PI Perspective #24

April 1998     View PDF

Double Protease Inhibitor Combinations

Dual protease combinations are of interest because some combinations offer the prospect of reducing the dose and dose frequency of the drugs compared to what is required when they are combined with the nucleoside analogue reverse transcriptase inhibitor (NRTI) drugs (such as AZT, ddI, ddC, d4T and 3TC). Another possible benefit of dual protease inhibitor combinations is to suppress virus replication for a longer period or to a deeper level than can be achieved with a combination using a single protease inhibitor. Initially, dual protease inhibitor combinations were most widely used in an effort to restore antiviral activity in people who experienced viral rebound on combinations using a single protease inhibitor.

Ritonavir Plus Saquinavir
One European study examined the usefulness of adding nucleoside analogue drugs to a dual protease combination. Most earlier studies of protease combinations used only the two protease inhibitors. The study compared ritonavir (Norvir) + hgc saquinavir (Invirase, the original version of saquinavir) to ritonavir + hgc saquinavir + d4T. Doses used were 400mg ritonavir, 400 mg of saquinavir and 40mg of d4T, all taken twice daily. Two hundred and eight people with an average CD4+ cell count of 260 and viral load of about 20,000 copies HIV RNA participated in this study. About half had been on prior NRTIs before joining in this study but all were using protease inhibitors for the first time. After 24 weeks, about 90% of the participants still remaining on the triple combination had viral loads below 400 copies HIV RNA compared to about 65% of people receiving the two-drug regimen. Both groups had about 150 CD4+ cell increases. Six people receiving the two-drug combination added d4T + 3TC after 18 weeks of the study because of increasing viral loads. All six participants subsequently had viral loads below 200 copies of HIV RNA. Mild to moderate diarrhea and tingling around the mouth were the most common reported side effects. In short, this study suggests adding one or more NRTI drugs provides a clear benefit over using a dual protease combination alone.

New data were presented from a long-running study of ritonavir + saquinavir (earlier reports of this study appear in prior issues of PI Perspective). Of importance is new information showing that 11% of the participants developed moderate to severe increases in triglyceride levels, but that drugs such as Lopid and Atromid were generally successful in reducing triglyceride levels. Another new finding concerned 27 people in the study who added up to two RT inhibitors (NRTIs) when their viral load began rising above the limit of detection. Most added d4T + 3TC. For 23 of the 27, adding the two nucleoside analogue drugs caused the viral load to fall back below the limit of detection (200 copies of HIV RNA) and this result has persisted through the study. These results are somewhat surprising as most people believed that dose intensification with two NRTIs would not be sufficient to get viral replication under control and would result in only a transient viral load drop.

Nelfinavir Plus Indinavir
A small study looked at the safety and antiviral effects of nelfinavir (Viracept) in combination with indinavir (Crixivan). Twenty-one people with a median CD4+ cell count of 259 and a viral load of about 50,000 copies of HIV RNA participated in this study. Approximately half of the participants had been on previous NRTIs but all were using a protease inhibitor for the first time. The doses studied were 1,000mg every twelve hours of indinavir and either 750mg every twelve hours or 1,000mg every twelve hours. of nelfinavir. After 32 weeks of the study, ten people experienced HIV RNA decreases to below the limit of detection (400 copies of HIV RNA) and of those ten, six had less than 50 copies of HIV RNA. Three people had to add NRTIs because they either had an increase in viral load or they did not have a sufficient antiviral response. There was a median increase of 133 CD4+ cells after 32 weeks of the study. This study found that indinavir did not increase nelfinavir levels in blood as much as anticipated and as a result future combinations of this regimen will use 1,000mg twice daily of indinavir and either 1,000mg or 1,250mg twice daily of nelfinavir.

Saquinavir Plus Nelfinavir
A European study of the combination of soft gel (sgc) saquinavir (Fortovase) plus nelfinavir (previously reported in PI Perspective) showed that this combination did not appear to offer any special or synergistic benefits. The dual protease combination may have about the same antiviral effects as either one of the two protease inhibitor combined with two NRTIs. Even the study group which combined both protease inhibitors plus two NRTIs did not appear to offer any advantage over the other combinations. The results after 32 weeks of the study are shown in Table 1.

Ritonavir Plus Nelfinavir
Preliminary results from a small study shows that the combination of nelfinavir + ritonavir has potent anti-HIV activity. Twenty people with a median CD4+ cell count of about 330 and a viral load of 33,000 copies of HIV RNA received 400mg twice a day of ritonavir and either 500mg or 750mg twice a day of nelfinavir. None of the participants had previously been on a protease inhibitor. There were no differences between the two nelfinavir doses in antiviral response. After twelve weeks of the study, there was a two log reduction in viral load and over a hundred CD4+ cell increase. About 70% of the participants had viral loads below 400 copies of HIV RNA. Almost half of the participants had mild to moderate diarrhea. Despite the use of ritonavir, however, there did not appear to be any special benefit to this combination, perhaps because there isn’t a strong interaction between ritonavir and nelfinavir. The preliminary results are good, but not of a higher order than typically seen of standard three-drug combinations.

The wider look at protease inhibitor combinations presented at the Retrovirus conference suggests that there are two general classes of protease inhibitor combinations. The first class describes combinations which produce some form of synergistic interaction when they are combined. The best example of this is the ritonavir and saquinavir combination, which greatly increases the activity of saquinavir because of drug interactions caused by ritonavir. The net result of this combination is the ability to achieve a very high level of antiviral activity while using lower doses of both drugs. Because of the lower doses, there is also a lower level of side effects from either drug and the net cost is lower than the standard cost of the two drugs combined. Almost all such synergistic combinations include ritonavir as one element, since this drug often has a profound effect on the way which other drugs are absorbed and metabolized by the body. The second class of combinations are those in which there is no particularly advantageous interaction. In this case, the net result at best some modest additive advantage in potency, if any. In some cases, there seems to be little obvious gain from using such combinations. Combinations of this type typically do not include ritonavir and thus they lack any special advantages from drug interaction.

While most of the double protease inhibitor combination studies are relatively small, they suggest that these combinations can be safely used and are sometimes quite potent. Some such combinations offer a significant benefit over standard triple combinations, while others do not. Whether dual protease inhibitor combinations should be used as a first-line therapy is still a matter of debate. Clearly, longer-term studies need to be conducted comparing dual protease inhibitor therapy to what is now considered first-line therapy (a protease inhibitor and two NRTIs). Additionally, it is not known which double protease inhibitor combination will be the best tolerated and most potent. Generally, double protease inhibitor regimens can be taken twice versus three times a day when they are used in combination with NRTIs. However, the potential downside might be that if someone were to fail a double protease regimen, chances are they will be cross-resistant (where resistance to one drug results in little or no benefit when switching to another) to all other available protease inhibitors.