Drug research shows easier dosing, new combinations are making gains

First head-to-head studies prove AZT and d4T comparable

Drug research results presented in January at the 5th Conference on Retroviruses and Opportunistic Infections in Chicago show that other triple-drug combinations are equivalent to the standard of care set by a federal task force last year, offering clinicians hard data to support their treatment decisions. And a new drug, hydroxyurea, garnered strong interest while a debate intensifies over the face-off between two antiretroviral mainstays — zidovudine (AZT) and stavudine (d4T).

Data were presented at the conference on the first head-to-head studies comparing AZT and d4T as first-line, standard-of-care options for double and triple therapy. The results showed that double- and triple-drug combinations using d4T were equivalent in CD4 cell increase and viral-load suppression to those containing AZT.

"The good news is there isn’t much difference in terms of the effect on viral load and CD4 cells, so for a clinician it is reassuring to be able to say, OK, this regimen has been tested, and given this set of circumstances, it looks like it is as good as what was considered the quote-unquote standard of care,’" says Kathleen Squires, MD, associate professor of medicine at the University of Alabama in Birmingham.

Squires was principal investigator in an open-label, randomized comparative study of d4T, 3TC (Epivir), and indinavir (Crixivan) vs. AZT, 3TC, and indinavir tested in 200 treatment-naive patients.1 The results were based on 24-week data presented at the conference. A second study showing similar equivalence compared d4T, ddI (didanosine), and indinavir with AZT, 3TC, and indinavir in a similar patient population (CD4 count above 200 and HIV RNA greater than 10,000 copies).2

The studies confirmed beliefs of researchers and clinicians that other combinations were as potent and safe as the AZT/3TC/indinavir combination that was used as the "standard of care" contained in the Public Health Service guidelines published last year. They also may push more clinicians and patients to use d4T as the drug of choice for initial therapy. Indeed, d4T’s several advantages over AZT have helped make the Bristol-Myers Squibb Co. drug a top seller. The company announced last month that d4T had surpassed AZT as the most commonly prescribed nucleoside reverse transcriptase inhibitor in the U.S. market.

When asked why d4T has become so popular, Squires says the decision to use it is based less on its attractive resistance profile than on the perception that it is less toxic and easier to use for some patients.

"I’d like to say it’s resistance, but I think it’s more what is tolerable to patients and what they are more likely to stay on and the toxicity profile," she tells AIDS Alert.

Interim analysis of the triple-combination trial showed little difference between the two arms when looking at the number of patients who reported grade 3 and 4 toxicity (cases where the drug had to be stopped or temporarily withheld). However, when looking at overall toxicity, "there is a suggestion — not statistically shown because these are interim results — that the AZT arm had more side effects in terms of GI, nausea, bloating," she says.

More studies will be required to determine whether AZT and d4T show similar equivalence in patients who have received previous treatment that failed. The combination studies will provide long-term follow-up to evaluate how the initial treatment held up over time, she adds.

The take-home message from the two studies is that clinicians now have choices to offer their patients, and can turn to individual scenarios to determine which drug is better, she explains. Now that AZT and 3TC are combined in a single drug, there may be an incentive to take AZT if compliance is a problem. However, that advantage has to be balanced against possible lower tolerability with AZT, as well as the differences in the two drugs’ toxicity profiles, she notes.

Adding to the debate over the pros and cons of the two drugs was a controversial study presented at the conference by researchers from the University of Alabama showing that pharmacological mechanisms of the two drugs may explain decreased virological effectiveness of d4T-3TC combinations in patients with previous AZT treatment.3

"They are suggesting that if you give AZT first, you affect intracellular phosphorylation pathways so that drugs like d4T in particular aren’t going to work as well. Whereas, if you start off with d4T, you don’t affect phosphorylation the same way," explains Kenneth Mayer, MD, director of the AIDS program at Brown University
in Providence, RI. "Some people think this is very compelling and others think it is not so impressive."

Hydroxyurea (Hydrea), an inhibitor of the cellular ribonucleotide reductase that boosts the efficacy of other drugs, has been the focus of intense interest following presentations at the conference showing impressive benefits of the drug used in combination with other drugs, such as d4T and ddI.4

One study showed how hydroxyurea, when added to a d4T/ddI regimen, stabilized and improved CD4 counts and viral load levels during a 28-week period, indicating that hydroxyurea may be a "sheltering" drug that keeps the virus from mutating as rapidly in combination with other drugs. Another study showed that combining hydroxyurea with d4T and ddI decreased viral load in some drug-experienced patients to levels below detection.

"Hydroxyurea is very intriguing, but it remains to be proven in large numbers of patients," Squires notes, adding that the drug has been used at her clinic primarily as salvage therapy with ddI. Nonetheless, more clinicians are considering using the drug as initial therapy, mainly because of its resistance profile.

"There are these tantalizing case reports, including one patient who stopped therapy and didn’t rebound," says Mayer. "As adjunctive salvage therapy, it seems to be reasonably well-tolerated. Because it’s not a true nucleoside, you don’t get the problems of resistance," he notes.

In efforts to create simpler regimens for aggressive antiretroviral therapy, drug companies have been experimenting with new combinations with different dosing. In one study presented at the conference, twice-daily doses of indinavir were given with AZT and 3TC. In 71% of patients who completed 32 weeks of treatment, HIV was suppressed below 500 copies and the median increase in CD4 cells was 64.

In a second study, a twice-daily regimen of indinavir was combined with the protease inhibitor nelfinavir (Viracept). The study showed that twice-daily dosing was possible and well-tolerated. After 32 weeks of therapy, 10 of 21 patients had undetectable viral load (<400 copies). "Adherence to drug regimens is critical to achieving maximum HIV suppression," says Emilio Emini, PhD, vice president of antiviral research at Merck Research Laboratories in Wilmington, DE, which makes indinavir. "Now, by combining potent therapies like Crixivan in new ways with other treatments, we are working to make regimens easier for patients."

Twice-daily dosing of nelfinavir produces anti-HIV effects similar to the standard three-times-daily regimen, researchers report. The only side effect appearing in more than 5% of patients was diarrhea, which also was found in dual-protease inhibitor combinations using nelfinavir.

"I think the BID [twice-daily] dosing regimens for indinavir and nelfinavir look very promising," Mayer says, "especially for people who have busy schedules and find that middle-of-the-day dose a killer."

New data also were presented at the conference on the investigational drug efavirenz (Sustiva), produced by Dupont Merck of Wilmington, DE. By combining once-daily regimens of the drug with indinavir, patients were able to maintain HIV RNA levels below quantifiable levels for more than a year. With patients who are drug-naive, combining efavirenz with AZT and 3TC reduced viral levels to below detection in all patients after 24 hours of treatment, company researchers reported.

References

1. Squires K, Gulick R, Santana J, et al. An open-label randomized comparative study of d4T-3TC-IDV versus ZDV-3TC-IDV in treatment-naive HIV-infected patients. Presented at the 5th Conference on Retroviruses and Opportunistic Infections. Chicago; 1998.

2. Eron S, Peterson D, Murphy R, et al. An open-label randomized comparative study of d4T-ddI-IDV versus ZDV-3TC-IDV in treatment-naive HIV-infected patients. Presented at the 5th Conference on Retroviruses and Opportunistic Infections. Chicago; 1998.

3. Sommadossi J, Zhou X, Moore J, et al. Impairment of d4T phosphorylation in patients receiving a combination of AZT and d4T. Presented at the 5th Conference on Retroviruses and Opportunistic Infections. Chicago; 1998.

4. Galpin E, Lori F, Globe D, et al. Safety, sheltering, and synergy of hydroxyurea with ddI or ddI plus d4T in HIV-positive patients. Presented at the 5th Conference on Retroviruses and Opportunistic Infections. Chicago; 1998.