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More News From ICAAC

By Charles E. Clifton and Enid Vázquez

March/April 2002

Switching Studies

In the SWATCH study (Netherlands), 69% of participants who switched between two different regimens every three months attained viral loads under 400, as compared to 57% of individuals who remained on the same regimen for 48 weeks. One group of 52 participants took Zerit, Videx and Sustiva. A second group of 54 took Epivir, Retrovir and Viracept. The third group of 55, the switching group, alternated between the two regimens. T cells were not statistically different among the three groups, however, cholesterol increased significantly among all three groups, when compared to baseline. Participants on Sustiva had an increase in HDL cholesterol levels, and Viracept treated individuals had an increase in LDL cholesterol.

At 48 weeks, the 106 participants who switched to Trizivir (Ziagen, Epivir, and Retrovir) from HAART (highly active antiretroviral therapy) regimens, continued to have the same rate of success (78%) of maintaining a viral load less than 400 as the 103 participants who remained on the same HAART regimen. In order to enter the study, participants had to have a viral load less than 50 and to have been on their current regimen for more than six months. The study also reported a sharper decline in fasting cholesterol and triglyceride levels in the participants who took Trizivir.

PI Mutations

In a study designed to observe protease mutation patterns associated with lopinavir, data at 96 weeks shows no drug resistance in treatment naive participants who were given a Kaletra-based regimen. Of the 326 individuals taking Kaletra in combination with Zerit and Epivir, 40 experienced a viral load rebound (greater than 400), but none had a protease inhibitor resistant HIV by genotypic testing.

Resistance Rampant?

Data from the HIV Cost and Services Utilization Study (HCSUS) indicated that 78% of HIV-positive adults, treated in early 1996, who had detectable viral load showed some form of drug resistance. A total of 1906 samples were collected from participants using ViroLogic's PhenoSense test. The HCSUS is a longitudinal study representing some 209,000 HIV-positive adults in the U.S. who were in treatment in 1996. The levels of resistance differed by drug class, with 42% for protease inhibitors (PIs), 70% for nucleoside reverse transcriptase inhibitors (NRTIs), and 31% for non-nucleoside reverse transcriptase inhibitors (NNRTIs). Male sex, lower CD4 T-cell count, and higher viral load were identified as key indicators of higher risk of drug resistance.

The report got treatment advocates to raise charges of media and research hype. As stated here before, the issue of resistance -- when the virus learns to resist the drugs thrown at it -- is very complicated. Sometimes the virus mutates before people go on meds, which means that their HIV may develop resistance to one or more of the HIV meds. One study found that even with a near-perfect adherence level of 95%, one out of five people will develop detectable viral load (one indication of drug resistance). And generally, if you go on HIV drugs, you develop HIV drug resistance. Maybe only a very little and maybe not even detectable by drug resistance tests. On top of that, it's not very clear what all the mutation patterns of the virus mean for clinical care.

Longtime activist and advocate Matt Sharp said the results of the survey are not surprising, and only indicate that HIV medications are too "mediocre" to control the virus. Another advocate pointed out that you can often still do well and be healthy with resistant virus -- absolutely true. Another important point: the majority of the people looked at in this analysis started out with suboptimal therapy, which contributes to the development of resistance. People taking HIV medications today start out with stronger therapy.

In his longtime, highly respected newsletter, AIDS Treatment News, John James concludes that, "...generally it is best to have HIV fully suppressed whenever antiretrovirals are used, so that there is little or no viral replication, and resistant virus cannot evolve. But for many patients this goal is not feasible. For these patients and for everyone else with HIV, we need new drugs that are more effective, less toxic, and less susceptible to viral resistance. We especially need new classes of treatments, including new targets for antiretrovirals, and immune-based therapies to help the body itself control HIV."

New Drug on the Block: Viread

Viread (tenofovir disoproxil fumarate, TDF) is a nucleotide reverse transcriptase inhibitor that was approved by the FDA last fall (see 2002 Positively Aware HIV Drug Guide). It is taken as a single 300 mg tablet once a day with food. Data was presented on Gilead 907 study, a phase III trial with 552 participants (viral load between 400-10,000 copies/mL) on a stable antiretroviral regimen. TDF was added to the regimen of 368 participants, and 184 were given a placebo (sugar tablet). At 24 weeks, the viral load of participants who added TDF had dropped 0.61 log; the viral load of 42% of the TDF recipients was less than 400 copies/mL; and less than 50 copies/mL in 22%.

The potential of cross-resistance between TDF and nucleoside analogs suggests that this is not a salvage drug. However, it has shown promise as a nucleoside alternative in the NRTI-experienced or for intensification in individuals with low-level viral load. Gilead's ongoing study 903 will provide much needed data on the effectiveness of this drug for treatment naive individuals.

Drugs on the Horizon

TMC 125 is a second generation NNRTI in the same class of drug as Sustiva and Viramune, that is being tested by Tibotec-Virco. It has shown promise in vitro against highly NNRTI-resistant virus. The results of a small phase II trial were presented. Twelve treatment naive participants received seven days of direct-observation monotherapy with TMC 125, at a dose of 900 mg twice a day, and were compared with six participants who received a placebo. Those who took TMC 125 experienced a very impressive 2 log drop (1.13-3.30 log) in viral load over the one-week treatment period. "As far as we know, no drug has shown this large of a viral load drop in this short of a time," said presenter Dr. G. Van 'T Klooster, who works for Tibotec-Virco. "This spells hope." Eight participants achieved viral loads less than 400 copies/mL and two achieved viral loads less than 50 copies/mL in seven days. However, participants taking TMC 125 in this trial had to swallow 18 pills twice a day! This means that some serious formulation issues will have to be resolved before TMC 125 can be expanded to larger clinical trials. Afterwards, they received standard of care therapy. The primary side effect was mild somnolence (sleepiness). Study participants were taking HIV medication for the first time. Doctors at the conference expressed enthusiasm for the drug's potential.

Tipranavir (TPV) is a non-peptidic protease inhibitor that has demonstrated potential against a wide range of PI-resistant strains, is being developed by Boehringer-Ingelheim. Data was presented from 16-weeks of an open-label trial comparing two doses of TPV/Norvir (ritonavir) [500/100 mg twice a day and 1,250/100 mg twice a day] with Fortovase (saquinavir soft-gel)/Norvir [400/400 mg twice a day] in participants who had failed a single PI (viral load greater than 1,000 c/mL) and who still had at least two NRTIs available. The data indicates that participants who received a higher dose of TPV/Norvir (55%) achieved viral loads less than 400 c/mL than those who received the lower dose TPV/Norvir or the Fortovase/Norvir based regimen. Nearly 42% of the participants in this study did not demonstrate PI resistance, despite failing a PI-based regimen. This would seem to indicate that more testing is called for with more PI-resistance participants.

If all goes well atazanavir (Zrivada), the once a day protease inhibitor, being developed by Bristol-Myers Squibb, will most likely be the next PI approved by the FDA. Results from BMS 008 were presented, in which treatment naive participants were randomized to receive either: atazanavir (400 or 600 mg once a day) or Viracept (nelfinavir, 1,250 mg twice-a-day) plus d4T/3TC (Zerit/Epivir). The observed reduction in viral load was similar in all three arms of the study. Most notable was the increased cholesterol level in 5-7% of those receiving atazanavir, compared to 20-25% receiving Viracept, and diarrhea was less common in participants taking atazanavir. Like Norvir, atazanavir increases the level of other PIs. However, atazanavir seems less likely to cause hyperlipidemia (heart disease) than Norvir. Atazanavir or "Taz" (as some doctors call it) also appears to have little if any adverse effect on lipid profiles. An expanded access program is expected to start soon; call toll-free 1-877-726-7327.

T-1249, the "Son of T-20" (as doctors call it), showed a good drop in viral load after two weeks, despite baseline resistance in the people using it. You would expect this fusion inhibitor to work for people with HIV drug resistance, since it's in a new class of antivirals. Nevertheless, the influence of resistance patterns needed to be examined. Half of the people in this tiny, early trial had relevant mutations to all three HIV drug classes now on the market. Like the people in T-20 trials (expected to be on the market this year), these participants had taken many other HIV drug combinations. Viral load drop varied according to the dose of the injections: an insignificant drop for people on the 6.25 mg dose per day vs. an excellent result in people taking 50 mg per day (-1.40 log).

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