Anti-HIV Drugs Update
Several studies of abacavir (Ziagen) were presented at the recent International Conference on AIDS in Durban. Most of the results are preliminary and are based only on interim analysis, but they do extend our knowledge of the use of the drug. They suggest that short-term use of a three-drug combination containing abacavir may be as effective as a three-drug combination including a protease inhibitor. If these results hold up in longer term use, it will suggest there are many reasonable options for achieving good success with an initial three drug regimen and perhaps it doesn't matter whether the combination employs a protease inhibitor, a non-nucleoside drug or three drugs from the nucleoside class.
Encouraging results were also presented from a study using lopinavir (Kaletra) among people who have previously taken multiple protease inhibitor-containing regimens.
One abacavir study involved 195 people who had not previously taken anti-HIV therapies and who had an average viral load of around 16,000 copies HIV RNA and CD4+ cell counts of about 400. Participants received either Combivir (AZT+3TC) + nelfinavir (Viracept) or Combivir + abacavir. The dose of nelfinavir used in this study was 750mg three times a day. The preliminary results after 24 weeks are shown in Table 1.
A similar study involved 342 people who had not previously taken anti-HIV therapies and who had an average viral load of around 63,000 copies HIV RNA and CD4+ cell counts averaging 300. In this study, participants received Combivir + abacavir or Combivir + indinavir (Crixivan). The preliminary results after 24 weeks are shown in Table 2.
Another study reported on results from using abacavir as part of a four-drug regimen. People received either a four-drug regimen of Combivir + abacavir + amprenavir (Agenerase) or a three-drug regimen of Combivir + nelfinavir. Combivir is a combination of AZT and 3TC in a single pill and thus counts as two drugs. The study followed 302 people who had not previously taken anti-HIV therapies and had an average viral load of about 40,000 copies HIV RNA and CD4+ cell counts of about 350. The final results, in terms of the percentage of people who sustained viral load under the limit of detection after 64 weeks are shown in Table 3.
Another concern is that ten percent of people on the four-drug regimen developed signs of a known problem with abacavir called hypersensitivity. Signs and symptoms of hypersensitivity usually include fever, rash, fatigue, nausea, vomiting, diarrhea, abdominal pain or respiratory symptoms such as pharyngitis (inflammation of the pharynx), difficulty in breathing or cough. People who develop or are thought to have these hypersensitivity symptoms should stop taking abacavir and should not try restarting the drug. However, there have been recent reports of people developing hypersensitivity reactions within hours to weeks of restarting abacavir even though they had no signs of hypersensitivity to the drug previously. People considering restarting abacavir should be particularly mindful of these symptoms and abacavir should be stopped if any of these hypersensitivity symptoms develop.
Kaletra (formerly ABT-378 or lopinavir)
Encouraging results were recently presented from a small study using lopinavir (Kaletra) in people who have been on multiple protease inhibitor regimens but have not previously received a non-nucleoside reverse transcriptase inhibitor (NNRTI). Lopinavir is a new protease inhibitor that is co-formulated with a low dose of ritonavir (Norvir). Each capsule contains 133mg of a protease inhibitor that was called ABT-378 and 33mg of ritonavir. Fifty-seven people with an average viral load of about 32,000 copies and average CD4+ cell count of 270 participated in this study. The majority had some degree of resistance to three or more of the currently approved protease inhibitors. All participants started out on three lopinavir capsules (twice daily) in combination with efavirenz (Sustiva) and any nucleoside analogue drugs (NARTIs) of their choice. After fourteen days, half of the volunteers continued on this regimen while the other half continued on efavirenz and NARTIs but had their lopinavir dose increased to four capsules. The results after 24 weeks are:
The Food and Drug Administration is likely to approve lopinavir in the fall of 2000 and it should be available in pharmacies shortly thereafter. Because lopinavir has a small quantity of ritonavir in it, people who have had reactions to ritonavir should use care when taking lopinavir.
The short-term results with abacavir are quite encouraging and seem consistent with earlier studies. But it remains to be seen whether the results will hold up in the long-term. What is abundantly clear is that the simpler dosing of an abacavir + Combivir combination results in better adherence, an important consideration in the `real world' setting. However, there is increasing concern over the risk for hypersensitivity to abacavir especially in light of the recent reports where people developed hypersensitivity reactions after restarting the drug even though they had no previous signs of hypersensitivity.
All of the studies with lopinavir have been very encouraging and the
drug is likely to benefit people who have not previously been on anti-HIV therapies as well as those who have been on extensive previous therapy. It is important that, if possible, lopinavir be used in combination with one or two new drugs in order to get the maximum benefit.
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