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3/26/2004

Retrovirus Conferees Discuss New Strategies

Cheryl A. Thompson

Despite the availability of 20 drugs to fight HIV infection, clinicians are still trying to outwit the wily nine-gene virus without forgetting the burden patients must bear with any antiretroviral regimen.

Speakers at the 11th Conference on Retroviruses and Opportunistic Infections, held February 8–11 in San Francisco, California, refrained from describing a cure for HIV infection or predicting the availability of an effective vaccine. Instead, they focused on making the best use of the medications available and held some hope for new agents under investigation.

A small portion of the presentations of interest to pharmacists is reported below. Abstracts of the presentations, including posters, are available at www.retroconference.org/2004/cd/ProgAbstr.htm.

Possible oversimplification of regimens. Long gone are the days when patients set an alarm to wake them so they would not miss a dose of zidovudine. Patients nowadays consume an assortment of medications one to three times a day with the goal of reducing their viral burden to an undetectable level.

"In our efforts to reduce the complexity of antiretroviral therapy and to make it convenient and well tolerated, we put medications together that can be taken once a day," said John W. Mellors, the principal investigator for the Adult AIDS Clinical Trials Group (ACTG) unit at the University of Pittsburgh Medical Center in Pennsylvania. "And we have learned that not all three-drug combinations are the same. . . . Now we've learned that triple nucleoside combinations are not up to the standard of the rest of front-line" therapies.

In the HIV gene encoding reverse transcriptase, a substitution of arginine for lysine at codon 65 (K65R) makes the enzyme resistant to most of the available nucleoside and nucleotide analogue reverse-transcriptase inhibitors (NRTIs).

Once considered rare, the K65R mutation has increased in prevalence, according to a recent analysis of the databases maintained by HIV genotype-assay firm VircoLab Inc.

Joseph Jemsek of the Jemsek Clinic in Huntersville, North Carolina, identified the K65R mutation in virus from 10 of his 20 patients who stopped once-daily didanosine–lamivudine–tenofovir therapy early because of a less-than-optimal response. All of the patients with a poor virological response had viral strains with a mutation at codon 184 of the gene encoding reverse transcriptase. Only 1 patient in the 24-week pilot study had a good virological response to the triple-NRTI regimen. Jemsek described the 22-person HIV-infected group as advanced cases new to antiretroviral therapy.

The poor virological responses and early emergence of drug resistance prompted Jemsek to contact the maker of tenofovir, Gilead Sciences Inc., which issued a "Dear Health Care Professional" letter about the problem in October 2003.

About a month later, the government-sponsored Panel on Clinical Practices for Treatment of HIV Infection added didanosine–lamivudine–tenofovir to the list of antiretroviral regimens that should not be offered at any time.

Zidovudine, the first NRTI available, said Richard A. Elion of George Washington University School of Medicine in Washington, D.C., "may play a role in impeding or delaying the development of K65R."

As part of a GlaxoSmithKline-supported study, Elion is investigating the efficacy and safety of initial once-daily quadruple-NRTI therapy with Trizir—a combination of the company's zidovudine, lamivudine, and abacavir—and tenofovir.

An interim analysis at week 24 of the ongoing study revealed that the viral burden for 78% of the patients had dropped to less than 400 HIV RNA copies/mL, Elion said. Sixty-seven percent of the patients had a viral burden of less than 50 copies/mL.

Of the eight patients at week 24 with a viral burden of at least 400 copies/mL, defined by the study's protocol as a virological nonresponse, seven had started with a high viral burden, Elion reported. The K65R mutation was found in virus from one of the eight patients and a codon-184 mutation in four—a lower-than-expected frequency for both mutations, he said.

Simple perinatal prophylaxis. Newly reported research from Thailand offered U.S. hospitals and clinics information on preventing mother-to-child transmission of HIV by infected women who do not seek prenatal care or viral-load testing until the last trimester.

WHO Considers Risk of Nevirapine Resistance

Two days before the start of the 11th Annual Retrovirus Conference, the World Health Organization (WHO) declared that the "most efficacious regimen" to prevent mother-to-child transmission of HIV by pregnant women not in need of antiretroviral treatment for their own infection is zidovudine from gestation week 28 through labor and a single dose of nevirapine at the onset of labor. The women's newborns should receive a single dose of nevirapine and one week of zidovudine therapy.

Participants in the February 5–6 WHO "technical consultation" considered the scientific evidence on the emergence of nevirapine-resistant HIV strains after a prophylaxis regimen, according to a statement summarizing the meeting.

The overall opinion was that, based on the available evidence, the benefits of a less-than-2% HIV transmission rate, simple regimen, and good safety profiles for mother and infant outweigh the unclear effect of a single nevirapine dose on subsequent antiretroviral treatment options for the mother.

A single 200-mg dose of nevirapine, a nonnucleoside analogue reverse-transcriptase inhibitor (NNRTI), given during labor to Thai women who had taken zidovudine since gestation week 28 reduced by 80%—down to 1.1%—the rate of HIV transmission to infants. The results, discovered in May 2002 at the study's first interim analysis, led to discontinuation of the zidovudine-only part of the Perinatal HIV Prevention Trial and assignment of all pregnant women to nevirapine treatment in addition to the routine zidovudine regimen. Enrollment in the study continued to March 2003, with a total of 1844 women enrolled.

In the end, 2.0% of the infants who received nevirapine 6 mg at birth had virological evidence of HIV infection, and 2.8% of those who received placebo had HIV infection. All of the infants were fed with formula and received zidovudine prophylaxis for the first week of life.

Marc Lallemant, principal investigator for the study and a researcher at France's Institute of Research for Development, said in a press release that "pediatric HIV infection could be almost eradicated" with the "simple combination" of the standard zidovudine regimen, one dose of nevirapine for the mother at delivery and for the baby soon afterward, and formula feeding. The release, issued jointly with the Thai Ministry of Public Health, indicated that Thailand's National Perinatal HIV Prevention program has added single-dose nevirapine to the official regimen.

Mary G. Fowler, a medical officer with the HIV epidemiology and surveillance division of the U.S. Centers for Disease Control and Prevention, said the study, as she heard it described by the Thailand–France–Boston research team, "shows quite dramatic results." But, she added, it will be particularly important to see how the new regimen affects the mothers in the long-term—more than six months after their one-time ingestion of nevirapine.

Pilot Study Finds Pharmacists Improve Adherence, Virological Outcomes

HIV-infected patients who received special attention from a pharmacist for the first 12 weeks of highly active antiretroviral therapy (HAART) adhered better to their regimen and had a better virological response through week 28 than counterparts who got normal service from their primary care provider, according to a pilot study at an indigent care clinic.

R. Chris Rathbun, an associate professor at the University of Oklahoma College of Pharmacy and a part-time pharmacist at the clinic, said the intervention reflected the level of service the pharmacists had been providing for some patients, "but we wanted to actually show that it made a difference."

With nothing in the literature indicating that a structured educational intervention makes a difference in patients' virological outcomes, Rathbun and colleagues designed a prospective, randomized, controlled pilot study to investigate the issue.

Thirty-three consecutive patients starting a new multiple-drug regimen with a protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor were assigned to receive education and monitoring from either their primary care provider or the pharmacists.

The seven-year-old clinic, part of the University of Oklahoma Health Sciences Center in Tulsa, is funded by the Ryan White Comprehensive AIDS Resource Emergency Act. Rathbun said a subcontract pays for clinical pharmacists to provide services for about 20 hours a week. Patients receive their antiretroviral agents at no charge.

The pharmacists discussed with their patients the role of HAART before they received their medications, reviewed the common adverse effects, designed a schedule for taking the doses, and discussed the consequences of not adhering to the regimen. Follow-ups were made by phone one week after the initial meeting, in person during the clinic visit at week 2 to assess adverse effects and dose-administration issues, again in person during the laboratory-associated clinic visit at week 4 to assess adherence, and at any time through week 12 as patients needed assistance.

Rathbun said a lot of the pharmacists' work at the clinic involves "getting the patient's trust up front and having them understand how they're actually going to be using the therapy."

"We spend a lot of time talking about side effects, a lot of time talking about how to individualize the drug regimen in terms of how they administer [doses] during the day based on their routine."

Many of the patients, he said, are HIV-infected women who must coordinate their medication regimen around their children's schedule. Other patients work outside their home but travel as part of their job, so they must manage medications on the road.

He said the therapies' gastrointestinal effects, such as diarrhea and nausea, "are a huge issue" for patients. "Vivid dreams," a possible central nervous system effect, "can be frightening for some patients," he said.

Because tachyphylaxis occurs with many of these adverse effects, Rathbun said the key to keeping adherence high was telling patients that "if you feel bad initially, you're not going to feel like this forever, and it's going to take time for your body to adjust." He described to patients how they may feel as a consequence of their particular regimen and what they should do to cope. Also, he told them to call if they have a problem rather than keep it a secret.

As a result, he said, "They didn't give up as soon as they hit a bump in the road."

Despite the positive results from the pilot study, Rathbun said, it would be difficult to expand the study and assign any new patients to the control group.

"All the persons that are starting on new therapy now receive adherence intervention," he said. "If anything, [the pilot study] just encouraged our physicians that this was a useful effort to fund and continue funding."

Funding for the study, undertaken with colleagues Kevin C. Farmer, Johnny R. Stephens, and Staci M. Lockhart, was provided by a grant from the Society of Infectious Diseases Pharmacists.

Ten days postpartum, 18% of a subgroup of the HIV-infected Thai mothers had at least one NNRTI-resistance mutation in the gene encoding reverse transcriptase. The research group also reported that, six months postpartum, women whose viral strain had at least one NNRTI-resistance mutation in the reverse-transcriptase gene tended, but not significantly so, to have a poorer response to NNRTI-containing antiretroviral regimens than women who did not receive intrapartum nevirapine. (The women who did not receive intrapartum nevirapine had been assigned to treatment before the first interim analysis of the main study.)

"There is a concern," said Neil Martinson from South Africa's National Institute for Communicable Diseases, "that if women come back for a second time, there'll be resistance" to nevirapine.

Nevirapine resistance after a single maternal dose during labor seems to persist for at least 36 weeks, according to preliminary findings of a South Africa study headed by Martinson. About 44% of the women in the study had viral strains with nevirapine-resistant reverse transcriptase for the first seven weeks postpartum. This resistance persisted for 10–36 weeks in 24% of the women who have progressed that far in the study.

Among the study's infants, all of whom had received one dose of nevirapine in the first 72 hours of life in addition to their mother's dose, 8.6% were infected with HIV, Martinson reported.

Agents in the pipeline. Two investigational drugs—an NRTI and a compound that binds to the T-cell chemokine receptor CCR5—well in dose-escalation studies and could be on the market in three and a half years, researchers said.

Antagonism at the CCR5 receptor. Because CCR5 acts as a secondary but necessary receptor for most HIV strains trying to enter CD4+ T cells, researchers have been searching for a substance that can stop the interaction.

A small molecule known as SCH D seems the most promising from a line of CCR5-receptor antagonists developed by Schering-Plough Research Institute.

Twice-daily oral treatment with SCH D for 14 days lowered patients' viral burden an average of 1.08 log copies/mL in the 10-mg/dose group, 1.56 log copies/mL in the 25-mg/dose group, and 1.62 log copies/mL in the 50-mg/dose group, said Mark Laughlin, director of clinical pharmacology at Schering-Plough.

None of the 48 HIV-infected participants had used an antiretroviral therapy for at least eight weeks before their first dose of SCH D or placebo. All of the patients, he said, started the study with a CD4+ T-cell count greater than 250/mm3 and a viral burden of 5,000–200,000 copies/mL.

Laughlin said three serious adverse reactions occurred in one of the dosage groups. A fever occurred on days 5–7 in one person, a syphilis-related rash developed in another person after the last dose, and a cerebrovascular accident occurred before a patient took the first dose of SCH D.

Schering-Plough does not intend to develop the drug for monotherapy, Laughlin said, noting that SCH D does not inhibit or promote the actions of cytochrome P-450 isoenzymes.

A second-generation NRTI. Ten-day treatment with Reverset, a once-daily NRTI with the chemical name beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, caused a fairly rapid decrease in viral burden among HIV-infected persons new to antiretroviral therapy, said Robert L. Murphy, a faculty member at Northwestern University in Chicago, Illinois, who is a principal investigator for the Adult ACTG. Viral burden after Reverset treatment ended slowly returned to baseline in the 28-day follow-up, as did the CD4+ T-cell count.

The ongoing study in Germany involves 24 men and 6 women who had a CD4+ T-cell count of more than 50 cells/mm3 and a viral burden exceeding 5000 copies/mL before taking their first dose of Reverset or placebo. Murphy said his presentation of preliminary results from the single-drug study was the first release of clinical information about a multiple-day Reverset regimen.

After 10 days of treatment, participants had an average decrease in viral burden of 1.67 log copies/mL from the 50-mg/day regimen, 1.8 log copies/mL from the 100-mg/day regimen, or 1.77 log copies/mL from the 200-mg/day regimen, Murphy said. No one discontinued treatment. Participants complained of cold symptoms, such as headache and fatigue, which Murphy said may have been related to the study being conducted in the fall.

He said no changes in HIV genotype were found in participants' plasma samples at the end of the study.

The next steps in development, Murphy said, are a meeting with FDA and the recruitment of international sites for Phase II studies involving at least 180 treatment-experienced patients with HIV infection. He said one goal of the studies is to examine in vivo the effect of the drug on HIV strains with NRTI-resistant reverse transcriptase.

Reverset was invented at Emory University in Atlanta, Georgia, and taken into clinical studies by Pharmasset Inc., a firm started in part by the drug's two inventors. Inctye Corp. in 2003 took over development of the drug for the U.S. market.