmithKline (abstract H-445) reported on GW8248, an experimental benzophenone NNRTI. This agent was active against HIV with NNRTI-resistance mutations, including K103N and Y181C, which confer resistance to all the currently approved drugs in this class. However, researchers were able to grow GW8248-resistant HIV in the laboratory.
New Drug Approvals
With a total of four, 2003 saw more new antiretroviral drug approvals than any year to date. As noted in the Summer 2003 issue of BETA, the U.S. Food and Drug Administration (FDA) approved the first entry inhibitor -- T-20 (enfuvirtide, Fuzeon) -- in March, and a new PI, atazanavir (Reyataz) in June. Atazanavir is noteworthy because it is the first once-daily PI and appears less likely to increase blood lipid levels than other drugs